Safe Clinical Use of Carbon Nanotubes as Innovative Biomaterials
- Naoto Saito
- ,
- Hisao Haniu
- ,
- Yuki Usui
- ,
- Kaoru Aoki
- ,
- Kazuo Hara
- ,
- Seiji Takanashi
- ,
- Masayuki Shimizu
- ,
- Nobuyo Narita
- ,
- Masanori Okamoto
- ,
- Shinsuke Kobayashi
- ,
- Hiroki Nomura
- ,
- Hiroyuki Kato
- ,
- Naoyuki Nishimura
- ,
- Seiichi Taruta
- , and
- Morinobu Endo
View Author Information
† Institute for Biomedical Sciences, Shinshu University, Asahi 3-1-1, Matsumoto 390-8621, Japan
‡ Department of Orthopaedic Surgery, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan
§ ∥ §Research Center for Exotic Nanocarbons, and ∥Faculty of Engineering, Shinshu University, Wakasato 4-17-1, Nagano 380-8553, Japan
⊥ R&D Center, Nakashima Medical Co. Ltd., Haga 5322, Kita-ku, Okayama 701-1221, Japan
*Tel.: +81 263 37 2409. Fax: +81 263 35 8844. E-mail: [email protected]
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1 Introduction
ARTICLE SECTIONS
Carbon nanotubes (CNTs) are structurally described as sheets of six-membered carbon atom rings (i.e., graphene) rolled up into cylinders. CNTs with only one layer are known as single-walled CNTs (SWCNTs), and those with two or more layers are known as multiwalled CNTs (MWCNTs). Cup-stacked carbon nanotubes and carbon nanohorns are also sometimes called CNTs. (1-3) Currently, these very attractive carbon materials and nanomaterials are a subject of vigorous product development in a broad range of fields. (4-11) The reasons are that CNTs have useful electrical, thermal, and mechanical characteristics, and their base material performance can be improved by combination with other materials. (12-23) A recent industrial application of CNTs as an electrode additive to lithium-ion batteries is based on their excellent electrical characteristics. Addition of CNTs prevents battery deterioration and substantially lengthens time to recharging. It is doubtless that the demand for high-performance batteries will grow increasingly with multifunctionalization of personal computers and mobile phones, development of new mobile terminals, spread of electric vehicles, and other factors. (24-30) Composite materials with the excellent mechanical characteristics of CNTs have already been used in sporting goods such as golf clubs, tennis rackets, and bicycles. CNTs are also expected to have applications that reduce the weight of aircraft and automobiles. (10, 14, 31-35) A wide variety of advantages are gained from the use CNTs in precision parts as well. CNTs are also used in transistors and memory devices, and enhance their efficiency. The use of CNTs in various displays and TV screens continues to increase in rate. CNTs are also widely used in products designed to prevent static electricity, to shield electromagnetic waves, to store electricity, and for other purposes. (36-45) Furthermore, Japan is now facing nuclear energy issues stemming from the accident at Tokyo Electric Power Company’s Fukushima No. 1 nuclear power plant. As a result, CNTs are expected to play a major role in developing new energy sources such as solar photovoltaic power generation and wind power generation. (46-52)
In the medical field, extensive research activities are underway to develop new CNTs biomaterials for use in the treatment and diagnosis of disease. For example, application of CNTs to cancer treatment and diagnosis, such as in drug delivery systems (DDSs) for treatment of cancer, hyperthermia, and in vivo imaging, has been investigated. (53-57) In a study that aimed at applying CNTs to regenerative medicine, CNTs were found to work excellently as scaffold materials for nerve and bone tissue regeneration. (58-63) Furthermore, R&D activities are underway to improve the mechanical strength and durability of implants by combining CNTs with existing biomaterials. (64-67) Besides, numerous ideas have been put forth about how CNTs can be used in the treatment of a variety of diseases.
Figure 1 shows the trend in the number of articles found in the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed/) (accessed 20 March 2014) by searches using “carbon nanotubes” and “biomaterials” as keywords. The number has been soaring since 2005, suggesting that CNTs research has become a highly competitive field worldwide over the past few years. Of course, numerous articles on the biological applications of CNTs do exist that cannot be captured with these two simple keywords, and the graphic representation of this trend is no more than an indicator of the increase in this research over time.
Figure 1
Figure 1. Time trends for the number of articles found in the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed/) (accessed 20 March 2014) by search using “carbon nanotubes” and “biomaterials” as keywords. Recent years have seen a rapidly increasing number of research articles on the application of CNTs to biomaterials; the number has been soaring since 2005, suggesting that the application of CNTs to biomaterials has become a highly competitive research field worldwide over the past few years. This graph indicates only a time course, and numerous articles on biological applications of CNTs do exist that cannot be captured with these two keywords.
One reason for the intense competition to find biomaterial applications of CNTs and for the great potential of CNTs to advance medical care is their small size (nanometers in diameter and micrometers in length), which makes them suitable to react with living organisms. (68-70) Hence, the size of CNTs, which is at the cell organelle level, is likely to facilitate their effect on living cells. Specifically, CNTs are similar in thickness and length to microtubules, which make up the cytoskeleton and mediate a wide variety of cellular activities such as motor protein activity. (71) Biomaterials containing CNTs of such size make reactions with cells more controllable and make treatment and diagnosis that focus on target cells more feasible, accurate, and less invasive to living organisms than conventional approaches. The second benefit from biologically applying CNTs is the ease with which they bind to a broad range of molecules thanks to the extremely high reactivity of CNT surfaces. (72, 73) CNTs serve as a platform for binding multiple molecular entities such as drugs for therapeutic purposes, marker molecules, cell-binding molecules, and molecules facilitating the transfer of drugs to target tissues. Thus, CNTs can facilitate the diagnosis and treatment of diseases by facilitating substance recognition, adhesion, and affection to target cells. This potential is expected to lead to a groundbreaking new technology with applications to cancer treatment and regenerative medicine. In the near future, it is more likely that CNTs will be used as biomaterials for treatment and diagnosis of various diseases than for industrial purposes such as in batteries and aircraft. CNTs are of paramount importance to future advances in medical care. On the other hand, the small size and high surface reactivity of CNTs, properties that underlie their advantage as biomaterials, can adversely affect the human body. CNTs have not yet been used clinically (despite the dramatically increasing amount of research into biomaterial applications worldwide) because of safety concerns associated with implantation of CNTs devices in the body. (74-77) Currently, the safety of CNTs (primarily the safety of inhaled CNTs) is being investigated throughout the world. (78-83) Inhalation is the most likely route of external exposure of the human body to CNTs used in industrial products, so that inhalation toxicity must be determined first. It should be noted, however, that the safety profile of CNTs as biomaterials differs completely from that of inhaled CNTs. (68, 69, 84) Part of the safety evaluation of CNTs for biomaterial application, unlike that for inhalation, must include studies of the biological toxicity of implants in vivo. In many cases, biomaterial-specific studies must include implant toxicity, cytotoxicity, carcinogenicity, and genotoxicity studies. The safety of CNTs must be confirmed in these toxicity studies before they can be used in biomaterials. For this reason, the number of reports on the safety of biomaterials containing CNTs has been increasing. (54, 68, 85-89) Although these reports have demonstrated the safety of these biomaterials, researchers are still unable to reach a definitive conclusion. This is because CNTs are essentially nanoparticles, and biomaterials containing CNTs do not fall within the scope of biomaterials as traditionally conceptualized. (68, 90) Of course, CNTs are not a drug, any other chemical substance, bulk material (as used herein, the term bulk material/biomaterial refers to a nonparticulate bulky material/biomaterial), or biodegradable material currently in use. Nanosized particulate substances lacking high biodegradability have not been used in the medical care field so far. Because of the nanosize of CNTs, many toxicity factors associated with nanosize will need to be investigated. Factors likely to impact the toxicity of CNTs and living organisms include thickness, length, specific surface area, and surface chemistry, as well as types of chemical modifications, defects in CNTs, and catalyst left unconsumed in the manufacturing process. (72) Factors affecting the administration of CNTs to living organisms include choice of dispersant, dispersant concentration, method of in vivo exposure, and duration of in vivo exposure. Furthermore, organ specificity, cell specificity, types and incidences of biologically adverse events, in vivo distribution, and other factors must be examined. (91) Collectively, these facts seem to suggest that developing biomaterial applications of CNTs will be difficult. Thus, absolutely no clinical applications have been found to date despite the rapid increase in the number of research articles dealing with CNT biomaterials. (10, 77) However, inasmuch as applying CNTs biomaterials has potentially great benefits, the research must continue. Now is the time to review the present status based on available safety evaluation studies, to identify and resolve issues, and to implement clinical applications. Essentially, the human body consists principally of water and organic molecules, so life can be described as being supported by carbon. (92) To date, no problems have been reported from the use of materials consisting of ultrapure carbon, such as pyrolytic carbon used in artificial heart valves, carbon fibers used in Achilles tendon sutures, and the amorphous diamonds used in artificial finger joints. (93-96)
When reviewing, in detail, research articles by a great many researchers, it is evident that the major problem with the development of biomaterial applications of CNTs has been the lack of a particulate substance to serve as a biological safety reference material, and hence the inability to establish criteria for evaluating biological safety. This critical issue was first pointed out in 2009 by Auffan et al. in Nature Nanotechnology, (68) and no appropriate reference has since been found. We consider that nanosized highly pure carbon black particles are suitable as a reference material for safety evaluation of CNTs. (97, 98) This is because no safety issues have appeared in the vast number of people who have black tattoos, containing principally nanosized highly pure carbon black. The use of carbon black as a reference is described in detail in section 5. Provided that same reference is used to conduct multifaceted extensive toxicity studies and provided that international standards of safety evaluation are established, it will be possible to apply CNT biomaterials in a wide range of clinical settings in the near future.
This Review covers many recent studies on biomaterial applications of CNTs mainly published between 2005 and 2013, and gives an outline of our published studies with new references. First, the findings in these studies are comprehensively discussed to evaluate the safety of CNTs as biomaterials. The way to realize safe clinical application of CNT-based biomaterials in the future is then proposed clearly. The challenge must always be kept in mind. Making the best use of all talents and abilities of researchers worldwide, this research will lead to a major revolution in the medical care field and benefit patients greatly. In this Review, we submit a proposal of paramount importance that we think will be the key to accomplishing this significant goal.
2 Present Status of Research into the Application of CNTs as Biomaterials
ARTICLE SECTIONS
As is evident from the recent increase in the number of relevant articles, research into application of CNTs as biomaterials is advancing rapidly (Figure 1). CNTs have applications to a broad range of fields, many of which, in addition, have top priorities in clinical medicine today (Figure 2). (84, 99-101) This section divides these applications into five categories: cancer treatment, regenerative medicine, implants, DDSs for noncancer targets, and other applications. Notably, many technologies utilizing CNTs are applicable to more than one of these fields. For example, the technology using CNTs as anticancer agent delivery systems is also useful for drug delivery systems targeting noncancer diseases. The technology for combining CNTs with other biomaterials is the key to successful application in new highly functional implants and in scaffolds used in regenerative medicine. Hence, this classification system was chosen only because it facilitates organization of the various published reports. In the future, classifying the studies on CNTs biomaterials with a focus on important technologies for their biological applications would be even more useful and expected to accelerate advances in relevant research.
Figure 2
Figure 2. Biological applications of CNTs encompass a broad range of fields, many of which, in addition, represent themes of top priority in today’s clinical medicine, such as cancer treatment and regenerative medicine. Modified from ref 84, which is published under the Creative Commons Attribution License.
All studies of biological applications reviewed below highlight at least one benefit of CNTs biomaterials, so these benefits are described below. The importance of these benefits has stimulated the rapid emergence and evolution of much research. (69)
2.1 Benefits from Application of CNTs as Biomaterials
The first benefit comes from the small size of CNTs. Although this benefit may have a negative impact on safety, it by far outweighs the possible risk. The following six capabilities can be attributed to the small size of CNTs:
| (1) | Reacting with cells by entering the cells or adhering to cell surfaces |
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| (2) | Acting on biological macromolecules and cell organelles of similar size |
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| (3) | Acting on parts of the body with fine structures |
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| (4) | Distributed via the bloodstream after intravenous injection and the like; thus they may be used in targeted drug delivery systems and in vivo imaging |
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| (5) | Rapidly eliminated from the body |
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| (6) | Having effects when combined with other biomaterials, for example, on fine structures to increase their mechanical strength |
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Because capabilities (4) and (5) assume that CNTs circulate in the bloodstream, the possibility that the risk of accumulation in particular organs and leading undesirable reactions to the organ outweighs the benefits must be taken into account. It is necessary to make the best use of these advantages, while minimizing the disadvantages. This is also true for other nanobiomaterials currently under investigation. Interactions between nanosized substances and living organisms will be further elucidated in the future. Nanobiomaterials are going to occupy an important position in nanomedicine, a research field that has only recently been established. (102-105) The second benefit is the ease of chemical modification. CNTs, because of their macromolecular size, have high chemical reactivity. (106) It is likely that the CNTs used in biological applications will be functionalized-CNTs (f-CNTs). When used as particles, rather than as a composite material, CNTs are likely to be f-CNTs. (73) CNTs can serve as a platform for concurrent binding of drugs, peptides, high molecular polymers, and other molecules that otherwise cannot be bound to each other (Figure 3). (107-112) Thus, it would be possible to construct CNTs with multiple functions that have not traditionally been co-occurrent, such as drug transport, cell adhesion, biomembrane transport, and release at targeted sites. For example, CNTs coupled with an anticancer agent and monoclonal antibody can be used to target cancer cells. (113, 114)
Figure 3
Figure 3. CNTs are capable of working as a platform for concurrently binding drugs such as anticancer agents, proteins, and peptides such as monoclonal antibodies, high molecular polymers, and other molecules that otherwise cannot be bound to each other. Making the best use of this feature, it would be possible to concurrently add to CNTs multiple functions that have traditionally been unable to concur, such as drug transportation, biomembrane passage, and release at targeted sites.
There are two types of interactions with CNT surfaces: those based on covalent bonds and those based on noncovalent bonds. Of course, covalently bound substances (in contrast to noncovalently bound substances) are unlikely to dissociate from CNTs, so the appropriate method of binding must be chosen according to the target site and intended use. CNTs synthesized using the chemical vapor deposition (CVD) technique have open ends to which chemical modifiers can be bound specifically. (24) More interestingly, it is possible to transport molecules, atoms, etc., that have been inserted into the cylindrical hollow structure unique to CNTs. CNTs with such chemical modifications are called peapods because of their shape. (115, 116) As such, CNT peapods can transport drugs in encapsulated form, and are expected to be increasingly investigated because of their potential application as DDSs and in vivo imaging. (117-119)
The third benefit derives from the chemical composition of CNTs, which is very pure carbon. Carbon has already been used in many implant devices, including artificial heart valves, and no adverse effect of such biomaterials on living organisms has been reported to date. (96) The following features of CNTs may be regarded as advantages:
| (1) | High biocompatibility |
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| (2) | High strength-to-weight ratio |
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| (3) | High tensile strength |
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| (4) | Forming flexible nanofibers |
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| (5) | High chemical reactivity |
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| (6) | Conferring increased strength and other favorable characteristics to other substances when combined with them |
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| (7) | Inducing slow but significant biodegradation |
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| (8) | Colored in black that is easily distinguishable and detectable using a light microscope |
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The fourth benefit is the excellent electrical, magnetic, and thermal characteristics of CNTs in biomaterials. In fact, studies have used CNTs (because of their electrical characteristics) for nerve regeneration (112, 120-122) and muscle actuation, (123, 124) and (because of their magnetic characteristics) for cancer treatment and DDSs. (55, 125) Furthermore, CNTs (because of their high photoenergy absorption capacity and thermal conductivity) have been proven effective for cancer thermotherapy. (56, 107, 126-128)
As stated above, CNTs (unlike conventional materials) can serve a wide variety of functions in tissues and cells of living organisms. This great potential has stimulated research into the application of CNTs as biomaterials in many fields. Overall, CNTs can be viewed as a revolutionary tool that will advance the practice of medicine, imposing expectations that biomaterials will be the main field of application of CNTs.
2.2 Application to Cancer Treatment
Currently, the most vigorously studied application of CNTs biomaterials is to cancer treatment. A wide variety of methods have been used to treat various cancers. (55, 129-133) Detection of foci as early as possible and administration of an effective treatment are of paramount importance in cancer treatment. CNTs are expected to lead to innovative therapeutic and diagnostic methods. Although many other ongoing studies are not included, the following is an overview of the applications of CNTs to cancer treatment that are currently attracting much attention. Thus, clinical application of CNTs is a very promising field of study.
2.2.1 Biomarkers and Imaging
There have been recent dramatic technical improvements in methodology for the early diagnosis of cancer, with remarkable advances being made in tumor marker tests and the diagnostic imaging of cancer. Even now, however, it is difficult to detect early asymptomatic cancer; cancer is often detected only in the terminal stage. Against this background, studies have been conducted to detect the expression of biomolecules in the initial stage of cancer using CNTs as biomarker detectors. The application of CNTs to the detection of a prostate cancer marker (PSA), colorectal cancer markers (CEA, CA19-9), and a hepatocarcinoma marker (AFP) has been reported. (134-137) Applicability is based on the small size of CNTs that facilitates distribution in living organisms, and some evidence showing direct detection of biomarkers in vivo has been reported. (138-141)
CNTs have been used in noninvasive imaging, including for highly sensitive detection of very small tumors, using single CNT molecules conjugated to contrast reagent for CT or MRI, a heavy metal (gadolinium, etc.), and an antibody with high affinity for cancer cells. (142-145) A study is also ongoing that examines the application of a heavy metal encapsulated by the aforementioned peapod CNT to cancer imaging. (146) The most investigated imaging application is MR molecular imaging, which is effective in early detection of cancer. Furthermore, studies on the use of CNTs for photoacoustic molecular imaging show that it enhances contrast and resolution necessary to in vivo imaging. High resolution using a blend of SWCNTs and fluorescent peptide as the contrast medium for photoacoustic imaging were obtained. (147) Tumor vascularization plays an important role in cancer development and metastasis. For this reason, noninvasive detection of vascularization activity is critical to cancer diagnosis and assessment of patient responses to cancer treatment. A wide variety of molecular targets relevant to tumor vascularization have been identified, and can be used for tumor vasculature targeting and imaging. A method of optical imaging using a new photoprobe with the optical properties of CNTs has been developed to facilitate visualization of vascularization events. (148, 149)
2.2.2 Drug Delivery Systems for Cancer Treatment
Of the biological applications of CNTs, DDSs for cancer treatment have been the most vigorously investigated. In cancer chemotherapy, adverse drug reactions are problematic, sometimes making it difficult to deliver adequate amounts of drugs to target organs. Because of their very large specific surface area that can bind many molecules beneficial to cancer treatment, CNTs can be used for DDSs in cancer treatment (89, 129, 150, 151) and have been used as a platform to facilitate targeted delivery of a drug, antibody, other protein or peptide, lipid, polysaccharide, etc. (Figure 3). For example, a highly efficient missile therapy consisting of a combination of a hydrophilic group, a monoclonal antibody to cancer cells, an anticancer agent, and other components has been reported. (117) Using a nanoscale vehicle such as CNTs, drugs can be delivered to cancer cells that could not otherwise be delivered by microscale vehicles. (152) This is because thus-functionalized CNTs can pass through the cell membrane via a mechanism for the cellular uptake of foreign substances, such as endocytosis. CNTs with attached peptides or ligand bind to specific receptors on the cancer cell surface, and enter the cancer cells where they release the therapeutic agent more safely and efficiently. A DDS can be described as ideal when it delivers the needed amounts of therapeutic agent to the target in a timely manner, and CNT-based DDSs have the potential to fulfill this requirement. (132, 153, 154)
SWCNTs coupled with a tumor-specific monoclonal anti-CD20 antibody (rituximab) intravenously injected into mice after intramedullary transplantation of a human B-cell lymphoma resulted in accumulation of SWCNTs in the lymphoma. (110, 155) Other researchers attached a tumor-recognizing module to the surface of hydrophilic f-SWCNTs to specifically bond with cancer cells, and then a prodrug module of an anticancer agent (a taxoid with a cleavable linker) to the surface of hydrophilic f-SWCNTs. They showed that the cytotoxicity of this tumor-targeting DDS is mediated via intracellular migration, drug release, and intracellular activation. (153) Moreover, the application of CNTs to gene therapy (i.e., as carriers of genes to targeted cancer cells) has been studied. (156-160) Because CNTs-based platforms are infinitely variable and easily designable, they are expected to lead to groundbreaking cancer treatment systems.
Before thus applying CNTs for DDSs, their pharmacokinetics after topical or intravenous injection must be clarified. The disposition of intravenously injected CNT–drug composite has been examined extensively. (105, 161-165) Factors that influence transport of the composite through the bloodstream include thickness, length, and flexibility of CNTs as well as changes in properties resulting from the binding of the drug. Of course, injection of CNTs-based DDS into the tumor site directly is a safer approach. Furthermore, the use of magnetized particles to facilitate efficient uptake of CNTs in cancer tissue has been studied. For example, treatment of lymph node metastasis by subjecting magnetic functionalized CNTs to a magnetic field to promote their migration to lymph nodes has been studied. (166, 167) Treatment with gemcitabine (GEM)-loaded magnetic functionalized CNTs subjected to a magnetic field resulted in regression of lymph node metastasis and suppression of metastatic growth both in vitro and in vivo. (55) In addition, many anticancer agent-loaded CNTs-based nanoscale DDSs have been developed. (101, 128, 168-170)
2.2.3 Cancer Treatment Using External Energy
CNTs absorb electromagnetic wave energy. On the basis of this property, the use of CNTs in cancer hyperthermia has been tested. (53, 171-174) For example, cancer lesions were exposed to CNTs loaded with a tumor-specific epitope (to be absorbed selectively), then to infrared rays, and cancer tissue was specifically destroyed by the heat generated. (107) Another report showed the method for treating peritoneal metastases from colorectal cancer consisted of rapidly heating the cancer mass to 42 °C within 10 s in the presence of oxaliplatin or mitomycin C using infrared rays absorbed by CNTs. (175) In a recently reported study, the generation of heat and reactive oxygen species generated upon exposure of CNTs to infrared rays for 10 min was harmful to human lung cancer cells. Specifically, 45% of the cancer cells had been killed 24 h later. (56) The microwave absorption characteristic of CNTs theoretically permits accurate heating; microwave thermotherapy for cancer treatment is also a promising technology. (173)
Meanwhile, various improvements have been made in the targeting methods. Using anti-CD22 antibody coupled with SWCNTs followed by exposure to laser radiation succeeded in shrinking B cell lymphoma. (176) A study proposed that cancer cells could be destroyed using bubbles generated by administering CNTs and ethanol and exposing the cancer cells to laser light. (177) Recently, a nanosecond pulse electrical field was used to kill the pancreatic cancer cell line PANC1 in the presence of MWCNTs and resulted in a 2.3-fold reduction in cell survival as compared to control cells. (178)
In other studies, effect of thermotherapy was mediated through a CNT/DNA/IgG antibody composite bound to target cancer cells, (179) and the effectiveness of a CNTs/polyethylenimine/siRNA composite was attributable to RNA interference and photothermal therapy. (128) Furthermore, cancer imaging and thermotherapy was carried out concurrently by conjugating quantum dots to CNTs. (180) The variety of CNT applications has been increasing.
CNT peapods encapsulating iron nanoparticles and a chemical modification that facilitates binding to cancer cells have been used in cancer thermotherapy. The iron in the CNTs is highly biocompatible because it is protected from reacting with the ambient environment, and the electromagnetic wave thermotherapy is safe and effective. (118) In conclusion, investigations of thermotherapy with CNT adducts of other materials are ongoing.
These cancer treatments based on the ability of CNTs to absorb external energy cannot be clinically applied before methods of electromagnetic wave exposure are investigated. This is because the body rapidly absorbs the energy. In the case of simple exposure, the utility of CNTs is limited to accessible cancers. However, when used in combination with an implanted energy source, the utility of CNTs extends to deep cancers. (171, 181, 182) Cancer thermotherapy involving the clinical application of CNTs is currently a rapidly growing field of research.
2.3 Application to Regenerative Medicine
The aim of regenerative medicine is repair and regeneration of human body tissues and organs affected or lost because of disease, trauma, and the like. Developments in embryonic stem cell (ES cell) research and the development of induced pluripotent stem cells (iPS cells) in 2007 further stimulated regenerative medicine research. (183, 184) Tissue regenerative therapies use cells, growth factors, genes, etc. Whichever means is used, no tissue can be regenerated without a scaffold. Thus, the scaffold is of paramount importance in therapy, and research aimed at developing CNTs as scaffold material has been increasing. (185-191)
2.3.1 Studies Assessing the Applicability of CNT Composites to Regenerative Medicine
The use of CNT composites in regenerative medicine has been vigorously investigated in vitro. Results showed that a CNT/collagen composite could be used as a scaffold for myocyte culture, and that a CNT/polyurethane composite could be used as a scaffold for fibroblasts growth and biosynthesis. (192-194) A CNT/polyurethane composite used as a scaffold for culturing vascular endothelial cells was effective in promoting their proliferation and suppressing thrombus formation. (195) A CNT/poly l-lactic acid/hydroxyapatite composite increased the adhesion and proliferation of periodontal ligament cells (PDLCs) by 30%. (196) Regenerated silk fibroin films incorporating MWCNTs were shown to support the adhesion and growth of human bone marrow stem cells. (197) SWCNTs nonwoven films enhanced long-term proliferation of many cell types. (198) While in vitro studies examining the reactions between cells and CNT composites used as scaffolds are numerous, there are few in vivo studies. (125, 174, 185-188, 190, 199, 200) It is hoped that in vivo animal experiments based on in vitro findings will be carried out in the future. The application of CNTs to bone tissue regeneration and nerve tissue regeneration is of paramount interest.
2.3.2 Bone Tissue Regeneration
Regarding bone tissue regeneration, a CNT/polylactic acid composite was shown to promote osteoblast proliferation in vitro as early as in 2002. (58, 201) Later, a CNT/polycarbonate urethane composite and a CNT/poly lactic-co-glycolic acid composite were reported to enhance the adhesion of osteoblasts. (202-204) In 2006, a study showed that SWCNTs and MWCNTs promoted the proliferation of osteocytes and osteoblasts when used alone. (205) This was followed by in vitro studies showing the wonderful effects of CNTs on bone-related cells. (66, 186, 206-212)
In 2008, we showed for the first time that CNTs promote bone tissue formation in vivo as well. (213) The study employed an experimental system that used recombinant bone morphogenetic protein-2 (rhBMP-2) to induce ectopic osteogenesis in mouse back muscle. (214) Bone formation on a collagen sheet was shown to occur earlier in the presence rhBMP-2 attached to a scaffold of MWCNTs than in the presence of rhBMP-2 alone (Figure 4). Later, other researchers confirmed that osteogenesis was promoted by CNTs in vivo. For example, a layer-by-layer assembled carbon nanotube composite promoted osteogenesis and bone repair when implanted in rat calvarial bone defects. (215) Carbon nanohorns, a type of CNT, were attached to a porous polytetrafluoroethylene membrane by vacuum filtration, and rat calvarial bone defects were covered with the membrane. The extent of osteogenesis was greater under the membrane containing carbon nanohorns than under the membrane without the carbon nanohorns, showing that carbon nanohorns accelerated bone regeneration. (216)
Figure 4
Figure 4. MWCNTs promote ectopic osteogenesis by rhBMP-2 and collagen. (a) A soft X-ray radiogram of newly formed bones extirpated 2 weeks after placement of rhBMP-2/collagen/MWCNT composite (upper lane) or rhBMP-2/collagen composite (lower lane) in mouse back muscle. Larger bones with more intense opacity were formed when using collagen conjugated with MWCNTs than without. (b) Bone mineral contents (BMCs) in bones formed at 2 weeks of implantation. A significantly higher BMC was observed in bones formed at 2 weeks of implantation of collagen conjugated with MWCNTs than without. Each error bar indicates the standard deviation of the mean (n = 8); asterisk, P = 0.016 between samples treated with carbon nanotubes and those without (unpaired Student’s t test). (c) Histological images of bones extirpated at 2 weeks. The trabecula was thicker and denser when using collagen conjugated with MWCNTs than collagen alone. The tissue around the implanted collagen–MWCNT conjugate was found to have MWCNTs absorbed uniformly in the trabecula and bone marrow. The MWCNTs were seen to have entered the trabecula and came in direct contact with bone substrate. Hematoxylin-eosin staining. Scale bars = 100 mm. Reprinted with permission from ref 213. Copyright 2008 John Wiley & Sons, Inc.
Later, we attempted to elucidate the mechanism underlying promotion of bone tissue regeneration by CNTs. In 2009, we showed that CNTs specifically suppressed the differentiation of osteoclasts as well as expression of the transcription factor NFκB in osteoclasts. (217) In 2011, we showed that CNTs could serve as the seed material for the crystallization of hydroxyapatite, the major component of bone, and that CNTs attracted Ca ions and activated osteoblasts. Another finding was that this activation was accompanied by the deposition of hydroxyapatite around the CNTs, which was catalyzed by alkaline phosphatase (ALP) released from osteoblasts. (218) These findings demonstrated that CNTs functioning as a scaffold interact with the body to promote osteogenesis and thereby the process of bone tissue regeneration. To date, no other scaffold has interacted with the body in this way; CNTs are expected to be breakthrough materials in regenerative medicine research as well.
2.3.3 Nerve Tissue Regeneration
Currently, brain injuries, spinal cord injuries, and large-gap peripheral nerve defects are intractable, and their treatment is an important goal of regenerative medicine. To enhance and stimulate the regeneration of these injured nerve cells and fibers, application of a wide variety of nerve conduits and synthetic guidance devices has been attempted but has failed to yield satisfactory results. (219) Applying CNTs is expected to lead to the development of new methods of nerve regenerative medicine and contribute to improvements in patient quality of life. (122, 220-224)
Use of CNTs as a scaffold for neural cell growth has been vigorously studied for more than 10 years and found to be useful for neural cell adhesion and axonal growth. (117, 225-227) CNTs promoted neurite elongation in a wide variety of cultured neurons. (228-230) CNTs were also reported to aid regeneration of Schwann cells. (231) Another study found that CNTs were useful in the differentiation of embryonic stem cells to nerve cells. (220) In these studies, electric stimulation was often used to promote neural cell growth, making the best use of the favorable electroconductivity of CNTs. (120) Regenerative medicine for nerve is an interesting research field that aims to apply in combination the electrical and mechanical properties of CNTs to biomaterials.
2.3.4 Regeneration of Other Tissues
The application of CNTs to the regenerative medicine of tissues other than bone and nerves has also been investigated. Cartilage regeneration was promoted by a composite of CNTs and polycarbonate urethane. (232) Other studies have examined the application of CNTs to skeletal muscle regeneration (233, 234) and heart muscle regeneration. For example, inducing differentiation of mesenchymal stem cells to cardiomyocyte lineage cells by electrical stimulation with CNTs was succeeded in vitro, and notably finding evidence of electrically stimulated cross talk among these cells. (235) CNTs also promoted heart muscle maturity and altered the electrical characteristics of heart muscle. (236)
In the future, CNTs will be used to stimulate the regeneration of many other tissues and organs. Regenerative medicine is a field of applied medicine that capitalizes on the unique features of CNTs such as nanoscale size, large specific surface area, and high surface reactivity, as well as electroconductivity. Furthermore, unexpected effects, such as the promotion of osteogenesis resulting from the interactions of CNTs with the body, may be found in a wide variety of tissues, so regenerative medicine is quite an interesting field of applied research.
2.4 Application to Implant Materials
Implant technologies have been used in many clinical settings, such as orthopedic surgery, dental and oral surgery, and craniofacial surgery. Artificial valves and artificial blood vessels have been used in heart and other surgeries. These implants are required to possess, in addition to mechanical characteristics such as strength and durability, high biological compatibility because they come in direct contact with living tissue. (237, 238) Many types of orthopedic implants, in particular, have long been used in clinical settings in many patients. Examples include artificial joints used to treat osteoarthritis and rheumatoid arthritis, plates and screws used to treat bone fractures, and cages and rods used for interbody fusion. Hence, many different materials are used in orthopedic implants. (239-241) Metals are used for bone fracture treatment and in artificial joints, including stainless steel, titanium alloys, cobalt–chromium, and tantalum. Ceramics (mostly alumina and zirconia ceramics) are used in artificial joints and artificial dental pulp. Ultrahigh molecular weight polyethylene (UHMWPE) is used in the sliding parts of artificial joints. Polyether ether ketone (PEEK) is often used for interbody fusion.
Since 2003, we have been working to conjugate CNTs to polyethylene for use in sliding parts and rotating parts of artificial joints. (58, 69) The sliding parts of a polyethylene artificial joint wear away with long-term use, leading to the breakage of the artificial joint and necessitating revision surgery. (242-245) With this in mind, we are developing more durable artificial joints made of polyethylene and CNTs to reduce the amount of wear loss. The sliding parts of artificial joints are sometimes made of ceramic instead of polyethylene. Although ceramics are generally unlikely to wear, alumina ceramics break easily, and zirconia ceramics are liable to deform due to phase transition in vivo. (246, 247) Hence, we are working to develop a new ceramic material (alumina ceramics combined with CNTs) that is unlikely to break down and deform. (248, 249) Although many difficulties exist, including homogenously blending CNTs and ceramics, we have already obtained a blend with improved fracture toughness values. The number of patients undergoing artificial joint replacement surgery has been increasing each year worldwide; accordingly, the number of patients undergoing revision surgery is increasing steadily. (250) Clinical application of CNT-based artificial joints would dramatically reduce the number of patients undergoing revision surgery and allow use of artificial joints by young patients.
Furthermore, we are developing a CNT/PEEK composite for spinal fusion cages used in interbody fusion surgery. Spine interbody fusion cages of PEEK material have already been used clinically; however, poor bone compatibility poses an obstacle to the bonding of the implant and bone around it. (251, 252) Hence, spine interbody fusion cages made of a CNT/PEEK composite of high bone compatibility are being developed by conjugating CNTs to PEEK, thereby utilizing the bone induction potential of CNTs described in section 2.3.2: Bone Tissue Regeneration. The development of these artificial joints and spine interbody fusion cages is further described in section 6.4.
In these composites, the CNT content ratio is up to 10 wt %, often about 5 wt %, with only a small amount of CNTs entering the body. Furthermore, because they are composite materials, there is little or no possibility that CNTs (that is particulate) will be directly exposed to living organisms. For this reason, CNT composites can be thought to be highly safe, with the reactions between CNT particles and living organism rarely posing a problem. In view of biological safety of CNT composites, we believe that the first application of CNTs should be in implants in the form of composites as described above. (253-255)
Taking into account the above-described utility of CNTs as a reinforcing material and their safety as composites, it is expected that a wide variety of CNT composite implants will be developed in the future. Although technically difficult, conjugating CNTs to metals and ceramics would produce great benefits. While this field has so far received only scant attention, we hope that more R&D effort will be directed to this field, where CNTs are most likely to find clinical applications.
2.5 Application to DDSs for Treatment of Noncancer Diseases
As stated in section 2.2.2: Drug Delivery Systems for Cancer Treatment, CNTs have large specific surface areas, possess high surface reactivity, and therefore can be conjugated with a wide variety of molecular species, including low-molecular-weight compounds, genes, proteins, and vaccines, in large amounts. In addition, because CNTs can be delivered to the small structures in living organisms, they are expected to act as an ideal DDS. (100, 117, 256-258) Research has recently been advancing rapidly toward the development of more useful CNT-based DDSs for various diseases. Many improvements have been made in the reactivity with the cell membrane, which is particularly important to DDS applications. For example, SWCNTs bound to an integrin monoclonal antibody were used to enhance their adhesion to cells. (114) Bonding of a bilayer-forming lipid to CNT surfaces was used to lessen the influence on the cell membrane. (54, 259) DDSs targeting a wide variety of diseases other than cancer have also been investigated. Some examples are described below.
As compared to alginate microspheres alone, a composite of CNTs and alginate microspheres exhibited improved drug encapsulation efficiency, resulting in decreased drug leakage. Hence, the release of theophylline, a drug used to treat respiratory diseases, was extended, suggesting a potential for application of this composite to prolong the sustained therapeutic effects of encapsulated drugs. (260) Moreover, a study showed that CNTs successfully coupled to a therapeutically active molecule could be delivered to cells of a pathogenic organism. (261-263) In addition, because of their distinct mechanism of action on resistant strains against which existing antibiotics are ineffective, CNTs have the potential to be an innovative therapy. (264) CNTs are reported to suppress bacterial proliferation. (265-268) Attempts have been made to treat diseases by immune activation or vaccination with modified CNTs. For example, a neutralizing B cell epitope conjugated to CNTs induced intensive antipeptide antibody responses to hand-foot-and-mouth disease virus, suggesting its potential as an immunotherapy. (269)
The use of CNTs in gene delivery systems is also under investigation. For example, DNA-wrapped MWCNTs prepared by sonication (because they are well and stably dispersed by sonication) are likely to have applications to gene therapy. (256) A composite consisting of MWCNTs with biomolecules immobilized by the addition of a polyamidoamine dendrimer was found to be a promising DDS for a wide variety of genes. (270) Regarding antisense therapy, two problems with antisense nucleic acids, rapid decomposition and poor diffusibility in the cell membrane, impose limitations on its application to clinical treatment. When bound to SWCNTs, however, antisense-myc was readily internalized by HL-60 cells and continued to control intracellular genes. (271) Furthermore, more than one report is available on the introduction of short interference RNA (siRNA) in cells using CNTs as a delivery system. (272-275) According to a 2010 report, the gene transfer efficiency is high at 95%, with no cytotoxicity observed. In conclusion, research aimed at the application of CNTs to gene DDSs has increased dramatically. While their application to gene therapy is expected, CNT-based gene DDSs may also be an important tool in biological research.
2.6 Other Biological Applications
In addition to the above-described applications for cancer treatment, regenerative medicine, implants, and DDSs, CNTs are expected to have biomaterial application in a wide variety of therapeutic settings. (276)
CNTs have a great potential for use as sensors and actuators in nanomedicine (89) and as sensors and stimulants in nerve tissue. Neuroblastoma NG108 and rat primary peripheral neurons produced high voltage-activated currents when electrically stimulated through conductive SWCNT films, demonstrating the electrical coupling of SWCNTs and neurons. This finding suggests that SWCNTs can be used to effectively control nerve tissue stimulation. (120) CNTs (because of their electrical properties) may also serve as muscle actuators or be directly applied to artificial muscles. (123, 277) At present, it is technically impossible to use CNTs as a substitute for muscles in living organisms, and we hope that these studies will evolve into research on the application of CNTs as biomaterials. Furthermore, a DNA actuator based on encapsulated DNA-MWCNT was designed using a computer. (278)
Another potential application of CNTs is as an in vivo sensor to measure glucose concentrations in diabetic patients using near-infrared rays in vivo, bearing in mind that CNTs are capable of controlling far-infrared luminescence. (279) Hence, specific biomolecules adsorbed to CNTs and applied to in vivo sensors can be used to monitor a wide variety of diseases. Application of CNTs to nanosized devices injected into the body or medical nanorobots for in vivo implantation (99, 280) is also under investigation.
As stated above, the electrical, thermal, and mechanical characteristics unique to CNTs are expected to give rise to new biomaterials that do not fall within the scope of existing concepts. Furthermore, CNTs, when brought into contact with various cells and tissues, may have unknown in vivo characteristics. Research into application of CNTs as biomaterials is expected to advance and lead to groundbreaking therapeutic approaches.
3 Present Status of Research into the in Vivo Toxicity of CNTs Used as Biomaterials
ARTICLE SECTIONS
Currently available studies of the in vivo toxicity of CNTs mostly concern inhalation toxicity. Research into the toxicity of inhaled CNTs has been advancing rapidly since the publication of two articles by Takagi et al. and Poland et al. in 2008; the revelation that intraperitoneal administration of CNTs causes inflammation and carcinogenesis attracted worldwide attention. (281, 282) These two studies used intraperitoneal administration as a surrogate for mesothelial tissue reactions to inhaled CNTs, bearing in mind that mesothelial tissue is present in both the thoracic and the peritoneal cavities. What was always problematic in these studies was that the CNTs were fibrous particles of similar size to asbestos particles. (283-287) It should be noted, however, that the toxicities of CNTs (very pure carbon particles) and asbestos (a mineral containing a large amount of impurities) are distinct. CNTs are highly flexible, whereas asbestos is rigid. Currently, intraperitoneal administration is often used to explore the mechanism of mesothelioma development and for other purposes, (80, 288, 289) and inhalation exposure or intratracheal administration is used to assess inhalation toxicity. (79, 82, 290-296) Recently, inhalation exposure studies have shown increasing accuracy, allowing extensive examination of gene expression in body tissues and blood after exposure. (297) Following these many studies, the Organization for Economic Co-operation and Development (OECD), the U.S. National Institute for Occupational Safety and Health (NIOSH), the National Institute of Advanced Industrial Science and Technology (AIST) in Japan, and other organizations have announced their findings. (298-302) Their reports showed that, as compared to asbestos, CNTs have much lower inhalation toxicity. The currently projected goal of toxicity assessment is to determine the threshold level of exposure triggering inflammation in the lung. In the near future, international criteria of exposure to inhaled CNTs will be established. Worldwide, the inhalation toxicity of few other substances has been investigated and discussed. In the context of production, use, and disposal of industrial products, CNTs are believed to be handleable, provided that safety measures based on the latest research findings are fully implemented, and that any available numerical criteria are met. (303) With respect to inhalation exposure, researchers and manufacturers of CNT-containing biomaterials should follow the same standards.
As stated in the section 1, the type of toxicity to the human body differs completely between the inhalation route and implantation route of exposure. Fewer studies have been conducted on the in vivo toxicity of CNTs biomaterials than on the inhalation toxicity of CNTs; however, the number of relevant reports has recently been increasing. (77, 91, 191, 304) Unfortunately, all of the reported experiments assessing the in vivo toxicity of CNTs biomaterials lacked reference materials. (68) Notably, many published articles have suggested that the toxicity of CNTs biomaterials is extremely low. (91, 191, 305, 306)
3.1 In Vivo Implantation Studies
This section reviews articles on implantation toxicity studies of CNTs as biomaterials. Most reports on local reactions following implantation of CNTs showed that mild inflammatory reactions occurred immediately after implant placement but disappeared early. Examples of such research include a study of subcutaneous implantation of alginate gel bound to SWCNTs, (307) a study of subcutaneous implantation of a poly(propylene fumarate) assembly bound to SWCNTs, (308) and a study of subcutaneous implantation of two MWCNTs with different lengths. (309) None of these studies found any indication of intense inflammatory reaction. In our study of subcutaneous implantation of MWCNTs in mice, mild inflammation persisted for about 1 week, resolved rapidly, and never turned into chronic inflammation. Histological profiling identified MWCNTs as phagocytosed by macrophages and remaining at the implantation site for a long period of time. (58) Studies of subcutaneously implanted CNTs by other researchers yielded similar results representing the body’s characteristic reactions to CNTs.
Although subcutaneous implantation studies are a representative and convenient method of assessing the general biological compatibility of biomaterials, it is also necessary to study CNTs biomaterials actually implanted in organs. (191) We conducted a bone implantation study of MWCNTs used as scaffolds for bone regeneration and as biomaterials in contact with bone. After implanting MWCNTs in bone defects artificially made in mouse tibias, we observed normal bone repair, with incorporation of MWCNTs particles into repaired bone substrate. Electron microscopy detected physical bonding of the bone substrate hydroxyapatite in contact with CNT particles. These results show that MWCNTs possess an extremely high compatibility for bone tissue (Figure 5). (213) On the other hand, when SWCNTs and MWCNTs were implanted in rat gluteal muscle, acute inflammation developed and progressed to chronic inflammation. (76) Further investigations will be needed to elucidate CNT–muscle compatibility. A wide variety of interactions between in vivo implants of CNTs and various organs can be observed in the bodies of living organisms, making it possible to elucidate the reaction of living organisms to CNTs bound to endogenous molecules (e.g., albumin, hemosiderin). We think that a consensus has now been reached that the inflammatory reactions are mild and disappear early after subcutaneous implantation. At the next stage, other sites for clinical application of implants should be investigated in detail along with the biological reactions at each site.
Figure 5
Figure 5. MWCNTs exhibiting good bone compatibility as they are absorbed in repaired bone without interfering with bone repair. (a) A histological image of a tibia extirpated 4 weeks after surgery for implant of MWCNTs in a pit drilled in tibial diaphysis after incising the anterior surface of a mouse leg. Cortical bone and a medullary cavity were normally formed to the extent of complete bone repair. The MWCNTs were found to have been absorbed in the newly formed bone tissue and enclosed in bone substrate. Hematoxylin-eosin staining. Scale bar = 100 mm. (b) An electron microscopic image of MWCNTs absorbed in repaired bone tissue at 4 weeks. The MWCNTs were found to be in direct contact with bone substrate hydroxyapatite. Scale bar = 1 mm. Reprinted with permission from ref 213. Copyright 2008 John Wiley & Sons, Inc.
3.2 In Vivo Kinetics
When applying CNTs to biomaterials, it is important to study their in vivo kinetics. (304, 310, 311) Specifically, it is necessary to determine whether CNTs circulate through the body via the bloodstream, whether they accumulate in particular organs, what reactions take place in the organ, and how they are excreted from the body. Of course, in vivo kinetics is of direct relevance in DDSs and imaging where localized accumulation of CNTs and distribution systemically via the bloodstream is expected. However, CNT composites used as implants do not enter the circulation, and even CNTs particles used topically hardly ever enter the bloodstream. It can also be hypothesized that small CNTs but not large CNTs enter the bloodstream to some extent.
The focus of in vivo kinetic studies has been on inhalation toxicity rather than on the applicability of CNTs to biomaterials. CNTs adsorbed to the lungs are thought to enter the bloodstream to some extent because the lung is the organ responsible for blood gas exchange. Therefore, it is necessary to examine the disposition of CNTs after they are inhaled and enter the pulmonary circulation. Some reports are available on the disposition of intravenously injected CNTs. (86, 144, 306, 312-315) These studies provide valuable information on applications of CNT biomaterials and topical applications of CNTs both involving their entry and assumed entry into the bloodstream. Reported studies mostly found that CNTs entering the bloodstream are nontoxic in individuals and various organs. (191, 310) For example, no sign of toxicity was registered at least 90 days after intravenous injection of pristine SWCNTs in mice. (312) No sign of acute toxicity was registered after intravenous injection of SWCNTs or MWCNTs conjugated with diethylenetriaminepentaacetic acid (DTPA) in mice. (306) Another study verified the safety of SWCNTs 24 h after intravenous injection. (305) No toxicity was found in mice 4 weeks after receiving an intravenous injection. (310) Variable findings have been reported depending on the sites of accumulation of intravenously injected CNTs in laboratory animals. Many studies found that most CNTs were excreted in urine, with only a small amount accumulating in the liver and spleen. (87, 191, 316) Intravenous injection studies notably found that both MWCNTs and SWCNTs were most likely to accumulate in the liver and spleen. (310, 317) Because CNTs enter capillaries and remain in various organs, it can be thought that the liver and spleen, which are rich in blood vessels, are the most likely organs of CNTs accumulation. The toxicity of CNTs accumulated in the liver and spleen is thought to be low. (86, 305, 306, 318, 319) Other organs where CNTs accumulate include the lung, urinary bladder, kidney, and gut. Although the doses used in these experiments are variable, they are often up to 20 μg/kg body weight. The solution used to disperse and inject CNTs is also variable, with phosphate buffered saline (PBS) being the most commonly used solution. (91)
Historically, various techniques for monitoring the migration of radioisotope-labeled CNTs in the body have been employed in disposition studies. 13C was used in 2002, followed by 14C. (320, 321) In rats injected with 14C-labeled MWCNTs, the liver accumulated most of the dose, followed by the lung, spleen, and kidney. The MWCNTs were gradually cleared from these organs, and quickly eliminated by excretion from the kidney. Analysis of the in vivo distribution of 125iodine-labeled hydroxylated SWCNTs showed rapid distribution throughout the body and then excretion in urine and feces. (322) A study of intravenously injected SWCNTs modified with 111indium-labeled DTPA and 99mTc-labeled MWCNTs found that these composites were rapidly removed from the blood via the kidney. In addition, electron microscopic examination of collected urine samples containing CNTs showed that the CNTs remained unchanged. (306, 323)14C-Taurine-labeled MWCNTs were administered via the intravenous route and oral route using a stomach tube. By 10 min after intravenous administration, a large amount of 14C-taurine-labeled MWCNTs had accumulated in the liver, with smaller amounts accumulating in the heart and lung; however, no accumulation was observed in any other organs. On day 90, retention of MWCNTs was found in the liver only. When administered through a stomach tube, 14C-taurine-labeled MWCNTs were detected only in the stomach, small intestine, and large intestine, with no vascular migration observed. The technique for labeling CNTs and tracking their migration used in these experiments is also applicable to disposition studies following in vivo implantation. (310)
Other methods of monitoring the disposition of CNTs have been investigated. The disposition of SWCNTs (possessing intrinsic Raman spectroscopic signatures) can be monitored by Raman spectroscopy. Liu et al. quantified intravenously injected SWCNTs in the blood circulation of mice, and detected SWCNTs by Raman spectroscopy in various organs and tissues including gut, feces, kidney, and urinary bladder, and their excretion via the bile and kidney. Autopsy, histological examination, and blood biochemistry did not reveal any sign of SWCNTs toxicity in mice. (86) A real-time technique for detecting CNTs in the circulation uses photoacoustic flow cytometry. (324) Recently, echography was used to visualize CNTs and may be used in future research into the disposition of CNTs. (139, 276)
The disposition of CNTs as biomaterials implanted in living organisms is a controversial issue, and some articles have suggested that SWCNTs but not MWCNTs, which have larger diameters, enter the bloodstream. (152, 155) While CNTs are mostly phagocytosed by macrophages at many sites in the body, these macrophages do not return to the bloodstream; therefore, the hypothesis that macrophages do not transport CNTs into the bloodstream is convincing. (325) In 2011, CNTs were reported to migrate from subcutaneous implants to other organs and to be associated with inflammatory cytokine alterations. According to the report, CNTs did not accumulate in the liver, spleen, kidney, or heart, and although their migration to regional lymph nodes was slight, the lymph nodes remained undamaged. Inflammatory cytokine levels initially rose slightly, but then returned to their original levels. Accordingly, it was concluded that CNTs do not affect the immune system. (326) Of course, special caution should be exercised when using CNTs in particular sites, for example, the heart and lung. Their use in the ovary and uterus, which lie within the abdominal cavity, should also be avoided. In cases where CNTs are topically used at other sites, little enters the bloodstream, and if a very small amount does enter, no systemic toxicity would be expected. This is the current conclusion.
Conversely, when CNTs are used as DDSs or in imaging (where they migrate via the bloodstream), SWCNTs may be more suitable than other composites. In this case, the toxicity and accumulation of SWCNTs in nontarget organs need to be examined in detail. For this reason, the first use of CNTs biomaterials should be topical, and their systemic use should be implemented with extreme caution.
Finally, an in vitro study on the influence of intravenous CNTs on microvascular endothelial cells, which serve as a blood–tissue barrier, showed that CNTs might increase endothelial cell permeability. The reasons for increased permeability include higher levels of ROS and reconstitution of actin filaments, with possible involvement of MCP-1 and ICAM-1. (327) Further research reflecting these findings in vivo is expected.
3.3 Effects of Chemical Modifications
In the in vivo implantation studies and in vivo kinetic studies of CNTs, attention should be paid to the difference between the body’s reactions to chemically modified functionalized-CNTs (f-CNTs), which can be a response to the binding partner molecule, and the body’s reactions to pristine CNTs. (292, 328) CNT is generally chemically modified by oxidatively destroying a C═C bond in it, attaching a carboxyl group, and reacting the carboxyl group with another molecular entity. (91, 329) The main purpose of the most commonly performed chemical modification of CNTs, coupling with polyethylene glycol (PEG), is to increase their water solubility, and many studies have found that PEG alters the body’s reactions to CNTs. PEG bound to CNTs was reported to stimulate immunocytes to produce inflammatory cytokines. (109, 330) A study concluded that the biological toxicity of chemical modifications of PEG-CNTs is influenced by PEG. Mice injected with SWCNTs modified by both PEG and another functional group had higher neutrophil counts than mice injected with SWCNTs modified by PEG alone. (87) In recent years, however, an increasing number of studies have shown that bound PEG reduces harmful effects. (77, 331, 332) A kinetic study of intravenous SWCNTs found that PEG conjugation accelerated the removal of SWCNTs from the body. (324) Numerous chemical modifications other than PEGylation can cause this phenomenon as well as a wide variety of changes in the distribution of SWCNTs in the body. For example, attachment of paclitaxel to SWCNTs resulted in increased localization in the gut and liver, and attachment of rituximab to CNTs increased levels of accumulation in the liver. (110, 333) This observation is attributed to differences in the affinity for or reactivity with a wide variety of cell types in various organs depending on the molecule bound to CNTs. Size of the binding functional group and the type of chemical modification (whether covalent or noncovalent bond) can also influence the biological toxicity. (88)
Likely reasons why appropriate f-CNTs are generally safer than pristine CNTs include decreased toxicity due to the presence of functional groups of high biocompatibility and increased dispersibility in water, thus preventing their aggregation. (72, 75, 86, 263, 331, 334-336) On the other hand, new forms of toxicity can emerge. In the application of particulate CNTs, f-CNTs are used in almost all cases. For this reason, it is necessary to build a library of data at least on representative f-CNTs, and, in particular, on the differences in reactions in vivo between chemically modified CNTs and pristine CNTs, which can be accessed by researchers worldwide.
3.4 Carcinogenicity Studies
Few in vivo studies have been conducted on the carcinogenicity of CNTs biomaterials implants. In the intraperitoneal administration studies to investigate inhalation-related mesothelioma carcinogenesis and its mechanism, the abdominal cavity, where mesothelial tissue is present, was used as a surrogate for the thoracic cavity. (281, 282, 288) Entry of intraperitoneally administered CNTs biomaterials into the abdominal cavity is unlikely. Conversely, use of CNTs in parts of the body from which entry into the abdominal cavity is likely (e.g., uterus, ovary) should be avoided. Even when CNTs biomaterials were implanted in common sites, nothing more than very mild transient acute inflammation developed, with no finding of carcinogenicity reported to date. Carbon, a substance of high biocompatibility, is very unlikely to be carcinogenic. Carcinogenesis might result, only if inflammation were persistent at the site of implantation. Because CNTs are fibrous nanoparticles, they have not been used as biomaterials. Subcutaneous implantation of CNTs has resulted in only brief, very mild inflammation. Persistent chronic inflammation is unlikely, provided that the site of implantation is appropriate. (58) However, it should be noted that the impurities and chemical modifier molecules present in CNTs can be carcinogenic.
In fact, no methodology has been established to assess the in vivo carcinogenicity of biomaterials whether they are particulate substances like CNTs or bulk biomaterials. We developed a new tool for assessing the carcinogenicity of CNTs involving subcutaneous implantation in genetically modified cancer-prone mice. (98) No carcinogenesis was detected in these mouse recipients of subcutaneous CNTs implants. This experimental study is described in detail in section 5.
3.5 Oxidative Stress
Because of its association with apoptosis and carcinogenicity, oxidative stress is a good indicator of toxicity. Whether CNTs induce oxidative stress is somewhat controversial. In vivo studies have revealed CNT-induced changes in oxidative stress markers. For example, intravenously injected SWCNTs induced high levels of oxidative stress markers in the lung and liver, (312) and a study with the antioxidant vitamin E found that SWCNTs played a major role in the induction of oxidative stress. (337) Hence, SWCNTs are likely to induce oxidative stress. (191) On the other hand, gene expression analysis in the liver and spleen found that intravenously injected MWCNTs significantly raised the level of the oxidative stress marker NAD(P)H in mice. (338) However, the prevailing opinion is that MWCNTs do not induce very much oxidative stress. (339-341) Even if oxidative stress is induced and is due to an essential property of CNTs, the underlying mechanism remains unclear. Metal catalysts remaining in CNTs have been suggested to induce oxidative stress. These facts are discussed in further detail in section 4.2.1 with a focus on cells.
3.6 Biodegradability
The biodegradability of CNTs is currently a hot research topic. Carbon fibers, which in the past were clinically used to reinforce the Achilles tendon, have been shown to fragment over a long time. This is attributable to the degradation of carbon fibers in the body. (96)
The degree of biodegradability of any biomaterial is an important toxicity issue. In the case of highly biodegradable materials, the toxicity of their decomposition products must also be assessed. On the other hand, if the material of interest is rapidly degraded in the body, the carcinogenicity and other forms of toxicity that are possibly exhibited by its original form will no longer be a concern. In 2008, pioneer investigators showed that CNTs are biodegradable. (342) Since then, the biodegradability of CNTs has been characterized as slight, and future advances in the relevant research are expected. (343-348) Even if CNTs biodegrade, however, their biodegradation occurs at extremely slow speeds; therefore, it can be thought that biodegradability has no major impact on the safety of CNTs biomaterials except in special cases such as where a single CNT fiber is used alone.
3.7 Other In Vivo Studies
In vivo studies have been conducted to assess carbon nanotube uptake and toxicity in the brain and spinal cord. A current focus is on migration of CNTs to the central nervous system (CNS), particularly to the brain. (349) Advances are expected in the application of CNTs as DDSs in the treatment of cerebral and spinal diseases. Accordingly, studies assessing neurocompatibility have been conducted using CNTs injected into the mouse brain and spinal cord. (70) However, research into CNTs interactions with the central nervous system is still at the very initial stage. (99, 350)
Other studies found that CNTs caused allergic reactions, (351) and aggravated infectious disease rates. (352, 353) Another study found that SWCNTs activate platelets and accelerate thrombus formation in the microcirculation. (354) These biological reactions to CNTs biomaterials are important and have to be examined extensively.
More recently, a nanoparticle-adhering protein was reported to possibly cover a part of the nanoparticle surface, reducing the targeting activity of nanoparticles in the body. (355, 356) This phenomenon is called “protein corona formation” and discussed again in section 4.3.
3.8 Body Size Differences between Humans and Small Animals
What should always be kept in mind in medical research is that results from animal experiments can differ from actual clinical findings. (357-360) Traditionally, small animals have been used in most animal experiments. It remains unknown whether assessments of CNTs toxicity shown in vivo in small animals are reproducible in humans, which have larger organs. In particular, the toxicity of small particulate substances has not been controversial and may be negligible as the body size increases. Conversely, the effects on finer structures of individual organs may increase the toxicity.
Differences in blood vessel thickness depending on animal body size can impact the disposition of CNTs. Most blood vessels are thicker in humans than in small animals. However, the thickness and structure of the terminal microvessels are thought to be nearly the same in different animal species. Hence, the migration of CNTs from tissue to the bloodstream and the obstruction of blood vessels by CNTs transported via the bloodstream are reproducible in small animals. For this reason, CNTs biomaterials can be deemed safer in humans because of the greater thickness of their central blood vessels, provided that no problems have been revealed by in vivo kinetic studies in small animals. Kinetic differences in the transport of CNTs (used in DDSs and imaging) through blood vessels and its dependence on animal body size must fully be taken into consideration.
Because cell size is the same in humans and small animals, the relationship between CNTs and cells and the effects of CNTs on cells are nearly the same. Therefore, even for basic body reactions to a small particulate substance, the results of animal experiments are considered to be highly representative.
Although these differences depending on animal body size may be resolved to some extent by conducting studies in larger animals such as dogs, it is difficult to maintain constant experimental conditions, making evaluation of a wide variety of CNTs impossible in large animals. As with ordinary biomaterials, for which International Standards Organization (ISO) and other standards are already available, it is reasonable to commence clinical application of CNTs biomaterials, provided that no problematic findings are obtained from assessments in small animals. It should always be borne in mind, however, that adverse reaction assessments can yield results inconsistent with findings from animal experiments.
4 Present Status of Research into in Vitro Toxicity of CNTs for Biomaterials
ARTICLE SECTIONS
Cells cultured to test for inhalation toxicity can be used to assess the in vitro toxicity of CNTs biomaterials. (361-365) A large number of studies have examined the use of macrophages to test for inhalation toxicity. Because macrophages play an important role in the in vivo response to CNTs implants, inhalation toxicity data obtained using this type of cell are relevant to toxicity assessment of CNTs biomaterials. (155)
Unlike drugs and other chemical substances, CNTs are nanosized particles possessing unique properties; therefore, special cautions should be exercised when investigating CNTs in vitro. For example, because CNTs are essentially hydrophobic and insoluble in water, a surfactant must be used as a dispersant in culture experiments. (329) One article reported that the chemical properties of such dispersants altered the toxicity of CNTs. (366-371) In addition, CNTs may adsorb phospholipids and albumin in the culture broth, which are recognized by and interact with cells. (372-374) Furthermore, attention should be paid to possible reactions between CNTs and test reagents. (91, 191) One study concluded that photometric methods were unsuitable because CNTs absorb light. (375-377) These factors affect the results of in vitro studies, making their interpretation difficult.
4.1 Cellular Uptake of CNTs
Cellular uptake of CNTs has been investigated in many types of cells by many researchers, and different studies have reported widely variable results. For example, SWCNTs have been reported to be absorbed by RAW264.7 cells in some studies and not in others. (340, 364, 372, 378) Firme et al. studied the mechanism of CNTs passage (e.g., endocytosis/phagocytosis and nanopenetration) through the cell membranes of many types of cells. (91) Endocytosis is a form of active uptake of small extracellular particles (diameter ≤100 nm), and phagocytosis is another form of active uptake in which relatively large particles enter immunocytes such as neutrophils, macrophages, and dendritic cells. On the other hand, nanopenetration is a form of passive uptake; some authors have hypothesized that chemically modified or molecule-adsorbing CNTs enter cells by nanopenetration. (75, 107, 157, 379-384)
We examined the cellular uptake of pristine CNTs, and reported that the mechanism of this uptake depended on the type of cell and choice of dispersant. We also reported that nonimmunocytes also actively absorbed CNTs mainly through endocytosis/phagocytosis (Figure 6). (385, 386) Other researchers likewise denied the role of nanopenetration in cellular uptake of SWCNTs. (387) Adhesion to cell surfaces has been observed even in cells that do not absorb CNTs; it remains unknown whether the molecules that facilitate CNTs adherence to cells and those that facilitate CNTs absorption are identical. It has been reported that cell membrane proteins are involved in the cellular uptake of CNTs. (384, 388) Furthermore, these membrane proteins may bind specifically to CNTs. (80, 389) However, it will be necessary to investigate the influence of protein-containing dispersants on this binding between membrane proteins and CNTs. (369, 371, 385) A recent report suggested that exposure to electromagnetic waves promotes CNTs entry not only into the cytoplasm of cells, but also into the nucleus. (390) In conclusion, much remains to be elucidated about the cellular uptake of CNTs and its underlying mechanism.
Figure 6
Figure 6. Cellular uptake of pristine MWCNTs varies depending on the type of cell and the choice of dispersant. (a) Combined images from bright field images and phase-contrast photomicrographs obtained 24 h after exposure of human malignant pleural mesothelioma cells (MESO-1), human bronchial epithelial cells (BEAS-2B), and human neuroblasts (IMR-32) to carbon black (CB, 50 nm diameter) and MWCNTs. Both CB and MWCNTs were absorbed in the MESO-1 cells and BEAS-2B cells, and localized around the respective exposure sites, whereas in the case of the IMR-32 cells, both CB and MWCNTs adhered but failed to be absorbed. CB and MWCNTs were added at 1 μg/mL for the treatment of BEAS-2B cells, and 10 μg/mL for the treatment of the other cells. Scale bars = 50 μm. Reprinted with permission from ref 384. Copyright 2011 Nature Publishing Group. (b) A comparison of cellular uptake in BEAS-2B observed 1 and 24 h after exposure to MWCNTs dispersed using different dispersants. Cellular uptake was determined in terms of the intensity of side scattered light (SSC) from MWCNTs absorbed in the cells using a flow cytometer. The MWCNTs dispersed in gelatin or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were increasingly absorbed over time, whereas those dispersed in carboxymethylcellulose (CMC) were little absorbed in the cells. Reprinted with permission from ref 385. Copyright 2011 Dove Medical Press.
To clarify the mechanism underlying the cellular uptake of CNTs, a wide variety of approaches have been developed. For example, light scattering analysis was used to qualitatively assess the cellular uptake of CNTs; a fluorescence detection technique was used to study the cell trafficking of CNTs; and 3-D dark-field scanning transmission electron microscopy was used to examine ultrastructural localization of CNTs in appropriately prepared target cells. (368, 391-393) Successful monitoring of the cellular uptake and intracellular behavior of CNTs would clarify the reactions between CNTs and cells in more detail. The mechanism behind the cellular uptake of CNTs and their intracellular behavior not only has a bearing on the cytotoxicity of CNTs, but also on their pharmacokinetics when used in DDSs; thus, much more of this research is expected.
4.2 Mechanism Behind the Cytotoxicity of CNTs
Many studies have assessed the cytotoxicity of CNTs. Some early studies found that CNTs and asbestos have equivalent cytotoxicity in macrophages and other cells. (75, 76, 394) Recent studies, however, found that CNTs have low cytotoxicity. (155) The reader of such in vitro cytotoxicity studies should be alert to the fact that CNTs above a certain level dose-dependently reduce cell counts regardless of cell type. This finding reflects a natural reaction of living cells to contact with foreign particulates such as CNTs. The issue is whether CNTs have a higher or lower degree of cytotoxicity than biologically safe substances.
The objective of the cytotoxicity study should also be noted. When safety is the aim of the CNTs biomaterials evaluation, concentrations in the toxic range (according to many reports; on the order of μg/mL) are used, which are much higher than the likely actual concentrations in vivo. Such high concentrations cannot occur in actual settings and can lead to an unreasonable emphasis on the toxicity. Rather, it would be more meaningful to determine the concentration at the lower limit of cytotoxicity and whether this lower limit can occur in vivo.
In addition, it should be well recognized that different types of cells can exhibit distinct responses even to the same kind of nanoparticles. This phenomenon was recently named the “cell vision” effect. (395) Exploring this effect will make it possible to clarify the mechanism for cytotoxicity. Mahmoudi et al. clarified the mechanism underlying this difference in cytotoxicity among the different cell types, and investigated the detoxification of nanoparticles. (396, 397)
In all cases, when applying CNTs to biomaterials, their cytotoxicity to living organisms should be as low as possible, and by establishing the mechanism underlying their cytotoxicity, less cytotoxic CNTs can be found. A wide variety of studies to elucidate this mechanism are ongoing. (156, 398, 399)
4.2.1 Oxidative Stress
Oxidative stress is a focus of studies aimed at determining the mechanism underlying the toxicity of CNTs in vitro as well as in vivo. Some articles but not others have reported that CNTs may induce cytotoxic oxidative stress. (400) This cytotoxicity from oxidative stress has been attributed to the persistence of catalytic metals (Fe, Co, Ni, etc.) used in producing CNTs. Many studies have found that the cytotoxicity of CNTs increased with increase in metal content ratio. (72, 368, 401, 402) Some CNTs contain in excess of 10% (w/w) metallic impurities, which can produce free radicals and thereby damage tissue. (263, 400, 403) This process can occur even after CNTs are phagocytosed by macrophage. For example, NADPH oxidase is intracellularly activated, and the resulting highly active superoxide radical kills bacteria and other pathogens. Residual Fe activates peroxides to produce hydroxyl (OH–) radicals leading to oxidative effects on cellular proteins, lipids, and DNA. Residual Co can produce chromosome anomalies. However, a study found that Ni has no cytotoxic effects, but this finding needs to be investigated further. (75, 290, 404) Oxidative stress may be induced by aggregation of CNTs. Shvedova et al. found that CNTs have low in vitro cytotoxicity provided they are properly dispersed using appropriate procedures and their metallic impurities are removed. (155) Our study concluded that there was no correlation between the amount of oxidative stress from CNTs with low residual iron content and cell proliferative response or inflammatory reaction. (386, 405) Carbon nanohorns, a type of carbon nanotubes without metallic impurities, were reported to be quite safe, with cytotoxicity less than 10% of the cytotoxicity of dust from road pavement. (406) However, it is unrealistic to expect that CNTs will contain absolutely no metallic impurities. Accordingly, an article discussed the limit of metallic impurity not affecting the redox properties of CNTs. (407) The susceptibility of CNTs to oxidation in the presence of metallic impurities was also analyzed. (408) In all cases, the lower was the level of metallic impurities, the lower was the level of induction of oxidative stress. Collectively, these available reports lead to the judgment that carbon purity level of 99% or more is not problematic.
On the other hand, it has long been suggested that when cells absorb CNTs, long fibers are left unabsorbed and induce oxidative stress. (281) This phenomenon is known as frustrated phagocytosis. A recent report stated that CNTs that are shorter than a given length are absorbed and not toxic, whereas longer CNTs are not absorbed but are toxic. (409-412) Consequences such as carcinogenesis may stem from prolonged inflammation due to frustrated phagocytosis in the thoracic cavity lasting long after CNTs are inhaled (Figure 7). Cytotoxicity due to frustrated phagocytosis in the context of use of CNTs as biomaterials is discussed in section 6.2.2.
Figure 7
Figure 7. A schematic diagram showing a hypothesized mechanism of carcinogenesis due to frustrated phagocytosis. If left unabsorbed, long CNTs in cells can produce oxidative stress and induce inflammation. It has been suggested that a long period of persistent inflammation in the thoracic cavity following inhalation of CNTs can lead to carcinogenesis. Currently, research into the inhalation toxicity of CNTs is facing a problem with the determination of the margin of inhalation exposure that does not cause persistent inflammation.
In September 2012, the National Institute of Standards and Technology (NIST) in the U.S. reported a finding that is completely inconsistent with findings that SWCNTs protect DNA from oxidative stress. (413) Hence, no consistent conclusion has been reached concerning oxidative stress. Collectively, previous studies using many types of cells under a wide variety of conditions have led to a near consensus that CNTs do not induce oxidative stress if their aggregability and length are limited. (155) A recent study showed that chemical treatment with, for example, triethylene glycol can reduce the likelihood of aggregation in biological fluids and toxicity of even long CNTs. (414)
4.2.2 Effects on Immunity
The second issue concerns the interactions of CNTs with immunocompetent cells, including cellular uptake and subsequent intracellular transport. As such, immunocompetent cells bear a direct relationship to the safety of CNTs in vivo. Of course, pristine CNTs (because they lack antigen-presenting protein) do not cause immune reactions other than those to a foreign substance. Hence, if localized inflammation is brief, immune reactions should resolve. However, immunocompetent cells may absorb CNTs because of their nanosize, may not absorb some CNTs completely because of their fibrous form, and may orchestrate the development of an inflammatory response to residual metals and other factors in CNTs. Keeping these possibilities in mind, it is necessary to understand how immunocompetent cells respond to CNTs. Many in vitro studies have reported no response of immunocompetent cells to very pure and very short CNTs. (155, 415) For example, CNTs did not have a remarkable effect on antigen-presenting cells (APCs) such as mouse macrophages (RAW 264.7 cells) and mouse bone marrow-derived dendritic cells (bmDCs). (416) An article reported that CNTs did not induce inflammatory cytokines in macrophages, whereas residual metals did. (85, 401, 402) If CNTs are shown to escape surveillance by immunocompetent cells, this finding will provide strong evidence for high safety of CNTs as biomaterials. Of course, it is theoretically impossible that pristine CNTs cause autoimmune disease.
4.2.3 Attempts To Lessen the Cytotoxicity
As stated above, various methods for minimizing the cytotoxicity of CNTs have been studied. For example, reducing nanotube cytotoxicity through chemical modification to change physicochemical properties and hence biological activity has been proposed. A library of 80 different surface-modified nanotubes was screened for protein bindability, cytotoxicity, and immune responses. Nanotubes had high biocompatibility, low protein adsorption properties, low cytotoxicity, and low immunostimulatory activity. (417) It has also been found that some shapes of CNTs are not cytotoxic, (309, 418) and change of the graphitization temperature during CNTs synthesis alters their biological activity. (405) Hence, expectations are for the minimization of CNTs cytotoxicity. To this end and for the above-described reasons, the cellular mechanisms of CNTs recognition and the effects of the physicochemical properties of CNTs on cytotoxicity need to be clarified. (396, 397, 419)
4.3 CNT–Protein Interactions
CNTs used in vivo are unavoidably exposed to proteins. For this reason, successful application requires an understanding of both the adsorption of proteins to CNTs and the resulting biological responses to protein-adsorbed CNTs. While attempts to functionalize CNTs using antibodies and receptors (that are peptides or proteins) are underway, (176, 420, 421) the influence of proteins on pristine CNTs should be investigated. CNTs specifically adsorb fibrinogen, apolipoproteins, and albumin from blood. (422) As such, albumin is a component of most CNT dispersants in common use for toxicity experiments, (366-368, 370) and it is necessary to determine whether CNTs toxicity assays actually assess pristine CNTs toxicity or albumin-adsorbed CNTs toxicity. Examination of the mode of adsorption to SWCNTs by plasma proteins fibrinogen, γ-globulin, transferrin, and bovine serum albumin using an atomic force microscope was reported, and protein binding reduced SWCNTs cytotoxicity. (423) However, the SWCNTs used in this experimental study contained many metals such as Cr, Fe, Mo, and Co, and their effect must also be taken into account.
The phenomenon in which various proteins coat the nanoparticle surface has recently been termed “protein corona” formation. (424) The protein corona is influenced by a wide variety of factors, including temperature, protein concentration, gradient concentration, protein source, and physicochemical properties of nanoparticles. The protein corona has also been reported to have major impacts on the biological reactions of cells and living organisms. For example, nanoparticles on cells and living organisms were shown to lose activity when their surface is partially covered by protein. (355, 356, 425-429) As such, the protein corona may determine the fate of CNTs in living organisms. In addition, changes on the nanoparticle surface caused by formation of the protein corona can alter the effects of chemically modified CNTs. Shannahan et al. compared the proteins coating MWCNTs with SWCNTs, and those coating modified with unmodified, which revealed a difference in protein composition between SWCNTs and MWCNTs and an increase in the variety of component proteins as a result of modification with COOH groups. (430) Functional deterioration of chemically modified nanoparticles has been repeatedly shown to occur; there is an urgent need to determine whether the same phenomenon can occur in CNTs.
On the other hand, to explain the decreased cytotoxicity of protein-bound CNTs, a recent study hypothesized that the human body developed a biological system mediated by protein binding to deal with exposure to numerous nanoparticles (i.e., developed a defensive mechanism against nanoparticles). (431) This suggests that CNTs research may elucidate the body’s defensive mechanism, which is unclear.
4.4 Mutagenicity, Genotoxicity, and Apoptotic Potential of CNTs
Assessments of the mutagenicity and genotoxicity of CNTs are also important in vitro safety studies. (432-441) This is because the results from these assessments reflect the carcinogenicity of CNTs. Relatively common approaches include the Ames test, comet assay, and micronucleus test.
The Ames test, also known as the reverse mutation test, is to quantify reverse mutation (i.e., restoration of amino acid biosynthesis capability in bacteria originally deprived of that capability through mutation). Ames test studies with Salmonella typhimurium and other test strains have often shown that neither SWCNTs nor MWCNTs are mutagenic. A mutagenesis study showed that the frequency of mutations in mammalian cells (Chinese hamster pulmonary fibroblasts) is not altered by MWCNTs. (438, 442-445)
The comet assay is a technique used to detect DNA damage in individual cells, enabling separate determination of early disorders induced at the DNA level, repair kinetics, and residual disorders. For this reason, comet assays have been performed on many types of cells exposed to SWCNTs and MWCNTs. CNTs induced DNA damage in some studies but not in others. The prevailing opinion is that any DNA damage caused by CNTs is mediated by reactive oxygen species (ROS). (446-449)
The purpose of the micronucleus test is to detect damage to the gene of interest in animal cells following administration of a test substance. Cells containing micronuclei can serve as an index of gene damage. Micronucleus test studies to assess the toxicity of SWCNTs and MWCNTs in many types of cells have yielded mixed results. (399, 404, 442)
Some studies of apoptosis induction by CNTs found induction of apoptosis signals in macrophages and other cells to induce apoptosis signals, while others did not find any sign of apoptosis induction. (318, 378, 450-452) Many cells incorporating CNTs underwent G1 phase arrest. (430) We reported that iron-rich MWCNTs caused nonapoptotic cell death. (453) On the other hand, other experiments found that highly pure MWCNTs caused apoptosis-like cell death, suggesting that the CNTs impurities have a major effect on apoptosis. (386)
In conclusion, the mutagenicity and genotoxicity of CNTs remain unclear; some studies judged CNTs to be mutagenic or genotoxic and others did not. (89, 432, 437, 443, 454-456) Results varied and depended on the cell type even within the same study. (442) In cases where genotoxicity was observed, authors hypothesized metals-induced oxidation of the DNA or suggested other hypotheses. (457) Variable results and conclusions are attributable to variable test conditions such as the dispersibility of CNTs in solution and the amount of CNTs used, as well as the amount of CNTs impurities, but not the form of CNTs (all studies assessed particulate substances). There is no current evidence in CNTs of high purity, although carcinogenicity from mutagenicity or genotoxicity calls for vigilance. (155) Further investigation will be necessary in different cell types to determine whether cells incorporating CNTs undergo apoptosis.
4.5 Cellular Signaling Events
Microarray or proteomics studies of cell signaling events induced by CNTs have been reported. (458) In a microarray study using human embryonic kidney cells exposed to SWCNTs for 2 days, decreased expression of cyclins and cdks (a gene affecting the G1 phase of the cell cycle) and increased expression of apoptosis-related genes were demonstrated. (318) Other researchers exposed foreskin cells to SWCNTs, and found that the expression of HMOX1, HMOX2, ERCC4, and HSPE1 and that of ATM, CCNC, DNAJB4, and GADD45A more than doubled when determined using stress and toxicity arrays and RT-PCR, respectively. (459) Using reporter gene assays of MWCNT-exposed bronchial epithelial cells, MWCNTs activated the transcription factor NF-κB to induce increased phosphorylation of p38, ERK1, and HSP27 in the MAP kinase pathway and the production of inflammatory cytokines. (369) Activation of NF-κB in macrophages was also reported. (460) We examined the effects of MWCNTs on cellular signaling events in osteoclasts and showed that MWCNTs suppressed osteoclast differentiation by inhibiting the nuclear migration of the transcription factor NFATc1. (217) In conclusion, the influences of CNTs on cell signaling events are important to the understanding of cellular function, and further research will be needed.
Proteomics-based studies have been conducted using keratinocytes and hepatoma cells. Results have shown changes in expression of proteins related to metabolism, stress, redox, cytoskeleton formation, apoptosis, etc., in both types of cell. (461, 462) Our proteomics analysis under low-cytotoxicity conditions using monoblastic leukemia cells that do not absorb MWCNTs confirmed these changes in proteins (Table 1). (463) Such comprehensive analyses of cell signaling events increase understanding of the essential features of cellular change. (464) It is hoped that research activities will identify the pathways on which CNTs have a direct impact, and make major contributions to the assessment of the cytotoxicity of CNTs.
Table 1. Proteins of Human Monoblastic Leukemia Cells (THP-1) Changed by Exposure to CNTs As Determined by Proteomic Analysisa
| gene ontology term | proteins |
|---|---|
| biosynthetic process | heat shock protein β-1, elongation factor 1-δ, DNA mismatch repair protein Msh2, 6-phosphogluconate dehydrogenase decarboxylating, triosephosphate isomerase |
| signal transduction/cell communication | elongation factor 1-δ, DNA mismatch repair protein Msh2, 14-3-3 protein γ, serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B α isoform, protein DJ-1 |
| carbohydrate metabolic process | 6-phosphogluconate dehydrogenase decarboxylating, triosephosphate isomerase, serine/threonine-protein phosphatase PP1-α catalytic subunit, α-ketoglutarate dehydrogenase, neutral α-glucosidase AB |
| nucleobase, nucleoside, nucleotide, and nucleic acid metabolic process | DNA mismatch repair protein Msh2, 6-phosphogluconate dehydrogenase decarboxylating, triosephosphate isomerase, DNA damage-binding protein 1 |
| protein metabolic process | actin related protein 2/3 complex subunit 2, serine/threonine-protein phosphatase PP1-α catalytic subunit, serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B α isoform, DNA damage-binding protein 1 |
| catalytic process | 6-phosphogluconate dehydrogenase decarboxylating, triosephosphate isomerase, α-ketoglutarate dehydrogenase, DNA damage-binding protein 1 |
| multicellular organismal development | DNA mismatch repair protein Msh2, triosephosphate isomerase, 14-3-3 protein γ, serine/threonine-protein phosphatase PP1-α catalytic subunit |
| response to stress | heat shock protein β-1, DNA mismatch repair protein Msh2, DNA damage-binding protein 1, protein DJ-1 |
| cell differentiation | heat shock protein β-1, DNA mismatch repair protein Msh2, 14-3-3 protein γ |
| cell cycle | DNA mismatch repair protein Msh2, serine/threonine-protein phosphatase PP1-α catalytic subunit, DNA damage-binding protein 1 |
| transport | 14-3-3 protein γ, protein DJ-1 |
| cell death | heat shock protein β-1, DNA mismatch repair protein Msh2 |
| organelle organization and biogenesis | actin related protein 2/3 complex subunit 2, DNA mismatch repair protein Msh2 |
| translation | heat shock protein β-1, elongation factor 1-δ |
| lipid metabolic process | triosephosphate isomerase |
a
Adapted with permission from ref 463. Copyright 2011 Elsevier.
4.6 Choice of Cells
To date, cytotoxicity studies have often been conducted using fibroblasts and macrophages such as RAW cells. However, cellular reactions to CNTs depend on the type of cell, (396, 397) and it can be thought that the reactions are specific for the organ bearing the target cells. For example, a study comparing the cytotoxicity of CNTs in the liver, spleen, and lung found that CNT-induced oxidative stress dose-dependently increased toxicity in the liver and lung, but not in the spleen. (465) We must clarify the mechanism underlying the reactions of different cell types and organs to CNTs. Because biological reactions to CNTs vary among types of cells and organs, toxicity studies using cells from likely sites of use will be needed before CNTs can be clinically applied.
For example, in a study assessing CNTs for use in nerve regeneration, human neuroblastoma cells and primary mouse neurons were exposed to MWCNTs, and their reactions were examined for effects on cell survival, oxidative stress, and apoptosis. (70) Another study examined the effects of CNTs on heart cells, specifically on impulse conduction characteristics, myofibril structure, and reactive oxygen species production in the patterned growth strands of neonatal rat ventricular cardiomyocytes. CNTs particles had much less effect than diesel exhaust particles and titanium dioxide nanoparticles. (466) To assess the use CNTs as a possible bone tissue regeneration scaffold, we examined in detail their effects on osteoblasts (bone-forming cells) and osteoclasts (bone-absorbing cells), as described in section 2.3.2. (217, 218)
5 Reference Materials for Safety Evaluation of CNTs as Biomaterials
ARTICLE SECTIONS
The safety of CNTs for biomaterial application remains unknown because toxicity studies have yielded inconsistent or even contradictory results as stated above. Moreover, no nanoparticle reference material has been shown to be safe to use in living organisms. All biomaterials are essentially foreign to living organisms, and hence exhibit some toxicity to living organisms. Of concern is the level of toxicity; the biological safety of CNTs cannot be assessed without conducting a toxicity study using as a reference substance that has already been recognized as safe to use in living organisms.
For example, in 2010, the cytotoxicity, genotoxicity, and apoptosis-inducing potential of MWCNTs was examined in human fibroblasts. Physiological saline admixed with a dispersant served as the only negative control. Results showed that MWCNTs exhibited dose-dependent toxicity in all dose groups as compared to the negative control, and that the cell survival rate decreased dramatically due to DNA damage, triggering pathways leading to programmed cell death. Hence, the conclusion was reached that CNTs are highly toxic. It should be noted, however, that it is scientifically incorrect to assess the toxicity of CNTs merely by comparing the results obtained in the presence and absence of CNTs. The solution (containing a dispersant) used in the reported study cannot serve as a reference for toxicity assessment. This study showed nothing more than that the experimental system used worked well, and no conclusion regarding CNTs toxicity can be drawn.
For researchers in this field, identification of an appropriate reference material for toxicity studies, which is presently unavailable, is a top priority. Kostarelos et al. pointed this out in 2009 in their review published in Nature Nanotechnology. (68) The reference substance must be a nanosized particulate with established biological safety. A substance can be judged as safe to use in living organisms only if it is shown to be equally or less toxic than its reference material. To render a judgment on the functioning of an experimental system, a conventional chemical substance can be used as a feasible alternative for the positive-control reference material. However, no best negative-control reference material has been found, so the safety of CNTs as biomaterials remains indeterminable.
5.1 Why Is There No Substance That Can Serve as a Reference for CNTs?
Researchers have been seeking a substance with many of the same properties as CNTs. Such references do not actually exist. Without a reference, CNTs cannot be used as biomaterials. From a broader viewpoint, any nanosized particulate substance should be considered to be a reference candidate. In fact, reference materials are specified for bulk biomaterials on the basis of this broad concept. For example, in cytotoxicity testing of bulk materials, a high-density polyethylene film serves as the negative reference material for the extraction method, and a polyurethane film containing zinc diethyldithiocarbamate (ZDEC) serves as the positive reference material. For the direct contact method, a plastic sheet for tissue culture serves as the negative reference material, and ZDEC-containing polyurethane serves as the positive reference material. These substances are specified in the ISO 10993-5 Biological evaluation of medical devices - Part 5: Tests for in vitro cytotoxicity (2009). (467) Hence, it is internationally accepted that a reference for a bulk biomaterial should be a bulk material of totally different nature. There is no rationale for viewing particulate materials as the only exception.
Essentially, the unfavorable criticism of nanosized fibrous particulate substances is due largely to the fact that asbestos causes cancer and other diseases. Because CNTs resemble asbestos in size and shape, their toxicity has created a stir in the media. (281, 282) It should be noted, however, the inhalation toxicity of CNTs is distinct from the toxicity of CNTs biomaterials. Recently, inhaled spherical titanium oxide particles were reported to be carcinogenic; (468) however, if the judgment is made on the basis of shape and size only, no spherical nanoparticles could be used as biomaterials, and almost all nanoparticles would be inapplicable to biomaterials. It is obvious to everyone that this claim makes no sense. Even if fibrous nature, thin and long shape, and large aspect ratio are problematic, we should keep in mind that carbon fiber biomaterials have long been used for Achilles tendon repair and other clinical purposes with absolutely no coincidence of carcinogenicity. (96, 469, 470) In conclusion, the most reasonable approach is to assess the toxicity of CNTs by focusing on biological reactions to nanosized particulate substances.
5.2 Biomaterials Comprising Artificial Nanosized Particles
The second reason for the inability to find a best reference material is that no nanosized particulate substance has been used as a biomaterial. This issue bears not only on CNTs, but also on a wide variety of nanoparticles, and research into biological application of nanoparticles has recently been rapidly growing. Some pharmaceuticals anchored to nanosized particles are already in clinical application. For example, abraxane, a nanoparticle substance prepared by conjugating the anticancer agent paclitaxel with albumin, degrades in the body, releasing the anticancer agent. Such conventional nanosized particles are specifically used as DDSs by making the best use of their biodegradability, and cannot be viewed in the same way as nanoparticulate biomaterials that are poorly degraded in the body. (301)
To date, only four kinds of artificial materials have been used in living organisms: chemical substances, materials with biodegradability, bulk materials lacking biodegradability, and micrometer-sized or larger particulate substances. Nanosized particulates have not been used in the body. Chemical substances, biomaterials with biodegradability, and bulk biomaterials have been used in the human body since ancient times, and many such substances have proven to be safe. For this empirical reason, researchers have been able to use these substances as references. When these substances were used as biomaterials for the first time, no scientific toxicity testing was needed. Those substances found over time to be safe to use in the human body remain in use today. Toxicity studies using some of these substances as references have been conducted to demonstrate the safety of other substances in the same category, and then using the other substances thus judged to be safe as references, the safety of still other similar substances has been demonstrated. Through this process, numerous substances have been made available for clinical application. The internationally accepted ISO standards dealing with safety evaluation are currently serving very well and have also emerged from this historical precedent. (467) The standard reference materials are known biologically safe substances rather than new reference materials evaluated to be safe for humans. Micrometer-sized or larger particulate biomaterials, for example, granular hydroxyapatite, have never posed a major problem even though they were subjected to the same safety evaluation process as conventional biomaterials. (471-473) Because CNTs and other nanosized particulate substances fall into a different category of biomaterials than micrometer-sized or larger particulate substances, the use of conventional bulk biomaterials and hydroxyapatite particles as reference materials for them is controversial. Because nanosized particulate substances have not been used in the human body, there is no implicit reference with established safety. (474)
For these reasons, obtaining a reference with confirmed biosafety in the human body for use in toxicity studies of CNTs appears to be impossible. From a broader perspective, however, otherwise unknown nanoparticles may be discovered. We considered that highly pure carbon black could serve as a reference for CNTs, because it is the primary component of the black ink used in tattoos, and also because black tattoo inks have long been injected into human bodies and are currently used by a tremendous number of people worldwide. Evidence showing that black tattoo inks are composed of nanosized carbon black particles is described below, with an overview of the biological safety of CNTs using carbon black as a reference.
5.3 Safety Evaluation of CNTs Using Nanosized Carbon Black Particles as a Reference
5.3.1 Nanosized Carbon Black Particles in Tattoo Ink
Two commercially available black tattoo inks (Sumi-Black, Unique Tattoos, Subiaco, Australia; Lining-Black, Classic Ink, Victoria, Australia) were purchased and extensively analyzed for components. Each was dried, and the resulting solid product was morphologically examined by scanning electron microscopy (SEM); particles with a nearly uniform diameter of several tens of nanometers were found to have accumulated (Figure 8a). After SEM examination, the particles were subjected to an elemental analysis using energy dispersive X-ray spectroscopy (EDS). Results showed that both inks had a C content of about 99.5 wt % and different impurity profiles, with trace amounts of Na and S detected and attributable to the surfactant added. A Raman analysis using common industrial carbon black (Vulcan XC 72, Cabot, Boston, MA) as a control revealed that Raman shift of both black tattoo inks was nearly the same as that of the control (Figure 8b). Furthermore, transmission electron microscopy (TEM) revealed that the particles in black tattoo inks had nearly the same shape as those of ordinary carbon black (Figure 8c). These findings identified the particles in tattoo inks as pure carbon black (i.e., nanosized carbon particles) as with MWCNTs. (97)
Figure 8
Figure 8. Having historically been proven safe to the human body, tattoos comprise nanosized highly pure carbon black, and hence serve well as a reference material for evaluating the safety of CNTs, which likewise occur in the form of nanosized carbon particles. (a) Scanning electron microscopy (SEM) images of tattoo carbon black-1 (TCB-1) and tattoo carbon black-2 (TCB-2) prepared by drying two different tattoos. TCB-1 and TCB-2 were found to have accumulated in the form of generally regular particles having a diameter of about 30–50 nm, and generally irregular particles having a diameter of about 50 nm, respectively. (b) Raman analysis of TCB-1, TCB-2, and ordinary carbon black. TCB-1 and TCB-2 exhibited nearly the same Raman shift pattern as with ordinary carbon black. D-band, turbostratic amorphous; G band, graphite crystal. (c) Transmission electron microscopy (TEM) images of TCB-1, TCB-2, and ordinary carbon black. These three substances were found to have nearly the same particle shape. Reprinted with permission from ref 97. Copyright 2011 Elsevier.
In 2012, on the other hand, a report titled “Chemical Substances in Tattoo Ink” was released from Denmark. (475) Concerning a research project implemented by the Danish Technological Institute in cooperation with Bispebjerg Hospital and the National Food Institute, Technical University of Denmark, the report explicitly described carbon black as the principal component of black tattoo ink, and toxicity assessments of carbon black found no biological safety problem.
An extremely large number of humans have received black tattoos since ancient times, and this practice has caused no major problems; tattoos are popular even today. Hence, carbon black can be described as a biomaterial that has been proven by historical evidence to be safe for use in the human body. As such, the nanosized carbon particles used in black tattoos, as with CNTs, are very pure carbon black; thus, carbon black should be considered as a good reference material for CNTs.
5.3.2 Comparison of Characteristics of CNTs and Carbon Black
To use the biologically safe carbon black tattoo ink as a reference material for CNTs, both substances should share some characteristics. Despite their considerably different characteristics, current reference materials for bulk materials have been used as international standards, and safety assessments have been conducted with no major problems. This has become feasible because of the large amount of data compiled throughout the long history of biomaterials research. However, references for nanoparticle biomaterials remain to be found. The accuracy of safety evaluation will be increased by using substances with similar characteristics in the beginning.
The characteristics (including composition, size, shape, and surface chemistry of the reference material used for CNTs [i.e., carbon black]) were compared to those of CNTs per se (Table 2). (476) Both substances are highly pure carbon particulates of similar size (i.e., they are nanosubstances, entities internationally recognized as being not less than 100 nm in one or more of the three dimensions). (477, 478) CNTs and carbon black have distinct shapes: fibrous particles and spherical particles, respectively. Although various classifications of surface chemistry are available, the most common practice is to characterize surfaces as hydrophilic or hydrophobic. The surfaces of CNTs are hydrophobic, and carbon black particles, without surface treatment, are essentially hydrophobic. Hence, three of the four representative characteristics of particulate substances are shared; therefore, it is reasonable to use carbon black as a reference for CNTs. Although some researchers may disagree based on the distinction between fibrous and spherical particles, no reference can have exactly the same characteristics as the test substance. Considering the absence of any other appropriate reference, it is very fortunate that carbon black with high similarity to CNTs has a long history of use in living organisms and demonstrated safety in the human body. Problems stemming from the fibrous nature of some nanoparticles are discussed in section 6.2. Despite these problems, it can be concluded that fibrous nanoparticles pose no hazard at sites of CNTs implantation if inflammation is not persistent.
Table 2. Comparison of Characteristics of CNTs and Carbon Black
| characteristic | CNT | carbon black |
|---|---|---|
| composition | high-purity carbon | high-purity carbon |
| size | nanosized | nanosized |
| shape | fibrous particle | spherical particle |
| surface chemistry | hydrophobic | hydrophobic |
All experiments can be performed using mass as an index because CNTs and carbon black are both highly pure carbon. For particulate substances, it is often difficult to measure the number and volume of particles; therefore, the ability to use mass as the simplest index is an obvious advantage in the evaluation of CNTs safety. Carbon black can also serve as a reference for the evaluation of the biological safety of other nanosubstances used as biomaterials. However, mass cannot be used as an index for safety comparison when density varies; therefore, another index such as particle count will have to be used, making the procedure more complicated and difficult to perform, and even reducing its accuracy.
Research into application of non-CNT carbon-based nanomaterials to biomaterials has also progressed steadily, although there are fewer non-CNTs studies than CNTs studies. The use of fullerenes or graphene for DDSs and imaging has been studied, and their biological safety has been evaluated. (479, 480) Additionally, nanosized carbon fibers, which traditionally have not been nanosized, are now available thanks to recent technical advances. Although carbon fiber products are promising candidates as nanobiomaterials because of their history of clinical use as biomaterials, their safety needs to be evaluated because of their nanosize, (214, 481) and carbon black can serve as an appropriate reference.
5.3.3 Safety Test
A skin implantation test with MWCNTs was conducted using carbon black tattoo ink as a reference material. Results showed that MWCNTs induced acute but mild inflammation reactions in subcutaneous tissue, which resolved early. The subcutaneously implanted MWCNTs were shown to be absorbed initially by macrophages and remained in the macrophages for a long time. These short- to long-time histological reactions to the MWCNTs were found to be very similar to the histological reactions to the carbon black tattoo ink particles (Figure 9). This finding shows that when implanted in vivo, MWCNTs (as with tattoo ink particles) exhibit good tissue affinity at the implantation site and stay intact in macrophages for a long time. (97)
Figure 9
Figure 9. Histological reactions to subcutaneously implanted MWCNTs are very similar to those to carbon black, showing good tissue compatibility. Hematoxylin-eosin staining. Scale bars = 20 μm. TCB-1, Tattoo carbon black-1; TCB-2, Tattoo carbon black-2 (see Figure 8). (a) Histological images from a negative control group (NC) of male ddY mice at 6 weeks of age receiving an injection of 10 μL of physiological saline and a surfactant given to a pocket created in subcutaneous tissue in the back. At 1 week of treatment, the subcutaneous tissue had been repaired nearly completely. Repair was complete at 4 weeks. No change was observed at 12 and 24 weeks. (b) Histological images of subcutaneous tissue from a group receiving an injection of 10 μL of MWCNT solution (4.0 mg/mL). Most particles were found to have been absorbed in macrophages at 1 week. In the areas around the injection site, accumulated fibroblasts, neutrophils, and lymphocytes were found, with weak inflammatory reactions observed. At 4 weeks, the MWCNTs remained incorporated in macrophages, and the inflammatory reactions around the injection site had resolved. The macrophages that had absorbed MWCNTs turned into multinucleated giant cells, creating an appearance like foreign-body granuloma. The histological profiles obtained at 12 and 24 weeks did not differ from the profile obtained at 4 weeks. (c) Histological images of subcutaneous tissue from a group receiving an injection of 10 μL of TCB-1 solution (4.0 mg/mL). At 1 week, most particles were found to have been absorbed in macrophages in the subcutaneous tissue, and as in the MWCNT group, accumulated fibroblasts, neutrophils, and lymphocytes were found, with weak inflammatory reactions observed. At 4 weeks, the inflammatory reactions around the injection site had resolved as in the MWCNT group. The histological profiles obtained at 12 and 24 weeks were similar to the profile obtained at 4 weeks. (d) Histological images of subcutaneous tissue from a group receiving an injection of 10 μL of TCB-2 solution (4.0 mg/mL). All histological profiles obtained at 1, 4, 12, and 24 weeks were similar to those obtained with the TCB-1 solution. (e) Histological images of subcutaneous tissue from a group receiving an injection of 10 μL of zinc dibutyldithiocarbamate (ZDBC) solution (4.0 mg/mL). At 1 week, accumulation of many types of inflammatory cells such as fibroblasts, neutrophils, lymphocytes, and plasma cells was observed, and intense inflammatory reactions had been induced over a wide area, with fat necrosis and nuclear debris formation observed. No accumulation of macrophages was observed. Even at 4 weeks, inflammatory cells remained and inflammatory reactions persisted, although the inflammation was going to disappear. At 12 and 24 weeks, the inflammatory reactions had resolved, and the subcutaneous tissue had been repaired into scar tissue with fibrosis. Reprinted with permission from ref 97. Copyright 2011 Elsevier.
We then conducted a colony formation assay to determine the in vitro cytotoxicity of MWCNTs using carbon black tattoo ink particles as a reference. Both MWCNTs and carbon black tattoo ink particles inhibited colony formation in a concentration-dependent fashion. At higher concentrations, colony counts were higher with exposure to MWCNTs than with exposure to carbon black tattoo ink particles (Figure 10). These findings demonstrated that the cytotoxicity of MWCNTs was not greater than that of carbon black tattoo ink particles. (97) When assessing the cytotoxicity of nanoparticles, the colony formation assay yields numerical results, and is currently considered to be the best (most sensitive and reproducible) method of toxicity assessment. (402)
Figure 10
Figure 10. The cytotoxicity of MWCNTs is not higher than that of carbon black. TCB-1, Tattoo carbon black-1; TCB-2, Tattoo carbon black-2 (see Figure 8). (a) Appropriateness of cytotoxicity assessment in colonization test. The colonization capacity of V79 cells (Chinese hamster lung fibroblast cell line JCRB0603) decreased as the concentration of the positive control ZDBC increased. The concentration for 50% colony count reduction (IC50, reference value range: 1–4 μg/mL) was found to be between 1 and 2 μg/mL, confirming that the cytotoxic action of the test substance was properly assessed. (b) Macroscopic photographs showing colonization test results. Colony counts of V79 cells cultured using a culture broth alone and those cultured in the presence of MWCNT solution, TCB-1 solution, and TCB-2 solution were compared. The concentrations in the solutions were 12.5, 50, 200, 400, 800, and 1600 μg/mL, respectively. (c) Colony counts versus carbon concentrations in MWCNT, TCB-1, and TCB-2 solutions. MWCNTs inhibited the colonization in a concentration-dependent fashion, and TCB-1 and TCB-2 likewise inhibited the colonization in a concentration-dependent fashion. When comparing colony counts, MWCNTs produced significantly higher colony counts than TCB-1 at concentrations of 200 μg/mL or more, and than TCB-2 at concentrations of 400 μg/mL or more. Error bars indicate standard deviations (n = 6); *, p < 0.001; **, p = 0.016. Reprinted with permission from ref 97. Copyright 2011 Elsevier.
Furthermore, we conducted a carcinogenicity test of CNTs in a trancegenic rasH2 mouse (482-485) using tattoo carbon black tattoo ink as a reference material. The rasH2 mouse has recently also been used in studies of bulk biomaterials. (486-488) We implanted MWCNTs or tattoo carbon black subcutaneously. Results showed that no neoplasms were produced because of implantation of MWCNTs. In the group with carbon black implanted as a reference, one animal died but had apparent tumors on histopathological examination (Figure 11, Table 3). The 75 mg/kg dose of MWCNTs implanted in this study was considerably higher than the doses that had been used in previous implantation studies in ordinary mice. (89, 91, 155, 304) In summary, the above-described test for assessing the carcinogenicity of subcutaneously implanted CNTs by in the trancegenic animals for the first time revealed no carcinogenesis from CNTs as well as tattoo carbon black tattoo ink. (98)
Figure 11
Figure 11. In a subcutaneous implantation test using cancer-developing transgenic rasH2 mice, MWCNTs were found to be not carcinogenic; their carcinogenicity was determined to be not higher than that of carbon black. (a) Changes over time in survival rate of rasH2 mice. All mice in the MWCNT group were alive at 26 weeks. In the carbon black group, 1 animal died at 22 weeks, and at 26 weeks, 9 of the 10 animals were alive. In the solvent group, all mice were alive at 26 weeks. In the N-methyl-N-nitrosourea (MNU) group, 1 animal died at 13, 14, 17, and 22 weeks each; 6 of the 10 animals were alive at 26 weeks. (b) Histological images of tumor masses in various organs of cancer-developing mice. (A) A tumor mass was observed in the spleen of 1 of the 10 mice in the MWCNT group that survived for 26 weeks; this was identified as an inflammatory pseudotumor, not a neoplasm. (B) A neoplasm developed in a lung of 1 mouse in the carbon black group that survived for 26 weeks; this was diagnosed as a benign adenoma. (C) All 10 mice in the MNU group had tumors. Proventricular tumors developed in all 10 animals, with abnormal squamous epithelial growth observed (upper left panel). Skin tumors developed in 6 of the 10 animals, which occurred as malignant skin tumors in the thigh (upper right panel). Genital tumors developed in 4 animals (lower left panel). A thymic tumor developed in 1 animal (lower right panel). Hematoxylin-eosin staining. Scale bars = 10 μm. (c) Histological images of subcutaneous implantation sites taken at 26 weeks. (A) In the MWCNT group, no neoplasm developed, with macrophages found to have accumulated while phagocytosing MWCNT particles. No inflammatory cells such as neutrophils and lymphocytes were observed around the implantation sites. (B) In the carbon black group, like in the MWCNT group, macrophages phagocytosed MWCNT particles, with no neoplasm observed. Arrow, MWCNTs; arrowhead, carbon black. Hematoxylin-eosin staining. Scale bars = 10 μm. Reprinted with permission from ref 98. Copyright 2012 Nature Publishing Group.
Table 3. Neoplastic Changes in rasH2 Mice Implanted with CNT, Carbon Black, Solvent, or N-Methyl-N-nitrosourea (MNU) Solutiona
| total number | |||||
|---|---|---|---|---|---|
| control | carbon black | CNT | MNU | ||
| organ | diagnosis | 10 | 10 | 10 | 10 |
| skin (back area) | papilloma | 0 | 0 | 0 | 2 |
| keratoacanthoma | 0 | 0 | 0 | 0 | |
| skin (face) | papilloma | 0 | 0 | 0 | 3 |
| keratoacanthoma | 0 | 0 | 0 | 0 | |
| skin (thigh) | papilloma | 0 | 0 | 0 | 1 |
| keratoacanthoma | 0 | 0 | 0 | 0 | |
| spleen | inflammatory pseudotumor | 0 | 0 | 1 | 0 |
| hemangioma | 0 | 1 | 0 | 0 | |
| hematopoietic system | malignant lymphoma | 0 | 0 | 0 | 2 |
| epithelial thymoma | 0 | 0 | 0 | 0 | |
| kidneys | hemangioma | 0 | 0 | 0 | 0 |
| pancreas | hemangioma | 0 | 0 | 0 | 0 |
| lungs | adenocarcinoma | 0 | 0 | 0 | 0 |
| adenoma | 0 | 1 | 0 | 1 | |
| hemangioma | 0 | 0 | 0 | 0 | |
| forestomach | papilloma | 0 | 0 | 0 | 10b |
| basal cell tumor | 0 | 0 | 0 | 0 | |
| squamous cell carcinoma | 0 | 0 | 0 | 0 | |
| perineal | papilloma | 0 | 0 | 0 | 5c |
a
Adapted with permission from ref 98. Copyright 2012 Nature Publishing Group.
b
Significant differences at p = 0.0000054125 (Fisher’s direct method).
c
Significant differences at p = 0.016254 (Fisher’s direct method).
The aforementioned tests showed that nanosized carbon black particles (a tattoo ink component) could be used as a reference for safety evaluation of CNTs. The in vivo implantation test, cytotoxicity test, carcinogenesis test (in transgenic mice), and other tests all found that the toxicity of CNTs is equal to or less than that of carbon black tattoo ink. If a safety test using a substance with verified biological safety as a reference material finds that CNTs exhibit a level of toxicity equivalent to, or lower than, that of the reference material, then it can be concluded that CNTs are safe. We are currently conducting mutagenesis and genotoxicity tests with highly pure carbon black as a reference material. So far, our results show that CNTs are as safe as carbon black particles under the experimental conditions used in the studies.
6 Discussion and Perspective
ARTICLE SECTIONS
6.1 Available Safety Evaluations Relevant to CNTs as Biomaterials
In this Review, studies on using CNTs as biomaterials have been reviewed, and currently available in vivo and in vitro studies on the evaluation of CNTs safety as biomaterials have been described separately. It is clear that many benefits will come from application of CNTs biomaterials to a wide range of important medical services, including cancer treatment, regenerative medicine, implants, and DDSs. (180, 489-491) Making the best use of the findings of these application studies would improve current clinical practices and ensure remarkable progress of medical care. For this reason, research into application of CNTs to biomaterials has been increasing rapidly (Figure 1); however, no clinical application of CNTs has been realized yet (77) because the evidence for the biological safety of CNTs as biomaterials is not definitive. It is easy to say that certain new materials pose risks to living organisms; when one study raises a safety-related question, the test substance can be said to be risky but cannot be said to be completely safe unless its safety is demonstrated in all situations where it is likely to be used. Safety cannot be assured without conducting numerous studies, and this is practically impossible. Therefore, as many studies as possible are needed to make a reasonable, acceptable consensus judgment based on a comprehensive assessment of the findings. It would otherwise be impossible to realize the clinical application of a new biomaterial. The accumulated research into the application of CNTs biomaterials is already sufficient to make such a judgment. The primary objective of this Review is to logically determine whether CNTs can be safely used as biomaterials in clinical settings.
Many pioneering studies have evaluated the safety of CNTs biomaterials. A wide variety of CNTs have been used in many different ways, and studied using various methodologies by many different researchers. Therefore, different studies have often yielded inconsistent results. However, the right judgment must be based on a comprehensive assessment of all such results. To this end, this Review has comprehensively reviewed the relevant published literature and described as many of the latest findings as possible. We conclude that the number of studies reporting the biological safety of CNTs as biomaterials is increasing and that most of the recently published reviews have concluded that CNTs are very safe. (91, 99, 191, 326, 492) Taken together, the findings suggest that CNTs will find clinical application as biomaterials through a stepwise process involving appropriate methods and sites of use.
6.1.1 In Vivo Studies
As stated above, no reported in vivo studies have found that CNTs are associated with life-threatening or otherwise serious toxicities such as carcinogenicity. Furthermore, recently reported studies for the most part have shown that inflammation in response to highly pure CNTs implanted in the body was not intense and resolved quickly. (58, 89, 91, 155, 304) The organ(s) sites of CNTs accumulation after transport through the bloodstream, the response of tissues and cells to the accumulation, and period of CNTs accumulation are important issues. No study has reported any problem resulting from intravenous injection of CNTs. (91, 191, 310) However, more accurate techniques must be developed for monitoring the behavior and disposition of CNTs intravenously injected in large amounts for use in DDSs and imaging. Bearing in mind that CNTs can enter the pulmonary circulation when inhaled, the development of such techniques is ongoing worldwide. (86, 144, 306, 312-315) Hence, the distribution of CNTs after passage through the bloodstream will be revealed in the near future. At present, researchers should refrain from clinically applying CNTs to sites with abundant blood supply until adequate data are available to verify its safety.
On the other hand, it is necessary to determine whether CNTs topically used as biomaterials enter the bloodstream. Because CNTs are particles, they should be limited by size from entering the bloodstream. MWCNTs above a certain size are thought to rarely enter the bloodstream. (310) Even if they enter from a local site, the concentration is expected to be too low to have a major impact on the body. (91, 139, 191, 310)
In conclusion, on the basis of available in vivo data, it can be concluded that MWCNTs are likely to be useful topical biomaterials. (152) Of course, sites of intensive inflammatory reaction to MWCNTs and likely sites of MWCNTs entry into the bloodstream appear to depend on the organ and tissue where the biomaterials are implanted. (304) For this reason, investigations should be conducted for each site separately to determine the hazard to each organ and each tissue.
6.1.2 In Vitro Studies
The results from in vitro toxicity studies are difficult to interpret. Scientific international standards, typically ISO standards, have been established to assess the toxicity of bulk biomaterials, (467) but not nanoparticles like CNTs, which have distinct properties. In most recent studies, CNTs (adequately dispersed in solution) are regarded as chemical substances. This assumption seems to be reasonable for purposes of assessing the safety of particulate substances. In 2012, the Organization for Economic Co-operation and Development (OECD) announced, “Although most testing/assessing methods for conventional chemical substances are also suitable for nanomaterials, corrections according to the characteristics of nanomaterials may be needed in some cases.” (493)
It should be noted that it is difficult to determine which of the many factors relevant to CNTs is being assessed in an assessment of in vitro CNTs toxicity. These factors include thickness, length, shape, surface reactivity, and aggregability as well as the influence of residual metals, dispersants, and assay reagents. (117, 263, 334) Because these factors are inter-related, their influences are difficult to determine separately. (494, 495) Variation in the thickness and length of CNTs may be associated with their cytotoxicity. SWCNTs and MWCNTs differ in toxicity profiles; for example, SWCNTs are more likely than MWCNTs to induce oxidative stress. Length is also important; long CNTs are likely to induce oxidative stress because they are not completely phagocytosed by macrophages. The toxicity of inhaled CNTs increases with increase in length above 10–20 μm, although this observation has not been confirmed. (412) While the maximum acceptable length of CNT particles used as biomaterials is unknown, long CNTs are not considered to pose a problem (such as an inhalation problem), as stated in section 6.2. Surface reactivity also differs depending on the type of CNTs; furthermore, the toxicity of chemically modified CNTs should be thoroughly examined for each modification. Although the influence of residual metals is not negligible, many studies have found that CNTs with a quite high purity pose no major problem. (72, 365, 400-402, 407, 408, 496) On the other hand, the influence of aggregability of CNTs and the choice of dispersant on toxicity do pose problems. (483) Many published studies are thought to have established the total toxicity of CNTs and dispersant. (371, 373, 385, 497) Furthermore, because the aggregability of CNTs and the choice of dispersant vary widely among different studies, the range of CNT concentrations used in respective toxicity studies is wide (from 1 ng/mL to 10 μg/mL), making assessment more difficult. (309, 447) From now on, in vitro studies should be conducted under a standard set of conditions (dispersant selected to not affect the test cells, and range of concentrations selected to avoid CNTs aggregation) whenever possible.
6.1.3 Correlations between in Vivo and in Vitro Data
For CNTs, unlike drugs and other chemical substances, little is known about correlations between in vivo and in vitro data. (498) One reason is that no in vivo data are available; nanoparticles have not yet been used as biomaterials, and this issue cannot be resolved until clinical application is realized. Another reason is that there are no standard ways for dealing with a wide variety of factors that can influence the results of correlation studies, such as the animal species, method of administration used in the in vivo studies, and the choice of cell and culture broth used in the in vitro studies. (91) In the future, it will be necessary to ensure these factors are consistent for all studies, to collect and analyze data from international sources, and to determine the correlations between in vivo and in vitro toxicity assessments of CNTs, at least in small animals such as mice. (191)
6.2 Appropriate References for Safety Evaluation of CNTs
6.2.1 Requirements for References
Only a few articles on the safety of CNTs biomaterials were published before 2010, and these reported many conflicting results. However, as the number of articles increased, the number of safety evaluations increased, and the conclusion drawn from these results is that CNTs are safe to use as biomaterials. (89, 91, 99, 191) Nevertheless, clinical application has been frustrated because researchers have been unable to rule out CNTs toxicity. This situation is due primarily to the lack of a best reference material for the evaluation of CNTs safety. The finding of such a reference would facilitate evaluation of CNTs safety. (68) CNTs biomaterials, like all other biomaterials, are foreign to living organisms irrespective of their biocompatibility. At concentrations exceeding a certain level, CNTs exhibit toxicity in vitro and in vivo. The absence of a reference with established safety makes it difficult to determine the in vivo safety of CNTs. For example, when test cells lose activity in the presence of CNTs at concentrations exceeding a certain level, it is wrong to conclude that the CNTs are cytotoxic. However, it is right to conclude that CNTs are not cytotoxic when test cells lose activity in the presence of a reference with established safety. Biological safety cannot be assessed without comparison to a reference that has been proven to be safe in living organisms as described above. However, unfortunately, no such reference has been found to evaluate the safety of CNTs biomaterials. Inevitably, CNT toxicity studies have yielded inconsistent results so that no safety evaluation has been regarded as reliable. The lack of a reference with confirmed biological safety is attributed to the traditional view that nanoparticulates are not biomaterials.
6.2.2 Carbon Black
We found a reference material (carbon black) and proposed its use as a reference in our research articles published in 2011 and 2012. (97, 98) Carbon black is the primary component of black tattoo ink, and tattooing of the human body has a long history dating back before ancient times, and is currently commonly performed. (475) Some researchers may dispute the use of carbon black as a reference for CNTs because CNTs particles are fibrous and carbon black particles are spherical. It is reasonable to attach importance to this difference if the research focus is on inhalation toxicity. Cells are unable to completely absorb long fibrous nanoparticles. It has been hypothesized that oxidative stress “frustrates” phagocytosis, and prolongs inflammation and other events. (281, 409, 411, 412) However, this merely accounts for prolonged inflammatory reactions to CNTs in the thoracic cavity, where inhalation exposure to CNTs occurs, and in the abdominal cavity (a surrogate for the thoracic cavity), where exposure to CNTs is experimentally mimicked. Many researchers have found that even when a considerable amount of CNTs is implanted subcutaneously and elsewhere, only transient, very mild inflammation develops and resolves quickly. (58, 307-309) This fact suggests that no frustrated phagocytosis occurs at least in subcutaneous tissue. Hence, because no in vivo implantation study found that CNTs cause frustrated phagocytosis at sites of transient inflammation, it can be concluded that fibrous nanoparticles pose no risk. Generally, animal experiments have shown the improbability that sites of prolonged CNT-induced inflammation contain CNTs particles. Therefore, provided that appropriately designed in vivo implantation studies produce no evidence of prolonged inflammation, then fibrous CNTs can be used as biomaterials without safety concerns.
Essentially, sharing all of the characteristics of the test material is not the only requirement for a substance to be used as a reference. This is also true for bulk biomaterials; even with different characteristics, they have been used as references with satisfactory results for desired effects. (467) Importantly, both CNTs and carbon black belong to a new category of biomaterials known as nanoparticulate substances. Logically, as with bulk biomaterials, no problem arises from the use of carbon black as a reference material for CNTs. Carbon black (like CNTs) is a nanosized particulate substance, even though other characteristics may be different. Another advantage of carbon black as reference is that mass can be used as an index because both CNTs and carbon black are pure carbon particulates. (97, 98) Mass is by far an easier index to use in toxicity studies than particle count and volume. In view of these facts, we propose the use of highly pure carbon black as a good reference material for CNTs.
Many articles are available on the use of carbon black as a reference for assessment of biological reactions to CNTs. (292, 365, 381, 499-506) However, no clear evidence has been presented supporting the claim that carbon black is safe to use in living organisms. According to many researchers who have used carbon black as a reference for CNTs, carbon black is intuitively the best reference. We have verified the scientific intuition of many researchers by providing them with a rationale (i.e., carbon black is safe because it is a component of black tattoo ink). Because there are a large number of such articles, we believe that many researchers will agree with the conclusion of this Review that carbon black is suitable as a reference material for safety evaluation of CNTs.
6.2.3 International Standards
What should happen soon after a consensus is reached that carbon black is suitable for use as a reference material for CNTs? The safety of CNTs should be evaluated both in vivo and in vitro using the new reference material. As stated above, it is easy to say, “Risk may exist”, but it is difficult to say, “No risk exists”. It is necessary for as many researchers as possible to conduct as many studies as possible. All studies then need to use standardized carbon black as a reference to allow the results to be assessed collectively and comprehensively compared.
There are many types of carbon black with somewhat variable biological safety. Above all, highly pure carbon black (a suspension of nanoparticles, which is equivalent to the carbon black used in tattoo ink) can be used as a reference for CNTs. (475) At present, we think that carbon black particles (diameter of about 50 nm and a purity of 99.5% or more) are suitable, but we would like to suggest here that many experts discuss extensively, choose, and designate the best carbon black powder as the international standard.
Special attention should be paid to the carbon black dispersant (usually a surfactant) because CNTs particles in the test solution are less dispersible than carbon black particles. (366-371) The same dispersant should be used in both the CNTs and the reference solutions, provided the dispersant (when used at concentrations that fully disperse the CNTs and reference particles) has no major impact on living organisms and cells. In vitro, in particular, particles precipitate over time, which can alter the cellular reactions depending on the precipitation rate. To ensure a valid comparison with the reference, it is desirable to use a dispersant that minimizes precipitation of particles. At present, we think polyvinyl alcohol is the best dispersant. (97) However, there may be better dispersants with higher dispersion efficacy, lower toxicity, greater ease of handling, and other superior characteristics; therefore, an internationally acceptable dispersant should be chosen after much discussion on the basis of a consensus of expert opinions.
6.2.4 Method of Safety Evaluation
CNTs with equal or less toxicity than that of the reference carbon black should be considered “safe”. This judgment can be made without further research. If the toxicity of CNTs is found to be greater than that of carbon black, the decision should be deferred. Strictly speaking, further assessment is impossible because carbon black is the only currently available reference. Particular attention should be paid if toxicity is far greater than that of carbon black (e.g., toxic concentrations one-tenth of the reference concentration). On the other hand, if neither CNTs nor carbon black is toxic, CNTs should be considered nontoxic, or the study conditions should be considered inappropriate. We propose to collect safety data through various evaluations of CNTs using carbon black as a common reference, while paying attention to these facts.
Unfortunately, carbon black cannot be used as a reference material in the assessment of in vivo kinetics because particle shape affects localized nanoparticle accumulation and nanoparticle migration from tissue to bloodstream. (327) As compared to CNTs particles (that are fibrous), carbon black particles (that are spherical) migrate more readily between tissues and the bloodstream. However, a reference is not needed to track the in vivo migration of CNTs. If CNTs accumulate in a certain organ, a study of CNT implantation may be conducted to assess the biological reactions at the site using carbon black as a reference.
6.3 Decision To Start Clinical Application of CNT-Based Biomaterials
As stated above, many researchers have shown that pristine (very pure) MWCNTs with few failures as biomaterials are very safe to use as biomaterials. MWCNTs are safe to use topically but not at special sites such as the lung and abdominal cavity. (91, 191, 305, 306) The safety of using MWCNTs as DDSs or the like and involving access to the bloodstream has not yet been verified. Furthermore, using tattoo carbon black as a reference, we showed that pristine MWCNTs are at least as safe as carbon black. (97, 98)
Because the above-described remarkable advances in research into the application of CNTs as biomaterials have led to the judgment that CNTs biomaterials are probably very safe (provided the method and site of use are appropriate), now is a time to start using CNTs clinically. We are planning to clinically apply MWCNTs (carbon purity, of 99.5% or more; mean diameter, about 60 nm [40–90 nm]; mean length, about 10 μm; and specific surface area, 25–30 m2/g; produced using the chemical vapor deposition technique [MWNT-7, Hodogaya Chemical, Tokyo, Japan]). Of course, a composite material containing 5 wt % or less of MWCNTs (the safest form of CNTs) will be used.
6.4 Path to Clinical Application of CNT-Based Biomaterials
Importantly, we will begin with the safest clinical application of CNTs and proceed in steps according to the magnitude of risk involved. We divided the time course into four stages differing in degree of risk estimated on the basis of the nature of the biomaterial (composite versus particulate), the site of use (topical versus systemic), and the degree of in vivo exposure to the particles (high versus low) (Table 4).
Table 4. Stages of Clinical Application of CNT-Based Biomaterialsa
| atage | nature of the biomaterial | site of use | degree of in vivo exposure | risk | example of use |
|---|---|---|---|---|---|
| stage 1 | composite | topical | none/low | none/low | artificial joints and interbody fusion materials |
| stage 2 | particulate | topical | intermediate | low/intermediate | DDSs and imaging for cancer treatment |
| stage 3 | particulate | topical | intermediate | low/intermediate | regenerative medicine scaffolds and DDS for topical treatments |
| stage 4b | particulate | systemic | high | high | DDSs and imaging that circulate via bloodstream |
a
Clinical application of CNTs to biomaterials should progress demonstrating the safety at each stage.
b
The decision of proceeding to stage 4 requires extremely careful consideration.
The first stage is characterized by the use of a CNTs composite material for implantation (stage 1). Generally, the CNT content in a composite material is not more than 10 wt %, and the likelihood of in vivo exposure to CNTs particles is zero or minimal. Therefore, problems due to CNTs in the human body are unlikely to occur. As the first biological application of CNTs, we are planning to use composites of MWCNTs with existing biomaterials in artificial joints or spine interbody fusion materials.
In application to artificial joints, we are developing an MWCNT/polyethylene composite material and an MWCNT/ceramics composite material. Although the polyethylene used in sliding parts of artificial joints is ultrahigh molecular weight polyethylene (UHMWPE), it wears during long-term use and can necessitate resurgery. (242-245, 507) For this reason, cross-linked UHMWPE has become commonly used, although its excessive hardness and easy breakability are problematic. (508-512) Having favorable characteristics that are absent in conventional materials, that is, high wear resistance and low breakability, MWCNT-conjugated UHMWPE is suitable as a sliding parts material for artificial joints (Figure 12). On the other hand, ceramics are also used in the sliding parts of artificial joints. Although ceramics wear very slightly, they are breakable so that resurgery is sometimes needed. (513-518) Combining CNTs with ceramics increases fracture toughness and can transform ceramics into an ideal, wear-free, antifracture, sliding parts material for artificial joints.
Figure 12
Figure 12. For application to sliding parts of artificial joints, an ultrahigh molecular weight polyethylene (UHMWPE) conjugated with MWCNTs has been developed. (a) A UHMWPE socket (left panel) and an MWCNT-conjugated UHMWP socket (right panel) for use in sliding parts of artificial joints. (b) A prototype artificial joint with a socket made of CNTs. Having favorable characteristics that have not been achieved with conventional materials, that is, high wear resistance and low breakability, MWCNT-conjugated UHMWPE is suitable as a sliding parts material for artificial joints.
To improve the quality of interbody fusion material, we are now engaged in developing an MWCNT/PEEK composite. PEEK is a highly biocompatible material possessing excellent biological safety and mechanical characteristics. (519, 520) Because of its low compatibility for bone tissue, however, PEEK has been associated with the problem of insufficient bone union when used in implants that are directly exposed to bone, such as interbody fusion cages. (521-524) MWCNTs have been reported by many research teams, including ours, to possess bone induction potential. (58, 62, 63, 67, 213, 215, 216, 218, 525, 526) If conjugation with MWCNTs further improves the mechanical characteristics of PEEK and also induces osteogenesis, then MWCNT/PEEK composite will become an ideal interbody fusion material (Figure 13).
Figure 13
Figure 13. For application to spine interbody fusion material, a polyetheretherketone (PEEK) composite with MWCNTs has been developed. (a) A conceptual diagram showing that PEEK, when conjugated with MWCNTs, will become an innovative spine interbody fusion material possessing excellent mechanical characteristics and bone compatibility. (A) The MWCNTs on the surface confer bone compatibility. (B) The internally conjugated MWCNTs control the elastic modulus. (b) (A) A PEEK spine interbody fusion cage (left panel) and an MWCNT-conjugated PEEK cage (right panel). (B) A prototype interbody fusion cage made of CNTs.
In 2012, the European Commission (EC) announced a draft regulation as amended to oblige manufacturers of medical equipment used to make nanomaterial-containing products, to properly label medical devices containing nanomaterials categorized under Class III (most dangerous substances). This rule shall apply only in cases where such medical devices are used for the intended purposes and in the absence of measures (such as encapsulation and coupling) to prevent nanomaterials from entering the patient’s body and the user’s body. (527) Hence, use of CNTs composites as biomaterials may not be subject to legal regulations because they are bound to the base material. For this reason, we believe that stage 1 poses only a minimal safety risk and can be safely implemented, provided the appropriate legal procedures of each country are followed.
In stage 2, CNTs particles are used within the body. This stage represents the first high barrier to clinical application of CNTs because nanoparticulate substances come into direct contact with the body. This usage is subject to legal regulations according to the definition of the EC, and is thought to require international approval from an ethical viewpoint as well. Hence, research activities cannot proceed to this stage until an extensive assessment is performed following the establishment of international standards for evaluation of biosafety. Initially, the use of CNTs must be limited to localized sites. Furthermore, top priority should be given to the use of CNTs in situations where the benefits from their use by far outweigh the risks involved. Specifically, the most likely field appears to be cancer treatment, where no other treatment is available or treatment with CNTs is highly advantageous over other treatments. This is currently the most hopeful field of clinical application of CNTs. It is evident that if CNTs become applicable to DDSs and imaging for cancer treatment, dramatic advances in the treatment and diagnosis of cancer will be achieved, which is expected to contribute substantially to the health and welfare of many patients.
Stage 3 also concerns the topical use of CNTs particles as in stage 2, but the coverage is expanded to include the treatment of diseases requiring higher safety than in stage 2. CNTs are used clinically in topical treatments (including regenerative medicine scaffolds) and for the treatment and diagnosis of diseases that are less life-threatening than cancer, such as diabetes mellitus. In this stage, coverage of target diseases and use sites is much wider, and application of CNTs biomaterials more common. Stages 2 and 3 involve the same level of risk but have different benefits.
Finally, we will proceed to stage 4 aimed at the treatment of diseases involving the injection of CNTs and their systemic circulation via the bloodstream for the purpose of drug delivery and whole-body imaging. However, this decision requires extremely careful consideration. (327) As of 2012, the EC had approved 20 nanopharmaceuticals (of course, other than CNTs). (301) Although drug delivery and whole-body imaging using CNTs are highly effective procedures, major risk arises from their systemic circulation via the bloodstream. No clinical application should be started until the disposition of CNT particles and their effects on the heart, lung, liver, spleen, kidney, and other organs are extensively investigated and sufficient data are available to obtain an international consensus. At present, it remains unknown whether research activities will advance to stage 4.
It is important to make steady progress through these stages of clinical application and exercise discretion to demonstrate the safety of CNTs at each stage. This biological application and technical improvements in the biological application of CNTs would help accelerate the development of groundbreaking new therapeutic methods.
6.5 Establishing International Standards for Biological Safety Evaluation
To date, studies evaluating CNTs biomaterials safety have been conducted all over the world; however, interpretation of the collective results has been problematic because different methods of assessment were used by different researchers. Hence, it has been impossible to build a centralized toxicity database, which is essential for the assessment of CNTs safety and efficiency in biological systems. (91) International standards for biological safety evaluation need to be established as soon as possible, to conduct toxicity studies using one method of assessment and one set of standards, and to provide access to all results internationally. By doing so, many reliable results from all over the world can be analyzed by many experts, allowing them to make the right consensus decision. There are a great many types of CNTs and numerous derivatives produced by chemical modification. To achieve safe clinical application of these CNTs as soon as possible, there is an urgent need to establish international standards for the evaluation of biosafety. (70, 191)
In the biological application of CNTs, it is critical to evaluate the safety of functionalized CNTs (f-CNTs), which are likely to find application as DDSs, for in vivo imaging, and in regenerative medicine scaffolds. Chemical modification is also important to increase the dispersion efficacy of CNTs, a key to successful biological application. (331) Of course, f-CNTs must be examined for safety individually. Furthermore, some researchers are working to functionalize CNTs to make them safer to living organisms. (257, 334, 528) To facilitate the application of numerous f-CNTs as biomaterials, it is of paramount importance to establish international standards for safety evaluation.
Provided that criteria are logically formulated on the basis of the published results from studies evaluating the safety of CNTs biomaterials, international standardization of the CNTs safety evaluation methodology would not be difficult. The first task is to establish standards for the topical use of CNTs. Specifically, in vivo and in vitro studies should first be conducted in the same manner as with ISO-standardized ordinary bulk biomaterials to assess the toxicity resulting from the dissolution of impurities contained in CNTs and some or all of the molecules bound to the CNTs. In vivo studies then should be conducted to assess the CNTs toxicity intrinsic to their identity as nanoparticles. This involves implantation of CNTs at the sites of their potential use to determine biocompatibility with a particular organ or tissue. The in vitro studies involve the dispersion of CNTs with a standard dispersant and use of ISO-compliant test methods similar to those used for ordinary chemical substances. (467) The in vivo and in vitro studies for determination of the intrinsic toxicity of CNTs involve comparison with a nanoparticulate reference material, carbon black as described above. With a standard reference, international standards for the evaluation of the biological safety of topically used CNTs particles can be established without delay.
Subsequently, efforts will be made to establish international standards for the evaluation of CNTs safety in applications involving passage through the bloodstream. Basically, in vivo studies on CNTs well dispersed in solution will be conducted using the same criteria as those used for ordinary chemical substances. However, it is unknown which substance (possibly an existing nanoparticulate material already used clinically in DDSs and possibly transported through the bloodstream, with confirmed safety and properties similar to those of CNTs) will be the appropriate reference material. Selection of a reference for this application of CNTs, which circulate in the bloodstream, is a major challenge to be tackled in the future.
In all cases, international standards for the evaluation of CNTs biosafety need to be established as soon as possible because ultimately CNTs will revolutionize cancer treatment and regenerative medicine, which are top priorities in today’s medicine. Now is the time to translate research on safe CNT composite implants into clinical applications. International standards for evaluation of CNTs biosafety must be established to enable the topical use of CNTs particles. Research into any important medical issue should always proceed without interruption.
7 Conclusion
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The study of the application of CNTs as biomaterials has been increasing dramatically because CNTs have been shown to be extremely effective and very safe biomaterials. Biomaterials that have doubtful biosafety are unlikely to find clinical application in the future. Although it is logically impossible to say that CNTs are completely safe to use in living organisms, CNTs can be judged to be extremely safe if no evidence of biological risk has been obtained by a vast number of studies investigating their biological application. Most researchers in this field think CNTs are safe to use in living organisms, provided that the appropriate method and site of delivery are used.
CNTs biomaterials if fully utilized could lead to many revolutionary and important medical technologies. Because of the extremely advantageous characteristics unique to CNTs, the biological safety evaluation issue making us reluctant to start their clinical application must be solved as soon as possible.
Thanks to the painstaking efforts of a great many researchers, much evidence supports the claim that CNTs are generally safe as biomaterials. Accordingly, now is the time to start clinical application of CNT composite implants, the biologically safest form of CNTs, because there is little possibility that CNTs will be directly exposed to the living organism. To quickly proceed topical use of CNTs particles, it is necessary for researchers to establish international standards for biosafety evaluation as soon as possible. In this process, the carbon black reference will play an important role. When taking the next and most risky step toward clinical application (that involves the entry of CNTs into the circulation), the utmost caution must be exercised to ensure safe use.
Because many researchers can now evaluate the biosafety of CNTs using the power of the latest science and technology, we should now embark on a journey toward the clinical use of CNT-based biomaterials in an ethical and courageous manner.
Biographies
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Naoto Saito
Naoto Saito is a professor and director of the Institute for Biomedical Sciences, Shinshu University. He is an experienced researcher specializing in biochemistry, cell biology, regenerative medicine, biomaterials, and nanobiotechnology. As the leader of Shinshu University’s Nanobiotechnology and Biomedical Engineering Team, he is working on developing CNT-based biomaterials.
Hisao Haniu
Hisao Haniu is serving as a lecturer in the Department of Orthopaedic Surgery, Shinshu University School of Medicine. He is a qualified clinical laboratory technician and specializes in physiology and biochemistry, especially in proteomics. He is engaged in research on the safety evaluation of nanomaterials and in the training of many young researchers.
Yuki Usui
Yuki Usui is an associate professor at the Research Center for Exotic Nanocarbons, Shinshu University. He is an orthopedist, specializing in research on the biological application of nanomaterials. He showed for the first time that CNTs promote bone formation in an animal study on bone tissue regeneration.
Kaoru Aoki
Kaoru Aoki is serving as a research associate in the Department of Orthopaedic Surgery, Shinshu University School of Medicine. He is a medical doctor specializing in bone and soft tissue tumors, and also a rehabilitation doctor. He is concurrently engaged in basic research and clinical research, conducting research to apply nanocarbons as drug delivery systems for anticancer agents.
Kazuo Hara
Kazuo Hara is an orthopaedic surgeon in the Department of Orthopaedic Surgery, Shinshu University School of Medicine. His special interest is evaluation of the biological safety of CNTs as biomaterials.
Seiji Takanashi
Seiji Takanashi is a researcher at the Shinshu University School of Medicine, and is also serving as a medical doctor in the Department of Orthopaedic Surgery. He is working on evaluating the carcinogenicity of CNTs in transgenic mice and clarifying the action of nanomaterials in cells.
Masayuki Shimizu
Masayuki Shimizu serves as a research associate in the Department of Orthopaedic Surgery, Shinshu University School of Medicine. He is a medical doctor specializing in spinal surgery, and conducts both basic and clinical research. He is exploring the mechanism of bone formation promotion by CNTs at the cellular level.
Nobuyo Narita
Nobuyo Narita is a research associate in the Department of Orthopaedic Surgery, Shinshu University School of Medicine. She specializes in lower limb surgery, serving as a leader of the foot surgery team at Shinshu University Hospital. She demonstrated using intracellular signals that CNTs suppress the function of osteoclasts.
Masanori Okamoto
Masanori Okamoto is a researcher at the Shinshu University School of Medicine, and is a medical doctor in the Department of Orthopaedic Surgery. He is now studying bone metabolism at Matsumoto Dental University and has a special interest in the action of Wnt5 in osteoblasts.
Shinsuke Kobayashi
Shinsuke Kobayashi is a researcher at the Shinshu University School of Medicine. He specializes in safety evaluation of nanomaterials, and is investigating the in vivo kinetics of CNTs using MRI and CT.
Hiroki Nomura
Hiroki Nomura is a researcher at the Shinshu University School of Medicine. As a member of the research and development team for application of CNT-conjugated polyethylene to artificial joints, he is engaged in evaluating the biological safety of CNTs and their composites.
Hiroyuki Kato
Hiroyuki Kato is a professor in the Department of Orthopaedic Surgery, Shinshu University School of Medicine. He specializes in hand surgery and conducts research on nerves and tendons. He provides research and clinical practice training to many physicians in the Department of Orthopaedics at Shinshu University Hospital.
Naoyuki Nishimura
Naoyuki Nishimura is the director of the R&D Center, Nakashima Medical Co. Ltd. He is developing artificial joints and spinal fixation devices made of CNT composites jointly with Shinshu University. He investigates safety and regulatory science with the aim of clinical application of CNT composites.
Seiichi Taruta
Seiichi Taruta is a professor in the Faculty of Engineering, Shinshu University. He is working on developing CNT-conjugate ceramics and bioactive ceramics. He is also a member of a medicine-engineering collaboration research project to develop CNT-based artificial joints.
Morinobu Endo
Morinobu Endo is a distinguished professor in the Faculty of Engineering, Shinshu University. As the discoverer of the manufacturing process for CNTs using a chemical vapor deposition approach, he has been a world leader in CNTs research. As head of the Research Center for Exotic Nanocarbons, he currently conducts research on multitargeted application of nanocarbons.
Acknowledgment
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This work was supported by a Grant-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Science, Sports, and Culture, Japan (nos. 19002007, 18201021, 24241045, and 24659670), by a Health Labour Sciences Research Grant from the Ministry of Health Labour and Welfare, Japan (no. 12103240), by the Regional Innovation Cluster Program (the second stage) of the Ministry of Education, Culture, Sports, Science and Technology, Japan (Shinshu Smart Device Cluster), Japan Regional Innovation Strategy program by the Excellence from Japan Science and Technology Agency (Exotic Nanocarbons), by Research and Development of Nanodevices for Practical Utilization of Nanotechnology of the New Energy and Industrial Technology Development Organization, Japan (no. 07001418-0), and by the Hospital-company collaboration support project for developing/improving problem-solving-type medical equipment by Ministry of Economy, Trade and Industry, Japan (nos. 143 and 24-055).
Abbreviations
ARTICLE SECTIONS
| AFP | α-fetoprotein |
| AIST | National Institute of Advanced Industrial Science and Technology |
| ALP | alkaline phosphatase |
| APC | antigen-presenting cell |
| bmDC | bone marrow-derived dendritic cell |
| CA19-9 | carbohydrate antigen 19-9 |
| CEA | carcinoembryonic antigen |
| CNS | central nervous system |
| CNT | carbon nanotube |
| CVD | chemical vapor deposition |
| DDS | drug delivery system |
| DTPA | diethylenetriaminepentaacetic acid |
| DTPA | diethylenetriaminepentaacetic acid |
| EDS | energy dispersive X-ray spectroscopy |
| ELISA | enzyme-linked immunosorbent assay |
| ES cell | embryonic stem cell |
| f-CNT | functionalized-CNT |
| GEM | gemcitabine |
| IC50 | half maximal inhibitory concentration |
| IL | interleukin |
| iPS cell | induced pluripotent stem cell |
| ISO | International Standards Organization |
| LPS | lipopolysaccharide |
| MNU | N-methyl-N-nitrosourea |
| MWCNT | multiwalled CNT |
| NIOSH | National Institute for Occupational Safety and Health |
| NIST | National Institute of Standards and Technology |
| OECD | Organization for Economic Co-operation and Development |
| PEEK | polyether ether ketone |
| PEG | polyethylene glycol |
| PSA | prostate specific antigen |
| rhBMP-2 | recombinant bone morphogenetic protein-2 |
| ROS | reactive oxygen species |
| SEM | scanning electron microscopy |
| siRNA | short interference RNA |
| SWCNT | one layer is known as single-walled CNT |
| TCB-1 | Tattoo carbon black-1 |
| TCB-2 | Tattoo carbon black-2 |
| TEM | transmission electron microscopy |
| TNF | tumor necrosis factor |
| UHMWPE | ultrahigh molecular weight polyethylene |
| ZDBC | zinc dibutyldithiocarbamate |
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ARTICLE SECTIONS
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19Bauhofer, W.; Kovacs, J. Z. Compos. Sci. Technol. 2009, 69, 1486Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXntlSis7g%253D&md5=b132f119499ffdaef45269fa89953f6cA review and analysis of electrical percolation in carbon nanotube polymer compositesBauhofer, Wolfgang; Kovacs, Josef Z.Composites Science and Technology (2009), 69 (10), 1486-1498CODEN: CSTCEH; ISSN:0266-3538. (Elsevier B.V.)A review. We review exptl. and theor. work on elec. percolation of carbon nanotubes (CNT) in polymer composites. We give a comprehensive survey of published data together with an attempt of systematization. Parameters like CNT type, synthesis method, treatment and dimensionality as well as polymer type and dispersion method are evaluated with respect to their impact on percolation threshold, scaling law exponent and max. cond. of the composite. Validity as well as limitations of commonly used statistical percolation theories are discussed, in particular with respect to the recently reported existence of a lower kinetic (allowing for re-aggregation) and a higher statistical percolation threshold.
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20Chou, T. W.; Gao, L.; Thostenson, E. T.; Zhang, Z.; Byun, J. H. Compos. Sci. Technol. 2010, 70, 1Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsV2mtLnP&md5=747eaf6a1618454ebcaba406b4ba3e82An assessment of the science and technology of carbon nanotube-based fibers and compositesChou, Tsu-Wei; Gao, Limin; Thostenson, Erik T.; Zhang, Zuoguang; Byun, Joon-HyungComposites Science and Technology (2009), 70 (1), 1-19CODEN: CSTCEH; ISSN:0266-3538. (Elsevier B.V.)A review. This paper examines the recent advancements in the science and technol. of carbon nanotube (CNT)-based fibers and composites. The assessment is made according to the hierarchical structural levels of CNTs used in composites, ranging from 1-D to 2-D to 3-D. At the 1-D level, fibers composed of pure CNTs or CNTs embedded in a polymeric matrix produced by various techniques are reviewed. At the 2-D level, the focuses are on CNT-modified advanced fibers, CNT-modified interlaminar surfaces and highly oriented CNTs in planar form. At the 3-D level, we examine the mech. and phys. properties CNT/polymer composites, CNT-based damage sensing, and textile assemblies of CNTs. The opportunities and challenges in basic research at these hierarchical levels have been discussed.
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21Xu, M.; Futaba, D. N.; Yamada, T.; Yumura, M.; Hata, K. Science 2010, 330, 1364Google ScholarThere is no corresponding record for this reference.
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22Bakshi, S. R.; Agarwal, A. Carbon 2011, 49, 533Google ScholarThere is no corresponding record for this reference.
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23Xiong, F.; Liao, A. D.; Estrada, D.; Pop, E. Science 2011, 332, 568Google ScholarThere is no corresponding record for this reference.
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24Endo, M.; Kim, Y. A.; Hayashi, T.; Nishimura, K.; Matusita, T.; Miyashita, K.; Dresselhaus, M. S. Carbon 2001, 39, 1287Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXktV2isb8%253D&md5=152ece41d2bc3029c989495f3bd6025bVapor-grown carbon fibers (VGCFs). Basic properties and their battery applicationsEndo, M.; Kim, Y. A.; Hayashi, T.; Nishimura, K.; Matusita, T.; Miyashita, K.; Dresselhaus, M. S.Carbon (2001), 39 (9), 1287-1297CODEN: CRBNAH; ISSN:0008-6223. (Elsevier Science Ltd.)Submicron vapor grown carbon fibers (VGCFs) obtained by a floating growth method were evaluated in terms of their microstructural development with heat treatment temp., phys. properties of a single fiber and of the bulk state, and addnl. effects, such as the filler in the electrode of a lead-acid battery and a Li-ion battery system. Its desirable properties, such as relatively high mech. strength and elec. cond., both in the single fiber state and in the bulk state, including their very special network-like morphol., improved the performance of the electrodes in lead-acid batteries and Li-ion batteries, esp. their cycle characteristics.
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25Kang, S. J.; Kocabas, C.; Ozel, T.; Shim, M.; Pimparkar, N.; Alam, M. A.; Rotkin, S. V.; Rogers, J. A. Nat. Nanotechnol. 2007, 2, 230Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXktVGhurc%253D&md5=74adaca1c0968d918dc7b430b672a623High-performance electronics using dense, perfectly aligned arrays of single-walled carbon nanotubesKang, Seong Jun; Kocabas, Coskun; Ozel, Taner; Shim, Moonsub; Pimparkar, Ninad; Alam, Muhammad A.; Rotkin, Slava V.; Rogers, John A.Nature Nanotechnology (2007), 2 (4), 230-236CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Single-walled carbon nanotubes (SWNTs) have many exceptional electronic properties. Realizing the full potential of SWNTs in realistic electronic systems requires a scalable approach to device and circuit integration. We report the use of dense, perfectly aligned arrays of long, perfectly linear SWNTs as an effective thin-film semiconductor suitable for integration into transistors and other classes of electronic devices. The large no. of SWNTs enable excellent device-level performance characteristics and good device-to-device uniformity, even with SWNTs that are electronically heterogeneous. Measurements on p- and n-channel transistors that involve as many as ∼2,100 SWNTs reveal device-level mobilities and scaled transconductances approaching ∼1,000 cm2 V-1 s-1 and ∼3,000 S m-1, resp., and with current outputs of up to ∼1 A in devices that use interdigitated electrodes. PMOS and CMOS logic gates and mech. flexible transistors on plastic provide examples of devices that can be formed with this approach. Collectively, these results may represent a route to large-scale integrated nanotube electronics.
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26Scrosati, B. Nat. Nanotechnol. 2007, 2, 598Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFWhsbjO&md5=1c4566c5fd2b9b598896749e59c74c73Paper powers battery breakthroughScrosati, BrunoNature Nanotechnology (2007), 2 (10), 598-599CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)A review. A combination of C nanotubes and nanoporous cellulose enabled fabrication of Li-ion batteries and supercapacitors that are both lighter and more flexible than existing devices.
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27Sotowa, C.; Origi, G.; Takeuchi, M.; Nishimura, Y.; Takeuchi, K.; Jang, I. Y.; Kim, Y. J.; Hayashi, T.; Kim, Y. A.; Endo, M.; Dresselhaus, M. S. ChemSusChem 2008, 1, 911Google ScholarThere is no corresponding record for this reference.
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28Lima, M. D.; Fang, S.; Lepro, X.; Lewis, C.; Ovalle-Robles, R.; Carretero-González, J.; Castillo-Martinez, E.; Kozlov, M. E.; Oh, J.; Rawat, N.; Haines, C. S.; Haque, M. H.; Aare, V.; Stoughton, S.; Zakhidov, A. A.; Baughman, R. H. Science 2011, 331, 51Google ScholarThere is no corresponding record for this reference.
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29Dai, L.; Chang, D. W.; Baek, J. B.; Lu, W. Small 2012, 8, 1130Google ScholarThere is no corresponding record for this reference.
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30Evanoff, K.; Khan, J.; Balandin, A. A.; Magasinski, A.; Ready, W. J.; Fuller, T. F.; Yushin, G. Adv. Mater. 2012, 24, 533Google ScholarThere is no corresponding record for this reference.
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31Pugno, N. M.; Bosia, F.; Carpinteri, A. Small 2008, 4, 1044Google ScholarThere is no corresponding record for this reference.
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32Byrne, M. T.; Gun’ko, Y. K. Adv. Mater. 2010, 22, 1672Google ScholarThere is no corresponding record for this reference.
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33Huang, W. M. Modern Mater. Trends 2010, 2, 9Google ScholarThere is no corresponding record for this reference.
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34Tan, D.; Zhang, Q. In Future Computer, Communication, Control and Automation; Zhang, T., Ed.; Springer: Berlin, 2012; AISC 119, pp 137– 146.Google ScholarThere is no corresponding record for this reference.
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35Choudhary, V.; Gupta, A. In Carbon Nanotubes - Polymer Nanocomposites; Yellampalli, S., Ed.; InTech: Shanghai, 2011; pp 65– 90.Google ScholarThere is no corresponding record for this reference.
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36Tans, S. J.; Verschueren, A. R. M.; Dekker, C. Nature 1998, 393, 49Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjt1aitb8%253D&md5=c92463158e339ccd47fe6b6e3591be74Room-temperature transistor based on a single carbon nanotubeTans, Sander J.; Verschueren, Alwin R. M.; Dekker, CeesNature (London) (1998), 393 (6680), 49-52CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)The authors report the fabrication of a field-effect transistor - a three-terminal switching device - that consists of one semiconducting single-wall C nanotube connected to two metal electrodes. By applying a voltage to a gate electrode, the nanotube can be switched from a conducting to a insulating state. The authors have previously reported similar behavior for a metallic single-wall carbon nanotube operated at extremely low temps. The present device, in contrast, operates at room temp., thereby meeting an important requirement for potential practical applications. Elec. measurements on the nanotube transistor indicate that its operation characteristics can be qual. described by the semiclassical band-bending models currently used for traditional semiconductor devices. The fabrication of the three-terminal switching device at the level of a single mol. represents an important step towards mol. electronics.
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37Rueckes, T.; Kim, K.; Joselevich, E.; Tseng, G. Y.; Cheung, C. L.; Lieber, C. M. Science 2000, 289, 94Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXlt1enu7Y%253D&md5=d2224a6f9d9bdff3c99c8ddc959e0975Carbon nanotube-based nonvolatile random access memory for molecular computingRueckes, Thomas; Kim, Kyoungha; Joselevich, Ernesto; Tseng, Greg Y.; Cheung, Chin-Li; Lieber, Charles M.Science (Washington, D. C.) (2000), 289 (5476), 94-97CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A concept for mol. electronics exploiting carbon nanotubes as both mol. device elements and mol. wires for reading and writing information was developed. Each device element is based on a suspended, crossed nanotube geometry that leads to bistable, electrostatically switchable ON/OFF states. The device elements are naturally addressable in large arrays by the carbon nanotube mol. wires making up the devices. These reversible, bistable device elements could be used to construct nonvolatile random access memory and logic function tables at an integration level approaching 10z1 elements per square centimeter and an element operation frequency in excess of 100 GHz. The viability of this concept is demonstrated by detailed calcns. and by the exptl. realization of a reversible, bistable nanotube-based bit.
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38Wu, Z.; Chen, Z.; Du, X.; Logan, J. M.; Sippel, J.; Nikolou, M.; Kamaras, K.; Reynolds, J. R.; Tanner, D. B.; Hebard, A. F.; Rinzler, A. G. Science 2004, 305, 1273Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmvFCitrg%253D&md5=6c6d43a612b45bff28d396e9fc213463Transparent, conductive carbon nanotube filmsWu, Zhuangchun; Chen, Zhihong; Du, Xu; Logan, Jonathan M.; Sippel, Jennifer; Nikolou, Maria; Kamaras, Katalin; Reynolds, John R.; Tanner, David B.; Hebard, Arthur F.; Rinzler, Andrew G.Science (Washington, DC, United States) (2004), 305 (5688), 1273-1277CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)The authors describe a simple process for the fabrication of ultrathin, transparent, optically homogeneous, elec. conducting films of pure single-walled carbon nanotubes and the transfer of those films to various substrates. For equivalent sheet resistance, the films exhibit optical transmittance comparable to that of com. indium tin oxide in the visible spectrum, but far superior transmittance in the technol. relevant 2- to 5-μm IR spectral band. These characteristics indicate broad applicability of the films for elec. coupling in photonic devices. In an example application, the films are used to construct an elec. field-activated optical modulator, which constitutes an optical analog to the nanotube-based field effect transistor.
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39Jensen, K.; Weldon, J.; Garcia, H.; Zettl, A. Nano Lett. 2007, 7, 3508Google ScholarThere is no corresponding record for this reference.
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40De, S.; King, P. J.; Lyons, P. E.; Khan, U.; Coleman, J. N. ACS Nano 2010, 4, 7064Google ScholarThere is no corresponding record for this reference.
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41Ionescu, A. M.; Riel, H. Nature 2011, 479, 329Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVykt7%252FM&md5=3663dce27097f959baeca512b5eb9699Tunnel field-effect transistors as energy-efficient electronic switchesIonescu, Adrian M.; Riel, HeikeNature (London, United Kingdom) (2011), 479 (7373), 329-337CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)A review. Power dissipation is a fundamental problem for nanoelectronic circuits. Scaling the supply voltage reduces the energy needed for switching, but the field-effect transistors (FETs) in today's integrated circuits require at least 60 mV of gate voltage to increase the current by one order of magnitude at room temp. Tunnel FETs avoid this limit by quantum-mech. band-to-band tunneling, rather than thermal injection, to inject charge carriers into the device channel. Tunnel FETs based on ultrathin semiconducting films or nanowires could achieve a 100-fold power redn. over complementary metal-oxide-semiconductor (CMOS) transistors, so integrating tunnel FETs with CMOS technol. could improve low-power integrated circuits.
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42McCarthy, M. A.; Liu, B.; Donoghue, E. P.; Kravchenko, I.; Kim, D. Y.; So, F.; Rinzler, A. G. Science 2011, 332, 570Google ScholarThere is no corresponding record for this reference.
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43Sun, D. M.; Timmermans, M. Y.; Tian, Y.; Nasibulin, A. G.; Kauppinen, E. I.; Kishimoto, S.; Mizutani, T.; Ohno, Y. Nat. Nanotechnol. 2011, 6, 156Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXislCjsr4%253D&md5=ff563715f3dcd538287a068b2388d221Flexible high-performance carbon nanotube integrated circuitsSun, Dong-ming; Timmermans, Marina Y.; Tian, Ying; Nasibulin, Albert G.; Kauppinen, Esko I.; Kishimoto, Shigeru; Mizutani, Takashi; Ohno, YutakaNature Nanotechnology (2011), 6 (3), 156-161CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)C nanotube thin-film transistors are expected to enable the fabrication of high-performance, flexible and transparent devices using relatively simple techniques. However, as-grown nanotube networks usually contain both metallic and semiconducting nanotubes, which leads to a trade-off between charge-carrier mobility (which increases with greater metallic tube content) and on/off ratio (which decreases). Many approaches to sepg. metallic nanotubes from semiconducting nanotubes were investigated, but most lead to contamination and shortening of the nanotubes, thus reducing performance. Here, we report the fabrication of high-performance thin-film transistors and integrated circuits on flexible and transparent substrates using floating-catalyst CVD followed by a simple gas-phase filtration and transfer process. The resulting nanotube network has a well-controlled d. and a unique morphol., consisting of long (∼10 μm) nanotubes connected by low-resistance Y-shaped junctions. The transistors simultaneously demonstrate a mobility of 35 cm2 V-1 s-1 and an on/off ratio of 6 × 106. We also demonstrate flexible integrated circuits, including a 21-stage ring oscillator and master-slave delay flip-flops that are capable of sequential logic. Our fabrication procedure should prove to be scalable, for example, by high-throughput printing techniques.
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44Franklin, A. D.; Luisier, M.; Han, S. J.; Tulevski, G.; Breslin, C. M.; Gignac, L.; Lundstrom, M. S.; Haensch, W. Nano Lett. 2012, 12, 758Google ScholarThere is no corresponding record for this reference.
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45Park, H.; Afzali, A.; Han, S. J.; Tulevski, G. S.; Franklin, A. D.; Tersoff, J.; Hannon, J. B.; Haensch, W. Nat. Nanotechnol. 2012, 7, 787Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFOmt7jL&md5=9d67e1b6645e60c0a504a343b76d5bbbHigh-density integration of carbon nanotubes via chemical self-assemblyPark, Hongsik; Afzali, Ali; Han, Shu-Jen; Tulevski, George S.; Franklin, Aaron D.; Tersoff, Jerry; Hannon, James B.; Haensch, WilfriedNature Nanotechnology (2012), 7 (12), 787-791CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Carbon nanotubes have potential in the development of high-speed and power-efficient logic applications. However, for such technologies to be viable, a high d. of semiconducting nanotubes must be placed at precise locations on a substrate. Here, we show that ion-exchange chem. can be used to fabricate arrays of individually positioned carbon nanotubes with a d. as high as 1 × 109 cm-2 two orders of magnitude higher than previous reports. With this approach, we assembled a high d. of carbon-nanotube transistors in a conventional semiconductor fabrication line and then elec. tested more than 10,000 devices in a single chip. The ability to characterize such large distributions of nanotube devices is crucial for analyzing transistor performance, yield and semiconducting nanotube purity.
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46Matsumoto, T.; Komatsu, T.; Arai, K.; Yamazaki, T.; Kijima, M.; Shimizu, H.; Takasawa, Y.; Nakamura, J. Chem. Commun. (Cambridge, U.K.) 2004, 7, 840Google ScholarThere is no corresponding record for this reference.
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47Holt, J. K.; Park, H. G.; Wang, Y.; Stadermann, M.; Artyukhin, A. B.; Grigoropoulos, C. P.; Noy, A.; Bakajin, O. Science 2006, 312, 1034Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xks1Wqtbg%253D&md5=93fb0c4e67412ab4c9538ddb961d09e5Fast Mass Transport Through Sub-2-Nanometer Carbon NanotubesHolt, Jason K.; Park, Hyung Gyu; Wang, Yinmin; Stadermann, Michael; Artyukhin, Alexander B.; Grigoropoulos, Costas P.; Noy, Aleksandr; Bakajin, OlgicaScience (Washington, DC, United States) (2006), 312 (5776), 1034-1037CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)We report gas and water flow measurements through microfabricated membranes in which aligned carbon nanotubes with diams. of less than 2 nm serve as pores. The measured gas flow exceeds predictions of the Knudsen diffusion model by more than an order of magnitude. The measured water flow exceeds values calcd. from continuum hydrodynamics models by more than three orders of magnitude and is comparable to flow rates extrapolated from mol. dynamics simulations. The gas and water permeabilities of these nanotube-based membranes are several orders of magnitude higher than those of com. polycarbonate membranes, despite having pore sizes an order of magnitude smaller. These membranes enable fundamental studies of mass transport in confined environments, as well as more energy-efficient nanoscale filtration.
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48Vaezzadeh, M.; Saeedi, M. R.; Barghi, T.; Sadeghi, M. R. Chem. Cent. J. 2007, 1, 22Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2snmvFyhug%253D%253D&md5=f4dd961e6371e67aad347fd78a2792daThe necessary length of carbon nanotubes required to optimize solar cellsVaezzadeh Majid; Saeedi Mohammad Reza; Barghi Tirdad; Sadeghi Mohammad RezaChemistry Central journal (2007), 1 (), 22 ISSN:.BACKGROUND: In recent years scientists have been trying both to increase the efficiency of solar cells, whilst at the same time reducing dimensions and costs. Increases in efficiency have been brought about by implanting carbon nanotubes onto the surface of solar cells in order to reduce the reflection of sunrays, as well as through the insertion of polymeric arrays into the intrinsic layer for charge separation. RESULTS: The experimental results show power rising linearly for intrinsic layer thicknesses between 0-50 nm. Wider thicknesses increase the possibility of recombination of electrons and holes, leading to perturbation of the linear behaviour of output power. This effect is studied and formulated as a function of thickness. Recognition of the critical intrinsic layer thickness can permit one to determine the length of carbon nanotube necessary for optimizing solar cells. CONCLUSION: In this study the behaviour of output power as a function of intrinsic layer thicknesses has been described physically and also simulated. In addition, the implantation of carbon nanotubes into the intrinsic layer and the necessary nanotube length required to optimize solar cells have been suggested.
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49Gabor, N. M.; Zhong, Z.; Bosnick, K.; Park, J.; McEuen, P. L. Science 2009, 325, 1367Google ScholarThere is no corresponding record for this reference.
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50Le Goff, A.; Artero, V.; Jousselme, B.; Tran, P. D.; Guillet, N.; Métayé, R.; Fihri, A.; Palacin, S.; Fontecave, M. Science 2009, 326, 1384Google ScholarThere is no corresponding record for this reference.
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51Jain, R. M.; Howden, R.; Tvrdy, K.; Shimizu, S.; Hilmer, A. J.; McNicholas, T. P.; Gleason, K. K.; Strano, M. S. Adv. Mater. 2012, 24, 4436Google ScholarThere is no corresponding record for this reference.
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52Calkins, J. O.; Umasankar, Y.; O’Neill, H.; Ramasamy, R. P. Energy Environ. Sci. 2013, 6, 1891Google ScholarThere is no corresponding record for this reference.
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53Shi Kam, N. W.; Jessop, T. C.; Wender, P. A.; Dai, H. J. Am. Chem. Soc. 2004, 126, 6850Google ScholarThere is no corresponding record for this reference.
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54Demming, A. Nanotechnology 2011, 22, 260201Google ScholarThere is no corresponding record for this reference.
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55Yang, F.; Jin, C.; Yang, D.; Jiang, Y.; Li, J.; Di, Y.; Hu, J.; Wang, C.; Ni, Q.; Fu, D. Eur. J. Cancer 2011, 47, 1873Google ScholarThere is no corresponding record for this reference.
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56Murakami, T.; Nakatsuji, H.; Inada, M.; Matoba, Y.; Umeyama, T.; Tsujimoto, M.; Isoda, S.; Hashida, M.; Imahori, H. J. Am. Chem. Soc. 2012, 134, 17862Google ScholarThere is no corresponding record for this reference.
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57Antaris, A. L.; Robinson, J. T.; Yaghi, O. K.; Hong, G.; Diao, S.; Luong, R.; Dai, H. ACS Nano 2013, 7, 3644Google ScholarThere is no corresponding record for this reference.
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58Saito, N.; Usui, Y.; Aoki, K.; Narita, N.; Shimizu, M.; Ogiwara, N.; Nakamura, K.; Ishigaki, N.; Kato, H.; Taruta, S.; Endo, M. Curr. Med. Chem. 2008, 15, 523Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnsVyisbo%253D&md5=7106e9db53f9b525e4d553046d0599c7Carbon nanotubes for biomaterials in contact with boneSaito, Naoto; Usui, Yuki; Aoki, Kaoru; Narita, Nobuyo; Shimizu, Masayuki; Ogiwara, Nobuhide; Nakamura, Koichi; Ishigaki, Norio; Kato, Hiroyuki; Taruta, Seiichi; Endo, MorinobuCurrent Medicinal Chemistry (2008), 15 (5), 523-527CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. Carbon nanotubes (CNTs) possess exceptional mech., thermal, and elec. properties, facilitating their use as reinforcements or additives in various materials to improve the properties of the materials. Furthermore, chem. modified CNTs can introduce novel functionalities. In the medical field, biomaterials are expected to be developed using CNTs for clin. use. Biomaterials often are placed adjacent to bone. The use of CNTs is anticipated in these biomaterials applied to bone mainly to improve their overall mech. properties, for applications such as high-strength arthroplasty prostheses or fixation plates and screws that will not fail. In addn., CNTs are expected to be used as local drug delivery systems (DDS) and/or scaffolds to promote and guide bone tissue regeneration. However, studies examg. the use of CNTs as biomaterials still are in the preliminary stages. In particular, the influence of CNTs on osteoblastic cells or bone tissue is extremely important for the use of CNTs in biomaterials placed in contact with bone, and some studies have explored this. This review paper clarifies the current state of knowledge in the context of the relationship between CNTs and bone to det. whether CNTs might perform in biomaterials in contact with bone, or as a DDS and/or scaffolding for bone regeneration.
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59Jin, G. Z.; Kim, M.; Shin, U. S.; Kim, H. W. Neurosci. Lett. 2011, 501, 10Google ScholarThere is no corresponding record for this reference.
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60Shokrgozar, M. A.; Mottaghitalab, F.; Mottaghitalab, V.; Farokhi, M. J. Biomed. Nanotechnol. 2011, 7, 276Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnt1Khtr8%253D&md5=c07a89a75ad60160be63d81f27fc70e9Fabrication of porous chitosan/poly(vinyl alcohol) reinforced single-walled carbon nanotube nanocomposites for neural tissue engineeringShokrgozar, Mohammad Ali; Mottaghitalab, Fatemeh; Mottaghitalab, Vahid; Farokhi, MehdiJournal of Biomedical Nanotechnology (2011), 7 (2), 276-284CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)With the ability to form a nano-sized fibrous structure with large pore sizes mimicking the extracellular matrix (ECM), electrospinning was used to fabricate chitosan/poly(vinyl alc.) nanofibers reinforced by single-walled carbon nanotube (SWNT-CS/PVA) for potential use in neural tissue engineering. Moreover, ultrasonication was performed to fabricate highly dispersed SWNT/CS soln. with 7%, 12%, and 17% SWNT content prior to electrospinning process. In the present study, a no. of properties of CS/PVA reinforced SWNTs nanocomposites were evaluated. The in vitro biocompatibility of the electrospun fiber mats was also assessed using human brain-derived cells and U373 cell lines. The results have shown that SWNTs as reinforcing phase can augment the morphol., porosity, and structural properties of CS/PVA nanofiber composites and thus benefit the proliferation rate of both cell types. In addn., the cells exhibit their normal morphol. while integrating with surrounding fibers. The results confirmed the potential of SWNT-CS/PVA nanocomposites as scaffold for neural tissue engineering.
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61Lee, S.; Hahm, M. G.; Vajtai, R.; Hashim, D. P.; Thurakitseree, T.; Chipara, A. C.; Ajayan, P. M.; Hafner, J. H. Adv. Mater. 2012, 24, 5261Google ScholarThere is no corresponding record for this reference.
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62Cheng, Q.; Rutledge, K.; Jabbarzadeh, E. Ann. Biomed. Eng. 2013, 41, 904Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s3mt1agsw%253D%253D&md5=76d27ec86e4bab911bb5913496d7ac85Carbon nanotube-poly(lactide-co-glycolide) composite scaffolds for bone tissue engineering applicationsCheng Qingsu; Rutledge Katy; Jabbarzadeh EhsanAnnals of biomedical engineering (2013), 41 (5), 904-16 ISSN:.Despite their indisputable clinical value, current tissue engineering strategies face major challenges in recapitulating the natural nano-structural and morphological features of native bone. The aim of this study is to take a step forward by developing a porous scaffold with appropriate mechanical strength and controllable surface roughness for bone repair. This was accomplished by homogenous dispersion of carbon nanotubes (CNTs) in a poly(lactide-co-glycolide) (PLGA) solution followed by a solvent casting/particulate leaching scaffold fabrication. Our results demonstrated that CNT/PLGA composite scaffolds possessed a significantly higher mechanical strength as compared to PLGA scaffolds. The incorporation of CNTs led to an enhanced surface roughness and resulted in an increase in the attachment and proliferation of MC3T3-E1 osteoblasts. Most interestingly, the in vitro osteogenesis studies demonstrated a significantly higher rate of differentiation on CNT/PLGA scaffolds compared to the control PLGA group. These results all together demonstrate the potential of CNT/PLGA scaffolds for bone tissue engineering as they possess the combined effects of mechanical strength and osteogenicity.
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63Dorj, B.; Won, J. E.; Kim, J. H.; Choi, S. J.; Shin, U. S.; Kim, H. W. J. Biomed. Mater. Res. A 2013, 101, 1670Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlslyhu7g%253D&md5=2b8b59af6b402a11557d9a9a86f6fb4cRobocasting nanocomposite scaffolds of poly(caprolactone)/hydroxyapatite incorporating modified carbon nanotubes for hard tissue reconstructionDorj, Biligzaya; Won, Jong-Eun; Kim, Joong-Hyun; Choi, Seong-Jun; Shin, Ueon Sang; Kim, Hae-WonJournal of Biomedical Materials Research, Part A (2013), 101A (6), 1670-1681CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Nanocomposite scaffolds with tailored 3D pore configuration are promising candidates for the reconstruction of bone. Here we fabricated novel nanocomposite bone scaffolds through robocasting. Poly(caprolactone) (PCL)-hydroxyapatite (HA) slurry contg. ionically modified carbon nanotubes (imCNTs) was robotic-dispensed and structured layer-by-layer into macrochanneled 3D scaffolds under adjusted processing conditions. Homogeneous dispersion of imCNTs (0.2 wt. % relative to PCL-HA) was achieved in acetone, aiding in the prepn. of PCL-HA-imCNTs slurry with good mixing property. Incorporation of imCNTs into PCL-HA compn. significantly improved the compressive strength and elastic modulus of the robotic-dispensed scaffolds (∼1.5-fold in strength and ∼2.5-fold in elastic modulus). When incubated in simulated body fluid (SBF), PCL-HA-imCNT nanocomposite scaffold induced substantial mineralization of apatite in a similar manner to the PCL-HA scaffold, which was contrasted in pure PCL scaffold. MC3T3-E1 cell culture on the scaffolds demonstrated that cell proliferation levels were significantly higher in both PCL-HA-imCNT and PCL-HA than in pure PCL, and no significant difference was found between the nanocomposite scaffolds. When the PCL-HA-imCNT scaffold was implanted into a rat s.c. tissue for 4 wk, soft fibrous tissues with neo-blood vessels formed well in the pore channels of the scaffolds without any significant inflammatory signs. Tissue reactions in PCL-HA-imCNT scaffold were similar to those in PCL-HA scaffold, suggesting incorporated imCNT did not negate the beneficial biol. roles of HA. While more long-term in vivo research in bone defect models is needed to confirm clin. availability, our results suggest robotic-dispensed PCL-HA-imCNT nanocomposite scaffolds can be considered promising new candidate matrixes for bone regeneration. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.
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64Kealley, C. S.; Latella, B. A.; van Riessen, A.; van Elcombe, M. M.; Ben-Nissan, B. J. Nanosci. Nanotechnol. 2008, 8, 3936Google ScholarThere is no corresponding record for this reference.
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65Joshi, B.; Gupta, S.; Kalra, N.; Gudyka, R.; Santhanam, K. S. J. Nanosci. Nanotechnol. 2010, 10, 3799Google ScholarThere is no corresponding record for this reference.
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66Lee, H. H.; Sang Shin, U.; Lee, J. H.; Kim, H. W. J. Biomed. Mater. Res., Part B 2011, 98B, 246Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXotl2rtL0%253D&md5=0a46885b83014f5773f0b51b84421a30Biomedical nanocomposites of poly(lactic acid) and calcium phosphate hybridized with modified carbon nanotubes for hard tissue implantsLee, Hae-Hyoung; Sang Shin, Ueon; Lee, Jae-Ho; Kim, Hae-WonJournal of Biomedical Materials Research, Part B: Applied Biomaterials (2011), 98B (2), 246-254CODEN: JBMRGL; ISSN:1552-4973. (John Wiley & Sons, Inc.)Degradable polymer-based materials are attractive in orthopedics and dentistry as an alternative to metallic implants for use as bone fixatives. Herein, a degradable polymer poly(lactic acid) (PLA) was combined with novel hybrid nanopowder of carbon nanotubes (CNTs)-calcium phosphate (CP) for this application. In particular, CNTs-CP hybrid nanopowders (0.1 and 0.25% CNTs) were prepd. from the soln. of ionically modified CNTs (mCNTs), which was specifically synthesized to be well-dispersed and thus to effectively adsorb onto the CP nanoparticles. The mCNTs-CP hybrid nanopowders were then mixed with PLA (up to 50%) to produce mCNTs-CP-PLA nanocomposites. The mech. tensile strength of the nanocomposites was significantly improved by the addn. of mCNTs-CP hybrid nanopowders. Moreover, nanocomposites contg. low concn. of mCNTs (0.1%) showed significantly stimulated biol. responses including cell proliferation and osteoblastic differentiation in terms of gene and protein expressions. Based on this study, the addn. of novel mCNT-CP hybrid nanopowders to PLA biopolymer may be considered a new material choice for developing hard tissue implants. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2011.
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67Wang, M.; Castro, N. J.; Li, J.; Keidar, M.; Zhang, L. G. J. Nanosci. Nanotechnol. 2012, 12, 7692Google ScholarThere is no corresponding record for this reference.
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68Kostarelos, K.; Bianco, A.; Prato, M. Nat. Nanotechnol. 2009, 4, 627Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1aqsLvN&md5=ea1bbc25d798cd544f9197f339fef6dfPromises, facts and challenges for carbon nanotubes in imaging and therapeuticsKostarelos, K.; Bianco, A.; Prato, M.Nature Nanotechnology (2009), 4 (10), 627-633CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)A review. The use of carbon nanotubes in medicine is now at the crossroads between a proof-of-principle concept and an established preclin. candidate for a variety of therapeutic and diagnostic applications. Progress towards clin. trials will depend on the outcomes of efficacy and toxicol. studies, which will provide the necessary risk-to-benefit assessments for carbon-nanotube-based materials. Here we focus on carbon nanotubes that have been studied in preclin. animal models, and draw attention to the promises, facts and challenges of these materials as they transition from research to the clin. phase. We address common questions regarding the use of carbon nanotubes in disease imaging and therapy, and highlight the opportunities and challenges ahead.
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69Saito, N.; Usui, Y.; Aoki, K.; Narita, N.; Shimizu, M.; Hara, K.; Ogiwara, N.; Nakamura, K.; Ishigaki, N.; Kato, H.; Taruta, S.; Endo, M. Chem. Soc. Rev. 2009, 38, 1897Google ScholarThere is no corresponding record for this reference.
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70Ciofani, G.; Raffa, V.; Vittorio, O.; Cuschieri, A.; Pizzorusso, T.; Costa, M.; Bardi, G. Methods Mol. Biol. 2010, 625, 67Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXoslyqtL0%253D&md5=099402ac722b3f02a13a36e856ced224In vitro and in vivo biocompatibility testing of functionalized carbon nanotubesCiofani, Gianni; Raffa, Vittoria; Vittorio, Orazio; Cuschieri, Alfred; Pizzorusso, Tommaso; Costa, Mario; Bardi, GiuseppeMethods in Molecular Biology (Totowa, NJ, United States) (2010), 625 (Carbon Nanotubes), 67-83CODEN: MMBIED; ISSN:1064-3745. (Humana Press Inc.)The explosive growth of nanotechnol. in the last years has led to dramatic innovations in pharmacol., and it is revolutioning the development of biol. active compds. Carbon nanotubes (CNTs) are widely explored for biomedical applications such as intracellular transporters for (bio)mols., and represent promising future tools for efficient and safe cell therapy. Due to their nanoscale dimensions, the ability to interact with cells, and their easy functionalization, CNTs are close-to-ideal vectors for an efficient and safe cell therapy, obviating the risks assocd. with the use of viral vectors. Notwithstanding, conflicting data concerning the biocompatibility of CNTs have been reported in the literature; while some studies point toward very low toxicity of CNTs both in vitro and in vivo, others reveal various toxic effects such as oxidative stress, DNA damage, and cell apoptosis. Thus, standardized methods and independent test systems are urgently needed to verify cytotoxicity data in this research field. In this chapter, we summarize the used methods and the achieved main results in our labs. concerning multiwalled carbon nanotubes (MWCNTs) biocompatibility studies. The in vitro response of human neuroblastoma cell line and primary mouse neurons was investigated following the exposure to different samples of MWCNTs in order to evaluate their effects on cell viability, oxidative stress, and apoptosis. Moreover, in vivo neurocompatibility tests were carried out through injections in mouse brains.
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71Rodriguez-Fernandez, L.; Valiente, R.; Gonzalez, J.; Villegas, J. C.; Fanarraga, M. L. ACS Nano 2012, 6, 6614Google ScholarThere is no corresponding record for this reference.
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72Lacerda, L.; Bianco, A.; Prato, M.; Kostarelos, K. Adv. Drug Delivery Rev. 2006, 58, 1460Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1KmtLbN&md5=8f92efcc604e233e7251ca06d0e13b8cCarbon nanotubes as nanomedicines: From toxicology to pharmacologyLacerda, Lara; Bianco, Alberto; Prato, Maurizio; Kostarelos, KostasAdvanced Drug Delivery Reviews (2006), 58 (14), 1460-1470CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Various biomedical applications of carbon nanotubes have been proposed in the last few years leading to the emergence of a new field in diagnostics and therapeutics. Most of these applications will involve the administration or implantation of carbon nanotubes and their matrixes into patients. The toxicol. and pharmacol. profile of such carbon nanotube systems developed as nanomedicines will have to be detd. prior to any clin. studies undertaken. This review brings together all the toxicol. and pharmacol. in vivo studies that have been carried out using carbon nanotubes, to offer the first summary of the state-of-the-art in the pharmaceutical development of carbon nanotubes on the road to becoming viable and effective nanomedicines.
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73Pagona, G.; Tagmatarchis, N. Curr. Med. Chem. 2006, 13, 1789Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmtVaisL0%253D&md5=13255d73d02a8fe192c3ce00a461a55aCarbon nanotubes: materials for medicinal chemistry and biotechnological applicationsPagona, Georgia; Tagmatarchis, NikosCurrent Medicinal Chemistry (2006), 13 (15), 1789-1798CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. Carbon nanotubes are considered as mol. wires exhibiting novel properties for diverse applications including medicinal and biotechnol. purposes. Surface chem. on carbon nanotubes results on their solubilization in org. solvents and/or aq./physiol. media. Herein, we will present how interfacing such novel carbon-based nanomaterials with biol. systems may lead to new applications in diagnostics, vaccine and drug delivery. Recent developments in this rapidly growing field will be presented thus suggesting exciting opportunities for the utilization of carbon nanotubes as useful tools for biotechnol. applications. Emphasis will be placed in the integration of biomaterials with carbon nanotubes, which enables the use of such hybrid systems as biosensor devices, immunosensors and DNA-sensors.
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74Soto, K.; Garza, K. M.; Murr, L. E. Acta Biomater. 2007, 3, 351Google ScholarThere is no corresponding record for this reference.
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75Wick, P.; Manser, P.; Limbach, L. K.; Dettlaff-Weglikowska, U.; Krumeich, F.; Roth, S.; Stark, W. J.; Bruinink, A. Toxicol. Lett. 2007, 168, 121Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXltV2nsA%253D%253D&md5=44abfcbb136814539b55711dcf0f1f4eThe degree and kind of agglomeration affect carbon nanotube cytotoxicityWick, Peter; Manser, Pius; Limbach, Ludwig K.; Dettlaff-Weglikowska, Ursula; Krumeich, Frank; Roth, Siegmar; Stark, Wendelin J.; Bruinink, ArieToxicology Letters (2007), 168 (2), 121-131CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)The urgent need for toxicol. studies on carbon nanotubes (CNTs) has arisen from the rapidly emerging applications of CNTs well beyond material science and engineering. In order to provide a basis for comparison to existing epidemiol. data, we have investigated CNTs at various degrees of agglomeration using an in vitro cytotoxicity study with human MSTO-211H cells. Non-cytotoxic polyoxyethylene sorbitan monooleate was found to well-disperse CNT. In the present study, the cytotoxic effects of well-dispersed CNT were compared with that of conventionally purified rope-like agglomerated CNTs and asbestos as a ref. While suspended CNT-bundles were less cytotoxic than asbestos, rope-like agglomerates induced more pronounced cytotoxic effects than asbestos fibers at the same concns. The study underlines the need for thorough materials characterization prior to toxicol. studies and corroborates the role of agglomeration in the cytotoxic effect of nanomaterials.
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76Fraczek, A.; Menaszek, E.; Paluszkiewicz, C.; Blazewicz, M. Acta Biomater. 2008, 4, 1593Google ScholarThere is no corresponding record for this reference.
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77Jain, K. K. Expert Opin. Drug Discovery 2012, 7, 1029Google ScholarThere is no corresponding record for this reference.
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78Ma-Hock, L.; Treumann, S.; Strauss, V.; Brill, S.; Luizi, F.; Mertler, M.; Wiench, K.; Gamer, A. O.; van Ravenzwaay, B.; Landsiedel, R. Toxicol. Sci. 2009, 112, 468Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVajurzI&md5=b87f2d6fb194803700c9803c4f34ad89Inhalation Toxicity of Multiwall Carbon Nanotubes in Rats Exposed for 3 MonthsMa-Hock, Lan; Treumann, Silke; Strauss, Volker; Brill, Sandra; Luizi, Frederic; Mertler, Michael; Wiench, Karin; Gamer, Armin O.; van Ravenzwaay, Bennard; Landsiedel, RobertToxicological Sciences (2009), 112 (2), 468-481CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)Carbon nanotubes (CNT) are of great com. interest. Theor., during processing and handling of CNT and in abrasion processes on composites contg. CNT, inhalable CNT particles might be set free. For hazard assessment, we performed a 90-day inhalation toxicity study with a multiwall CNT (MWCNT) material (Nanocyl NC 7000) according to Organization for Economic Co-operation and Development test guideline 413. Wistar rats were head-nose exposed for 6 h/day, 5 days/wk, 13 wk, total 65 exposures, to MWCNT concns. of 0 (control), 0.1, 0.5, or 2.5 mg/m3. Highly respirable dust aerosols were produced with a proprietary brush generator which neither damaged the tube structure nor increased reactive oxygen species on the surface. Inhalation exposure to MWCNT produced no systemic toxicity. However, increased lung wts., pronounced multifocal granulomatous inflammation, diffuse histocytic and neutrophilic inflammation, and intra-alveolar lipoproteinosis were obsd. in lung and lung-assocd. lymph nodes at 0.5 and 2.5 mg/m3. These effects were accompanied by slight blood neutrophilia at 2.5 mg/m3. Incidence and severity of the effects were concn. related. At 0.1 mg/m3, there was still minimal granulomatous inflammation in the lung and in lung-assocd. lymph nodes; a no obsd. effect concn. was therefore not established in this study. The test substance has low dust-forming potential, as demonstrated by dustiness measurements, but nonetheless strict industrial hygiene measures must be taken during handling and processing. Toxicity and dustiness data such as these can be used to compare different MWCNT materials and to select the material with the lowest risk potential for a given application.
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79Porter, D. W.; Hubbs, A. F.; Mercer, R. R.; Wu, N.; Wolfarth, M. G.; Sriram, K.; Leonard, S.; Battelli, L.; Schwegler-Berry, D.; Friend, S.; Andrew, M.; Chen, B. T.; Tsuruoka, S.; Endo, M.; Castranova, V. Toxicology 2010, 269, 136Google ScholarThere is no corresponding record for this reference.
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80Nagai, H.; Okazaki, Y.; Chew, S. H.; Misawa, N.; Yamashita, Y.; Akatsuka, S.; Ishihara, T.; Yamashita, K.; Yoshikawa, Y.; Yasui, H.; Jiang, L.; Ohara, H.; Takahashi, T.; Ichihara, G.; Kostarelos, K.; Miyata, Y.; Shinohara, H.; Toyokuni, S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, E1330Google ScholarThere is no corresponding record for this reference.
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81Oyabu, T.; Myojo, T.; Morimoto, Y.; Ogami, A.; Hirohashi, M.; Yamamoto, M.; Todoroki, M.; Mizuguchi, Y.; Hashiba, M.; Lee, B. W.; Shimada, M.; Wang, W. N.; Uchida, K.; Endoh, S.; Kobayashi, N.; Yamamoto, K.; Fujita, K.; Mizuno, K.; Inada, M.; Nakazato, T.; Nakanishi, J.; Tanaka, I. Inhalation Toxicol. 2011, 23, 784Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlyjsb7F&md5=cddb6a34ef5d1fddf9700805d4d7013dBiopersistence of inhaled MWCNT in rat lungs in a 4-week well-characterized exposureOyabu, Takako; Myojo, Toshihiko; Morimoto, Yasuo; Ogami, Akira; Hirohashi, Masami; Yamamoto, Makoto; Todoroki, Motoi; Mizuguchi, Yohei; Hashiba, Masayoshi; Lee, Byeong Woo; Shimada, Manabu; Wang, Wei-Ning; Uchida, Kunio; Endoh, Shigehisa; Kobayashi, Norihiro; Yamamoto, Kazuhiro; Fujita, Katsuhide; Mizuno, Kohei; Inada, Masaharu; Nakazato, Tetsuya; Nakanishi, Junko; Tanaka, IsamuInhalation Toxicology (2011), 23 (13), 784-791CODEN: INHTE5; ISSN:0895-8378. (Informa Healthcare)It is important to conduct a risk assessment that includes hazard assessment and exposure assessment for the safe prodn. and handling of newly developed nanomaterials. We conducted an inhalation study of a multi-wall carbon nanotube (MWCNT) as a hazard assessment. Male Wistar rats were exposed to well-dispersed MWCNT for 4 wk by whole body inhalation. The exposure concn. in the chamber was 0.37 ± 0.18 mg/m3. About 70% of the MWCNTs in the chamber were single fiber. The geometric mean diam. (geometric std. deviation, GSD) and geometric mean length (GSD) of the aerosolized MWCNTs in the chamber were 63 nm (1.5) and 1.1 μm (2.7), resp. The amts. of MWCNT deposited in the rat lungs were detd. by the x-ray diffraction method and elemental C anal. The av. deposited amts. at 3 days after the inhalation were 68 μg/lung by the x-ray diffraction method and 76 μg/lung by elemental C anal. The calcd. deposition fractions were 18% and 20% in each anal. The amt. of retained MWCNT in the lungs until 3 mo after the inhalation decreased exponentially and the calcd. biol. half times of MWCNT were 51 days and 54 days, resp. The clearance was not delayed, but a slight increase in lung wt. at 3 days after the inhalation was obsd.
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82Delorme, M. P.; Muro, Y.; Arai, T.; Banas, D. A.; Frame, S. R.; Reed, K. L.; Warheit, D. B. Toxicol. Sci. 2012, 128, 449Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1enurbL&md5=c658cc064f3366f3c60081f58bf98563Ninety-Day Inhalation Toxicity Study With A Vapor Grown Carbon Nanofiber in RatsDeLorme, Michael P.; Muro, Yukihiro; Arai, Toshihiro; Banas, Deborah A.; Frame, Steven R.; Reed, Kenneth L.; Warheit, David B.Toxicological Sciences (2012), 128 (2), 449-460CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)A subchronic inhalation toxicity study of inhaled vapor grown carbon nanofibers (CNF) (VGCF-H) was conducted in male and female Sprague Dawley rats. The CNF test sample was composed of > 99.5% carbon with virtually no catalyst metals; Brunauer, Emmett, and Teller (BET) surface area measurements of 13.8 m2/g; and mean lengths and diams. of 5.8 μm and 158 nm, resp. Four groups of rats per sex were exposed nose-only, 6 h/day, for 5 days/wk to target concns. of 0, 0.50, 2.5, or 25 mg/m3 VGCF-H over a 90-day period and evaluated 1 day later. Assessments included conventional clin. and histopathol. methods, bronchoalveolar lavage fluid (BALF) anal., and cell proliferation (CP) studies of the terminal bronchiole (TB), alveolar duct (AD), and subpleural regions of the respiratory tract. In addn., groups of 0 and 25 mg/m3 exposed rats were evaluated at 3 mo postexposure (PE). Aerosol exposures of rats to 0.54 (4.9 f/cc), 2.5 (56 f/cc), and 25 (252 f/cc) mg/m3 of VGCF-H CNFs produced concn.-related small, detectable accumulation of extrapulmonary fibers with no adverse tissue effects. At the two highest concns., inflammation of the TB and AD regions of the respiratory tract was noted wherein fiber-laden alveolar macrophages had accumulated. This finding was characterized by minimal infiltrates of inflammatory cells in rats exposed to 2.5mg/m3 CNF, inflammation along with some thickening of interstitial walls, and hypertrophy/hyperplasia of type II epithelial cells, graded as slight for the 25mg/m3 concn. At 3 mo PE, the inflammation in the high dose was reduced. No adverse effects were obsd. at 0.54mg/m3. BALF and CP endpoint increases vs. controls were noted at 25mg/m3 VGCF-H but not different from control values at 0.54 or 2.5mg/m3. After 90 days PE, BALF biomarkers were still increased at 25mg/m3, indicating that the inflammatory response was not fully resolved. Greater than 90% of CNF-exposed, BALF-recovered alveolar macrophages from the 25 and 2.5mg/m3 exposure groups contained nanofibers (> 60% for 0.5mg/m3). A nonspecific inflammatory response was also noted in the nasal passages. The no-obsd.-adverse-effect level for VGCF-H nanofibers was considered to be 0.54mg/m3 (4.9 fibers/cc) for male and female rats, based on the minimal inflammation in the terminal bronchiole and alveolar duct areas of the lungs at 2.5mg/m3 exposures. It is noteworthy that the histopathol. observations at the 2.5mg/m3 exposure level did not correlate with the CP or BALF data at that exposure concn. In addn., the results with CNF are compared with published findings of 90-day inhalation studies in rats with carbon nanotubes, and hypotheses are presented for potency differences based on CNT physicochem. characteristics. Finally, the (lack of) relevance of CNF for the high aspect ratio nanomaterials/fiber paradigm is discussed.
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83Xu, J.; Futakuchi, M.; Shimizu, H.; Alexander, D. B.; Yanagihara, K.; Fukamachi, K.; Suzui, M.; Kanno, J.; Hirose, A.; Ogata, A.; Sakamoto, Y.; Nakae, D.; Omori, T.; Tsuda, H. Cancer Sci. 2012, 103, 2045Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslOlsrbL&md5=feb9bff89dd33afca838221fe46b4b39Multi-walled carbon nanotubes translocate into the pleural cavity and induce visceral mesothelial proliferation in ratsXu, Jiegou; Futakuchi, Mitsuru; Shimizu, Hideo; Alexander, David B.; Yanagihara, Kazuyoshi; Fukamachi, Katsumi; Suzui, Masumi; Kanno, Jun; Hirose, Akihiko; Ogata, Akio; Sakamoto, Yoshimitsu; Nakae, Dai; Omori, Toyonori; Tsuda, HiroyukiCancer Science (2012), 103 (12), 2045-2050CODEN: CSACCM; ISSN:1349-7006. (Wiley-Blackwell)Multi-walled C nanotubes have a fibrous structure similar to asbestos and induce mesothelioma when injected into the peritoneal cavity. In the present study, we investigated whether C nanotubes administered into the lung through the trachea induce mesothelial lesions. Male F344 rats were treated with 0.5 mL of 500 μg/mL suspensions of multi-walled C nanotubes or crocidolite 5 times over a 9-day period by intrapulmonary spraying. Pleural cavity lavage fluid, lung and chest wall were then collected. Multi-walled carbon nanotubes and crocidolite were found mainly in alveolar macrophages and mediastinal lymph nodes. Importantly, the fibers were also found in the cell pellets of the pleural cavity lavage, mostly in macrophages. Both multi-walled C nanotube and crocidolite treatment induced hyperplastic proliferative lesions of the visceral mesothelium, with their proliferating cell nuclear antigen indexes approx. 10-fold that of the vehicle control. The hyperplastic lesions were assocd. with inflammatory cell infiltration and inflammation-induced fibrotic lesions of the pleural tissues. The fibers were not found in the mesothelial proliferative lesions themselves. In the pleural cavity, abundant inflammatory cell infiltration, mainly composed of macrophages, was obsd. Conditioned cell culture media of macrophages treated with multi-walled carbon nanotubes and crocidolite and the supernatants of pleural cavity lavage fluid from the dosed rats increased mesothelial cell proliferation in vitro, suggesting that mesothelial proliferative lesions were induced by inflammatory events in the lung and pleural cavity and likely mediated by macrophages. In conclusion, intrapulmonary administration of multi-walled carbon nanotubes, like asbestos, induced mesothelial proliferation potentially assocd. with mesothelioma development.
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84Usui, Y.; Haniu, H.; Tsuruoka, S.; Saito, N. Med. Chem. 2012, 2, 105Google ScholarThere is no corresponding record for this reference.
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85Fiorito, S.; Serafino, A.; Andreola, F.; Togna, A.; Togna, G. J. Nanosci. Nanotechnol. 2006, 6, 591Google ScholarThere is no corresponding record for this reference.
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86Liu, Z.; Davis, C.; Cai, W.; He, L.; Chen, X.; Dai, H. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 1410Google ScholarThere is no corresponding record for this reference.
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87Schipper, M. L.; Nakayama-Ratchford, N.; Davis, C. R.; Kam, N. W.; Chu, P.; Liu, Z.; Sun, X.; Dai, H.; Gambhir, S. S. Nat. Nanotechnol. 2008, 3, 216Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXkt1Slu7w%253D&md5=814b1f01559c4f5071a5b81c4e94c64aA pilot toxicology study of single-walled carbon nanotubes in a small sample of miceSchipper, Meike L.; Nakayama-Ratchford, Nozomi; Davis, Corrine R.; Kam, Nadine Wong Shi; Chu, Pauline; Liu, Zhuang; Sun, Xiaoming; Dai, Hongjie; Gambhir, Sanjiv S.Nature Nanotechnology (2008), 3 (4), 216-221CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Single-walled carbon nanotubes are currently under evaluation in biomedical applications, including in vivo delivery of drugs, proteins, peptides, and nucleic acids (for gene transfer or gene silencing), in vivo tumor imaging, and tumor targeting of single-walled carbon nanotubes as an antineoplastic treatment. However, concerns about the potential toxicity of single-walled carbon nanotubes have been raised. Here the authors examine the acute and chronic toxicity of functionalized single-walled carbon nanotubes when injected into the bloodstream of mice. Survival, clin., and lab. parameters reveal no evidence of toxicity over 4 mo. Upon killing, careful necropsy and tissue histol. show age-related changes only. Histol. and Raman microscopic mapping demonstrate that functionalized single-walled carbon nanotubes persisted within liver and spleen macrophages for 4 mo without apparent toxicity. Although this is a preliminary study with a small group of animals, the results encourage further confirmation studies with larger groups of animals.
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88Lee, Y.; Geckeler, K. E. Adv. Mater. 2010, 22, 4076Google ScholarThere is no corresponding record for this reference.
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89Beg, S.; Rizwan, M.; Sheikh, A. M.; Hasnain, M. S.; Anwer, K.; Kohli, K. J. Pharm. Pharmacol. 2011, 63, 141Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsl2qsb8%253D&md5=f800be62875197edd899cef00929df25Advancement in carbon nanotubes: basics, biomedical applications and toxicityBeg, Sarwar; Rizwan, Mohammad; Sheikh, Asif M.; Hasnain, M. Saquib; Anwer, Khalid; Kohli, KanchanJournal of Pharmacy and Pharmacology (2011), 63 (2), 141-163CODEN: JPPMAB; ISSN:0022-3573. (John Wiley & Sons Ltd.)A review. Objectives Carbon nanotubes (CNTs) have attracted much attention by researchers worldwide in recent years for their small dimensions and unique architecture, and for having immense potential in nanomedicine as biocompatible and supportive substrates, as a novel tool for the delivery of therapeutic mols. including peptides, RNA and DNA, and also as sensors, actuators and composites. Key findings CNTs have been employed in the development of mol. electronic, composite materials and others due to their unique at. structure, high surface area-to-vol. ratio and excellent electronic, mech. and thermal properties. Recently they have been exploited as novel nanocarriers in drug delivery systems and biomedical applications. Their larger inner vol. as compared with the dimensions of the tube and easy immobilization of their outer surface with biocompatible materials make CNTs a superior nanomaterial for drug delivery. Literature reveals that CNTs are versatile carriers for controlled and targeted drug delivery, esp. for cancer cells, because of their cell membrane penetrability. Summary This review enlightens the biomedical application of CNTs with special emphasis on utilization in controlled and targeted drug delivery, as a diagnostics tool and other possible uses in therapeutic systems. The review also focuses on the toxicity aspects of CNTs, and revealed that genotoxic potential, mutagenic and carcinogenic effects of different types of CNTs must be explored and overcome by formulating safe biomaterial for drug delivery. The review also describes the regulatory aspects and clin. and market status of CNTs.
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90Lanone, S.; Boczkowski, J. Curr. Mol. Med. 2006, 6, 651Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XosVeksbo%253D&md5=0358c92e1516daa1f126c10e6c44fbc1Biomedical applications and potential health risks of nanomaterials: molecular mechanismsLanone, Sophie; Boczkowski, JorgeCurrent Molecular Medicine (2006), 6 (6), 651-663CODEN: CMMUBP; ISSN:1566-5240. (Bentham Science Publishers Ltd.)A review. Nanotechnologies, defined as techniques aimed to conceive, characterize and produce material at the nanometer scale, represent a fully expanding domain, and one can predict without risk that prodn. and utilization of nanomaterials will increase exponentially in the coming years. Applications of nanotechnologies are numerous, in const. development, and their potential use in the medical field as diagnosis and therapeutics tools is very attractive. The size particularity of these nanomaterials gives them novel properties, allowing them to adopt new comportments because of the laws of quantum physics that exist at this scale. However, worries are expressed regarding the exact properties that make these nanomaterials attractive, and questions are raised regarding their potential toxicity, their long-term secondary effects or their biodegradability, particularly when thinking of their use in the (nano)medical field. These questions are justified by the knowledge of the toxic effects of atm. pollution micrometric particles on health, and the fear to get an amplification of these effects because of the size of the materials blamed. In this paper, the authors first expose the sensed medical applications of nanomaterials, and the physicochem. and mol. determinants potentially responsible for nanomaterials biol. effects. Finally, the authors present a synthesis of the actual knowledge regarding toxicol. effects of nanomaterials. It is clear that, in regard to the almost empty field of what is known on the subject, there's an urge to better understand biol. effects of nanomaterials, which will allow their safe use, in particular in the nanomedicine field.
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91Firme, C. P., III; Bandaru, P. R. Nanomedicine 2010, 6, 245Google ScholarThere is no corresponding record for this reference.
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92Alberts, B.; Bray, D.; Hopkin, K.; Johnson, A.; Lewis, J.; Raff, M.; Roberts, K.; Walter, P. Essential Cell Biology, 3rd ed.; Garland Science: New York, 2010.Google ScholarThere is no corresponding record for this reference.
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93Cook, S. D.; Beckenbaugh, R. D.; Redondo, J.; Popich, L. S.; Klawitter, J. J.; Linscheid, R. L. J. Bone Jt. Surg., Am. Vol. 1999, 81, 635Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1M3oslCgtQ%253D%253D&md5=4014804b9b5cdbae2a6ee0257da571d1Long-term follow-up of pyrolytic carbon metacarpophalangeal implantsCook S D; Beckenbaugh R D; Redondo J; Popich L S; Klawitter J J; Linscheid R LThe Journal of bone and joint surgery. American volume (1999), 81 (5), 635-48 ISSN:0021-9355.BACKGROUND: The metacarpophalangeal joint is the most commonly involved joint when rheumatoid arthritis affects the hand. Many prosthetic implants have been designed for the replacement of this joint. Although studies of these implants have shown relief of pain, they have generally demonstrated a poor range of motion, progression of ulnar drift, and bone loss, as well as failure, fracture, and dislocation of the implant. METHODS: From December 1979 to February 1987, 151 pyrolytic carbon metacarpophalangeal implants were inserted in fifty-three patients. The implants had an articulating, unconstrained design with a hemispherical head and grooved, offset stems. Forty-four patients had rheumatoid arthritis; five, posttraumatic arthritis; three, osteoarthritis; and one, systemic lupus erythematosus. Three patients (eleven implants) were lost to long-term follow-up, and twenty patients (fifty-one functioning implants) died after the implant had been in situ for an average of 7.2 years. Eighteen implants (12 percent) in eleven patients were revised. Fourteen of the eighteen implants were replaced with a silicone-elastomer or another type of implant, and the remaining four were removed and a pyrolytic carbon implant was reinserted with the addition of bone cement or bone graft, or both. Twenty-six patients (seventy-one implants) were available for long-term review at an average of 11.7 years (range, 10.1 to 16.0 years) after implantation. RESULTS: The implants improved the arc of motion of the fingers by an average of 13 degrees and elevated the arc by an average of 16 degrees. As a result, fingers were in a more functional, extended position. A complete set of preoperative, postoperative, and follow-up radiographs was available for fifty-three of the seventy-one implants that were followed long term. There was a high prevalence of joint stability: fifty (94 percent) of the fifty-three implants were in a reduced position postoperatively, and forty-one (82 percent) of those fifty implants were still in the postoperative reduced position at the time of long-term follow-up. Ulnar deviation averaged 20 degrees preoperatively and 19 degrees at the time of follow-up, with only the long finger having an increase in deviation. No adverse remodeling or resorption of bone was seen. Fifty (94 percent) of the fifty-three implants had evidence of osseointegration, with sclerosis around the end and shaft of the prosthetic stems. Radiolucent changes were seen adjacent to twelve implants. There was minimum-to-moderate subsidence (four millimeters or less) of thirty-four implants; most of the subsidence occurred immediately postoperatively. Survivorship analysis demonstrated an average annual failure rate of 2.1 percent and a sixteen-year survival rate of 70.3 percent. The five and ten-year survival rates were 82.3 percent (95 percent confidence interval, 74.6 to 88.2 percent) and 81.4 percent (95 percent confidence interval, 73.0 to 87.8 percent), respectively. None of the revised implants had any visible changes of wear or deformity of the surfaces or stems. Four instances of chronic inflammatory tissue and three instances of proliferative synovitis were noted histologically. Focal pigment deposits were seen in three fingers, one of which had removal of the implant two months after a fracture. No evidence of intracellular particles or particulate synovitis was found. CONCLUSIONS: The results of this study demonstrate that pyrolytic carbon is a biologically and biomechanically compatible, wear-resistant, and durable material for arthroplasty of the metacarpophalangeal joint.
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94Brantigan, J. W.; Neidre, A.; Toohey, J. S. Spine J. 2004, 4, 681Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2crntVOjtA%253D%253D&md5=ac224c6e85b634603638f3a4adeb4a00The Lumbar I/F Cage for posterior lumbar interbody fusion with the variable screw placement system: 10-year results of a Food and Drug Administration clinical trialBrantigan John W; Neidre Arvo; Toohey John SThe spine journal : official journal of the North American Spine Society (2004), 4 (6), 681-8 ISSN:1529-9430.BACKGROUND CONTEXT: The Lumbar I/F Cage is a carbon fiber reinforced polymer (CFRP) device designed to separate the mechanical and device functions of interbody fusion. A Investigational Device Exemption (IDE) clinical study of the CFRP cage was conducted during an enrollment period from 1991 to 1993. Based on the 2-year results of this study, the cage was approved by the US Food and Drug Administration (FDA) in February 1999. Since then, the Lumbar I/F Cage device has become widely used in the United States. PURPOSE: This study was designed to determine the long-term results of patients who received this device during the 1991-1993 enrollments. STUDY DESIGN/SETTING: Investigators from the original study were asked to evaluate their original patients according to FDA-reviewed case report forms. Although many of the centers were unable to provide significant follow-up, two centers that enrolled almost half of the original study group provided reports on a high percentage of their original patients. This paper reviews the results in those patients. PATIENT SAMPLE: Inclusion criteria included patients with degenerative disc disease who had at least one failed lumbar discectomy or decompression procedure at one or more levels. OUTCOME MEASURES: Clinical success was defined by a modified Prolo score evaluating pain, function, medication usage and economic status. Fusion success, determined by evaluation of plain radiographs, was defined by continuous bone bridging the fusion area with no lucencies. Flexion-extension X-rays were done on patients who had previous removal of pedicle screw implants. Any motion on flexion-extension films indicated pseudarthrosis. METHODS: All patients were contacted at their last known address. Internet search services were used to locate additional patients. Thirty-three of 43 eligible patients (77%) were evaluated, including 31 patients who reported for examination and X-ray and 2 additional patients by telephone survey and written questionnaire. RESULTS: Clinical success was achieved in 32 of 37 patients (86.5%) at 24 months and in 29 of 33 patients (87.8%) at 10 years. This included 61% excellent, 27% good, and 12% fair results. Fusion success was reported in 37 of 37 patients (100%) at 24 months and in 29 of 30 patients (96.7%) at 10 years. Patient satisfaction was reported in 31 of 33 (93.9%). Further lumbar surgery was done in 23 patients: in 18 patients for elective removal of pedicle screws and in 5 patients to extend the fusion to adjacent levels. Adjacent segment degeneration occurred in 61% of patients but was clinically significant in only 20%. Smokers had equal clinical and fusion success with nonsmokers at 24 months and 10 years and had adjacent segment degeneration in 37%, a rate significantly lower than nonsmokers at 87%. CONCLUSIONS: The high rate of clinical success, fusion success, and patient satisfaction at 24 months was maintained at 10-year follow-up. Adjacent segment degeneration was common but was usually not clinically significant.
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95Williams, M. A.; van Riet, S. J. Heart Valve Dis. 2006, 15, 80Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28%252FptlygsA%253D%253D&md5=70933f3c42f7500a89970a60b0352055The On-X heart valve: mid-term results in a poorly anticoagulated populationWilliams Mervyn A; van Riet SoniaThe Journal of heart valve disease (2006), 15 (1), 80-6 ISSN:0966-8519.BACKGROUND AND AIM OF THE STUDY: The study aim was to evaluate the clinical performance of the On-X heart valve in a socioeconomically disadvantaged population. Most patients were from an indigenous, poorly educated and geographically dispersed segment of the population where anticoagulation therapy was generally erratic. METHODS: Between 1999 and 2004, a total of 530 valves (242 mitral valves, 104 aortic valves, 92 double valves) was implanted in 438 patients (average age 33 years; range: 3-78 years). The most common reason for surgery was rheumatic valve disease (57%), followed by degenerative valve disease (11%) and infective endocarditis (9%). Follow up was 95% complete for a total of 746 patient-years (pt-yr). Among the patient population, 40% were either not anticoagulated or were unsatisfactorily anticoagulated. RESULTS: Hospital mortality was 2.3%, and none of the hospital deaths was valve-related. Mean (+/- SE) actuarial survival (including hospital deaths) at four years was: AVR 73.8 +/- 8.1%, MVR 83.4 +/- 5.7% and DVR 60.9 +/- 10.3%. Linearized rates (for AVR, MVR and DVR, respectively) for late complications (%/ pt-yr) were: bleeding events 0.6, 1.0, and 2.3; thrombosis 0.0, 0.2, and 0.0; endocarditis 0.6, 1.0, and 2.3; paravalvular leak 0.6, 0.2, and 0.0; systemic embolism 1.1, 1.5, and 3.5. Most systemic emboli were related to infective endocarditis. Among patients there were seven uncomplicated, full-term pregnancies. CONCLUSION: Bearing in mind the erratic anticoagulation coverage and high incidence of infective endocarditis, the results of this study may be regarded as encouraging. The low incidence of valve thrombosis (one case) was noteworthy. These data also suggest that the On-X valve may be implanted with relative safety in women wishing to have children.
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96Saito, N.; Aoki, K.; Usui, Y.; Shimizu, M.; Hara, K.; Narita, N.; Ogihara, N.; Nakamura, K.; Ishigaki, N.; Kato, H.; Haniu, H.; Taruta, S.; Kim, Y. A.; Endo, M. Chem. Soc. Rev. 2011, 40, 3824Google ScholarThere is no corresponding record for this reference.
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97Hara, K.; Aoki, K.; Usui, Y.; Shimizu, M.; Narita, N.; Ogihara, N.; Nakamura, K.; Ishigaki, N.; Sano, K.; Haniu, H.; Kato, H.; Nishimura, N.; Kim, Y. A.; Taruta, S.; Saito, N. Mater. Today 2011, 14, 434Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFWjs7nP&md5=f59f6ab06c9cda4b62396a40c86175dbEvaluation of CNT toxicity by comparison to tattoo inkHara, Kazuo; Aoki, Kaoru; Usui, Yuki; Shimizu, Masayuki; Narita, Nobuyo; Ogihara, Nobuhide; Nakamura, Koichi; Ishigaki, Norio; Sano, Kenji; Haniu, Hisao; Kato, Hiroyuki; Nishimura, Naoyuki; Kim, Yoong Ahm; Taruta, Seiichi; Saito, NaotoMaterials Today (Oxford, United Kingdom) (2011), 14 (9), 434-440CODEN: MTOUAN; ISSN:1369-7021. (Elsevier Ltd.)The absence of an optimal nano-sized ref. material has been the biggest obstacle in evaluating the safety of carbon nanotubes as biomaterials. In this study, black tattoo inks, which have a long history of use by humans, are shown to be suitable ref. materials composed of nano-sized carbon black particles. We have also demonstrated that multi-walled carbon nanotubes have comparable basic safety properties to those of tattoo inks when used as biomaterials.
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98Takanashi, S.; Hara, K.; Aoki, K.; Usui, Y.; Shimizu, M.; Haniu, H.; Ogihara, N.; Ishigaki, N.; Nakamura, K.; Okamoto, M.; Kobayashi, S.; Kato, H.; Sano, K.; Nishimura, N.; Tsutsumi, H.; Machida, K.; Saito, N. Sci. Rep. 2012, 2, 498Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs12rur7F&md5=df21786aac7ee347c7868d24dfae5754Carcinogenicity evaluation for the application of carbon nanotubes as biomaterials in rasH2 miceTakanashi, Seiji; Hara, Kazuo; Aoki, Kaoru; Usui, Yuki; Shimizu, Masayuki; Haniu, Hisao; Ogihara, Nobuhide; Ishigaki, Norio; Nakamura, Koichi; Okamoto, Masanori; Kobayashi, Shinsuke; Kato, Hiroyuki; Sano, Kenji; Nishimura, Naoyuki; Tsutsumi, Hideki; Machida, Kazuhiko; Saito, NaotoScientific Reports (2012), 2 (), srep00498, 7 pp.CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)The application of carbon nanotubes (CNTs) as biomaterials is of wide interest, and studies examg. their application in medicine have had considerable significance. Biol. safety is the most important factor when considering the clin. application of CNTs as biomaterials, and various toxicity evaluations are required. Among these evaluations, carcinogenicity should be examd. with the highest priority; however, no report using transgenic mice to evaluate the carcinogenicity of CNTs has been published to date. Here, we performed a carcinogenicity test by implanting multi-walled CNTs (MWCNTs) into the s.c. tissue of rasH2 mice, using the carbon black present in black tattoo ink as a ref. material for safety. The rasH2 mice did not develop neoplasms after being injected with MWCNTs; instead, MWCNTs showed lower carcinogenicity than carbon black. Such evaluations should facilitate the clin. application and development of CNTs for use in important medical fields.
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99Wang, J.; Sun, P.; Bao, Y.; Liu, J.; An, L. Toxicol. In Vitro 2011, 25, 242Google ScholarThere is no corresponding record for this reference.
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100Devadasu, V. R.; Bhardwaj, V.; Kumar, M. N. Chem. Rev. 2013, 113, 1686Google ScholarThere is no corresponding record for this reference.
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101Iannazzo, D.; Piperno, A.; Pistone, A.; Grassi, G.; Galvagno, S. Curr. Med. Chem. 2013, 20, 1333Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmt1yns7Y%253D&md5=527a93e973edaa5af5a588f65c907382Recent advances in carbon nanotubes as delivery systems for anticancer drugsIannazzo, Daniela; Piperno, Anna; Pistone, Alessandro; Grassi, Giovanni; Galvagno, SignorinoCurrent Medicinal Chemistry (2013), 20 (11), 1333-1354CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. Problems assocd. with the administration of anticancer drugs, such as limited soly., poor biodistribution, lack of selectivity, and healthy tissue damage, can be overcome by the implementation of drug delivery systems. A wide range of materials, including liposomes, microspheres, polymers and recently, carbon nanotubes (CNTs), were investigated for delivering anticancer drugs on the purpose of reducing the no. of necessary administrations, providing more localized and better use of the active agents, and increasing patient compliance. Carbon nanotubes (CNTs) have attracted particular attention as carriers of biol. relevant mols. due to their unique phys., chem. and physiol. properties. The exact relationship between the phys.-chem. properties of carbon nanotubes, their cell-to-cell interactions, reactivity, and biol./systemic consequences are relevant issues and it is important to know such inter-relationships beforehand to employ the benefits of these nanomaterials without the hazardous consequences. The purpose of this review is to present highlight of recent developments in the application of carbon nanotubes as cargoes for anticancer drugs and in the diagnosis of cancer diseases.
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102Veetil, J. V.; Ye, K. Biotechnol. Prog. 2009, 25, 709Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXotlWltrs%253D&md5=f3bd6f9f80418fccddc610d170f0f90dTailored carbon nanotubes for tissue engineering applicationsVeetil, Jithesh V.; Ye, KaimingBiotechnology Progress (2009), 25 (3), 709-721CODEN: BIPRET; ISSN:8756-7938. (Wiley-Blackwell)A review. A decade of aggressive researches on carbon nanotubes (CNTs) has paved way for extending these unique nanomaterials into a wide range of applications. In the relatively new arena of nanobiotechnol., a vast majority of applications are based on CNTs, ranging from miniaturized biosensors to organ regeneration. Nevertheless, the complexity of biol. systems poses a significant challenge in developing CNT-based tissue engineering applications. This review focuses on the recent developments of CNT-based tissue engineering, where the interaction between living cells/tissues and the nanotubes were transformed into a variety of novel techniques. This integration has already resulted in a revaluation of tissue engineering and organ regeneration techniques. Some of the new treatments that were not possible previously become reachable now. Because of the advent of surface chem., the CNT's biocompatibility was significantly improved, making it possible to serve as tissue scaffolding materials to enhance the organ regeneration. The superior mechanic strength and chem. inert also makes it ideal for blood compatible applications, esp. for cardiopulmonary bypass surgery. The applications of CNTs in these cardiovascular surgeries led to a remarkable improvement in mech. strength of implanted catheters and reduced thrombogenicity after surgery. Moreover, the functionalized CNTs were extensively explored for in vivo targeted drug or gene delivery, which could potentially improve the efficiency of many cancer treatments. However, just like other nanomaterials, the cytotoxicity of CNTs was not well established. Hence, more extensive cytotoxic studies are warranted while converting the hydrophobic CNTs into biocompatible nanomaterials.
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103Watari, F.; Takashi, N.; Yokoyama, A.; Uo, M.; Akasaka, T.; Sato, Y.; Abe, S.; Totsuka, Y.; Tohji, K. J. R. Soc. Interface 2009, 6, S371Google ScholarThere is no corresponding record for this reference.
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104Prabhu, P.; Patravale, V. J. Biomed. Nanotechnol. 2012, 8, 859Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVWgtrvP&md5=2b982dc803aba3f5c42debb083e886deThe upcoming field of theranostic nanomedicine: an overviewPrabhu, Priyanka; Patravale, VandanaJournal of Biomedical Nanotechnology (2012), 8 (6), 859-882CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)A review. Nanocarriers have drastically changed the face of health care by making a mark in diverse arenas of diagnosis, drug delivery, and gene delivery to name a few. The recent feat in nanotechnol. was the birth of nanotheranostics which aims at blending both therapeutic and diagnostic functions within a single nanoscaffold. The field of theranostic nanomedicine is a result of fruitful advances in fields of material science, imaging modalities, formulation development, and mol. biol. Theranostic nanomedicine that was at first developed for enhancing the quality of treatment meted out to cancer patients has now been explored even in atherosclerosis and infections, albeit to a lower extent. The review summarizes various types of nanocarriers that were explored with one or sometimes multiple imaging modalities for an array of applications ranging from drug delivery and gene delivery to photosensitizing agent delivery for photodynamic therapy. The article also highlights the few but significant developments made in the field of theranostic nanomedicine for atherosclerosis and infections. In conclusion, theranostic nanomedicine is a rapidly growing field. However, there are a few problems that need to be addressed before theranostic nanocarriers carve a niche for themselves in the clinic.
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105Drbohlavova, J.; Chomoucka, J.; Adam, V.; Ryvolova, M.; Eckschlager, T.; Hubalek, J.; Kizek, R. Curr. Drug Metab. 2013, 14, 547Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1yhsLvI&md5=27e03e68b3c54c38eb8cd1da0d111d9eNanocarriers for Anticancer Drugs - New Trends in NanomedicineDrbohlavova, Jana; Chomoucka, Jana; Adam, Vojtech; Ryvolova, Marketa; Eckschlager, Tomas; Hubalek, Jaromir; Kizek, ReneCurrent Drug Metabolism (2013), 14 (5), 547-564CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)This review provides a brief overview of the variety of carriers employed for targeted drug delivery used in cancer therapy and summarizes advantages and disadvantages of each approach. Particularly, the attention was paid to polymeric nanocarriers, liposomes, micelles, polyethylene glycol, poly(lactic-co-glycolic acid), dendrimers, gold and magnetic nanoparticles, quantum dots, silica nanoparticles, and carbon nanotubes. Further, this paper briefly focuses on several anticancer agents (paclitaxel, docetaxel, camptothecin, doxorubicin, daunorubicin, cisplatin, curcumin, and geldanamycin) and on the influence of their combination with nanoparticulate transporters to their properties such as cytotoxicity, short life time and/or soly.
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106Karousis, N.; Tagmatarchis, N.; Tasis, D. Chem. Rev. 2010, 110, 5366Google ScholarThere is no corresponding record for this reference.
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107Kam, N. W.; O’Connell, M.; Wisdom, J. A.; Dai, H. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 11600Google ScholarThere is no corresponding record for this reference.
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108Venkatesan, N.; Yoshimitsu, J.; Ito, Y.; Shibata, N.; Takada, K. Biomaterials 2005, 26, 7154Google ScholarThere is no corresponding record for this reference.
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109Dumortier, H.; Lacotte, S.; Pastorin, G.; Marega, R.; Wu, W.; Bonifazi, D.; Briand, J. P.; Prato, M.; Muller, S.; Bianco, A. Nano Lett. 2006, 6, 1522Google ScholarThere is no corresponding record for this reference.
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110McDevitt, M. R.; Chattopadhyay, D.; Kappel, B. J.; Jaggi, J. S.; Schiffman, S. R.; Antczak, C.; Njardarson, J. T.; Brentjens, R.; Scheinberg, D. A. J. Nucl. Med. 2007, 48, 1180Google ScholarThere is no corresponding record for this reference.
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111Liu, Z.; Jiao, L.; Yao, Y.; Xian, X.; Zhang, J. Adv. Mater. 2010, 22, 2285Google ScholarThere is no corresponding record for this reference.
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112Hwang, J. Y.; Shin, U. S.; Jang, W. C.; Hyun, J. K.; Wall, I. B.; Kim, H. W. Nanoscale 2013, 5, 487Google ScholarThere is no corresponding record for this reference.
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113Ferrari, M. Nat. Rev. Cancer 2005, 5, 161Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhslSnt7o%253D&md5=b4e4a4aacb2a265e76c261c4cc4b77c7Cancer nanotechnology: opportunities and challengesFerrari, MauroNature Reviews Cancer (2005), 5 (3), 161-171CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. Nanotechnol. is a multidisciplinary field, which covers a vast and diverse array of devices derived from engineering, biol., physics and chem. These devices include nanovectors for the targeted delivery of anticancer drugs and imaging contrast agents. Nanowires and nanocantilever arrays are among the leading approaches under development for the early detection of precancerous and malignant lesions from biol. fluids. These and other nanodevices can provide essential breakthroughs in the fight against cancer.
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114Ou, Z.; Wu, B.; Xing, D.; Zhou, F.; Wang, H.; Tang, Y. Nanotechnology 2009, 20, 105102Google ScholarThere is no corresponding record for this reference.
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115Okada, S.; Saito, S.; Oshiyama, A. Phys. Rev. Lett. 2001, 86, 3835Google ScholarThere is no corresponding record for this reference.
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116Kavan, L.; Dunsch, L. ChemPhysChem 2003, 4, 944Google ScholarThere is no corresponding record for this reference.
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117Foldvari, M.; Bagonluri, M. Nanomedicine 2008, 4, 183Google ScholarThere is no corresponding record for this reference.
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118Taylor, A.; Lipert, K.; Kramer, K.; Hampel, S.; Fussel, S.; Meye, A.; Klingeler, R.; Ritschel, M.; Leonhardt, A.; Büchner, B.; Wirth, M. P. J. Nanosci. Nanotechnol. 2009, 9, 5709Google ScholarThere is no corresponding record for this reference.
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119Hong, S. Y.; Tobias, G.; Al-Jamal, K. T.; Ballesteros, B.; Ali-Boucetta, H.; Lozano-Perez, S.; Nellist, P. D.; Sim, R. B.; Finucane, C.; Mather, S. J.; Green, M. L.; Kostarelos, K.; Davis, B. G. Nat. Mater. 2010, 9, 485Google ScholarThere is no corresponding record for this reference.
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120Liopo, A. V.; Stewart, M. P.; Hudson, J.; Tour, J. M.; Pappas, T. C. J. Nanosci. Nanotechnol. 2006, 6, 1365Google ScholarThere is no corresponding record for this reference.
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121Keefer, E. W.; Botterman, B. R.; Romero, M. I.; Rossi, A. F.; Gross, G. W. Nat. Nanotechnol. 2008, 3, 434Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXotFehsb8%253D&md5=698b815116aae4e8a0e229bebfe6b650Carbon nanotube coating improves neuronal recordingsKeefer, Edward W.; Botterman, Barry R.; Romero, Mario I.; Rossi, Andrew F.; Gross, Guenter W.Nature Nanotechnology (2008), 3 (7), 434-439CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Implanting elec. devices in the nervous system to treat neural diseases is becoming very common. The success of these brain-machine interfaces depends on the electrodes that come into contact with the neural tissue. Here the authors show that conventional tungsten and stainless steel wire electrodes can be coated with carbon nanotubes using electrochem. techniques under ambient conditions. The carbon nanotube coating enhanced both recording and elec. stimulation of neurons in culture, rats and monkeys by decreasing the electrode impedance and increasing charge transfer. Carbon nanotube-coated electrodes are expected to improve current electrophysiol. techniques and to facilitate the development of long-lasting brain-machine interface devices. Coating conventional tungsten and stainless steel electrodes with carbon nanotubes improves their performance in research involving the implantation of elec. devices into the nervous system. The results could have an impact on electrophysiol. and the development of brain-machine interfaces.
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122Nunes, A.; Al-Jamal, K.; Nakajima, T.; Hariz, M.; Kostarelos, K. Arch. Toxicol. 2012, 86, 1009Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmtlWnu7Y%253D&md5=1f174dbcb962424f0791944af3fb26f8Application of carbon nanotubes in neurology: clinical perspectives and toxicological risksNunes, Antonio; Al-Jamal, Khuloud; Nakajima, Takeshi; Hariz, Marwan; Kostarelos, KostasArchives of Toxicology (2012), 86 (7), 1009-1020CODEN: ARTODN; ISSN:0340-5761. (Springer)A review. Nanomedicine is an emerging field that proposes the application of precisely engineered nanomaterials for the prevention, diagnosis and therapy of certain diseases, including neurol. pathologies. Carbon nanotubes (CNT) are a new class of nanomaterials, which were shown to be promising in different areas of nanomedicine. In this review, the application of CNT interfacing with the central nervous system (CNS) will be described, and representative examples of neuroprosthetic devices, such as neuronal implants and electrodes will be discussed. Furthermore, the possible application of CNT-based materials as regenerative matrixes of neuronal tissue and as delivery systems for the therapy of CNS will be presented.
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123Baughman, R. H.; Cui, C.; Zakhidov, A. A.; Iqbal, Z.; Barisci, J. N.; Spinks, G. M.; Wallace, G. G.; Mazzoldi, A.; De Rossi, D.; Rinzler, A. G.; Jaschinski, O.; Roth, S.; Kertesz, M. Science 1999, 284, 1340Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXjs1Wjtb4%253D&md5=62360d4dbaf1c8b5f85391a246e35d05Carbon nanotube actuatorsBaughman, Ray H.; Cui, Changxing; Zakhidov, Anvar A.; Iqbal, Zafar; Barisci, Joseph N.; Spinks, Geoff M.; Wallace, Gordon G.; Mazzoldi, Alberto; De Rossi, danilo; Rinzler, Andrew G.; Jaschinski, Oliver; Roth, Siegmar; Kertesz, MiklosScience (Washington, D. C.) (1999), 284 (5418), 1340-1344CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Electromech. actuators based on sheets of single-walled carbon nanotubes were shown to generate higher stresses than natural muscle and higher strains than high-modulus ferroelecs. Like natural muscles, the macroscopic actuators are assemblies of billions of individual nanoscale actuators. The actuation mechanism (quantum chem.-based expansion due to electrochem. double-layer charging) does not require ion intercalation, which limits the life and rate of faradaic conducting polymer actuators. Unlike conventional ferroelec. actuators, low operating voltages of a few volts generate large actuator strains. Predictions based on measurements suggest that actuators using optimized nanotube sheets may eventually provide substantially higher work densities per cycle than any previously known technol.
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124Chen, L.; Liu, C.; Liu, K.; Meng, C.; Hu, C.; Wang, J.; Fan, S. ACS Nano 2011, 5, 1588Google ScholarThere is no corresponding record for this reference.
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125Vittorio, O.; Quaranta, P.; Raffa, V.; Funel, N.; Campani, D.; Pelliccioni, S.; Longoni, B.; Mosca, F.; Pietrabissa, A.; Cuschieri, A. Nanomedicine (London, U.K.) 2011, 6, 43Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1WntbnF&md5=cd57bdc6cea971b30295502a96dac065Magnetic carbon nanotubes: a new tool for shepherding mesenchymal stem cells by magnetic fieldsVittorio, Orazio; Quaranta, Paola; Raffa, Vittoria; Funel, Niccola; Campani, Daniela; Pelliccioni, Serena; Longoni, Biancamaria; Mosca, Franco; Pietrabissa, Andrea; Cuschieri, AlfredNanomedicine (London, United Kingdom) (2011), 6 (1), 43-54CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)Aims: We investigated the interaction between magnetic carbon nanotubes (CNTs) and mesenchymal stem cells (MSCs), and their ability to guide these i.v. injected cells in living rats by using an external magnetic field. Materials & methods: Multiwalled CNTs were used to treat MSCs derived from rat bone marrow. Cytotoxicity induced by nanotubes was studied using the WST-1 proliferation and Hoechest 33258 apoptosis assays. The effects of nanotubes on MSCs were evaluated by monitoring the effects on cellular growth rates, immunophenotyping and differentiation, and on the arrangement of cytoskeletal actin. MSCs loaded with nanotubes were injected in vivo in the portal vein of rats driving their localization in the liver by magnetic field. An histol. anal. was performed on the liver, lungs and kidneys of all animals. Results: CNTs did not affect cell viability and their ability to differentiate in osteocytes and adipocytes. Both the CNTs and the magnetic field did not alter the cell growth rate, phenotype and cytoskeletal conformation. CNTs, when exposed to magnetic fields, are able to shepherd MSCs towards the magnetic source in vitro. Moreover, the application of a magnetic field alters the biodistribution of CNT-labeled MSCs after i.v. injection into rats, increasing the accumulation of cells into the target organ (liver). Conclusion: Multiwalled CNTs hold the potential for use as nanodevices to improve therapeutic protocols for transplantation and homing of stem cells in vivo. This could pave the way for the development of new strategies for the manipulation/guidance of MSCs in regenerative medicine and cell transplantation.
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126Hong, C.; Kang, J.; Kim, H.; Lee, C. J. Nanosci. Nanotechnol. 2012, 12, 4352Google ScholarThere is no corresponding record for this reference.
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127Madani, S. Y.; Tan, A.; Naderi, N.; Seifalian, A. M. J. Nanosci. Nanotechnol. 2012, 12, 9018Google ScholarThere is no corresponding record for this reference.
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128Wang, L.; Shi, J.; Zhang, H.; Li, H.; Gao, Y.; Wang, Z.; Wang, H.; Li, L.; Zhang, C.; Chen, C.; Zhang, Z.; Zhang, Y. Biomaterials 2013, 34, 262Google ScholarThere is no corresponding record for this reference.
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129Bhirde, A. A.; Patel, V.; Gavard, J.; Zhang, G.; Sousa, A. A.; Masedunskas, A.; Leapman, R. D.; Weigert, R.; Gutkind, J. S.; Rusling, J. F. ACS Nano 2009, 3, 307Google ScholarThere is no corresponding record for this reference.
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130Chaudhuri, P.; Harfouche, R.; Soni, S.; Hentschel, D. M.; Sengupta, S. ACS Nano 2010, 4, 574Google ScholarThere is no corresponding record for this reference.
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131Ruggiero, A.; Villa, C. H.; Holland, J. P.; Sprinkle, S. R.; May, C.; Lewis, J. S.; Scheinberg, D. A.; McDevitt, M. R. Int. J. Nanomed. 2010, 5, 783Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1OiurfI&md5=9bec85125af54c54919d24166e719554Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubesRuggiero, Alessandro; Villa, Carlos H.; Holland, Jason P.; Sprinkle, Shanna R.; May, Chad; Lewis, Jason S.; Scheinberg, David A.; McDevitt, Michael R.International Journal of Nanomedicine (2010), 5 (), 783-802CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)Single wall carbon nanotube (SWCNT) constructs were covalently appended with radiometal-ion chelates (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA] or desferrioxamine B [DFO]) and the tumor neovascular-targeting antibody E4G10. The E4G10 antibody specifically targeted the monomeric vascular endothelial-cadherin (VE-cad) epitope expressed in the tumor angiogenic vessels. The construct specific activity and blood compartment clearance kinetics were significantly improved relative to corresponding antibody-alone constructs. We performed targeted radioimmunotherapy with a SWCNT-([225Ac]DOTA)(E4G10) construct directed at the tumor vasculature in a murine xenograft model of human colon adenocarcinoma (LS174T). The specific construct reduced tumor vol. and improved median survival relative to controls. We also performed positron emission tomog. (PET) radioimmunoimaging of the tumor vessels with a SWCNT-([89Zr]DFO)(E4G10) construct in the same murine LS174T xenograft model and compared the results to appropriate controls. Dynamic and longitudinal PET imaging of LS174T tumor-bearing mice demonstrated rapid blood clearance (<1 h) and specific tumor accumulation of the specific construct. Incorporation of the SWCNT scaffold into the construct design permitted us to amplify the specific activity to improve the signal-to-noise ratio without detrimentally impacting the immunoreactivity of the targeting antibody moiety. Furthermore, we were able to exploit the SWCNT pharmacokinetic (PK) profile to favorably alter the blood clearance and provide an advantage for rapid imaging. Near-IR three-dimensional fluorescent-mediated tomog. was used to image the LS174T tumor model, collect antibody-alone PK data, and calc. the no. of copies of VE-cad epitope per cell. All of these studies were performed as a single administration of construct and were found to be safe and well tolerated by the murine model. These data have implications that support further imaging and radiotherapy studies using a SWCNT-based platform and focusing on the tumor vessels as the target.
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132Singh, S. J. Nanosci. Nanotechnol. 2010, 10, 7906Google ScholarThere is no corresponding record for this reference.
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133Elhissi, A. M.; Ahmed, W.; Hassan, I. U.; Dhanak, V. R.; D’Emanuele, A. J. Drug Delivery 2012, 2012, 837327Google ScholarThere is no corresponding record for this reference.
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134Ding, Y.; Liu, J.; Jin, X.; Lu, H.; Shen, G.; Yu, R. Analyst 2008, 133, 184Google ScholarThere is no corresponding record for this reference.
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135Kim, J. P.; Lee, B. Y.; Lee, J.; Hong, S.; Sim, S. J. Biosens. Bioelectron. 2009, 24, 3372Google ScholarThere is no corresponding record for this reference.
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136Lin, J.; He, C.; Zhang, L.; Zhang, S. Anal. Biochem. 2009, 384, 130Google ScholarThere is no corresponding record for this reference.
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137Li, Q.; Tang, D.; Tang, J.; Su, B.; Huang, J.; Chen, G. Talanta 2011, 84, 538Google ScholarThere is no corresponding record for this reference.
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138Gul, H.; Lu, W.; Xu, P.; Xing, J.; Chen, J. Nanotechnology 2010, 21, 155101Google ScholarThere is no corresponding record for this reference.
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139Delogu, L. G.; Vidili, G.; Venturelli, E.; Ménard-Moyon, C.; Zoroddu, M. A.; Pilo, G.; Nicolussi, P.; Ligios, C.; Bedognetti, D.; Sgarrella, F.; Manetti, R.; Bianco, A. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 16612Google ScholarThere is no corresponding record for this reference.
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140Chang, Y. T.; Huang, J. H.; Tu, M. C.; Chang, P.; Yew, T. R. Biosens. Bioelectron. 2013, 41, 898Google ScholarThere is no corresponding record for this reference.
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141Lu, X.; Cheng, H.; Huang, P.; Yang, L.; Yu, P.; Mao, L. Anal. Chem. 2013, 85, 4007Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktVOitbc%253D&md5=af562990a1ea60b1344ed52d582b833fHybridization of Bioelectrochemically Functional Infinite Coordination Polymer Nanoparticles with Carbon Nanotubes for Highly Sensitive and Selective In Vivo Electrochemical MonitoringLu, Xulin; Cheng, Hanjun; Huang, Pengcheng; Yang, Lifen; Yu, Ping; Mao, LanqunAnalytical Chemistry (Washington, DC, United States) (2013), 85 (8), 4007-4013CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)This study demonstrates the formation of a three-dimensional conducting framework through hybridization of bioelectrochem. active infinite coordination polymer (ICP) nanoparticles with single-walled carbon nanotubes (SWNTs) for highly sensitive and selective in vivo electrochem. monitoring with combination with in vivo microdialysis. The bioelectrochem. active ICP nanoparticles were synthesized through the self-assembly process of NAD+ and Tb3+, in which all biosensing elements including an electrocatalyst (i.e., methylene green, MG), cofactor (i.e., β-NAD, NAD+), and enzyme (i.e., glucose dehydrogenase, GDH) are adaptively encapsulated. The ICP/SWNT-based biosensors are simply prepd. by drop-coating the as-formed ICP/SWNT nanocomposite onto a glassy carbon substrate. Electrochem. studies demonstrate that the simply prepd. ICP/SWNT-based biosensors exhibit excellent biosensing properties with a higher sensitivity and stability than the ICP-based biosensors prepd. only with ICP nanoparticles (i.e., without hybridization of SWNTs). By using a GDH-based electrochem. biosensor as an example, the authors demonstrate a tech. simple yet effective online electroanal. platform for continuously monitoring glucose in the brain of guinea pigs with the ICP/SWNT-based biosensor as an online detector in a continuous-flow system combined with in vivo microdialysis. Under the exptl. conditions employed here, the dynamic linear range for glucose with the ICP/SWNT-biosensor is 50-1000 μM. Moreover, in vivo selectivity studies with the biosensors prepd. by the GDH-free ICPs reveal that ICP/SWNT-based biosensors are very selective for the measurement of glucose in the cerebral system. The basal level of glucose in the microdialyzates from the striatum of guinea pigs is 0.31 ± 0.03 mM (n = 3). The study offers a simple route to the prepn. of electrochem. biosensors, which is envisaged to be particularly useful for probing the chem. events involved in some physiol. and pathol. processes.
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142Sitharaman, B.; Van Der Zande, M.; Ananta, J. S.; Shi, X.; Veltien, A.; Walboomers, X. F.; Wilson, L. J.; Mikos, A. G.; Heerschap, A.; Jansen, J. A. J. Biomed. Mater. Res., Part A 2010, 93, 1454Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlt1Smsrw%253D&md5=d592fbf57f6022b82fb159d9745ba5d0Magnetic resonance imaging studies on gadonanotube-reinforced biodegradable polymer nanocompositesSitharaman, Balaji; Van Der Zande, Meike; Ananta, Jeyarama S.; Shi, Xinfeng; Veltien, Andor; Walboomers, X. Frank; Wilson, Lon J.; Mikos, Antonios G.; Heerschap, Arend; Jansen, John A.Journal of Biomedical Materials Research, Part A (2010), 93A (4), 1454-1462CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)We report about the in vitro cytotoxicity and MRI studies of Gd3+ions-doped ultra-short single-walled carbon nanotube (gadonanotubes), gadonanotubes-reinforced poly(lactic-co-glycolic acid) (PLGA) polymer nanocomposites and in vivo small animal MRI studies using the gadonanotubes. These studies were performed to explore the suitability of gadonanotubes-reinforced PLGA polymer nanocomposite as a model scaffold for noninvasive magnetic resonance imaging (MRI) to evaluate nanotube release during the degrdn. process of the scaffold and their biodistribution upon release from the polymer matrix in vivo. The gadonanotubes at 1-100 ppm and the gadonanotubes/PLGA nanocomposites (2 wt % gadonanotubes) did not show any cytotoxicity in vitro as demonstrated using the LIVE/DEAD viability assay. For the first time, r2 relaxivity measurements were obtained for the superparamagnetic gadonanotubes. In vitro 7T MRI of the superparamagnetic gadonanotubes ([Gd] = 0.15 mM) suspended in a biocompatible 1% Pluronic F127 soln., gave a r2 value of 578 mM-1 s-1. Upon s.c. injection of the gadonanotubes suspension into the dorsal region of rats, the high r2 value translated into excellent and prolonged neg. contrast enhancement of in vivo T2 weighted proton MRI images. The in vitro characterization of the nanocomposite disks and their degrdn. process by MRI, showed strong influence of the gadonanotube on water proton relaxations. These results indicate that the gadonanotubes/PLGA nanocomposites are suitable for further in vivo studies to track by MRI the biodegrdn. release and biodistribution of gadonanotubes. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010.
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143Minati, L.; Antonini, V.; Dalla Serra, M.; Speranza, G. Langmuir 2012, 28, 15900Google ScholarThere is no corresponding record for this reference.
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144Avti, P. K.; Talukdar, Y.; Sirotkin, M. V.; Shroyer, K. R.; Sitharaman, B. J. Biomed. Mater. Res., Part B 2013, 101, 1039Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVyksLfI&md5=2ef391b4ac33f29bc3cd8d4ef0a071c3Toward single-walled carbon nanotube-gadolinium complex as advanced MRI contrast agents: Pharmacodynamics and global genomic response in small animalsAvti, Pramod K.; Talukdar, Yahfi; Sirotkin, Matvey V.; Shroyer, Kenneth R.; Sitharaman, BalajiJournal of Biomedical Materials Research, Part B: Applied Biomaterials (2013), 101B (6), 1039-1049CODEN: JBMRGL; ISSN:1552-4973. (John Wiley & Sons, Inc.)Gadolinium nanoparticle-catalyzed single-walled carbon nanotubes (Gd-SWCNTs) have recently shown potential in vitro as high-performance T1 magnetic resonance imaging (MRI) contrast agents (CAs). Their preclin. safety assessment at nontoxic dosages is essential for MRI applications. Herein, the in vivo (in rats) pharmacodynamics of Gd-SWCNTs (water solubilized with the amphiphilic polymer PEG-DSPE) at the organ, tissue, mol., and genetic level is reported. Gd-SWCNT, com. available iron catalyzed SWCNTs (Fe-SWCNTs, control 1) and PEG-DSPE (control 2) solns. were i.v. injected at a potential nontoxic therapeutic dose (0.5 mg/kg body wt., single bolus). Postinjection, bright-field optical microscopy showed their macroscale distribution in lung, liver, kidney, brain, and spleen up to 5 days. Raman and transmission electron microscopy (TEM) showed their presence at the nanoscale within hepatocytes. Their effects on the host organ tissue, mol., and genetic level were analyzed after 1, 5, 10, 20, and 30 days by histol., biomol. [lipid peroxidn., plasma tumor necrosis factor TNF-α assay, microarrays] assays. The results indicate that Gd-SWCNTs neither cause any inflammation, nor damage to the above organs, nor any significant change in the lipid peroxidn. or plasma proinflammatory cytokine (TNF-α) levels for all the groups at all time points. Global gene expression profile of liver (main organ for the metab.) after day 1 treatment with Gd-SWCNTs shows that the gene regulation is directed toward maintaining normal homeostasis. The results taken together indicate that PEG-DSPE water-solubilized Gd-SWCNTs at potentially nontoxic dosages have pharmacodynamics similar to other com. available Fe-SWCNTs and are suitable for future preclin. development as in vivo MRI CAs. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013.
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145Ou, Z.; Wu, B. J. Nanosci. Nanotechnol. 2013, 13, 1212Google ScholarThere is no corresponding record for this reference.
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146Hartman, K. B.; Wilson, L. J. Adv. Exp. Med. Biol. 2007, 620, 74Google ScholarThere is no corresponding record for this reference.
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147De la Zerda, A.; Zavaleta, C.; Keren, S.; Vaithilingam, S.; Bodapati, S.; Liu, Z.; Levi, J.; Smith, B. R.; Ma, T. J.; Oralkan, O.; Cheng, Z.; Chen, X.; Dai, H.; Khuri-Yakub, B. T.; Gambhir, S. S. Nat. Nanotechnol. 2008, 3, 557Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVOqsLvO&md5=45244da12fb9416414189428db00b06cCarbon nanotubes as photoacoustic molecular imaging agents in living miceDe La Zerda, Adam; Zavaleta, Cristina; Keren, Shay; Vaithilingam, Srikant; Bodapati, Sunil; Liu, Zhuang; Levi, Jelena; Smith, Bryan R.; Ma, Te-Jen; Oralkan, Omer; Cheng, Zhen; Chen, Xiaoyuan; Dai, Hongjie; Khuri-Yakub, Butrus T.; Gambhir, Sanjiv S.Nature Nanotechnology (2008), 3 (9), 557-562CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Photoacoustic imaging of living subjects offers higher spatial resoln. and allows deeper tissues to be imaged compared with most optical imaging techniques. As many diseases do not exhibit a natural photoacoustic contrast, esp. in their early stages, it is necessary to administer a photoacoustic contrast agent. A no. of contrast agents for photoacoustic imaging have been suggested previously, but most were not shown to target a diseased site in living subjects. Here the authors show that single-walled carbon nanotubes conjugated with cyclic Arg-Gly-Asp (RGD) peptides can be used as a contrast agent for photoacoustic imaging of tumors. I.v. administration of these targeted nanotubes to mice bearing tumors showed eight times greater photoacoustic signal in the tumor than mice injected with nontargeted nanotubes. These results were verified ex vivo using Raman microscopy. Photoacoustic imaging of targeted single-walled carbon nanotubes may contribute to noninvasive cancer imaging and monitoring of nanotherapeutics in living subjects. Photoacoustic imaging offers higher spatial resoln. than most optical imaging techniques, but contrast agents are needed because many diseases in their early stages do not display a natural photoacoustic contrast. Using single-walled carbon nanotubes conjugated with a peptide as a contrast agent allows the noninvasive photoacoustic imaging of tumors in animals.
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148Heller, D. A.; Baik, S.; Eurell, T. E.; Strano, M. S. Adv. Mater. 2005, 17, 2793Google ScholarThere is no corresponding record for this reference.
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149Liu, Z.; Peng, R. Eur. J. Nucl. Med. Mol. Imaging 2010, 37, S147Google ScholarThere is no corresponding record for this reference.
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150Liu, Z.; Sun, X.; Nakayama-Ratchford, N.; Dai, H. ACS Nano 2007, 1, 50Google ScholarThere is no corresponding record for this reference.
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151Adeli, M.; Soleyman, R.; Beiranvand, Z.; Madani, F. Chem. Soc. Rev. 2013, 42, 5231Google ScholarThere is no corresponding record for this reference.
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152Liu, H.; Xu, H.; Wang, Y.; He, Z.; Li, S. Drug Dev. Ind. Pharm. 2012, 38, 1031Google ScholarThere is no corresponding record for this reference.
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153Chen, J.; Chen, S.; Zhao, X.; Kuznetsova, L. V.; Wong, S. S.; Ojima, I. J. Am. Chem. Soc. 2008, 130, 16778Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlyitr%252FK&md5=199a741769044f2912f270c2f71d90f2Functionalized Single-Walled Carbon Nanotubes as Rationally Designed Vehicles for Tumor-Targeted Drug DeliveryChen, Jingyi; Chen, Shuyi; Zhao, Xianrui; Kuznetsova, Larisa V.; Wong, Stanislaus S.; Ojima, IwaoJournal of the American Chemical Society (2008), 130 (49), 16778-16785CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A novel single-walled carbon nanotube (SWNT)-based tumor-targeted drug delivery system (DDS) has been developed, which consists of a functionalized SWNT linked to tumor-targeting modules as well as prodrug modules. There are three key features of this nanoscale DDS: (a) use of functionalized SWNTs as a biocompatible platform for the delivery of therapeutic drugs or diagnostics, (b) conjugation of prodrug modules of an anticancer agent (taxoid with a cleavable linker) that is activated to its cytotoxic form inside the tumor cells upon internalization and in situ drug release, and (c) attachment of tumor-recognition modules (biotin and a spacer) to the nanotube surface. To prove the efficacy of this DDS, three fluorescent and fluorogenic mol. probes were designed, synthesized, characterized, and subjected to the anal. of the receptor-mediated endocytosis and drug release inside the cancer cells (L1210FR leukemia cell line) by means of confocal fluorescence microscopy. The specificity and cytotoxicity of the conjugate have also been assessed and compared with L1210 and human noncancerous cell lines. Then, it has unambiguously been proven that this tumor-targeting DDS works exactly as designed and shows high potency toward specific cancer cell lines, thereby forming a solid foundation for further development.
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154Zhang, X.; Meng, L.; Lu, Q.; Fei, Z.; Dyson, P. J. Biomaterials 2009, 30, 6041Google ScholarThere is no corresponding record for this reference.
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155Shvedova, A. A.; Kisin, E. R.; Porter, D.; Schulte, P.; Kagan, V. E.; Fadeel, B.; Castranova, V. Pharmacol. Ther. 2009, 121, 192Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXitVOks70%253D&md5=a81cfbe5b2f7dc6b6fff6062ae5fc309Mechanisms of pulmonary toxicity and medical applications of carbon nanotubes: Two faces of Janus?Shvedova, A. A.; Kisin, E. R.; Porter, D.; Schulte, P.; Kagan, V. E.; Fadeel, B.; Castranova, V.Pharmacology & Therapeutics (2009), 121 (2), 192-204CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)A review. Nanotechnol. is an emerging science involving manipulation of materials at the nanometer scale. There are several exciting prospects for the application of engineered nanomaterials in medicine. However, concerns over adverse and unanticipated effects on human health have also been raised. In fact, the same properties that make engineered nanomaterials attractive from a technol. and biomedical perspective could also make these novel materials harmful to human health and the environment. Carbon nanotubes are cylinders of one or several coaxial graphite layer(s) with a diam. in the order of nanometers, and serve as an instructive example of the Janus-like properties of nanomaterials. Numerous in vitro and in vivo studies have shown that carbon nanotubes and(or) assocd. contaminants or catalytic materials that arise during the prodn. process may induce oxidative stress and prominent pulmonary inflammation. Recent studies also suggest some similarities between the pathogenic properties of multi-walled carbon nanotubes and those of asbestos fibers. On the other hand, carbon nanotubes can be readily functionalized and several studies on the use of carbon nanotubes as versatile excipients for drug delivery and imaging of disease processes have been reported, suggesting that carbon nanotubes may have a place in the armamentarium for treatment and monitoring of cancer, infection, and other disease conditions. Nanomedicine is an emerging field that holds great promise; however, close attention to safety issues is required to ensure that the opportunities that carbon nanotubes and other engineered nanoparticles offer can be translated into feasible and safe constructs for the treatment of human disease.
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156Pantarotto, D.; Singh, R.; McCarthy, D.; Erhardt, M.; Briand, J. P.; Prato, M.; Kostarelos, K.; Bianco, A. Angew. Chem., Int. Ed. 2004, 43, 5242Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXos1ygt7Y%253D&md5=c675eaef7643ed0d3ae93df492b5230cFunctionalized carbon nanotubes for plasmid DNA gene deliveryPantarotto, Davide; Singh, Ravi; McCarthy, David; Erhardt, Mathieu; Briand, Jean-Paul; Prato, Maurizio; Kostarelos, Kostas; Bianco, AlbertoAngewandte Chemie, International Edition (2004), 43 (39), 5242-5246CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Genetic vaccination and gene therapy research could benefit from the application of carbon nanotubes. Functionalized, pos. charged, water-sol. carbon nanotubes are able to penetrate into cells and can transport plasmid DNA by formation of noncovalent DNA-nanotube complexes. Such nanotubes can be used as novel nonviral delivery systems for gene transfer.
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157Singh, R.; Pantarotto, D.; McCarthy, D.; Chaloin, O.; Hoebeke, J.; Partidos, C. D.; Briand, J. P.; Prato, M.; Bianco, A.; Kostarelos, K. J. Am. Chem. Soc. 2005, 127, 4388Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXitVShs7Y%253D&md5=8679d4e683e3806a94b299b5a716aadaBinding and Condensation of Plasmid DNA onto Functionalized Carbon Nanotubes: Toward the Construction of Nanotube-Based Gene Delivery VectorsSingh, Ravi; Pantarotto, Davide; McCarthy, David; Chaloin, Olivier; Hoebeke, Johan; Partidos, Charalambos D.; Briand, Jean-Paul; Prato, Maurizio; Bianco, Alberto; Kostarelos, KostasJournal of the American Chemical Society (2005), 127 (12), 4388-4396CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Carbon nanotubes (CNTs) constitute a class of nanomaterials that possess characteristics suitable for a variety of possible applications. Their compatibility with aq. environments has been made possible by the chem. functionalization of their surface, allowing for exploration of their interactions with biol. components including mammalian cells. Functionalized CNTs (f-CNTs) are being intensively explored in advanced biotechnol. applications ranging from mol. biosensors to cellular growth substrates. We have been exploring the potential of f-CNTs as delivery vehicles of biol. active mols. in view of possible biomedical applications, including vaccination and gene delivery. Recently we reported the capability of ammonium-functionalized single-walled CNTs to penetrate human and murine cells and facilitate the delivery of plasmid DNA leading to expression of marker genes. To optimize f-CNTs as gene delivery vehicles, it is essential to characterize their interactions with DNA. In the present report, we study the interactions of three types of f-CNTs, ammonium-functionalized single-walled and multiwalled carbon nanotubes (SWNT-NH3+; MWNT-NH3+), and lysine-functionalized single-walled carbon nanotubes (SWNT-Lys-NH3+), with plasmid DNA. Nanotube-DNA complexes were analyzed by SEM, surface plasmon resonance, PicoGreen dye exclusion, and agarose gel shift assay. The results indicate that all three types of cationic carbon nanotubes are able to condense DNA to varying degrees, indicating that both nanotube surface area and charge d. are crit. parameters that det. the interaction and electrostatic complex formation between f-CNTs with DNA. All three different f-CNT types in this study exhibited upregulation of marker gene expression over naked DNA using a mammalian (human) cell line. Differences in the levels of gene expression were correlated with the structural and biophys. data obtained for the f-CNT:DNA complexes to suggest that large surface area leading to very efficient DNA condensation is not necessary for effective gene transfer. However, it will require further investigation to det. whether the degree of binding and tight assocn. between DNA and nanotubes is a desirable trait to increase gene expression efficiency in vitro or in vivo. This study constitutes the first thorough investigation into the physicochem. interactions between cationic functionalized carbon nanotubes and DNA toward construction of carbon nanotube-based gene transfer vector systems.
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158Kateb, B.; Van Handel, M.; Zhang, L.; Bronikowski, M. J.; Manohara, H.; Badie, B. Neuroimage 2007, 37, S9Google ScholarThere is no corresponding record for this reference.
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159Herrero, M. A.; Toma, F. M.; Al-Jamal, K. T.; Kostarelos, K.; Bianco, A.; Da Ros, T.; Bano, F.; Casalis, L.; Scoles, G.; Prato, M. J. Am. Chem. Soc. 2009, 131, 9843Google ScholarThere is no corresponding record for this reference.
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160Podesta, J. E.; Al-Jamal, K. T.; Herrero, M. A.; Tian, B.; Ali-Boucetta, H.; Hegde, V.; Bianco, A.; Prato, M.; Kostarelos, K. Small 2009, 5, 1176Google ScholarThere is no corresponding record for this reference.
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161Ji, S. R.; Liu, C.; Zhang, B.; Yang, F.; Xu, J.; Long, J.; Jin, C.; Fu, D. L.; Ni, Q. X.; Yu, X. J. Biochim. Biophys. Acta 2010, 1806, 29Google ScholarThere is no corresponding record for this reference.
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162Patel, S.; Bhirde, A. A.; Rusling, J. F.; Chen, X.; Gutkind, J. S.; Patel, V. Pharmaceutics 2011, 3, 34Google ScholarThere is no corresponding record for this reference.
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163Prakash, S.; Malhotra, M.; Shao, W.; Tomaro-Duchesneau, C.; Abbasi, S. Adv. Drug Delivery Rev. 2011, 63, 1340Google ScholarThere is no corresponding record for this reference.
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164Wang, L.; Zhang, M.; Zhang, N.; Shi, J.; Zhang, H.; Li, M.; Lu, C.; Zhang, Z. Int. J. Nanomed. 2011, 6, 2641Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1entL7K&md5=013ad71c31ef75e67b3c0ebd48edfedcSynergistic enhancement of cancer therapy using a combination of docetaxel and photothermal ablation induced by single-walled carbon nanotubesWang, Lei; Zhang, Mingyue; Zhang, Nan; Shi, Jinjin; Zhang, Hongling; Li, Min; Lu, Chao; Zhang, ZhenzhongInternational Journal of Nanomedicine (2011), 6 (), 2641-2652CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)Background: Single-walled carbon nanotubes (SWNT) are poorly sol. in water, so their applications are limited. Therefore, aq. solns. of SWNT, designed by noncovalent functionalization and without toxicity, are required for biomedical applications. Methods: In this study, we conjugated docetaxel with SWNT via π-π accumulation and used a surfactant to functionalize SWNT noncovalently. The SWNT were then conjugated with docetaxel (DTX-SWNT) and linked with NGR (Asn-Gly-Arg) peptide, which targets tumor angiogenesis, to obtain a water-sol. and tumor-targeting SWNT-NGR-DTX drug delivery system. Results: SWNT-NGR-DTX showed higher efficacy than docetaxel in suppressing tumor growth in a cultured PC3 cell line in vitro and in a murine S180 cancer model. Tumor vols. in the S180 mouse model decreased considerably under near-IR radiation compared with the control group. Conclusion: The SWNT-NGR-DTX drug delivery system may be promising for high treatment efficacy with minimal side effects in future cancer therapy.
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165Mattheolabakis, G.; Rigas, B.; Constantinides, P. P. Nanomedicine (London, U.K.) 2012, 7, 1577Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1GlsLnK&md5=8d1efa760ba0be2410b25102e70c9734Nanodelivery strategies in cancer chemotherapy: biological rationale and pharmaceutical perspectivesMattheolabakis, George; Rigas, Basil; Constantinides, Panayiotis P.Nanomedicine (London, United Kingdom) (2012), 7 (10), 1577-1590CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)A review. Nanotechnol. is revolutionizing the authors' approach to drug delivery, a key determinant of drug efficacy. Here, the authors present cancer drug delivery strategies that exploit nanotechnol., providing first an overview of tumor biol. aspects that critically affect the design of drug delivery carriers, namely the enhanced permeability and retention effect, the lower tumor extracellular pH and tumor-specific antigens. In general, nanoscience-based approaches have circumvented limitations in the delivery of cancer therapeutics, related to their poor aq. soly. and toxicity issues with conventional vehicles and resulted in improved pharmacokinetics and biodistribution. Included in the discussion are promising examples and pharmaceutical perspectives on liposomes, nanoemulsions, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, carbon nanotubes and magnetic nanoparticles. As the cardinal features of the ideal multifunctional cancer drug nanocarrier are becoming clear, and drug development challenges are proactively addressed, the authors anticipate that future advances will enhance therapeutic outcomes by refining the delivery and targeting of complex payloads.
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166Cai, D.; Mataraza, J. M.; Qin, Z. H.; Huang, Z.; Huang, J.; Chiles, T. C.; Carnahan, D.; Kempa, K.; Ren, Z. Nat. Methods 2005, 2, 449Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXktlWhsrc%253D&md5=6f19e836a1f039aa6a20a0caa4b3890eHighly efficient molecular delivery into mammalian cells using carbon nanotube spearingCai, Dong; Mataraza, Jennifer M.; Qin, Zheng-Hong; Huang, Zhongping; Huang, Jianyu; Chiles, Thomas C.; Carnahan, David; Kempa, Kris; Ren, ZhifengNature Methods (2005), 2 (6), 449-454CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)Introduction of exogenous DNA into mammalian cells represents a powerful approach for manipulating signal transduction. The available techniques, however, are limited by low transduction efficiency and low cell viability after transduction. Here the authors report a highly efficient mol. delivery technique, named nanotube spearing, based on the penetration of nickel-embedded nanotubes into cell membranes by magnetic field driving. DNA plasmids contg. the enhanced green fluorescent protein (EGFP) sequence were immobilized onto the nanotubes, and subsequently speared into targeted cells. The authors have achieved an unprecedented high transduction efficiency in Bal17 B-lymphoma, ex vivo B cells and primary neurons with high viability after transduction. This technique may provide a powerful tool for highly efficient gene transfer into a variety of cells, esp. the hard-to-transfect cells.
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167Dobson, J. Gene Ther. 2006, 13, 283Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFaju78%253D&md5=6eb4f729a642c00f819ff26e849bc79bGene therapy progress and prospects: magnetic nanoparticle-based gene deliveryDobson, J.Gene Therapy (2006), 13 (4), 283-287CODEN: GETHEC; ISSN:0969-7128. (Nature Publishing Group)A review. The recent emphasis on the development of non-viral transfection agents for gene delivery has led to new physics and chem.-based techniques, which take advantage of charge interactions and energetic processes. One of these techniques which shows much promise for both in vitro and in vivo transfection involves the use of biocompatible magnetic nanoparticles for gene delivery. In these systems, therapeutic or reporter genes are attached to magnetic nanoparticles, which are then focused to the target site/cells via high-field/high-gradient magnets. The technique promotes rapid transfection and, as more recent work indicates, excellent overall transfection levels as well. The advantages and difficulties assocd. with magnetic nanoparticle-based transfection will be discussed as will the underlying phys. principles, recent studies and potential future applications.
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168Chen, M. L.; He, Y. J.; Chen, X. W.; Wang, J. H. Langmuir 2012, 28, 16469Google ScholarThere is no corresponding record for this reference.
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169Yu, J. G.; Jiao, F. P.; Chen, X. Q.; Jiang, X. Y.; Peng, Z. G.; Zeng, D. M.; Huang, D. S. J. Cancer Res. Ther. 2012, 8, 348Google Scholar169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjt1ygsw%253D%253D&md5=2b632bdc1b0a2c553fbd467dd5b5671aIrradiation-mediated carbon nanotubes' use in cancer therapyYu, Jin-Gang; Jiao, Fei-Peng; Chen, Xiao-Qing; Jiang, Xin-Yu; Peng, Zhi-Guang; Zeng, Dong-Ming; Huang, Du-ShuJournal of Cancer Research and Therapeutics (2012), 8 (3), 348-354CODEN: JCRTBK; ISSN:0973-1482. (Medknow Publications and Media Pvt. Ltd.)A review. Anticancer drugs such as biol. therapeutic proteins and peptides are used for treatment of a variety of tumors. However, their wider use has been hindered by their poor bioavailability and the uncontrollable sites of action in vivo. Cancer nano-therapeutics is rapidly progressing, which is being applied for solving some limitations of conventional drug delivery systems. To improve the bio-distribution of anticancer drugs, carbon nanotubes have been used as one of the most effective drug carriers. This review discusses the carbon nanotubes-mediated methods for the delivery of anticancer drugs, with emphasis on the radiation-induced drug-targeted releasing and selective photo-thermal cancer therapy.
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170Assali, M.; Cid, J. J.; Pernía-Leal, M.; Muñoz-Bravo, M.; Fernández, I.; Wellinger, R. E.; Khiar, N. ACS Nano 2013, 7, 2145Google ScholarThere is no corresponding record for this reference.
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171Gannon, C. J.; Cherukuri, P.; Yakobson, B. I.; Cognet, L.; Kanzius, J. S.; Kittrell, C.; Weisman, R. B.; Pasquali, M.; Schmidt, H. K.; Smalley, R. E.; Curley, S. A. Cancer 2007, 110, 2654Google ScholarThere is no corresponding record for this reference.
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172Biris, A. S.; Boldor, D.; Palmer, J.; Monroe, W. T.; Mahmood, M.; Dervishi, E.; Xu, Y.; Li, Z.; Galanzha, E. I.; Zharov, V. P. J. Biomed. Opt. 2009, 14, 021007Google ScholarThere is no corresponding record for this reference.
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173Vázquez, E.; Prato, M. ACS Nano 2009, 3, 3819Google ScholarThere is no corresponding record for this reference.
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174Tan, A.; Madani, S. Y.; Rajadas, J.; Pastorin, G.; Seifalian, A. M. J. Nanobiotechnol. 2012, 10, 34Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslyisbjO&md5=c55798010160b38abcccf2ca2368357aSynergistic photothermal ablative effects of functionalizing carbon nanotubes with a POSS-PCU nanocomposite polymerTan, Aaron; Madani, Seyed Yazdan; Rajadas, Jayakumar; Pastorin, Giorgia; Seifalian, Alexander M.Journal of Nanobiotechnology (2012), 10 (), 34CODEN: JNOAAO; ISSN:1477-3155. (BioMed Central Ltd.)Background: The application of nanotechnol. in biol. and medicine represents a significant paradigm shift in the approach to the treatment of cancer. Evidence suggests that when exposed to near-IR radiation (NIR), carbon nanotubes (CNTs) dissipate a substantial amt. of heat energy. We have developed a novel nanocomposite polymer, polyhedral oligomeric silsesquioxane poly (carbonate-urea) urethane (POSS-PCU). POSS-PCU displays excellent biocompatibility and has been used in making artificial organs as well as protective coatings for medical devices. Results: Functionalizing (or "coating") CNTs with POSS-PCU confers biocompatibility and increase the amt. of heat energy generated, by enhancing dispersion. Here we demonstrate that POSS-PCU-functionalized multi-walled CNTs (MWNTs) act synergistically together when exposed to NIR to thermally ablate cancer cells. Conclusion: Given that POSS-PCU has already been used in human in first-in-man studies as trachea, lacrimal duct, bypass graft and other organs, our long-term goal is to take POSS-PCU coated CNTs to clin. studies to address the treatment of cancer by optimizing its therapeutic index and increasing its specificity via antibody conjugation.
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175Levi-Polyachenko, N. H.; Merkel, E. J.; Jones, B. T.; Carroll, D. L.; Stewart, J. H., IV. Mol. Pharmaceutics 2009, 6, 1092Google Scholar175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXotV2msLg%253D&md5=e2779e7a6953a4e2bf98989b7c702648Rapid Photothermal Intracellular Drug Delivery Using Multiwalled Carbon NanotubesLevi-Polyachenko, Nicole H.; Merkel, Eric J.; Jones, Bradley T.; Carroll, David L.; Stewart, John H., IVMolecular Pharmaceutics (2009), 6 (4), 1092-1099CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Carbon nanotubes are unique materials that absorb IR radiation, esp. between 700 and 1100 nm, where body tissues are most transparent. Absorbed IR promotes mol. oscillation leading to efficient heating of the surrounding environment. A method to enhance drug localization for peritoneal malignancies is perfusion of warm (40-42°) chemotherapeutic agents in the abdomen. However, all tissues in the peritoneal cavity are subjected to enhanced drug delivery due to increased cell membrane permeability at hyperthermic temps. Here we show that rapid heating (within ten seconds) of colorectal cancer cells to 42°, using IR stimulation of nanotubes as a heat source, in the presence of the drugs oxaliplatin or mitomycin C, is as effective as two hours of radiative heating at 42° for the treatment of peritoneal dissemination of colorectal cancer. We demonstrate increased cell membrane permeability due to hyperthermia from multiwalled carbon nanotubes in close proximity to cell membranes and that the amt. of drug internalized by colorectal cancer cells heated quickly using carbon nanotubes equals levels achieved during routine application of hyperthermia at 42°. This approach has the potential to be used as a rapid bench to bedside clin. therapeutic agent with significant impact for localizing chemotherapy agents during the surgical management of peritoneal dissemination of colorectal cancer.
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176Chakravarty, P.; Marches, R.; Zimmerman, N. S.; Swafford, A. D.; Bajaj, P.; Musselman, I. H.; Pantano, P.; Draper, R. K.; Vitetta, E. S. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 8697Google ScholarThere is no corresponding record for this reference.
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177Kim, J. W.; Shashkov, E. V.; Galanzha, E. I.; Kotagiri, N.; Zharov, V. P. Lasers Surg. Med. 2007, 39, 622Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2srnt1OgtA%253D%253D&md5=80b85023b981701dde5dfb8b146e5637Photothermal antimicrobial nanotherapy and nanodiagnostics with self-assembling carbon nanotube clustersKim Jin-Woo; Shashkov Evgeny V; Galanzha Ekaterina I; Kotagiri Nalinikanth; Zharov Vladimir PLasers in surgery and medicine (2007), 39 (7), 622-34 ISSN:0196-8092.BACKGROUND AND OBJECTIVES: Unique properties of carbon nanotubes (CNTs) would open new avenues for addressing challenges to realize rapid and sensitive antimicrobial diagnostics and therapy for human pathogens. In this study, new CNTs' capabilities for photothermal (PT) antimicrobial nanotherapy were explored in vitro using Escherichia coli as a model bacterium. STUDY DESIGN/MATERIALS AND METHODS: Single-walled carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs) were incubated with E. coli K12 strain. CNTs' locations in bacteria and laser-induced thermal and accompanied effects around CNTs were estimated with TEM and PT microscopy, respectively. Multi-pulse lasers at 532 and 1064 nm with 12-ns pulse duration were used for irradiating sample mixtures at different laser fluences. Cell viability was evaluated using a bacterial viability test kit and epi-fluorescence microscopy. RESULTS: This study revealed CNTs' high binding affinity to bacteria, their capability to self-assemble as clusters at bacteria surfaces, and their inherent near-infrared (NIR) laser responsiveness. Cell viability was affected neither by CNTs alone nor by NIR irradiations alone. Notable changes in bacteria viability, caused by local thermal and accompanied bubble-formation phenomena, were observed starting at laser fluences of 0.1-0.5 J/cm(2) with complete bacteria disintegration at 2-3 J/cm(2) at both wavelengths. Furthermore, ethanol in reaction mixtures significantly (more than one order) enhanced bubble formation phenomena. CONCLUSION: This first application of laser-activated CNTs as PT contrast antimicrobial agents demonstrated its great potential to cause irreparable damages to disease-causing pathogens as well as to detect the pathogens at single bacterium level. This unique integration of laser and nanotechnology may also be used for drinking water treatment, food processing, disinfection of medical instrumentation, and purification of grafts and implants. Furthermore, the significant ethanol-induced enhancement of bubble formation provides another unique possibility to improve the efficiency of selective nanophotothermolysis for treating cancers, wounds, and vascular legions.
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178Stacey, M.; Osgood, C.; Kalluri, B. S.; Cao, W.; Elsayed-Ali, H.; Abdel-Fattah, T. Biomed. Mater. 2011, 6, 011002Google ScholarThere is no corresponding record for this reference.
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179Kawaguchi, M.; Yamazaki, J.; Ohno, J.; Fukushima, T. Int. J. Nanomed. 2012, 7, 4363Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1SnsL7O&md5=5d82cdfcdd9e7ace3478d685d8d06917Preparation and binding study of a complex made of DNA-treated single-walled carbon nanotubes and antibody for specific delivery of a "molecular heater" platformKawaguchi, Minoru; Yamazaki, Jun; Ohno, Jun; Fukushima, TadaoInternational Journal of Nanomedicine (2012), 7 (), 4363-4372CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)Carbon nanotubes have been explored as heat-delivery vehicles for thermal ablation of tumors. To use single-walled carbon nanotubes (SWNT) as a "mol. heater" for hyperthermia therapy in cancer, stable dispersibility and smart-delivery potential will be needed, as well as lack of toxicity. This paper reports the prepn. of a model complex comprising DNA-treated SWNT and anti-human IgG antibody and the specific binding ability of this model complex with the targeted protein, i.e., human IgG. Treatment with double-stranded DNA enabled stable dispersibility of a complex composed of SWNT and the antibody under physiol. conditions. Quartz crystal microbalance results suggest that there was one immobilized IgG mol. to every 21,700 carbon atoms in the complex contg. DNA-treated SWNT and the antibody. The DNA-SWNT antibody complex showed good selectivity for binding to the targeted protein. Binding anal. revealed that treatment with DNA did not interfere with binding affinity or capacity between the immobilized antibody and the targeted protein. The results of this study demonstrate that the DNA-SWNT antibody complex is a useful tool for use as a smart "mol. heater" platform applicable to various types of antibodies targeting a specific antigen.
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180Tan, A.; Yildirimer, L.; Rajadas, J.; De La Peña, H.; Pastorin, G.; Seifalian, A. Nanomedicine (London, U.K.) 2011, 6, 1101Google ScholarThere is no corresponding record for this reference.
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181Moon, H. K.; Lee, S. H.; Choi, H. C. ACS Nano 2009, 3, 3707Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlCkur7F&md5=1246d3a800f6cf3858f1a629fff9467bIn Vivo Near-Infrared Mediated Tumor Destruction by Photothermal Effect of Carbon NanotubesMoon, Hye-Kyung; Lee, Sang-Ho; Choi, Hee-CheulACS Nano (2009), 3 (11), 3707-3713CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)The photothermal therapy using nanomaterials has been recently attracted as an efficient strategy for the next generation of cancer treatments. Single walled carbon nanotube (SWNT) is an upcoming potent candidate for the photothermal therapeutic agent since it generates significant amts. of heat upon excitation with near-IR light (NIR, λ = 700-1100 nm) which is transparent to biol. systems including skins. Such a photothermal effect can be employed to induce thermal cell death in a noninvasive manner. Here, we demonstrate in vivo obliteration of solid malignant tumors by the combined treatments of SWNTs and NIR irradn. The photothermally treated mice displayed complete destruction of the tumors without harmful side effects or recurrence of tumors over 6 mo, while the tumors treated in other control groups were continuously grown until the death of the mice. Most of the injected SWNTs were almost completely excreted from mice bodies in about 2 mo through biliary or urinary pathway. These results suggest that SWNTs may potentially serve as an effective photothermal agent and pave the way to future cancer therapeutics.
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182Iancu, C.; Mocan, L. Int. J. Nanomed. 2011, 6, 1675Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFGkt7vO&md5=5ae1f075c68ddae65fbc481e169a7ea8Advances in cancer therapy through the use of carbon nanotube-mediated targeted hyperthermiaIancu, Cornel; Mocan, LucianInternational Journal of Nanomedicine (2011), 6 (), 1675-1684CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)A review. Carbon nanotubes (CNTs) are emerging versatile tools in nanomedicine applications, particularly in the field of cancer targeting. Due to diverse surface chem. and unique thermal properties, CNTs can act as strong optical absorbers in near IR light where biol. systems prove to be highly transparent. The process of laser-mediated ablation of cancer cells marked with biofunctionalized CNTs is frequently termed "nanophotothermolysis". This paper illustrates the potential of engineered CNTs as laser-activated photothermal agents for the selective nanophotothermolysis of cancer cells.
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183Evans, M.; Kaufman, M. Nature 1981, 292, 154Google ScholarThere is no corresponding record for this reference.
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184Takahashi, K.; Tanabe, K.; Ohnuki, M.; Narita, M.; Ichisaka, T.; Tomoda, K.; Yamanaka, S. Cell 2007, 131, 861Google ScholarThere is no corresponding record for this reference.
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185Harrison, B. S.; Atala, A. Biomaterials 2007, 28, 344Google ScholarThere is no corresponding record for this reference.
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186Abarrategi, A.; Gutiérrez, M. C.; Moreno-Vicente, C.; Hortigüela, M. J.; Ramos, V.; López-Lacomba, J. L.; Ferrer, M. L.; del Monte, F. Biomaterials 2008, 29, 94Google ScholarThere is no corresponding record for this reference.
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187Tran, P. A.; Zhang, L.; Webster, T. J. Adv. Drug Delivery Rev. 2009, 61, 1097Google ScholarThere is no corresponding record for this reference.
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188Zhang, L.; Webster, T. J. Nano Today 2009, 4, 66– 80Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXkvFGit7k%253D&md5=c5429e83ab7d03baebe8911f1def821bNanotechnology and nanomaterials: promises for improved tissue regenerationZhang, Lijie; Webster, Thomas J.Nano Today (2009), 4 (1), 66-80CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)A review. Tissue engineering and regenerative medicine aim to develop biol. substitutes that restore, maintain, or improve damaged tissue and organ functionality. While tissue engineering and regenerative medicine have hinted at much promise in the last several decades, significant research is still required to provide exciting alternative materials to finally solve the numerous problems assocd. with traditional implants. Nanotechnol., or the use of nanomaterials (defined as those materials with constituent dimensions less than 100 nm), may have the answers since only these materials can mimic surface properties (including topog., energy, etc.) of natural tissues. For these reasons, over the last decade, nanomaterials have been highlighted as promising candidates for improving traditional tissue engineering materials. Importantly, these efforts have highlighted that nanomaterials exhibit superior cytocompatible, mech., elec., optical, catalytic and magnetic properties compared to conventional (or micron structured) materials. These unique properties of nanomaterials have helped to improve various tissue growth over what is achievable today. In this review paper, the promise of nanomaterials for bone, cartilage, vascular, neural and bladder tissue engineering applications will be reviewed. Moreover, as an important future area of research, the potential risk and toxicity of nanomaterial synthesis and use related to human health are emphasized.
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189Kubinová, S.; Syková, E. Minim. Invasive Ther. Allied Technol. 2010, 19, 144Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3czlvV2gtw%253D%253D&md5=2e2562b4c3caae1724847b88907aa739Nanotechnologies in regenerative medicineKubinova Sarka; Sykova EvaMinimally invasive therapy & allied technologies : MITAT : official journal of the Society for Minimally Invasive Therapy (2010), 19 (3), 144-56 ISSN:.Nanotechnology offers promising perspectives in biomedical research as well as in clinical practice. To cover some of the latest nanotechnology trends in regenerative medicine, this review will focus on the use of nanomaterials for tissue engineering and cell therapy. Nanofibrous materials that mimic the native extracellular matrix and promote the adhesion of various cells are being developed as tissue-engineered scaffolds for the skin, bone, vasculature, heart, cornea, nervous system, and other tissues. A range of novel materials has been developed to enhance the bioactive or therapeutic properties of these nanofibrous scaffolds via surface modifications, including the immobilization of functional cell-adhesive ligands and bioactive molecules such as drugs, enzymes and cytokines. As a new approach, nanofibers prepared by using industrial scale needleless technology have been recently introduced, and their use as scaffolds to treat spinal cord injury or as cell carriers for the regeneration of the injured cornea is the subject of much current study. Cell therapy is a modern approach of regenerative medicine for the treatment of various diseases or injuries. To follow the migration and fate of transplanted cells, superparamagnetic iron oxide nanoparticles have been developed for cell labeling and non-invasive MRI monitoring of cells in the living organism, with successful applications in, e.g, the central nervous system, heart, liver and kidney and also in pancreatic islet and stem cell transplantation.
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190Dvir, T.; Timko, B. P.; Kohane, D. S.; Langer, R. Nat. Nanotechnol. 2011, 6, 13Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1Wju73E&md5=ce31677488ed9ca2549efacac9a67c0fNanotechnological strategies for engineering complex tissuesDvir, Tal; Timko, Brian P.; Kohane, Daniel S.; Langer, RobertNature Nanotechnology (2011), 6 (1), 13-22CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)A review. Tissue engineering aims at developing functional substitutes for damaged tissues and organs. Before transplantation, cells are generally seeded on biomaterial scaffolds that recapitulate the extracellular matrix and provide cells with information that is important for tissue development. Here we review the nanocomposite nature of the extracellular matrix, describe the design considerations for different tissues and discuss the impact of nanostructures on the properties of scaffolds and their uses in monitoring the behavior of engineered tissues. We also examine the different nanodevices used to trigger certain processes for tissue development, and offer our view on the principal challenges and prospects of applying nanotechnol. in tissue engineering.
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191van der Zande, M.; Junker, R.; Walboomers, X. F.; Jansen, J. A. Tissue Eng., Part B 2011, 17, 57Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpvFSrtw%253D%253D&md5=e84c5020bbeb3f4e86478ee5967a05c6Carbon Nanotubes in Animal Models: A Systematic Review on Toxic Potentialvan der Zande, Meike; Junker, Ruediger; Walboomers, X. Frank; Jansen, John A.Tissue Engineering, Part B: Reviews (2011), 17 (1), 57-69CODEN: TEPBAB; ISSN:1937-3368. (Mary Ann Liebert, Inc.)A review. Amongst the engineered nanomaterials, esp. carbon nanotubes (CNTs) have received considerable attention for application in tissue engineering scaffolds. CNTs are considered promising on behalf of their physicochem. properties, yet such nanomaterials also have been assocd. with potentially hazardous effects on human health. To gain insight into the toxicity aspects of CNTs in vivo, the present study presents a systematic review of literature. After screening of literature through defined inclusion and exclusion criteria, and subsequent data extn., it can be concluded that pulmonary administered CNTs have the capacity to induce toxicity in the lung area. However, conclusions for other organs, or on systemic toxicity, are yet premature. In addn., the carcinogenic potential of CNTs is also still ambiguous, because contradictive results are presented. Intrinsic factors, such as material characteristics, and assocd. distribution and agglomeration patterns influence the toxic potential of CNTs. Similarly, environmental factors such as the exposure route, preexisting allergies, pathol. infections, or air pollutant exposure are significant. Despite the many reports published currently, more studies will be required to gain full understanding of the toxic potential of CNTs and esp. the underlying mechanisms. For this end, development of standardized protocols and reliable nanodetection techniques will form prerequisites.
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192MacDonald, R. A.; Laurenzi, B. F.; Viswanathan, G.; Ajayan, P. M.; Stegemann, J. P. J. Biomed. Mater. Res., Part A 2005, 74, 489Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXpsFaitr0%253D&md5=e2a959135aa3fa36b615836444b27ed3Collagen-carbon nanotube composite materials as scaffolds in tissue engineeringMacDonald, Rebecca A.; Laurenzi, Brendan F.; Viswanathan, Gunaranjan; Ajayan, Pulickel M.; Stegemann, Jan P.Journal of Biomedical Materials Research, Part A (2005), 74A (3), 489-496CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Carbon nanotubes (CNT) are attractive for use in fiber-reinforced composite materials due to their very high aspect ratio, combined with outstanding mech. and elec. properties. Composite materials comprising a collagen matrix with embedded CNT were prepd. by mixing solubilized Type I collagen with solns. of carboxylated single-walled carbon nanotubes (SWNT) at concns. of 0, 0.2, 0.4, 0.8, and 2.0 wt.%. Living smooth muscle cells were incorporated at the time of collagen gelation to produce cell-seeded collagen-CNT composite matrixes. Constructs contg. 2.0 wt.% CNT exhibited delayed gel compaction, relative to lower concns. that compacted at the same rate as pure collagen controls. Cell viability in all constructs was consistently above 85% at both day 3 and day 7, whereas cell no. in CNT-contg. constructs was lower than in control constructs at day 3, though statistically unchanged by day 7. SEM showed phys. interactions between CNT and collagen matrix. Raman spectroscopy confirmed the presence of CNT at the expected diam. (0.85-1.30 nm), but did not indicate strong mol. interactions between the collagen and CNT components. Such collagen-CNT composite matrixes may have utility as scaffolds in tissue engineering, or as components of biosensors or other medical devices.
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193Cao, Y.; Zhou, Y. M.; Shan, Y.; Ju, H. X.; Xue, X. J. J Nanosci. Nanotechnol. 2007, 7, 447Google ScholarThere is no corresponding record for this reference.
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194Meng, J.; Kong, H.; Han, Z.; Wang, C.; Zhu, G.; Xie, S.; Xu, H. J. Biomed. Mater. Res., Part A 2009, 88, 105Google Scholar194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cjlsVOiug%253D%253D&md5=2eeb378f1715011ed0d303e33982b733Enhancement of nanofibrous scaffold of multiwalled carbon nanotubes/polyurethane composite to the fibroblasts growth and biosynthesisMeng Jie; Kong Hua; Han Zhaozhao; Wang Chaoying; Zhu Guangjin; Xie Sishen; Xu HaiyanJournal of biomedical materials research. Part A (2009), 88 (1), 105-16 ISSN:.In this work, the effect of nanofibrous structure and multiwalled carbon nanotubes (MWNTs) incorporation in the polyurethane (PU) on the fibroblasts growth behavior was studied. The nanofibrous scaffold of multiwalled carbon nanotubes and polyurethane composite (MWNT/PU) with an average fiber diameter of 300-500 nm was fabricated by electrospinning technique. The nanofibrous scaffold of PU, smooth film of PU, and MWNT/PU were also prepared as controls. Cell viability assay, laser confocal microscopy, and scanning electron microscopy were applied to evaluate cell adhesion, proliferation, and cytoskeletal development on the scaffolds, respectively. Cell-released protein was analyzed by Bradford protein assay, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), mass spectrometry, and transwell assay, respectively. Experimental results demonstrated that the scaffold with nanofibrous structure and MWNTs incorporation exhibited highest enhancement not only to the cell adhesion and proliferation but also to the cell migration and aggregation. Besides, cells cultured on the nanofibrous scaffold of MWNT/PU released the largest amount of proteins including collagen in comparison with those on the other substrates. Hence, the nanofibrous architecture and MWNTs incorporation provided favorite interactions to the cells, which implied the application potentials of the nanofibrous composite for tissue repair and regeneration.
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195Han, Z.; Kong, H.; Meng, J.; Wang, C.; Xie, S.; Xu, H. J. Nanosci. Nanotechnol. 2009, 9, 1400Google ScholarThere is no corresponding record for this reference.
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196Mei, F.; Zhong, J.; Yang, X.; Ouyang, X.; Zhang, S.; Hu, X.; Ma, Q.; Lu, J.; Ryu, S.; Deng, X. Biomacromolecules 2007, 8, 3729Google ScholarThere is no corresponding record for this reference.
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197Cho, S. Y.; Yun, Y. S.; Kim, E. S.; Kim, M. S.; Jin, H. J. J. Nanosci. Nanotechnol. 2011, 11, 801Google ScholarThere is no corresponding record for this reference.
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198Meng, J.; Song, L.; Kong, H.; Zhu, G.; Wang, C.; Xu, L.; Xie, S.; Xu, H. J. Biomed. Mater. Res., Part A 2006, 79, 298Google Scholar198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFarsrfJ&md5=cedbdc432f474254ac2cd985ea30448dUsing single-walled carbon nanotubes nonwoven films as scaffolds to enhance long-term cell proliferation in vitroMeng, Jie; Song, Li; Meng, Jie; Kong, Hua; Zhu, Guangjin; Wang, Chaoying; Xu, Lianghua; Xie, Sishen; Xu, HaiyanJournal of Biomedical Materials Research, Part A (2006), 79A (2), 298-306CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Carbon nanotubes have attracted intensive interests in biomedical research in recent years. In this study, a novel type of carbon nanotubes material so called nonwoven single-walled carbon nanotubes (SWNTs) with nanotopog. structure and macroscopic vol. was used as cell growing scaffold. The morphol. and surface chem. of nonwoven SWNTs were obsd. and characterized through SEM and XPS, resp. The cells were cultivated in nonwoven SWNTs and in other types of substrate as control. The cells growth behaviors including adhesion, proliferation, and cytoskeletal development was investigated by using cell viability assay and confocal observation. The exptl. results indicated that nonwoven SWNTs exhibited significant enhancement to the cells adhesion and proliferation in at least 3 wk. Numerous and highly organized cytoskeletal structures were obsd. when the cells were cultured in nonwoven SWNTs. Furthermore, an obvious promotional influence of the cells cultivated in nonwoven SWNTs scaffold upon the proliferation of those growing in the other kind of substrate through cell-cell communication had been found. The results obtained in this work are of significance to in vitro cell amplification in large scale, tissue regeneration, or guided repair, as well as biomedical device application.
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199Antoniadou, E. V.; Cousins, B. G.; Seifalian, A. M. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2010, 2010, 815Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cbptVCitg%253D%253D&md5=009d475caaed8d23055c1d2a1581b009Development of conductive polymer with carbon nanotubes for regenerative medicine applicationsAntoniadou Eleni V; Cousins Brian G; Seifalian Alexander MConference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference (2010), 2010 (), 815-8 ISSN:1557-170X.Multi-wall carbon nanotube (MWCNT)/polymer composites are hybrid materials that combine numerous mechanical, electrical and chemical properties and thus, constitute ideal biomaterials for a wide range of regenerative medicine applications. Although, complete dispersion of MWCNT in a polymer matrix has rarely been achieved, in this study we have studied the dispersibility of MWCNT in POSS-PCU, a novel polymer based on polyprolactone and polycarbonate polyurethane (PCU) with an incorporated polyhedral oligomeric silsesquioxane (POSS). Furthermore, we developed a computational model that can visualise MWCNTs in order to predict the range of dispersibility and provide a 3-D mathematical model that can predict the chemical concentration for ideal nanocomposites.
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200Mackle, J. N.; Blond, D. J.; Mooney, E.; McDonnell, C.; Blau, W. J.; Shaw, G.; Barry, F. P.; Murphy, J. M.; Barron, V. Macromol. Biosci. 2011, 11, 1272Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFSksLzM&md5=067ccbcb0c26d7fb2d2e1374b23b5deeIn vitro Characterization of an Electroactive Carbon-Nanotube-Based Nanofiber Scaffold for Tissue EngineeringMackle, Joseph N.; Blond, David J.-P.; Mooney, Emma; McDonnell, Caitlin; Blau, Werner J.; Shaw, Georgina; Barry, Frank P.; Murphy, J. Mary; Barron, ValerieMacromolecular Bioscience (2011), 11 (9), 1272-1282CODEN: MBAIBU; ISSN:1616-5187. (Wiley-VCH Verlag GmbH & Co. KGaA)In an effort to reduce organ replacement and enhance tissue repair, there was a tremendous effort to create biomechanically optimized scaffolds for tissue engineering applications. In contrast, the development and characterization of electroactive scaffolds has attracted little attention. Consequently, the creation and characterization of a carbon nanotube based poly(lactic acid) nanofiber scaffold is described herein. After 28 d in physiol. soln. at 37 °C, a change in the mass, chem. properties and polymer morphol. is seen, while the mech. properties and phys. integrity are unaltered. No adverse cytotoxic affects are seen when mesenchymal stem cells are cultured in the presence of the scaffold. Taken together, these data auger well for electroactive tissue engineering.
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201Supronowicz, P. R.; Ajayan, P. M.; Ullmann, K. R.; Arulanandam, B. P.; Metzger, D. W.; Bizios, R. J. Biomed. Mater. Res. 2002, 59, 499Google ScholarThere is no corresponding record for this reference.
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202Bajaj, P.; Khang, D.; Webster, T. J. Int. J. Nanomed. 2006, 1, 361Google Scholar202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xhtlantb%252FP&md5=297f043265bba7b9bb3b7c171a173214Control of spatial cell attachment on carbon nanofiber patterns on polycarbonate urethaneBajaj, Piyush; Khang, Dongwoo; Webster, Thomas J.International Journal of Nanomedicine (2006), 1 (3), 361-365CODEN: IJNNHQ; ISSN:1176-9114. (Dove Medical Press (NZ) Ltd.)A highly aligned pattern of carbon nanofibers (CNF) on polycarbonate urethane (PCU) for tissue engineering applications was created by placing a CNF-ethanol soln. in 30μm width copper grid grooves on top of PCU. In vitro results provided the first evidence that fibroblasts and vascular smooth muscle cells selectively adhered to the PCU regions. However, endothelial cells did not display a preference for adhesion to the CNF compared with PCU regions. Previous studies have shown selective adhesion of osteoblasts (bone-forming cells) on CNF compared with PCU regions. Thus, the present results suggest that CNF aligned on PCU may be useful substrates for the control of spatial cell attachment, criteria useful for the design of a wide range of tissue engineering materials, from orthopedic to vascular.
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203Shi, X.; Hudson, J. L.; Spicer, P. P.; Tour, J. M.; Krishnamoorti, R.; Mikos, A. G. Biomacromolecules 2006, 7, 2237Google ScholarThere is no corresponding record for this reference.
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204Lin, C.; Wang, Y.; Lai, Y.; Yang, W.; Jiao, F.; Zhang, H.; Ye, S.; Zhang, Q. Colloids Surf., B 2011, 83, 367Google ScholarThere is no corresponding record for this reference.
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205Zanello, L. P.; Zhao, B.; Hu, H.; Haddon, R. C. Nano Lett. 2006, 6, 562Google ScholarThere is no corresponding record for this reference.
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206Akasaka, T.; Warari, F.; Sato, Y.; Tohji, K. Mater. Sci. Eng., C 2006, 26, 675Google Scholar206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjvFynsb8%253D&md5=81a8b0ac6844846de34c839bd137c595Apatite formation on carbon nanotubesAkasaka, Tsukasa; Watari, Fumio; Sato, Yoshinori; Tohji, KazuyukiMaterials Science & Engineering, C: Biomimetic and Supramolecular Systems (2006), 26 (4), 675-678CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)Apatite coating on C nanotubes (CNTs) was done with a biomimetic coating method. The multi-walled CNTs (MWNTs) of curled shape with ∼30 nm in diam. were immersed for 2 wk in the simulated body fluid. Observation by SEM showed the formation of apatite on the MWNTs surface. The clusters of spherules consisting of needle-shaped apatite crystallites were massively grown on the aggregated MWNTs. The crystallites of 100 nm in width and 200-500 nm in length were grown perpendicularly to the longitudinal direction and radially originating from a common center of a single MWNT. Thus, the architecture of cryst. apatite at nano-scale levels could be produced by simple method and the MWNT may be acting as core for initial crystn. of apatite.
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207Balani, K.; Anderson, R.; Laha, T.; Andara, M.; Tercero, J.; Crumpler, E.; Agarwal, A. Biomaterials 2007, 28, 618Google ScholarThere is no corresponding record for this reference.
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208Giannona, S.; Firkowska, I.; Rojas-Chapana, J.; Giersig, M. J. Nanosci. Nanotechnol. 2007, 7, 1679Google ScholarThere is no corresponding record for this reference.
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209Wang, W.; Watari, F.; Omori, M.; Liao, S.; Zhu, Y.; Yokoyama, A.; Uo, M.; Kimura, H.; Ohkubo, A. J. Biomed. Mater. Res., Part B 2007, 82, 223Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXntlykurc%253D&md5=e917710ba2a9983b8f2e90bb51ec6ec9Mechanical properties and biological behavior of carbon nanotube/polycarbosilane composites for implant materialsWang, Wei; Watari, Fumio; Omori, Mamoru; Liao, Susan; Zhu, Yuhe; Yokoyama, Atsuro; Uo, Motohiro; Kimura, Hisamichi; Ohkubo, AkiraJournal of Biomedical Materials Research, Part B: Applied Biomaterials (2007), 82B (1), 223-230CODEN: JBMRGL; ISSN:1552-4973. (John Wiley & Sons, Inc.)Multiwalled carbon nanotube/polycarbosilane (MWCNT/PCS) composites were fabricated by the spark plasma sintering (SPS) method. The MWCNT/PCS composites consisted of MWCNTs and nanosized SiC particles pyrolyzed from PCS and possessing good mech. properties for bone tissue repair or dental implantation. The MWCNT/PCS composites were implanted in the s.c. tissue and femur of rats at 1 and 4 wk after implantation. Histol. investigations showed that there was little inflammatory response in the s.c. tissue, and newly formed bone tissue was obsd. in the femur. These results indicated that the MWCNT/PCS composite had little prophlogistic effect and good osteocond. The study suggested the possibility that the MWCNT/PCS composite could be a candidate bone-substitute and dental-implant material in the future.
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210Nayak, T. R.; Jian, L.; Phua, L. C.; Ho, H. K.; Ren, Y.; Pastorin, G. ACS Nano 2010, 4, 7717Google ScholarThere is no corresponding record for this reference.
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211Niu, L.; Kua, H.; Chua, D. H. Langmuir 2010, 26, 4069Google ScholarThere is no corresponding record for this reference.
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212Ciapetti, G.; Granchi, D.; Devescovi, V.; Baglio, S. R.; Leonardi, E.; Martini, D.; Jurado, M. J.; Olalde, B.; Armentano, I.; Kenny, J. M.; Walboomers, F. X.; Alava, J. I.; Baldini, N. Int. J. Mol. Sci. 2012, 13, 2439Google Scholar212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjsFyhsbg%253D&md5=dd590fa894587de8c03e10e89b635f86Enhancing osteoconduction of PLLA-based nanocomposite scaffolds for bone regeneration using different biomimetic signals to MSCsCiapetti, Gabriela; Granchi, Donatella; Devescovi, Valentina; Baglio, Serena R.; Leonardi, Elisa; Martini, Desiree; Jurado, Maria Jesus; Olalde, Beatriz; Armentano, Ilaria; Kenny, Jose M.; Walboomers, Frank X.; Alava, Jose Inaki; Baldini, NicolaInternational Journal of Molecular Sciences (2012), 13 (), 2439-2458CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)In bone engineering, the adhesion, proliferation and differentiation of mesenchymal stromal cells rely on signaling from chemico-phys. structure of the substrate, therefore prompting the design of mimetic "extracellular matrix"-like scaffolds. In this study, three-dimensional porous poly--lactic acid (PLLA)-based scaffolds have been mixed with different components, including single walled carbon nanotubes (CNT), micro-hydroxyapatite particles (HA), and BMP2, and treated with plasma (PT), to obtain four different nanocomposites: PLLA + CNT, PLLA + CNTHA, PLLA + CNT + HA + BMP2 and PLLA + CNT + HA + PT. Adult bone marrow mesenchymal stromal cells (MSCs) were derived from the femur of orthopaedic patients, seeded on the scaffolds and cultured under osteogenic induction up to differentiation and mineralization. The release of specific metabolites and temporal gene expression profiles of marrow-derived osteoprogenitors were analyzed at definite time points, relevant to in vitro culture as well as in vivo differentiation. As a result, the role of the different biomimetic components added to the PLLA matrix was deciphered, with BMP2-added scaffolds showing the highest biomimetic activity on cells differentiating to mature osteoblasts. The modification of a polymeric scaffold with reinforcing components which also work as biomimetic cues for cells can effectively direct osteoprogenitor cells differentiation, so as to shorten the time required for mineralization.
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213Usui, Y.; Aoki, K.; Narita, N.; Murakami, N.; Nakamura, I.; Nakamura, K.; Ishigaki, N.; Yamazaki, H.; Horiuchi, H.; Kato, H.; Taruta, S.; Kim, Y. A.; Endo, M.; Saito, N. Small 2008, 4, 240Google ScholarThere is no corresponding record for this reference.
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214Saito, N.; Okada, T.; Horiuchi, H.; Murakami, N.; Takahashi, J.; Nawata, M.; Ota, H.; Nozaki, K.; Takaoka, K. Nat. Biotechnol. 2001, 19, 332Google ScholarThere is no corresponding record for this reference.
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215Bhattacharya, M.; Wutticharoenmongkol-Thitiwongsawet, P.; Hamamoto, D. T.; Lee, D.; Cui, T.; Prasad, H. S.; Ahmad, M. J. Biomed. Mater. Res., Part A 2011, 96, 75Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVGku7zM&md5=7e3c0d86d0b66a99725a428bbe40b226Bone formation on carbon nanotube compositeBhattacharya, Mrinal; Wutticharoenmongkol-Thitiwongsawet, Patcharaporn; Hamamoto, Darryl T.; Lee, Dongjin; Cui, Tianhong; Prasad, Hari S.; Ahmad, MansurJournal of Biomedical Materials Research, Part A (2011), 96A (1), 75-82CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)The effects of a layer-by-layer assembled carbon nanotube composite (CNT-comp) on osteoblasts in vitro and bone tissue in vivo in rats were studied. The effects of CNT-comp on osteoblasts were compared against the effects by com. pure titanium (cpTi) and tissue culture dishes. Cell proliferation on the CNT-comp and cpTi were similar. However, cell differentiation, measured by alk. phosphatase activity and matrix mineralization, was better on the CNT-comp. When implanted in crit.-sized rat calvarial defect, the CNT-comp permitted bone formation and bone repair without signs of rejection or inflammation. These data indicate that CNT-comp may be a promising substrate for use as a bone implant or as a scaffold for tissue engineering. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2010.
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216Kasai, T.; Matsumura, S.; Iizuka, T.; Shiba, K.; Kanamori, T.; Yudasaka, M.; Iijima, S.; Yokoyama, A. Nanotechnology 2011, 22, 065102Google ScholarThere is no corresponding record for this reference.
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217Narita, N.; Kobayashi, Y.; Nakamura, H.; Maeda, K.; Ishihara, A.; Mizoguchi, T.; Usui, Y.; Aoki, K.; Simizu, M.; Kato, H.; Ozawa, H.; Udagawa, N.; Endo, M.; Takahashi, N.; Saito, N. Nano Lett. 2009, 9, 1406Google ScholarThere is no corresponding record for this reference.
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218Shimizu, M.; Kobayashi, Y.; Mizoguchi, T.; Nakamura, H.; Kawahara, I.; Narita, N.; Usui, Y.; Aoki, K.; Hara, K.; Haniu, H.; Ogihara, N.; Ishigaki, N.; Nakamura, K.; Kato, H.; Kawakubo, M.; Dohi, Y.; Taruta, S.; Kim, Y. A.; Endo, M.; Ozawa, H.; Udagawa, N.; Takahashi, N.; Saito, N. Adv. Mater. 2012, 24, 2176Google ScholarThere is no corresponding record for this reference.
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219Olakowska, E.; Woszczycka-Korczyńska, I.; Jędrzejowska-Szypułka, H.; Lewin-Kowalik, J. Folia Neuropathol. 2010, 48, 231Google Scholar219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1yqu7c%253D&md5=09e3e1a6389bbc15368feec76f6765d5Application of nanotubes and nanofibres in nerve repair. A reviewOlakowska, Edyta; Woszczycka-Korczynska, Izabella; Jedrzejowska-Szypulka, Halina; Lewin-Kowalik, JoannaFolia Neuropathologica (2010), 48 (4), 231-237CODEN: FONEEW; ISSN:1641-4640. (Termedia Publishing House)A review. Nanoscience is the science of small particles of materials on a nanometer scale in at least one dimension. Nanomaterials can interact with tissues at the mol. level with a very high degree of functional specificity and control. A large group of nanomaterials includes nanotubes, nanofibres, liposomes, nanoparticles, polymeric micelles, nanogels and dendrimers. Such materials can be tailored to react with specific biol. systems at a mol. or even supra-mol. level and respond to the cell environment while minimizing undesired side effects. Neuron injuries lead to complex cellular and mol. interactions at the lesion site in an effort to repair the damaged tissue and to regenerate the axon for reconnection with its target organ. Strategies to enhance and stimulate regeneration use various nerve conduits and synthetic guidance devices. A promising strategy for treatment of neuronal injuries is to support and promote axonal growth by means of nanotubes and nanofibres. Nanotubes can be produced from various materials, such as carbon, synthetic polymers, DNA, proteins, lipids, silicon and glass. Carbon nanotubes are not biodegradable and can be used as implants. Moreover, they serve as an extracellular scaffold to guide directed axonal growth. In the review we summarize the results of nanotube and nanofibre application in nerve repair after injury.
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220Chao, T. I.; Xiang, S.; Chen, C. S.; Chin, W. C.; Nelson, A. J.; Wang, C.; Lu, J. Biochem. Biophys. Res. Commun. 2009, 384, 426Google ScholarThere is no corresponding record for this reference.
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221Antoniadou, E. V.; Ahmad, R. K.; Jackman, R. B.; Seifalian, A. M. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2011, 2011, 3253Google Scholar221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC387lsFahug%253D%253D&md5=7129e5a1869d5426e914b9fd19afc987Next generation brain implant coatings and nerve regeneration via novel conductive nanocomposite developmentAntoniadou Eleni V; Ahmad Rezal K; Jackman Richard B; Seifalian Alexander MConference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference (2011), 2011 (), 3253-7 ISSN:1557-170X.Composite materials based on the coupling of conductive organic polymers and carbon nanotubes have shown that they possess properties of the individual components with a synergistic effect. Multi-wall carbon nanotube (MWCNT)/ polymer composites are hybrid materials that combine numerous mechanical, electrical and chemical properties and thus, constitute ideal biomaterials for a wide range of regenerative medicine applications. Although, complete dispersion of CNT in a polymer matrix has rarely been achieved, in this study we have succeeded high dispersibility of CNT in POSS-PCU and POSS-PCL, novel polymers based on polyprolactone and polycarbonate polyurethane (PCU) and poly(caprolactoneurea)urethane both having incorporated polyhedral oligomeric silsesquioxane (POSS). We report the synthesis and characterization of a novel biomaterial that possesses unique properties of being electrically conducting and thus being capable of electronic interfacing with tissue. To this end, POSS-PCU/MWCNT composite can be used as a biomaterial for the development of nerve guidance channels to promote nerve regeneration and POSS-PCL/MWCNT as a substrate to increase electronic interfacing between neurons and micro-machined electrodes for potential applications in neural probes, prosthetic devices and brain implants.
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222Lee, H. J.; Park, J.; Yoon, O. J.; Kim, H. W.; Lee do, Y.; Kim do, H.; Lee, W. B.; Lee, N. E.; Bonventre, J. V.; Kim, S. S. Nat. Nanotechnol. 2011, 6, 121Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVOrurs%253D&md5=20cd429604b2e0873423799f2bf680c5Amine-modified single-walled carbon nanotubes protect neurons from injury in a rat stroke modelLee, Hyun Jung; Park, Jiae; Yoon, Ok Ja; Kim, Hyun Woo; Lee, Do Yeon; Kim, Do Hee; Lee, Won Bok; Lee, Nae-Eung; Bonventre, Joseph V.; Kim, Sung SuNature Nanotechnology (2011), 6 (2), 121-125CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Stroke results in the disruption of tissue architecture and is the third leading cause of death in the United States. Transplanting scaffolds contg. stem cells into the injured areas of the brain has been proposed as a treatment strategy, and carbon nanotubes show promise in this regard, with pos. outcomes when used as scaffolds in neural cells and brain tissues. Here, we show that pretreating rats with amine-modified single-walled carbon nanotubes can protect neurons and enhance the recovery of behavioral functions in rats with induced stroke. Treated rats showed less tissue damage than controls and took longer to fall from a rotating rod, suggesting better motor functions after injury. Low levels of apoptotic, angiogenic and inflammation markers indicated that amine-modified single-walled carbon nanotubes protected the brains of treated rats from ischemic injury.
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223Chen, C. S.; Soni, S.; Le, C.; Biasca, M.; Farr, E.; Chen, E. Y.; Chin, W. C. Nanoscale Res. Lett. 2012, 7, 126Google Scholar223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotFKkurk%253D&md5=c50211baecbe11fcec8bb9d7d2e34ca7Human stem cell neuronal differentiation on silk-carbon nanotube compositeChen, Chi-Shuo; Soni, Sushant; Le, Catherine; Biasca, Matthew; Farr, Erik; Chen, Eric Y.-T.; Chin, Wei-ChunNanoscale Research Letters (2012), 7 (1), 126, 7 pp.CODEN: NRLAAD; ISSN:1556-276X. (Springer)Human embryonic stem cells [hESCs] are able to differentiate into specific lineages corresponding to regulated spatial and temporal signals. This unique attribute holds great promise for regenerative medicine and cell-based therapy for many human diseases such as spinal cord injury [SCI] and multiple sclerosis [MS]. Carbon nanotubes [CNTs] have been successfully used to promote neuronal differentiation, and silk has been widely applied in tissue engineering. This study aims to build silk-CNT composite scaffolds for improved neuron differentiation efficiency from hESCs. Two neuronal markers (β-III tubulin and nestin) were utilized to det. the hESC neuronal lineage differentiation. In addn., axonal lengths were measured to evaluate the progress of neuronal development. The results demonstrated that cells on silk-CNT scaffolds have a higher β-III tubulin and nestin expression, suggesting augmented neuronal differentiation. In addn., longer axons with higher d. were found to assoc. with silk-CNT scaffolds. Our silk-CNT-based composite scaffolds can promote neuronal differentiation of hESCs. The silk-CNT composite scaffolds developed here can serve as efficient supporting matrixes for stem cell-derived neuronal transplants, offering a promising opportunity for nerve repair treatments for SCI and MS patients.
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224Kim, J. A.; Jang, E. Y.; Kang, T. J.; Yoon, S.; Ovalle-Robles, R.; Rhee, W. J.; Kim, T.; Baughman, R. H.; Kim, Y. H.; Park, T. H. Integr. Biol. 2012, 4, 587Google Scholar224https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnvVOqt7w%253D&md5=8aa9363c6701e264607aba898744a386Regulation of morphogenesis and neural differentiation of human mesenchymal stem cells using carbon nanotube sheetsKim, Jeong Ah; Jang, Eui Yun; Kang, Tae June; Yoon, Sungjun; Ovalle-Robles, Raquel; Rhee, Won Jong; Kim, Taewoo; Baughman, Ray H.; Kim, Yong Hyup; Park, Tai HyunIntegrative Biology (2012), 4 (6), 587-594CODEN: IBNIFL; ISSN:1757-9694. (Royal Society of Chemistry)In order to successfully utilize stem cells for therapeutic applications in regenerative medicine, efficient differentiation into a specific cell lineage and guidance of axons in a desired direction is crucial. Here, we used aligned multi-walled carbon nanotube (MWCNT) sheets to differentiate human mesenchymal stem cells (hMSCs) into neural cells. Human MSCs present a preferential adhesion to aligned CNT sheets with longitudinal stretch parallel to the CNT orientation direction. Cell elongation was 2-fold higher than the control and most of the cells were aligned on CNT sheets within 5° from the CNT orientation direction. Furthermore, a significant, synergistic enhancement of neural differentiation was obsd. in hMSCs cultured on the CNT sheets. Axon outgrowth was also controlled using nanoscale patterning of CNTs. This CNT sheet provides a new cellular scaffold platform that can regulate morphogenesis and differentiation of stem cells, which could open up a new approach for tissue and stem cell regeneration.
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225Mattson, M. P.; Haddon, R. C.; Rao, A. M. J. Mol. Neurosci. 2000, 14, 175Google Scholar225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmsVahtLY%253D&md5=42dc02d8b544edd825a7ca973f7e0615Molecular functionalization of carbon nanotubes and use as substrates for neuronal growthMattson, Mark P.; Haddon, Robert C.; Rao, Apparao M.Journal of Molecular Neuroscience (2000), 14 (3), 175-182CODEN: JMNEES; ISSN:0895-8696. (Humana Press Inc.)Carbon nanotubes are strong, flexible, conduct elec. current, and can be functionalized with different mols., properties that may be useful in basic and applied neuroscience research. We report the first application of carbon nanotube technol. to neuroscience research. Methods were developed for growing embryonic rat-brain neurons on multiwalled carbon nanotubes. On unmodified nanotubes, neurons extend only one or two neurites, which exhibit very few branches. In contrast, neurons grown on nanotubes coated with the bioactive mol. 4-hydroxynonenal elaborate multiple neurites, which exhibit extensive branching. These findings establish the feasibility of using nanotubes as substrates for nerve cell growth and as probes of neuronal function at the nanometer scale.
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226Dubin, R. A.; Callegari, G.; Kohn, J.; Neimark, A. IEEE Trans. Nanobiosci. 2008, 7, 11Google ScholarThere is no corresponding record for this reference.
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227Sucapane, A.; Cellot, G.; Prato, M.; Giugliano, M.; Parpura, V.; Ballerini, L. J. Nanoneurosci. 2009, 1, 10Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlvV2qurk%253D&md5=2dcea949c8379b5b063d4107fafd9160Interactions between cultured neurons and carbon nanotubes: a nanoneuroscience vignetteSucapane, Antonietta; Cellot, Giada; Prato, Maurizio; Giugliano, Michele; Parpura, Vladimir; Ballerini, LauraJournal of Nanoneuroscience (2009), 1 (1), 10-16CODEN: JNOAFT; ISSN:1939-0637. (American Scientific Publishers)A review. Carbon nanotubes, owing to their elec., chem., mech., and thermal properties, are one of the most promising nanomaterials for the electronics, computer, and aerospace industries. More recently, these unique materials are finding their niche in neuroscience. Here, we discuss the use of carbon nanotubes as scaffolds for neuronal growth. The chem. properties of carbon nanotubes can be systematically varied by attaching different functional groups. Such functionalized carbon nanotubes can be used to control the outgrowth and branching pattern of neuronal processes. We also discuss elec. interactions between neurons and carbon nanotubes. The elec. properties of nanotubes can provide a mechanism to monitor or stimulate neurons through the scaffold itself. The ease of which carbon nanotubes can be patterned makes them attractive for studying the organization of neural networks and has the potential to develop new devices for neural prosthesis. We note that addnl. toxicity studies of carbon nanotubes are necessary so that exposure guidelines and safety regulations can be set.
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228Lee, W.; Parpura, V. Prog. Brain Res. 2009, 180, 110Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c3htlWntg%253D%253D&md5=ef2fa719aa29d7c20caeb773402cfcb0Chapter 6 - Carbon nanotubes as substrates/scaffolds for neural cell growthLee William; Parpura VladimirProgress in brain research (2009), 180 (), 110-25 ISSN:.Carbon nanotubes (CNTs) due to their unique properties have sparked interest for their use in biomedical applications in recent years. In particular, the use of CNTs as substrates/scaffolds for neural cell growth has been an area of active research over the past decade. CNTs, either native or functionalized with various chemical groups, are biocompatible with neuronal cell adhesion and growth. Functionalized CNTs can modulate the neuronal growth in graded manner; positively charged CNTs promoted neurite outgrowth of hippocampal neurons in culture to a greater extent than when these cells were grown on neutral or negatively charged CNTs. Conductivity and mechanical properties of CNTs have been shown to affect neuronal morphology as well. Other neural cells, such as stem and glial cells, can also be successfully grown on CNT substrates. While currently the acute toxicity of CNTs is considered comparable to that of other forms of carbon, the long-term exposures limits need to be established in order to use these materials as neural prosthesis. Nonetheless, accumulating data support the use of CNTs as a biocompatible and permissive substrate/scaffold for neural cells and such application holds great potential in biomedicine.
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229Matsumoto, K.; Sato, C.; Naka, Y.; Whitby, R.; Shimizu, N. Nanotechnology 2010, 21, 115101Google ScholarThere is no corresponding record for this reference.
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230Parpura, V.; Silva, G. A.; Tass, P. A.; Bennet, K. E.; Meyyappan, M.; Koehne, J.; Lee, K. H.; Andrews, R. J. J. Neurochem. 2013, 124, 436Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVOmsrY%253D&md5=1608881c7c07addfa2214d1b06145b64Neuromodulation: selected approaches and challengesParpura, Vladimir; Silva, Gabriel A.; Tass, Peter A.; Bennet, Kevin E.; Meyyappan, M.; Koehne, Jessica; Lee, Kendall H.; Andrews, Russell J.Journal of Neurochemistry (2013), 124 (3&4), 436-453CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)A review. The brain operates through complex interactions in the flow of information and signal processing within neural networks. The 'wiring' of such networks, being neuronal or glial, can phys. and/or functionally go rogue in various pathol. states. Neuromodulation, as a multidisciplinary venture, attempts to correct such faulty nets. In this review, selected approaches and challenges in neuromodulation are discussed. The use of water-dispersible carbon nanotubes has been proven effective in the modulation of neurite outgrowth in culture and in aiding regeneration after spinal cord injury in vivo. Studying neural circuits using computational biol. and anal. engineering approaches brings to light geometrical mapping of dynamics within neural networks, much needed information for stimulation interventions in medical practice. Indeed, sophisticated desynchronization approaches used for brain stimulation have been successful in coaxing 'misfiring' neuronal circuits to resume productive firing patterns in various human disorders. Devices have been developed for the real-time measurement of various neurotransmitters as well as elec. activity in the human brain during elec. deep brain stimulation. Such devices can establish the dynamics of electrochem. changes in the brain during stimulation. With increasing application of nanomaterials in devices for elec. and chem. recording and stimulating in the brain, the era of cellular, and even intracellular, precision neuromodulation will soon be upon us.
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231Behan, B. L.; DeWitt, D. G.; Bogdanowicz, D. R.; Koppes, A. N.; Bale, S. S.; Thompson, D. M. J. Biomed. Mater. Res., Part A 2011, 96, 46Google Scholar231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVGku7zE&md5=841004c82c8f9ff490546c65a3a9a960Single-walled carbon nanotubes alter Schwann cell behavior differentially within 2D and 3D environmentsBehan, Brenda L.; DeWitt, Daniel G.; Bogdanowicz, Danielle R.; Koppes, Abigail N.; Bale, Shyam S.; Thompson, Deanna M.Journal of Biomedical Materials Research, Part A (2011), 96A (1), 46-57CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Both spinal cord injury (SCI) and large-gap peripheral nerve defects can be debilitating affecting a patient's long-term quality of life and presently, there is no suitable treatment for functional regeneration of these injured tissues. A no. of works have suggested the benefits of elec. stimulation to promote both glial migration and neuronal extension. In this work, an elec. conductive hydrogel contg. single-walled carbon nanotubes (SWCNT) for neural engineering applications is presented and the Schwann cell (SC) response to SWCNT is examd. in both 2D and 3D microenvironments. Results from clonogenic and alamarBlue assays in 2D indicate that SWCNT (10-50 μg mL-1) inhibit SC proliferation but do not affect cell viability. Following SWCNT exposure in 2D, changes in SC morphol. can be obsd. with the nanomaterial attached to the cell membrane at concns. as low as 10 μg mL-1. In contrast to the results gathered in 2D, SC embedded within the 3D hydrogel loaded with 10-50 μg mL-1 of SWCNT exhibited little or no measurable change in cell proliferation, viability, or morphol. as assessed using a digestion assay, alamarBlue, and confocal microscopy. Collectively, this highlights that an elec.-conductive SWCNT collagen I-Matrigel biomaterial may be suitable for neural tissue engineering and is able to sustain populations of SC. Findings suggest that 2D nanoparticle toxicity assays may not be accurate predictors of the 3D response, further motivating the examn. of these materials in a more physiol. relevant environment. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2010.
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232Khang, D.; Park, G. E.; Webster, T. J. J. Biomed. Mater. Res., Part A 2008, 86, 253Google Scholar232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXntFaku7s%253D&md5=93b4db83338c9b3c63144b081f3fec43Enhanced chondrocyte densities on carbon nanotube composites: the combined role of nanosurface roughness and electrical stimulationKhang, Dongwoo; Park, Grace E.; Webster, Thomas J.Journal of Biomedical Materials Research, Part A (2008), 86A (1), 253-260CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Simultaneous incorporation of intrinsic nanosurface roughness and external elec. stimulation may maximize the regeneration of articular cartilage tissue more than on nanosmooth, elec. nonstimulated biomaterials. Here, we report enhanced functions of chondrocytes (cartilage synthesizing cells) on elec. and nonelec. stimulated highly dispersed carbon nanotubes (CNT) in polycarbonate urethane (PCU) compared to, resp., stimulated pure PCU. Specifically, compared to conventional longitudinal (or vertical) elec. stimulation of chondrocytes on conducting surfaces which require high voltage, we developed a lateral elec. stimulation across CNT/PCU composite films of low voltage that enhanced chondrocyte functions. Chondrocyte adhesion and long-term cell densities (up to 2 days) were enhanced (more than 50%) on CNT/PCU composites compared to PCU alone without elec. stimulation. This study further explained why by measuring greater amts. of initial fibronectin adsorption (a key protein that mediates chondrocyte adhesion) on CNT/PCU composites which were more hydrophilic (than pure PCU) due to greater nanometer roughness. Importantly, the same trend was obsd. and was even significantly enhanced when chondrocytes were subjected to elec. stimulation (more than 200%) compared to non-stimulated CNT/PCU. For this reason, this study provided direct evidence of the pos. role that conductive CNT/PCU films can play in promoting functions of chondrocytes for cartilage regeneration.
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233Sirivisoot, S.; Harrison, B. S. Int. J. Nanomed. 2011, 6, 2483Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1ent7fP&md5=2bcecac47f09fe56f71a39023de670bcSkeletal myotube formation enhanced by electrospun polyurethane carbon nanotube scaffoldsSirivisoot, Sirinrath; Harrison, Benjamin S.International Journal of Nanomedicine (2011), 6 (), 2483-2497CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)Background: This study examd. the effects of elec. conductive materials made from electrospun single- or multi-walled carbon nanotubes with polyurethane to promote myoblast differentiation into myotubes in the presence and absence of elec. stimulation. Methods and Results: After elec. stimulation, the no. of multinucleated myotubes on the electrospun polyurethane carbon nanotube scaffolds was significantly larger than that on nonconductive electrospun polyurethane scaffolds (5% and 10% w/v polyurethane). In the absence of elec. stimulation, myoblasts also differentiated on the electrospun polyurethane carbon nanotube scaffolds, as evidenced by expression of Myf-5 and myosin heavy chains. The myotube no. and length were significantly greater on the electrospun carbon nanotubes with 10% w/v polyurethane than on those with 5% w/v polyurethane. The results suggest that, in the absence of elec. stimulation, skeletal myotube formation is dependent on the morphol. of the electrospun scaffolds, while with elec. stimulation it is dependent on the elec. cond. of the scaffolds. Conclusion: This study indicates that electrospun polyurethane carbon nanotubes can be used to modulate skeletal myotube formation with or without application of elec. stimulation.
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234Quigley, A. F.; Razal, J. M.; Kita, M.; Jalili, R.; Gelmi, A.; Penington, A.; Ovalle-Robles, R.; Baughman, R. H.; Clark, G. M.; Wallace, G. G.; Kapsa, R. M. Adv. Healthcare Mater. 2012, 1, 801Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1Sht7%252FK&md5=a630e7d045395797960a6dd18c23c7b2Electrical Stimulation of Myoblast Proliferation and Differentiation on Aligned Nanostructured Conductive Polymer PlatformsQuigley, Anita F.; Razal, Joselito M.; Kita, Magdalena; Jalili, Rohoullah; Gelmi, Amy; Penington, Anthony; Ovalle-Robles, Raquel; Baughman, Ray H.; Clark, Graeme M.; Wallace, Gordon G.; Kapsa, Robert M. I.Advanced Healthcare Materials (2012), 1 (6), 801-808CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)The current study utilizes conducting polymer (CP) templates to investigate how the effects of aligned nanotopog. in conjunction with charge-balanced biphasic influences the orientation and growth behavior of primary myoblasts in vitro.
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235Mooney, E.; Mackle, J. N.; Blond, D. J.; O’Cearbhaill, E.; Shaw, G.; Blau, W. J.; Barry, F. P.; Barron, V.; Murphy, J. M. Biomaterials 2012, 33, 6132Google ScholarThere is no corresponding record for this reference.
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236Martinelli, V.; Cellot, G.; Toma, F. M.; Long, C. S.; Caldwell, J. H.; Zentilin, L.; Giacca, M.; Turco, A.; Prato, M.; Ballerini, L.; Mestroni, L. Nano Lett. 2012, 12, 1831Google ScholarThere is no corresponding record for this reference.
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237Holzapfel, B. M.; Reichert, J. C.; Schantz, J. T.; Gbureck, U.; Rackwitz, L.; Noth, U.; Jakob, F.; Rudert, M.; Groll, J.; Hutmacher, D. W. Adv. Drug Delivery Rev. 2013, 65, 581Google ScholarThere is no corresponding record for this reference.
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238Nakabayashi, N.; Ishihara, K.; Iwasaki, Y. Biomaterial; Japan Society of Medical Electronics and Biological Engineering; Corona Publishing Co., Ltd.: Tokyo, 1999.Google ScholarThere is no corresponding record for this reference.
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239Katti, K. S. Colloids Surf., B 2004, 39, 133Google ScholarThere is no corresponding record for this reference.
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240Del Bravo, V.; Graci, C.; Spinelli, M. S.; Muratori, F.; Maccauro, G. Int. J. Immunopathol. Pharmacol. 2011, 24, 91Google Scholar240https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MfmslOntQ%253D%253D&md5=513a5b0bf8ae062bd9a045d908cfaa30Histological and ultrastructural reaction to different materials for orthopaedic applicationDel Bravo V; Graci C; Spinelli M S; Muratori F; Maccauro GInternational journal of immunopathology and pharmacology (2011), 24 (1 Suppl 2), 91-4 ISSN:0394-6320.Prosthetic joints loosening in absence of infection is the most common reason for revision surgery and is known as aseptic loosening. A significant role in the pathogenesis of implant failure undoubtedly played by the generation of wear debris, mainly from the load bearing joint surfaces, and the cellular reaction through the formation of tissue membrane around implants. This article analyzes histologic, immunohistochemical ad ultrastructural aspects of periprosthetic tissue membrane collected at time of surgical revision, paying attention on cell host response to different materials: metals, polyethylene and ceramics. Dimension of particles seems to be crucial in the activation of different cell population to wear debris.
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241Wang, W.; Ouyang, Y.; Poh, C. K. Ann. Acad. Med. Singapore 2011, 40, 237Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MnhtVekuw%253D%253D&md5=c5d161bc0f782efc34c6d8ad18c48748Orthopaedic implant technology: biomaterials from past to futureWang Wilson; Ouyang Youheng; Poh Chye KhoonAnnals of the Academy of Medicine, Singapore (2011), 40 (5), 237-44 ISSN:0304-4602.Orthopaedic implant technology is heavily based on the development and use of biomaterials. These are non-living materials (e.g. metals, polymers and ceramics) that are introduced into the human body as constituents of implants that fulfill or replace some important function. Examples would be prosthetic joint replacements and fracture fixation implants. For orthopaedic biomaterials to succeed in their desired functions and outcomes in the body, a number of factors need to be considered. The most obvious mechanical properties of the implants are that they need to suit their intended function, and various classes and types of biomaterials have been developed and characterised for use in different implant components depending on their demands. Less well understood but no less important are the interactions that occur between the constituent biomaterials and the living cells and tissues, both of the human host as well as pathogens such as bacteria. Biomaterials used for orthopaedic applications are generally considered to be biocompatible. However, adverse effects arising from interactions at the implant interface can result in various modes of implant failure, such as aseptic loosening and implant infection. This review paper uses the illustrative example of total hip replacement (which has been called the operation of the century) to highlight key points in the evolution of orthopaedic biomaterials. It will also examine research strategies that seek to address some of the major problems that orthopaedic implant surgery are facing today.
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242Coventry, M. B. J. Bone Jt. Surg., Am. Vol. 1985, 67, 832Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2M3mtFCqsQ%253D%253D&md5=17d4ca9afc263171d9371ab7c89961d2Late dislocations in patients with Charnley total hip arthroplastyCoventry M BThe Journal of bone and joint surgery. American volume (1985), 67 (6), 832-41 ISSN:0021-9355.I analyzed the cases of thirty-two patients in whom a Charnley total hip arthroplasty had dislocated for the first time between five and ten years postoperatively. I evaluated the possible factors that caused the late dislocations. Most of the factors were similar to those that were also present in a control group of patients who had had an arthroplasty that had not dislocated and in a group in which dislocation had occurred at variable times postoperatively. Two significant factors did emerge. First, the patients with late dislocation had a greater range of motion, especially in flexion, than those in the two control groups. Second, the acetabular component showed radiographic evidence of loosening in more of the patients in the group with late dislocation than in either of the control groups. I postulated, but did not prove, that stretching of the pseudocapsule of the hip over time and extremes of motion may lessen soft-tissue constraints and allow for late dislocation.
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243Parvizi, J.; Wade, F. A.; Rapuri, V.; Springer, B. D.; Berry, D. J.; Hozack, W. J. Clin. Orthop. Relat. Res. 2006, 447, 66Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28zmsFSitA%253D%253D&md5=761320376c976b2997e4e592cd82f5acRevision hip arthroplasty for late instability secondary to polyethylene wearParvizi Javad; Wade Frazer A; Rapuri Venkat; Springer Bryan D; Berry Daniel J; Hozack William JClinical orthopaedics and related research (2006), 447 (), 66-9 ISSN:0009-921X.We evaluated the outcome of revision arthroplasty for polyethylene wear presenting as late dislocation. The computerized databases at two institutions were reviewed to identify all patients presenting with first time dislocation five or more years after total hip arthroplasty. Records and radiographs were then evaluated, and patients whose late dislocation occurred in the presence of greater than two millimeters of polyethylene liner wear with no other etiology for dislocation were identified. There were 22 patients with a mean age of 57.8 years at primary procedure. The average time from initial arthroplasty to dislocation was 9.0 years. Revision surgery to address polyethylene wear and instability was performed at a mean of 11.1 years (range 5.8 to 23 years). Revision surgery restored stability to eighteen patients (eighty-two percent). Polyethylene wear can and is associated with late dislocation after hip arthroplasty. Exchange of polyethylene lining of a metal backed implant or revision of the all polyethylene acetabular component can successfully address late instability in the majority of patients.
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244Tarasevicius, S.; Robertsson, O.; Kesteris, U.; Kalesinskas, R. J.; Wingstrand, H. Acta Orthop. 2008, 79, 489Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1crnslOmsg%253D%253D&md5=b1896f9e45ac423156f7cd9912040a77Effect of femoral head size on polyethylene wear and synovitis after total hip arthroplasty: a sonographic and radiographic study of 39 patientsTarasevicius Sarunas; Robertsson Otto; Kesteris Uldis; Kalesinskas Romas Jonas; Wingstrand HansActa orthopaedica (2008), 79 (4), 489-93 ISSN:.BACKGROUND AND PURPOSE: The role of synovitis and high fluid pressure in the loosening process after total hip arthroplasty has gained increasing attention. We investigated the correlation between head size, polyethylene wear, and capsular distention. PATIENTS AND METHODS: We analyzed 39 unrevised, radiographically stable hips that had been operated with 28 or 32 mm femoral heads 10 years earlier because of osteoarthritis. We evaluated radiographic signs of loosening, linear and volumetric polyethylene wear, body mass index, activity level, and age. Sonographic examination was performed to measure capsular distance i.e. the distance between the prosthetic femoral neck and the anterior capsule. RESULTS: Linear wear was 0.09 mm/year and 0.18 mm/year in the 28 mm and 32 mm groups, respectively (p < 0.001). The volumetric wear was 51 mm(3)/year and 136 mm(3)/year (p < 0.001) and the capsular distance was 13 mm and 17 mm, respectively (p < 0.001). There was a correlation between linear wear (r = 0.54), volumetric wear (r = 0.62), and capsular distance (p < 0.001). INTERPRETATION: Wear was greater for the larger femoral head and was correlated to capsular distension.
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245Goodman, S. B.; Ma, T. Biomaterials 2010, 31, 5045Google ScholarThere is no corresponding record for this reference.
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246Krell, A.; Klimake, J. J. Am. Ceram. Soc. 2006, 89, 1985Google ScholarThere is no corresponding record for this reference.
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247Carter, C. B.; Norton, M. G. Ceramic Materials Science and Engineering; Springer: New York, 2007; pp 619– 651.Google ScholarThere is no corresponding record for this reference.
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248Ueda, N.; Yamakami, T.; Yamaguchi, T.; Kitajima, K.; Usui, Y.; Aoki, K.; Nakanishi, T.; Miyaji, F.; Endo, M.; Saito, N.; Taruta, S. J. Ceram. Soc. Jpn. 2010, 118, 847Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFejsr7I&md5=7c1b5e2d7cac305705b569974f2ee081Fabrication and mechanical properties of high-dispersion-treated carbon nanofiber/alumina compositesUeda, Naoki; Yamakami, Tomohiko; Yamaguchi, Tomohiro; Kitajima, Kunio; Usui, Yuki; Aoki, Kaoru; Nakanishi, Takefumi; Miyaji, Fumiaki; Endo, Morinobu; Saito, Naoto; Taruta, SeiichiJournal of the Ceramic Society of Japan (2010), 118 (Sept.), 847-854CODEN: JCSJEW; ISSN:1882-0743. (Ceramic Society of Japan)High-dispersion-treated C nanofibers (CNFs) were used to fabricate uniformly-dispersed CNFs-alumina composites with enhanced mech. properties. The treatment was effective in obtaining dense and uniform composites. The composites contg. 0.4-0.8% CNFs were densified to a relative d. of >99% by vacuum sintering and subsequent hot isostatic pressing, and those contg. 1.6-2.5% CNFs were densified to full d. by plasma activated sintering. The max. bending strength of the composites (1050 MPa) was approx. the same as the bending strength of monolithic alumina (1079 MPa). The max. fracture toughness of the composites was 5.9 MPa m0.5, which was a 69% increase compared with the fracture toughness of monolithic alumina (3.5 MPa m0.5). Fracture toughness (KIC) increased rapidly with a decrease in alumina grain size (G), and the relation could be expressed by the following equation: KIC = (k1/G2) + k2 (k1 and k2 are consts.).
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249Ogihara, N.; Usui, Y.; Aoki, K.; Shimizu, M.; Narita, N.; Hara, K.; Nakamura, K.; Ishigaki, N.; Takanashi, S.; Okamoto, M.; Kato, H.; Haniu, H.; Ogiwara, N.; Nakayama, N.; Taruta, S.; Saito, N. Nanomedicine (London, U.K.) 2012, 7, 981Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFWjsr3M&md5=9307b020d5fadabc2557048a1c3cc293Biocompatibility and bone tissue compatibility of alumina ceramics reinforced with carbon nanotubesOgihara, Nobuhide; Usui, Yuki; Aoki, Kaoru; Shimizu, Masayuki; Narita, Nobuyo; Hara, Kazuo; Nakamura, Koichi; Ishigaki, Norio; Takanashi, Seiji; Okamoto, Masanori; Kato, Hiroyuki; Haniu, Hisao; Ogiwara, Naoko; Nakayama, Noboru; Taruta, Seiichi; Saito, NaotoNanomedicine (London, United Kingdom) (2012), 7 (7), 981-993CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)The addn. of carbon nanotubes (CNTs) remarkably improves the mech. characteristics of base materials. CNT/alumina ceramic composites are expected to be highly functional biomaterials useful in a variety of medical fields. Biocompatibility and bone tissue compatibility were studied for the application of CNT/alumina composites as biomaterials. Inflammation reactions in response to the composite were as mild as those of alumina ceramic alone in a s.c. implantation study. In bone implantation testing, the composite showed good bone tissue compatibility and connected directly to new bone. An in vitro cell attachment test was performed for osteoblasts, chondrocytes, fibroblasts and smooth muscle cells, and CNT/alumina composite showed cell attachment similar to that of alumina ceramic. Owing to proven good biocompatibility and bone tissue compatibility, the application of CNT/alumina composites as biomaterials that contact bone, such as prostheses in arthroplasty and devices for bone repair, are expected. Original submitted 23 March 2011; Revised submitted 16 Nov. 2011; Published online 8 March 2012.
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250Barrack, R. L.; McClure, J. T.; Burak, C. F.; Clohisy, J. C.; Parvizi, J.; Hozack, W. Clin. Orthop. Relat. Res. 2006, 453, 173Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s7htVOmsg%253D%253D&md5=3ef463f52a805539d0bcdbb89de59f63Revision total hip arthroplasty: the patient's perspectiveBarrack Robert L; McClure J Thomas; Burak Corey F; Clohisy John C; Parvizi Javad; Hozack WilliamClinical orthopaedics and related research (2006), 453 (), 173-7 ISSN:0009-921X.We evaluated a consecutive series of patients followed for at least 1 year after revision total hip arthroplasty. We surveyed 488 patients treated at three referral centers from 1998 to 2002. An experienced medical interviewer contacted patients and rated their degree of satisfaction with the original and revision arthroplasties, the reason of original arthroplasty failure, and their expectations for revision arthroplasty longevity. Surveys were completed on 320 of the 488 patients (66%). A member of the research team reviewed patients' operative reports, clinical records, and radiographs to determine the diagnosis at revision, procedure performed, and the most likely cause of failure. Patient satisfaction with the primary procedure was directly related to the time to revision. Most patients (214 of 320; 67%) expected their revision to last longer than their primary arthroplasty regardless of revision diagnosis or how long the primary procedure lasted before revision. The surgeons' failure assessments agreed with the patients' failure assessments only 36% of the time. Although the majority of patients (262 of 320; 82%) were satisfied with the results of the revision procedure, most did not agree with their surgeon as to why the original arthroplasty failed, and most had unrealistic expectations regarding revision longevity.
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251Pape, D.; Adam, F.; Fritsch, E.; Müller, K.; Kohn, D. Spine (Philadelphia) 2000, 25, 2514Google Scholar251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3M%252FhslShsg%253D%253D&md5=4d4eefb2043bb9ed113f78c402e67c03Primary lumbosacral stability after open posterior and endoscopic anterior fusion with interbody implants: a roentgen stereophotogrammetric analysisPape D; Adam F; Fritsch E; Muller K; Kohn DSpine (2000), 25 (19), 2514-8 ISSN:0362-2436.STUDY DESIGN: After posterior stabilization of the spondylolytic lumbosacral level, mobility of the fused vertebrae could be studied before and after an additional anterior endoscopic interbody fusion using roentgen stereophotogrammetric analysis. OBJECTIVE: To determine the in vivo primary lumbosacral stability of additional anterior interbody fusion after transpedicular screw fixation. SUMMARY OF BACKGROUND DATA: In vitro studies indicate a significant decrease in segmental motion after pedicle screw fixation and additional anterior fusion. Roentgen stereophotogrammetric studies demonstrate the adequacy of transpedicular lumbar instrumentation in posterolateral fusions. There are no studies examining the effect of additional anterior interbody fusion after posterior instrumentation in vivo. METHODS: In this study, 15 patients with low-grade spondylolisthesis at L5-S1 underwent a two-stage open posterior and endoscopic anterior lumbar fusion using carbon fiber (Brantigan I/F) cages. At surgery, tantalum markers were implanted into the fifth lumbar (L5) and the first sacral (S1) vertebra. All the patients were examined by roentgen stereophotogrammetric analysis after the first and second surgical procedures. RESULTS: After implantation of the posterior pedicle system only, the mean intervertebral mobility determined by roentgen stereophotogrammetric analysis was 0.23 mm in the transverse (x), 0.54 mm in the vertical (y), and 1.2 mm in the sagittal (z) axes. After additional anterior endoscopic fusion with carbon cages, the remaining translation between the fused segment L5/S1 decreased to 0.17 mm in the x, 0.16 mm in the y, and 0.44 mm in the z axes. CONCLUSION: Anterior endoscopic lumbosacral fusion significantly increases the primary stability of the posterior fusion with a pedicle system in two axes of motion.
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252Rousseau, M. A.; Lazennec, J. Y.; Saillant, G. J. Spinal Disord. Tech. 2007, 20, 278Google Scholar252https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2szisFyluw%253D%253D&md5=8310cf4b770199603578be5528c586a1Circumferential arthrodesis using PEEK cages at the lumbar spineRousseau Marc-Antoine; Lazennec Jean-Yves; Saillant GerardJournal of spinal disorders & techniques (2007), 20 (4), 278-81 ISSN:1536-0652.Usual interbody cages at the lumbar spine are made of titanium or carbon fiber-polyetheretherketone (PEEK). Pure PEEK cages have more recently been proposed for its lower elasticity modulus. The goal of our study was to investigate a series of patients with circumferential fixation using anterior PEEK cages for degenerative lumbar spine disorders with a specific interest in the local lordosis. Fifty-seven consecutive patients aged 54.6 years (29 to 75) were reviewed. The level of arthrodesis varied from L2L3 to L5S1. The clinical status and the radiologic variations in local lordosis at the level of arthrodesis were measured. Decrease in lordosis at follow-up was tested in a multivariate analysis regarding age, obesity, spinal level, bone graft amount, type of posterior instrumentation, postoperative lordosis increase, and cage height. The average follow-up was 5.7 years (4 to 8). Clinical outcomes were excellent or good in 49 cases. Fusion was definite in 56 cases. Although 47 patients had no change in lordosis after surgery, 10 cases showed lordosis increase (8.2 degrees; 5 to 12). At follow-up, local lordosis decreased in 13 cases (5.6 degrees; 4 to 8). The linear model was significant (P<0.001; R=0.590) showing that loss in lordosis was related with postoperative lordosis increase (P=0.01), cage height (P<0.001), posterior instrumentation rigidity (P=0.026), age (P=0.047), and low level (P=0.013). Lumbar circumferential arthrodesis using PEEK cages provided good clinical results and fusion rate. However, lordosis correction was not maintained at follow-up, especially at lower levels, using high cages, in older patients, and when associated with a rigid primary posterior instrumentation. Regarding the last point, this is likely that the order of the instrumentation (posterior first, then anterior) played a role in the loss of lordosis in case of rigid posterior fixation.
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253Webster, T. J.; Waid, M. C.; McKenzie, J. L.; Price, R. L.; Ejiofor, J. U. Nanotechnology 2004, 15, 48Google ScholarThere is no corresponding record for this reference.
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254Arnould, C.; Koranyi, T. I.; Delhalle, J.; Mekhalif, Z. J. Colloid Interface Sci. 2010, 344, 390Google ScholarThere is no corresponding record for this reference.
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255Nayagam, D. A.; Williams, R. A.; Chen, J.; Magee, K. A.; Irwin, J.; Tan, J.; Innis, P.; Leung, R. T.; Finch, S.; Williams, C. E.; Clark, G. M.; Wallace, G. G. Small 2011, 7, 1035Google ScholarThere is no corresponding record for this reference.
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256Li, Z.; Wu, Z.; Li, K. Anal. Biochem. 2009, 387, 267Google ScholarThere is no corresponding record for this reference.
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257Gulati, N.; Gupta, H. Crit. Rev. Ther. Drug Carrier Syst. 2012, 29, 65Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmsFemsbY%253D&md5=316e4252a796979c5ba292683931b45eTwo faces of carbon nanotube: toxicities and pharmaceutical applicationsGulati, Neha; Gupta, HimanshuCritical Reviews in Therapeutic Drug Carrier Systems (2012), 29 (1), 65-88CODEN: CRTSEO; ISSN:0743-4863. (Begell House, Inc.)A review. In the field of nanotechnol., carbon nanotube (CNT) is gaining importance for the delivery of therapeutic agents and diagnosis of diseases. CNT is emerging as an efficient nanocarrier system with cylindrical nanostructure. Due to its nanoscale dimensions, CNTs have a high cell-penetration quality that allows its use in site-specific targeting. Another aspect of the utilization of CNT lies in its hollow structure through which an active moiety can be delivered in a controlled manner via CNTs' nano channels. Despite these pos. aspects of CNT, scientists are still working to improve its biocompatibility and soly. and eliminating toxicity in vivo, which are creating problems with the use of CNTs. Therefore, functionalization becomes an important aspect to be studied because it decreases the toxicity of CNTs and make them nonimmunogenic. In this review, different functionalization techniques of CNTs and their biomedical applications-in particular for cancer therapy to date-are reviewed in detail to present the potential of this nanovector.
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258Ilbasmis-Tamer, S.; Degim, I. T. Expert Opin. Drug Delivery 2012, 9, 991Google ScholarThere is no corresponding record for this reference.
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259Wallace, E. J.; Sansom, M. S. Nanotechnology 2009, 20, 045101Google ScholarThere is no corresponding record for this reference.
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260Zhang, X.; Hui, Z.; Wan, D.; Huang, H.; Huang, J.; Yuan, H.; Yu, J. Int. J. Biol. Macromol. 2010, 47, 389Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpvFWns7k%253D&md5=fe3146b8008a81192f1690772d220d56Alginate microsphere filled with carbon nanotube as drug carrierZhang, Xiao-Lan; Hui, Zhong-Ying; Wan, Da-Xin; Huang, Hai-Tao; Huang, Jin; Yuan, Hong; Yu, Jia-HuiInternational Journal of Biological Macromolecules (2010), 47 (3), 389-395CODEN: IJBMDR; ISSN:0141-8130. (Elsevier B.V.)The potential biomedical application of carbon nanotube (CNT) becomes a driving force to incorporate polymer-assisted dispersed CNT into the alginate (AL) microsphere as a drug carrier. The results of XRD and SEM showed that the addn. of CNT had no evident effect on the structures and morphologies of microspheres. As expected, the incorporation of CNT enhanced the storage modulus of the AL sol, and hence improved the mech. stability of the AL/CNT microspheres. Although the swelling degree had no obvious change after the same interval under various pH conditions, the preserving time of the AL/CNT microspheres obviously increased under the pH conditions of 6.8, 7.0 and 7.4. Furthermore, the encapsulation efficiency of drug in the AL/CNT microspheres was enhanced while the drug leakage was decreased. The results of drug release with theophylline as a drug model showed that the AL/CNT microspheres inherited the pH sensitivity of the AL microspheres while the character of sustaining release was more predominant. In virtue of the cytotoxicity of the CNT-filled AL microspheres equiv. to the neat AL microspheres proved by the tests of cell viability assay, the AL/CNT microspheres, with higher stability, less drug leakage and predominant sustaining release profile, showed the potential application as a drug delivery system to intestine and colon.
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261Chin, S. F.; Baughman, R. H.; Dalton, A. B.; Dieckmann, G. R.; Draper, R. K.; Mikoryak, C.; Musselman, I. H.; Poenitzsch, V. Z.; Xie, H.; Pantano, P. Exp. Biol. Med. (Maywood, NJ, U.S.) 2007, 232, 1236Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFKnurbN&md5=e415e17afcc999b4556289863762a2a3Amphiphilic helical peptide enhances the uptake of single-walled carbon nanotubes by living cellsChin, Shook-Fong; Baughman, Ray H.; Dalton, Alan B.; Dickmann, Gregg R.; Draper, Rockford K.; Mikoryak, Carole; Musselman, Inga H.; Poenitzsch, Vasiliki Z.; Xie, Hui; Pantano, PaulExperimental Biology and Medicine (Maywood, NJ, United States) (2007), 232 (9), 1236-1244CODEN: EBMMBE; ISSN:1535-3702. (Society for Experimental Biology and Medicine)The success of many projected applications of carbon nanotubes (CNTs) to living cells, such as intracellular sensors and nanovectors, will depend on how many CNTs are taken up by cells. Here we report the enhanced uptake by HeLa cells of single-walled CNTs coated with a designed peptide termed nano-1. At. force microscopy showed that the dispersions were composed of individual and small bundles of nano-1 CNTs with 0.7- to 32-nm diams. and 100- to 400-nm lengths. Spectroscopic characterizations revealed that nano-1 disperses CNTs in a non-covalent fashion that preserves CNT optical properties. Elemental anal. indicated that our sample prepn. protocol involving sonication and centrifugation effectively eliminated metal impurities assocd. with CNT manufg. processes. We further showed that the purified CNT dispersions are taken up by HeLa cells in a time- and temp.-dependent fashion, and that they do not affect the HeLa cell growth rate, evidence that the CNTs inside cells are not toxic under these conditions. Finally, we discovered that ∼6-fold more CNTs are taken up by cells in the presence of nano-1 compared with medium contg. serum but no peptide. The fact that coating CNTs with a peptide enhances uptake offers a strategy for improving the performance of applications that require CNTs to be inside cells.
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262Kostarelos, K.; Lacerda, L.; Pastorin, G.; Wu, W.; Wieckowski, S.; Luangsivilay, J.; Godefroy, S.; Pantarotto, D.; Briand, J. P.; Muller, S.; Prato, M.; Bianco, A. Nat. Nanotechnol. 2007, 2, 108Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXit1Wrtrs%253D&md5=030c99a00e958dd35bc1a8607c882a54Cellular uptake of functionalized carbon nanotubes is independent of functional group and cell typeKostarelos, Kostas; Lacerda, Lara; Pastorin, Giorgia; Wu, Wei; Wieckowski, Sebastien; Luangsivilay, Jacqueline; Godefroy, Sylvie; Pantarotto, Davide; Briand, Jean-Paul; Muller, Sylviane; Prato, Maurizio; Bianco, AlbertoNature Nanotechnology (2007), 2 (2), 108-113CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)The development of nanomaterials for biomedical and biotechnol. applications is an area of research that holds great promise and intense interest, and carbon-based nanostructures in particular, such as carbon nanotubes (CNTs), are attracting an increasing level of attention. One of the key advantages that CNTs offer is the possibility of effectively crossing biol. barriers, which would allow their use in the delivery of therapeutically active mols. The authors' labs. have been investigating the use of CNTs in biomedical applications, and in particular as nanovectors for therapeutic agent delivery. The interaction between cells and CNTs is a crit. issue that will det. any future biol. application of such structures. Various types of functionalized carbon nanotubes (f-CNTs) exhibit a capacity to be taken up by a wide range of cells and can intracellularly traffic through different cellular barriers.
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263Zhang, L. W.; Zeng, L.; Barron, A. R.; Monteiro-Riviere, N. A. Int. J. Toxicol. 2007, 26, 103Google Scholar263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlsVSrtr4%253D&md5=bf4db9db99e1086cb15fa8086439fabaBiological interactions of functionalized single-wall carbon nanotubes in human epidermal keratinocytesZhang, Leshuai W.; Zeng, Liling; Barron, Andrew R.; Monteiro-Riviere, Nancy A.International Journal of Toxicology (2007), 26 (2), 103-113CODEN: IJTOFN; ISSN:1091-5818. (Informa Healthcare USA, Inc.)Carbon nanotube-based nanovectors, esp. functionalized nanotubes, have shown potential for therapeutic drug delivery. 6-Aminohexanoic acid-derivatized single-wall carbon nanotubes (AHA-SWNTs) are sol. in aq. stock solns. over a wide range of physiol. relevant conditions; however, their interactions with cells and their biol. compatibility has not been explored. Human epidermal keratinocytes (HEKs) were dosed with AHA-SWNTs ranging in concn. from 0.00000005 to 0.05 mg/mL. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell viability decreased significantly (p < .05) from 0.00005 to 0.05 mg/mL after 24 h. The proinflammatory mediators of inflammation cytokines interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, IL-10, and IL-1β were also assessed. Cytokine anal. did not show a significant increase in IL-6 and IL-8 in the medium contg. 0.000005 mg/mL of AHA-SWNTs from 1 to 48 h. IL-6 increased in cells treated with 0.05 mg/mL of AHA-SWNTs from 1 to 48 h, whereas IL-8 showed a significant increase at 24 and 48 h. No significant difference (p < .05) was noted with TNF-α, IL-10, and IL-1β expression at any time point. Transmission electron microscopy of HEKs treated with 0.05 mg/mL AHA-SWNTs for 24 h depicted AHA-SWNTs localized within intracytoplasmic vacuoles in HEKs. Treatment with the surfactant 1% Pluronic F127 caused dispersion of the AHA-SWNT aggregates in the culture medium and less toxicity. These data showed that the lower concn. of 0.000005 mg/mL of AHA-SWNTs maintains cell viability and induces a mild cytotoxicity, but 0.05 mg/mL of AHA-SWNTs demonstrated an irritation response by the increase in IL-8.
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264Rosen, Y.; Elman, N. M. Expert Opin. Drug Delivery 2009, 6, 517Google ScholarThere is no corresponding record for this reference.
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265Kang, S.; Pinault, M.; Pfefferle, L. D.; Elimelech, M. Langmuir 2007, 23, 8670Google ScholarThere is no corresponding record for this reference.
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266Arias, L. R.; Yang, L. Langmuir 2009, 25, 3003Google ScholarThere is no corresponding record for this reference.
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267Liu, S.; Ng, A. K.; Xu, R.; Wei, J.; Tan, C. M.; Yang, Y.; Chen, Y. Nanoscale 2010, 2, 2744Google ScholarThere is no corresponding record for this reference.
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268Yang, C.; Mamouni, J.; Tang, Y.; Yang, L. Langmuir 2010, 26, 16013Google ScholarThere is no corresponding record for this reference.
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269Pantarotto, D.; Partidos, C. D.; Hoebeke, J.; Brown, F.; Kramer, E.; Briand, J. P.; Muller, S.; Prato, M.; Bianco, A. Chem. Biol. 2003, 10, 961Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXosVyksb4%253D&md5=92a0e71f951c5658affa735ee166b05cImmunization with Peptide-Functionalized Carbon Nanotubes Enhances Virus-Specific Neutralizing Antibody ResponsesPantarotto, Davide; Partidos, Charalambos D.; Hoebeke, Johan; Brown, Fred; Kramer, Ed; Briand, Jean-Paul; Muller, Sylviane; Prato, Maurizio; Bianco, AlbertoChemistry & Biology (2003), 10 (10), 961-966CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)Functionalized carbon nanotubes (CNTs) hold a lot of promise for application in medicinal chem. Based on a method for prepn. of water-sol. CNTs, the authors covalently linked a neutralizing B cell epitope from the foot-and-mouth disease virus (FMDV) to mono- and bis-derivatized CNTs. Immunol. characterization of these conjugates revealed that the epitope was appropriately presented after conjugation to CNTs for recognition by antibodies as measured by BIAcore technol. Moreover, peptide-carbon nanotubes elicited strong anti-peptide antibody responses in mice with no detectable cross-reactivity to the carbon nanotubes. However, only the mono-derivatized CNT conjugate induced high levels of virus-neutralizing antibodies. These findings highlight for the first time the potential of CNTs to present biol. important epitopes in an appropriate conformation both in vitro and in vivo and open up the possibility for their use in vaccine delivery.
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270Zhang, B.; Chen, Q.; Tang, H.; Xie, Q.; Ma, M.; Tan, L.; Zhang, Y.; Yao, S. Colloids Surf., B 2010, 80, 18Google ScholarThere is no corresponding record for this reference.
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271Cui, D.; Tian, F.; Coyer, S. R.; Wang, J.; Pan, B.; Gao, F.; He, R.; Zhang, Y. J. Nanosci. Nanotechnol. 2007, 7, 1639Google ScholarThere is no corresponding record for this reference.
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272Kam, N. W.; Liu, Z.; Dai, H. J. Am. Chem. Soc. 2005, 127, 12492Google ScholarThere is no corresponding record for this reference.
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273Krajcik, R.; Jung, A.; Hirsch, A.; Neuhuber, W.; Zolk, O. Biochem. Biophys. Res. Commun. 2008, 369, 595Google ScholarThere is no corresponding record for this reference.
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274Giljohann, D. A.; Seferos, D. S.; Prigodich, A. E.; Patel, P. C.; Mirkin, C. A. J. Am. Chem. Soc. 2009, 131, 2072Google ScholarThere is no corresponding record for this reference.
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275Ladeira, M. S.; Andrade, V. A.; Gomes, E. R.; Aguiar, C. J.; Moraes, E. R.; Soares, J. S.; Silva, E. E.; Lacerda, R. G.; Ladeira, L. O.; Jorio, A.; Lima, P.; Leite, M. F.; Resende, R. R.; Guatimosim, S. Nanotechnology 2010, 21, 385101Google ScholarThere is no corresponding record for this reference.
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276Sandhiya, S.; Dkhar, S. A.; Surendiran, A. Fundam. Clin. Pharmacol. 2009, 23, 263Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnvVemur0%253D&md5=8774f48258af1455312fa2a1c2ee2c8bEmerging trends of nanomedicine - an overviewSandhiya, Selvarajan; Dkhar, Steven Aibor; Surendiran, A.Fundamental & Clinical Pharmacology (2009), 23 (3), 263-269CODEN: FCPHEZ; ISSN:0767-3981. (Wiley-Blackwell)A review. Nanotechnol. is an emerging branch of science for designing tools and devices of size 1 to 100 nm with unique function at the cellular, at. and mol. levels. The concept of using nanotechnol. in medical research and clin. practice is known as nanomedicine. Nanoparticles possess some novel properties not seen with the macro mols. and they can be manipulated by attaching therapeutic components to help in diagnosis and treatment. They can also be used to probe cellular movements and mol. changes assocd. with pathol. states. Nanodevices like carbon nanotubes to locate and deliver anticancer drugs at the specific tumor site are under research. Nanotechnol. promises construction of artificial cells, enzymes and genes. This will help in the replacement therapy of many disorders which are due to deficiency of enzymes, mutation of genes or any repair in the synthesis of proteins. Currently nanodevices like respirocytes, microbivores and probes encapsulated by biol. localized embedding have a greater application in treatment of anemia and infections. Thus in the present scenario, nanotechnol. is spreading its wings to address the key problems in the field of medicine. Hence this review discusses in detail the applications of nanotechnol. in medicine with more emphasis on drug delivery and therapy.
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277Lima, M. D.; Li, N.; Jung de Andrade, M.; Fang, S.; Oh, J.; Spinks, G. M.; Kozlov, M. E.; Haines, C. S.; Suh, D.; Foroughi, J.; Kim, S. J.; Chen, Y.; Ware, T.; Shin, M. K.; Machado, L. D.; Fonseca, A. F.; Madden, J. D.; Voit, W. E.; Galvao, D. S.; Baughman, R. H. Science 2012, 338, 928Google ScholarThere is no corresponding record for this reference.
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278Hamdi, M. Nanotechnology 2009, 20, 485501Google ScholarThere is no corresponding record for this reference.
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279Barone, P. W.; Baik, S.; Heller, D. A.; Strano, M. S. Nat. Mater. 2005, 4, 86Google Scholar279https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXksl2q&md5=42c0fd7870a1f0e11335489bfb209c5fNear-infrared optical sensors based on single-walled carbon nanotubesBarone, Paul W.; Baik, Seunghyun; Heller, Daniel A.; Strano, Michael S.Nature Materials (2005), 4 (1), 86-92CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)Mol. detection using near-IR light between 0.9 and 1.3 eV has important biomedical applications because of greater tissue penetration and reduced auto-fluorescent background in thick tissue or whole-blood media. Carbon nanotubes have a tunable near-IR emission that responds to changes in the local dielec. function but remains stable to permanent photobleaching. In this work, we report the synthesis and successful testing of soln.-phase, near-IR sensors, with β-D-glucose sensing as a model system, using single-walled carbon nanotubes that modulate their emission in response to the adsorption of specific biomols. New types of non-covalent functionalization using electron-withdrawing mols. are shown to provide sites for transferring electrons in and out of the nanotube. We also show two distinct mechanisms of signal transduction-fluorescence quenching and charge transfer. The results demonstrate new opportunities for nanoparticle optical sensors that operate in strongly absorbing media of relevance to medicine or biol.
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280Popov, A. M.; Lozovik, Y. E.; Fiorito, S.; Yahia, L. Int. J. Nanomed. 2007, 2, 361Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlektbvO&md5=4bef98215a45bad8b34be3d0604d5c61Biocompatibility and applications of carbon nanotubes in medical nanorobotsPopov, Andrei M.; Lozovik, Yurii E.; Fiorito, Silvana; Yahia, L'HocineInternational Journal of Nanomedicine (2007), 2 (3), 361-372CODEN: IJNNHQ; ISSN:1176-9114. (Dove Medical Press (NZ) Ltd.)A review. The set of nanoelectromech. systems (NEMS) based on relative motion of carbon nanotubes walls is proposed for use in medical nanorobots. This set includes electromech. nanothermometer, jet nanoengine, nanosyringe (the last can be used simultaneously as nanoprobe for individual biol. mols. and drug nanodeliver). Principal schemes of these NEMS are considered. Operational characteristics of nanothermometer are analyzed. The possible methods of these NEMS actuation are considered. The present-day progress in nanotechnol. techniques which are necessary for assembling of NEMS under consideration is discussed. Biocompatibility of carbon nanotubes is analyzed in connection with perspectives of their application in nanomedicine.
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281Poland, C. A.; Duffin, R.; Kinloch, I.; Maynard, A.; Wallace, W. A.; Seaton, A.; Stone, V.; Brown, S.; Macnee, W.; Donaldson, K. Nat. Nanotechnol. 2008, 3, 423Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXotFehs7o%253D&md5=54ae8b1abbe311ade69bb8255891b407Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot studyPoland, Craig A.; Duffin, Rodger; Kinloch, Ian; Maynard, Andrew; Wallace, William A. H.; Seaton, Anthony; Stone, Vicki; Brown, Simon; MacNee, William; Donaldson, KenNature Nanotechnology (2008), 3 (7), 423-428CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Carbon nanotubes have distinctive characteristics, but their needle-like fiber shape has been compared to asbestos, raising concerns that widespread use of carbon nanotubes may lead to mesothelioma, cancer of the lining of the lungs caused by exposure to asbestos. Exposing the mesothelial lining of the body cavity of mice, as a surrogate for the mesothelial lining of the chest cavity, to long multiwalled carbon nanotubes results in asbestos-like, length-dependent, pathogenic behavior. This includes inflammation and the formation of lesions known as granulomas. This is of considerable importance, because research and business communities continue to invest heavily in carbon nanotubes for a wide range of products under the assumption that they are no more hazardous than graphite. The authors' results suggest the need for further research and great caution before introducing such products into the market if long-term harm is to be avoided. A pilot study in a small no. of mice shows that long multiwalled carbon nanotubes introduced into the abdominal cavity can cause asbestos-like pathogenic behavior. The results suggest the need for further research and caution before introducing nanotube products into the market.
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282Takagi, A.; Hirose, A.; Nishimura, T.; Fukumori, N.; Ogata, A.; Ohashi, N.; Kitajima, S.; Kanno, J. J. Toxicol. Sci. 2008, 33, 105Google Scholar282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmtFKksLw%253D&md5=f437c911ffcf1d60fa4e69181553a977Induction of mesothelioma in p53+/-mouse by intraperitoneal application of multi-wall carbon nanotubeTakagi, Atsuya; Hirose, Akihiko; Nishimura, Tetsuji; Fukumori, Nobutaka; Ogata, Akio; Ohashi, Norio; Kitajima, Satoshi; Kanno, JunJournal of Toxicological Sciences (2008), 33 (1), 105-116CODEN: JTSCDR; ISSN:0388-1350. (Japanese Society of Toxicology)Nanomaterials of carbon origin tend to form various shapes of particles in micrometer dimensions. Among them, multi-wall carbon nanotubes (MWCNT) form fibrous or rod-shaped particles of length around 10 to 20 μm with an aspect ratio of more than three. Fibrous particles of this dimension including asbestos and some man-made fibers are reported to be carcinogenic, typically inducing mesothelioma. Here we report that MWCNT induces mesothelioma along with a pos. control, crocidolite (blue asbestos), when administered i.p. to p53 heterozygous mice that have been reported to be sensitive to asbestos. Our results point out the possibility that carbon-made fibrous or rod-shaped micrometer particles may share the carcinogenic mechanisms postulated for asbestos. To maintain sound activity of industrialization of nanomaterials, it would be prudent to implement strategies to keep good control of exposure to fibrous or rod-shaped carbon materials both in the workplace and in the future market until the biol./carcinogenic properties, esp. of their long-term biodurability, are fully assessed.
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283Kisin, E. R.; Murray, A. R.; Sargent, L.; Lowry, D.; Chirila, M.; Siegrist, K. J.; Schwegler-Berry, D.; Leonard, S.; Castranova, V.; Fadeel, B.; Kagan, V. E.; Shvedova, A. A. Toxicol. Appl. Pharmacol. 2011, 252, 1Google Scholar283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjtFGgsLo%253D&md5=bb5baaea379ecf922d3e234567033c1eGenotoxicity of carbon nanofibers: Are they potentially more or less dangerous than carbon nanotubes or asbestos?Kisin, E. R.; Murray, A. R.; Sargent, L.; Lowry, D.; Chirila, M.; Siegrist, K. J.; Schwegler-Berry, D.; Leonard, S.; Castranova, V.; Fadeel, B.; Kagan, V. E.; Shvedova, A. A.Toxicology and Applied Pharmacology (2011), 252 (1), 1-10CODEN: TXAPA9; ISSN:0041-008X. (Elsevier B.V.)The prodn. of carbon nanofibers and nanotubes (CNF/CNT) and their composite products is increasing globally. CNF are generating great interest in industrial sectors such as energy prodn. and electronics, where alternative materials may have limited performance or are produced at a much higher cost. However, despite the increasing industrial use of carbon nanofibers, information on their potential adverse health effects is limited. In the current study, we examine the cytotoxic and genotoxic potential of carbon-based nanofibers (Pyrograf-III) and compare this material with the effects of asbestos fibers (crocidolite) or single-walled carbon nanotubes (SWCNT). The genotoxic effects in the lung fibroblast (V79) cell line were examd. using two complementary assays: the comet assay and micronucleus (MN) test. In addn., we utilized fluorescence in situ hybridization to detect the chromatin pan-centromeric signals within the MN indicating their origin by aneugenic (chromosomal malsegregation) or clastogenic (chromosome breakage) mechanisms. Cytotoxicity tests revealed a concn.- and time-dependent loss of V79 cell viability after exposure to all tested materials in the following sequence: asbestos > CNF > SWCNT. Addnl., cellular uptake and generation of oxygen radicals was seen in the murine RAW264.7 macrophages following exposure to CNF or asbestos but not after administration of SWCNT. DNA damage and MN induction were found after exposure to all tested materials with the strongest effect seen for CNF. Finally, we demonstrated that CNF induced predominately centromere-pos. MN in primary human small airway epithelial cells (SAEC) indicating aneugenic events. Further investigations are warranted to elucidate the possible mechanisms involved in CNF-induced genotoxicity.
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284Osmond-McLeod, M. J.; Poland, C. A.; Murphy, F.; Waddington, L.; Morris, H.; Hawkins, S. C.; Clark, S.; Aitken, R.; McCall, M. J.; Donaldson, K. Part. Fibre Toxicol. 2011, 8, 15Google Scholar284https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmt1Omur4%253D&md5=a8ae6fd962c052f8b7511bc65c88bce3Durability and inflammogenic impact of carbon nanotubes compared with asbestos fibresOsmond-McLeod, Megan J.; Poland, Craig A.; Murphy, Fiona; Waddington, Lynne; Morris, Howard; Hawkins, Stephen C.; Clark, Steve; Aitken, Rob; McCall, Maxine J.; Donaldson, KenParticle and Fibre Toxicology (2011), 8 (), 15CODEN: PFTABQ; ISSN:1743-8977. (BioMed Central Ltd.)Background: It has been suggested that carbon nanotubes might conform to the fiber pathogenicity paradigm that explains the toxicities of asbestos and other fibers on a continuum based on length, aspect ratio and biopersistence. Some types of carbon nanotubes satisfy the first two aspects of the fiber paradigm but only recently has their biopersistence begun to be investigated. Biopersistence is complex and requires in vivo testing and anal. However durability, the chem. mimicking of the process of fiber dissoln. using in vitro treatment, is closely related to biopersistence and more readily detd. Here, we describe an exptl. process to det. the durability of four types of carbon nanotubes in simulated biol. fluid (Gambles soln.), and their subsequent pathogenicity in vivo using a mouse model sensitive to inflammogenic effects of fibers. The in vitro and in vivo results were compared with well-characterized glass wool and asbestos fiber controls. Results: After incubation for up to 24 wk in Gambles soln., our control fibers were recovered at percentages consistent with their known in vitro durabilities and/or in vivo persistence, and three out of the four types of carbon nanotubes tested [single walled (CNTSW) and multi walled (CNTTANG2, CNTSPIN)] showed no, or minimal, loss of mass or change in fiber length or morphol. when examd. by electron microscopy. However, the fourth type [multi walled (CNTLONG1)] lost 30% of its original mass within the first three weeks of incubation, after which there was no further loss. Electron microscopy of CNTLONG1 samples incubated for 10 wk confirmed that the proportion of long fibers had decreased compared to samples briefly exposed to the Gambles soln. This loss of mass and fiber shortening was accompanied by a loss of pathogenicity when injected into the peritoneal cavities of C57Bl/6 mice compared to fibers incubated briefly. CNTSW did not elicit an inflammogenic effect in the peritoneal cavity assay used here. Conclusions: These results support the view that carbon nanotubes are generally durable but may be subject to bio-modification in a sample-specific manner. They also suggest that pristine carbon nanotubes, either individually or in rope-like aggregates of sufficient length and aspect ratio, can induce asbestos-like responses in mice, but that the effect may be mitigated for certain types that are less durable in biol. systems. Results indicate that durable carbon nanotubes that are either short or form tightly bundled aggregates with no isolated long fibers are less inflammogenic in fiber specific assays.
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285Kim, J. S.; Song, K. S.; Lee, J. K.; Choi, Y. C.; Bang, I. S.; Kang, C. S.; Yu, I. J. Arch. Toxicol. 2012, 86, 553Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVCktr%252FF&md5=9e9de75753ed4dc11531ad8bd38f5e58Toxicogenomic comparison of multi-wall carbon nanotubes (MWCNTs) and asbestosKim, Jin Sik; Song, Kyung Seuk; Lee, Jin Kyu; Choi, Young C.; Bang, In Seok; Kang, Chang Soo; Yu, Il JeArchives of Toxicology (2012), 86 (4), 553-562CODEN: ARTODN; ISSN:0340-5761. (Springer)Carbon nanotubes (CNTs) have specific properties, including elec. and thermal cond., great strength, and rigidity, that allow them to be used in many fields. However, this increasing contact with humans and the environment is also raising health and safety concerns. Thus, research on the safety of CNTs has attracted much interest, including a comparison of the toxic effects of asbestos and carbon nanotubes, due to their phys. similarity of a high aspect ratio (length/diam.). Nonetheless, there has not yet been a toxicogenomic comparison. Therefore, to examine toxicogenomic effects, the 50% growth inhibition (GI50) concn. was detd. for multi-wall carbon nanotubes (MWCNTs) and asbestos (crocidolite) and found to be approx. 0.0135 and 0.066%, resp., in the case of 24-h treatment of normal human bronchial epithelia (NHBE) cells. Using these GI50 concns., NHBE cells were then treated with MWCNTs and asbestos for 6 and 24 h, followed by a DNA microarray anal. Among 31,647 genes, 1,201 and 1,252 were up-regulated by both asbestos and MWCNTs after 6 and 24 h of exposure, resp. Meanwhile, 1,977 and 1,542 genes were down-regulated by both asbestos and MWNCTs after 6 and 24 h of exposure, resp. In particular, the asbestos and MWCNTs both induced an over twofold up- and down-regulated expression of 12 mesothelioma-related genes and 22 lung cancer-related genes when compared with the neg. control. Plus, the genes induced by the MWCNT exposure were expressed in the brain, lungs, epithelium, liver, and colon.
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286Murray, A. R.; Kisin, E. R.; Tkach, A. V.; Yanamala, N.; Mercer, R.; Young, S. H.; Fadeel, B.; Kagan, V. E.; Shvedova, A. A. Part. Fibre Toxicol. 2012, 9, 10Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFWlsrjE&md5=85a99e97112163382f51812e9d45054cFactoring-in agglomeration of carbon nanotubes and nanofibers for better prediction of their toxicity versus asbestosMurray, Ashley R.; Kisin, Elena R.; Tkach, Alexey V.; Yanamala, Naveena; Mercer, Robert; Young, Shih-Houng; Fadeel, Bengt; Kagan, Valerian E.; Shvedova, Anna A.Particle and Fibre Toxicology (2012), 9 (), 10CODEN: PFTABQ; ISSN:1743-8977. (BioMed Central Ltd.)Background: Carbon nanotubes (CNT) and carbon nanofibers (CNF) are allotropes of carbon featuring fibrous morphol. The dimensions and high aspect ratio of CNT and CNF have prompted the comparison with naturally occurring asbestos fibers which are known to be extremely pathogenic. While the toxicity and hazardous outcomes elicited by airborne exposure to single-walled CNT or asbestos have been widely reported, very limited data are currently available describing adverse effects of respirable CNF. Results: Here, we assessed pulmonary inflammation, fibrosis, oxidative stress markers and systemic immune responses to respirable CNF in comparison to single-walled CNT (SWCNT) and asbestos. Pulmonary inflammatory and fibrogenic responses to CNF, SWCNT and asbestos varied depending upon the agglomeration state of the particles/fibers. Foci of granulomatous lesions and collagen deposition were assocd. with dense particle-like SWCNT agglomerates, while no granuloma formation was found following exposure to fiber-like CNF or asbestos. The av. thickness of the alveolar connective tissue - a marker of interstitial fibrosis - was increased 28 days post SWCNT, CNF or asbestos exposure. Exposure to SWCNT, CNF or asbestos resulted in oxidative stress evidenced by accumulations of 4-HNE and carbonylated proteins in the lung tissues. Addnl., local inflammatory and fibrogenic responses were accompanied by modified systemic immunity, as documented by decreased proliferation of splenic T cells ex vivo on day 28 post exposure. The accuracies of assessments of effective surface area for asbestos, SWCNT and CNF (based on geometrical anal. of their agglomeration) vs. ests. of mass dose and no. of particles were compared as predictors of toxicol. outcomes. Conclusions: We provide evidence that effective surface area along with mass dose rather than sp. surface area or particle no. are significantly correlated with toxicol. responses to carbonaceous fibrous nanoparticles. Therefore, they could be useful dose metrics for risk assessment and management.
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287Sharifi, S.; Behzadi, S.; Laurent, S.; Forrest, M. L.; Stroeve, P.; Mahmoudi, M. Chem. Soc. Rev. 2012, 41, 2323Google Scholar287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivFWlsbk%253D&md5=cc3ebec4e8ccddb05d3ad7a0a0aeff13Toxicity of nanomaterialsSharifi, Shahriar; Behzadi, Shahed; Laurent, Sophie; Laird Forrest, M.; Stroeve, Pieter; Mahmoudi, MortezaChemical Society Reviews (2012), 41 (6), 2323-2343CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Nanoscience has matured significantly during the last decade as it has transitioned from bench top science to applied technol. Presently, nanomaterials are used in a wide variety of com. products such as electronic components, sports equipment, sun creams and biomedical applications. There are few studies of the long-term consequences of nanoparticles on human health, but governmental agencies, including the United States National Institute for Occupational Safety and Health and Japan's Ministry of Health, have recently raised the question of whether seemingly innocuous materials such as carbon-based nanotubes should be treated with the same caution afforded known carcinogens such as asbestos. Since nanomaterials are increasing a part of everyday consumer products, manufg. processes, and medical products, it is imperative that both workers and end-users be protected from inhalation of potentially toxic NPs. It also suggests that NPs may need to be sequestered into products so that the NPs are not released into the atm. during the product's life or during recycling. Further, non-inhalation routes of NP absorption, including dermal and medical injectables, must be studied in order to understand possible toxic effects. Fewer studies to date have addressed whether the body can eventually eliminate nanomaterials to prevent particle build-up in tissues or organs. This crit. review discusses the biophysicochem. properties of various nanomaterials with emphasis on currently available toxicol. data and methodologies for evaluating nanoparticle toxicity (286 refs.).
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288Muller, J.; Delos, M.; Panin, N.; Rabolli, V.; Huaux, F.; Lison, D. Toxicol. Sci. 2009, 110, 442Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosFWjsb8%253D&md5=36d511744ff04804dfc2dc60ff38fd22Absence of Carcinogenic Response to Multiwall Carbon Nanotubes in a 2-Year Bioassay in the Peritoneal Cavity of the RatMuller, Julie; Delos, Monique; Panin, Nadtha; Rabolli, Virginie; Huaux, Francois; Lison, DominiqueToxicological Sciences (2009), 110 (2), 442-448CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)Toxicol. investigations of carbon nanotubes have shown that they can induce pulmonary toxicity, and similarities with asbestos fibers have been suggested. The authors previously reported that multiwall carbon nanotubes (MWCNT) induced lung inflammation, granulomas and fibrotic reactions. The same MWCNT also caused mutations in epithelial cells in vitro and in vivo. These inflammatory and genotoxic activities were related to the presence of defects in the structure of the nanotubes. In view of the strong links between inflammation, mutations and cancer, these observations prompted the authors to explore the carcinogenic potential of these MWCNT in the peritoneal cavity of rats. The incidence of mesothelioma and other tumors was recorded in three groups of 50 male Wistar rats injected i.p. with a single dose of MWCNT with defects (2 or 20 mg/animal) and MWCNT without defects (20 mg/animal). Two addnl. groups of 26 rats were used as pos. (2 mg UICC crocidolite/animal) and vehicle controls. After 24 mo, although crocidolite induced a clear carcinogenic response (34.6% animals with mesothelioma vs. 3.8% in vehicle controls), MWCNT with or without structural defects did not induce mesothelioma in this bioassay (4, 0, or 6%, resp.). The incidence of tumors other than mesothelioma was not significantly increased across the groups. The initial hypothesis of a contrasting carcinogenic activity between MWCNT with and without defects could not be verified in this bioassay. The authors discuss the possible reasons for this absence of carcinogenic response, including the length of the MWCNT tested (<1 μm on av.), the absence of a sustained inflammatory reaction to MWCNT, and the capacity of these MWCNT to quench free radicals.
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289Sakamoto, Y.; Nakae, D.; Fukumori, N.; Tayama, K.; Maekawa, A.; Imai, K.; Hirose, A.; Nishimura, T.; Ohashi, N.; Ogata, A. J. Toxicol. Sci. 2009, 34, 65Google Scholar289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjsVKntrY%253D&md5=0c48c36f4ccc67c8b275ca358723c4c5Induction of mesothelioma by a single intrascrotal administration of multi-wall carbon nanotube in intact male Fischer 344 ratsSakamoto, Yoshimitsu; Nakae, Dai; Fukumori, Nobutaka; Tayama, Kuniaki; Maekawa, Akihiko; Imai, Kiyoshi; Hirose, Akihiko; Nishimura, Tetsuji; Ohashi, Norio; Ogata, AkioJournal of Toxicological Sciences (2009), 34 (1), 65-76CODEN: JTSCDR; ISSN:0388-1350. (Japanese Society of Toxicology)The present study assessed a carcinogenic hazard of multi-wall carbon nanotube (MWCNT) in intact (not genetically modified) rodents. MWCNT (1 mg/kg body wt., 7 animals), crocidolite (2 mg/kg body wt., 10 animals) or vehicle (2% CM-cellulose, 5 animals) was administered to male Fischer 344 rats (12 wk old) by a single intrascrotal injection. Rats were autopsied immediately after death, when becoming moribund or at the end of the maximal observation period scheduled to be 52 wk. After 37-40 wk, however, 6 MWCNT-treated animals died or became moribund due to i.p. disseminated mesothelioma (6/7, 85.7%) with bloody ascites. Peritoneal mesothelium was generally hypertrophic, and numerous nodular or papillary lesions of mesothelioma and mesothelial hyperplasia were developed. While mesothelioid cells were predominant in relatively early stage tumors, advanced stage mesotheliomas were constituted by 2 portions occupied by mesothelioid cells on the surface and spindle-shaped sarcomatous cells in the depth. In the latter, the histol. transition was apparently obsd. between these 2 portions. Mesotheliomas were invasive to adjacent organs and tissues, and frequently metastasized into the pleura. Only 1 rat survived for 52 wk in the MWCNT-treated group, and similar findings except mesothelioma were obsd. All 10 crocidolite-treated and 5 vehicle-treated rats survived for 52 wk without any particular changes except deposition of asbestos in the former case. It is thus indicated that MWCNT possesses carcinogenicity causing mesothelioma at a high rate in intact male rats under the present exptl. conditions. The present data identifies a carcinogenic hazard of MWCNT and will serve as one of the indispensable evidences to be used for the risk assessment crucial for not only protection and improvement of human health and welfare, but also safe and acceptable development and prevalence of this and similar upcoming materials.
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290Lam, C. W.; James, J. T.; McCluskey, R.; Hunter, R. L. Toxicol. Sci. 2004, 77, 126Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXnslKk&md5=888792409ef5a908b6af59d4e8143799Pulmonary Toxicity of Single-Wall Carbon Nanotubes in Mice 7 and 90 Days After Intratracheal InstillationLam, Chiu-Wing; James, John T.; McCluskey, Richard; Hunter, Robert L.Toxicological Sciences (2004), 77 (1), 126-134CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)Nanomaterials are part of an industrial revolution to develop lightwt. but strong materials for a variety of purposes. Single-wall carbon nanotubes are an important member of this class of materials. They structurally resemble rolled-up graphite sheets, usually with one end capped; individually they are about 1 nm in diam. and several microns long, but they often pack tightly together to form rods or ropes of microscopic sizes. Carbon nanotubes possess unique elec., mech., and thermal properties and have many potential applications in the electronics, computer, and aerospace industries. Unprocessed nanotubes are very light and could become airborne and potentially reach the lungs. Because the toxicity of nanotubes in the lung is not known, their pulmonary toxicity was investigated. The three products studied were made by different methods and contained different types and amts. of residual catalytic metals. Mice were intratracheally instilled with 0, 0.1, or 0.5 mg of carbon nanotubes, a carbon black neg. control, or a quartz pos. control and euthanized 7 d or 90 d after the single treatment for histopathol. study of the lungs. All nanotube products induced dose-dependent epithelioid granulomas and, in some cases, interstitial inflammation in the animals of the 7-d groups. These lesions persisted and were more pronounced in the 90-d groups; the lungs of some animals also revealed peribronchial inflammation and necrosis that had extended into the alveolar septa. The lungs of mice treated with carbon black were normal, whereas those treated with high-dose quartz revealed mild to moderate inflammation. These results show that, for the test conditions described here and on an equal-wt. basis, if carbon nanotubes reach the lungs, they are much more toxic than carbon black and can be more toxic than quartz, which is considered a serious occupational health hazard in chronic inhalation exposures.
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291Li, Z.; Hulderman, T.; Salmen, R.; Chapman, R.; Leonard, S. S.; Young, S. H.; Shvedova, A.; Luster, M. I.; Simeonova, P. P. Environ. Health Perspect. 2007, 115, 377Google Scholar291https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjvFWnur4%253D&md5=584a376c89f8a589602336c05974435eCardiovascular effects of pulmonary exposure to single-wall carbon nanotubesLi, Zheng; Hulderman, Tracy; Salmen, Rebecca; Chapman, Rebecca; Leonard, Stephen S.; Young, Shih-Houng; Shvedova, Anna; Luster, Michael I.; Simeonova, Petia P.Environmental Health Perspectives (2007), 115 (3), 377-382CODEN: EVHPAZ; ISSN:0091-6765. (U. S. Department of Health and Human Services, Public Health Services)Background: Engineered nanosized materials, such as single-wall carbon nanotubes (SWCNT), are emerging as technol. important in different industries. Objective: The unique phys. characteristics and the pulmonary toxicity of SWCNTs raised concerns that respiratory exposure to these materials may be assocd. with cardiovascular adverse effects. Methods: In these studies we evaluated aortic mitochondrial alterations by oxidative stress assays, including quant. polymerase chain reaction of mitochondrial (mt) DNA and plaque formation by morphometric anal. in mice exposed to SWCNTs. Results: A single intrapharyngeal instillation of SWCNTs induced activation of heme oxygenase-1 (HO-1), a marker of oxidative insults, in lung, aorta, and heart tissue in HO-1 reporter transgenic mice. Furthermore, we found that C57BL/6 mice, exposed to SWCNT (10 and 40 μg/mouse), developed aortic mtDNA damage at 7, 28, and 60 days after exposure. MtDNA damage was accompanied by changes in aortic mitochondrial glutathione and protein carbonyl levels. Because these modifications have been related to cardiovascular diseases, we evaluated whether repeated exposure to SWCNTs (20 μg/mouse once every other week for 8 wk) stimulates the progression of atherosclerosis in ApoE-/- transgenic mice. Although SWCNT exposure did not modify the lipid profiles of these mice, it resulted in accelerated plaque formation in ApoE-/- mice fed an atherogenic diet. Plaque areas in the aortas, measured by the en face method, and in the brachiocephalic arteries, measured histopathol., were significantly increased in the SWCNT-treated mice. This response was accompanied by increased mtDNA damage but not inflammation. Conclusions: Taken together, the findings are of sufficient significance to warrant further studies to evaluate the systemic effects of SWCNT under workplace or environmental exposure paradigms.
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292Tong, H.; McGee, J. K.; Saxena, R. K.; Kodavanti, U. P.; Devlin, R. B.; Gilmour, M. I. Toxicol. Appl. Pharmacol. 2009, 239, 224Google Scholar292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVKku7zJ&md5=592ff72b4984e340cc01602500ecacf2Influence of acid functionalization on the cardiopulmonary toxicity of carbon nanotubes and carbon black particles in miceTong, Haiyan; McGee, John K.; Saxena, Rajiv K.; Kodavanti, Urmila P.; Devlin, Robert B.; Gilmour, M. IanToxicology and Applied Pharmacology (2009), 239 (3), 224-232CODEN: TXAPA9; ISSN:0041-008X. (Elsevier B.V.)Engineered carbon nanotubes are being developed for a wide range of industrial and medical applications. Because of their unique properties, nanotubes can impose potentially toxic effects, particularly if they have been modified to express functionally reactive chem. groups on their surface. The present study was designed to evaluate whether acid functionalization (AF) enhanced the cardiopulmonary toxicity of single-walled carbon nanotubes (SWCNT) as well as control carbon black particles. Mice were exposed by oropharyngeal aspiration to 10 or 40 μg of saline-suspended single-walled carbon nanotubes (SWCNTs), acid-functionalized SWCNTs (AF-SWCNTs), ultrafine carbon black (UFCB), AF-UFCB, or 2 μg LPS. 24 h later, pulmonary inflammatory responses and cardiac effects were assessed by bronchoalveolar lavage and isolated cardiac perfusion resp., and compared to saline or LPS-instilled animals. Addnl. mice were assessed for histol. changes in lung and heart. Instillation of 40 μg of AF-SWCNTs, UFCB and AF-UFCB increased percentage of pulmonary neutrophils. No significant effects were obsd. at the lower particle concn. Sporadic clumps of particles from each treatment group were obsd. in the small airways and interstitial areas of the lungs according to particle dose. Patches of cellular infiltration and edema in both the small airways and in the interstitium were also obsd. in the high dose group. Isolated perfused hearts from mice exposed to 40 μg of AF-SWCNTs had significantly lower cardiac functional recovery, greater infarct size, and higher coronary flow rate than other particle-exposed animals and controls, and also exhibited signs of focal cardiac myofiber degeneration. No particles were detected in heart tissue under light microscopy. This study indicates that while acid functionalization increases the pulmonary toxicity of both UFCB and SWCNTs, this treatment caused cardiac effects only with the AF-carbon nanotubes. Further expts. are needed to understand the physico-chem. processes involved in this phenomenon.
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293Kobayashi, N.; Naya, M.; Ema, M.; Endoh, S.; Maru, J.; Mizuno, K.; Nakanishi, J. Toxicology 2010, 276, 143Google ScholarThere is no corresponding record for this reference.
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294Reddy, A. R.; Krishna, D. R.; Reddy, Y. N.; Himabindu, V. Toxicol. Mech. Methods 2010, 20, 267Google Scholar294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmt12mt7w%253D&md5=c658b16aa7608b9cc08195315b995857Translocation and extra pulmonary toxicities of multi wall carbon nanotubes in ratsReddy, A. Rama Narsimha; Krishna, Devarakonda R.; Reddy, Y. Narsimha; Himabindu, V.Toxicology Mechanisms and Methods (2010), 20 (5), 267-272CODEN: TMMOCP; ISSN:1537-6516. (Informa Healthcare)This study evaluated the ability of the multi wall carbon nanotubes (MWCNT) to induce extra pulmonary toxicities in rats following intra-tracheal (IT) instillation of two MWCNT. Two carbon nanoparticles were instilled into the lungs of rats (0.2, 1, and 5 mg/kg b.w.) and at different post-exposure intervals, blood and organs like liver, kidney, etc. were collected. The histopathol. examn. of liver tissues revealed a dose-dependent periportal lymphocytic infiltration, ballooning, foamy degeneration, and necrosis at all post-instillation periods. However, examn. of kidney revealed the tubular necrosis and interstitial nephritis with 5 mg/kg dose at 1 mo of post-instillation of both MWCNT. These liver and kidney toxicities were further confirmed by the elevated levels of resp. tissue damage biomarkers. These results suggest the extra pulmonary toxicities of these carbon nanoparticles might be due to the translocation into the liver and kidney.
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295Ge, C.; Meng, L.; Xu, L.; Bai, R.; Du, J.; Zhang, L.; Li, Y.; Chang, Y.; Zhao, Y.; Chen, C. Nanotoxicology 2012, 6, 526Google ScholarThere is no corresponding record for this reference.
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296Zhang, Y.; Deng, J.; Guo, F.; Li, C.; Zou, Z.; Xi, W.; Tang, J.; Sun, Y.; Yang, P.; Han, Z.; Li, D.; Jiang, C. J. Mol. Med. (Heidelberg, Ger.) 2013, 91, 117Google Scholar296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlt1Ghuw%253D%253D&md5=69f9d158a7b4588594fb9e353ec3aa97Functionalized single-walled carbon nanotubes cause reversible acute lung injury and induce fibrosis in miceZhang, Yanli; Deng, Jiejie; Zhang, Yanxu; Guo, Feng; Li, Chenggang; Zou, Zhen; Xi, Wen; Tang, Jun; Sun, Yang; Yang, Peng; Han, Zongsheng; Li, Dangsheng; Jiang, ChengyuJournal of Molecular Medicine (Heidelberg, Germany) (2013), 91 (1), 117-128CODEN: JMLME8; ISSN:0946-2716. (Springer)Nanotechnol. is one of today's most promising technol. developments, but safety concerns raise questions about its development. Risk assessments of nanomaterials during occupational exposure are crucial for their development. Here, we assessed the lung toxicity of functionalized single-walled carbon nanotube (f-SWCNT) exposure in C57BL/6 mice, elucidated the underlying mol. mechanism, and evaluated the self-repair ability and lung fibrosis of the mice. Sol. f-SWCNTs were administered to mice. After 18 h or 14 days, the lung histopathol., bronchoalveolar lavage fluid, lung edema, vascular permeability, and PaO2 levels were evaluated, and biochem. and immunostaining tests were also performed. We found that some f-SWCNTs could induce acute lung injury (ALI) in mice via proinflammatory cytokine storm signaling through the NF-κB pathway in vivo. We illustrated that corticosteroid treatments could ameliorate the ALI induced by the f-SWCNTs in mice. Surprisingly, the ALI was almost completely reversed within 14 days, while mild to moderate fibrosis, granuloma, and DNA damage remained in the mice at day 14. Our studies indicate potential remedies to address the growing concerns about the safety of nanomaterials. In addn., we notify that the type of functional groups should be considered in nanomedicine application as differently functionalized SWCNTs generated different effects on the lung toxicity.
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297Erdely, A.; Liston, A.; Salmen-Muniz, R.; Hulderman, T.; Young, S. H.; Zeidler-Erdely, P. C.; Castranova, V.; Simeonova, P. P. J. Occup. Environ. Med. 2011, 53, S80Google ScholarThere is no corresponding record for this reference.
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298Zhang, Q.; Huang, J. Q.; Zhao, M. Q.; Qian, W. Z.; Wei, F. ChemSusChem 2011, 4, 864Google ScholarThere is no corresponding record for this reference.
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299Department of health and human services, Centers for disease control and prevention, National Institute for Occupational Safety and Health. Occupational exposure to carbon nanotubes and nanofibers. , 2013; p 65.Google ScholarThere is no corresponding record for this reference.
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300Environment directorate joint meeting of the chemicals committee and the working party on chemicals, pesticides, and biotechnology. Inhalation toxicity testing: expert meeting on potential revisions to OECD test guidelines and guidance document. , 2012; p 35.Google ScholarThere is no corresponding record for this reference.
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301European Commission. Communicationfrom the commission to the European parliament, thecouncil and the european economic and social committee: Second regulatoryreview on nanomaterials. COM (2012, 572 final.Google ScholarThere is no corresponding record for this reference.
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302Nakanishi, J. Risk Assessment of Manufactured Nanomaterials: Carbon Nanotubes (CNT); Final report issued on 12 August 2011, NEDO project (P06041); New Energy and IndustrialTechnology Development Organization: Kawasaki, 2011.Google ScholarThere is no corresponding record for this reference.
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303Pauluhn, J. Regul. Toxicol. Pharmacol. 2010, 57, 78Google Scholar303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXkvFCltrw%253D&md5=e0591da6e84d1534d24da31c47e346dcMulti-walled carbon nanotubes (Baytubes): Approach for derivation of occupational exposure limitPauluhn, JuergenRegulatory Toxicology and Pharmacology (2010), 57 (1), 78-89CODEN: RTOPDW; ISSN:0273-2300. (Elsevier B.V.)Carbon nanotubes come in a variety of types, but one of the most common forms is multi-walled carbon nanotubes (MWCNT). This paper focuses on the dose-response and time course of pulmonary toxicity of Baytubes, a more flexible MWCNT type with the tendency to form assemblages of nanotubes. This MWCNT has been examd. in previous single and repeated exposure 13-wk rat inhalation studies. Kinetic endpoints and the potential to translocate to extrapulmonary organs have been examd. during postexposure periods of 3 and 6 mo, resp. The focus of both studies was to compare dosimetric endpoints and the time course of pulmonary inflammation characterized by repeated bronchoalveolar lavage and histopathol. during the resp. follow-up periods. To better understand the etiopathol. of pulmonary inflammation and time-related lung remodeling, two metrics of retained lung dose were compared. The first used the mass metric based on the exposure concn. obtained by filter analyses and aerodynamic particle size of airborne MWCNT. The second was based on calcd. volumetric lung burdens of retained MWCNT. Kinetic analyses of lung burdens support the conclusion that Baytubes, in principal, act like poorly sol. agglomerated carbonaceous particulates. However, the difference in pulmonary toxic potency (mass-based) appears to be assocd. with the low-d. (≈0.1-0.3 g/m3) of the MWCNT assemblages. Of note is that assemblages of MWCNT were found predominantly both in the exposure atm. and in digested alveolar macrophages. Isolated fibers were not obsd. in exposure atmospheres or biol. specimens. All findings support the conclusion that the low specific d. of microstructures was conducive to attaining the volumetric lung overload-related inflammatory response conditions earlier than conventional particles. Evidence of extrapulmonary translocation or toxicity was not found in any study. Thus, pulmonary overload is believed to trigger the cascade of events leading to a stasis of clearance and consequently increased MWCNT doses high enough to trigger sustained pulmonary inflammation. This mechanism served as conceptual basis for the calcn. of the human equiv. concn. Accordingly, multiple interspecies adjustments were necessary which included species-specific differences in alveolar deposition, differences in ventilation, and the time-dependent particle accumulation accounting for the known species-specific differences in particle clearance half-times in rats and humans. Based on this rationale and the NOAEL (no-obsd. adverse effect level) from the 13-wk subchronic inhalation study on rats, an occupational exposure limit (OEL) of 0.05 mg Baytubes/m3 (time weighted av.) is considered to be reasonably protective to prevent lung injury to occur in the workplace environment.
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304Yang, K.; Liu, Z. Curr. Drug Metab. 2012, 13, 1057Google Scholar304https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVWgtbjI&md5=9c7d12acb205697ed79a3dba48143f1cIn vivo biodistribution, pharmacokinetics, and toxicology of carbon nanotubesYang, Kai; Liu, ZhuangCurrent Drug Metabolism (2012), 13 (8), 1057-1067CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)A review. Owing to their interesting phys. and chem. properties, carbon nanotubes (CNTs) have attracted wide attention in nanomedicine for applications in biol. sensing, drug delivery, as well as biomedical imaging. The in vivo behaviors and toxicol. of CNTs in biol. systems, which are important fundamental questions, although have been intensively studied in recent years, remain to be clarified as distinctive results have been reported by various teams, confusing the scientific community as well as the public. In this article, we review the research on the in vivo behaviors of CNTs, and summarize the toxicity studies of CNTs in animals by different groups. Similar to other nanomaterials, the in vivo pharmacokinetics and biodistribution of CNTs are closely assocd. with their surface coatings. The excretion of CNTs from animals may happen via renal and fecal pathways, depending on the CNT surface chem., shape, and sizes. Regarding the toxicol. of CNTs, which has been a debating topic for years, the administration routes, doses, and again the surface functionalization are crit. to the in vivo toxicity of nanotubes. Much more efforts are still required to develop functional CNT bioconjugates with improved biocompatible coatings and controllable optimal sizes to achieve fast excretion and minimal toxicity, for various applications in biomedicine.
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305Cherukuri, P.; Gannon, C. J.; Leeuw, T. K.; Schmidt, H. K.; Smalley, R. E.; Curley, S. A.; Weisman, R. B. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 18882Google ScholarThere is no corresponding record for this reference.
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306Singh, R.; Pantarotto, D.; Lacerda, L.; Pastorin, G.; Klumpp, C.; Prato, M.; Bianco, A.; Kostarelos, K. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 3357Google ScholarThere is no corresponding record for this reference.
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307Kawaguchi, M.; Fukushima, T.; Hayakawa, T.; Nakashima, N.; Inoue, Y.; Takeda, S.; Okamura, K.; Taniguchi, K. Dent. Mater. J. 2006, 25, 719Google Scholar307https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjtlylsbc%253D&md5=bc2707fe86085ffc4f06c8527d4537edPreparation of carbon nanotube-alginate nanocomposite gel for tissue engineeringKawaguchi, Minoru; Fukushima, Tadao; Hayakawa, Toru; Nakashima, Naotoshi; Inoue, Yusuke; Takeda, Shoji; Okamura, Kazuhiko; Taniguchi, KunihisaDental Materials Journal (2006), 25 (4), 719-725CODEN: DMJOD5; ISSN:0287-4547. (Japan Society for Dental Materials and Devices)A novel scaffold material based on an alginate hydrogel which contained carbon nanotubes (CNTs) was prepd., and its mech. property and biocompatibility evaluated. Sol. CNTs were prepd. with acid treatment and dispersed in sodium alginate soln. as a cross-linker. After which, the mech. property (elastic deformation), saline sorption, histol. reaction, and cell viability of the resultant nanocomposite gel (CNT-Alg gel) were evaluated. The CNT-Alg gel showed faster gelling and higher mech. strength than the conventional alginate gel. Saline sorption amt. of freeze-dried CNT-Alg gel was equal to that of the alginate gel. In terms of histol. evaluation and cell viability assay, CNT-Alg gel exhibited a mild inflammatory response and non-cytotoxicity. These results thus suggested that CNT-Alg gel could be useful as a scaffold material in tissue engineering with the sidewalls of CNTs acting as active sites for chem. functionalization.
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308Sitharaman, B.; Shi, X.; Walboomers, X. F.; Liao, H.; Cuijpers, V.; Wilson, L. J.; Mikos, A. G.; Jansen, J. A. Bone 2008, 43, 362Google ScholarThere is no corresponding record for this reference.
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309Sato, Y.; Yokoyama, A.; Shibata, K.; Akimoto, Y.; Ogino, S.; Nodasaka, Y.; Kohgo, T.; Tamura, K.; Akasaka, T.; Uo, M.; Motomiya, K.; Jeyadevan, B.; Ishiguro, M.; Hatakeyama, R.; Watari, F.; Tohji, K. Mol. Biosyst. 2005, 1, 176Google Scholar309https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXntlCmtro%253D&md5=5a747eb5e70c28fb14a43106bddc85bfInfluence of length on cytotoxicity of multi-walled carbon nanotubes against human acute monocytic leukemia cell line THP-1 in vitro and subcutaneous tissue of rats in vivoSato, Yoshinori; Yokoyama, Atsuro; Shibata, Ken-ichiro; Akimoto, Yuki; Ogino, Shin-ichi; Nodasaka, Yoshinobu; Kohgo, Takao; Tamura, Kazuchika; Akasaka, Tsukasa; Uo, Motohiro; Motomiya, Kenichi; Jeyadevan, Balachandran; Ishiguro, Mikio; Hatakeyama, Rikizo; Watari, Fumio; Tohji, KazuyukiMolecular BioSystems (2005), 1 (2), 176-182CODEN: MBOIBW; ISSN:1742-206X. (Royal Society of Chemistry)Carbon nanotubes (CNTs) are single- or multi-cylindrical graphene structures that possess diams. of a few nanometers, while the length can be up to a few micrometers. These could have unusual toxicol. properties, in that they share intermediate morphol. characteristics of both fibers and nanoparticles. To date, no detailed study was carried out to det. the effect of length on CNT cytotoxicity. In this paper, the authors investigated the activation of the human acute monocytic leukemia cell line THP-1 in vitro and the response in s.c. tissue in vivo to CNTs of different lengths. The authors used 220 nm and 825 nm-long CNT samples for testing, referred to as "220-CNTs" and "825-CNTs", resp. 220-CNTs and 825-CNTs induced human monocytes in vitro, although the activity was significantly lower than that of microbial lipopeptide and lipopolysaccharide, and no activity appeared following variation in the length of CNTs. On the other hand, the degree of inflammatory response in s.c. tissue in rats around the 220-CNTs was slight in comparison with that around the 825-CNTs. These results indicated that the degree of inflammation around 825-CNTs was stronger than that around 220-CNTs since macrophages could envelop 220-CNTs more readily than 825-CNTs. However, no severe inflammatory response such as necrosis, degeneration or neutrophil infiltration in vivo was obsd. around both CNTs examd. throughout the exptl. period.
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310Deng, X.; Jia, G.; Wang, H.; Sun, H.; Wang, X.; Yang, S.; Wang, T.; Liu, Y. Carbon 2007, 45, 1419Google Scholar310https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmtVGktrg%253D&md5=a9ad312bc30e357ccbe8e3ece7d004c8Translocation and fate of multi-walled carbon nanotubes in vivoDeng, X.; Jia, G.; Wang, H.; Sun, H.; Wang, X.; Yang, S.; Wang, T.; Liu, Y.Carbon (2007), 45 (7), 1419-1424CODEN: CRBNAH; ISSN:0008-6223. (Elsevier Ltd.)Carbon nanotube (CNT) mediated delivery system of drugs etc. has currently aroused a large interest. Because the delivery system will be ultimately introduced into the human body, the information about the in vivo biol. behavior and consequences of CNTs becomes very important. Here, using [14C-taurine]-multi-walled CNTs (MWCNTs) as tracers, the authors show the biodistribution and translocation pathways of MWCNTs in mice by 3 different routes. After mice were exposed by i.v. injection, MWCNTs predominately accumulated in liver and retained for long time. Transmission electron micrographs clearly show the remarkable entrapment of MWCNTs in hepatic macrophages (Kupffer cells). The biol. index examns. indicate low liver acute toxicity of MWCNTs. Some favorable aspects of MWCNTs being used as a drug nanovehicle are also discussed.
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311Bai, Y.; Zhang, Y.; Zhang, J.; Mu, Q.; Zhang, W.; Butch, E. R.; Snyder, S. E.; Yan, B. Nat. Nanotechnol. 2010, 5, 683Google Scholar311https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFajsrbN&md5=6421c975774532fc0a532bd5f969187dRepeated administrations of carbon nanotubes in male mice cause reversible testis damage without affecting fertilityBai, Yuhong; Zhang, Yi; Zhang, Jingping; Mu, Qingxin; Zhang, Weidong; Butch, Elizabeth R.; Snyder, Scott E.; Yan, BingNature Nanotechnology (2010), 5 (9), 683-689CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Sol. carbon nanotubes show promise as materials for in vivo delivery and imaging applications. Several reports have described the in vivo toxicity of carbon nanotubes, but their effects on male reprodn. have not been examd. Here, the authors show that repeated i.v. injections of water-sol. multiwalled carbon nanotubes into male mice can cause reversible testis damage without affecting fertility. Nanotubes accumulated in the testes, generated oxidative stress and decreased the thickness of the seminiferous epithelium in the testis at day 15, but the damage was repaired at 60 and 90 days. The quantity, quality and integrity of the sperm and the levels of three major sex hormones were not significantly affected throughout the 90-day period. The fertility of treated male mice was unaffected; the pregnancy rate and delivery success of female mice that mated with the treated male mice did not differ from those that mated with untreated male mice.
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312Yang, S. T.; Wang, X.; Jia, G.; Gu, Y.; Wang, T.; Nie, H.; Ge, C.; Wang, H.; Liu, Y. Toxicol. Lett. 2008, 181, 182Google Scholar312https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtFekurbK&md5=7b4d62b4c86cdf155e2b447bbcc014e7Long-term accumulation and low toxicity of single-walled carbon nanotubes in intravenously exposed miceYang, Sheng-Tao; Wang, Xiang; Jia, Guang; Gu, Yiqun; Wang, Tiancheng; Nie, Haiyu; Ge, Cuicui; Wang, Haifang; Liu, YuanfangToxicology Letters (2008), 181 (3), 182-189CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)The biomedical application of single-walled carbon nanotubes (SWCNTs), such as drug delivery and cancer treatment, requires a clear understanding of their fate and toxicol. profile after i.v. administration. In this study, the long-term accumulation and toxicity of i.v. injected SWCNTs in the main organs (such as liver, lung and spleen) in mice were carefully studied. Although SWCNTs stayed in mice over 3 mo, they showed low toxicity to mice. The long-term accumulation of SWCNTs in the main organs was evidenced by using Raman spectroscopy and TEM technique. Statistically significant changes in organ indexes and serum biochem. parameters (LDH, ALT and AST) were obsd. The histol. observations demonstrate that slight inflammation and inflammatory cell infiltration occurred in lung, but the serum immunol. indicators (CH 50 level and TNF-α level) remained unchanged. No apoptosis was induced in the main organs. The decreasing glutathione (GSH) level and increasing malondialdehyde (MDA) level suggest that the toxicity of SWCNTs might be due to the oxidative stress.
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313Al Faraj, A.; Fauvelle, F.; Luciani, N.; Lacroix, G.; Levy, M.; Crémillieux, Y.; Canet-Soulas, E. Int. J. Nanomed. 2011, 6, 351Google Scholar313https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXislChtb8%253D&md5=e7a67b9581fc77418c80f5c494ea9a34In vivo biodistribution and biological impact of injected carbon nanotubes using magnetic resonance techniquesAl Faraj, Achraf; Fauvelle, Florence; Luciani, Nathalie; Lacroix, Ghislaine; Levy, Michael; Cremillieux, Yannick; Canet-Soulas, EmmanuelleInternational Journal of Nanomedicine (2011), 6 (), 351-361CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)Single-walled carbon nanotubes (SWCNT) hold promise for applications as contrast agents and target delivery carriers in the field of nanomedicine. When administered in vivo, their biodistribution and pharmacol. profile needs to be fully characterized. The tissue distribution of carbon nanotubes and their potential impact on metab. depend on their shape, coating, and metallic impurities. Because std. radiolabeled or fluorescently-labeled pharmaceuticals are not well suited for long-term in vivo follow-up of carbon nanotubes, alternative methods are required. In this study, noninvasive in vivo magnetic resonance imaging (MRI) investigations combined with high-resoln. magic angle spinning (HR-MAS), Raman spectroscopy, iron assays, and histol. anal. ex vivo were proposed and applied to assess the biodistribution and biol. impact of i.v. injected pristine (raw and purified) and functionalized SWCNT in a 2-wk longitudinal study. Iron impurities allowed raw detection of SWCNT in vivo by susceptibility-weighted MRI. A transitional accumulation in the spleen and liver was obsd. by MRI. Raman spectroscopy, iron assays, and histol. findings confirmed the MRI readouts. Moreover, no acute toxicol. effect on the liver metabolic profile was obsd. using the HR-MAS technique, as confirmed by quant. real-time polymerase chain reaction anal. This study illustrates the potential of noninvasive MRI protocols for longitudinal assessment of the biodistribution of SWCNT with assocd. intrinsic metal impurities. The same approach can be used for any other magnetically-labeled nanoparticles.
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314Wu, H.; Liu, G.; Zhuang, Y.; Wu, D.; Zhang, H.; Yang, H.; Hu, H.; Yang, S. Biomaterials 2011, 32, 4867Google ScholarThere is no corresponding record for this reference.
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315Wei, Q.; Zhan, L.; Juanjuan, B.; Jing, W.; Jianjun, W.; Taoli, S.; Yi’an, G.; Wangsuo, W. Nanoscale Res. Lett. 2012, 7, 473Google Scholar315https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38bgsVWgsg%253D%253D&md5=78725c2234bfb35cdabca8d3c5d7e696Biodistribution of co-exposure to multi-walled carbon nanotubes and nanodiamonds in miceWei Qi; Zhan Li; Juanjuan Bi; Jing Wang; Jianjun Wang; Taoli Sun; Yi'an Guo; Wangsuo WuNanoscale research letters (2012), 7 (1), 473 ISSN:.In this work, technetium-99 (99mTc) was used as the radiolabeling isotope to study the biodistribution of oxidized multi-walled carbon nanotubes (oMWCNTs) and/or nanodiamonds (NDs) in mice after intravenous administration. The histological impact of non-radiolabeled oMWCNTs or NDs was investigated in comparison to the co-exposure groups. 99mTc-labeled nanomaterials had high stability in vivo and fast clearance from blood. After a single injection of oMWCNTs, the highest distribution was found in the lungs, with lower uptake in the liver/spleen. As for NDs injected alone, high distribution in the liver, spleen, and lungs was observed right after. However, uptake in the lungs was decreased obviously after 24 h, while high accumulation in the liver or spleen continued. After co-injection of oMWCNTs and NDs, oMWCNTs significantly affected the distribution pattern of NDs in vivo. Meanwhile, the increasing dose of oMWCNTs decreased the hepatic and splenic accumulation of NDs and gradually increased lung retention. On the contrary, the NDs had no significant effects on the distribution of oMWCNTs in mice. Histological photographs showed that oMWCNTs were mainly captured by lung macrophages, and NDs were located in the bronchi and alveoli after co-administration. oMWCNTs and NDs had different modes of micro-cells. In conclusion, the behavior and fate of NDs in mice depended strongly on oMWCNTs, but NDs had a small influence on the biodistribution and excretion pattern of oMWCNTs.
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316Simon-Deckers, A.; Gouget, B.; Mayne-L’hermite, M.; Herlin-Boime, N.; Reynaud, C.; Carriere, M. Toxicology 2008, 253, 137Google ScholarThere is no corresponding record for this reference.
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317Gomez-Gualdrón, D. A.; Burgos, J. C.; Yu, J.; Balbuena, P. B. Prog. Mol. Biol. Transl. Sci. 2011, 104, 175Google Scholar317https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivFOjtL8%253D&md5=616f88b27863c5fee22069edd3b6bb59Carbon nanotubes: engineering biomedical applicationsGomez-Gualdron, Diego A.; Burgos, Juan C.; Yu, Jiamei; Balbuena, Perla B.Progress in Molecular Biology and Translational Science (2011), 104 (Nanoparticles in Translational Science and Medicine), 175-245,, 8 platesCODEN: PNARC5 ISSN:. (Elsevier Inc.)A review. Carbon nanotubes (CNTs) are cylinder-shaped allotropic forms of carbon, most widely produced under chem. vapor deposition. They possess astounding chem., electronic, mech., and optical properties. Being among the most promising materials in nanotechnol., they are also likely to revolutionize medicine. Among other biomedical applications, after proper functionalization carbon nanotubes can be transformed into sophisticated biosensing and biocompatible drug-delivery systems, for specific targeting and elimination of tumor cells. This chapter provides an introduction to the chem. and electronic structure and properties of single-walled carbon nanotubes, followed by a description of the main synthesis and post-synthesis methods. These sections allow the reader to become familiar with the specific characteristics of these materials and the manner in which these properties may be dependent on the specific synthesis and post-synthesis processes. The chapter ends with a review of the current biomedical applications of carbon nanotubes, highlighting successes and challenges.
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318Cui, D.; Tian, F.; Ozkan, C. S.; Wang, M.; Gao, H. Toxicol. Lett. 2005, 155, 73Google Scholar318https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVCktrjP&md5=399fb2a7692374a1a69a7e63bee35a8eEffect of single wall carbon nanotubes on human HEK293 cellsCui, Daxiang; Tian, Furong; Ozkan, Cengiz S.; Wang, Mao; Gao, HuajianToxicology Letters (2005), 155 (1), 73-85CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)The influence of single-walled carbon nanotubes (SWCNTs) on human HEK293 cells is investigated with the aim of exploring SWCNTs biocompatibility. Results showed that SWCNTs can inhibit HEK293 cell proliferation, decrease cell adhesive ability in a dose- and time-dependent manner. HEK293 cells exhibit active responses to SWCNTs such as secretion of some 20-30 kd proteins to wrap SWCNTs, aggregation of cells attached by SWCNTs and formation of nodular structures. Cell cycle anal. showed that 25 μg/mL SWCNTs in medium induced G1 arrest and cell apoptosis in HEK293 cells. Biochip anal. showed that SWCNTs can induce up-regulation expression of cell cycle-assocd. genes such as p16, bax, p57, hrk, cdc42 and cdc37, down-regulation expression of cell cycle genes such as cdk2, cdk4, cdk6 and cyclin D3, and down-regulation expression of signal transduction-assocd. genes such as mad2, jak1, ttk, pcdha9 and erk. Western blot anal. showed that SWCNTs can induce down-regulation expression of adhesion-assocd. proteins such as laminin, fibronectin, cadherin, FAK and collagen IV. These results suggest that down-regulation of G1-assocd. cdks and cyclins and upregulation of apoptosis-assocd. genes may contribute to SWCNTs induced G1 phase arrest and cell apoptosis. In conclusion, SWCNTs can inhibit HEK293 cells growth by inducing cell apoptosis and decreasing cellular adhesion ability.
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319Jain, S.; Thakare, V. S.; Das, M.; Godugu, C.; Jain, A. K.; Mathur, R.; Chuttani, K.; Mishra, A. K. Chem. Res. Toxicol. 2011, 24, 2028Google ScholarThere is no corresponding record for this reference.
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320Oberdörster, G.; Sharp, Z.; Atudorei, V.; Elder, A.; Gelein, R.; Lunts, A.; Kreyling, W.; Cox, C. J. Toxicol. Environ. Health, Part A 2002, 65, 1531Google Scholar320https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XosF2lsb0%253D&md5=877963d4e9368fbf52bfc48d5acb3798Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of ratsOberdorster, Gunter; Sharp, Zachary; Atudorei, Viorel; Elder, Alison; Gelein, Robert; Lunts, Alex; Kreyling, Wolfgang; Cox, ChristopherJournal of Toxicology and Environmental Health, Part A (2002), 65 (20), 1531-1543CODEN: JTEHF8; ISSN:1528-7394. (Taylor & Francis Inc.)Studies with i.v. injected ultrafine particles have shown that the liver is the major organ of their uptake from the blood circulation. Measuring translocation of inhaled ultrafine particles to extrapulmonary organs via the blood compartment is hampered by methodol. difficulties (i.e., label may come off, partial solubilization) and anal. limitations (measurement of very small amts.). The objective of our pilot study was to det. whether ultrafine elemental carbon particles translocate to the liver and other extrapulmonary organs following inhalation as singlet particles by rats. We generated ultrafine 13C particles as an aerosol with count median diams. (CMDs) of 20-29 nm (GSD 1.7) using elec. spark discharge of 13C graphite electrodes in argon. Nine Fischer 344 rats were exposed to these particles for 6 h. in whole-body inhalation chambers at concns. of 180 and 80 μg/m3; 3 animals each were killed at 0.5, 18, and 24 h postexposure. Six unexposed rats served as controls. Lung lobes, liver, heart, brain, olfactory bulb, and kidney were excised, homogenized, and freeze-dried for anal. of the added 13C by isotope ratio mass spectrometry. Org. 13C was not detected in the 13C particles. The 13C retained in the lung at 0.5 h postexposure was about 70% less than predicted by rat deposition models for ultrafine particles, and did not change significantly during the 24-h postexposure period. Normalized to exposure concn., the added 13C per g of lung on av. in the postexposure period was ∼9 ng/g organ/μg/m3. Significant amts. of 13C had accumulated in the liver by 0.5 h postinhalation only at the high exposure concn., whereas by 18 and 24 h postexposure the 13C amt. of the livers of all exposed rats was about fivefold greater than the 13C burden retained in the lung. No significant increase in 13C was detected in the other organs which were examd. These results demonstrate effective translocation of ultrafine elemental carbon particles to the liver by 1 d after inhalation exposure. Translocation pathways include direct input into the blood compartment from ultrafine carbon particles deposited throughout the respiratory tract. However, since predictive particle deposition models indicate that respiratory tract deposits alone may not fully account for the hepatic 13C burden, input from ultrafine particles present in the GI tract needs to be considered as well. Such translocation to blood and extrapulmonary tissues may well be different between ultrafine carbon and other insol. (metal) ultrafine particles.
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321Georgin, D.; Czarny, B.; Botquin, M.; Mayne-L’hermite, M.; Pinault, M.; Bouchet-Fabre, B.; Carriere, M.; Poncy, J. L.; Chau, Q.; Maximilien, R.; Dive, V.; Taran, F. J. Am. Chem. Soc. 2009, 131, 14658Google ScholarThere is no corresponding record for this reference.
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322Wang, H.; Wang, J.; Deng, X.; Sun, H.; Shi, Z.; Gu, Z.; Liu, Y.; Zhao, Y. J. Nanosci. Nanotechnol. 2004, 4, 1019Google ScholarThere is no corresponding record for this reference.
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323Guo, J.; Zhang, X.; Li, Q.; Li, W. Nucl. Med. Biol. 2007, 34, 579Google Scholar323https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmvV2itb0%253D&md5=f3a5f0b7498a2e60e1e4870f1f83675aBiodistribution of functionalized multiwall carbon nanotubes in miceGuo, Jinxue; Zhang, Xiao; Li, Qingnuan; Li, WenxinNuclear Medicine and Biology (2007), 34 (5), 579-583CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Inc.)With the application of carbon nanotubes in biomedical and pharmaceutical sciences, its basic biol. properties in vivo have become an issue of strong concern. Water-sol. functionalized multiwall carbon nanotubes (MWNTs) were labeled with radioactive 99mTc atoms, and then a tracer was used to study the distribution of MWNTs modified with glucosamine in mice. It shows that MWNTs moved easily among the compartments and tissues of the body, behaving like active mols. although their apparent mean mol. wt. is tremendously large. In this study, water-sol. MWNTs were labeled with 99mTc for the first time, and all results on the distribution of MWNTs in animals provide useful data for their use in the biomedical field.
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324Zharov, V. P.; Galanzha, E. I.; Shashkov, E. V.; Kim, J. W.; Khlebtsov, N. G.; Tuchin, V. V. J. Biomed. Opt. 2007, 12, 051503Google ScholarThere is no corresponding record for this reference.
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325Barrett, K. E.; Boitano, S.; Brooks, H. Immunity, Infection, & Inflammation. Ganong’s Review of Medical Physiology, 23rd ed.; The McGraw-Hill Co., Inc.: New York, 2010; pp 63– 78.Google ScholarThere is no corresponding record for this reference.
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326Meng, J.; Yang, M.; Jia, F.; Xu, Z.; Kong, H.; Xu, H. Nanotoxicology 2011, 5, 583Google ScholarThere is no corresponding record for this reference.
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327Pacurari, M.; Qian, Y.; Fu, W.; Schwegler-Berry, D.; Ding, M.; Castranova, V.; Guo, N. L. J. Toxicol. Environ. Health, Part A 2012, 75, 129Google ScholarThere is no corresponding record for this reference.
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328Nimmagadda, A.; Thurston, K.; Nollert, M. U.; McFetridge, P. S. J. Biomed. Mater. Res., Part A 2006, 76, 614Google Scholar328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhslGisb8%253D&md5=497b0c005495c687aa0db391002436b3Chemical modification of SWNT alters in vitro cell-SWNT interactionsNimmagadda, Aditya; Thurston, Karen; Nollert, Matthias U.; McFetridge, Peter S.Journal of Biomedical Materials Research, Part A (2006), 76A (3), 614-625CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Single-walled carbon nanotubes (SWNT) have been the focus of considerable attention as a material with extraordinary mech. and elec. properties. SWNT have been proposed in a no. of biomedical applications, including neural, bone, and dental tissue engineering. In these applications, it is clear that surrounding tissues will come into surface contact with SWNT composites, and compatibility between SWNT and host cells must be addressed. This investigation describes the gross phys. and chem. effects of different SWNT prepns. on in vitro cell viability and metabolic activity. Three different SWNT prepns. were analyzed: as purchased (AP-NT), purified (PUR-NT), and functionalized with glucosamine (GA-NT), over concns. of 0.001-1.0% (wt./vol.). With the exception of the lowest SWNT concns., increasing concns. of SWNT resulted in a decrease of cell viability, which was dependent on SWNT prepn. The metabolic activity of 3T3 cells was also dependent on SWNT prepn. and concn. These investigations have shown that these SWNT prepns. have significant effects on in vitro cellular function that cannot be attributed to one factor alone, but are more likely the result of several unfavorable interactions. Effects, such as destabilizing the cell membrane, sol. toxic contaminants, and limitations in mass transfer as the SWNT coalesce into sheets, may all play a role in these interactions. Using comprehensive purifn. processes and modifying the NT-surface chem. to introduce functional groups or reduce hydrophobicity or both, these interactions can be significantly improved.
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329Balasubramanian, K.; Burghard, M. Small 2005, 1, 180Google ScholarThere is no corresponding record for this reference.
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330Portney, N. G.; Ozkan, M. Anal. Bioanal. Chem. 2006, 384, 620Google Scholar330https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xhtl2msLc%253D&md5=79bd00bf33d5c66c7c7375f813ab17b0Nano-oncology: drug delivery, imaging, and sensingPortney, Nathaniel G.; Ozkan, MihrimahAnalytical and Bioanalytical Chemistry (2006), 384 (3), 620-630CODEN: ABCNBP; ISSN:1618-2642. (Springer)A review. Innovation in the last decade has endowed nanotechnol. with an assortment of tools for delivery, imaging, and sensing in cancer research-stealthy nanoparticle vectors circulating in vivo, assembled with exquisite mol. control, capable of selective tumor targeting and potent delivery of therapeutics; intense and photostable quantum dot-based tumor imaging, enabling multicolor detection of cell receptors with a single optical excitation source; arrays of semiconducting nanowire and carbon nanotube sensor elements for selective multiplexed sensing of cancer markers without the need for probe labeling. These rapidly emerging tools are indicative of a burgeoning field ready to expand into medical applications. This review attempts to outline most of the current nanoparticle toolset for therapeutic release by liposomes, dendrimers, smart polymers, and virus-based systems. Advantages of nanoparticle-based imaging and targeting by use of nanoshells and quantum dots are also explored. Finally, emerging nanoelectronics-based sensing and a global discussion on the utility of each nanoparticle system addresses their fundamental advantages and shortcomings in cancer research.
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331Heister, E.; Lamprecht, C.; Neves, V.; Tilmaciu, C.; Datas, L.; Flahaut, E.; Soula, B.; Hinterdorfer, P.; Coley, H. M.; Silva, S. R.; McFadden, J. ACS Nano 2010, 4, 2615Google ScholarThere is no corresponding record for this reference.
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332Bottini, M.; Rosato, N.; Bottini, N. Biomacromolecules 2011, 12, 3381Google ScholarThere is no corresponding record for this reference.
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333Liu, Z.; Chen, K.; Davis, C.; Sherlock, S.; Cao, Q.; Chen, X.; Dai, H. Cancer Res. 2008, 68, 6652Google ScholarThere is no corresponding record for this reference.
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334Sayes, C. M.; Liang, F.; Hudson, J. L.; Mendez, J.; Guo, W.; Beach, J. M.; Moore, V. C.; Doyle, C. D.; West, J. L.; Billups, W. E.; Ausman, K. D.; Colvin, V. L. Toxicol. Lett. 2006, 161, 135Google Scholar334https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtlWqtLvP&md5=8b4e91a6b19335e464ddf7f744977359Functionalization density dependence of single-walled carbon nanotubes cytotoxicity in vitroSayes, Christie M.; Liang, Feng; Hudson, Jared L.; Mendez, Joe; Guo, Wenhua; Beach, Jonathan M.; Moore, Valerie C.; Doyle, Condell D.; West, Jennifer L.; Billups, W. Edward; Ausman, Kevin D.; Colvin, Vicki L.Toxicology Letters (2006), 161 (2), 135-142CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)The cytotoxic response of cells in culture is dependant on the degree of functionalization of the single-walled carbon nanotube (SWNT). After characterizing a set of water-dispersible SWNTs, the authors performed in vitro cytotoxicity screens on cultured human dermal fibroblasts (HDF). The SWNT samples used in this exposure include SWNT-phenyl-SO3H and SWNT-phenyl-SO3Na (6 samples with carbon/-phenyl-SO3X ratios of 18, 41, and 80), SWNT-phenyl-(COOH)2 (1 sample with carbon/-phenyl-(COOH)2 ratio of 23), and underivatized SWNT stabilized in 1% Pluronic F108. As the degree of sidewall functionalization increased, the SWNT sample became less cytotoxic. Further, sidewall functionalized SWNT samples are substantially less cytotoxic than surfactant stabilized SWNTs. Even though cell death did not exceed 50% for cells dosed with sidewall functionalized SWNTs, optical and at. force microscopies show direct contact between cellular membranes and water-dispersible SWNTs; i.e. the SWNTs in aq. suspension ppt. out and selectively deposit on the membrane.
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335Smith, C. J.; Shaw, B. J.; Handy, R. D. Aquat. Toxicol. 2007, 82, 94Google Scholar335https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjs1Kqsr4%253D&md5=d04d16f2a66b7b7e73c79a0f039834bfToxicity of single walled carbon nanotubes to rainbow trout, (Oncorhynchus mykiss): Respiratory toxicity, organ pathologies, and other physiological effectsSmith, Catherine J.; Shaw, Benjamin J.; Handy, Richard D.Aquatic Toxicology (2007), 82 (2), 94-109CODEN: AQTODG; ISSN:0166-445X. (Elsevier B.V.)Mammalian studies have raised concerns about the toxicity of carbon nanotubes (CNTs), but there is very limited data on ecotoxicity to aquatic life. The authors describe the 1st detailed report on the toxicity of single walled carbon nanotubes (SWCNT) to rainbow trout, using a body systems approach. Stock solns. of dispersed SWCNT were prepd. using a combination of solvent (sodium dodecyl sulfate, SDS) and sonication. A semi-static test system was used to expose rainbow trout to either a freshwater control, solvent control, 0.1, 0.25 or 0.5 mg l-1 SWCNT for up to 10 days. SWCNT exposure caused a dose-dependent rise in ventilation rate, gill pathologies (edema, altered mucocytes, hyperplasia), and mucus secretion with SWCNT pptn. on the gill mucus. No major haematol. or blood disturbances were obsd. in terms of red and white blood cell counts, haematocrits, whole blood Hb, and plasma Na+ or K+. Tissue metal levels (Na+, K+, Ca2+, Cu, Zn and Co) were generally unaffected. However some dose-dependent changes in brain and gill Zn or Cu were obsd. (but not tissue Ca2+), that were also partly attributed to the solvent. SWCNT exposure caused statistically significant increases in Na+K+-ATPase activity in the gills and intestine, but not in the brain. Thiobarbituric acid reactive substances (TBARS) showed dose-dependent and statistically significant decreases esp. in the gill, brain and liver during SWCNT exposure compared to controls. SWCNT exposure caused statistically significant increases in the total glutathione levels in the gills (28%) and livers (18%), compared to the solvent control. Total glutathione in the brain and intestine remained stable in all treatments. Pathologies in the brain included possible aneurisms or swellings on the ventral surface of the cerebellum. Liver cells exposed to SWCNT showed condensed nuclear bodies (apoptotic bodies) and cells in abnormal nuclear division. Overt fatty change or wide spread lipidosis was absent in the liver. Fish ingested water contg. SWCNT during exposure (presumably stress-induced drinking) which resulted in pptd. SWCNT in the gut lumen and intestinal pathol. Aggressive behavior and fin nipping caused some mortalities at the end of the expt., which may be assocd. with the gill irritation and brain injury, although the solvent may also partly contributed to aggression. Overall the authors conclude that SWCNTs are a respiratory toxicant in trout, the fish are able to manage oxidative stress and osmoregulatory disturbances, but other cellular pathologies raise concerns about cell cycle defects, neurotoxicity, and as yet unidentified blood borne factors that possibly mediate systemic pathologies.
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336Prato, M.; Kostarelos, K.; Bianco, A. Acc. Chem. Res. 2008, 41, 60Google ScholarThere is no corresponding record for this reference.
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337Shvedova, A. A.; Kisin, E. R.; Murray, A. R.; Gorelik, O.; Arepalli, S.; Castranova, V.; Young, S. H.; Gao, F.; Tyurina, Y. Y.; Oury, T. D.; Kagan, V. E. Toxicol. Appl. Pharmacol. 2007, 221, 339Google Scholar337https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmtlSmtb8%253D&md5=754ced2f0d0289d41ba3b6a10a3caf96Vitamin E deficiency enhances pulmonary inflammatory response and oxidative stress induced by single-walled carbon nanotubes in C57BL/6 miceShvedova, Anna A.; Kisin, Elena R.; Murray, Ashley R.; Gorelik, Olga; Arepalli, Sivaram; Castranova, Vincent; Young, Shih-Hong; Gao, Fei; Tyurina, Yulia Y.; Oury, Tim D.; Kagan, Valerian E.Toxicology and Applied Pharmacology (2007), 221 (3), 339-348CODEN: TXAPA9; ISSN:0041-008X. (Elsevier)Exposure of mice to single-walled carbon nanotubes (SWCNTs) induces an unusually robust pulmonary inflammatory response with an early onset of fibrosis, which is accompanied by oxidative stress and antioxidant depletion. The role of specific components of the antioxidant protective system, specifically vitamin E, the major lipid-sol. antioxidant, in the SWCNT-induced reactions has not been characterized. We used C57BL/6 mice, maintained on vitamin E-sufficient or vitamin E-deficient diets, to explore and compare the pulmonary inflammatory reactions to aspired SWCNTs. The vitamin E-deficient diet caused a 90-fold depletion of α-tocopherol in the lung tissue and resulted in a significant decline of other antioxidants (GSH, ascorbate) as well as accumulation of lipid peroxidn. products. A greater decrease of pulmonary antioxidants was detected in SWCNT-treated vitamin E-deficient mice as compared to controls. Lowered levels of antioxidants in vitamin E-deficient mice were assocd. with a higher sensitivity to SWCNT-induced acute inflammation (total no. of inflammatory cells, no. of polymorphonuclear leukocytes, released LDH, total protein content and levels of pro-inflammatory cytokines, TNF-α and IL-6) and enhanced profibrotic responses (elevation of TGF-β and collagen deposition). Exposure to SWCNTs markedly shifted the ratio of cleaved to full-length extracellular superoxide dismutase (EC-SOD). Given that pulmonary levels of vitamin E can be manipulated through diet, its effects on SWCNT-induced inflammation may be of practical importance in optimizing protective strategies.
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338Han, S. G.; Andrews, R.; Gairola, C. G. Inhal. Toxicol. 2010, 22, 340Google Scholar338https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhvFegu78%253D&md5=d17b7b2f4d581da6dff96796f4e6cd5dAcute pulmonary response of mice to multi-wall carbon nanotubesHan, Sung Gu; Andrews, Rodney; Gairola, C. GaryInhalation Toxicology (2010), 22 (4), 340-347CODEN: INHTE5; ISSN:0895-8378. (Informa Healthcare)Widespread use of carbon nanotubes is predicted for future and concerns have been raised about their potential health effects. The present study detd. the pulmonary response of mice to multi-wall carbon nanotubes (MWCNTs). The MWCNT suspension in sterile phosphate-buffered saline (PBS) was introduced into mice lungs by oropharyngeal aspiration. Female C57Bl mice were treated with either 20 or 40 μg of MWCNTs in 40 μl PBS and control groups received equal vol. of PBS. From each group, half of the mice were euthanized at day 1 and the remaining half at day 7 post treatment. Bronchoalveolar lavage (BAL) fluids, serum, and lung tissue samples were analyzed for inflammatory and oxidative stress markers. The results showed significant cellular influx by a single exposure to MWCNTs. Yields of total cells and the no. of polymorphonuclear leukocytes in BAL cells were significantly elevated in MWCNT-treated mice post-treatment days 1 and 7. Anal. of cell-free BAL fluids showed significantly increased levels of total proteins, lactate dehydrogenase, tumor necrosis factor-α, interleukin-1β, mucin, and surfactant protein-D (SP-D) in MWCNT-treated mice at day 1 post treatment. However, these biomarkers returned to basal levels by day 7 post exposure except mucin and SP-D. An increase in the urinary level of 8-hydroxy-2'-deoxyguanosine in mice treated with MWCNT suggested systemic oxidative stress. Western anal. of lung tissue showed decreased levels of extracellular superoxide dismutase (SOD) protein in MWCNT-treated mice but copper/zinc and manganese SOD remained unchanged. It is concluded that a single treatment of MWCNT is capable of inducing cytotoxic and inflammatory response in the lungs of mice.
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339Mitchell, L. A.; Gao, J.; Wal, R. V.; Gigliotti, A.; Burchiel, S. W.; McDonald, J. D. Toxicol. Sci. 2007, 100, 203Google Scholar339https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFKlsLrJ&md5=a9503e582d6af05864f16d652a4aade7Pulmonary and systemic immune response to inhaled multiwalled carbon nanotubesMitchell, Leah A.; Gao, Jun; Vander Wal, Randy; Gigliotti, Andrew; Burchiel, Scott W.; McDonald, Jacob D.Toxicological Sciences (2007), 100 (1), 203-214CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)Inhalation of multiwalled carbon nanotubes (MWCNTs) at particle concns. ranging from 0.3-5 mg/m3 did not result in significant lung inflammation or tissue damage, but caused systemic immune function alterations. C57BL/6 adult (10- to 12-wk) male mice were exposed by whole-body inhalation to control air or 0.3, 1, or 5 mg/m3 respirable aggregates of MWCNTs for 7 or 14 days (6 h/day). Histopathol. of lungs from exposed animals showed alveolar macrophages contg. black particles; however, there was no inflammation or tissue damage obsd. Bronchial alveolar lavage fluid also demonstrated particle-laden macrophages; however, white blood cell counts were not increased compared to controls. MWCNT exposures to 0.3 mg/m3 and higher particle concns. caused nonmonotonic systemic immunosuppression after 14 days but not after 7 days. Immunosuppression was characterized by reduced T-cell-dependent antibody response to sheep erythrocytes as well as T-cell proliferative ability in presence of mitogen, Con A. Assessment of nonspecific natural killer (NK) cell activity showed that animals exposed to 1 mg/m3 had decreased NK cell function. Gene expression anal. of selected cytokines and an indicator of oxidative stress were assessed in lung tissue and spleen. No changes in gene expression were obsd. in lung; however, interleukin-10 (IL-10) and NAD(P)H oxidoreductase 1 mRNA levels were increased in spleen.
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340Pulskamp, K.; Diabate, S.; Krug, H. F. Toxicol. Lett. 2007, 168, 58Google Scholar340https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtlaltrjI&md5=a56335dc6377fd5e7000806706527a02Carbon nanotubes show no sign of acute toxicity but induce intracellular reactive oxygen species in dependence on contaminantsPulskamp, Karin; Diabate, Silvia; Krug, Harald F.Toxicology Letters (2007), 168 (1), 58-74CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)Today nanosciences are experiencing massive investment worldwide although research on toxicol. aspects of these nano-sized particles has just begun and to date, no clear guidelines exist to quantify the effects. In the present study, we focus on C nanotubes (CNTs), which represent one of the most widely investigated carbon nanoparticles. The present data indicate that CNTs are able to cross the cell membrane of rat macrophages (NR8383) and, therefore, might have an influence on cell physiol. and function. NR8383 and human A549 lung cells were incubated with com. single-walled (NT-1) and multi-walled (NT-2, NT-3) CNTs, carbon black and quartz as ref. particles as well as an acid-treated single-walled CNT prepn. (SWCNT a.t.) with reduced metal catalyst content. We did not observe any acute toxicity on cell viability (WST-1, PI-staining) upon incubation with all CNT products. None of the CNTs induced the inflammatory mediators NO, TNF-α and IL-8. A rising tendency of TNF-α release from LPS-primed cells due to CNT treatment could be obsd. We detected however, a dose- and time-dependent increase of intracellular reactive oxygen species and a decrease of the mitochondrial membrane potential with the com. CNTs in both cell types after particle treatment whereas incubation with the purified CNTs (SWCNT a.t.) had no effect. This leads us to the conclusion that metal traces assocd. with the com. nanotubes are responsible for the biol. effects.
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341Ji, Z.; Zhang, D.; Li, L.; Shen, X.; Deng, X.; Dong, L.; Wu, M.; Liu, Y. Nanotechnology 2009, 20, 445101Google ScholarThere is no corresponding record for this reference.
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342Allen, B. L.; Kichambare, P. D.; Gou, P.; Vlasova, I. I.; Kapralov, A. A.; Konduru, N.; Kagan, V. E.; Star, A. Nano Lett. 2008, 8, 3899Google ScholarThere is no corresponding record for this reference.
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343Allen, B. L.; Kotchey, G. P.; Chen, Y.; Yanamala, N. V.; Klein-Seetharaman, J.; Kagan, V. E.; Star, A. J. Am. Chem. Soc. 2009, 131, 17194Google ScholarThere is no corresponding record for this reference.
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344Liu, X.; Hurt, R. H.; Kane, A. B. Carbon 2010, 48, 1961Google ScholarThere is no corresponding record for this reference.
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345Bianco, A.; Kostarelos, K.; Prato, M. Chem. Commun. (Cambridge, U.K.) 2011, 47, 10182Google Scholar345https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFWqtbnO&md5=00655ac3f83f6ffdb667350fde1e6148Making carbon nanotubes biocompatible and biodegradableBianco, Alberto; Kostarelos, Kostas; Prato, MaurizioChemical Communications (Cambridge, United Kingdom) (2011), 47 (37), 10182-10188CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. Carbon nanotubes are promising nanomaterials with great potential in the field of nanomedicine for both therapeutic and diagnostic applications. Different approaches have been developed to render this material biocompatible and to modulate any ensuing toxic effects. In the context of medical use, although chem. functionalized carbon nanotubes display reduced toxicity, they are still considered with scepticism due to their perceived non-biodegradability. Recently, it has been demonstrated that functionalized carbon nanotubes can be degraded by oxidative enzymes. This finding is offering a new perspective for the development of carbon nanotubes in medicine. This article highlights recent advances that can act as paradigm-shifts towards the design of biocompatible and biodegradable functionalized carbon nanotubes and allow their translation into the clinic.
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346Zhao, Y.; Allen, B. L.; Star, A. J. Phys. Chem. A 2011, 115, 9536Google ScholarThere is no corresponding record for this reference.
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347Kotchey, G. P.; Hasan, S. A.; Kapralov, A. A.; Ha, S. H.; Kim, K.; Shvedova, A. A.; Kagan, V. E.; Star, A. Acc. Chem. Res. 2012, 45, 1770Google Scholar347https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVyns77I&md5=6c8c62fc0d73ec30db3eb396be97aac5A Natural Vanishing Act: The Enzyme-Catalyzed Degradation of Carbon NanomaterialsKotchey, Gregg P.; Hasan, Saad A.; Kapralov, Alexander A.; Ha, Seung Han; Kim, Kang; Shvedova, Anna A.; Kagan, Valerian E.; Star, AlexanderAccounts of Chemical Research (2012), 45 (10), 1770-1781CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Over the past three decades, revolutionary research in nanotechnol. by the scientific, medical, and engineering communities has yielded a treasure trove of discoveries with diverse applications that promise to benefit humanity. With their unique electronic and mech. properties, carbon nanomaterials (CNMs) represent a prime example of the promise of nanotechnol. with applications in areas that include electronics, fuel cells, composites, and nanomedicine. Because of toxicol. issues assocd. with CNMs, however, their full com. potential may not be achieved. The ex vitro, in vitro, and in vivo data presented in this Account provide fundamental insights into the biopersistence of CNMs, such as carbon nanotubes and graphene, and their oxidn./biodegrdn. processes as catalyzed by peroxidase enzymes. We also communicate our current understanding of the mechanism for the enzymic oxidn. and biodegrdn. Finally, we outline potential future directions that could enhance our mechanistic understanding of the CNM oxidn. and biodegrdn. and could yield benefits in terms of human health and environmental safety. The conclusions presented in this Account may catalyze a rational rethinking of CNM incorporation in diverse applications. For example, armed with an understanding of how and why CNMs undergo enzyme-catalyzed oxidn. and biodegrdn., researchers can tailor the structure of CNMs to either promote or inhibit these processes. In nanomedical applications such as drug delivery, the incorporation of carboxylate functional groups could facilitate biodegrdn. of the nanomaterial after delivery of the cargo. On the other hand, in the construction of aircraft, a CNM composite should be stable to oxidizing conditions in the environment. Therefore, pristine, inert CNMs would be ideal for this application. Finally, the incorporation of CNMs with defect sites in consumer goods could provide a facile mechanism that promotes the degrdn. of these materials once these products reach landfills.
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348Seabra, A. B.; Paula, A. J.; Duran, N. Biotechnol. Prog. 2013, 29, 1Google Scholar348https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitlCqsro%253D&md5=2ab6de4e4bd59196dbb3d169cad713b9Redox-enzymes, cells and micro-organisms acting on carbon nanostructures transformation: a mini-reviewSeabra, Amedea B.; Paula, Amauri J.; Duran, NelsonBiotechnology Progress (2013), 29 (1), 1-10CODEN: BIPRET; ISSN:1520-6033. (Wiley-Blackwell)A review. Carbon nanotubes, graphene and fullerenes are actual nanomaterials with many applications in different industrial areas, with increasing potentialities in the field of nanomedicine. Recently, different proactive approaches on toxicol. and safety management have become the focus of intense interest once the industrial prodn. of these materials had a significant growth in the last years, even though their short- and long-term behaviors are not yet fully understood. The most important concerns involving these carbon-based nanomaterials are their stability and potential effects of their life cycles on animals, humans, and environment. In this context, this mini review discuss the biodegradability of these materials, particularly through redox-enzymes, microorganisms and cells, to contribute toward the design of biocompatible and biodegradable functionalized carbon nanostructures, to use these materials safely and with min. impact on the environment.
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349Oberdörster, G.; Oberdörster, E.; Oberdörster, J. Environ. Health Perspect. 2005, 113, 823Google ScholarThere is no corresponding record for this reference.
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350Zhang, L.; Alizadeh, D.; Badie, B. Methods Mol. Biol. 2010, 625, 55Google Scholar350https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXoslyqtL4%253D&md5=c00ba55dbeb2b231da0e64b2a98298bcCarbon nanotube uptake and toxicity in the brainZhang, Leying; Alizadeh, Darya; Badie, BehnamMethods in Molecular Biology (Totowa, NJ, United States) (2010), 625 (Carbon Nanotubes), 55-65CODEN: MMBIED; ISSN:1064-3745. (Humana Press Inc.)The development of novel drug delivery systems is essential for the improvement of therapeutics for most human diseases. Currently used cellular delivery systems, such as viral vectors, liposomes, cationic lipids, and polymers, may have limited clin. efficacy because of safety issues, low gene transfer efficiency, or cytotoxicity. Carbon nanotubes (CNTs) have garnered much interest as possible biol. vectors after the recent discovery of their capacity to penetrate cells. Inspite of the prominence of CNT studies in the nanotechnol. literature, exploration of their application to central nervous system (CNS) therapeutics is at a very early stage. Before CNTs are used for treatment of brain and spinal cord disorders, however, several issues such as their CNS penetration and toxicity need to be addressed. Here, we discuss methods by which CNT uptake and toxicity can be assessed in animal models.
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351Nygaard, U. C.; Hansen, J. S.; Samuelsen, M.; Alberg, T.; Marioara, C. D.; Løvik, M. Toxicol. Sci. 2009, 109, 113Google Scholar351https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlsVGiurg%253D&md5=e2e7ec7f7f9d1c4464d78afbfe9db729Single-Walled and Multi-Walled Carbon Nanotubes Promote Allergic Immune Responses in MiceNygaard, Unni C.; Hansen, Jitka S.; Samuelsen, Mari; Alberg, Torunn; Marioara, Calin D.; Lovik, MartinusToxicological Sciences (2009), 109 (1), 113-123CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)The adjuvant effect of particles on allergic immune responses has been shown to increase with decreasing particle size and increasing particle surface area. Like ultrafine particles, carbon nanotubes (CNTs) have nano-sized dimensions and a large relative surface area and might thus increase allergic responses. Therefore, we examd. whether single-walled (sw) and multi-walled (mw) CNTs have the capacity to promote allergic responses in mice, first in an s.c. injection model and thereafter in an intranasal model. Balb/cA mice were exposed to three doses of swCNT, mwCNT, as well as ultrafine carbon black particles (ufCBPs, Printex90) during sensitization with the allergen ovalbumin (OVA). Five days after an OVA booster, OVA-specific IgE, IgG1, and IgG2a antibodies in serum and the nos. of inflammatory cells and cytokine levels in bronchoalveolar lavage fluid (BALF) were detd. Furthermore, ex vivo OVA-induced cytokine release from mediastinal lymph node (MLN) cells was measured. In sep. expts., differential cell counts were detd. in BALF 24 h after a single intranasal exposure to the particles in the absence of allergen. We demonstrate that both swCNT and mwCNT together with OVA strongly increased serum levels of OVA-specific IgE, the no. of eosinophils in BALF, and the secretion of Th2-assocd. cytokines in the MLN. On the other hand, only mwCNT and ufCBP with OVA increased IgG2a levels, neutrophil cell nos., and tumor necrosis factor-alpha and monocyte chemoattractant protein-1 levels in BALF, as well as the acute influx of neutrophils after exposure to the particles alone. This study demonstrates that CNTs promote allergic responses in mice.
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352Inoue, K.; Takano, H.; Koike, E.; Yanagisawa, R.; Sakurai, M.; Tasaka, S.; Ishizaka, A.; Shimada, A. Exp. Biol. Med. (Maywood, NJ, U.S.) 2008, 233, 1583Google Scholar352https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVOjtLnO&md5=bed820cf7ff8e6a35263658b00780880Effects of pulmonary exposure to carbon nanotubes on lung and systemic inflammation with coagulatory disturbance induced by lipopolysaccharide in miceInoue, Ken-ichiro; Takano, Hirohisa; Koike, Eiko; Yanagisawa, Rie; Sakurai, Miho; Tasaka, Sadatomo; Ishizaka, Akitoshi; Shimada, AkinoriExperimental Biology and Medicine (Maywood, NJ, United States) (2008), 233 (12), 1583-1590CODEN: EBMMBE; ISSN:1535-3702. (Society for Experimental Biology and Medicine)Despite intensive research as to the pathogenesis of lipopolysaccharide (LPS)-related inflammation with coagulatory disturbance, their exacerbating factors have not been well explored. This study examd. the effects of pulmonary exposure to two types of nano-sized materials (carbon nanotubes: CNT [single-wall: SWCNT, and multi-wall: MWCNT]) on lung inflammation and consequent systemic inflammation with coagulatory disturbance induced by pulmonary exposure to LPS in mice and their cellular mechanisms in vitro. ICR male mice were divided into 6 exptl. groups that intratracheally received the vehicle, two types of CNT (4 mg/kg), LPS (33 μg/kg), or LPS plus either type of CNT. Twenty-four hours after treatment, both types of CNT alone induced lung inflammation with enhanced lung expression of proinflammatory cytokines, but did not synergistically exacerbate lung inflammation elicited by LPS. SWCNT significantly induced/enhanced pulmonary permeability and hyperfibrinogenemia and reduced activated protein C in the absence or presence of LPS, whereas MWCNT did moderately. Both CNT moderately, but not significantly, elevated circulatory levels of proinflammatory cytokines and chemokines. In the presence of LPS, CNT tended to elevate the levels of the mediators with an overall trend, which was more prominent with SWCNT than with MWCNT. In vitro study showed that both CNT amplified LPS-induced cytokine prodn. from peripheral blood monocytes. These results suggest that CNT can facilitate systemic inflammation with coagulatory disturbance, at least in part, via the activation of mononuclear cells, which is accompanied by moderate enhancement of acute lung inflammation related to LPS.
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353Ryman-Rasmussen, J. P.; Tewksbury, E. W.; Moss, O. R.; Cesta, M. F.; Wong, B. A.; Bonner, J. C. Am. J. Respir. Cell Mol. Biol. 2009, 40, 349Google Scholar353https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXislalt70%253D&md5=6317d20bcbbd32b8ee91b11500707663Inhaled multiwalled carbon nanotubes potentiate airway fibrosis in murine allergic asthmaRyman-Rasmussen, Jessica P.; Tewksbury, Earl W.; Moss, Owen R.; Cesta, Mark F.; Wong, Brian A.; Bonner, James C.American Journal of Respiratory Cell and Molecular Biology (2009), 40 (3), 349-358CODEN: AJRBEL; ISSN:1044-1549. (American Thoracic Society)C nanotubes are gaining increasing attention due to possible health risks from occupational or environmental exposures. This study tested the hypothesis that inhaled multiwalled carbon nanotubes (MWCNT) would increase airway fibrosis in mice with allergic asthma. Normal and ovalbumin-sensitized mice were exposed to a MWCNT aerosol (100 mg/m3) or saline aerosol for 6 h. Lung injury, inflammation, and fibrosis were examd. by histopathol., clin. chem., ELISA, or RT-PCR for cytokines/chemokines, growth factors, and collagen at 1 and 14 days after inhalation. Inhaled MWCNT were distributed throughout the lung and found in macrophages by light microscopy, but were also evident in epithelial cells by electron microscopy. Quant. morphometry showed significant airway fibrosis at 14 days in mice that received a combination of ovalbumin and MWCNT, but not in mice that received ovalbumin or MWCNT only. Ovalbumin-sensitized mice that did not inhale MWCNT had elevated levels IL-13 and transforming growth factor (TGF)-β1 in lung lavage fluid, but not platelet-derived growth factor (PDGF)-AA. In contrast, unsensitized mice that inhaled MWCNT had elevated PDGF-AA, but not increased levels of TGF-β1 and IL-13. This suggested that airway fibrosis resulting from combined ovalbumin sensitization and MWCNT inhalation requires PDGF, a potent fibroblast mitogen, and TGF-β1, which stimulates collagen prodn. Combined ovalbumin sensitization and MWCNT inhalation also synergistically increased IL-5 mRNA levels, which could further contribute to airway fibrosis. These data indicate that inhaled MWCNT require pre-existing inflammation to cause airway fibrosis. These findings suggest that individuals with pre-existing allergic inflammation may be susceptible to airway fibrosis from inhaled MWCNT.
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354Bihari, P.; Holzer, M.; Praetner, M.; Fent, J.; Lerchenberger, M.; Reichel, C. A.; Rehberg, M.; Lakatos, S.; Krombach, F. Toxicology 2010, 269, 148Google ScholarThere is no corresponding record for this reference.
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355Salvati, A.; Pitek, A. S.; Monopoli, M. P.; Prapainop, K.; Bombelli, F. B.; Hristov, D. R.; Kelly, P. M.; Åberg, C.; Mahon, E.; Dawson, K. A. Nat. Nanotechnol. 2013, 8, 137Google Scholar355https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFSjtLg%253D&md5=cf3fbdf4d460fc8f016bbc2337719d96Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surfaceSalvati, Anna; Pitek, Andrzej S.; Monopoli, Marco P.; Prapainop, Kanlaya; Bombelli, Francesca Baldelli; Hristov, Delyan R.; Kelly, Philip M.; Aberg, Christoffer; Mahon, Eugene; Dawson, Kenneth A.Nature Nanotechnology (2013), 8 (2), 137-143CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Nanoparticles have been proposed as carriers for drugs, genes and therapies to treat various diseases. Many strategies have been developed to target nanomaterials to specific or over-expressed receptors in diseased cells, and these typically involve functionalizing the surface of nanoparticles with proteins, antibodies or other biomols. Here, we show that the targeting ability of such functionalized nanoparticles may disappear when they are placed in a biol. environment. Using transferrin-conjugated nanoparticles, we found that proteins in the media can shield transferrin from binding to both its targeted receptors on cells and sol. transferrin receptors. Although nanoparticles continue to enter cells, the targeting specificity of transferrin is lost. Our results suggest that when nanoparticles are placed in a complex biol. environment, interaction with other proteins in the medium and the formation of a protein corona can 'screen' the targeting mols. on the surface of nanoparticles and cause loss of specificity in targeting.
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356Mirshafiee, V.; Mahmoudi, M.; Lou, K.; Cheng, J.; Kraft, M. L. Chem. Commun. (Cambridge, U.K.) 2013, 49, 2557Google Scholar356https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtlyjt78%253D&md5=087a2a958fb63218af984eac9f6ac415Protein corona significantly reduces active targeting yieldMirshafiee, Vahid; Mahmoudi, Morteza; Lou, Kaiyan; Cheng, Jianjun; Kraft, Mary L.Chemical Communications (Cambridge, United Kingdom) (2013), 49 (25), 2557-2559CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)When nanoparticles (NPs) are exposed to the biol. environment, their surfaces become covered with proteins and biomols. (e.g. lipids). Here, the authors report that this protein coating, or corona, reduces the targeting capability of surface engineered NPs by screening the active sites of the targeting ligands.
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357Guo, L.; Von Dem Bussche, A.; Buechner, M.; Yan, A.; Kane, A. B.; Hurt, R. H. Small 2008, 4, 721Google ScholarThere is no corresponding record for this reference.
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358Raven, K. Nat. Med. 2012, 18, 998Google Scholar358https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvFGgtbo%253D&md5=c209c6caa2fc8e1c1df98a9512c5c294Rodent models of sepsis found shockingly lackingRaven, KathleenNature Medicine (New York, NY, United States) (2012), 18 (7), 998CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)Some in the field are developing new ways to fine-tune the induction system so that it better mimics the poor health that many sick people are in when they develop sepsis. For example, Robert Star and his colleagues at the US National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, recently stimulated chronic kidney disease in mice before they proceeded with traditional CLP to provoke sepsis. In a study published last year, they showed that the kidney disease worsened the sepsis severity and sepsis-induced organ damage seen in the mice, as evidenced by increased blood levels of HMGB1, vascular endothelial growth factor and other inflammatory cytokines (Kidney Int.80, 1198-1211, 2011). "Animal models have to mimic the epidemiol. causes [of sepsis]," Star says. "You have to replicate whatever you have found in humans." In the end, though, most experts agree that tweaks like these are just minor improvements and that the field really needs to radically redesign animal models of sepsis from the ground up. "Clearly, current animal models seem to be incapable of predicting results in human trials of new agents," says Mitchell Fink, a surgeon at the University of California-Los Angeles. Alas, until they do, few drug developers will be willing to move forward with a drug like Tracey's antibody to HMGB1, despite the promising preclin. results.
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359Wekerle, H.; Flugel, A.; Fugger, L.; Schett, G.; Serreze, D. Nat. Med. 2012, 18, 66Google Scholar359https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlsF2mug%253D%253D&md5=bf9dde20197e5fda15ead1df3898015eAutoimmunity's next top modelsWekerle, Hartmut; Fluegel, Alexander; Fugger, Lars; Schett, Georg; Serreze, DavidNature Medicine (New York, NY, United States) (2012), 18 (1), 66-70CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)A review. Animal models are indispensable for studying disease pathogenesis and discovering new treatments for human organ-specific autoimmune diseases. However, there is a need of more refined paradigms for these models. Ideally, a small-animal model should represent the clin. features of human disease in their entirety. Disease in the animals should develop spontaneously, should be followed over an extended period of time and should involve the genetic, mol. and cellular elements that contribute to human pathogenesis.
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360Seok, J.; Warren, H. S.; Cuenca, A. G.; Mindrinos, M. N.; Baker, H. V.; Xu, W.; Richards, D. R.; McDonald-Smith, G. P.; Gao, H.; Hennessy, L.; Finnerty, C. C.; López, C. M.; Honari, S.; Moore, E. E.; Minei, J. P.; Cuschieri, J.; Bankey, P. E.; Johnson, J. L.; Sperry, J.; Nathens, A. B.; Billiar, T. R.; West, M. A.; Jeschke, M. G.; Klein, M. B.; Gamelli, R. L.; Gibran, N. S.; Brownstein, B. H.; Miller-Graziano, C.; Calvano, S. E.; Mason, P. H.; Cobb, J. P.; Rahme, L. G.; Lowry, S. F.; Maier, R. V.; Moldawer, L. L.; Herndon, D. N.; Davis, R. W.; Xiao, W.; Tompkins, R. G. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 3507Google ScholarThere is no corresponding record for this reference.
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361Muller, J.; Huaux, F.; Moreau, N.; Misson, P.; Heilier, J. F.; Delos, M.; Arras, M.; Fonseca, A.; Nagy, J. B.; Lison, D. Toxicol. Appl. Pharmacol. 2005, 207, 221Google Scholar361https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXpslyjtrc%253D&md5=88526aefd88c6084558b3031e71a31baRespiratory toxicity of multi-wall carbon nanotubesMuller, Julie; Huaux, Francois; Moreau, Nicolas; Misson, Pierre; Heilier, Jean-Francois; Delos, Monique; Arras, Mohammed; Fonseca, Antonio; Nagy, Janos B.; Lison, DominiqueToxicology and Applied Pharmacology (2005), 207 (3), 221-231CODEN: TXAPA9; ISSN:0041-008X. (Elsevier)Carbon nanotubes focus the attention of many scientists because of their huge potential of industrial applications, but there is a paucity of information on the toxicol. properties of this material. The aim of this exptl. study was to characterize the biol. reactivity of purified multi-wall carbon nanotubes in the rat lung and in vitro. Multi-wall carbon nanotubes (CNT) or ground CNT were administered intratracheally (0.5, 2 or 5 mg) to Sprague-Dawley rats and we estd. lung persistence, inflammation and fibrosis biochem. and histol. CNT and ground CNT were still present in the lung after 60 days (80% and 40% of the lowest dose) and both induced inflammatory and fibrotic reactions. At 2 mo, pulmonary lesions induced by CNT were characterized by the formation of collagen-rich granulomas protruding in the bronchial lumen, in assocn. with alveolitis in the surrounding tissues. These lesions were caused by the accumulation of large CNT agglomerates in the airways. Ground CNT were better dispersed in the lung parenchyma and also induced inflammatory and fibrotic responses. Both CNT and ground CNT stimulated the prodn. of TNF-α in the lung of treated animals. In vitro, ground CNT induced the overprodn. of TNF-α by macrophages. These results suggest that carbon nanotubes are potentially toxic to humans and that strict industrial hygiene measures should to be taken to limit exposure during their manipulation.
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362Fenoglio, I.; Greco, G.; Tomatis, M.; Muller, J.; Raymundo-Piñero, E.; Béguin, F.; Fonseca, A.; Nagy, J. B.; Lison, D.; Fubini, B. Chem. Res. Toxicol. 2008, 21, 1690Google ScholarThere is no corresponding record for this reference.
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363Li, N.; Xia, T.; Nel, A. E. Free Radical Biol. Med. 2008, 44, 1689Google Scholar363https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXks1GmsbY%253D&md5=21f6a0d574cae45a88567530d5380464The role of oxidative stress in ambient particulate matter-induced lung diseases and its implications in the toxicity of engineered nanoparticlesLi, Ning; Xia, Tian; Nel, Andre E.Free Radical Biology & Medicine (2008), 44 (9), 1689-1699CODEN: FRBMEH; ISSN:0891-5849. (Elsevier)A review. Ambient particulate matter (PM) is an environmental factor that has been assocd. with increased respiratory morbidity and mortality. The major effect of ambient PM on the pulmonary system is the exacerbation of inflammation, esp. in susceptible people. One of the mechanisms by which ambient PM exerts its proinflammatory effects is the generation of oxidative stress by its chem. compds. and metals. Cellular responses to PM-induced oxidative stress include activation of antioxidant defense, inflammation, and toxicity. The proinflammatory effect of PM in the lung is characterized by increased cytokine/chemokine prodn. and adhesion mol. expression. Moreover, there is evidence that ambient PM can act as an adjuvant for allergic sensitization, which raises the possibility that long-term PM exposure may lead to increased prevalence of asthma. In addn. to ambient PM, rapid expansion of nanotechnol. has introduced the potential that engineered nanoparticles (NP) may also become airborne and may contribute to pulmonary diseases by novel mechanisms that could include oxidant injury. Currently, little is known about the potential adverse health effects of these particles. In this communication, the mechanisms by which particulate pollutants, including ambient PM and engineered NP, exert their adverse effects through the generation of oxidative stress and the impacts of oxidant injury in the respiratory tract will be reviewed. The importance of cellular antioxidant and detoxification pathways in protecting against particle-induced lung damage will also be discussed.
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364Mercer, R. R.; Scabilloni, J.; Wang, L.; Kisin, E.; Murray, A. R.; Schwegler-Berry, D.; Shvedova, A. A.; Castranova, V. Am. J. Physiol.: Lung Cell. Mol. Physiol. 2008, 294, L87Google ScholarThere is no corresponding record for this reference.
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365Shvedova, A. A.; Kisin, E.; Murray, A. R.; Johnson, V. J.; Gorelik, O.; Arepalli, S.; Hubbs, A. F.; Mercer, R. R.; Keohavong, P.; Sussman, N.; Jin, J.; Yin, J.; Stone, S.; Chen, B. T.; Deye, G.; Maynard, A.; Castranova, V.; Baron, P. A.; Kagan, V. E. Am. J. Physiol.: Lung Cell. Mol. Physiol. 2008, 295, L552Google ScholarThere is no corresponding record for this reference.
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366Foucaud, L.; Wilson, M. R.; Brown, D. M.; Stone, V. Toxicol. Lett. 2007, 174, 1Google Scholar366https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1anurnK&md5=50ebf2951c83f598d6c3de8496147bb5Measurement of reactive species production by nanoparticles prepared in biologically relevant mediaFoucaud, L.; Wilson, M. R.; Brown, D. M.; Stone, V.Toxicology Letters (2007), 174 (1-3), 1-9CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)Exposure to nanoparticles may pose a risk to health and this hypothesis is currently being investigated by toxicologists. Although the mechanism of nanoparticle toxicity has been shown to be mediated, in part, by oxidative stress, the precise mechanism and mols. involved are still unknown. In light of this, the evaluation of the oxidative potential of nanoparticles is an important consideration in measuring their toxicity. The aim of this study was to examine the use of a fluorogenic probe, 2',7'-dichlorofluorescin (DCFH), in a cell-free assay system and to assess the relationship between the results obtained with this method and with the reactive species formation obsd. in cells. In order to obtain a well-dispersed nanoparticle suspension, bovine serum albumin (BSA) and dipalmitoyl phosphatidyl choline (DPPC) addn. in suspension medium was investigated. Both 1% BSA and 0.025% DPPC added to the medium significantly improved the stability of the nanoparticle suspension, decreasing the extent of particle agglomeration and settling over time. In a cell-free system, reactive oxygen species (ROS) prodn. by 14 nm carbon black particles (CB) suspended in DPPC was higher than that measured with the other suspensions (saline or 1% BSA). A greater ROS prodn. was obsd. in MonoMac 6 cells (MM6) following treatment with 14 nm CB suspended in medium contg. BSA and/or DPPC compared to medium alone. In conclusion, 1% BSA and 0.025% DPPC soln. was the most efficient for the prepn. of a nanoparticle suspension and to measure their oxidative potential.
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367Bihari, P.; Vippola, M.; Schultes, S.; Praetner, M.; Khandoga, A. G.; Reichel, C. A.; Coester, C.; Tuomi, T.; Rehberg, M.; Krombach, F. Part. Fibre Toxicol. 2008, 5, 14Google Scholar367https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cjltFWktQ%253D%253D&md5=cc2db2c23a9b97a82794d0f4adf31234Optimized dispersion of nanoparticles for biological in vitro and in vivo studiesBihari Peter; Vippola Minnamari; Schultes Stephan; Praetner Marc; Khandoga Alexander G; Reichel Christoph A; Coester Conrad; Tuomi Timo; Rehberg Markus; Krombach FritzParticle and fibre toxicology (2008), 5 (), 14 ISSN:.BACKGROUND: The aim of this study was to establish and validate a practical method to disperse nanoparticles in physiological solutions for biological in vitro and in vivo studies. RESULTS: TiO2 (rutile) dispersions were prepared in distilled water, PBS, or RPMI 1640 cell culture medium. Different ultrasound energies, various dispersion stabilizers (human, bovine, and mouse serum albumin, Tween 80, and mouse serum), various concentrations of stabilizers, and different sequences of preparation steps were applied. The size distribution of dispersed nanoparticles was analyzed by dynamic light scattering and zeta potential was measured using phase analysis light scattering. Nanoparticle size was also verified by transmission electron microscopy. A specific ultrasound energy of 4.2 x 105 kJ/m3 was sufficient to disaggregate TiO2 (rutile) nanoparticles, whereas higher energy input did not further improve size reduction. The optimal sequence was first to sonicate the nanoparticles in water, then to add dispersion stabilizers, and finally to add buffered salt solution to the dispersion. The formation of coarse TiO2 (rutile) agglomerates in PBS or RPMI was prevented by addition of 1.5 mg/ml of human, bovine or mouse serum albumin, or mouse serum. The required concentration of albumin to stabilize the nanoparticle dispersion depended on the concentration of the nanoparticles in the dispersion. TiO2 (rutile) particle dispersions at a concentration lower than 0.2 mg/ml could be stabilized by the addition of 1.5 mg/ml albumin. TiO2 (rutile) particle dispersions prepared by this method were stable for up to at least 1 week. This method was suitable for preparing dispersions without coarse agglomerates (average diameter < 290 nm) from nanosized TiO2 (rutile), ZnO, Ag, SiOx, SWNT, MWNT, and diesel SRM2975 particulate matter. CONCLUSION: The optimized dispersion method presented here appears to be effective and practicable for preparing dispersions of nanoparticles in physiological solutions without creating coarse agglomerates.
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368Cheng, C.; Muller, K. H.; Koziol, K. K.; Skepper, J. N.; Midgley, P. A.; Welland, M. E.; Porter, A. E. Biomaterials 2009, 30, 4152Google ScholarThere is no corresponding record for this reference.
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369Hirano, S.; Fujitani, Y.; Furuyama, A.; Kanno, S. Toxicol. Appl. Pharmacol. 2010, 249, 8Google Scholar369https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlSjt7jP&md5=7f5755525b7224562ba1cd8dbf8a10acUptake and cytotoxic effects of multi-walled carbon nanotubes in human bronchial epithelial cellsHirano, Seishiro; Fujitani, Yuji; Furuyama, Akiko; Kanno, SanaeToxicology and Applied Pharmacology (2010), 249 (1), 8-15CODEN: TXAPA9; ISSN:0041-008X. (Elsevier B.V.)Carbon nanotubes (CNT) are cytotoxic to several cell types. However, the mechanism of CNT toxicity has not been fully studied, and dosimetric analyses of CNT in the cell culture system are lacking. Here, we describe a novel, high throughput method to measure cellular uptake of CNT using turbimetry. BEAS-2B, a human bronchial epithelial cell line, was used to investigate cellular uptake, cytotoxicity, and inflammatory effects of multi-walled CNT (MWCNT). The cytotoxicity of MWCNT was higher than that of crocidolite asbestos in BEAS-2B cells. The IC50 of MWCNT was 12 μg/mL, whereas that of asbestos (crocidolite) was 678 μg/mL. Over the course of 5 to 8 h, BEAS-2B cells took up 17-18% of the MWCNT when they were added to the culture medium at a concn. of 10 μg/mL. BEAS-2B cells were exposed to 2, 5, or 10 μg/mL of MWCNT, and total RNA was extd. for cytokine cDNA primer array assays. The culture supernatant was collected for cytokine antibody array assays. Cytokines IL-6 and IL-8 increased in a dose dependent manner at both the mRNA and protein levels. Migration inhibitory factor (MIF) also increased in the culture supernatant in response to MWCNT. A phosphokinase array study using lysates from BEAS-2B cells exposed to MWCNT indicated that phosphorylation of p38, ERK1, and HSP27 increased significantly in response to MWCNT. Results from a reporter gene assays using the NF-κB or AP-1 promoter linked to the luciferase gene in transiently transfected CHO-KI cells revealed that NF-κB was activated following MWCNT exposure, while AP-1 was not changed. Collectively, MWCNT activated NF-κB, enhanced phosphorylation of MAP kinase pathway components, and increased prodn. of proinflammatory cytokines in human bronchial epithelial cells.
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370Holt, B. D.; Dahl, K. N.; Islam, M. F. Small 2011, 22, 2348Google ScholarThere is no corresponding record for this reference.
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371Kim, J. S.; Song, K. S.; Lee, J. H.; Yu, I. J. Arch. Toxicol. 2011, 85, 1499Google Scholar371https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXntFKlsbY%253D&md5=1de6c94eed4893a5e5aa972340047d19Evaluation of biocompatible dispersants for carbon nanotube toxicity testsKim, Jin Sik; Song, Kyung Seuk; Lee, Ji Hyun; Yu, Il JeArchives of Toxicology (2011), 85 (12), 1499-1508CODEN: ARTODN; ISSN:0340-5761. (Springer)Dispersion is one of the key obstacles to evaluating the in vitro and in vivo toxicity of carbon nanotubes (CNTs), as the aggregation or agglomeration of CNTs in culture media or vehicles complicates the interpretation of the toxicity test results. Thus, to test the dispersion of CNTs in biocompatible solns., 5 known biocompatible dispersants were selected that are widely used for nanomaterial toxicity evaluation studies. Single-wall nanotubes (SWCNTs) and multi-wall nanotubes (MWCNTs) were both dispersed in these dispersants and their macrodispersion evaluated using a light absorbance method. The dispersion stability of the dispersed SWCNTs and MWCNTs was also evaluated for 16 wk, plus the dispersants were tested for their innate toxicity using trypan blue dye exclusion, lactate dehydrogenase (LDH) leakage, and neutral red assays. All the dispersants were found to be biocompatible in the cytotoxicity tests when compared with a pos. control of 2% Triton X-100. In the dispersion tests, 0.02, 0.1, and 0.5% MWCNTs and SWCNTs were dild. in the resp. dispersants. Distd. water and dimethylsulfoxide (DMSO) both showed a poor macrodispersion of only 1-13% for the various CNT concns. In 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), the 0.02 and 0.1% MWCNTs showed a macrodispersion of 11 and 74%, resp., while the 0.02 and 0.1% SWCNTs showed a macrodispersion of 15 and 16%, resp. In 0.5% bovine serum albumin (BSA), the 0.02, 0.1, and 0.5% MWCNTs showed a very good macrodispersion of 32, 53, and 70%, resp., yet the 0.02% SWCNTs only showed a macrodispersion of 17%. In 1% Tween 80, the 0.02-0.5% SWNCTs exhibited a good macrodispersion of 27-81%, whereas the 0.02-05% MWCNTs only showed a macrodispersion of 13-23%. The dispersion stability of the CNTs during 16 wk was in the following descending order of BSA, Tween 80, DPPC, and DMSO for the MWCNTs and BSA, DPPC, Tween 80, and DMSO for the SWNCTs. Thus, appropriate dispersants are proposed according to the type of CNT, expt. concn., and treatment duration. Also, it is suggested that the dispersibility, dispersion stability, and biocompatibility of the selected dispersant should all be confirmed before a toxicity evaluation.
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372Dutta, D.; Sundaram, S. K.; Teeguarden, J. G.; Riley, B. J.; Fifield, L. S.; Jacobs, J. M.; Addleman, S. R.; Kaysen, G. A.; Moudgil, B. M.; Weber, T. J. Toxicol. Sci. 2007, 100, 303Google Scholar372https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFKlsLvE&md5=e6f80d531350136d566a0dc0acb26376Adsorbed Proteins Influence the Biological Activity and Molecular Targeting of NanomaterialsDutta, Debamitra; Sundaram, Shanmugavelayutham Kamakshi; Teeguarden, Justin Gary; Riley, Brian Joseph; Fifield, Leonard Sheldon; Jacobs, Jon Morrell; Addleman, Shane Raymond; Kaysen, George Alan; Moudgil, Brij Mohan; Weber, Thomas JosephToxicological Sciences (2007), 100 (1), 303-315CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)The possible combination of specific physicochem. properties operating at unique sites of action within cells and tissues has led to considerable uncertainty surrounding nanomaterial toxic potential. We have investigated the importance of proteins adsorbed onto the surface of two distinct classes of nanomaterials (single-walled carbon nanotubes [SWCNTs]; 10-nm amorphous silica) in guiding nanomaterial uptake or toxicity in the RAW 264.7 macrophage-like model. Albumin was identified as the major fetal bovine or human serum/plasma protein adsorbed onto SWCNTs, while a distinct protein adsorption profile was obsd. when plasma from the Nagase analbuminemic rat was used. Damaged or structurally altered albumin is rapidly cleared from systemic circulation by scavenger receptors. We obsd. that SWCNTs inhibited the induction of cyclooxygenase-2 (Cox-2) by lipopolysaccharide (LPS; 1 ng/mL, 6 h) and this anti-inflammatory response was inhibited by fucoidan (scavenger receptor antagonist). Fucoidan also reduced the uptake of fluorescent SWCNTs (Alexa647). Precoating SWCNTs with a nonionic surfactant (Pluronic F127) inhibited albumin adsorption and anti-inflammatory properties. Albumin-coated SWCNTs reduced LPS-mediated Cox-2 induction under serum-free conditions. SWCNTs did not reduce binding of LPSAlexa488 to RAW 264.7 cells. The profile of proteins adsorbed onto amorphous silica particles (50-1000 nm) was qual. different, relative to SWCNTs, and precoating amorphous silica with Pluronic F127 dramatically reduced the adsorption of serum proteins and toxicity. Collectively, these observations suggest an important role for adsorbed proteins in modulating the uptake and toxicity of SWCNTs and nano-sized amorphous silica.
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373Porter, D. W.; Sriram, K.; Wolfarth, M. G.; Jefferson, A. M.; Schwegler-Berry, D.; Andrew, M. E.; Castranova, V. Nanotoxicology 2008, 2, 144Google ScholarThere is no corresponding record for this reference.
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374Konduru, N. V.; Tyurina, Y. Y.; Feng, W.; Basova, L. V.; Belikova, N. A.; Bayir, H.; Clark, K.; Rubin, M.; Stolz, D.; Vallhov, H.; Scheynius, A.; Witasp, E.; Fadeel, B.; Kichambare, P. D.; Star, A.; Kisin, E. R.; Murray, A. R.; Shvedova, A. A.; Kagan, V. E. PLoS One 2009, 4, e4398Google ScholarThere is no corresponding record for this reference.
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375Worle-Knirsch, J. M.; Pulskamp, K.; Krug, H. F. Nano Lett. 2006, 6, 1261Google ScholarThere is no corresponding record for this reference.
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376Casey, A.; Herzog, E.; Davoren, M.; Lyng, F. M.; Byrne, H. J.; Chambers, G. Carbon 2007, 45, 1425Google ScholarThere is no corresponding record for this reference.
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377Monteiro-Riviere, N. A.; Inman, A. O.; Zhang, L. W. Toxicol. Appl. Pharmacol. 2009, 234, 222Google Scholar377https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXksVentg%253D%253D&md5=c125eee54344689101cccef2d02445c3Limitations and relative utility of screening assays to assess engineered nanoparticle toxicity in a human cell lineMonteiro-Riviere, N. A.; Inman, A. O.; Zhang, L. W.Toxicology and Applied Pharmacology (2009), 234 (2), 222-235CODEN: TXAPA9; ISSN:0041-008X. (Elsevier B.V.)Single-walled carbon nanotubes (SWCNT), fullerenes (C60), carbon black (CB), nC60, and quantum dots (QD) have been studied in vitro to det. their toxicity in a no. of cell types. Here, the authors report that classical dye-based assays such as MTT and neutral red (NR) that det. cell viability produce invalid results with some NM (nanomaterials) due to NM/dye interactions and/or NM adsorption of the dye/dye products. In this study, human epidermal keratinocytes (HEK) were exposed in vitro to CB, SWCNT, C60, nC60, and QD to assess viability with calcein AM (CAM), Live/Dead (LD), NR, MTT, Celltiter 96 Aq. One (96 AQ), alamar Blue (aB), Celltiter-Blue (CTB), CytoTox One (CTO), and flow cytometry. In addn., trypan blue (TB) was quantitated by light microscopy. Assay linearity (R2 value) was detd. with HEK plated at concns. from 0 to 25,000 cells per well in 96-well plates. HEK were treated with serial dilns. of each NM for 24 h and assessed with each of the viability assays. TB, CAM and LD assays, which depend on direct staining of living and/or dead cells, were difficult to interpret due to phys. interference of the NM with cells. Results of the dye-based assays varied a great deal, depending on the interactions of the dye/dye product with the carbon nanomaterials (CNM). Results show the optimal high throughput assay for use with carbon and noncarbon NM was 96 AQ. This study shows that, unlike small mols., CNM interact with assay markers to cause variable results with classical toxicol. assays and may not be suitable for assessing nanoparticle cytotoxicity. Therefore, more than one assay may be required when detg. nanoparticle toxicity for risk assessment.
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378Shvedova, A. A.; Kisin, E. R.; Mercer, R.; Murray, A. R.; Johnson, V. J.; Potapovich, A. I.; Tyurina, Y. Y.; Gorelik, O.; Arepalli, S.; Schwegler-Berry, D.; Hubbs, A. F.; Antonini, J.; Evans, D. E.; Ku, B. K.; Ramsey, D.; Maynard, A.; Kagan, V. E.; Castranova, V.; Baron, P. Am. J. Physiol.: Lung Cell. Mol. Physiol. 2005, 289, L698Google Scholar378https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1Cnt73I&md5=39bb1660d513632e748b238cf4b478a0Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in miceShvedova, Anna A.; Kisin, Elena R.; Mercer, Robert; Murray, Ashley R.; Johnson, Victor J.; Potapovich, Alla I.; Tyurina, Yulia Y.; Gorelik, Olga; Arepalli, Sevaram; Schwegler-Berry, Diane; Hubbs, Ann F.; Antonini, James; Evans, Douglas E.; Ku, Bon-Ki; Ramsey, Dawn; Maynard, Andrew; Kagan, Valerian E.; Castranova, Vincent; Baron, PaulAmerican Journal of Physiology (2005), 289 (5, Pt. 1), L698-L708CODEN: AJPHAP; ISSN:0002-9513. (American Physiological Society)Single-walled carbon nanotubes (SWCNT) are new materials of emerging technol. importance. As SWCNT are introduced into the life cycle of com. products, their effects on human health and environment should be addressed. We demonstrated that pharyngeal aspiration of SWCNT elicited unusual pulmonary effects in C57BL/6 mice that combined a robust but acute inflammation with early onset yet progressive fibrosis and granulomas. A dose-dependent increase in the protein, LDH, and γ-glutamyl transferase activities in bronchoalveolar lavage were found along with accumulation of 4-hydroxynonenal (oxidative biomarker) and depletion of glutathione in lungs. An early neutrophils accumulation (day 1), followed by lymphocyte (day 3) and macrophage (day 7) influx, was accompanied by early elevation of proinflammatory cytokines (TNF-α, IL-1β; day 1) followed by fibrogenic transforming growth factor (TGF)-β1 (peaked on day 7). A rapid progressive fibrosis found in mice exhibited two distinct morphologies: 1) SWCNT-induced granulomas mainly assocd. with hypertrophied epithelial cells surrounding SWCNT aggregates and 2) diffuse interstitial fibrosis and alveolar wall thickening likely assocd. with dispersed SWCNT. In vitro exposure of murine RAW 264.7 macrophages to SWCNT triggered TGF-β1 prodn. similarly to zymosan but generated less TNF-α and IL-1β. SWCNT did not cause superoxide or NO · prodn., active SWCNT engulfment, or apoptosis in RAW 264.7 macrophages. Functional respiratory deficiencies and decreased bacterial clearance (Listeria monocytogenes) were found in mice treated with SWCNT. Equal doses of ultrafine carbon black particles or fine cryst. silica (SiO2) did not induce granulomas or alveolar wall thickening and caused a significantly weaker pulmonary inflammation and damage.
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379Mukherjee, S.; Ghosh, R. N.; Maxfield, F. R. Physiol. Rev. 1997, 77, 759Google Scholar379https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXltlWlurk%253D&md5=f0619efffa77bb9be8be4f220a52c0b4EndocytosisMukherjee, Sushmita; Ghosh, Richik N.; Maxfield, Frederick R.Physiological Reviews (1997), 77 (3), 759-803CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)A review, with 554 refs. Mammalian cells take up extracellular material by a variety of different mechanisms that are collectively termed endocytosis. Endocytic mechanisms serve many important cellular functions including the uptake of extracellular nutrients, regulation of cell-surface receptor expression, maintenance of cell polarity, and antigen presentation. Endocytic pathways are also utilized by viruses, toxins, and symbiotic microorganisms to gain entry into cells. One of the best-characterized endocytic mechanisms is receptor-mediated endocytosis via clathrin-coated pits. This type of endocytosis constitutes the major emphasis of this review, with a brief discussion of other endocytic mechanisms and their comparison with the receptor-mediated pathway. This review describes and evaluates critically current understanding of the mechanisms of entry of plasma membrane components such as the receptor-ligand complexes and membrane lipids as well as the extracellular fluid into cells. The intracellular sorting and trafficking of these mols. upon internalization are also described. The roles of endocytosis in physiol. and pathol. processes are discussed. These include maintenance of cell polarization, antigen presentation, glucose transport, atherosclerosis, Alzheimer's disease, and the endocytosis of toxins and viruses.
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380Marsh, M.; McMahon, H. T. Science 1999, 285, 215Google ScholarThere is no corresponding record for this reference.
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381Cherukuri, P.; Bachilo, S. M.; Litovsky, S. H.; Weisman, R. B. J. Am. Chem. Soc. 2004, 126, 15638Google Scholar381https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpsFKkurc%253D&md5=6d6d1e3174ff0fb2a5a23dd86d843987Near-infrared fluorescence microscopy of single-walled carbon nanotubes in phagocytic cellsCherukuri, Paul; Bachilo, Sergei M.; Litovsky, Silvio H.; Weisman, R. BruceJournal of the American Chemical Society (2004), 126 (48), 15638-15639CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The uptake of pristine single-walled carbon nanotubes into macrophage-like cells has been studied using the nanotubes' intrinsic near-IR fluorescence. Macrophage samples that have been incubated in growth media contg. suspended single-walled nanotubes show characteristic nanotube fluorescence spectra. The fluorescence intensities increase smoothly with incubation time and external nanotube concn. Near-IR fluorescence microscopy at wavelengths above 1,100 nm provides high contrast images indicating localization of nanotubes in numerous intracellular vesicles. Nanotube uptake appears to occur through phagocytosis. Population growth of macrophage cultures is unaffected by exposure to single-walled nanotube concns. of ∼ 4 μg/mL for up to 96 h.
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382Pantarotto, D.; Briand, J. P.; Prato, M.; Bianco, A. Chem. Commun. (Cambridge, U.K.) 2004, 1, 16Google ScholarThere is no corresponding record for this reference.
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383VanHandel, M.; Alizadeh, D.; Zhang, L.; Kateb, B.; Bronikowski, M.; Manohara, H.; Badie, B. J. Neuroimmunol. 2009, 208, 3Google Scholar383https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjsV2muro%253D&md5=59fdd75ddd47d8f218d83a7859120de5Selective uptake of multi-walled carbon nanotubes by tumor macrophages in a murine glioma modelVanHandel, Michelle; Alizadeh, Darya; Zhang, Leying; Kateb, Babak; Bronikowski, Michael; Manohara, Harish; Badie, BehnamJournal of Neuroimmunology (2009), 208 (1-2), 3-9CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)C nanotubes (CNTs) are emerging as a new family of nanovectors for drug and gene delivery into biol. systems. To evaluate potential application of this technol. for brain tumor therapy, we studied uptake and toxicity of multi-walled CNTs (MWCNTs) in the GL261 murine intracranial glioma model. Within 24 h of a single intratumoral injection of labeled MWCNTs (5 μg), nearly 10-20% of total cells demonstrated CNT internalization. Most CNT uptake, however, occurred by tumor-assocd. macrophages (MP), which accounted for most (75%) MWCNT-pos. cells. Within 24 h of injection, nearly 30% of tumor MP became MWCNT-pos. Despite a transient increase in inflammatory cell infiltration into both normal and tumor-bearing brains following MWCNT injection, no significant toxicity was noted in mice, and minor changes in tumor cytokine expression were obsd. This study suggests that MWCNTs could potentially be used as a novel and non-toxic vehicle for targeting MP in brain tumors.
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384Shi, X.; von dem Bussche, A.; Hurt, R. H.; Kane, A. B.; Gao, H. Nat. Nanotechnol. 2011, 6, 714Google Scholar384https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtF2isLnM&md5=a327a19aa89eab4a0883ce97b9c7ee3fCell entry of one-dimensional nanomaterials occurs by tip recognition and rotationShi, Xinghua; von dem Bussche, Annette; Hurt, Robert H.; Kane, Agnes B.; Gao, HuajianNature Nanotechnology (2011), 6 (11), 714-719CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Materials with high aspect ratio, such as carbon nanotubes and asbestos fibers, have been shown to cause length-dependent toxicity in certain cells because these long materials prevent complete ingestion and this frustrates the cell. Biophys. models have been proposed to explain how spheres and elliptical nanostructures enter cells, but one-dimensional nanomaterials have not been examd. Here, we show exptl. and theor. that cylindrical one-dimensional nanomaterials such as carbon nanotubes enter cells through the tip first. For nanotubes with end caps or carbon shells at their tips, uptake involves tip recognition through receptor binding, rotation that is driven by asym. elastic strain at the tube-bilayer interface, and near-vertical entry. The precise angle of entry is governed by the relative timescales for tube rotation and receptor diffusion. Nanotubes without caps or shells on their tips show a different mode of membrane interaction, posing an interesting question as to whether modifying the tips of tubes may help avoid frustrated uptake by cells.
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385Haniu, H.; Saito, N.; Matsuda, Y.; Kim, Y. A.; Park, K. C.; Tsukahara, T.; Usui, Y.; Aoki, K.; Shimizu, M.; Ogihara, N.; Hara, K.; Takanashi, S.; Okamoto, M.; Ishigaki, N.; Nakamura, K.; Kato, H. Int. J. Nanomed. 2011, 6, 3295Google Scholar385https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvVw%253D&md5=0d00d88c046bf1e0afe5ca1614e86c70Effect of dispersants of multi-walled carbon nanotubes on cellular uptake and biological responsesHaniu, Hisao; Saito, Naoto; Matsuda, Yoshikazu; Kim, Yoong-Ahm; Park, Ki Chul; Tsukahara, Tamotsu; Usui, Yuki; Aoki, Kaoru; Shimizu, Masayuki; Ogihara, Nobuhide; Hara, Kazuo; Takanashi, Seiji; Okamoto, Masanori; Ishigaki, Norio; Nakamura, Koichi; Kato, HiroyukiInternational Journal of Nanomedicine (2011), 6 (), 3295-3307CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)Although there have been many reports about the cytotoxicity of multi-walled carbon nanotubes (MWCNTs), the results are still controversial. To investigate one possible reason, the authors investigated the influence of MWCNT dispersants on cellular uptake and cytotoxicity. Cytotoxicity was examd. (measured by alamarBlue assay), as well as intracellular MWCNT concn. and cytokine secretion (measured by flow cytometry) in human bronchial epithelial cells (BEAS-2B) exposed to a type of highly purified MWCNT vapor grown carbon fiber (VGCF, Showa Denko Kabushiki-gaisha, Tokyo, Japan) in three different dispersants (gelatin, carboxylmethyl cellulose, and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine). The authors also researched the relationship between the intracellular concn. of MWCNTs and cytotoxicity by using two cell lines, BEAS-2B and MESO-1 human malignant pleural mesothelioma cells. The intracellular concn. of VGCF was different for each of the three dispersants, and the levels of cytotoxicity and inflammatory response were correlated with the intracellular concn. of VGCF. A relationship between the intracellular concn. of VGCF and cytotoxic effects was obsd. in both cell lines. The results indicate that dispersants affect VGCF uptake into cells and that cytotoxicity depends on the intracellular concn. of VGCF, not on the exposed dosage. Thus, toxicity appears to depend on exposure time, even at low VGCF concns., because VGCF is biopersistent.
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386Haniu, H.; Saito, N.; Matsuda, Y.; Kim, Y. A.; Park, K. C.; Tsukahara, T.; Usui, Y.; Aoki, K.; Shimizu, M.; Ogihara, N.; Hara, K.; Takanashi, S.; Okamoto, M.; Ishigaki, N.; Nakamura, K.; Kato, H. Int. J. Nanomed. 2011, 6, 3487Google Scholar386https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht12nsLc%253D&md5=8ba6a4f924f80ec264458c37bdd079d6Elucidation mechanism of different biological responses to multi-walled carbon nanotubes using four cell linesHaniu, Hisao; Saito, Naoto; Matsuda, Yoshikazu; Kim, Yoong-Ahm; Park, Ki Chul; Tsukahara, Tamotsu; Usui, Yuki; Aoki, Kaoru; Shimizu, Masayuki; Ogihara, Nobuhide; Hara, Kazuo; Takanashi, Seiji; Okamoto, Masanori; Ishigaki, Norio; Nakamura, Koichi; Kato, HiroyukiInternational Journal of Nanomedicine (2011), 6 (), 3487-3497CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)We examd. differences in cellular responses to multi-walled carbon nanotubes (MWCNTs) using malignant pleural mesothelioma cells (MESO-1), bronchial epithelial cells (BEAS-2B), neuroblastoma cells (IMR-32), and monoblastic cells (THP-1), before and after differentiation. MESO-1, BEAS-2B and differentiated THP-1 cells actively endocytosed MWCNTs, resulting in cytotoxicity with lysosomal injury. However, cytotoxicity did not occur in IMR-32 or undifferentiated THP-1 cells. Both differentiated and undifferentiated THP-1 cells exhibited an inflammatory response. Carbon blacks were endocytosed by the same cell types without lysosomal damage and caused cytokine secretion, but they did not cause cytotoxicity. These results indicate that the cytotoxicity of MWCNTs requires not only cellular uptake but also lysosomal injury. Furthermore, it seems that membrane permeability or cytokine secretion without cytotoxicity results from several active mechanisms. Clarification of the cellular recognition mechanism for MWCNTs is important for developing safer MWCNTs.
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387Yaron, P. N.; Holt, B. D.; Short, P. A.; Lösche, M.; Islam, M. F.; Dahl, K. N. J. Nanobiotechnol. 2011, 9, 45Google Scholar387https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1Khu77L&md5=cad4f77848a895bc48d8dfdac844e2d8Single wall carbon nanotubes enter cells by endocytosis and not membrane penetrationYaron, Peter N.; Holt, Brian D.; Short, Philip A.; Losche, Mathias; Islam, Mohammad F.; Dahl, Kris NoelJournal of Nanobiotechnology (2011), 9 (), 45CODEN: JNOAAO; ISSN:1477-3155. (BioMed Central Ltd.)Background: Carbon nanotubes are increasingly being tested for use in cellular applications. Detg. the mode of entry is essential to control and regulate specific interactions with cells, to understand toxicol. effects of nanotubes, and to develop nanotube-based cellular technologies. We investigated cellular uptake of Pluronic copolymer-stabilized, purified ∼145 nm long single wall carbon nanotubes (SWCNTs) through a series of complementary cellular, cell-mimetic, and in vitro model membrane expts. Results: SWCNTs localized within fluorescently labeled endosomes, and confocal Raman spectroscopy showed a dramatic redn. in SWCNT uptake into cells at 4°C compared with 37°C. These data suggest energy-dependent endocytosis, as shown previously. We also examd. the possibility for non-specific phys. penetration of SWCNTs through the plasma membrane. Electrochem. impedance spectroscopy and Langmuir monolayer film balance measurements showed that Pluronic-stabilized SWCNTs assocd. with membranes but did not possess sufficient insertion energy to penetrate through the membrane. SWCNTs assocd. with vesicles made from plasma membranes but did not rupture the vesicles. Conclusions: These measurements, combined, demonstrate that Pluronic-stabilized SWCNTs only enter cells via energy-dependent endocytosis, and assocn. of SWCNTs to membrane likely increases uptake.
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388Gao, H.; Shi, W.; Freund, L. B. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 9469Google ScholarThere is no corresponding record for this reference.
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389Tabet, L.; Bussy, C.; Amara, N.; Setyan, A.; Grodet, A.; Rossi, M. J.; Pairon, J. C.; Boczkowski, J.; Lanone, S. J. Toxicol. Environ. Health, Part A 2009, 72, 60Google ScholarThere is no corresponding record for this reference.
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390Raffa, V.; Gherardini, L.; Vittorio, O.; Bardi, G.; Ziaei, A.; Pizzorusso, T.; Riggio, C.; Nitodas, S.; Karachalios, T.; Al-Jamal, K. T.; Kostarelos, K.; Costa, M.; Cuschieri, A. Nanomedicine (London, U.K.) 2011, 6, 1709Google Scholar390https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFCms7bL&md5=e4dbb4601db6b2355e2a7cebe7c0ddb2Carbon nanotube-mediated wireless cell permeabilization: drug and gene uptakeRaffa, Vittoria; Gherardini, Lisa; Vittorio, Orazio; Bardi, Giuseppe; Ziaei, Afshin; Pizzorusso, Tommaso; Riggio, Cristina; Nitodas, Stephanos; Karachalios, Theodoros; Al-Jamal, Khuloud T.; Kostarelos, Kostas; Costa, Mario; Cuschieri, AlfredNanomedicine (London, United Kingdom) (2011), 6 (10), 1709-1718CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)This work aims to exploit the antenna properties of multiwalled carbon nanotubes (MWCNTs). They can be used to induce cell permeabilization in order to transfer drugs (normally impermeable to cell membranes) both in in vitro and in vivo models. The performance of the MWCNTs as receiver antenna was modeled by finite element modeling. Once the appropriate field has been identified, the antenna properties of MWCNTs were investigated in sequential expts. involving immortalized fibroblast cell line (drug model: doxorubicin chemothererapeutic agent) and living mice (drug model: bcl-2 antiapoptotic gene) following stereotactic injection in the cerebral motor cortex. Finite element modeling anal. predicts that our MWCNTs irradiated in the radiofrequency field resemble thin-wire dipole antennas. In vitro expts. confirmed that combination of MWCNTs and electromagnetic field treatment dramatically favors intracellular drug uptake and, most importantly, drug nuclear localization. Finally, the brain of each irradiated animal exhibits a significantly higher no. of transfected cells compared with the appropriate controls. This wireless application has the potential for MWCNT-based intracellular drug delivery and electro-stimulation therapies.
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391Al-Jamal, K. T.; Kostarelos, K. Methods Mol. Biol. 2010, 625, 123Google Scholar391https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXoslyqtb4%253D&md5=78741953499f91a98361af3d74038cadAssessment of cellular uptake and cytotoxicity of carbon nanotubes using flow cytometryAl-Jamal, Khuloud T.; Kostarelos, KostasMethods in Molecular Biology (Totowa, NJ, United States) (2010), 625 (Carbon Nanotubes), 123-134CODEN: MMBIED; ISSN:1064-3745. (Humana Press Inc.)The field of carbon nanotube (CNT) functionalization is increasingly growing for the purpose of enhancing the biocompatibility of CNT for medical and biol. applications. Properties of CNT such as the type of functionalization, charge d., and the dispersibility profile are expected to modulate CNT cellular uptake and toxicity profile in vitro. The assay described here allows for rapid screening of CNT cellular uptake in vitro and assessing the acute cytotoxicity simultaneously. CNT cellular uptake is measured qual. by light scattering anal. without differentiating between cell binding and internalization of the CNT by the cells. In addn., flow cytometry is used to combine light scattering anal. with flow cytometry-based Annexin V/propidium iodide assay to measure the cytotoxicity. This assay is rapid, reliable, and allows for comparative anal. between various types of CNT studied.
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392Lamm, M. H.; Ke, P. C. Methods Mol. Biol. 2010, 625, 135Google Scholar392https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXoslyqtbw%253D&md5=0711ff2a977dffe9a66b2021ff3937a4Cell trafficking of carbon nanotubes based on fluorescence detectionLamm, Monica H.; Ke, Pu ChunMethods in Molecular Biology (Totowa, NJ, United States) (2010), 625 (Carbon Nanotubes), 135-151CODEN: MMBIED; ISSN:1064-3745. (Humana Press Inc.)Cell trafficking of carbon nanotubes (CNTs) is an area of scientific inquiry that has great implications in medicine, biosensing, and environmental science and engineering. The essence of this inquiry resides in the interaction of carbon nanostructures and cell membranes, regulated by the laws of mol. cell biol. and the physiochem. properties of the nanostructures. Of equal importance to this inquiry is a description of cellular responses to the integration of man-made materials; yet, how cellular responses may invoke whole-organism level reaction remains unclear. In this chapter, we show three exptl. studies, which may be beneficial to obtaining such an understanding. Among the reservoir of methodologies, which have proved of merit, we focus our attention on fluorescence microscopy, one of the most powerful and yet least invasive means of probing nanoparticles in biol. systems. Esp., we present the method of fluorescence energy transfer induced between a lysophospholipid mol. and a single-walled CNT upon cellular uptake, and describe coating nanotubes with RNA and suspending fullerenes with phenolic acids for facilitating their translocation across cell membranes and shuttling between cell organelles. Finally, we comment on the perspective of using mol. simulations for facilitating and guiding such expts.
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393Schrand, A. M.; Schlager, J. J.; Dai, L.; Hussain, S. M. Nat. Protoc. 2010, 5, 744Google ScholarThere is no corresponding record for this reference.
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394Murr, L. E.; Garza, K. M.; Soto, K. F.; Carrasco, A.; Powell, T. G.; Ramirez, D. A.; Guerrero, P. A.; Lopez, D. A.; Venzor, J., III. Int. J. Environ. Res. Public Health 2005, 2, 31Google ScholarThere is no corresponding record for this reference.
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395Mahmoudi, M.; Laurent, S.; Shokrgozar, M. A.; Hosseinkhani, M. ACS Nano 2011, 5, 7263Google ScholarThere is no corresponding record for this reference.
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396Mahmoudi, M.; Saeedi-Eslami, S. N.; Shokrgozar, M. A.; Azadmanesh, K.; Hassanlou, M.; Kalhor, H. R.; Burtea, C.; Rothen-Rutishauser, B.; Laurent, S.; Sheibani, S.; Vali, H. Nanoscale 2012, 4, 5461Google ScholarThere is no corresponding record for this reference.
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397Laurent, S.; Burtea, C.; Thirifays, C.; Häfeli, U. O.; Mahmoudi, M. PLoS One 2012, 7, e29997Google ScholarThere is no corresponding record for this reference.
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398Bianco, A.; Kostarelos, K.; Partidos, C. D.; Prato, M. Chem. Commun. (Cambridge, U.K.) 2005, 5, 571Google ScholarThere is no corresponding record for this reference.
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399Bottini, M.; Bruckner, S.; Nika, K.; Bottini, N.; Bellucci, S.; Magrini, A.; Bergamaschi, A.; Mustelin, T. Toxicol. Lett. 2006, 160, 121Google Scholar399https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFOhtbjI&md5=13e974f57fc918db376466a7409cba1aMulti-walled carbon nanotubes induce T lymphocyte apoptosisBottini, Massimo; Bruckner, Shane; Nika, Konstantina; Bottini, Nunzio; Bellucci, Stefano; Magrini, Andrea; Bergamaschi, Antonio; Mustelin, TomasToxicology Letters (2006), 160 (2), 121-126CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)Carbon nanotubes are a man-made form of carbon that did not exist in the environment until very recently. Due to their unique chem., phys., optical, and magnetic properties, carbon nanotubes have found many uses in industrial products and in the field of nanotechnol., including in nanomedicine. However, very little is yet known about the toxicity of carbon nanotubes. Here, the authors compare the toxicity of pristine and oxidized multi-walled carbon nanotubes on human T cells and find that the latter are more toxic and induce massive loss of cell viability through programmed cell death at doses of 400 μg/mL, which corresponds to approx. 10 million carbon nanotubes per cell. Pristine, hydrophobic, carbon nanotubes were less toxic and a 10-fold lower concn. of either carbon nanotube type were not nearly as toxic. The authors' results suggest that carbon nanotubes indeed can be very toxic at sufficiently high concns. and that careful toxicity studies need to be undertaken particularly in conjunction with nanomedical applications of carbon nanotubes.
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400Shvedova, A. A.; Castranova, V.; Kisin, E. R.; Schwegler-Berry, D.; Murray, A. R.; Gandelsman, V. Z.; Maynard, A.; Baron, P. J. Toxicol. Environ. Health, Part A 2003, 66, 1909Google Scholar400https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXns1Gqsb0%253D&md5=e648e99fdcbaf6779d6ae2d29255e7f1Exposure to Carbon Nanotube Material: Assessment of Nanotube Cytotoxicity using Human Keratinocyte CellsShvedova, Anna; Castranova, Vincent; Kisin, Elena; Schwegler-Berry, Diane; Murray, Ashley; Gandelsman, Vadim; Maynard, Andrew; Baron, PaulJournal of Toxicology and Environmental Health, Part A (2003), 66 (20), 1909-1926CODEN: JTEHF8; ISSN:1528-7394. (Taylor & Francis, Inc.)Carbon nanotubes are new members of carbon allotropes similar to fullerenes and graphite. Because of their unique elec., mech., and thermal properties, carbon nanotubes are important for novel applications in the electronics, aerospace, and computer industries. Exposure to graphite and carbon materials has been assocd. with increased incidence of skin diseases, such as carbon fiber dermatitis, hyperkeratosis, and naevi. The authors investigated adverse effects of single-wall carbon nanotubes (SWCNT) using a cell culture of immortalized human epidermal keratinocytes (HaCaT). After 18 h of exposure of HaCaT to SWCNT, oxidative stress and cellular toxicity were indicated by formation of free radicals, accumulation of peroxidative products, antioxidant depletion, and loss of cell viability. Exposure to SWCNT also resulted in ultrastructural and morphol. changes in cultured skin cells. These data indicate that dermal exposure to unrefined SWCNT may lead to dermal toxicity due to accelerated oxidative stress in the skin of exposed workers.
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401Kagan, V. E.; Tyurina, Y. Y.; Tyurin, V. A.; Konduru, N. V.; Potapovich, A. I.; Osipov, A. N.; Kisin, E. R.; Schwegler-Berry, D.; Mercer, R.; Castranova, V.; Shvedova, A. A. Toxicol. Lett. 2006, 165, 88Google Scholar401https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XlvF2nsrY%253D&md5=1cc017a92ff6b432025cd4a8e3e85411Direct and indirect effects of single walled carbon nanotubes on RAW 264.7 macrophages: Role of ironKagan, V. E.; Tyurina, Y. Y.; Tyurin, V. A.; Konduru, N. V.; Potapovich, A. I.; Osipov, A. N.; Kisin, E. R.; Schwegler-Berry, D.; Mercer, R.; Castranova, V.; Shvedova, A. A.Toxicology Letters (2006), 165 (1), 88-100CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)Single-walled carbon nanotubes (SWCNT), nano-cylinders with an extremely small diam. (1-2 nm) and high aspect ratio, have unique physico-chem., electronic and mech. properties and may exhibit unusual interactions with cells and tissues, thus necessitating studies of their toxicity and health effects. Manufd. SWCNT usually contain significant amts. of Fe that may act as a catalyst of oxidative stress. Because macrophages are the primary responders to different particles that initiate and propagate inflammatory reactions and oxidative stress, we utilized 2 types of SWCNT: (1) Fe-rich (non-purified) SWCNT (26 wt.% of Fe) and (2) Fe-stripped (purified) SWCNT (0.23 wt.% of Fe) to study their interactions with RAW 264.7 macrophages. Ultrasonication resulted in predominantly well-dispersed and sepd. SWCNT strands as evidenced by SEM. Neither purified nor non-purified SWCNT were able to generate intracellular prodn. of superoxide radicals or NO in RAW 264.7 macrophages as documented by flow-cytometry and fluorescence microscopy. SWCNT with different Fe content displayed different redox activity in a cell-free model system as revealed by EPR-detectable formation of ascorbate radicals resulting from ascorbate oxidn. In the presence of zymosan-stimulated RAW 264.7 macrophages, non-purified Fe-rich SWCNT were more effective in generating hydroxyl radicals (documented by EPR spin-trapping with 5,5-dimethyl-1-pyrroline-N-oxide, DMPO) than purified SWCNT. Similarly, EPR spin-trapping expts. in the presence of zymosan-stimulated RAW 264.7 macrophages showed that non-purified SWCNT more effectively converted superoxide radicals generated by xanthine oxidase/xanthine into hydroxyl radicals as compared to purified SWCNT. Fe-rich SWCNT caused significant loss of intracellular low mol. wt. thiols (GSH) and accumulation of lipid hydroperoxides in both zymosan-and PMA-stimulated RAW 264.7 macrophages. Catalase was able to partially protect macrophages against SWCNT induced elevation of biomarkers of oxidative stress (enhancement of lipid peroxidn. and GSH depletion). Thus, the presence of Fe in SWCNT may be important in detg. redox-dependent responses of macrophages.
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402Herzog, E.; Casey, A.; Lyng, F. M.; Chambers, G.; Byrne, H. J.; Davoren, M. Toxicol. Lett. 2007, 174, 49Google Scholar402https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1anurbJ&md5=eee2bdd51f7d8c709d3c009d006ee59eA new approach to the toxicity testing of carbon-based nanomaterials-The clonogenic assayHerzog, Eva; Casey, Alan; Lyng, Fiona M.; Chambers, Gordon; Byrne, Hugh J.; Davoren, MariaToxicology Letters (2007), 174 (1-3), 49-60CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)The cellular toxicity of three types of carbon nanoparticles, namely HiPco single-walled carbon nanotubes (SWCNT), arc discharge SWCNT and Printex 90 carbon black nanoparticles, was studied on three different cell models including the human alveolar carcinoma epithelial cell line (A549), the normal human bronchial epithelial cell line (BEAS-2B) and the human keratinocyte cell line (HaCaT) using the clonogenic assay. Carbon nanomaterials are known to interact with colorimetric indicator dyes frequently used in cytotoxicity assays. By employing the clonogenic assay, any such interactions could be avoided, allowing a more reliable method for the in vitro toxicity assessment of carbon-based nanoparticles. It could be shown that the toxicity of as produced SWCNT samples differs between cell lines and the SWCNT prodn. method used, with HiPco SWCNT samples being more reactive compared to arc discharge produced SWCNT samples, both eliciting a stronger cytotoxic response than carbon black. Furthermore, it was possible to distinguish between effects on cell viability and cell proliferation by including colony size as an addnl. endpoint in the clonogenic assay. All three particle types were highly effective in inhibiting cell proliferation in all three cell lines, whereas only HaCaT and BEAS-2B cells also showed decreased cell viability.
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403Balavoine, F.; Schultz, P.; Richard, C.; Mallouh, V.; Ebbesen, T. W.; Mioskowski, C. Angew. Chem., Int. Ed. 1999, 38, 1912Google ScholarThere is no corresponding record for this reference.
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404Muller, J.; Decordier, I.; Hoet, P. H.; Lombaert, N.; Thomassen, L.; Huaux, F.; Lison, D.; Kirsch-Volders, M. Carcinogenesis 2008, 29, 427Google ScholarThere is no corresponding record for this reference.
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405Haniu, H.; Saito, N.; Matsuda, Y.; Usui, Y.; Aoki, K.; Shimizu, M.; Ogihara, N.; Hara, K.; Takanashi, S.; Okamoto, M.; Nakamura, K.; Ishigaki, N.; Tsukahara, T.; Kato, H. J. Nanotechnol. 2012, 2012, 937819Google ScholarThere is no corresponding record for this reference.
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406Isobe, H.; Tanaka, T.; Maeda, R.; Noiri, E.; Solin, N.; Yudasaka, M.; Iijima, S.; Nakamura, E. Angew. Chem., Int. Ed. 2006, 45, 6676Google ScholarThere is no corresponding record for this reference.
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407Pumera, M.; Miyahara, Y. Nanoscale 2009, 1, 260Google ScholarThere is no corresponding record for this reference.
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408Ambrosi, A.; Pumera, M. Chemistry (Easton) 2010, 16, 1786Google Scholar408https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVKjsb8%253D&md5=c1711cbd59aa18779f107ce2e92bf631Regulatory Peptides Are Susceptible to Oxidation by Metallic Impurities within Carbon NanotubesAmbrosi, Adriano; Pumera, MartinChemistry - A European Journal (2010), 16 (6), 1786-1792CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)In this article, we show that the redox properties of the regulatory peptide L-glutathione are affected by the presence of nickel oxide impurities within single-walled carbon nanotubes (SWCNTs). Glutathione is a powerful antioxidant that protects cells from oxidative stress by removing free radicals and peroxides. We show that the L-cysteine moiety in L-glutathione is responsible for the susceptibility to oxidn. by metallic impurities present in the carbon nanotubes. These results have great significance for assessing the toxicity of carbon-nanotube materials. The SWCNTs were characterized by Raman spectroscopy, high-resoln. XPS, transmission electron microscopy, and energy dispersive X-ray spectroscopy.
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409Brown, D. M.; Donaldson, K.; Stone, V. J. Biomed. Nanotechnol. 2010, 6, 224Google Scholar409https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVKrt73E&md5=108482d72882579329dcfcb49174beb3Nuclear translocation of Nrf2 and expression of antioxidant defence genes in THP-1 cells exposed to carbon nanotubesBrown, David M.; Donaldson, Kenneth; Stone, VickiJournal of Biomedical Nanotechnology (2010), 6 (3), 224-233CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)Carbon nanotubes have a wide range of applications in various industries and their use is likely to rise in the future. Currently, a major concern is that with the increasing use and prodn. of these materials, there may be increased health risks to exposed workers. Long (> 15 μm) straight nanotubes may undergo frustrated phagocytosis which is likely to result in reduced clearance. We examine here the effects of multiwalled carbon nanotubes of different sizes on monocytic THP-1 cells, with regard to their ability to stimulate increased expression of the HO-1 and GST genes and their ability to produce nuclear translocation of the transcription factor, Nrf2, as well as the release of several pro-inflammatory cytokines and mediators of inflammation. Our results suggest that long (50 μm) carbon nanotubes (62.5 μg/mL for 4 h) produce increased nuclear translocation of Nrf2 and increased HO-1 gene expression compared with shorter entangled nanotubes. There was no increased gene expression for GST. The long nanotubes (NT1) caused increased release of the proinflammatory cytokine IL-1β, an effect which was diminished by the antioxidant trolox, suggesting a role of oxidative stress in the upregulation of this cytokine. Tentatively, our study suggests that long carbon nanotubes may exert their effect in THP-1 cells in part via an oxidative stress mechanism.
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410Donaldson, K.; Murphy, F. A.; Duffin, R.; Poland, C. A. Part. Fibre Toxicol. 2010, 7, 5Google Scholar410https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c3nsF2jtg%253D%253D&md5=49db73fee80b155964e544fd639835b8Asbestos, carbon nanotubes and the pleural mesothelium: a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesotheliomaDonaldson Ken; Murphy Fiona A; Duffin Rodger; Poland Craig AParticle and fibre toxicology (2010), 7 (), 5 ISSN:.The unique hazard posed to the pleural mesothelium by asbestos has engendered concern in potential for a similar risk from high aspect ratio nanoparticles (HARN) such as carbon nanotubes. In the course of studying the potential impact of HARN on the pleura we have utilised the existing hypothesis regarding the role of the parietal pleura in the response to long fibres. This review seeks to synthesise our new data with multi-walled carbon nanotubes (CNT) with that hypothesis for the behaviour of long fibres in the lung and their retention in the parietal pleura leading to the initiation of inflammation and pleural pathology such as mesothelioma. We describe evidence that a fraction of all deposited particles reach the pleura and that a mechanism of particle clearance from the pleura exits, through stomata in the parietal pleura. We suggest that these stomata are the site of retention of long fibres which cannot negotiate them leading to inflammation and pleural pathology including mesothelioma. We cite thoracoscopic data to support the contention, as would be anticipated from the preceding, that the parietal pleura is the site of origin of pleural mesothelioma. This mechanism, if it finds support, has important implications for future research into the mesothelioma hazard from HARN and also for our current view of the origins of asbestos-initiated pleural mesothelioma and the common use of lung parenchymal asbestos fibre burden as a correlate of this tumour, which actually arises in the parietal pleura.
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411Murphy, F. A.; Schinwald, A.; Poland, C. A.; Donaldson, K. Part. Fibre Toxicol. 2012, 9, 8Google Scholar411https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotFKqurg%253D&md5=85cee97a266ff604dae0a21e2ea0265eThe mechanism of pleural inflammation by long carbon nanotubes: interaction of long fibres with macrophages stimulates them to amplify pro-inflammatory responses in mesothelial cellsMurphy, Fiona A.; Schinwald, Anja; Poland, Craig A.; Donaldson, KenParticle and Fibre Toxicology (2012), 9 (), 8CODEN: PFTABQ; ISSN:1743-8977. (BioMed Central Ltd.)Carbon nanotubes (CNT) are high aspect ratio nanoparticles with diams. in the nanometer range but lengths extending up to hundreds of microns. The structural similarities between CNT and asbestos have raised concern that they may pose a similar inhalation hazard. Recently CNT have been shown to elicit a length-dependent, asbestos-like inflammatory response in the pleural cavity of mice, where long fibers caused inflammation but short fibers did not. However the cellular mechanisms governing this response have yet to be elucidated. This study examd. the in vitro effects of a range of CNT for their ability to stimulate the release of the acute phase cytokines; IL-1β, TNFα, IL-6 and the chemokine, IL-8 from both Met5a mesothelial cells and THP-1 macrophages. Results showed that direct exposure to CNT resulted in significant cytokine release from the macrophages but not mesothelial cells. This pro-inflammatory response was length dependent but modest and was shown to be a result of frustrated phagocytosis. Furthermore the indirect actions of the CNT were examd. by treating the mesothelial cells with conditioned media from CNT-treated macrophages. This resulted in a dramatic amplification of the cytokine release from the mesothelial cells, a response which could be attenuated by inhibition of phagocytosis during the initial macrophage CNT treatments. We therefore hypothesize that long fibers elicit an inflammatory response in the pleural cavity via frustrated phagocytosis in pleural macrophages. The activated macrophages then stimulate an amplified pro-inflammatory cytokine response from the adjacent pleural mesothelial cells. This mechanism for producing a pro-inflammatory environment in the pleural space exposed to long CNT has implications for the general understanding of fiber-related pleural disease and design of safe nanofibers.
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412van Berlo, D.; Clift, M. J.; Albrecht, C.; Schins, R. P. Swiss Med. Wkly. 2012, 142, w13698Google ScholarThere is no corresponding record for this reference.
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413Petersen, E. J.; Tu, X.; Dizdaroglu, M.; Zheng, M.; Nelson, B. C. Small 2013, 9, 205Google ScholarThere is no corresponding record for this reference.
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414Ali-Boucetta, H.; Nunes, A.; Sainz, R.; Herrero, M. A.; Tian, B.; Prato, M.; Bianco, A.; Kostarelos, K. Angew. Chem., Int. Ed. 2013, 52, 2274Google ScholarThere is no corresponding record for this reference.
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415Chiaretti, M.; Mazzanti, G.; Bosco, S. B. S.; Cucina, A.; Le Foche, F. G.; Carru, A.; Mastrangelo, S.; Di Sotto, A.; Masciangelo, R.; Chiaretti, A. M.; Balasubramanian, C.; De Bellis, G.; Micciulla, F.; Porta, N.; Deriu, G.; Tiberia, A. J. Phys.: Condens. Matter 2008, 20, 474203Google Scholar415https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFahsLzE&md5=d8cbc4d128ac1d6b762b8e1a5f6b3ec8Carbon nanotubes toxicology and effects on metabolism and immunological modification in vitro and in vivoChiaretti, M.; Mazzanti, G.; Bosco, S.; Bellucci, S.; Cucina, A.; Le Foche, F.; Carru, G. A.; Mastrangelo, S.; Di Sotto, A.; Masciangelo, R.; Chiaretti, A. M.; Balasubramanian, C.; De Bellis, G.; Micciulla, F.; Porta, N.; Deriu, G.; Tiberia, A.Journal of Physics: Condensed Matter (2008), 20 (47), 474203/1-474203/10CODEN: JCOMEL; ISSN:0953-8984. (Institute of Physics Publishing)The aim of this research is focused on the biol. effects of multi wall carbon nanotubes (MWCNTs) on three different human cell types, lab. animals in vivo, and immunol. effects. Large nos. of researchers are directly involved in the handling of nanostructured materials such as MWCNTs and nanoparticles. It is important to assess the potential health risks related to their daily exposure to carbon nanotubes. The administration of sterilized nanosamples has been performed on lab. animals, in both acute and chronic administration, and the pathol. effects on the parenchymal tissues have been investigated. The authors studied the serum immunol. modifications after i.p. administration of the MWCNTs. The authors did not observe any antigenic reaction; the screening of ANA, anti-ENA, anti-cardiolipin, C-ANCA and P-ANCA was neg. No quant. modification of Igs was obsd., hence no modification of humoral immunity was documented. The authors also studied the effects of MWCNTs on the proliferation of three different cell types. MCF-7 showed a significant inhibition of proliferation for all conditions studied, whereas hSMCs demonstrated a redn. of cell growth only for the highest MWCNTs concns. after 72 h. Also, no growth modification was obsd. in the Caco-2 cell line. The authors obsd. that a low quantity of MWCNTs does not provoke any inflammatory reaction. However, for future medical applications, it is important to realize prosthesis based on MWCNTs, through studying the corresponding implantation effects. Moreover, it has to be emphasized that this investigation does not address, at the moment, the carcinogenicity of MWCNTs, which requires a detailed follow-up investigation on the specific topic. In view of the subsequent and more extensive use of MWCNTs, esp. in applications where carbon nanotubes are injected into the human body for drug delivery, as a contrast agent carrying entities for MRI, or as the basic material of a new prosthesis generation, more extended tests and expts. are necessary.
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416Palomäki, J.; Karisola, P.; Pylkkänen, L.; Savolainen, K.; Alenius, H. Toxicology 2010, 267, 125Google ScholarThere is no corresponding record for this reference.
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417Zhang, Q.; Zhou, H.; Yan, B. Methods Mol. Biol. 2010, 625, 95Google Scholar417https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXoslyqtLg%253D&md5=c531c3804eb58fdf3a1ba68f688956d0Reducing nanotube cytotoxicity using a nano-combinatorial library approachZhang, Qiu; Zhou, Hongyu; Yan, BingMethods in Molecular Biology (Totowa, NJ, United States) (2010), 625 (Carbon Nanotubes), 95-107CODEN: MMBIED; ISSN:1064-3745. (Humana Press Inc.)Carbon nanotubes (CNTs) have a great potential for applications in medicine. However, their biocompatibility and toxicity cause a great concern. Due to the large surface area of CNTs, chem. modification can dramatically alter their physiochem. properties and hence biol. activity. Using a combinatorial chem. approach, we report the synthesis of an 80-member surface-modified nanotube library. Based upon screening of this library with respect to protein-binding capacity, cytotoxicity, and immune response, we were able to select highly biocompatible nanotubes with reduced protein-binding cytotoxicity and immune response.
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418Johnston, H. J.; Hutchison, G. R.; Christensen, F. M.; Peters, S.; Hankin, S.; Aschberger, K.; Stone, V. Nanotoxicology 2010, 4, 207Google ScholarThere is no corresponding record for this reference.
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419Rauch, J.; Kolch, W.; Mahmoudi, M. Sci. Rep. 2012, 2, 868Google Scholar419https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVKru7nO&md5=d68aa8410a507e46e0c7cff2ab1fae2fCell type-specific activation of AKT and ERK signaling pathways by small negatively-charged magnetic nanoparticlesRauch, Jens; Kolch, Walter; Mahmoudi, MortezaScientific Reports (2012), 2 (), srep00868, 9 pp.CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)The interaction of nanoparticles (NPs) with living organisms has become a focus of public and scientific debate due to their potential wide applications in biomedicine, but also because of unwanted side effects. Here, we show that superparamagnetic iron oxide NPs (SPIONs) with different surface coatings can differentially affect signal transduction pathways. Using isogenic pairs of breast and colon derived cell lines we found that the stimulation of ERK and AKT signaling pathways by SPIONs is selectively dependent on the cell type and SPION type. In general, cells with Ras mutations respond better than their non-mutant counterparts. Small neg. charged SPIONs (snSPIONs) activated ERK to a similar extent as epidermal growth factor (EGF), and used the same upstream signaling components including activation of the EGF receptor. Importantly, snSPIONs stimulated the proliferation of Ras transformed breast epithelial cells as efficiently as EGF suggesting that NPs can mimic physiol. growth factors.
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420Pantarotto, D.; Partidos, C. D.; Graff, R.; Hoebeke, J.; Briand, J. P.; Prato, M.; Bianco, A. J. Am. Chem. Soc. 2003, 125, 6160Google ScholarThere is no corresponding record for this reference.
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421Zhang, Y. B.; Kanungo, M.; Ho, A. J.; Freimuth, P.; van der Lelie, D.; Chen, M.; Khamis, S. M.; Datta, S. S.; Johnson, A. T.; Misewich, J. A.; Wong, S. S. Nano Lett. 2007, 7, 3086Google ScholarThere is no corresponding record for this reference.
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422Salvador-Morales, C.; Flahaut, E.; Sim, E.; Sloan, J.; Green, M. L.; Sim, R. B. Mol. Immunol. 2006, 43, 193Google Scholar422https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVCltbrJ&md5=6064b0a365787301a4f5a6815730e143Complement activation and protein adsorption by carbon nanotubesSalvador-Morales, Carolina; Flahaut, Emmanuel; Sim, Edith; Sloan, Jeremy; Green, Malcolm L. H.; Sim, Robert B.Molecular Immunology (2006), 43 (3), 193-201CODEN: MOIMD5; ISSN:0161-5890. (Elsevier B.V.)As a first step to validate the use of carbon nanotubes as novel vaccine or drug delivery devices, their interaction with a part of the human immune system, complement, has been explored. Hemolytic assays were conducted to investigate the activation of the human serum complement system via the classical and alternative pathways. Western blot and SDS-PAGE techniques were used to elucidate the mechanism of activation of complement via the classical pathway, and to analyze the interaction of complement and other plasma proteins with carbon nanotubes. The authors report for the first time that carbon nanotubes activate human complement via both classical and alternative pathways. The authors conclude that complement activation by nanotubes is consistent with reported adjuvant effects, and might also in various circumstances promote damaging effects of excessive complement activation, such as inflammation and granuloma formation. C1q binds directly to carbon nanotubes. Protein binding to carbon nanotubes is highly selective, since out of the many different proteins in plasma, very few bind to the carbon nanotubes. Fibrinogen and apolipoproteins (AI, AIV and CIII) were the proteins that bound to carbon nanotubes in greatest quantity.
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423Ge, C.; Du, J.; Zhao, L.; Wang, L.; Liu, Y.; Li, D.; Yang, Y.; Zhou, R.; Zhao, Y.; Chai, Z.; Chen, C. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 16968Google ScholarThere is no corresponding record for this reference.
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424Cedervall, T.; Lynch, I.; Lindman, S.; Berggård, T.; Thulin, E.; Nilsson, H.; Dawson, K. A.; Linse, S. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 2050Google Scholar424https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXisVWrsro%253D&md5=83bdd8651591208f7867d50100606285Understanding the nanoparticle-protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticlesCedervall, Tommy; Lynch, Iseult; Lindman, Stina; Berggard, Tord; Thulin, Eva; Nilsson, Hanna; Dawson, Kenneth A.; Linse, SaraProceedings of the National Academy of Sciences of the United States of America (2007), 104 (7), 2050-2055CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Due to their small size, nanoparticles have distinct properties compared with the bulk form of the same materials. These properties are rapidly revolutionizing many areas of medicine and technol. Despite the remarkable speed of development of nanoscience, relatively little is known about the interaction of nanoscale objects with living systems. In a biol. fluid, proteins assoc. with nanoparticles, and the amt. and presentation of the proteins on the surface of the particles leads to an in vivo response. Proteins compete for the nanoparticle "surface," leading to a protein "corona" that largely defines the biol. identity of the particle. Thus, knowledge of rates, affinities, and stoichiometries of protein assocn. with, and dissocn. from, nanoparticles is important for understanding the nature of the particle surface seen by the functional machinery of cells. Here the authors develop approaches to study these parameters and apply them to plasma and simple model systems, albumin and fibrinogen. A series of copolymer nanoparticles are used with variation of size and compn. (hydrophobicity). The authors show that isothermal titrn. calorimetry is suitable for studying the affinity and stoichiometry of protein binding to nanoparticles. The authors det. the rates of protein assocn. and dissocn. using surface plasmon resonance technol. with nanoparticles that are thiol-linked to gold, and through size exclusion chromatog. of protein-nanoparticle mixts. This method is less perturbing than centrifugation, and is developed into a systematic methodol. to isolate nanoparticle-assocd. proteins. The kinetic and equil. binding properties depend on protein identity as well as particle surface characteristics and size.
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425Mahmoudi, M.; Lynch, I.; Ejtehadi, M. R.; Monopoli, M. P.; Bombelli, F. B.; Laurent, S. Chem. Rev. 2011, 111, 5610Google ScholarThere is no corresponding record for this reference.
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426Rauch, J.; Kolch, W.; Laurent, S.; Mahmoudi, M. Chem. Rev. 2013, 113, 3391Google ScholarThere is no corresponding record for this reference.
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427Walczyk, D.; Bombelli, F. B.; Monopoli, M. P; Lynch, I.; Dawson, K. A. J. Am. Chem. Soc. 2010, 132, 5761Google Scholar427https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXktFeks78%253D&md5=ce9efabdf94b4cb3e40fd6826e48242eWhat the Cell "Sees" in BionanoscienceWalczyk, Dorota; Bombelli, Francesca Baldelli; Monopoli, Marco P.; Lynch, Iseult; Dawson, Kenneth A.Journal of the American Chemical Society (2010), 132 (16), 5761-5768CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)What the biol. cell, organ, or barrier actually "sees" when interacting with a nanoparticle dispersed in a biol. medium likely matters more than the bare material properties of the particle itself. Typically the bare surface of the particle is covered by several biomols., including a select group of proteins drawn from the biol. medium. Here, we apply several different methodologies, in a time-resolved manner, to follow the lifetime of such biomol. "coronas" both in situ and isolated from the excess plasma. We find that such particle-biomol. complexes can be phys. isolated from the surrounding medium and studied in some detail, without altering their structure. For several nanomaterial types, we find that blood plasma-derived coronas are sufficiently long-lived that they, rather than the nanomaterial surface, are likely to be what the cell sees. From fundamental science to regulatory safety, current efforts to classify the biol. impacts of nanomaterials (currently according to bare material type and bare surface properties) may be assisted by the methodol. and understanding reported here.
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428Monopoli, M. P.; Walczyk, D.; Campbell, A.; Elia, G.; Lynch, I.; Bombelli, F. B.; Dawson, K. A. J. Am. Chem. Soc. 2011, 133, 2525Google Scholar428https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVOnt7w%253D&md5=a93981208087f4c615ac8c7df33a20ddPhysical-Chemical Aspects of Protein Corona: Relevance to in Vitro and in Vivo Biological Impacts of NanoparticlesMonopoli, Marco P.; Walczyk, Dorota; Campbell, Abigail; Elia, Giuliano; Lynch, Iseult; Baldelli Bombelli, Francesca; Dawson, Kenneth A.Journal of the American Chemical Society (2011), 133 (8), 2525-2534CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)It is now clearly emerging that besides size and shape, the other primary defining element of nanoscale objects in biol. media is their long-lived protein ("hard") corona. This corona may be expressed as a durable, stabilizing coating of the bare surface of nanoparticle (NP) monomers, or it may be reflected in different subpopulations of particle assemblies, each presenting a durable protein coating. Using the approach and concepts of phys. chem., we relate studies on the compn. of the protein corona at different plasma concns. with structural data on the complexes both in situ and free from excess plasma. This enables a high degree of confidence in the meaning of the hard protein corona in a biol. context. Here, we present the protein adsorption for two compositionally different NPs, namely sulfonated polystyrene and silica NPs. NP-protein complexes are characterized by differential centrifugal sedimentation, dynamic light scattering, and zeta-potential both in situ and once isolated from plasma as a function of the protein/NP surface area ratio. We then introduce a semiquant. detn. of their hard corona compn. using one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and electrospray liq. chromatog. mass spectrometry, which allows us to follow the total binding isotherms for the particles, identifying simultaneously the nature and amt. of the most relevant proteins as a function of the plasma concn. We find that the hard corona can evolve quite significantly as one passes from protein concns. appropriate to in vitro cell studies to those present in in vivo studies, which has deep implications for in vitro-in vivo extrapolations and will require some consideration in the future.
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429Mahmoudi, M.; Abdelmonem, A. M.; Behzadi, S.; Clement, J. H.; Dutz, S.; Ejtehadi, M. R.; Hartmann, R.; Kantner, K.; Linne, U.; Maffre, P.; Metzler, S.; Moghadam, M. K.; Pfeiffer, C.; Rezaei, M.; Ruiz-Lozano, P.; Serpooshan, V.; Shokrgozar, M. A.; Nienhaus, G. U.; Parak, W. J. ACS Nano 2013, 7, 6555Google ScholarThere is no corresponding record for this reference.
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430Shannahan, J. H.; Brown, J. M.; Chen, R.; Ke, P. C.; Lai, X.; Mitra, S.; Witzmann, F. A. Small 2013, 9, 2171Google ScholarThere is no corresponding record for this reference.
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431Riehemann, K. Small 2012, 8, 1970Google ScholarThere is no corresponding record for this reference.
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432Kagan, V. E.; Bayir, H.; Shvedova, A. A. Nanomedicine 2005, 1, 313Google ScholarThere is no corresponding record for this reference.
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433Donaldson, K.; Aitken, R.; Tran, L.; Stone, V.; Duffin, R.; Forrest, G.; Alexander, A. Toxicol. Sci. 2006, 92, 5Google Scholar433https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmsVehtrY%253D&md5=f24ea6a94d708d8cb11d5fe862c432deCarbon Nanotubes: A Review of Their Properties in Relation to Pulmonary Toxicology and Workplace SafetyDonaldson, Ken; Aitken, Robert; Tran, Lang; Stone, Vicki; Duffin, Rodger; Forrest, Gavin; Alexander, AndrewToxicological Sciences (2006), 92 (1), 5-22CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)A review. Carbon nanotubes (CNT) are an important new class of technol. materials that have numerous novel and useful properties. The forecast increase in manuf. makes it likely that increasing human exposure will occur, and as a result, CNT are beginning to come under toxicol. scrutiny. This review seeks to set out the toxicol. paradigms applicable to the toxicity of inhaled CNT, building on the toxicol. database on nanoparticles (NP) and fibers. Relevant workplace regulation regarding exposure is also considered in the light of our knowledge of CNT. CNT could have features of both NP and conventional fibers, and so the current paradigm for fiber toxicol., which is based on mineral fibers and synthetic vitreous fibers, is discussed. The NP toxicol. paradigm is also discussed in relation to CNT. The available peer-reviewed literature suggests that CNT may have unusual toxicity properties. In particular, CNT seem to have a special ability to stimulate mesenchymal cell growth and to cause granuloma formation and fibrogenesis. In several studies, CNT have more adverse effects than the same mass of NP carbon and quartz, the latter a commonly used benchmark of particle toxicity. There is, however, no definitive inhalation study available that would avoid the potential for artifactual effects due to large mats and aggregates forming during instillation exposure procedures. Studies also show that CNT may exhibit some of their effects through oxidative stress and inflammation. CNT represent a group of particles that are growing in prodn. and use, and therefore, research into their toxicol. and safe use is warranted.
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434Roco, M. C. Ann. N. Y. Acad. Sci. 2006, 1093, 1Google ScholarThere is no corresponding record for this reference.
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435Singh, S.; Nalwa, H. S. J. Nanosci. Nanotechnol. 2007, 7, 3048Google ScholarThere is no corresponding record for this reference.
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436Zhu, L.; Chang, D. W.; Dai, L.; Hong, Y. Nano Lett. 2007, 7, 3592Google ScholarThere is no corresponding record for this reference.
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437Szendi, K.; Varga, C. Anticancer Res. 2008, 28, 349Google Scholar437https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjslWhtbo%253D&md5=b5358db4c137fbe5ebd4586fcf4bfa61Lack of genotoxicity of carbon nanotubes in a pilot studySzendi, Katalin; Varga, CsabaAnticancer Research (2008), 28 (1A), 349-352CODEN: ANTRD4; ISSN:0250-7005. (International Institute of Anticancer Research)Background: Different types of carbon nanotubes may represent toxic hazards due to their size distribution and massive surface area. They may adsorb other toxic agents that can consequently be transported into the body. The aim of the present study was to det. the possible genotoxicity of carbon nanotubes. Materials and Methods: In vivo bacterial mutagenicity and in vitro cytogenetic studies were performed on single-walled and multi-walled carbon nanotubes. Results: Oral exposure to nanotubes did not increase urinary mutagenicity in rats as studied using Ames test. No genotoxic effect was found in the in vitro micronucleus and sister chromatid exchange assays, either. Mitotic inhibition, a possible cytotoxic effect, however, was obsd. in the human lymphocyte cultures upon treatment with single-walled tubes. Conclusion: Due to the limited toxicity data on carbon nanotubes, these results may be particularly important for risk assessment purposes.
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438Di Sotto, A.; Chiaretti, M.; Carru, G. A.; Bellucci, S.; Mazzanti, G. Toxicol. Lett. 2009, 184, 192Google Scholar438https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVCgtLo%253D&md5=e623333003347c238942e5b957819436Multi-walled carbon nanotubes: Lack of mutagenic activity in the bacterial reverse mutation assayDi Sotto, Antonella; Chiaretti, Massimo; Carru, Giovanna Angela; Bellucci, Stefano; Mazzanti, GabrielaToxicology Letters (2009), 184 (3), 192-197CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)The mutagenic effect of multi-walled carbon nanotubes (MWCNTs) characterized by small surface/vol. ratio, high diam. and less than 0.1% of metal contaminants was evaluated by the bacterial reverse mutation assay (Ames test) on Salmonella typhimurium TA 98 and TA 100 strains, and on Escherichia coli WP2uvrA strain, in presence and in absence of the metabolic activation system S9. A preliminary cytotoxicity assay was carried out to ensure that cytotoxicity did not interfere with response. MWCNTs resulted devoid of mutagenic effect in the bacterial cellular systems tested in that they did not significantly increase the no. of revertant colonies. The mutagenic activity did not even appear in presence of the metabolic activator, so we can exclude that MWCNTs metabolites, produced via cytochrome-based P 450 metabolic oxidn. system, may act as mutagens. Carbon nanomaterials seem to exhibit different biol. activities and different toxicities in relation to their physico-chem. characteristics, size, shape, crystallinity and presence of metal traces, so it is difficult to establish their health risk. Due to the limited background of genotoxicity studies and the increased occupational and public exposure to nanomaterials, present results appear useful to extend the knowledge on the safety of carbon nanotubes in view of their possible applications.
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439Singh, N.; Manshian, B.; Jenkins, G. J.; Griffiths, S. M.; Williams, P. M.; Maffeis, T. G.; Wright, C. J.; Doak, S. H. Biomaterials 2009, 30, 3891Google ScholarThere is no corresponding record for this reference.
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440Naya, M.; Kobayashi, N.; Mizuno, K.; Matsumoto, K.; Ema, M.; Nakanishi, J. Regul. Toxicol. Pharmacol. 2011, 61, 192Google Scholar440https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1ymt7jJ&md5=1712c0e1beb1a02a0cbf9dfd1b1caf72Evaluation of the genotoxic potential of single-wall carbon nanotubes by using a battery of in vitro and in vivo genotoxicity assaysNaya, Masato; Kobayashi, Norihiro; Mizuno, Kohei; Matsumoto, Kyomu; Ema, Makoto; Nakanishi, JunkoRegulatory Toxicology and Pharmacology (2011), 61 (2), 192-198CODEN: RTOPDW; ISSN:0273-2300. (Elsevier B.V.)The genotoxic potential of a high purity sample of single-wall carbon nanotubes (SWCNTs) was evaluated using a battery of in vitro and in vivo genotoxicity assays. These comprised a bacterial reverse mutation test (Ames test), an in vitro chromosomal aberration test, and an in vivo mouse bone marrow micronucleus test. The SWCNTs exerted no genotoxicity in Salmonella typhimurium TA97, TA98, TA100, and TA1535, or in Escherichia coli WP2 uvrA/pKM101, whether in the absence or presence of metabolic activation and at concns. of 12.5-500 μg/plate. In the chromosomal aberration test, at 300-1000 μg/mL, the SWCNTs did not increase the no. of structural or numerical chromosomal aberrations, whether the test was conducted with or without metabolic activation. In the in vivo bone marrow micronucleus test, doses of 60 mg/kg and 200 mg/kg SWCNTs did not affect the proportions of immature and total erythrocytes, nor did it increase the no. of micronuclei in the immature erythrocytes of mice. The results of these studies show that the high purity and well-dispersed sample of SWCNTs are not genotoxic under the conditions of the in vitro bacterial reverse mutation assay, chromosomal aberration assay, or in vivo bone marrow micronucleus test, and thus appear not to pose a genotoxic risk to human health in vivo.
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441Thurnherr, T.; Brandenberger, C.; Fischer, K.; Diener, L.; Manser, P.; Maeder-Althaus, X.; Kaiser, J. P.; Krug, H. F.; Rothen-Rutishauser, B.; Wick, P. Toxicol. Lett. 2011, 200, 176Google Scholar441https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnsVWqug%253D%253D&md5=01fcc87fca2689dba1dc2fea67e34641A comparison of acute and long-term effects of industrial multiwalled carbon nanotubes on human lung and immune cells in vitroThurnherr, Tina; Brandenberger, Christina; Fischer, Kathrin; Diener, Liliane; Manser, Pius; Maeder-Althaus, Xenia; Kaiser, Jean-Pierre; Krug, Harald F.; Rothen-Rutishauser, Barbara; Wick, PeterToxicology Letters (2011), 200 (3), 176-186CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)The close resemblance of carbon nanotubes to asbestos fibers regarding their high aspect ratio, biopersistence and reactivity increases public concerns on the widespread use of these materials. The purpose of this study was not only to address the acute adverse effects of industrially produced multiwalled carbon nanotubes (MWCNTs) on human lung and immune cells in vitro but also to further understand if their accumulation and biopersistence leads to long-term consequences or induces adaptive changes in these cells. In contrast to asbestos fibers, pristine MWCNTs did not induce overt cell death in A549 lung epithelial cells and Jurkat T lymphocytes after acute exposure to high doses of this material (up to 30 μg/mL). Nevertheless, very high levels of reactive oxygen species (ROS) and decreased metabolic activity were obsd. which might affect long-term viability of these cells. However, the continuous presence of low amts. of MWCNTs (0.5 μg/mL) for 6 mo did not have major adverse long-term effects although large amts. of nanotubes accumulated at least in A549 cells. Moreover, MWCNTs did not appear to induce adaptive mechanisms against particle stress in long-term treated A549 cells. Our study demonstrates that despite the high potential for ROS formation, pristine MWCNTs can accumulate and persist within cells without having major long-term consequences or inducing adaptive mechanisms.
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442Kisin, E. R.; Murray, A. R.; Keane, M. J.; Shi, X. C.; Schwegler-Berry, D.; Gorelik, O.; Arepalli, S.; Castranova, V.; Wallace, W. E.; Kagan, V. E.; Shvedova, A. A. J. Toxicol. Environ. Health, Part A 2007, 70, 2071Google ScholarThere is no corresponding record for this reference.
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443Jacobsen, N. R.; Pojana, G.; White, P.; Møller, P.; Cohn, C. A.; Korsholm, K. S.; Vogel, U.; Marcomini, A.; Loft, S.; Wallin, H. Environ. Mol. Mutagen. 2008, 49, 476Google ScholarThere is no corresponding record for this reference.
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444Wirnitzer, U.; Herbold, B.; Voetz, M.; Ragot, J. Toxicol. Lett. 2009, 186, 160Google Scholar444https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtF2jsbs%253D&md5=99240b13f4bf2a24b4fefbe64659c4cfStudies on the in vitro genotoxicity of baytubes, agglomerates of engineered multi-walled carbon-nanotubes (MWCNT)Wirnitzer, U.; Herbold, B.; Voetz, M.; Ragot, J.Toxicology Letters (2009), 186 (3), 160-165CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)The increasing prodn. and expanding application of nanoparticles in multiple aspects of life necessitate reliable safety assessment. In this context the authors here report on the evaluation of the potential genotoxicity of baytubes, i.e., agglomerates of multi-walled carbon-nanotubes (MWCNT). Testing for chromosome aberrations was done in V79 cells and for gene mutations in the Salmonella microsome test. Baytubes were formulated in deionized water at 10 mg/mL and treated with ultrasound for 30 min at 25°. Particle size distribution was detd. under the incubation conditions in the in vitro studies. In the chromosome aberration test V79 cells (OECD TG 473) were exposed in the absence or presence of S9 mix for 4 h to concns. of 2.5, 5 and 10 μg/mL of baytubes (visible from concn. of 5 μg/mL and higher). Harvest was 18 h after the beginning of the treatment. In addn., cells treated with 10 μg/mL were harvested 30 h after the beginning of the treatment. An addnl. expt. was performed using continuous treatment at 2.5, 5 and 10 μg/mL for 18 h (no S9 mix) with subsequent harvest. Under these conditions and in the concn. range tested there were no cytotoxic and no clastogenic effects. In the Salmonella microsome (Ames) test (OECD TG 471) concns. up to 5000 μg/plate were tested in Salmonella typhimurium (strains TA 1535, TA 100, TA 1537, TA 98 and TA 102) in the absence or presence of S9 mix. Under these conditions and in the concn. range tested there were no bacteriotoxic and no mutagenic effects.
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445Asakura, M.; Sasaki, T.; Sugiyama, T.; Takaya, M.; Koda, S.; Nagano, K.; Arito, H.; Fukushima, S. J. Occup. Health 2010, 52, 155Google Scholar445https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovFagtL0%253D&md5=35ddeba17fa9cb4c8141f567148ded12Genotoxicity and cytotoxicity of multi-wall carbon nanotubes in cultured Chinese hamster lung cells in comparison with chrysotile A fibersAsakura, Masumi; Sasaki, Toshiaki; Sugiyama, Toshie; Takaya, Mitsutoshi; Koda, Shigeki; Nagano, Kasuke; Arito, Heihachiro; Fukushima, ShojiJournal of Occupational Health (2010), 52 (3), 155-166CODEN: JOCHFV; ISSN:1341-9145. (Japan Society for Occupational Health)Objectives: The potential applications and industrial prodn. of multi-wall carbon nanotubes (MWCNT) have raised serious concerns about their safety for human health and the environment. The present study was designed to examine the in vitro cytotoxicity and genotoxicity of MWCNT and UICC chrysotile A (chrysotile). Methods: Cytotoxicity using both colony formation and lactate dehydrogenase (LDH) assays and genotoxicity including chromosome aberration, micronucleus induction and hgprt mutagenicity were examd. by exposing cultured Chinese hamster lung (CHL/IU) cells to MWCNT or chrysotile at different concns. Results: The in vitro cytotoxicity of MWCNT depended on the solvent used for suspension of MWCNT and ultrasonication duration of the MWCNT suspension. A combination of DMSO/culture medium and 3-min ultrasonication resulted in a well-dispersed medium with dispersion and isolation of agglomerated MWCNT by ultrasonication which manifested the highest cytotoxicity. The cytotoxicity was more potent for chrysotile than MWCNT. The genotoxicity of MWCNT was characterized by the formation of polyploidy without structural chromosome aberration, and an increased no. of bi- and multi-nucleated cells without micronucleus induction, as well as neg. hgprt mutagenicity. Chrysotile exhibited essentially the same genotoxicity as MWCNT, except for marginal but significant induction of micronuclei. MWCNT and chrysotile were incompletely internalized in the cells and localized in the cytoplasm. Conclusions: MWCNT and chrysotile were cytotoxic and genotoxic in Chinese hamster lung cells, but might interact indirectly with DNA. The results suggest that both test substances interfere phys. with biol. processes during cytokinesis.
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446Lindberg, H. K.; Falck, G. C.; Suhonen, S.; Vippola, M.; Vanhala, E.; Catalan, J.; Savolainen, K.; Norppa, H. Toxicol. Lett. 2009, 186, 166Google Scholar446https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtF2jsbg%253D&md5=c175ba5abb584c1b20becb1509d43c41Genotoxicity of nanomaterials: DNA damage and micronuclei induced by carbon nanotubes and graphite nanofibres in human bronchial epithelial cells in vitroLindberg, Hanna K.; Falck, Ghita C.-M.; Suhonen, Satu; Vippola, Minnamari; Vanhala, Esa; Catalan, Julia; Savolainen, Kai; Norppa, HannuToxicology Letters (2009), 186 (3), 166-173CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)Despite the increasing industrial use of different nanomaterials, data on their genotoxicity are scant. In the present study, we examd. the potential genotoxic effects of carbon nanotubes (CNTs; >50% single-walled, ∼40% other CNTs; 1.1 nm × 0.5-100 μm; Sigma-Aldrich) and graphite nanofibres (GNFs; 95%; outer diam. 80-200 nm, inner diam. 30-50 nm, length 5-20 μm; Sigma-Aldrich) in vitro. Genotoxicity was assessed by the single cell gel electrophoresis (comet) assay and the micronucleus assay (cytokinesis-block method) in human bronchial epithelial BEAS 2B cells cultured for 24 h, 48 h, or 72 h with various doses (1-100 μg/cm2, corresponding to 3.8-380 μg/mL) of the carbon nanomaterials. In the comet assay, CNTs induced a dose-dependent increase in DNA damage at all treatment times, with a statistically significant effect starting at the lowest dose tested. GNFs increased DNA damage at all doses in the 24-h treatment, at two doses (40 and 100 μg/cm2) in the 48-h treatment (dose-dependent effect) and at four doses (lowest 10 μg/cm2) in the 72-h treatment. In the micronucleus assay, no increase in micronucleated cells was obsd. with either of the nanomaterials after the 24-h treatment or with CNTs after the 72-h treatment. The 48-h treatment caused a significant increase in micronucleated cells at three doses (lowest 10 μg/cm2) of CNTs and at two doses (5 and 10 μg/cm2) of GNFs. The 72-h treatment with GNFs increased micronucleated cells at four doses (lowest 10 μg/cm2). No dose-dependent effects were seen in the micronucleus assay. The presence of carbon nanomaterial on the microscopic slides disturbed the micronucleus anal. and made it impossible at levels higher than 20 μg/cm2 of GNFs in the 24-h and 48-h treatments. In conclusion, our results suggest that both CNTs and GNFs are genotoxic in human bronchial epithelial BEAS 2B cells in vitro. This activity may be due to the fibrous nature of these carbon nanomaterials with a possible contribution by catalyst metals present in the materials-Co and Mo in CNTs (<5 wt.%) and Fe (<3 wt.%) in GNFs.
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447Yang, H.; Liu, C.; Yang, D.; Zhang, H.; Xi, Z. J. Appl. Toxicol. 2009, 29, 69Google Scholar447https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXptV2quw%253D%253D&md5=456ad454664878fb8f2bd567340f90baComparative study of cytotoxicity, oxidative stress and genotoxicity induced by four typical nanomaterials: the role of particle size, shape and compositionYang, Hui; Liu, Chao; Yang, Danfeng; Zhang, Huashan; Xi, ZhugeJournal of Applied Toxicology (2009), 29 (1), 69-78CODEN: JJATDK; ISSN:0260-437X. (John Wiley & Sons Ltd.)Although the biol. effects of some nanomaterials have already been assessed, information on toxicity and possible mechanisms of various particle types are insufficient. Moreover, the role of particle properties in the toxic reaction remains to be fully understood. In this paper, the authors aimed to explore the interrelation between particle size, shape, chem. compn., and toxicol. effects of 4 typical nanomaterials with comparable properties: carbon black (CB), single wall carbon nanotube, silicon dioxide (SiO2) and zinc oxide (ZnO) nanoparticles. The authors investigated the cytotoxicity, genotoxicity, and oxidative effects of particles on primary mouse embryo fibroblast cells. As obsd. in the Me thiazolyl tetrazolium (MTT) and water-sol. tetrazolium (WST) assays, ZnO induced much greater cytotoxicity than non-metal nanoparticles. This was significantly in accordance with intracellular oxidative stress levels measured by glutathione depletion, malondialdehyde prodn., superoxide dismutase inhibition as well as reactive oxygen species generation. The results indicated that oxidative stress may be a key route in inducing the cytotoxicity of nanoparticles. Compared with ZnO nanoparticles, carbon nanotubes were moderately cytotoxic but induced more DNA damage detd. by the comet assay. CB and SiO2 seemed to be less effective. The comparative anal. demonstrated that particle compn. probably played a primary role in the cytotoxic effects of different nanoparticles. However, the potential genotoxicity might be mostly attributed to particle shape.
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448Cveticanin, J.; Joksic, G.; Leskovac, A.; Petrovic, S.; Sobot, A. V.; Neskovic, O. Nanotechnology 2010, 21, 015102Google ScholarThere is no corresponding record for this reference.
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449Migliore, L.; Saracino, D.; Bonelli, A.; Colognato, R.; D’Errico, M. R.; Magrini, A.; Bergamaschi, A.; Bergamaschi, E. Environ. Mol. Mutagen. 2010, 51, 294Google ScholarThere is no corresponding record for this reference.
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450Fadeel, B.; Kagan, V. E. Redox Rep. 2003, 8, 143Google Scholar450https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXntVChtrY%253D&md5=ba2ee6f6cd4f6be85133c11560b8ac51Apoptosis and macrophage clearance of neutrophils: regulation by reactive oxygen speciesFadeel, Bengt; Kagan, Valerian E.Redox Report (2003), 8 (3), 143-150CODEN: RDRPE4; ISSN:1351-0002. (Maney Publishing)A review. Inflammation is a beneficial host response to foreign challenge involving numerous sol. factors and cell types, including polymorphonuclear granulocytes or neutrophils. Programmed cell death (apoptosis) of neutrophils has been documented in vitro as well as in vivo, and is thought to be important for the resoln. of inflammation, as this process allows for engulfment and removal of senescent cells prior to their necrotic disintegration. Studies in recent years have begun to unravel the mechanism of macrophage clearance of apoptotic cells, and evidence has accrued for a crit. role of externalization and oxidn. of plasma membrane phosphatidylserine, and its subsequent recognition by macrophage receptors, in this process. Activated neutrophils generate vast amts. of reactive oxygen species for the purpose of killing ingested microorganisms, and these reactive metabolites may also modulate the life-span, as well as the clearance, of the neutrophil itself. The authors address the latter topic, and summarize current knowledge on the mol. mechanisms of neutrophil apoptosis and macrophage clearance of these cells at the site of inflammation.
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451Pacurari, M.; Yin, X. J.; Zhao, J.; Ding, M.; Leonard, S. S.; Schwegler-Berry, D.; Ducatman, B. S.; Sbarra, D.; Hoover, M. D.; Castranova, V.; Vallyathan, V. Environ. Health Perspect. 2008, 116, 1211Google ScholarThere is no corresponding record for this reference.
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452Vittorio, O.; Raffa, V.; Cuschieri, A. Nanomedicine 2009, 5, 424Google ScholarThere is no corresponding record for this reference.
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453Haniu, H.; Matsuda, Y.; Takeuchi, K.; Kim, Y. A.; Hayashi, T.; Endo, M. Toxicol. Appl. Pharmacol. 2010, 242, 256Google Scholar453https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjt12htw%253D%253D&md5=f374d7ecafb04bf36ac6a84ccacc3075Proteomics-based safety evaluation of multi-walled carbon nanotubesHaniu, Hisao; Matsuda, Yoshikazu; Takeuchi, Kenji; Kim, Yoong-Ahm; Hayashi, Takuya; Endo, MorinobuToxicology and Applied Pharmacology (2010), 242 (3), 256-262CODEN: TXAPA9; ISSN:0041-008X. (Elsevier B.V.)This study evaluated the biol. responses to multi-walled carbon nanotubes (MWCNTs). Human monoblastic leukemia cells (U937) were exposed to As-grown MWCNTs and MWCNTs that were thermally treated at 1800° (HTT1800) and 2800° (HTT2800). Cell proliferation was highly inhibited by As-grown but not HTT2800. However, both As-grown and HTT1800, which include some impurities, were cytotoxic. Proteomics anal. of MWCNT-exposed cells revealed 37 protein spots on 2-dimensional electrophoresis gels that significantly changed after exposure to HTT1800 with a little iron and 20 spots that changed after exposure to HTT2800. Peptide mass fingerprinting identified 45 proteins that included heat shock protein β-1, neutral α-glucosidase AB, and DNA mismatch repair protein Msh2. These altered proteins play roles in metab., biosynthesis, response to stress, and cell differentiation. Although HTT2800 did not inhibit cell proliferation or cause cytotoxicity in vitro, some proteins related to the response to stress were changed. Moreover, DJ-1 protein, which is a biomarker of Parkinson's disease and is related to cancer, was identified after exposure to both MWCNTs. These results show that the cytotoxicity of MWCNTs depends on their impurities, such as iron, while MWCNTs themselves cause some biol. responses directly and/or indirectly in vitro. The authors' proteomics-based approach for detecting biol. responses to nanomaterials is a promising new method for detailed safety evaluations.
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454Vinzents, P. S.; Møller, P.; Sørensen, M.; Knudsen, L. E.; Hertel, O.; Jensen, F. P.; Schibye, B.; Loft, S. Environ. Health Perspect. 2005, 113, 1485Google ScholarThere is no corresponding record for this reference.
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455Patlolla, A. K.; Hussain, S. M.; Schlager, J. J.; Patlolla, S.; Tchounwou, P. B. Environ. Toxicol. 2010, 25, 608Google ScholarThere is no corresponding record for this reference.
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456Sargent, L. M.; Reynolds, S. H.; Castranova, V. Nanotoxicology 2010, 4, 396Google ScholarThere is no corresponding record for this reference.
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457Karlsson, H. L.; Cronholm, P.; Gustafsson, J.; Möller, L. Chem. Res. Toxicol. 2008, 21, 1726Google Scholar457https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXpvFOht7Y%253D&md5=7736cadbc686269be5ca42b28ecfe297Copper Oxide Nanoparticles Are Highly Toxic: A Comparison between Metal Oxide Nanoparticles and Carbon NanotubesKarlsson, Hanna L.; Cronholm, Pontus; Gustafsson, Johanna; Moeller, LennartChemical Research in Toxicology (2008), 21 (9), 1726-1732CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Since the manuf. and use of nanoparticles are increasing, humans are more likely to be exposed occupationally or via consumer products and the environment. However, so far toxicity data for most manufd. nanoparticles are limited. The aim of this study was to investigate and compare different nanoparticles and nanotubes regarding cytotoxicity and ability to cause DNA damage and oxidative stress. The study was focused on different metal oxide particles (CuO, TiO2, ZnO, CuZnFe2O4, Fe3O4, Fe2O3), and the toxicity was compared to that of carbon nanoparticles and multiwalled carbon nanotubes (MWCNT). The human lung epithelial cell line A549 was exposed to the particles, and cytotoxicity was analyzed using trypan blue staining. DNA damage and oxidative lesions were detd. using the comet assay, and intracellular prodn. of reactive oxygen species (ROS) was measured using the oxidn.-sensitive fluoroprobe 2',7'-dichlorofluorescin diacetate (DCFH-DA). The results showed that there was a high variation among different nanoparticles concerning their ability to cause toxic effects. CuO nanoparticles were most potent regarding cytotoxicity and DNA damage. The toxicity was likely not explained by Cu ions released to the cell medium. These particles also caused oxidative lesions and were the only particles that induced an almost significant increase (p = 0.058) in intracellular ROS. ZnO showed effects on cell viability as well as DNA damage, whereas the TiO2 particles (a mix of rutile and anatase) only caused DNA damage. For iron oxide particles (Fe3O4, Fe2O3), no or low toxicity was obsd., but CuZnFe2O4 particles were rather potent in inducing DNA lesions. Finally, the carbon nanotubes showed cytotoxic effects and caused DNA damage in the lowest dose tested. The effects were not explained by sol. metal impurities. In conclusion, this study highlights the in vitro toxicity of CuO nanoparticles.
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458Deng, Z. J.; Liang, M.; Monteiro, M.; Toth, I.; Minchin, R. F. Nat. Nanotechnol. 2011, 6, 39Google Scholar458https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1Wju73P&md5=de9f322b14e197e47e6b1fe034525498Nanoparticle-induced unfolding of fibrinogen promotes Mac-1 receptor activation and inflammationDeng, Zhou J.; Liang, Mingtao; Monteiro, Michael; Toth, Istvan; Minchin, Rodney F.Nature Nanotechnology (2011), 6 (1), 39-44CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)The chem. compn., size, shape and surface characteristics of nanoparticles affect the way proteins bind to these particles, and this in turn influences the way in which nanoparticles interact with cells and tissues. Nanomaterials bound with proteins can result in physiol. and pathol. changes, including macrophage uptake, blood coagulation, protein aggregation and complement activation, but the mechanisms that lead to these changes remain poorly understood. Here, we show that neg. charged poly(acrylic acid)-conjugated gold nanoparticles bind to and induce unfolding of fibrinogen, which promotes interaction with the integrin receptor, Mac-1. Activation of this receptor increases the NF-κB signalling pathway, resulting in the release of inflammatory cytokines. However, not all nanoparticles that bind to fibrinogen demonstrated this effect. Our results show that the binding of certain nanoparticles to fibrinogen in plasma offers an alternative mechanism to the more commonly described role of oxidative stress in the inflammatory response to nanomaterials.
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459Sarkar, S.; Sharma, C.; Yog, R.; Periakaruppan, A.; Jejelowo, O.; Thomas, R.; Barrera, E. V.; Rice-Ficht, A. C.; Wilson, B. L.; Ramesh, G. T. J. Nanosci. Nanotechnol. 2007, 7, 584Google ScholarThere is no corresponding record for this reference.
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460He, X.; Young, S. H.; Schwegler-Berry, D.; Chisholm, W. P.; Fernback, J. E.; Ma, Q. Chem. Res. Toxicol. 2011, 24, 2237Google ScholarThere is no corresponding record for this reference.
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461Witzmann, F. A.; Monteiro-Riviere, N. A. Nanomedicine 2006, 2, 158Google ScholarThere is no corresponding record for this reference.
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462Yuan, J.; Gao, H.; Ching, C. B. Toxicol. Lett. 2011, 207, 213Google Scholar462https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtl2htrrL&md5=bb50a718aa915a403025a530e623f7acComparative protein profile of human hepatoma HepG2 cells treated with graphene and single-walled carbon nanotubes: An iTRAQ-coupled 2D LC-MS/MS proteome analysisYuan, Jifeng; Gao, Hongcai; Ching, Chi BunToxicology Letters (2011), 207 (3), 213-221CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)Graphitic nanomaterials are promising candidates for applications in electronics, energy, materials and biomedical areas. Nevertheless, few detailed studies related to the mechanistic understanding of these nanomaterials with the living systems have been performed to date. In the present study, the authors' group applied the iTRAQ-coupled 2D LC-MS/MS approach to analyze the protein profile change of human hepatoma HepG2 cells treated with graphene and single-walled carbon nanotubes (SWCNTs), with the purpose of characterizing the interactions between living system and these nanomaterials at mol. level. Overall 37 differentially expressed proteins involved in metabolic pathway, redox regulation, cytoskeleton formation and cell growth were identified. Based on the protein profile, the authors found SWCNTs severely interfered the intracellular metabolic routes, protein synthesis and cytoskeletal systems. Moreover, the authors' data suggested that SWCNTs might induce oxidative stress, thereby activating p53-mediated DNA damage checkpoint signals and leading to apoptosis. However, only moderate variation of protein levels for the cells treated with graphene was obsd., which indicated graphene was less toxic and might be promising candidate for biomedical applications. The authors envision that this systematic characterization of cellular response at protein expression level will be of great importance to evaluate biocompatibility of nanomaterials.
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463Haniu, H.; Matsuda, Y.; Usui, Y.; Aoki, K.; Shimizu, M.; Ogihara, N.; Hara, K.; Okamoto, M.; Takanashi, S.; Ishigaki, N.; Nakamura, K.; Kato, H.; Saito, N. J. Proteomics 2011, 74, 2703Google Scholar463https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVOjt77E&md5=328d0cb0fba04777b76adc8c59d2aa29Toxicoproteomic evaluation of carbon nanomaterials in vitroHaniu, Hisao; Matsuda, Yoshikazu; Usui, Yuki; Aoki, Kaoru; Shimizu, Masayuki; Ogihara, Nobuhide; Hara, Kazuo; Okamoto, Masanori; Takanashi, Seiji; Ishigaki, Norio; Nakamura, Koichi; Kato, Hiroyuki; Saito, NaotoJournal of Proteomics (2011), 74 (12), 2703-2712CODEN: JPORFQ; ISSN:1874-3919. (Elsevier B.V.)A review. Carbon nanotubes (CNTs) have already been successfully implemented in various fields, and they are anticipated to have innovative applications in medical science. However, CNTs have asbestos-like properties, such as their nanoscale size and high aspect ratio (> 100). Moreover, CNTs may persist in the body for a long time. These properties are thought to cause malignant mesothelioma and lung cancer. However, based on conventional toxicity assessment systems, the carcinogenicity of asbestos and CNTs is unclear. The reason for late countermeasures against asbestos is that reliable, long-term safety assessments have not yet been developed by toxicologists. Therefore, a new type of long-term safety assessment, different from the existing methods, is needed for carbon nanomaterials. Recently, we applied a proteomic approach to the safety assessment of carbon nanomaterials. In this review, we discuss the basic concept of our approach, the results, the problems, and the possibility of a long-term safety assessment for carbon nanomaterials using the toxicoproteomic approach.
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464Snyder-Talkington, B. N.; Pacurari, M.; Dong, C.; Leonard, S. S.; Schwegler-Berry, D.; Castranova, V.; Qian, Y.; Guo, N. L. Toxicol. Sci. 2013, 133, 79Google Scholar464https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmt1Ohtr0%253D&md5=ad4c2a8954f782ca23e0077edd6188aaSystematic Analysis of Multiwalled Carbon Nanotube-Induced Cellular Signaling and Gene Expression in Human Small Airway Epithelial CellsSnyder-Talkington, Brandi N.; Pacurari, Maricica; Dong, Chunlin; Leonard, Stephen S.; Schwegler-Berry, Diane; Castranova, Vincent; Qian, Yong; Guo, Nancy L.Toxicological Sciences (2013), 133 (1), 79-89CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)Multiwalled carbon nanotubes (MWCNT) are one of the most commonly produced nanomaterials, and pulmonary exposure during prodn., use, and disposal is a concern for the developing nanotechnol. field. The airway epithelium is the first line of defense against inhaled particles. In a mouse model, MWCNT were reported to reach the alveolar space of the lung after in vivo exposure, penetrate the epithelial lining, and result in inflammation and progressive fibrosis. This study sought to det. the cellular and gene expression changes in small airway epithelial cells (SAEC) after in vitro exposure to MWCNT in an effort to elucidate potential toxicity mechanisms and signaling pathways. A direct interaction between SAEC and MWCNT was confirmed by both internalization of MWCNT and interaction at the cell periphery. Following exposure, SAEC showed time-dependent increases in reactive oxygen species prodn., total protein phosphotyrosine and phosphothreonine levels, and migratory behavior. Anal. of gene and protein expression suggested altered regulation of multiple biomarkers of lung damage, carcinogenesis, and tumor progression, as well as genes involved in related signaling pathways. These results demonstrate that MWCNT exposure resulted in the activation of SAEC. Gene expression data derived from MWCNT exposure provide information that may be used to elucidate the underlying mode of action of MWCNT in the small airway and suggest potential prognostic gene signatures for risk assessment.
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465Lacerda, L.; Herrero, M. A.; Venner, K.; Bianco, A.; Prato, M.; Kostarelos, K. Small 2008, 4, 1130Google ScholarThere is no corresponding record for this reference.
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466Helfenstein, M.; Miragoli, M.; Rohr, S.; Muller, L.; Wick, P.; Mohr, M.; Gehr, P.; Rothen-Rutishauser, B. Toxicology 2008, 253, 70Google ScholarThere is no corresponding record for this reference.
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467ISO 10993. Biological Evaluation of Medical Devices. 2000–2012.Google ScholarThere is no corresponding record for this reference.
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468Shi, H.; Magaye, R.; Castranova, V.; Zhao, J. Part. Fibre Toxicol. 2013, 10, 15Google Scholar468https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXns1Ors74%253D&md5=ba824ec86ab5bb3bd6f203acf969b3f3Titanium dioxide nanoparticles: a review of current toxicological dataShi, Hongbo; Magaye, Ruth; Castranova, Vincent; Zhao, JinshunParticle and Fibre Toxicology (2013), 10 (), 15CODEN: PFTABQ; ISSN:1743-8977. (BioMed Central Ltd.)A review. Titanium dioxide (TiO2) nanoparticles (NPs) are manufd. worldwide in large quantities for use in a wide range of applications. TiO2 NPs possess different physicochem. properties compared to their fine particle (FP) analogs, which might alter their bioactivity. Most of the literature cited here has focused on the respiratory system, showing the importance of inhalation as the primary route for TiO2 NP exposure in the workplace. TiO2 NPs may translocate to systemic organs from the lung and gastrointestinal tract (GIT) although the rate of translocation appears low. There have also been studies focusing on other potential routes of human exposure. Oral exposure mainly occurs through food products contg. TiO2 NP-additives. Most dermal exposure studies, whether in vivo or in vitro, report that TiO2 NPs do not penetrate the stratum corneum (SC). In the field of nanomedicine, I.V. injection can deliver TiO2 nanoparticulate carriers directly into the human body. Upon I.V. exposure, TiO2 NPs can induce pathol. lesions of the liver, spleen, kidneys, and brain. We have also shown here that most of these effects may be due to the use of very high doses of TiO2 NPs. There is also an enormous lack of epidemiol. data regarding TiO2 NPs in spite of its increased prodn. and use. However, long-term inhalation studies in rats have reported lung tumors. This review summarizes the current knowledge on the toxicol. of TiO2 NPs and points out areas where further information is needed.
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469Kashuk, K. B.; Haber, E. Clin. Podiatry 1984, 1, 131Google Scholar469https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2M3lsFGktw%253D%253D&md5=7115f04963cfe8e03ff4744772efcf38Tendon and ligament prosthesesKashuk K B; Haber EClinics in podiatry (1984), 1 (1), 131-43 ISSN:0742-0668.The topic of artificial tendons and ligaments for the foot and ankle has been investigated. Close attention has been given to three implants, the Silastic-rod implant, the carbon-fiber implant, and Marlex mesh. A brief historical background was given to the development of the lateral ankle reconstructive procedures and to the development of the individual artificial prostheses. The biologic reactions produced by the implants have been presented. Carbon-fiber implants and Marlex mesh induce a fibrous growth that produces a neotendon or neoligament, depending on their use. Silastic-rod implantation establishes a hollow tube with qualities very similar to the normal tendon sheath. Carbon fiber and Marlex mesh are directly implanted and used as a temporary tendon or ligament. During this time, they act as a scaffold on which the new tendon or ligament is formed. Silastic-rod implants are incorporated into a two-stage tendon-graft procedure. The Silastic rod is used during stage one to develop a new tendon sheath. Placement of an autologous tendon within the newly formed sheath occurs in stage two. Details of the actual procedure have been presented. Any tendon used in the transfer should be of similar strength with similar expansive qualities. These implants have many potential uses in podiatry. They are particularly useful in trauma cases and patients that present with ankle instability. Research pertaining to the development of an ideal suture and anastomosis technique is still needed.
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470Parsons, J. R.; Weiss, A. B.; Schenk, R. S.; Alexander, H.; Pavlisko, F. Foot Ankle 1989, 9, 179Google Scholar470https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1M3nslSrsQ%253D%253D&md5=f6d1479ec2711804b36c4e4b91530d02Long-term follow-up of achilles tendon repair with an absorbable polymer carbon fiber compositeParsons J R; Weiss A B; Schenk R S; Alexander H; Pavlisko FFoot & ankle (1989), 9 (4), 179-84 ISSN:0198-0211.In this cooperative multicenter study for surgical repair of Achilles tendon rupture using a composite implant, 48 patients underwent 52 procedures. This implant is composed of filamentous uniaxially aligned carbon fibers coated with an absorbable polymer. This highly biocompatible implant acts as a scaffold for regrowth of collagenous tissue. The early strength of this repair is provided by the composite implant and by the rapid ingrowth and attachment of new tissue, which allows for an earlier and more vigorous rehabilitation program. Patients with a minimum follow-up of 1 year form the basis of this article. The overall average follow-up is 2.1 years. Three cohort groups were observed on a temporal basis and quantitatively evaluated at 1 year (N = 29), 18 months (N = 22), and 2 years (N = 20), respectively. These three groups demonstrated continuous improvement during the first postoperative year. A high level of function was maintained throughout the second year. Repair of chronic injuries (N = 15) was compared with repair of acute injuries (N = 12) at 1 year following surgery. Both groups greatly improved. However, the acute group had more serious preoperative deficits but improved to a slightly better overall level. Of the patients having at least 1 year follow-up, 86% had a good or excellent result. There was no increased morbidity associated with the use of the carbon implant.
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471Moreira-Gonzalez, A.; Jackson, I. T.; Miyawaki, T.; DiNick, V.; Yavuzer, R. Plast. Reconstr. Surg. 2003, 111, 1808Google Scholar471https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s7ptlSjtA%253D%253D&md5=fef1898a74767bf3b9b4525ec9e6481eAugmentation of the craniomaxillofacial region using porous hydroxyapatite granulesMoreira-Gonzalez Andrea; Jackson Ian T; Miyawaki Takeshi; DiNick Vincent; Yavuzer RehaPlastic and reconstructive surgery (2003), 111 (6), 1808-17 ISSN:0032-1052.Augmentation of the craniomaxillofacial region is required for many aesthetic and reconstructive procedures. A variety of different materials and techniques have been used. Coralline hydroxyapatite has proved to have biocompatible properties as a bone graft substitute. This study further analyzes the use of porous coral-derived hydroxyapatite granules in craniomaxillofacial augmentation for cosmetic and reconstructive purposes and evaluates the long-term clinical result. This retrospective study reviewed the use of porous coral-derived hydroxyapatite granules over a 20-year period, between 1981 and 2001, in 180 patients, in whom 393 procedures were performed. The surgical technique is described and discussed. Statistical significance was evaluated by descriptive statistics and the correlation bivariate Spearman's test (p > 0.05). For 61.6 percent of the procedures, the surgical indication was reconstructive and in 38.4 percent, cosmetic. The maxilla was the most common site of surgery (44.3 percent), followed by the mandible (21.6 percent) and zygoma (15.4 percent). The complication rate was 5.6 percent (n = 22 of 393), with contour irregularities being responsible for 59 percent (n = 13 of 22). Both infection and granule extrusion were responsible for 1.3 percent of the complications. Good results were achieved in 96.4 percent of the procedures. Porous coral-derived hydroxyapatite granules have shown considerable efficacy and versatility in craniofacial contour refinement and augmentation. They are stable, biocompatible, and safe. A sterile technique is advised, with care taken not to tear the periosteum in the pocket design and with subperiosteal placement of the granules, compaction of the granules at the site, overcorrection of 15 percent of the required total volume, watertight closure, and postoperative taping to prevent mobilization. The correct surgical indications and adherence to the principles stated above will result in a very satisfactory long-term outcome.
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472Tamimi, F.; Torres, J.; Bassett, D.; Barralet, J.; Cabarcos, E. L. Biomaterials 2010, 31, 2762Google ScholarThere is no corresponding record for this reference.
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473Goff, T.; Kanakaris, N. K.; Giannoudis, P. V. Injury 2013, 44, S86Google ScholarThere is no corresponding record for this reference.
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474Ciftcioglu, N.; Aho, K. M.; McKay, D. S.; Kajander, E. O. Lancet 2007, 369, 2078Google ScholarThere is no corresponding record for this reference.
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475Jacobsen, E.; Tønning, K.; Pedersen, E.; Serup, J.; Nielsen, E. Chemical Substances in Tattoo Ink. Survey of chemical substances in consumer products no. 116; Miljøstyrelsen: København, 2012.Google ScholarThere is no corresponding record for this reference.
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476Lehman, J. H.; Terrones, M.; Mansfield, E.; Hurst, K.; Muenier, V. Carbon 2011, 49, 2581Google ScholarThere is no corresponding record for this reference.
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477U.S. Department of Health and Human Services Food and Drug Administration Office of the Commissioner. Considering whether an FDA-regulated product involves the application of nanotechnology: guidance for industry. Regulatory Information, 2011.Google ScholarThere is no corresponding record for this reference.
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478ISO/TS 27687: 2008, Nanotechnologies - Terminology and definitions for nano-objects -nanoparticle, nanofibre and nanoplatè, 2008.Google ScholarThere is no corresponding record for this reference.
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479Chen, Z.; Mao, R.; Liu, Y. Curr. Drug Metab. 2012, 13, 1035Google Scholar479https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVWgtbjM&md5=4aca96cbf3b0db139368a7f9a98e75e1Fullerenes for cancer diagnosis and therapy: preparation, biological and clinical perspectivesChen, Zhiyun; Mao, Ruoqing; Liu, YingCurrent Drug Metabolism (2012), 13 (8), 1035-1045CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)A review. Cancer is a major public health problem in the world. There is a great need to apply novel technologies and drugs to revolutionize multiple aspects of cancer diagnosis and therapy. Advances in nanotechnol. and nanomaterials have the potential to achieve the objective of early diagnosis and early therapy of cancer in the future. During the past few years, fullerene and its derivs. have been considered as some of the most promising nanomaterials because of their unique properties that enable a variety of medicinal applications. They can deliver drugs or small therapeutic mols. to the cancer cells. In this review, we will discuss how fullerene derivs. have been introduced into the field of cancer diagnosis and therapy. It will be highlighted that fullerene derivs. are used as anti-tumor drugs. Furthermore, prepn., characterization, pharmacokinetics and bio-distribution of fullerene and its derivs. reported in recent years will be summarized.
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480Mao, H. Y.; Laurent, S.; Chen, W.; Akhavan, O.; Imani, M.; Ashkarran, A. A.; Mahmoudi, M. Chem. Rev. 2013, 113, 3407Google Scholar480https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtlWgsr4%253D&md5=60b2210538d933d20f63c16e30e365e7Graphene: Promises, Facts, Opportunities, and Challenges in NanomedicineMao, Hong Ying; Laurent, Sophie; Chen, Wei; Akhavan, Omid; Imani, Mohammad; Ashkarran, Ali Akbar; Mahmoudi, MortezaChemical Reviews (Washington, DC, United States) (2013), 113 (5), 3407-3424CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review about the synthesis, toxicity, and biomedical applications of graphene and graphene oxide.
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481Misra, R. D.; Chaudhari, P. M. J. Biomed. Mater. Res., Part A 2013, 101, 528Google Scholar481https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVCkt73M&md5=cac1839e1d71f75d1fae517394b61098Cellular interactions and stimulated biological functions mediated by nanostructured carbon for tissue reconstruction and tracheal tubes and suturesMisra, R. D. K.; Chaudhari, P. M.Journal of Biomedical Materials Research, Part A (2013), 101A (2), 528-536CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Nylon 6,6 is used for biol. applications including gastrointestinal segments, tracheal tubes and sutures, vascular graft, and for hard tissue reconstruction. While it is a relatively inexpensive polymer, it is not widely acceptable as a preferred biomaterial because of bioactivity. To this end, we have discovered the exciting evidence that introduction of a novel nanostructured carbon, graphene, in the void space between the nylon chains and processing at elevated pressure favorably stimulates cellular functions and provides high degree of cytocompatibility. The cell-substrate interactions on stand alone Nylon 6,6 and Nylon 6,6-graphene oxide hybrid system were investigated in terms of cell attachment, viability, proliferation, and assessment of proteins, actin, vinculin, and fibronectin. The enhanced biol. functions in the nanostructured hybrid system are attributed to relatively superior hydrophilicity of the surface and to the presence of graphene. Furthermore, it is proposed that the neg. charged graphene interacts with the polar nature of cells and the culture medium, such that the interaction is promoted through polar forces. This is accomplished by investigating cell attachment, proliferation, and morphol., including cytomorphometry evaluation, and quant. assessment of prominent proteins, actin, vinculin, and fibronectin that are sensitive to cell-substrate interactions. Osteoblasts were studied to establish the practical viability of the hybrid nanostructured biomaterial. The study strengthens the foundation for utilizing nano- or quantum-size effects of nanostructured biomaterials. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.
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482Ando, K.; Saitoh, A.; Hino, O.; Takahashi, R.; Kimura, M.; Katsuki, M. Cancer Res. 1992, 52, 978Google ScholarThere is no corresponding record for this reference.
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483Long, G. G.; Morton, D.; Peters, T.; Short, B.; Skydsgaard, M. Toxicol. Pathol. 2010, 38, 43Google Scholar483https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c7isFSqsg%253D%253D&md5=439f5af98f835038f1d63e693f74874eAlternative mouse models for carcinogenicity assessment: industry use and issues with pathology interpretationLong Gerald G; Morton Daniel; Peters Terry; Short Brian; Skydsgaard MikalaToxicologic pathology (2010), 38 (1), 43-50 ISSN:.The Carcinogenicity Alternative Mouse Models (CAMM) Working Group of the Society of Toxicologic Pathology (STP) surveyed the membership to define current practices and opinions in industry regarding the use of alternative mouse models for carcinogenicity testing. The results of the survey indicated that CAMM are used most often to fulfill a regulatory requirement (e.g., to replace the two-year mouse bioassay) and are being accepted by regulatory agencies. Alternative models are also sometimes used for internal decision making or to address a mechanistic question. The CAMM most commonly used are the p53+/- and rasH2. The rasH2 appears to be the currently accepted model for general carcinogenicity testing. Problems with study interpretation included lack of historic background data, unexpected tumor finding, and tumor identification/characterization of early lesions. Problems with implementation or conduct of the study included extent of the pathology evaluation, numbers of animals, survival, and study duration. Recommendations were developed for, frequency and type of positive control testing, extent of histopathologic examination of test article-treated and positive control animals, current use and future development of diagnostic criteria; increased availability and use of historic data, and use of other genetically modified mice in carcinogenicity testing.
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484Boverhof, D. R.; Chamberlain, M. P.; Elcombe, C. R.; Gonzalez, F. J.; Heflich, R. H.; Hernandez, L. G.; Jacobs, A. C.; Jacobson-Kram, D.; Luijten, M.; Maggi, A.; Manjanatha, M. G.; Benthem, J.; Gollapudi, B. B. Toxicol. Sci. 2011, 121, 207Google Scholar484https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmsVykt7c%253D&md5=bfd834146966cb6a405e173a60ee64e6Transgenic Animal Models in Toxicology: Historical Perspectives and Future OutlookBoverhof, Darrell R.; Chamberlain, Mark P.; Elcombe, Clifford R.; Gonzalez, Frank J.; Heflich, Robert H.; Hernandez, Lya G.; Jacobs, Abigail C.; Jacobson-Kram, David; Luijten, Mirjam; Maggi, Adriana; Manjanatha, Mugimane G.; van Benthem, Jan; Gollapudi, B. BhaskarToxicological Sciences (2011), 121 (2), 207-233CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)A review. Transgenic animal models are powerful tools for developing a more detailed understanding on the roles of specific genes in biol. pathways and systems. Applications of these models have been made within the field of toxicol., most notably for the screening of mutagenic and carcinogenic potential and for the characterization of toxic mechanisms of action. It has long been a goal of research toxicologists to use the data from these models to refine hazard identification and characterization to better inform human health risk assessments. This review provides an overview on the applications of transgenic animal models in the assessment of mutagenicity and carcinogenicity, their use as reporter systems, and as tools for understanding the roles of xenobiotic-metabolizing enzymes and biol. receptors in the etiol. of chem. toxicity. Perspectives are also shared on the future outlook for these models in toxicol. and risk assessment and how transgenic technologies are likely to be an integral tool for toxicity testing in the 21st century.
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485Urano, K.; Tamaoki, N.; Nomura, T. Vet. Pathol. 2012, 49, 16Google Scholar485https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivVejsb4%253D&md5=2dd4dbedc4c952a00922cb7f9796cacbEstablishing a laboratory animal model from a transgenic animal: RasH2 mice as a model for carcinogenicity studies in regulatory scienceUrano, K.; Tamaoki, N.; Nomura, T.Veterinary Pathology (2012), 49 (1), 16-23CODEN: VTPHAK; ISSN:0300-9858. (Sage Publications)A review. Transgenic animal models have been used in small nos. in gene function studies in vivo for a period of time, but more recently, the use of a single transgenic animal model has been approved as a second species, 6-mo alternative (to the routine 2-yr, 2-animal model) used in short-term carcinogenicity studies for generating regulatory application data of new drugs. This article addresses many of the issues assocd. with the creation and use of one of these transgenic models, the rasH2 mouse, for regulatory science. The discussion includes strategies for mass producing mice with the same stable phenotype, including constructing the transgene, choosing a founder mouse, and controlling both the transgene and background genes; strategies for developing the model for regulatory science, including measurements of carcinogen susceptibility, stability of a large-scale prodn. system, and monitoring for uniform carcinogenicity responses; and finally, efficient use of the transgenic animal model on study. Approx. 20% of mouse carcinogenicity studies for new drug applications in the United States currently use transgenic models, typically the rasH2 mouse. The rasH2 mouse could contribute to animal welfare by reducing the nos. of animals used as well as reducing the cost of carcinogenicity studies. A better understanding of the advantages and disadvantages of the transgenic rasH2 mouse will result in greater and more efficient use of this animal model in the future.
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486Urano, K.; Suzuki, S.; Machida, K.; Sawa, N.; Eguchi, N.; Kikuchi, K.; Fukasawa, K.; Taguchi, F.; Usui, T. J. Toxicol. Sci. 2006, 31, 407Google Scholar486https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s%252FgslWitA%253D%253D&md5=94864429ab756a7c31157cdf52312042Use of IC tags in short-term carcinogenicity study on CB6F1 TGrasH2 miceUrano Koji; Suzuki Syuzo; Machida Kazuhiko; Sawa Nobuko; Eguchi Natsuko; Kikuchi Koji; Fukasawa Kazumasa; Taguchi Fukushi; Usui ToshimiThe Journal of toxicological sciences (2006), 31 (5), 407-18 ISSN:0388-1350.We studied the effect of IC tags, subcutaneously implanted animal identification tools, on rasH2 mice. A 26-week short-term carcinogenicity study was performed on a total of 299 mice including 75 male and female rasH2 mice each, and 74 male and 75 female non-Tg mice from the same litter as the rasH2 mice divided into a non-IC tag group, the IC-tag group, acetone group, TPA group and MNU group (all of the animals except for those in the non-IC tag group) had IC tags implanted subcutaneously in their backs. The administration methods of the positive control drugs TPA (2.5 micro g/kg, 3 times/week, percutaneously) and MNU (75 mg/kg, single intraperitoneal injection) were based on the protocol of the ILSI/HESI international collaborative study. The results showed no differences in the tumorigenic incidence and organs developing tumors between the IC tag and non-IC tag groups in both rasH2 and non-Tg mice. In the positive control MNU group, the tumorigenic incidence and organs developing tumors were the same as the background data and no promotion of carcinogenesis was observed. In all IC tag groups including the TPA group and MNU group, a fibrous capsule was formed around the IC tags subcutaneously, but no inflammatory changes or neoplastic changes were observed. From these findings, it was concluded that the IC tag has no effect on a 26-week carcinogenicity test of rasH2 mice under the conditions of the present study.
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487Urano, K.; Suzuki, S.; Machida, K.; Eguchi, N.; Sawa, N.; Kikuchi, K.; Hattori, Y.; Usui, T. J. Toxicol. Sci. 2007, 32, 367Google Scholar487https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXitV2jtw%253D%253D&md5=c6a01ce981199fae1c30e1a378dafe63Examination of percutaneous application in a 26-week carcinogenicity test in CB6F1-TG rasH2 miceUrano, Koji; Suzuki, Shuzo; Machida, Kazuhiko; Eguchi, Natsuko; Sawa, Nobuko; Kikuchi, Koji; Hattori, Yuji; Usui, ToshimiJournal of Toxicological Sciences (2007), 32 (4), 367-375CODEN: JTSCDR; ISSN:0388-1350. (Japanese Society of Toxicology)We examd. the possibility of expanding applications of rasH2 mice, which are genetically manipulated mice for short-term carcinogenicity tests, to percutaneous application. A 26-wk short-term carcinogenicity study was performed on a total of 300 mice including 75 male and female rasH2 mice each, and 75 male and female non-Tg mice each from the same litter as the rasH2 mice divided into untreated group, an ethanol group, a white Vaseline group, an acetone group, and a phorbol 12-myristate 13-acetate (TPA) group. Only shaving of dorsal skin was performed on the untreated mice. As a pos. control, TPA was administered percutaneously at a dose of 2.5 μg/kg and 3 times/wk for 26 wk based on the protocol for Tg.AC mice in the ILSI/HESI international validation study. In the ethanol, white Vaseline, and acetone groups, no tumorous changes were obsd. on the skin at the administration site. In the TPA group, nodular changes at the administration site were obsd. from seven weeks after the start of administration in rasH2 mice, and the incidence in males and females was 50.0% (7/14) and 53.3% (8/15), resp. In a pathol. examn., nodules in 21.4% (3/14) of males and 46.7% (7/15) of females were diagnosed as skin papilloma or keratoacanthoma, and the rest as squamous cell hyperplasia. In the non-Tg mice, no nodules or tumorigenic changes were obsd. at the administration site. These findings show that percutaneous application in rasH2 mice is possible in 26-wk carcinogenicity tests.
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488Palazzi, X.; Kergozien-Framery, S. Exp. Toxicol. Pathol. 2009, 61, 433Google Scholar488https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MrlsVOktQ%253D%253D&md5=31809ecaa45974be189dba8edaa33c9fUse of rasH2 transgenic mice for carcinogenesis testing of medical implantsPalazzi Xavier; Kergozien-Framery SylvieExperimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie (2009), 61 (5), 433-41 ISSN:.Several transgenic mice models are accepted by regulatory agencies to determine the carcinogenic potential and predict the human response to exposure of chemicals, as an alternative to the conventional 2-year rodent bioassay. The rasH2 transgenic mouse model has been proposed to evaluate the carcinogenic potential of medical devices, but few data are currently available regarding study design--namely appropriate positive and negative controls to be used--as well as historical pathology data. BIOMATECH-NAMSA recently conducted a 26-week carcinogenicity study following subcutaneous implantation in the transgenic rasH2 mouse model. This paper describes the study design and the main results obtained in the positive and negative control groups. The survival rate statistical (Kaplan-Meier) analysis showed that the survival rate was significantly affected by the occurrence of tumors in the positive control group when compared to the negative control group, in both genders. Thymic malignant lymphomas and squamous cell papillomas were reported to occur at a higher incidence in rasH2 mice exposed to a known chemical carcinogen, for terminally sacrificed animals as well as for unscheduled and terminally sacrificed animals considered together. Background and age-related lesions were few. Taken together, these data confirmed the reliability and usefulness of the rasH2 transgenic model in the assessment of carcinogenic properties of medical devices. A major beneficial property of this animal model consisted in the ability to demonstrate chemical carcinogenesis response without the solid-state tumorigenesis response seen in traditional 2-year rodent bioassays.
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489Madani, S. Y.; Naderi, N.; Dissanayake, O.; Tan, A.; Seifalian, A. M. Int. J. Nanomed. 2011, 6, 2963Google Scholar489https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1entL3L&md5=5167b76f2c82fbc9c43abba3eb7b003eA new era of cancer treatment: carbon nanotubes as drug delivery toolsMadani, Seyed Yazdan; Naderi, Naghmeh; Dissanayake, Oshani; Tan, Aaron; Seifalian, Alexander M.International Journal of Nanomedicine (2011), 6 (), 2963-2979CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)A review. Cancer is a generic term that encompasses a group of diseases characterized by an uncontrolled proliferation of cells. There are over 200 different types of cancer, each of which gains its nomenclature according to the type of tissue the cell originates in. Many patients who succumb to cancer do not die as a result of the primary tumor, but because of the systemic effects of metastases on other regions away from the original site. One of the aims of cancer therapy is to prevent the metastatic process as early as possible. There are currently many therapies in clin. use and recent advances in biotechnol. lend credence to the potential of nanotechnol. in the fight against cancer. Nanomaterials such as carbon nanotubes (CNTs), quantum dots and dendrimers have unique properties that can be exploited for diagnostic purposes, thermal ablation and drug delivery in cancer. CNTs are tubular materials with nanometer-sized diams. and axial symmetry, giving them unique properties that can be exploited in the diagnosis and treatment of cancer. In addn., CNTs have the potential to deliver drugs directly to targeted cells and tissues. Alongside the rapid advances in the development of nanotechnol.-based materials, elucidating the toxicity of nanoparticles is also imperative. Hence, in this review, we seek to explore the biomedical applications of CNTs, with particular emphasis on their use as therapeutic platforms in oncol.
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490Heister, E.; Brunner, E. W.; Dieckmann, G. R.; Jurewicz, I.; Dalton, A. B. ACS Appl. Mater. Interfaces 2013, 5, 1870Google ScholarThere is no corresponding record for this reference.
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491Madani, S. Y.; Shabani, F.; Dwek, M. V.; Seifalian, A. M. Int. J. Nanomed. 2013, 8, 941Google ScholarThere is no corresponding record for this reference.
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492Tang, S.; Tang, Y.; Zhong, L.; Murat, K.; Asan, G.; Yu, J.; Jian, R.; Wang, C.; Zhou, P. J. Appl. Toxicol. 2012, 32, 900Google Scholar492https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvVektLw%253D&md5=4afc234d3aa5537d8af864b9a2225319Short- and long-term toxicities of multi-walled carbon nanotubes in vivo and in vitroTang, Shaoxian; Tang, Yuechao; Zhong, Lingling; Murat, Kumuruz; Asan, Gvlqikra; Yu, Jerry; Jian, Rongrong; Wang, Changchun; Zhou, PingJournal of Applied Toxicology (2012), 32 (11), 900-912CODEN: JJATDK; ISSN:0260-437X. (John Wiley & Sons Ltd.)As nanomaterials are developed and applied, their potential for health hazards needs to be detd. In the present study, we used com. nude multi-walled carbon nanotubes (MWCNTs) trimmed to a short length (50-200 nm; s-MWCNTs) and synthesized functionalized MWCNTs with polyethylene glycol (PEG) (s-MWCNTs-PEG). We then studied the toxic effects of s-MWCNTs and s-MWCNTs-PEG on cultured cells and in a mouse model. Peripheral haemograms and various biochem. markers of the heart, liver and kidney were measured. We found no toxicity of either type of nanotube on the viability of human SKBR-3 breast carcinoma cells or control cells. There were no differences in vivo on inflammatory responses, the coagulation system, haemograms or vital organ functions between the test and control groups. Addnl., we found no toxicity of these nanotubes on male mouse sperm prodn. or mutagenesis in the long term. In conclusion, both s-MWCNTs and s-MWCNTs-PEG displayed good in vitro and in vivo biocompatibility, making future applications in biol. and clin. therapy as a carrier for drug delivery feasible. Copyright © 2012 John Wiley & Sons, Ltd.
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493The Organisation for Economic Cooperation and Development (OECD). Six years of OECD work on the safety of manufactured nanomaterials: Achievements and future opportunities. OECD brochure: Overview, 2012.Google ScholarThere is no corresponding record for this reference.
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494Jia, G.; Wang, H.; Yan, L.; Wang, X.; Pei, R.; Yan, T.; Zhao, Y.; Guo, X. Environ. Sci. Technol. 2005, 39, 1378Google Scholar494https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1Grtw%253D%253D&md5=873bc79c2ce6f8b05b5efd10dd7a2e3fCytotoxicity of Carbon Nanomaterials: Single-Wall Nanotube, Multi-Wall Nanotube, and FullereneJia, Guang; Wang, Haifang; Yan, Lei; Wang, Xiang; Pei, Rongjuan; Yan, Tao; Zhao, Yuliang; Guo, XinbiaoEnvironmental Science and Technology (2005), 39 (5), 1378-1383CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)A cytotoxicity test protocol for single-wall nanotubes (SWNTs), multi-wall nanotubes (with diams. ranging from 10 to 20 nm, MWNT10), and fullerene (C60) was tested. Profound cytotoxicity of SWNTs was obsd. in alveolar macrophage (AM) after a 6-h exposure in vitro. The cytotoxicity increases by as high as ∼35% when the dosage of SWNTs was increased by 11.30 μg/cm2. No significant toxicity was obsd. for C60 up to a dose of 226.00 μg/cm2. The cytotoxicity apparently follows a sequence order on a mass basis: SWNTs > MWNT10 > quartz > C60. SWNTs significantly impaired phagocytosis of AM at the low dose of 0.38 μg/cm2, whereas MWNT10 and C60 induced injury only at the high dose of 3.06 μg/cm2. The macrophages exposed to SWNTs or MWNT10 of 3.06 μg/cm2 showed characteristic features of necrosis and degeneration. A sign of apoptotic cell death likely existed. Carbon nanomaterials with different geometric structures exhibit quite different cytotoxicity and bioactivity in vitro, although they may not be accurately reflected in the comparative toxicity in vivo.
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495Nerl, H. C.; Cheng, C.; Goode, A. E.; Bergin, S. D.; Lich, B.; Gass, M.; Porter, A. E. Nanomedicine 2011, 6, 849Google ScholarThere is no corresponding record for this reference.
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496Qu, G.; Bai, Y.; Zhang, Y.; Jia, Q.; Zhang, W.; Yan, B. Carbon 2009, 47, 2060Google ScholarThere is no corresponding record for this reference.
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497Buford, M. C.; Hamilton, R. F., Jr.; Holian, A. Part. Fibre Toxicol. 2007, 4, 6Google Scholar497https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2svptF2iuw%253D%253D&md5=697f3404a28269d3931a563488934750A comparison of dispersing media for various engineered carbon nanoparticlesBuford Mary C; Hamilton Raymond F Jr; Holian AndrijParticle and fibre toxicology (2007), 4 (), 6 ISSN:.BACKGROUND: With the increased manufacture and use of carbon nanoparticles (CNP) there has been increasing concern about the potential toxicity of fugitive CNP in the workplace and ambient environment. To address this matter a number of investigators have conducted in vitro and in vivo toxicity assessments. However, a variety of different approaches for suspension of these particles (culture media, Tween 80, dimethyl sulfoxide, phosphate-buffered saline, fetal calf serum, and others), and different sources of materials have generated potentially conflicting outcomes. The quality of the dispersion of nanoparticles is very dependent on the medium used to suspend them, and this then will most likely affect the biological outcomes. RESULTS: In this work, the distributions of different CNP (sources and types) have been characterized in various media. Furthermore, the outcome of instilling the different agglomerates, or size distributions, was examined in mouse lungs after one and seven days. Our results demonstrated that CNP suspended in serum produced particle suspensions with the fewest large agglomerates, and the most uniform distribution in mouse lungs. In addition, no apparent clearance of instilled CNP took place from lungs even after seven days. CONCLUSION: This work demonstrates that CNP agglomerates are present in all dispersing vehicles to some degree. The vehicle that contains some protein, lipid or protein/lipid component disperses the CNP best, producing fewer large CNP agglomerates. In contrast, vehicles absent of lipid and protein produce the largest CNP agglomerates. The source of the CNP is also a factor in the degree of particle agglomeration within the same vehicle.
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498Snyder-Talkington, B. N.; Qian, Y.; Castranova, V.; Guo, N. L. J. Toxicol. Environ. Health., Part B 2012, 15, 468Google ScholarThere is no corresponding record for this reference.
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499Donaldson, K. Nanomedicine 2006, 1, 229Google ScholarThere is no corresponding record for this reference.
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500Lam, C. W.; James, J. T.; McCluskey, R.; Arepalli, S.; Hunter, R. L. Crit. Rev. Toxicol. 2006, 36, 189Google Scholar500https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xjt1Cks7Y%253D&md5=6f580f33625a1c428d79a4489b368bffA Review of Carbon Nanotube Toxicity and Assessment of Potential Occupational and Environmental Health RisksLam, Chiu-wing; James, John T.; McCluskey, Richard; Arepalli, Sivaram; Hunter, Robert L.Critical Reviews in Toxicology (2006), 36 (3), 189-217CODEN: CRTXB2; ISSN:1040-8444. (Taylor & Francis, Inc.)A review. Nanotechnol. has emerged at the forefront of science research and technol. development. Carbon nanotubes (CNTs) are major building blocks of this new technol. They possess unique elec., mech., and thermal properties, with potential wide applications in the electronics, computer, aerospace, and other industries. CNTs exist in two forms, single-wall (SWCNTs) and multi-wall (MWCNTs). They are manufd. predominately by elec. arc discharge, laser ablation and chem. vapor deposition processes; these processes involve thermally stripping carbon atoms off from carbon-bearing compds. SWCNT formation requires catalytic metals. There has been a great concern that if CNTs, which are very light, enter the working environment as suspended particulate matter (PM) of respirable sizes, they could pose an occupational inhalation exposure hazard. Very recently, MWCNTs and other carbonaceous nanoparticles in fine (<2.5 μm) PM aggregates have been found in combustion streams of methane, propane, and natural-gas flames of typical stoves; indoor and outdoor fine PM samples were reported to contain significant fractions of MWCNTs. Here we review several rodent studies in which test dusts were administered intratracheally or intrapharyngeally to assess the pulmonary toxicity of manufd. CNTs, and a few in vitro studies to assess biomarkers of toxicity released in CNT-treated skin cell cultures. The results of the rodent studies collectively showed that regardless of the process by which CNTs were synthesized and the types and amts. of metals they contained, CNTs were capable of producing inflammation, epithelioid granulomas (microscopic nodules), fibrosis, and biochem./toxicol. changes in the lungs. Comparative toxicity studies in which mice were given equal wts. of test materials showed that SWCNTs were more toxic than quartz, which is considered a serious occupational health hazard if it is chronically inhaled; ultrafine carbon black was shown to produce minimal lung responses. The differences in opinions of the investigators about the potential hazards of exposures to CNTs are discussed here. Presented here are also the possible mechanisms of CNT pathogenesis in the lung and the impact of residual metals and other impurities on the toxicol. manifestations. The toxicol. hazard assessment of potential human exposures to airborne CNTs and occupational exposure limits for these novel compds. are discussed in detail. Environmental fine PM is known to form mainly from combustion of fuels, and has been reported to be a major contributor to the induction of cardiopulmonary diseases by pollutants. Given that manufd. SWCNTs and MWCNTs were found to elicit pathol. changes in the lungs, and SWCNTs (administered to the lungs of mice) were further shown to produce respiratory function impairments, retard bacterial clearance after bacterial inoculation, damage the mitochondrial DNA in aorta, increase the percent of aortic plaque, and induce atherosclerotic lesions in the brachiocephalic artery of the heart, it is speculated that exposure to combustion-generated MWCNTs in fine PM may play a significant role in air pollution-related cardiopulmonary diseases. Therefore, CNTs from manufd. and combustion sources in the environment could have adverse effects on human health.
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501Wang, L.; Castranova, V.; Mishra, A.; Chen, B.; Mercer, R. R.; Schwegler-Berry, D.; Rojanasakul, Y. Part. Fibre Toxicol. 2010, 7, 31Google Scholar501https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cbktFKgtw%253D%253D&md5=7c61669935e2ac2988088745d8336c29Dispersion of single-walled carbon nanotubes by a natural lung surfactant for pulmonary in vitro and in vivo toxicity studiesWang Liying; Castranova Vincent; Mishra Anurag; Chen Bean; Mercer Robert R; Schwegler-Berry Diane; Rojanasakul YonParticle and fibre toxicology (2010), 7 (), 31 ISSN:.BACKGROUND: Accumulating evidence indicate that the degree of dispersion of nanoparticles has a strong influence on their biological activities. The aims of this study were to develop a simple and rapid method of nanoparticle dispersion using a natural lung surfactant and to evaluate the effect of dispersion status of SWCNT on cytotoxicity and fibrogenicity in vitro and in vivo. RESULTS: The natural lung surfactant Survanta® was used to disperse single-walled carbon nanotubes (SWCNT) in a biological medium. At physiologically relevant concentrations, Survanta® produced well dispersed SWCNT without causing a cytotoxic or fibrogenic effect. In vitro studies show that Survanta®-dispersed SWCNT (SD-SWCNT) stimulated proliferation of lung epithelial cells at low doses (0.04-0.12 μg/ml or 0.02-0.06 μg/cm2 exposed surface area) but had a suppressive effect at high doses. Non-dispersed SWCNT (ND-SWCNT) did not exhibit these effects, suggesting the importance of dispersion status of SWCNT on bioactivities. Studies using cultured human lung fibroblasts show that SD-SWCNT stimulated collagen production of the cells. This result is supported by a similar observation using Acetone/sonication dispersed SWCNT (AD-SWCNT), suggesting that Survanta® did not mask the bioactivity of SWCNT. Likewise, in vivo studies show that both SD-SWCNT and AD-SWCNT induced lung fibrosis in mice, whereas the dispersing agent Survanta® alone or Survanta®-dispersed control ultrafine carbon black had no effect. CONCLUSIONS: The results indicate that Survanta® was effective in dispersing SWCNT in biological media without causing cytotoxic effects at the test concentrations used in this study. SD-SWCNT stimulated collagen production of lung fibroblasts in vitro and induced lung fibrosis in vivo. Similar results were observed with AD-SWCNT, supporting the conclusion that Survanta® did not mask the bioactivities of SWCNT and thus can be used as an effective dispersing agent. Since excessive collagen production is a hallmark of lung fibrosis, the results of this study suggest that the in vitro model using lung fibroblasts may be an effective and rapid screening tool for prediction of the fibrogenic potential of SWCNT in vivo.
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502Palomäki, J.; Välimäki, E.; Sund, J.; Vippola, M.; Clausen, P. A.; Jensen, K. A.; Savolainen, K.; Matikainen, S.; Alenius, H. ACS Nano 2011, 5, 6861Google ScholarThere is no corresponding record for this reference.
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503Patlolla, A. K.; Berry, A.; Tchounwou, P. B. Mol. Cell. Biochem. 2011, 358, 189Google ScholarThere is no corresponding record for this reference.
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504Sanchez, V. C.; Weston, P.; Yan, A.; Hurt, R. H.; Kane, A. B. Part. Fibre Toxicol. 2011, 8, 17Google Scholar504https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmvVKrsrw%253D&md5=4f05f67113707d8535dadf33eaa2d858A 3-dimensional in vitro model of epithelioid granulomas induced by high aspect ratio nanomaterialsSanchez, Vanesa C.; Weston, Paula; Yan, Aihui; Hurt, Robert H.; Kane, Agnes B.Particle and Fibre Toxicology (2011), 8 (), 17CODEN: PFTABQ; ISSN:1743-8977. (BioMed Central Ltd.)Background: The most common causes of granulomatous inflammation are persistent pathogens and poorly-degradable irritating materials. A characteristic pathol. reaction to intratracheal instillation, pharyngeal aspiration, or inhalation of carbon nanotubes is formation of epithelioid granulomas accompanied by interstitial fibrosis in the lungs. In the mesothelium, a similar response is induced by high aspect ratio nanomaterials, including asbestos fibers, following i.p. injection. This asbestos-like behavior of some engineered nanomaterials is a concern for their potential adverse health effects in the lungs and mesothelium. We hypothesize that high aspect ratio nanomaterials will induce epithelioid granulomas in nonadherent macrophages in 3D cultures. Results: Carbon black particles (Printex 90) and crocidolite asbestos fibers were used as well-characterized ref. materials and compared with three com. samples of multiwalled carbon nanotubes (MWCNTs). Doses were identified in 2D and 3D cultures in order to minimize acute toxicity and to reflect realistic occupational exposures in humans and in previous inhalation studies in rodents. Under serum-free conditions, exposure of nonadherent primary murine bone marrow-derived macrophages to 0.5 μg/mL (0.38 μg/cm2) of crocidolite asbestos fibers or MWCNTs, but not carbon black, induced macrophage differentiation into epithelioid cells and formation of stable aggregates with the characteristic morphol. of granulomas. Formation of multinucleated giant cells was also induced by asbestos fibers or MWCNTs in this 3D in vitro model. After 7-14 days, macrophages exposed to high aspect ratio nanomaterials co-expressed proinflammatory (M1) as well as profibrotic (M2) phenotypic markers. Conclusions: Induction of epithelioid granulomas appears to correlate with high aspect ratio and complex 3D structure of carbon nanotubes, not with their iron content or surface area. This model offers a time- and cost-effective platform to evaluate the potential of engineered high aspect ratio nanomaterials, including carbon nanotubes, nanofibers, nanorods and metallic nanowires, to induce granulomas following inhalation.
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505Teeguarden, J. G.; Webb-Robertson, B. J.; Waters, K. M.; Murray, A. R.; Kisin, E. R.; Varnum, S. M.; Jacobs, J. M.; Pounds, J. G.; Zanger, R. C.; Shvedova, A. A. Toxicol. Sci. 2011, 120, 123Google Scholar505https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXis1eksLo%253D&md5=89665aea5667a223bf084a4a36b1f30fComparative Proteomics and Pulmonary Toxicity of Instilled Single-Walled Carbon Nanotubes, Crocidolite Asbestos, and Ultrafine Carbon Black in MiceTeeguarden, Justin G.; Webb-Robertson, Bobbie-Jo; Waters, Katrina M.; Murray, Ashley R.; Kisin, Elena R.; Varnum, Susan M.; Jacobs, Jon M.; Pounds, Joel G.; Zanger, Richard C.; Shvedova, Anna A.Toxicological Sciences (2011), 120 (1), 123-135CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)Reflecting their exceptional potential to advance a range of biomedical, aeronautic, and other industrial products, carbon nanotube (CNT) prodn. and the potential for human exposure to aerosolized CNTs are increasing. CNTs have toxicol. significant structural and chem. similarities to asbestos (AB) and have repeatedly been shown to cause pulmonary inflammation, granuloma formation, and fibrosis after inhalation/instillation/aspiration exposure in rodents, a pattern of effects similar to those obsd. following exposure to AB. To det. the degree to which responses to single-walled CNTs (SWCNT) and AB are similar or different, the pulmonary response of C57BL/6 mice to repeated exposures to SWCNTs, crocidolite AB, and ultrafine carbon black (UFCB) were compared using high-throughput global high-performance liq. chromatog. Fourier-transform ion cyclotron resonance mass spectrometry (HPLC-FTICR-MS) proteomics, histopathol., and bronchoalveolar lavage cytokine analyses. Mice were exposed to material suspensions (40 μg per mouse) twice a week for 3 wk by pharyngeal aspiration. Histol., the incidence and severity of inflammatory and fibrotic responses were greatest in mice treated with SWCNTs. SWCNT treatment affected the greatest changes in abundance of identified lung tissue proteins. The trend in no. of proteins affected (SWCNT [376] > AB [231] > UFCB [184]) followed the potency of these materials in 3 biochem. assays of inflammation (cytokines). SWCNT treatment uniquely affected the abundance of 109 proteins, but these proteins largely represent cellular processes affected by AB treatment as well, further evidence of broad similarity in the tissue-level response to AB and SWCNTs. Two high-sensitivity markers of inflammation, one (S100a9) obsd. in humans exposed to AB, were found and may be promising biomarkers of human response to SWCNT exposure.
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506Patlolla, A. K.; Berry, A.; May, L.; Tchounwou, P. B. Int. J. Environ. Res. Public Health 2012, 9, 1649Google ScholarThere is no corresponding record for this reference.
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507Atkins, G. J.; Haynes, D. R.; Howie, D. W.; Findlay, D. M. World J. Orthop. 2011, 2, 93Google Scholar507https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38ritFOhsA%253D%253D&md5=b858f7039eef67dff81fd8f1abe998dfRole of polyethylene particles in peri-prosthetic osteolysis: A reviewAtkins Gerald J; Haynes David R; Howie Donald W; Findlay David MWorld journal of orthopedics (2011), 2 (10), 93-101 ISSN:.There is convincing evidence that particles produced by the wear of joint prostheses are causal in the peri-prosthetic loss of bone, or osteolysis, which, if it progresses, leads to the phenomenon of aseptic loosening. It is important to fully understand the biology of this bone loss because it threatens prosthesis survival, and loosened implants can result in peri-prosthetic fracture, which is disastrous for the patient and presents a difficult surgical scenario. The focus of this review is the bioactivity of polyethylene (PE) particles, since there is evidence that these are major players in the development and progression of osteolysis around prostheses which use PE as the bearing surface. The review describes the biological consequences of interaction of PE particles with macrophages, osteoclasts and cells of the osteoblast lineage, including osteocytes. It explores the possible cellular mechanisms of action of PE and seeks to use the findings to date to propose potential non-surgical treatments for osteolysis. In particular, a non-surgical approach is likely to be applicable to implants containing newer, highly cross-linked PEs (HXLPEs), for which osteolysis seems to occur with much reduced PE wear compared with conventional PEs. The caveat here is that we know little as yet about the bioactivity of HXLPE particles and addressing this constitutes our next challenge.
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508Blumenfeld, T. J.; McKellop, H. A.; Schmalzried, T. P.; Billi, F. J. Arthroplasty 2011, 26, 666 e5Google ScholarThere is no corresponding record for this reference.
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509Furmanski, J.; Kraay, M. J.; Rimnac, C. M. J. Arthroplasty 2011, 26, 796Google Scholar509https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MnpvVyqtQ%253D%253D&md5=724482ba56ad8fbc1659c6841af27c23Crack initiation in retrieved cross-linked highly cross-linked ultrahigh-molecular-weight polyethylene acetabular liners: an investigation of 9 casesFurmanski Jevan; Kraay Matthew J; Rimnac Clare MThe Journal of arthroplasty (2011), 26 (5), 796-801 ISSN:.Nine cross-linked highly cross-linked ultrahigh-molecular weight polyethylene acetabular liners were retrieved at revision surgery. Eight of the liners were fully intact and functional at retrieval. Six cases contained shallow initiated cracks at the root of rim notches; 1 crack had propagated several millimeters. Optical and electron microscopic inspection of the crack surfaces revealed clam shell markings, which are characteristic of fatigue crack initiation. Crack initiation at notches has been identified in reports of catastrophic cross-linked liner failures, with crack initiation sites exhibiting similar morphology and clam shell markings. Thus, we believe that the shallow cracks identified in this case series are precursors to catastrophic rim fracture. The results of this study recommend further investigations to clarify the etiology and prevalence of crack initiation in cross-linked acetabular liners.
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510Goldstein, M. J.; Ast, M. P.; Dimaio, F. R. Orthopedics 2012, 35, e1119Google ScholarThere is no corresponding record for this reference.
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511Waewsawangwong, W.; Goodman, S. B. J. Arthroplasty 2012, 27, 323 e1Google ScholarThere is no corresponding record for this reference.
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512Pruitt, L. A.; Ansari, F.; Kury, M.; Mehdizah, A.; Patten, E. W.; Huddlestein, J.; Mickelson, D.; Chang, J.; Hubert, K.; Ries, M. D. J. Biomed. Mater. Res., Part B 2013, 101, 476Google Scholar512https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktVGhurY%253D&md5=d9a2a012250665d93dd6989a0d1b55acClinical trade-offs in cross-linked ultrahigh-molecular-weight polyethylene used in total joint arthroplastyPruitt, Lisa A.; Ansari, Farzana; Kury, Matt; Mehdizah, Amir; Patten, Elias W.; Huddlestein, James; Mickelson, Dayne; Chang, Jennifer; Hubert, Kim; Ries, Michael D.Journal of Biomedical Materials Research, Part B: Applied Biomaterials (2013), 101B (3), 476-484CODEN: JBMRGL; ISSN:1552-4973. (John Wiley & Sons, Inc.)Highly cross-linked formulations of ultrahigh-mol.-wt. polyethylene (XLPE) offer exceptional wear resistance for total joint arthroplasty but are offset with a redn. in postyield and fatigue fracture properties in comparison to conventional ultrahigh-mol.-wt. polyethylene (UHMWPE). Oxidn. resistance is also an important property for the longevity of total joint replacements (TJRs) as formulations of UHMWPE or XLPE utilizing radiation methods are susceptible to free radical generation and subsequent embrittlement. The balance of oxidn., wear, and fracture properties is an enduring concern for orthopedic polymers used as the bearing surface in total joint arthroplasty. Optimization of material properties is further challenged in designs that make use of locking mechanisms, notches, or other stress concns. that can render the polymer susceptible to fracture due to elevated local stresses. Clin. complications involving impingements, dislocations, or other biomech. overloads can exacerbate stresses and negate benefits of improved wear resistance provided by XLPE. This work examines trade-offs that factor into the use of XLPE in TJR implants. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 101B: 476-484, 2013.
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513Regis, D.; Sandri, A.; Bartolozzi, P. Orthopedics 2008, 31.Google ScholarThere is no corresponding record for this reference.
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514Lee, Y. K.; Yoo, J. J.; Koo, K. H.; Yoon, K. S.; Kim, H. J. J. Orthop. Res. 2011, 29, 218Google Scholar514https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M%252FmtlSrtA%253D%253D&md5=b641bef82e5287ce5aa852727ef227efMetal neck and liner impingement in ceramic bearing total hip arthroplastyLee Young-Kyun; Yoo Jeong Joon; Koo Kyung-Hoi; Yoon Kang Sup; Kim Hee JoongJournal of orthopaedic research : official publication of the Orthopaedic Research Society (2011), 29 (2), 218-22 ISSN:.Although impingement between the neck of the metallic stem and the ceramic liner has been suspected to be the cause of ceramic liner failure in ceramic-on-ceramic total hip arthroplasty (THA), no report has directly demonstrated microscopic damage on ceramic liner. We performed 18 reoperations on 18 patients who had undergone third generation ceramic-on-ceramic THA. Considering impingement, 16 patients, who were reoperated more than 1 year after previous ceramic bearing THA, were evaluated. Retrieved alumina liners, showing evidence of impingement, were examined by means of visual inspection and scanning electron microscopy (SEM). Four of the 16 hips showed neck notching and black stained liners, evidence of metallic neck to ceramic impingement. Impinged alumina bearings had been implanted for an average of 62.5 months (range: 35-99 months) before reoperation. SEM of the black stained area demonstrated disruptive wear and loss of surface integrity. Furthermore, one liner had multiple microcracks, and its cross-sectional SEM analysis revealed one microcrack propagating into the deep portion of the ceramic liner. Our observations suggest that metal neck-to-ceramic impingement in ceramic-on-ceramic THA can cause microcrack formation in ceramic liner.
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515Lopes, R.; Philippeau, J. M.; Passuti, N.; Gouin, F. Clin. Orthop. Relat. Res. 2012, 470, 1705Google Scholar515https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38vltVKqsw%253D%253D&md5=0d7b839f6172944a32477af32c52526aHigh rate of ceramic sandwich liner fractureLopes Ronny; Philippeau Jean M; Passuti Norbert; Gouin FrancoisClinical orthopaedics and related research (2012), 470 (6), 1705-10 ISSN:.BACKGROUND: Ceramic bearing surfaces for THA were introduced to reduce the risk of wear. However, owing to liner fracture in some of the early series and presumption that the fractures were the result of the modulus mismatch of the implant and the bone, a ceramic sandwich liner with lower structural rigidity was introduced. Fractures of these devices also were reported subsequently, although the incidence is unclear and it is unknown whether there are any risk factors associated with the fractures. QUESTIONS/PURPOSES: We therefore determined the incidence of these fractures. METHODS: We retrospectively reviewed 298 active patients in whom we implanted 353 ceramic-polyethylene sandwich liner acetabular components between November 1999 and February 2008. The mean age of the patients was 53.6 years (range, 17-84 years). The minimum followup was 6 months (mean, 41 months; range, 6-106 months). All patients were assessed clinically and radiographically. RESULTS: Seven of the 353 (2%) ceramic sandwich liners fractured at a mean of 4.3 years (range, 1.3-7.6 years) after surgery without trauma. Neither patient-related factors nor radiographic position of the implants were risk factors for fracture. CONCLUSIONS: Owing to the high rate of fractures of the sandwich ceramic polyethylene liners in our patients, we have discontinued use of this device. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
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516Traina, F.; De Fine, M.; Bordini, B.; Toni, A. Hip Int. 2012, 22, 607Google Scholar516https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s3gtl2gsQ%253D%253D&md5=dc972a13c11615332f674bc02ff5ce5dRisk factors for ceramic liner fracture after total hip arthroplastyTraina Francesco; De Fine Marcello; Bordini Barbara; Toni AldoHip international : the journal of clinical and experimental research on hip pathology and therapy (2012), 22 (6), 607-14 ISSN:.The aim of this study was to detect risk factors for ceramic liner fractures. 26 cementless ceramic on ceramic (COC) total hip arthroplasties (THA) revised because of ceramic liner fracture in 24 patients were compared with 49 well-functioning COC THA performed in 49 patients. Demographic parameters, type of ceramic of the liner, size and neck length of the femoral head, cup abduction angle, cup anteversion, femoral off-set, height of the centre of rotation and the incidence of noisy hips during follow-up examination were compared. A greater number of cups placed outside the optimal range of cup anteversion was found in the fracture group (p = 0.03). An audible noise was detected in 21 cases (80.7%) in the fracture group and in 3 cases (6.1%) in the non-fracture group (p = 0.001). A cup anteversion angle out of the optimal range of 15+/-10 was found to be a risk factor for ceramic liner fracture and the presence of a noisy hip frequently anticipated the failure. In our opinion neck-to-cup impingement with head subluxation and edge loading on the liner rim could have an important role in the onset of noise and subsequent liner failure, and cup malposition contributes to this mechanism of failure.
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517Kawano, S.; Sonohata, M.; Shimazaki, T.; Kitajima, M.; Mawatari, M.; Hotokebuchi, T.J. Arthroplasty 2013.Google ScholarThere is no corresponding record for this reference.
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518Koo, K. H.; Ha, Y. C.; Kim, S. Y.; Yoon, K. S.; Min, B. W.; Kim, S. R.J. Arthroplasty 2013.Google ScholarThere is no corresponding record for this reference.
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519Kulkarni, A. G.; Hee, H. T.; Wong, H. K. Spine J. 2007, 7, 205Google Scholar519https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s7it1Srsg%253D%253D&md5=b3ca20bfb07709eb4c8a5ce87c29e75aSolis cage (PEEK) for anterior cervical fusion: preliminary radiological results with emphasis on fusion and subsidenceKulkarni Arvind G; Hee Hwan T; Wong Hee KThe spine journal : official journal of the North American Spine Society (2007), 7 (2), 205-9 ISSN:1529-9430.BACKGROUND CONTEXT: Recent literature has raised some apprehensions with regard to the usage of cervical cages. PURPOSE: Radiological review of cases performed at our institution with a novel cage made of polyetheretherketone (PEEK). STUDY DESIGN: Retrospective study. METHODS: A retrospective review of the first 15 consecutive cases of single-level anterior cervical interbody fusion using the Solis cage (PEEK material) for cervical spondylotic radiculopathy or myelopathy was performed. The follow-up ranged from 12 to 35 months (average 18 months). Anteroposterior and lateral radiographs were taken immediately after the surgery and at intervals of 3, 6, 12, and 24 months after surgery. Anterior disc height (ADH), posterior disc height (PDH), interbody height ratio (IBHR), distance between the posterior margin of the cage and the posterior wall of the vertebral body (D-CPW), and interbody angle (IBA) were measured on the lateral radiographs and compared. Fusion was assessed by examining for trabecular continuity, bridging of bone across the disc space, and sclerosis at the vertebral end plates on both sides. The parameters assessed were time for fusion, subsidence, segmental sagittal alignment of the operated segment, and presence/absence of migration of the cage. Data were analyzed using the Mann-Whitney nonparametric test. RESULTS: Fusion was evident at 3-6 months postsurgery in all cases except one (93.33% fusion rate at 6 months). At the last follow-up, fusion was maintained in all cases. The immediate postoperative ADH and PDH was significantly greater than the respective preoperative values and was maintained at the last follow-up though there was a significant amount of subsidence when the follow-up radiographs were compared with the immediate postoperative X-rays. The immediate postoperative IBHR was significantly greater than the preoperative IBHR, and was maintained at the last follow-up, but not statistically significant. The immediate postoperative IBA (lordotic angle) was greater than the preoperative IBA but was not statistically significant. The IBA at the last follow-up was lesser than the preoperative value but with no statistical significance. The IBA measured at the last follow-up was less than the value at the immediate postoperative period, but not statistically significant. There was no migration or extrusion of the cage at latest follow-up. CONCLUSIONS: The high fusion rate, low subsidence, stability provided by the cage, and facilitation of radiological assessment are the result of the physical properties of the PEEK material as well as the design of the cage.
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520Kurtz, S. M.; Devine, J. N. Biomaterials 2007, 28, 4845Google ScholarThere is no corresponding record for this reference.
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521Yang, J. J.; Yu, C. H.; Chang, B. S.; Yeom, J. S.; Lee, J. H.; Lee, C. K. Clin. Orthop. Surg. 2011, 3, 16Google Scholar521https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M3jsVOisQ%253D%253D&md5=302da002ae21615c855cb9ea6710265bSubsidence and nonunion after anterior cervical interbody fusion using a stand-alone polyetheretherketone (PEEK) cageYang Jae Jun; Yu Chang Hun; Chang Bong-Soon; Yeom Jin Sup; Lee Jae Hyup; Lee Choon-KiClinics in orthopedic surgery (2011), 3 (1), 16-23 ISSN:.BACKGROUND: The purposes of the present study are to evaluate the subsidence and nonunion that occurred after anterior cervical discectomy and fusion using a stand-alone intervertebral cage and to analyze the risk factors for the complications. METHODS: Thirty-eight patients (47 segments) who underwent anterior cervical fusion using a stand-alone polyetheretherketone (PEEK) cage and an autologous cancellous iliac bone graft from June 2003 to August 2008 were enrolled in this study. The anterior and posterior segmental heights and the distance from the anterior edge of the upper vertebra to the anterior margin of the cage were measured on the plain radiographs. Subsidence was defined as ≥ a 2 mm (minor) or 3 mm (major) decrease of the segmental height at the final follow-up compared to that measured at the immediate postoperative period. Nonunion was evaluated according to the instability being ≥ 2 mm in the interspinous distance on the flexion-extension lateral radiographs. RESULTS: The anterior and posterior segmental heights decreased from the immediate postoperative period to the final follow-up at 1.33 ± 1.46 mm and 0.81 ± 1.27 mm, respectively. Subsidence ≥ 2 mm and 3 mm were observed in 12 segments (25.5%) and 7 segments (14.9%), respectively. Among the expected risk factors for subsidence, a smaller anteroposterior (AP) diameter (14 mm vs. 12 mm) of cages (p = 0.034; odds ratio [OR], 0.017) and larger intraoperative distraction (p = 0.041; OR, 3.988) had a significantly higher risk of subsidence. Intervertebral nonunion was observed in 7 segments (7/47, 14.9%). Compared with the union group, the nonunion group had a significantly higher ratio of two-level fusion to one-level fusions (p = 0.001). CONCLUSIONS: Anterior cervical fusion using a stand-alone cage with a large AP diameter while preventing anterior intraoperative over-distraction will be helpful to prevent the subsidence of cages. Two-level cervical fusion might require more careful attention for avoiding nonunion.
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522Le, T. V.; Baaj, A. A.; Dakwar, E.; Burkett, C. J.; Murray, G.; Smith, D. A.; Uribe, J. S. Spine (Philadelphia) 2012, 37, 1268Google Scholar522https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38jhsVyqsw%253D%253D&md5=2eafcac870d73fe197a08e8faa56ee63Subsidence of polyetheretherketone intervertebral cages in minimally invasive lateral retroperitoneal transpsoas lumbar interbody fusionLe Tien V; Baaj Ali A; Dakwar Elias; Burkett Clinton J; Murray Gisela; Smith Donald A; Uribe Juan SSpine (2012), 37 (14), 1268-73 ISSN:.STUDY DESIGN: A retrospective review. OBJECTIVE: The objective is to evaluate subsidence related to minimally invasive lateral retroperitoneal lumbar interbody fusion by reviewing our experience with this procedure. SUMMARY OF BACKGROUND DATA: Polyetheretherketone intervertebral cages of different lengths, widths, and heights filled with various allograft types are commonly used as spacers in lumbar fusions. Subsidence is a potential complication. To date, there are no published reports specifically addressing subsidence, because it relates to a series of patients undergoing minimally invasive lateral retroperitoneal transpsoas lumbar interbody fusion. METHODS: An institutional review board-approved, retrospective review of a prospectively collected database was conducted. One hundred forty consecutive patients who underwent this procedure between L1 and L5 during a 2-year period were included. All patients had T scores of -2.5 or more. Postoperative radiographs during routine follow-ups were reviewed for subsidence, defined as any violation of the vertebral end plate. RESULTS: Radiographical subsidence occurred in 14.3% (20 of 140), whereas clinical subsidence occurred in 2.1%. Subsidence occurred in 8.8% (21 of 238) of levels fused. Construct length had a significant positive correlation with increasing subsidence rates. Subsidence rates decreased progressively with lower levels in the lumbar spine, but had a higher than expected rate at L4-L5. Subsidence rates of 14.1% (19 of 135) and 1.9% (2 of 103) were associated with 18-and 22-mm-wide cages, respectively. No significant trends were observed with cage lengths. Supplemental lateral plates had a higher rate of subsidence than bilateral pedicle screws. Subsidence occurred at the superior end plate 70% of the time. CONCLUSION: The use of wider intervertebral cages leads to a significantly lower rate of subsidence, but a longer cage does not necessarily offer a similar advantage. Wide cages are protective against subsidence, and the widest cages should be used whenever feasible for interbody fusion in the lumbar spine to protect indirect compression and promote arthrodesis.
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523Olivares-Navarrete, R.; Gittens, R. A.; Schneider, J. M.; Hyzy, S. L.; Haithcock, D. A.; Ullrich, P. F.; Schwartz, Z.; Boyan, B. D. Spine J. 2012, 12, 265Google Scholar523https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38vnt1Ciug%253D%253D&md5=569445d9bb1d1087c27107b352559a11Osteoblasts exhibit a more differentiated phenotype and increased bone morphogenetic protein production on titanium alloy substrates than on poly-ether-ether-ketoneOlivares-Navarrete Rene; Gittens Rolando A; Schneider Jennifer M; Hyzy Sharon L; Haithcock David A; Ullrich Peter F; Schwartz Zvi; Boyan Barbara DThe spine journal : official journal of the North American Spine Society (2012), 12 (3), 265-72 ISSN:.BACKGROUND CONTEXT: Multiple biomaterials are clinically available to spine surgeons for performing interbody fusion. Poly-ether-ether-ketone (PEEK) is used frequently for lumbar spine interbody fusion, but alternative materials are also used, including titanium (Ti) alloys. Previously, we showed that osteoblasts exhibit a more differentiated phenotype when grown on machined or grit-blasted titanium aluminum vanadium (Ti6Al4V) alloys with micron-scale roughened surfaces than when grown on smoother Ti6Al4V surfaces or on tissue culture polystyrene (TCPS). We hypothesized that osteoblasts cultured on rough Ti alloy substrates would present a more mature osteoblast phenotype than cells cultured on PEEK, suggesting that textured Ti6Al4V implants may provide a more osteogenic surface for interbody fusion devices. PURPOSE: The aim of the present study was to compare osteoblast response to smooth Ti6Al4V (sTiAlV) and roughened Ti6Al4V (rTiAlV) with their response to PEEK with respect to differentiation and production of factors associated with osteogenesis. STUDY DESIGN: This in vitro study compared the phenotype of human MG63 osteoblast-like cells cultured on PEEK, sTiAlV, or rTiAlV surfaces and their production of bone morphogenetic proteins (BMPs). METHODS: Surface properties of PEEK, sTiAlV, and rTiAlV discs were determined. Human MG63 cells were grown on TCPS and the discs. Confluent cultures were harvested, and cell number, alkaline phosphatase-specific activity, and osteocalcin were measured as indicators of osteoblast maturation. Expression of messenger RNA (mRNA) for BMP2 and BMP4 was measured by real-time polymerase chain reaction. Levels of BMP2, BMP4, and BMP7 proteins were also measured in the conditioned media of the cell cultures. RESULTS: Although roughness measurements for sTiAlV (S(a)=0.09±0.01), PEEK (S(a)=0.43±0.07), and rTiAlV (S(a)=1.81±0.51) varied, substrates had similar contact angles, indicating comparable wettability. Cell morphology differed depending on the surface. Cells cultured on Ti6Al4V had lower cell number and increased alkaline phosphatase specific activity, osteocalcin, BMP2, BMP4, and BMP7 levels in comparison to PEEK. In particular, roughness significantly increased the mRNA levels of BMP2 and BMP4 and secreted levels of BMP4. CONCLUSIONS: These data demonstrate that rTiAlV substrates increase osteoblast maturation and produce an osteogenic environment that contains BMP2, BMP4, and BMP7. The results show that modifying surface structure is sufficient to create an osteogenic environment without addition of exogenous factors, which may induce better and faster bone during interbody fusion.
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524Barz, T.; Lange, J.; Melloh, M.; Staub, L. P.; Merk, H. R.; Kloting, I.; Follak, N. Spine (Philadelphia) 2013, 38, E263Google ScholarThere is no corresponding record for this reference.
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525Chen, L.; Hu, J.; Shen, X.; Tong, H. J. Mater. Sci.: Mater. Med. 2013, 24, 1843Google Scholar525https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFWjurvP&md5=8155a487731f2cbe84529045185ca2deSynthesis and characterization of chitosan-multiwalled carbon nanotubes/hydroxyapatite nanocomposites for bone tissue engineeringChen, Li; Hu, Jingxiao; Shen, Xinyu; Tong, HuaJournal of Materials Science: Materials in Medicine (2013), 24 (8), 1843-1851CODEN: JSMMEL; ISSN:0957-4530. (Springer)Chitosan-multiwalled carbon nanotubes/hydroxyapatite nanocomposites were synthesized by a novel in situ pptn. method. The electrostatic adsorption between multiwalled carbon nanotubes and chitosan was investigated and explained by Fourier transform IR spectroscopy anal. Morphol. studies showed that uniform distribution of hydroxyapatite particles and multiwalled carbon nanotubes in the polymer matrix was obsd. In chitosan-multiwalled carbon nanotubes/hydroxyapatite nanocomposites, the diams. of multiwalled carbon nanotubes were about 10 nm. The mech. properties of the composites were evaluated by measuring their compressive strength and elastic modulus. The elastic modulus and compressive strength increased sharply from 509.9 to 1089.1 MPa and from 33.2 to 105.5 MPa with an increase of multiwalled carbon/chitosan wt. ratios from 0 to 5 %, resp. Finally, the cell biocompatibility of the composites was tested in vitro, which showed that they have good biocompatibility. These results suggest that the chitosan-multiwalled carbon nanotubes/hydroxyapatite nanocomposites are promising biomaterials for bone tissue engineering.
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526Gupta, A.; Woods, M. D.; Illingworth, K. D.; Niemeier, R.; Schafer, I.; Cady, C.; Filip, P.; El-Amin, S. F., III. J. Orthop. Res. 2013, 31, 1374Google Scholar526https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFGms73P&md5=9742a9f8a36ecd7bef2ae394cac29cdaSingle walled carbon nanotube composites for bone tissue engineeringGupta, Ashim; Woods, Mia D.; Illingworth, Kenneth David; Niemeier, Ryan; Schafer, Isaac; Cady, Craig; Filip, Peter; El-Amin, Saadiq F., IIIJournal of Orthopaedic Research (2013), 31 (9), 1374-1381CODEN: JOREDR; ISSN:0736-0266. (John Wiley & Sons, Inc.)The purpose of this study was to develop single walled carbon nanotubes (SWCNT) and poly lactic-co-glycolic acid (PLAGA) composites for orthopedic applications and to evaluate the interaction of human stem cells (hBMSCs) and osteoblasts (MC3T3-E1 cells) via cell growth, proliferation, gene expression, extracellular matrix prodn. and mineralization. PLAGA and SWCNT/PLAGA composites were fabricated with various amts. of SWCNT (5, 10, 20, 40, and 100 mg), characterized and degrdn. studies were performed. Cells were seeded and cell adhesion/morphol., growth/survival, proliferation and gene expression anal. were performed to evaluate biocompatibility. Imaging studies demonstrated uniform incorporation of SWCNT into the PLAGA matrix and addn. of SWCNT did not affect the degrdn. rate. Imaging studies revealed that MC3T3-E1 and hBMSCs cells exhibited normal, non-stressed morphol. on the composites and all were biocompatible. Composites with 10 mg SWCNT resulted in highest rate of cell proliferation (p < 0.05) among all composites. Gene expression of alk. phosphatase, collagen I, osteocalcin, osteopontin, Runx-2, and Bone Sialoprotein was obsd. on all composites. In conclusion, SWCNT/PLAGA composites imparted beneficial cellular growth capabilities and gene expression, and mineralization abilities were well established. These results demonstrate the potential of SWCNT/PLAGA composites for musculoskeletal regeneration and bone tissue engineering (BTE) and are promising for orthopedic applications. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1374-1381, 2013.
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527European Commission. Proposal for a regulation of the european parliament and of thecouncil on medical devices, and amending directive 2001/83/ec, regulation(ec) no 178/2002 and regulation (EC) No 1223/2009. COM 2012, 542 final.Google ScholarThere is no corresponding record for this reference.
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528Vardharajula, S.; Ali, S. Z.; Tiwari, P. M.; Eroğlu, E.; Vig, K.; Dennis, V. A.; Singh, S. R. Int. J. Nanomed. 2012, 7, 5361Google Scholar528https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFylu7zI&md5=d6d34474594e1d54ad95459386f814e7Functionalized carbon nanotubes: biomedical applicationsVardharajula, Sandhya; Ali, Sk. Z.; Tiwari, Pooja M.; Eroglu, Erdal; Vig, Komal; Dennis, Vida A.; Singh, Shree R.International Journal of Nanomedicine (2012), 7 (), 5361-5374CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)A review. Carbon nanotubes (CNTs) are emerging as novel nanomaterials for various biomedical applications. CNTs can be used to deliver a variety of therapeutic agents, including biomols., to the target disease sites. In addn., their unparalleled optical and elec. properties make them excellent candidates for bioimaging and other biomedical applications. However, the high cytotoxicity of CNTs limits their use in humans and many biol. systems. The biocompatibility and low cytotoxicity of CNTs are attributed to size, dose, duration, testing systems, and surface functionalization. The functionalization of CNTs improves their soly. and biocompatibility and alters their cellular interaction pathways, resulting in much-reduced cytotoxic effects. Functionalized CNTs are promising novel materials for a variety of biomedical applications. These potential applications are particularly enhanced by their ability to penetrate biol. membranes with relatively low cytotoxicity. This review is directed towards the overview of CNTs and their functionalization for biomedical applications with minimal cytotoxicity.
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Abstract
Figure 1
Figure 1. Time trends for the number of articles found in the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed/) (accessed 20 March 2014) by search using “carbon nanotubes” and “biomaterials” as keywords. Recent years have seen a rapidly increasing number of research articles on the application of CNTs to biomaterials; the number has been soaring since 2005, suggesting that the application of CNTs to biomaterials has become a highly competitive research field worldwide over the past few years. This graph indicates only a time course, and numerous articles on biological applications of CNTs do exist that cannot be captured with these two keywords.
Figure 2
Figure 2. Biological applications of CNTs encompass a broad range of fields, many of which, in addition, represent themes of top priority in today’s clinical medicine, such as cancer treatment and regenerative medicine. Modified from ref 84, which is published under the Creative Commons Attribution License.
Figure 3
Figure 3. CNTs are capable of working as a platform for concurrently binding drugs such as anticancer agents, proteins, and peptides such as monoclonal antibodies, high molecular polymers, and other molecules that otherwise cannot be bound to each other. Making the best use of this feature, it would be possible to concurrently add to CNTs multiple functions that have traditionally been unable to concur, such as drug transportation, biomembrane passage, and release at targeted sites.
Figure 4
Figure 4. MWCNTs promote ectopic osteogenesis by rhBMP-2 and collagen. (a) A soft X-ray radiogram of newly formed bones extirpated 2 weeks after placement of rhBMP-2/collagen/MWCNT composite (upper lane) or rhBMP-2/collagen composite (lower lane) in mouse back muscle. Larger bones with more intense opacity were formed when using collagen conjugated with MWCNTs than without. (b) Bone mineral contents (BMCs) in bones formed at 2 weeks of implantation. A significantly higher BMC was observed in bones formed at 2 weeks of implantation of collagen conjugated with MWCNTs than without. Each error bar indicates the standard deviation of the mean (n = 8); asterisk, P = 0.016 between samples treated with carbon nanotubes and those without (unpaired Student’s t test). (c) Histological images of bones extirpated at 2 weeks. The trabecula was thicker and denser when using collagen conjugated with MWCNTs than collagen alone. The tissue around the implanted collagen–MWCNT conjugate was found to have MWCNTs absorbed uniformly in the trabecula and bone marrow. The MWCNTs were seen to have entered the trabecula and came in direct contact with bone substrate. Hematoxylin-eosin staining. Scale bars = 100 mm. Reprinted with permission from ref 213. Copyright 2008 John Wiley & Sons, Inc.
Figure 5
Figure 5. MWCNTs exhibiting good bone compatibility as they are absorbed in repaired bone without interfering with bone repair. (a) A histological image of a tibia extirpated 4 weeks after surgery for implant of MWCNTs in a pit drilled in tibial diaphysis after incising the anterior surface of a mouse leg. Cortical bone and a medullary cavity were normally formed to the extent of complete bone repair. The MWCNTs were found to have been absorbed in the newly formed bone tissue and enclosed in bone substrate. Hematoxylin-eosin staining. Scale bar = 100 mm. (b) An electron microscopic image of MWCNTs absorbed in repaired bone tissue at 4 weeks. The MWCNTs were found to be in direct contact with bone substrate hydroxyapatite. Scale bar = 1 mm. Reprinted with permission from ref 213. Copyright 2008 John Wiley & Sons, Inc.
Figure 6
Figure 6. Cellular uptake of pristine MWCNTs varies depending on the type of cell and the choice of dispersant. (a) Combined images from bright field images and phase-contrast photomicrographs obtained 24 h after exposure of human malignant pleural mesothelioma cells (MESO-1), human bronchial epithelial cells (BEAS-2B), and human neuroblasts (IMR-32) to carbon black (CB, 50 nm diameter) and MWCNTs. Both CB and MWCNTs were absorbed in the MESO-1 cells and BEAS-2B cells, and localized around the respective exposure sites, whereas in the case of the IMR-32 cells, both CB and MWCNTs adhered but failed to be absorbed. CB and MWCNTs were added at 1 μg/mL for the treatment of BEAS-2B cells, and 10 μg/mL for the treatment of the other cells. Scale bars = 50 μm. Reprinted with permission from ref 384. Copyright 2011 Nature Publishing Group. (b) A comparison of cellular uptake in BEAS-2B observed 1 and 24 h after exposure to MWCNTs dispersed using different dispersants. Cellular uptake was determined in terms of the intensity of side scattered light (SSC) from MWCNTs absorbed in the cells using a flow cytometer. The MWCNTs dispersed in gelatin or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were increasingly absorbed over time, whereas those dispersed in carboxymethylcellulose (CMC) were little absorbed in the cells. Reprinted with permission from ref 385. Copyright 2011 Dove Medical Press.
Figure 7
Figure 7. A schematic diagram showing a hypothesized mechanism of carcinogenesis due to frustrated phagocytosis. If left unabsorbed, long CNTs in cells can produce oxidative stress and induce inflammation. It has been suggested that a long period of persistent inflammation in the thoracic cavity following inhalation of CNTs can lead to carcinogenesis. Currently, research into the inhalation toxicity of CNTs is facing a problem with the determination of the margin of inhalation exposure that does not cause persistent inflammation.
Figure 8
Figure 8. Having historically been proven safe to the human body, tattoos comprise nanosized highly pure carbon black, and hence serve well as a reference material for evaluating the safety of CNTs, which likewise occur in the form of nanosized carbon particles. (a) Scanning electron microscopy (SEM) images of tattoo carbon black-1 (TCB-1) and tattoo carbon black-2 (TCB-2) prepared by drying two different tattoos. TCB-1 and TCB-2 were found to have accumulated in the form of generally regular particles having a diameter of about 30–50 nm, and generally irregular particles having a diameter of about 50 nm, respectively. (b) Raman analysis of TCB-1, TCB-2, and ordinary carbon black. TCB-1 and TCB-2 exhibited nearly the same Raman shift pattern as with ordinary carbon black. D-band, turbostratic amorphous; G band, graphite crystal. (c) Transmission electron microscopy (TEM) images of TCB-1, TCB-2, and ordinary carbon black. These three substances were found to have nearly the same particle shape. Reprinted with permission from ref 97. Copyright 2011 Elsevier.
Figure 9
Figure 9. Histological reactions to subcutaneously implanted MWCNTs are very similar to those to carbon black, showing good tissue compatibility. Hematoxylin-eosin staining. Scale bars = 20 μm. TCB-1, Tattoo carbon black-1; TCB-2, Tattoo carbon black-2 (see Figure 8). (a) Histological images from a negative control group (NC) of male ddY mice at 6 weeks of age receiving an injection of 10 μL of physiological saline and a surfactant given to a pocket created in subcutaneous tissue in the back. At 1 week of treatment, the subcutaneous tissue had been repaired nearly completely. Repair was complete at 4 weeks. No change was observed at 12 and 24 weeks. (b) Histological images of subcutaneous tissue from a group receiving an injection of 10 μL of MWCNT solution (4.0 mg/mL). Most particles were found to have been absorbed in macrophages at 1 week. In the areas around the injection site, accumulated fibroblasts, neutrophils, and lymphocytes were found, with weak inflammatory reactions observed. At 4 weeks, the MWCNTs remained incorporated in macrophages, and the inflammatory reactions around the injection site had resolved. The macrophages that had absorbed MWCNTs turned into multinucleated giant cells, creating an appearance like foreign-body granuloma. The histological profiles obtained at 12 and 24 weeks did not differ from the profile obtained at 4 weeks. (c) Histological images of subcutaneous tissue from a group receiving an injection of 10 μL of TCB-1 solution (4.0 mg/mL). At 1 week, most particles were found to have been absorbed in macrophages in the subcutaneous tissue, and as in the MWCNT group, accumulated fibroblasts, neutrophils, and lymphocytes were found, with weak inflammatory reactions observed. At 4 weeks, the inflammatory reactions around the injection site had resolved as in the MWCNT group. The histological profiles obtained at 12 and 24 weeks were similar to the profile obtained at 4 weeks. (d) Histological images of subcutaneous tissue from a group receiving an injection of 10 μL of TCB-2 solution (4.0 mg/mL). All histological profiles obtained at 1, 4, 12, and 24 weeks were similar to those obtained with the TCB-1 solution. (e) Histological images of subcutaneous tissue from a group receiving an injection of 10 μL of zinc dibutyldithiocarbamate (ZDBC) solution (4.0 mg/mL). At 1 week, accumulation of many types of inflammatory cells such as fibroblasts, neutrophils, lymphocytes, and plasma cells was observed, and intense inflammatory reactions had been induced over a wide area, with fat necrosis and nuclear debris formation observed. No accumulation of macrophages was observed. Even at 4 weeks, inflammatory cells remained and inflammatory reactions persisted, although the inflammation was going to disappear. At 12 and 24 weeks, the inflammatory reactions had resolved, and the subcutaneous tissue had been repaired into scar tissue with fibrosis. Reprinted with permission from ref 97. Copyright 2011 Elsevier.
Figure 10
Figure 10. The cytotoxicity of MWCNTs is not higher than that of carbon black. TCB-1, Tattoo carbon black-1; TCB-2, Tattoo carbon black-2 (see Figure 8). (a) Appropriateness of cytotoxicity assessment in colonization test. The colonization capacity of V79 cells (Chinese hamster lung fibroblast cell line JCRB0603) decreased as the concentration of the positive control ZDBC increased. The concentration for 50% colony count reduction (IC50, reference value range: 1–4 μg/mL) was found to be between 1 and 2 μg/mL, confirming that the cytotoxic action of the test substance was properly assessed. (b) Macroscopic photographs showing colonization test results. Colony counts of V79 cells cultured using a culture broth alone and those cultured in the presence of MWCNT solution, TCB-1 solution, and TCB-2 solution were compared. The concentrations in the solutions were 12.5, 50, 200, 400, 800, and 1600 μg/mL, respectively. (c) Colony counts versus carbon concentrations in MWCNT, TCB-1, and TCB-2 solutions. MWCNTs inhibited the colonization in a concentration-dependent fashion, and TCB-1 and TCB-2 likewise inhibited the colonization in a concentration-dependent fashion. When comparing colony counts, MWCNTs produced significantly higher colony counts than TCB-1 at concentrations of 200 μg/mL or more, and than TCB-2 at concentrations of 400 μg/mL or more. Error bars indicate standard deviations (n = 6); *, p < 0.001; **, p = 0.016. Reprinted with permission from ref 97. Copyright 2011 Elsevier.
Figure 11
Figure 11. In a subcutaneous implantation test using cancer-developing transgenic rasH2 mice, MWCNTs were found to be not carcinogenic; their carcinogenicity was determined to be not higher than that of carbon black. (a) Changes over time in survival rate of rasH2 mice. All mice in the MWCNT group were alive at 26 weeks. In the carbon black group, 1 animal died at 22 weeks, and at 26 weeks, 9 of the 10 animals were alive. In the solvent group, all mice were alive at 26 weeks. In the N-methyl-N-nitrosourea (MNU) group, 1 animal died at 13, 14, 17, and 22 weeks each; 6 of the 10 animals were alive at 26 weeks. (b) Histological images of tumor masses in various organs of cancer-developing mice. (A) A tumor mass was observed in the spleen of 1 of the 10 mice in the MWCNT group that survived for 26 weeks; this was identified as an inflammatory pseudotumor, not a neoplasm. (B) A neoplasm developed in a lung of 1 mouse in the carbon black group that survived for 26 weeks; this was diagnosed as a benign adenoma. (C) All 10 mice in the MNU group had tumors. Proventricular tumors developed in all 10 animals, with abnormal squamous epithelial growth observed (upper left panel). Skin tumors developed in 6 of the 10 animals, which occurred as malignant skin tumors in the thigh (upper right panel). Genital tumors developed in 4 animals (lower left panel). A thymic tumor developed in 1 animal (lower right panel). Hematoxylin-eosin staining. Scale bars = 10 μm. (c) Histological images of subcutaneous implantation sites taken at 26 weeks. (A) In the MWCNT group, no neoplasm developed, with macrophages found to have accumulated while phagocytosing MWCNT particles. No inflammatory cells such as neutrophils and lymphocytes were observed around the implantation sites. (B) In the carbon black group, like in the MWCNT group, macrophages phagocytosed MWCNT particles, with no neoplasm observed. Arrow, MWCNTs; arrowhead, carbon black. Hematoxylin-eosin staining. Scale bars = 10 μm. Reprinted with permission from ref 98. Copyright 2012 Nature Publishing Group.
Figure 12
Figure 12. For application to sliding parts of artificial joints, an ultrahigh molecular weight polyethylene (UHMWPE) conjugated with MWCNTs has been developed. (a) A UHMWPE socket (left panel) and an MWCNT-conjugated UHMWP socket (right panel) for use in sliding parts of artificial joints. (b) A prototype artificial joint with a socket made of CNTs. Having favorable characteristics that have not been achieved with conventional materials, that is, high wear resistance and low breakability, MWCNT-conjugated UHMWPE is suitable as a sliding parts material for artificial joints.
Figure 13
Figure 13. For application to spine interbody fusion material, a polyetheretherketone (PEEK) composite with MWCNTs has been developed. (a) A conceptual diagram showing that PEEK, when conjugated with MWCNTs, will become an innovative spine interbody fusion material possessing excellent mechanical characteristics and bone compatibility. (A) The MWCNTs on the surface confer bone compatibility. (B) The internally conjugated MWCNTs control the elastic modulus. (b) (A) A PEEK spine interbody fusion cage (left panel) and an MWCNT-conjugated PEEK cage (right panel). (B) A prototype interbody fusion cage made of CNTs.
Naoto Saito
Naoto Saito is a professor and director of the Institute for Biomedical Sciences, Shinshu University. He is an experienced researcher specializing in biochemistry, cell biology, regenerative medicine, biomaterials, and nanobiotechnology. As the leader of Shinshu University’s Nanobiotechnology and Biomedical Engineering Team, he is working on developing CNT-based biomaterials.
Hisao Haniu
Hisao Haniu is serving as a lecturer in the Department of Orthopaedic Surgery, Shinshu University School of Medicine. He is a qualified clinical laboratory technician and specializes in physiology and biochemistry, especially in proteomics. He is engaged in research on the safety evaluation of nanomaterials and in the training of many young researchers.
Yuki Usui
Yuki Usui is an associate professor at the Research Center for Exotic Nanocarbons, Shinshu University. He is an orthopedist, specializing in research on the biological application of nanomaterials. He showed for the first time that CNTs promote bone formation in an animal study on bone tissue regeneration.
Kaoru Aoki
Kaoru Aoki is serving as a research associate in the Department of Orthopaedic Surgery, Shinshu University School of Medicine. He is a medical doctor specializing in bone and soft tissue tumors, and also a rehabilitation doctor. He is concurrently engaged in basic research and clinical research, conducting research to apply nanocarbons as drug delivery systems for anticancer agents.
Kazuo Hara
Kazuo Hara is an orthopaedic surgeon in the Department of Orthopaedic Surgery, Shinshu University School of Medicine. His special interest is evaluation of the biological safety of CNTs as biomaterials.
Seiji Takanashi
Seiji Takanashi is a researcher at the Shinshu University School of Medicine, and is also serving as a medical doctor in the Department of Orthopaedic Surgery. He is working on evaluating the carcinogenicity of CNTs in transgenic mice and clarifying the action of nanomaterials in cells.
Masayuki Shimizu
Masayuki Shimizu serves as a research associate in the Department of Orthopaedic Surgery, Shinshu University School of Medicine. He is a medical doctor specializing in spinal surgery, and conducts both basic and clinical research. He is exploring the mechanism of bone formation promotion by CNTs at the cellular level.
Nobuyo Narita
Nobuyo Narita is a research associate in the Department of Orthopaedic Surgery, Shinshu University School of Medicine. She specializes in lower limb surgery, serving as a leader of the foot surgery team at Shinshu University Hospital. She demonstrated using intracellular signals that CNTs suppress the function of osteoclasts.
Masanori Okamoto
Masanori Okamoto is a researcher at the Shinshu University School of Medicine, and is a medical doctor in the Department of Orthopaedic Surgery. He is now studying bone metabolism at Matsumoto Dental University and has a special interest in the action of Wnt5 in osteoblasts.
Shinsuke Kobayashi
Shinsuke Kobayashi is a researcher at the Shinshu University School of Medicine. He specializes in safety evaluation of nanomaterials, and is investigating the in vivo kinetics of CNTs using MRI and CT.
Hiroki Nomura
Hiroki Nomura is a researcher at the Shinshu University School of Medicine. As a member of the research and development team for application of CNT-conjugated polyethylene to artificial joints, he is engaged in evaluating the biological safety of CNTs and their composites.
Hiroyuki Kato
Hiroyuki Kato is a professor in the Department of Orthopaedic Surgery, Shinshu University School of Medicine. He specializes in hand surgery and conducts research on nerves and tendons. He provides research and clinical practice training to many physicians in the Department of Orthopaedics at Shinshu University Hospital.
Naoyuki Nishimura
Naoyuki Nishimura is the director of the R&D Center, Nakashima Medical Co. Ltd. He is developing artificial joints and spinal fixation devices made of CNT composites jointly with Shinshu University. He investigates safety and regulatory science with the aim of clinical application of CNT composites.
Seiichi Taruta
Seiichi Taruta is a professor in the Faculty of Engineering, Shinshu University. He is working on developing CNT-conjugate ceramics and bioactive ceramics. He is also a member of a medicine-engineering collaboration research project to develop CNT-based artificial joints.
Morinobu Endo
Morinobu Endo is a distinguished professor in the Faculty of Engineering, Shinshu University. As the discoverer of the manufacturing process for CNTs using a chemical vapor deposition approach, he has been a world leader in CNTs research. As head of the Research Center for Exotic Nanocarbons, he currently conducts research on multitargeted application of nanocarbons.
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4Aliev, A. E.; Oh, J.; Kozlov, M. E.; Kuznetsov, A. A.; Fang, S.; Fonseca, A. F.; Ovalle, R.; Lima, M. D.; Haque, M. H.; Gartstein, Y. N.; Zhang, M.; Zakhidov, A. A.; Baughman, R. H. Science 2009, 323, 1575There is no corresponding record for this reference.
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5Toma, F. M.; Sartorel, A.; Iurlo, M.; Carraro, M.; Parisse, P.; Maccato, C.; Rapino, S.; Gonzalez, B. R.; Amenitsch, H.; Da Ros, T.; Casalis, L.; Goldoni, A.; Marcaccio, M.; Scorrano, G.; Scoles, G.; Paolucci, F.; Prato, M.; Bonchio, M. Nat. Chem. 2010, 2, 8265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtF2ms7fF&md5=4cf85282d33c9034a7c26a21fa03e7f2Efficient water oxidation at carbon nanotube-polyoxometalate electrocatalytic interfacesToma, Francesca M.; Sartorel, Andrea; Iurlo, Matteo; Carraro, Mauro; Parisse, Pietro; Maccato, Chiara; Rapino, Stefania; Gonzalez, Benito Rodriguez; Amenitsch, Heinz; Da Ros, Tatiana; Casalis, Loredana; Goldoni, Andrea; Marcaccio, Massimo; Scorrano, Gianfranco; Scoles, Giacinto; Paolucci, Francesco; Prato, Maurizio; Bonchio, MarcellaNature Chemistry (2010), 2 (10), 826-831CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)Water is the renewable, bulk chem. that nature uses to enable carbohydrate prodn. from carbon dioxide. The dream goal of energy research is to transpose this incredibly efficient process and make an artificial device whereby the catalytic splitting of water is finalized to give a continuous prodn. of oxygen and hydrogen. Success in this task would guarantee the generation of hydrogen as a carbon-free fuel to satisfy our energy demands at no environmental cost. Here we show that very efficient and stable nanostructured, oxygen-evolving anodes are obtained by the assembly of an oxygen-evolving polyoxometalate cluster (a totally inorg. ruthenium catalyst) with a conducting bed of multiwalled carbon nanotubes. Our bioinspired electrode addresses the one major challenge of artificial photosynthesis, namely efficient water oxidn., which brings us closer to being able to power the planet with carbon-free fuels.
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6Foroughi, J.; Spinks, G. M.; Wallace, G. G.; Oh, J.; Kozlov, M. E.; Fang, S.; Mirfakhrai, T.; Madden, J. D.; Shin, M. K.; Kim, S. J.; Baughman, R. H. Science 2011, 334, 494There is no corresponding record for this reference.
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7Kreupl, F. Nature 2012, 484, 321There is no corresponding record for this reference.
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8Behabtu, N.; Young, C. C.; Tsentalovich, D. E.; Kleinerman, O.; Wang, X.; Ma, A. W.; Bengio, E. A.; ter Waarbeek, R. F.; de Jong, J. J.; Hoogerwerf, R. E.; Fairchild, S. B.; Ferguson, J. B.; Maruyama, B.; Kono, J.; Talmon, Y.; Cohen, Y.; Otto, M. J.; Pasquali, M. Science 2013, 339, 182There is no corresponding record for this reference.
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9Cao, Q.; Han, S. J.; Tulevski, G. S.; Zhu, Y.; Lu, D. D.; Haensch, W. Nat. Nanotechnol. 2013, 8, 1809https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVejt7g%253D&md5=06979b12f186b9175dbab0763542babdArrays of single-walled carbon nanotubes with full surface coverage for high-performance electronicsCao, Qing; Han, Shu-jen; Tulevski, George S.; Zhu, Yu; Lu, Darsen D.; Haensch, WilfriedNature Nanotechnology (2013), 8 (3), 180-186CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Single-walled carbon nanotubes have exceptional electronic properties and were proposed as a replacement for silicon in applications such as low-cost thin-film transistors and high-performance logic devices. However, practical devices will require dense, aligned arrays of electronically pure nanotubes to optimize performance, maximize device packing d. and provide sufficient drive current (or power output) for each transistor. Here, we show that aligned arrays of semiconducting carbon nanotubes can be assembled using the Langmuir-Schaefer method. The arrays have a semiconducting nanotube purity of 99% and can fully cover a surface with a nanotube d. of >500 tubes/μm. The nanotube pitch is self-limited by the diam. of the nanotube plus the van der Waals sepn., and the intrinsic mobility of the nanotubes is preserved after array assembly. Transistors fabricated using this approach exhibit significant device performance characteristics with a drive c.d. of \>120 μA μm-1, transconductance greater than 40 μS μm-1 and on/off ratios of ∼1 × 103.
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10De Volder, M. F.; Tawfick, S. H.; Baughman, R. H.; Hart, A. J. Science 2013, 339, 535There is no corresponding record for this reference.
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11Ganzhorn, M.; Klyatskaya, S.; Ruben, M.; Wernsdorfer, W. Nat. Nanotechnol. 2013, 8, 16511https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFSmsrs%253D&md5=542178a56aaa9a42abee0c40aff066a1Strong spin-phonon coupling between a single-molecule magnet and a carbon nanotube nanoelectromechanical systemGanzhorn, Marc; Klyatskaya, Svetlana; Ruben, Mario; Wernsdorfer, WolfgangNature Nanotechnology (2013), 8 (3), 165-169CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Magnetic relaxation processes were 1st discussed for a crystal of paramagnetic transition ions. Probably mech. vibrations of the crystal lattice (phonons) modulate the crystal elec. field of the magnetic ion, thus inducing a direct' relaxation between two different spin states. Direct relaxation also was predicted for single-mol. magnets with a large spin and a high magnetic anisotropy and was 1st demonstrated in a Mn12 acetate crystal. The spin-lattice relaxation time for such a direct transition is limited by the phonon d. of states at the spin resonance. In a three-dimensional system, such as a single-mol. magnet crystal, the phonon energy spectrum is continuous, but in a 1-dimensional system, like a suspended C nanotube, the spectrum is discrete and can be engineered to an extremely low d. of states. An individual single-mol. magnet, coupled to a suspended C nanotube, should therefore exhibit extremely long relaxation times and the system's reduced size should result in a strong spin-phonon coupling. Here, the authors provide the 1st exptl. evidence for a strong spin-phonon coupling between a single mol. spin and a C nanotube resonator, ultimately enabling coherent spin manipulation and quantum entanglement.
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12Baughman, R. H.; Zakhidov, A. A.; de Heer, W. A. Science 2002, 297, 78712https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XlvVyhsrw%253D&md5=1102737a224e934b7a370610de566773Carbon nanotubes-the route toward applicationsBaughman, Ray H.; Zakhidov, Anvar A.; de Heer, Walt A.Science (Washington, DC, United States) (2002), 297 (5582), 787-792CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A review. Many potential applications are proposed for carbon nanotubes, including conductive and high-strength composites; energy storage and energy conversion devices sensors; field emission displays and radiation sources; hydrogen storage media; and nanometer-sized semiconductor devices, probes, and interconnects. Some of these applications are now realized in products. Others are demonstrated in early to advanced devices and one, hydrogen storage, is clouded by controversy. Nanotube cost, polydispersity in nanotube type, and limitations in processing and assembly methods are important barriers for some applications of single-walled nanotubes.
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13Kashiwagi, T.; Du, F.; Douglas, J. F.; Winey, K. I.; Harris, R. H., Jr.; Shields, J. R. Nat. Mater. 2005, 4, 928There is no corresponding record for this reference.
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14Coleman, J. N.; Khan, U.; Blau, W. J.; Gun’ko, Y. K. Carbon 2006, 44, 162414https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XkslGkt7w%253D&md5=af04f27408ff58fdd5e917019c95d4dcSmall but strong: A review of the mechanical properties of carbon nanotube-polymer compositesColeman, Jonathan N.; Khan, Umar; Blau, Werner J.; Gun'ko, Yurii K.Carbon (2006), 44 (9), 1624-1652CODEN: CRBNAH; ISSN:0008-6223. (Elsevier Ltd.)A review. The superlative mech. properties of carbon nanotubes make them the filler material of choice for composite reinforcement. In this paper we review the progress to date in the field of mech. reinforcement of polymers using nanotubes. Initially, the basics of fiber reinforced composites are introduced and the prerequisites for successful reinforcement discussed. The effectiveness of different processing methods is compared and the state of the art demonstrated. In addn. we discuss the levels of reinforcement that have actually been achieved. While the focus will be on enhancement of Young's modulus we will also discuss enhancement of strength and toughness. Finally we compare and tabulate these results. This leads to a discussion of the most promising processing methods for mech. reinforcement and the outlook for the future.
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15Veedu, V. P.; Cao, A.; Li, X.; Ma, K.; Soldano, C.; Kar, S.; Ajayan, P. M.; Ghasemi-Nejhad, M. N. Nat. Mater. 2006, 5, 457There is no corresponding record for this reference.
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16Peng, B.; Locascio, M.; Zapol, P.; Li, S.; Mielke, S. L.; Schatz, G. C.; Espinosa, H. D. Nat. Nanotechnol. 2008, 3, 62616https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1SlurjO&md5=1db357912e47b4b297fe494df3d2d9f2Measurements of near-ultimate strength for multiwalled carbon nanotubes and irradiation-induced crosslinking improvementsPeng, Bei; Locascio, Mark; Zapol, Peter; Li, Shuyou; Mielke, Steven L.; Schatz, George C.; Espinosa, Horacio D.Nature Nanotechnology (2008), 3 (10), 626-631CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)The excellent mech. properties of carbon nanotubes are being exploited in a growing no. of applications from ballistic armor to nanoelectronics. However, measurements of these properties have not achieved the values predicted by theory due to a combination of artifacts introduced during sample prepn. and inadequate measurements. Here we report multiwalled carbon nanotubes with a mean fracture strength >100 GPa, which exceeds earlier observations by a factor of ∼3. These results are in excellent agreement with quantum-mech. ests. for nanotubes contg. only an occasional vacancy defect, and are ∼80% of the values expected for defect-free tubes. This performance is made possible by omitting chem. treatments from the sample prepn. process, thus avoiding the formation of defects. High-resoln. imaging was used to directly det. the no. of fractured shells and the chirality of the outer shell. Electron irradn. at 200 keV for 10, 100 and 1800 s led to improvements in the max. sustainable loads by factors of 2.4, 7.9 and 11.6 compared with non-irradiated samples of similar diam. This effect is attributed to crosslinking between the shells. Computer simulations also illustrate the effects of various irradn.-induced crosslinking defects on load sharing between the shells.
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17Qu, L.; Dai, L.; Stone, M.; Xia, Z.; Wang, Z. L. Science 2008, 322, 238There is no corresponding record for this reference.
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18Shannon, M. A.; Bohn, P. W.; Elimelech, M.; Georgiadis, J. G.; Mariñas, B. J.; Mayes, A. M. Nature 2008, 452, 301There is no corresponding record for this reference.
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19Bauhofer, W.; Kovacs, J. Z. Compos. Sci. Technol. 2009, 69, 148619https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXntlSis7g%253D&md5=b132f119499ffdaef45269fa89953f6cA review and analysis of electrical percolation in carbon nanotube polymer compositesBauhofer, Wolfgang; Kovacs, Josef Z.Composites Science and Technology (2009), 69 (10), 1486-1498CODEN: CSTCEH; ISSN:0266-3538. (Elsevier B.V.)A review. We review exptl. and theor. work on elec. percolation of carbon nanotubes (CNT) in polymer composites. We give a comprehensive survey of published data together with an attempt of systematization. Parameters like CNT type, synthesis method, treatment and dimensionality as well as polymer type and dispersion method are evaluated with respect to their impact on percolation threshold, scaling law exponent and max. cond. of the composite. Validity as well as limitations of commonly used statistical percolation theories are discussed, in particular with respect to the recently reported existence of a lower kinetic (allowing for re-aggregation) and a higher statistical percolation threshold.
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20Chou, T. W.; Gao, L.; Thostenson, E. T.; Zhang, Z.; Byun, J. H. Compos. Sci. Technol. 2010, 70, 120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsV2mtLnP&md5=747eaf6a1618454ebcaba406b4ba3e82An assessment of the science and technology of carbon nanotube-based fibers and compositesChou, Tsu-Wei; Gao, Limin; Thostenson, Erik T.; Zhang, Zuoguang; Byun, Joon-HyungComposites Science and Technology (2009), 70 (1), 1-19CODEN: CSTCEH; ISSN:0266-3538. (Elsevier B.V.)A review. This paper examines the recent advancements in the science and technol. of carbon nanotube (CNT)-based fibers and composites. The assessment is made according to the hierarchical structural levels of CNTs used in composites, ranging from 1-D to 2-D to 3-D. At the 1-D level, fibers composed of pure CNTs or CNTs embedded in a polymeric matrix produced by various techniques are reviewed. At the 2-D level, the focuses are on CNT-modified advanced fibers, CNT-modified interlaminar surfaces and highly oriented CNTs in planar form. At the 3-D level, we examine the mech. and phys. properties CNT/polymer composites, CNT-based damage sensing, and textile assemblies of CNTs. The opportunities and challenges in basic research at these hierarchical levels have been discussed.
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21Xu, M.; Futaba, D. N.; Yamada, T.; Yumura, M.; Hata, K. Science 2010, 330, 1364There is no corresponding record for this reference.
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22Bakshi, S. R.; Agarwal, A. Carbon 2011, 49, 533There is no corresponding record for this reference.
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23Xiong, F.; Liao, A. D.; Estrada, D.; Pop, E. Science 2011, 332, 568There is no corresponding record for this reference.
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24Endo, M.; Kim, Y. A.; Hayashi, T.; Nishimura, K.; Matusita, T.; Miyashita, K.; Dresselhaus, M. S. Carbon 2001, 39, 128724https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXktV2isb8%253D&md5=152ece41d2bc3029c989495f3bd6025bVapor-grown carbon fibers (VGCFs). Basic properties and their battery applicationsEndo, M.; Kim, Y. A.; Hayashi, T.; Nishimura, K.; Matusita, T.; Miyashita, K.; Dresselhaus, M. S.Carbon (2001), 39 (9), 1287-1297CODEN: CRBNAH; ISSN:0008-6223. (Elsevier Science Ltd.)Submicron vapor grown carbon fibers (VGCFs) obtained by a floating growth method were evaluated in terms of their microstructural development with heat treatment temp., phys. properties of a single fiber and of the bulk state, and addnl. effects, such as the filler in the electrode of a lead-acid battery and a Li-ion battery system. Its desirable properties, such as relatively high mech. strength and elec. cond., both in the single fiber state and in the bulk state, including their very special network-like morphol., improved the performance of the electrodes in lead-acid batteries and Li-ion batteries, esp. their cycle characteristics.
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25Kang, S. J.; Kocabas, C.; Ozel, T.; Shim, M.; Pimparkar, N.; Alam, M. A.; Rotkin, S. V.; Rogers, J. A. Nat. Nanotechnol. 2007, 2, 23025https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXktVGhurc%253D&md5=74adaca1c0968d918dc7b430b672a623High-performance electronics using dense, perfectly aligned arrays of single-walled carbon nanotubesKang, Seong Jun; Kocabas, Coskun; Ozel, Taner; Shim, Moonsub; Pimparkar, Ninad; Alam, Muhammad A.; Rotkin, Slava V.; Rogers, John A.Nature Nanotechnology (2007), 2 (4), 230-236CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Single-walled carbon nanotubes (SWNTs) have many exceptional electronic properties. Realizing the full potential of SWNTs in realistic electronic systems requires a scalable approach to device and circuit integration. We report the use of dense, perfectly aligned arrays of long, perfectly linear SWNTs as an effective thin-film semiconductor suitable for integration into transistors and other classes of electronic devices. The large no. of SWNTs enable excellent device-level performance characteristics and good device-to-device uniformity, even with SWNTs that are electronically heterogeneous. Measurements on p- and n-channel transistors that involve as many as ∼2,100 SWNTs reveal device-level mobilities and scaled transconductances approaching ∼1,000 cm2 V-1 s-1 and ∼3,000 S m-1, resp., and with current outputs of up to ∼1 A in devices that use interdigitated electrodes. PMOS and CMOS logic gates and mech. flexible transistors on plastic provide examples of devices that can be formed with this approach. Collectively, these results may represent a route to large-scale integrated nanotube electronics.
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26Scrosati, B. Nat. Nanotechnol. 2007, 2, 59826https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFWhsbjO&md5=1c4566c5fd2b9b598896749e59c74c73Paper powers battery breakthroughScrosati, BrunoNature Nanotechnology (2007), 2 (10), 598-599CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)A review. A combination of C nanotubes and nanoporous cellulose enabled fabrication of Li-ion batteries and supercapacitors that are both lighter and more flexible than existing devices.
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27Sotowa, C.; Origi, G.; Takeuchi, M.; Nishimura, Y.; Takeuchi, K.; Jang, I. Y.; Kim, Y. J.; Hayashi, T.; Kim, Y. A.; Endo, M.; Dresselhaus, M. S. ChemSusChem 2008, 1, 911There is no corresponding record for this reference.
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28Lima, M. D.; Fang, S.; Lepro, X.; Lewis, C.; Ovalle-Robles, R.; Carretero-González, J.; Castillo-Martinez, E.; Kozlov, M. E.; Oh, J.; Rawat, N.; Haines, C. S.; Haque, M. H.; Aare, V.; Stoughton, S.; Zakhidov, A. A.; Baughman, R. H. Science 2011, 331, 51There is no corresponding record for this reference.
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29Dai, L.; Chang, D. W.; Baek, J. B.; Lu, W. Small 2012, 8, 1130There is no corresponding record for this reference.
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30Evanoff, K.; Khan, J.; Balandin, A. A.; Magasinski, A.; Ready, W. J.; Fuller, T. F.; Yushin, G. Adv. Mater. 2012, 24, 533There is no corresponding record for this reference.
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31Pugno, N. M.; Bosia, F.; Carpinteri, A. Small 2008, 4, 1044There is no corresponding record for this reference.
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32Byrne, M. T.; Gun’ko, Y. K. Adv. Mater. 2010, 22, 1672There is no corresponding record for this reference.
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33Huang, W. M. Modern Mater. Trends 2010, 2, 9There is no corresponding record for this reference.
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34Tan, D.; Zhang, Q. In Future Computer, Communication, Control and Automation; Zhang, T., Ed.; Springer: Berlin, 2012; AISC 119, pp 137– 146.There is no corresponding record for this reference.
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35Choudhary, V.; Gupta, A. In Carbon Nanotubes - Polymer Nanocomposites; Yellampalli, S., Ed.; InTech: Shanghai, 2011; pp 65– 90.There is no corresponding record for this reference.
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36Tans, S. J.; Verschueren, A. R. M.; Dekker, C. Nature 1998, 393, 4936https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjt1aitb8%253D&md5=c92463158e339ccd47fe6b6e3591be74Room-temperature transistor based on a single carbon nanotubeTans, Sander J.; Verschueren, Alwin R. M.; Dekker, CeesNature (London) (1998), 393 (6680), 49-52CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)The authors report the fabrication of a field-effect transistor - a three-terminal switching device - that consists of one semiconducting single-wall C nanotube connected to two metal electrodes. By applying a voltage to a gate electrode, the nanotube can be switched from a conducting to a insulating state. The authors have previously reported similar behavior for a metallic single-wall carbon nanotube operated at extremely low temps. The present device, in contrast, operates at room temp., thereby meeting an important requirement for potential practical applications. Elec. measurements on the nanotube transistor indicate that its operation characteristics can be qual. described by the semiclassical band-bending models currently used for traditional semiconductor devices. The fabrication of the three-terminal switching device at the level of a single mol. represents an important step towards mol. electronics.
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37Rueckes, T.; Kim, K.; Joselevich, E.; Tseng, G. Y.; Cheung, C. L.; Lieber, C. M. Science 2000, 289, 9437https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXlt1enu7Y%253D&md5=d2224a6f9d9bdff3c99c8ddc959e0975Carbon nanotube-based nonvolatile random access memory for molecular computingRueckes, Thomas; Kim, Kyoungha; Joselevich, Ernesto; Tseng, Greg Y.; Cheung, Chin-Li; Lieber, Charles M.Science (Washington, D. C.) (2000), 289 (5476), 94-97CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A concept for mol. electronics exploiting carbon nanotubes as both mol. device elements and mol. wires for reading and writing information was developed. Each device element is based on a suspended, crossed nanotube geometry that leads to bistable, electrostatically switchable ON/OFF states. The device elements are naturally addressable in large arrays by the carbon nanotube mol. wires making up the devices. These reversible, bistable device elements could be used to construct nonvolatile random access memory and logic function tables at an integration level approaching 10z1 elements per square centimeter and an element operation frequency in excess of 100 GHz. The viability of this concept is demonstrated by detailed calcns. and by the exptl. realization of a reversible, bistable nanotube-based bit.
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38Wu, Z.; Chen, Z.; Du, X.; Logan, J. M.; Sippel, J.; Nikolou, M.; Kamaras, K.; Reynolds, J. R.; Tanner, D. B.; Hebard, A. F.; Rinzler, A. G. Science 2004, 305, 127338https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmvFCitrg%253D&md5=6c6d43a612b45bff28d396e9fc213463Transparent, conductive carbon nanotube filmsWu, Zhuangchun; Chen, Zhihong; Du, Xu; Logan, Jonathan M.; Sippel, Jennifer; Nikolou, Maria; Kamaras, Katalin; Reynolds, John R.; Tanner, David B.; Hebard, Arthur F.; Rinzler, Andrew G.Science (Washington, DC, United States) (2004), 305 (5688), 1273-1277CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)The authors describe a simple process for the fabrication of ultrathin, transparent, optically homogeneous, elec. conducting films of pure single-walled carbon nanotubes and the transfer of those films to various substrates. For equivalent sheet resistance, the films exhibit optical transmittance comparable to that of com. indium tin oxide in the visible spectrum, but far superior transmittance in the technol. relevant 2- to 5-μm IR spectral band. These characteristics indicate broad applicability of the films for elec. coupling in photonic devices. In an example application, the films are used to construct an elec. field-activated optical modulator, which constitutes an optical analog to the nanotube-based field effect transistor.
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39Jensen, K.; Weldon, J.; Garcia, H.; Zettl, A. Nano Lett. 2007, 7, 3508There is no corresponding record for this reference.
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40De, S.; King, P. J.; Lyons, P. E.; Khan, U.; Coleman, J. N. ACS Nano 2010, 4, 7064There is no corresponding record for this reference.
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41Ionescu, A. M.; Riel, H. Nature 2011, 479, 32941https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVykt7%252FM&md5=3663dce27097f959baeca512b5eb9699Tunnel field-effect transistors as energy-efficient electronic switchesIonescu, Adrian M.; Riel, HeikeNature (London, United Kingdom) (2011), 479 (7373), 329-337CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)A review. Power dissipation is a fundamental problem for nanoelectronic circuits. Scaling the supply voltage reduces the energy needed for switching, but the field-effect transistors (FETs) in today's integrated circuits require at least 60 mV of gate voltage to increase the current by one order of magnitude at room temp. Tunnel FETs avoid this limit by quantum-mech. band-to-band tunneling, rather than thermal injection, to inject charge carriers into the device channel. Tunnel FETs based on ultrathin semiconducting films or nanowires could achieve a 100-fold power redn. over complementary metal-oxide-semiconductor (CMOS) transistors, so integrating tunnel FETs with CMOS technol. could improve low-power integrated circuits.
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42McCarthy, M. A.; Liu, B.; Donoghue, E. P.; Kravchenko, I.; Kim, D. Y.; So, F.; Rinzler, A. G. Science 2011, 332, 570There is no corresponding record for this reference.
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43Sun, D. M.; Timmermans, M. Y.; Tian, Y.; Nasibulin, A. G.; Kauppinen, E. I.; Kishimoto, S.; Mizutani, T.; Ohno, Y. Nat. Nanotechnol. 2011, 6, 15643https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXislCjsr4%253D&md5=ff563715f3dcd538287a068b2388d221Flexible high-performance carbon nanotube integrated circuitsSun, Dong-ming; Timmermans, Marina Y.; Tian, Ying; Nasibulin, Albert G.; Kauppinen, Esko I.; Kishimoto, Shigeru; Mizutani, Takashi; Ohno, YutakaNature Nanotechnology (2011), 6 (3), 156-161CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)C nanotube thin-film transistors are expected to enable the fabrication of high-performance, flexible and transparent devices using relatively simple techniques. However, as-grown nanotube networks usually contain both metallic and semiconducting nanotubes, which leads to a trade-off between charge-carrier mobility (which increases with greater metallic tube content) and on/off ratio (which decreases). Many approaches to sepg. metallic nanotubes from semiconducting nanotubes were investigated, but most lead to contamination and shortening of the nanotubes, thus reducing performance. Here, we report the fabrication of high-performance thin-film transistors and integrated circuits on flexible and transparent substrates using floating-catalyst CVD followed by a simple gas-phase filtration and transfer process. The resulting nanotube network has a well-controlled d. and a unique morphol., consisting of long (∼10 μm) nanotubes connected by low-resistance Y-shaped junctions. The transistors simultaneously demonstrate a mobility of 35 cm2 V-1 s-1 and an on/off ratio of 6 × 106. We also demonstrate flexible integrated circuits, including a 21-stage ring oscillator and master-slave delay flip-flops that are capable of sequential logic. Our fabrication procedure should prove to be scalable, for example, by high-throughput printing techniques.
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44Franklin, A. D.; Luisier, M.; Han, S. J.; Tulevski, G.; Breslin, C. M.; Gignac, L.; Lundstrom, M. S.; Haensch, W. Nano Lett. 2012, 12, 758There is no corresponding record for this reference.
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45Park, H.; Afzali, A.; Han, S. J.; Tulevski, G. S.; Franklin, A. D.; Tersoff, J.; Hannon, J. B.; Haensch, W. Nat. Nanotechnol. 2012, 7, 78745https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFOmt7jL&md5=9d67e1b6645e60c0a504a343b76d5bbbHigh-density integration of carbon nanotubes via chemical self-assemblyPark, Hongsik; Afzali, Ali; Han, Shu-Jen; Tulevski, George S.; Franklin, Aaron D.; Tersoff, Jerry; Hannon, James B.; Haensch, WilfriedNature Nanotechnology (2012), 7 (12), 787-791CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Carbon nanotubes have potential in the development of high-speed and power-efficient logic applications. However, for such technologies to be viable, a high d. of semiconducting nanotubes must be placed at precise locations on a substrate. Here, we show that ion-exchange chem. can be used to fabricate arrays of individually positioned carbon nanotubes with a d. as high as 1 × 109 cm-2 two orders of magnitude higher than previous reports. With this approach, we assembled a high d. of carbon-nanotube transistors in a conventional semiconductor fabrication line and then elec. tested more than 10,000 devices in a single chip. The ability to characterize such large distributions of nanotube devices is crucial for analyzing transistor performance, yield and semiconducting nanotube purity.
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46Matsumoto, T.; Komatsu, T.; Arai, K.; Yamazaki, T.; Kijima, M.; Shimizu, H.; Takasawa, Y.; Nakamura, J. Chem. Commun. (Cambridge, U.K.) 2004, 7, 840There is no corresponding record for this reference.
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47Holt, J. K.; Park, H. G.; Wang, Y.; Stadermann, M.; Artyukhin, A. B.; Grigoropoulos, C. P.; Noy, A.; Bakajin, O. Science 2006, 312, 103447https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xks1Wqtbg%253D&md5=93fb0c4e67412ab4c9538ddb961d09e5Fast Mass Transport Through Sub-2-Nanometer Carbon NanotubesHolt, Jason K.; Park, Hyung Gyu; Wang, Yinmin; Stadermann, Michael; Artyukhin, Alexander B.; Grigoropoulos, Costas P.; Noy, Aleksandr; Bakajin, OlgicaScience (Washington, DC, United States) (2006), 312 (5776), 1034-1037CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)We report gas and water flow measurements through microfabricated membranes in which aligned carbon nanotubes with diams. of less than 2 nm serve as pores. The measured gas flow exceeds predictions of the Knudsen diffusion model by more than an order of magnitude. The measured water flow exceeds values calcd. from continuum hydrodynamics models by more than three orders of magnitude and is comparable to flow rates extrapolated from mol. dynamics simulations. The gas and water permeabilities of these nanotube-based membranes are several orders of magnitude higher than those of com. polycarbonate membranes, despite having pore sizes an order of magnitude smaller. These membranes enable fundamental studies of mass transport in confined environments, as well as more energy-efficient nanoscale filtration.
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48Vaezzadeh, M.; Saeedi, M. R.; Barghi, T.; Sadeghi, M. R. Chem. Cent. J. 2007, 1, 2248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2snmvFyhug%253D%253D&md5=f4dd961e6371e67aad347fd78a2792daThe necessary length of carbon nanotubes required to optimize solar cellsVaezzadeh Majid; Saeedi Mohammad Reza; Barghi Tirdad; Sadeghi Mohammad RezaChemistry Central journal (2007), 1 (), 22 ISSN:.BACKGROUND: In recent years scientists have been trying both to increase the efficiency of solar cells, whilst at the same time reducing dimensions and costs. Increases in efficiency have been brought about by implanting carbon nanotubes onto the surface of solar cells in order to reduce the reflection of sunrays, as well as through the insertion of polymeric arrays into the intrinsic layer for charge separation. RESULTS: The experimental results show power rising linearly for intrinsic layer thicknesses between 0-50 nm. Wider thicknesses increase the possibility of recombination of electrons and holes, leading to perturbation of the linear behaviour of output power. This effect is studied and formulated as a function of thickness. Recognition of the critical intrinsic layer thickness can permit one to determine the length of carbon nanotube necessary for optimizing solar cells. CONCLUSION: In this study the behaviour of output power as a function of intrinsic layer thicknesses has been described physically and also simulated. In addition, the implantation of carbon nanotubes into the intrinsic layer and the necessary nanotube length required to optimize solar cells have been suggested.
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49Gabor, N. M.; Zhong, Z.; Bosnick, K.; Park, J.; McEuen, P. L. Science 2009, 325, 1367There is no corresponding record for this reference.
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50Le Goff, A.; Artero, V.; Jousselme, B.; Tran, P. D.; Guillet, N.; Métayé, R.; Fihri, A.; Palacin, S.; Fontecave, M. Science 2009, 326, 1384There is no corresponding record for this reference.
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51Jain, R. M.; Howden, R.; Tvrdy, K.; Shimizu, S.; Hilmer, A. J.; McNicholas, T. P.; Gleason, K. K.; Strano, M. S. Adv. Mater. 2012, 24, 4436There is no corresponding record for this reference.
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52Calkins, J. O.; Umasankar, Y.; O’Neill, H.; Ramasamy, R. P. Energy Environ. Sci. 2013, 6, 1891There is no corresponding record for this reference.
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53Shi Kam, N. W.; Jessop, T. C.; Wender, P. A.; Dai, H. J. Am. Chem. Soc. 2004, 126, 6850There is no corresponding record for this reference.
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54Demming, A. Nanotechnology 2011, 22, 260201There is no corresponding record for this reference.
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55Yang, F.; Jin, C.; Yang, D.; Jiang, Y.; Li, J.; Di, Y.; Hu, J.; Wang, C.; Ni, Q.; Fu, D. Eur. J. Cancer 2011, 47, 1873There is no corresponding record for this reference.
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56Murakami, T.; Nakatsuji, H.; Inada, M.; Matoba, Y.; Umeyama, T.; Tsujimoto, M.; Isoda, S.; Hashida, M.; Imahori, H. J. Am. Chem. Soc. 2012, 134, 17862There is no corresponding record for this reference.
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57Antaris, A. L.; Robinson, J. T.; Yaghi, O. K.; Hong, G.; Diao, S.; Luong, R.; Dai, H. ACS Nano 2013, 7, 3644There is no corresponding record for this reference.
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58Saito, N.; Usui, Y.; Aoki, K.; Narita, N.; Shimizu, M.; Ogiwara, N.; Nakamura, K.; Ishigaki, N.; Kato, H.; Taruta, S.; Endo, M. Curr. Med. Chem. 2008, 15, 52358https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnsVyisbo%253D&md5=7106e9db53f9b525e4d553046d0599c7Carbon nanotubes for biomaterials in contact with boneSaito, Naoto; Usui, Yuki; Aoki, Kaoru; Narita, Nobuyo; Shimizu, Masayuki; Ogiwara, Nobuhide; Nakamura, Koichi; Ishigaki, Norio; Kato, Hiroyuki; Taruta, Seiichi; Endo, MorinobuCurrent Medicinal Chemistry (2008), 15 (5), 523-527CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. Carbon nanotubes (CNTs) possess exceptional mech., thermal, and elec. properties, facilitating their use as reinforcements or additives in various materials to improve the properties of the materials. Furthermore, chem. modified CNTs can introduce novel functionalities. In the medical field, biomaterials are expected to be developed using CNTs for clin. use. Biomaterials often are placed adjacent to bone. The use of CNTs is anticipated in these biomaterials applied to bone mainly to improve their overall mech. properties, for applications such as high-strength arthroplasty prostheses or fixation plates and screws that will not fail. In addn., CNTs are expected to be used as local drug delivery systems (DDS) and/or scaffolds to promote and guide bone tissue regeneration. However, studies examg. the use of CNTs as biomaterials still are in the preliminary stages. In particular, the influence of CNTs on osteoblastic cells or bone tissue is extremely important for the use of CNTs in biomaterials placed in contact with bone, and some studies have explored this. This review paper clarifies the current state of knowledge in the context of the relationship between CNTs and bone to det. whether CNTs might perform in biomaterials in contact with bone, or as a DDS and/or scaffolding for bone regeneration.
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59Jin, G. Z.; Kim, M.; Shin, U. S.; Kim, H. W. Neurosci. Lett. 2011, 501, 10There is no corresponding record for this reference.
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60Shokrgozar, M. A.; Mottaghitalab, F.; Mottaghitalab, V.; Farokhi, M. J. Biomed. Nanotechnol. 2011, 7, 27660https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnt1Khtr8%253D&md5=c07a89a75ad60160be63d81f27fc70e9Fabrication of porous chitosan/poly(vinyl alcohol) reinforced single-walled carbon nanotube nanocomposites for neural tissue engineeringShokrgozar, Mohammad Ali; Mottaghitalab, Fatemeh; Mottaghitalab, Vahid; Farokhi, MehdiJournal of Biomedical Nanotechnology (2011), 7 (2), 276-284CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)With the ability to form a nano-sized fibrous structure with large pore sizes mimicking the extracellular matrix (ECM), electrospinning was used to fabricate chitosan/poly(vinyl alc.) nanofibers reinforced by single-walled carbon nanotube (SWNT-CS/PVA) for potential use in neural tissue engineering. Moreover, ultrasonication was performed to fabricate highly dispersed SWNT/CS soln. with 7%, 12%, and 17% SWNT content prior to electrospinning process. In the present study, a no. of properties of CS/PVA reinforced SWNTs nanocomposites were evaluated. The in vitro biocompatibility of the electrospun fiber mats was also assessed using human brain-derived cells and U373 cell lines. The results have shown that SWNTs as reinforcing phase can augment the morphol., porosity, and structural properties of CS/PVA nanofiber composites and thus benefit the proliferation rate of both cell types. In addn., the cells exhibit their normal morphol. while integrating with surrounding fibers. The results confirmed the potential of SWNT-CS/PVA nanocomposites as scaffold for neural tissue engineering.
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61Lee, S.; Hahm, M. G.; Vajtai, R.; Hashim, D. P.; Thurakitseree, T.; Chipara, A. C.; Ajayan, P. M.; Hafner, J. H. Adv. Mater. 2012, 24, 5261There is no corresponding record for this reference.
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62Cheng, Q.; Rutledge, K.; Jabbarzadeh, E. Ann. Biomed. Eng. 2013, 41, 90462https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s3mt1agsw%253D%253D&md5=76d27ec86e4bab911bb5913496d7ac85Carbon nanotube-poly(lactide-co-glycolide) composite scaffolds for bone tissue engineering applicationsCheng Qingsu; Rutledge Katy; Jabbarzadeh EhsanAnnals of biomedical engineering (2013), 41 (5), 904-16 ISSN:.Despite their indisputable clinical value, current tissue engineering strategies face major challenges in recapitulating the natural nano-structural and morphological features of native bone. The aim of this study is to take a step forward by developing a porous scaffold with appropriate mechanical strength and controllable surface roughness for bone repair. This was accomplished by homogenous dispersion of carbon nanotubes (CNTs) in a poly(lactide-co-glycolide) (PLGA) solution followed by a solvent casting/particulate leaching scaffold fabrication. Our results demonstrated that CNT/PLGA composite scaffolds possessed a significantly higher mechanical strength as compared to PLGA scaffolds. The incorporation of CNTs led to an enhanced surface roughness and resulted in an increase in the attachment and proliferation of MC3T3-E1 osteoblasts. Most interestingly, the in vitro osteogenesis studies demonstrated a significantly higher rate of differentiation on CNT/PLGA scaffolds compared to the control PLGA group. These results all together demonstrate the potential of CNT/PLGA scaffolds for bone tissue engineering as they possess the combined effects of mechanical strength and osteogenicity.
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63Dorj, B.; Won, J. E.; Kim, J. H.; Choi, S. J.; Shin, U. S.; Kim, H. W. J. Biomed. Mater. Res. A 2013, 101, 167063https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlslyhu7g%253D&md5=2b8b59af6b402a11557d9a9a86f6fb4cRobocasting nanocomposite scaffolds of poly(caprolactone)/hydroxyapatite incorporating modified carbon nanotubes for hard tissue reconstructionDorj, Biligzaya; Won, Jong-Eun; Kim, Joong-Hyun; Choi, Seong-Jun; Shin, Ueon Sang; Kim, Hae-WonJournal of Biomedical Materials Research, Part A (2013), 101A (6), 1670-1681CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Nanocomposite scaffolds with tailored 3D pore configuration are promising candidates for the reconstruction of bone. Here we fabricated novel nanocomposite bone scaffolds through robocasting. Poly(caprolactone) (PCL)-hydroxyapatite (HA) slurry contg. ionically modified carbon nanotubes (imCNTs) was robotic-dispensed and structured layer-by-layer into macrochanneled 3D scaffolds under adjusted processing conditions. Homogeneous dispersion of imCNTs (0.2 wt. % relative to PCL-HA) was achieved in acetone, aiding in the prepn. of PCL-HA-imCNTs slurry with good mixing property. Incorporation of imCNTs into PCL-HA compn. significantly improved the compressive strength and elastic modulus of the robotic-dispensed scaffolds (∼1.5-fold in strength and ∼2.5-fold in elastic modulus). When incubated in simulated body fluid (SBF), PCL-HA-imCNT nanocomposite scaffold induced substantial mineralization of apatite in a similar manner to the PCL-HA scaffold, which was contrasted in pure PCL scaffold. MC3T3-E1 cell culture on the scaffolds demonstrated that cell proliferation levels were significantly higher in both PCL-HA-imCNT and PCL-HA than in pure PCL, and no significant difference was found between the nanocomposite scaffolds. When the PCL-HA-imCNT scaffold was implanted into a rat s.c. tissue for 4 wk, soft fibrous tissues with neo-blood vessels formed well in the pore channels of the scaffolds without any significant inflammatory signs. Tissue reactions in PCL-HA-imCNT scaffold were similar to those in PCL-HA scaffold, suggesting incorporated imCNT did not negate the beneficial biol. roles of HA. While more long-term in vivo research in bone defect models is needed to confirm clin. availability, our results suggest robotic-dispensed PCL-HA-imCNT nanocomposite scaffolds can be considered promising new candidate matrixes for bone regeneration. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.
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64Kealley, C. S.; Latella, B. A.; van Riessen, A.; van Elcombe, M. M.; Ben-Nissan, B. J. Nanosci. Nanotechnol. 2008, 8, 3936There is no corresponding record for this reference.
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65Joshi, B.; Gupta, S.; Kalra, N.; Gudyka, R.; Santhanam, K. S. J. Nanosci. Nanotechnol. 2010, 10, 3799There is no corresponding record for this reference.
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66Lee, H. H.; Sang Shin, U.; Lee, J. H.; Kim, H. W. J. Biomed. Mater. Res., Part B 2011, 98B, 24666https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXotl2rtL0%253D&md5=0a46885b83014f5773f0b51b84421a30Biomedical nanocomposites of poly(lactic acid) and calcium phosphate hybridized with modified carbon nanotubes for hard tissue implantsLee, Hae-Hyoung; Sang Shin, Ueon; Lee, Jae-Ho; Kim, Hae-WonJournal of Biomedical Materials Research, Part B: Applied Biomaterials (2011), 98B (2), 246-254CODEN: JBMRGL; ISSN:1552-4973. (John Wiley & Sons, Inc.)Degradable polymer-based materials are attractive in orthopedics and dentistry as an alternative to metallic implants for use as bone fixatives. Herein, a degradable polymer poly(lactic acid) (PLA) was combined with novel hybrid nanopowder of carbon nanotubes (CNTs)-calcium phosphate (CP) for this application. In particular, CNTs-CP hybrid nanopowders (0.1 and 0.25% CNTs) were prepd. from the soln. of ionically modified CNTs (mCNTs), which was specifically synthesized to be well-dispersed and thus to effectively adsorb onto the CP nanoparticles. The mCNTs-CP hybrid nanopowders were then mixed with PLA (up to 50%) to produce mCNTs-CP-PLA nanocomposites. The mech. tensile strength of the nanocomposites was significantly improved by the addn. of mCNTs-CP hybrid nanopowders. Moreover, nanocomposites contg. low concn. of mCNTs (0.1%) showed significantly stimulated biol. responses including cell proliferation and osteoblastic differentiation in terms of gene and protein expressions. Based on this study, the addn. of novel mCNT-CP hybrid nanopowders to PLA biopolymer may be considered a new material choice for developing hard tissue implants. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2011.
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67Wang, M.; Castro, N. J.; Li, J.; Keidar, M.; Zhang, L. G. J. Nanosci. Nanotechnol. 2012, 12, 7692There is no corresponding record for this reference.
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68Kostarelos, K.; Bianco, A.; Prato, M. Nat. Nanotechnol. 2009, 4, 62768https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1aqsLvN&md5=ea1bbc25d798cd544f9197f339fef6dfPromises, facts and challenges for carbon nanotubes in imaging and therapeuticsKostarelos, K.; Bianco, A.; Prato, M.Nature Nanotechnology (2009), 4 (10), 627-633CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)A review. The use of carbon nanotubes in medicine is now at the crossroads between a proof-of-principle concept and an established preclin. candidate for a variety of therapeutic and diagnostic applications. Progress towards clin. trials will depend on the outcomes of efficacy and toxicol. studies, which will provide the necessary risk-to-benefit assessments for carbon-nanotube-based materials. Here we focus on carbon nanotubes that have been studied in preclin. animal models, and draw attention to the promises, facts and challenges of these materials as they transition from research to the clin. phase. We address common questions regarding the use of carbon nanotubes in disease imaging and therapy, and highlight the opportunities and challenges ahead.
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69Saito, N.; Usui, Y.; Aoki, K.; Narita, N.; Shimizu, M.; Hara, K.; Ogiwara, N.; Nakamura, K.; Ishigaki, N.; Kato, H.; Taruta, S.; Endo, M. Chem. Soc. Rev. 2009, 38, 1897There is no corresponding record for this reference.
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70Ciofani, G.; Raffa, V.; Vittorio, O.; Cuschieri, A.; Pizzorusso, T.; Costa, M.; Bardi, G. Methods Mol. Biol. 2010, 625, 6770https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXoslyqtL0%253D&md5=099402ac722b3f02a13a36e856ced224In vitro and in vivo biocompatibility testing of functionalized carbon nanotubesCiofani, Gianni; Raffa, Vittoria; Vittorio, Orazio; Cuschieri, Alfred; Pizzorusso, Tommaso; Costa, Mario; Bardi, GiuseppeMethods in Molecular Biology (Totowa, NJ, United States) (2010), 625 (Carbon Nanotubes), 67-83CODEN: MMBIED; ISSN:1064-3745. (Humana Press Inc.)The explosive growth of nanotechnol. in the last years has led to dramatic innovations in pharmacol., and it is revolutioning the development of biol. active compds. Carbon nanotubes (CNTs) are widely explored for biomedical applications such as intracellular transporters for (bio)mols., and represent promising future tools for efficient and safe cell therapy. Due to their nanoscale dimensions, the ability to interact with cells, and their easy functionalization, CNTs are close-to-ideal vectors for an efficient and safe cell therapy, obviating the risks assocd. with the use of viral vectors. Notwithstanding, conflicting data concerning the biocompatibility of CNTs have been reported in the literature; while some studies point toward very low toxicity of CNTs both in vitro and in vivo, others reveal various toxic effects such as oxidative stress, DNA damage, and cell apoptosis. Thus, standardized methods and independent test systems are urgently needed to verify cytotoxicity data in this research field. In this chapter, we summarize the used methods and the achieved main results in our labs. concerning multiwalled carbon nanotubes (MWCNTs) biocompatibility studies. The in vitro response of human neuroblastoma cell line and primary mouse neurons was investigated following the exposure to different samples of MWCNTs in order to evaluate their effects on cell viability, oxidative stress, and apoptosis. Moreover, in vivo neurocompatibility tests were carried out through injections in mouse brains.
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71Rodriguez-Fernandez, L.; Valiente, R.; Gonzalez, J.; Villegas, J. C.; Fanarraga, M. L. ACS Nano 2012, 6, 6614There is no corresponding record for this reference.
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72Lacerda, L.; Bianco, A.; Prato, M.; Kostarelos, K. Adv. Drug Delivery Rev. 2006, 58, 146072https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1KmtLbN&md5=8f92efcc604e233e7251ca06d0e13b8cCarbon nanotubes as nanomedicines: From toxicology to pharmacologyLacerda, Lara; Bianco, Alberto; Prato, Maurizio; Kostarelos, KostasAdvanced Drug Delivery Reviews (2006), 58 (14), 1460-1470CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Various biomedical applications of carbon nanotubes have been proposed in the last few years leading to the emergence of a new field in diagnostics and therapeutics. Most of these applications will involve the administration or implantation of carbon nanotubes and their matrixes into patients. The toxicol. and pharmacol. profile of such carbon nanotube systems developed as nanomedicines will have to be detd. prior to any clin. studies undertaken. This review brings together all the toxicol. and pharmacol. in vivo studies that have been carried out using carbon nanotubes, to offer the first summary of the state-of-the-art in the pharmaceutical development of carbon nanotubes on the road to becoming viable and effective nanomedicines.
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73Pagona, G.; Tagmatarchis, N. Curr. Med. Chem. 2006, 13, 178973https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmtVaisL0%253D&md5=13255d73d02a8fe192c3ce00a461a55aCarbon nanotubes: materials for medicinal chemistry and biotechnological applicationsPagona, Georgia; Tagmatarchis, NikosCurrent Medicinal Chemistry (2006), 13 (15), 1789-1798CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. Carbon nanotubes are considered as mol. wires exhibiting novel properties for diverse applications including medicinal and biotechnol. purposes. Surface chem. on carbon nanotubes results on their solubilization in org. solvents and/or aq./physiol. media. Herein, we will present how interfacing such novel carbon-based nanomaterials with biol. systems may lead to new applications in diagnostics, vaccine and drug delivery. Recent developments in this rapidly growing field will be presented thus suggesting exciting opportunities for the utilization of carbon nanotubes as useful tools for biotechnol. applications. Emphasis will be placed in the integration of biomaterials with carbon nanotubes, which enables the use of such hybrid systems as biosensor devices, immunosensors and DNA-sensors.
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74Soto, K.; Garza, K. M.; Murr, L. E. Acta Biomater. 2007, 3, 351There is no corresponding record for this reference.
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75Wick, P.; Manser, P.; Limbach, L. K.; Dettlaff-Weglikowska, U.; Krumeich, F.; Roth, S.; Stark, W. J.; Bruinink, A. Toxicol. Lett. 2007, 168, 12175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXltV2nsA%253D%253D&md5=44abfcbb136814539b55711dcf0f1f4eThe degree and kind of agglomeration affect carbon nanotube cytotoxicityWick, Peter; Manser, Pius; Limbach, Ludwig K.; Dettlaff-Weglikowska, Ursula; Krumeich, Frank; Roth, Siegmar; Stark, Wendelin J.; Bruinink, ArieToxicology Letters (2007), 168 (2), 121-131CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)The urgent need for toxicol. studies on carbon nanotubes (CNTs) has arisen from the rapidly emerging applications of CNTs well beyond material science and engineering. In order to provide a basis for comparison to existing epidemiol. data, we have investigated CNTs at various degrees of agglomeration using an in vitro cytotoxicity study with human MSTO-211H cells. Non-cytotoxic polyoxyethylene sorbitan monooleate was found to well-disperse CNT. In the present study, the cytotoxic effects of well-dispersed CNT were compared with that of conventionally purified rope-like agglomerated CNTs and asbestos as a ref. While suspended CNT-bundles were less cytotoxic than asbestos, rope-like agglomerates induced more pronounced cytotoxic effects than asbestos fibers at the same concns. The study underlines the need for thorough materials characterization prior to toxicol. studies and corroborates the role of agglomeration in the cytotoxic effect of nanomaterials.
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76Fraczek, A.; Menaszek, E.; Paluszkiewicz, C.; Blazewicz, M. Acta Biomater. 2008, 4, 1593There is no corresponding record for this reference.
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77Jain, K. K. Expert Opin. Drug Discovery 2012, 7, 1029There is no corresponding record for this reference.
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78Ma-Hock, L.; Treumann, S.; Strauss, V.; Brill, S.; Luizi, F.; Mertler, M.; Wiench, K.; Gamer, A. O.; van Ravenzwaay, B.; Landsiedel, R. Toxicol. Sci. 2009, 112, 46878https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVajurzI&md5=b87f2d6fb194803700c9803c4f34ad89Inhalation Toxicity of Multiwall Carbon Nanotubes in Rats Exposed for 3 MonthsMa-Hock, Lan; Treumann, Silke; Strauss, Volker; Brill, Sandra; Luizi, Frederic; Mertler, Michael; Wiench, Karin; Gamer, Armin O.; van Ravenzwaay, Bennard; Landsiedel, RobertToxicological Sciences (2009), 112 (2), 468-481CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)Carbon nanotubes (CNT) are of great com. interest. Theor., during processing and handling of CNT and in abrasion processes on composites contg. CNT, inhalable CNT particles might be set free. For hazard assessment, we performed a 90-day inhalation toxicity study with a multiwall CNT (MWCNT) material (Nanocyl NC 7000) according to Organization for Economic Co-operation and Development test guideline 413. Wistar rats were head-nose exposed for 6 h/day, 5 days/wk, 13 wk, total 65 exposures, to MWCNT concns. of 0 (control), 0.1, 0.5, or 2.5 mg/m3. Highly respirable dust aerosols were produced with a proprietary brush generator which neither damaged the tube structure nor increased reactive oxygen species on the surface. Inhalation exposure to MWCNT produced no systemic toxicity. However, increased lung wts., pronounced multifocal granulomatous inflammation, diffuse histocytic and neutrophilic inflammation, and intra-alveolar lipoproteinosis were obsd. in lung and lung-assocd. lymph nodes at 0.5 and 2.5 mg/m3. These effects were accompanied by slight blood neutrophilia at 2.5 mg/m3. Incidence and severity of the effects were concn. related. At 0.1 mg/m3, there was still minimal granulomatous inflammation in the lung and in lung-assocd. lymph nodes; a no obsd. effect concn. was therefore not established in this study. The test substance has low dust-forming potential, as demonstrated by dustiness measurements, but nonetheless strict industrial hygiene measures must be taken during handling and processing. Toxicity and dustiness data such as these can be used to compare different MWCNT materials and to select the material with the lowest risk potential for a given application.
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79Porter, D. W.; Hubbs, A. F.; Mercer, R. R.; Wu, N.; Wolfarth, M. G.; Sriram, K.; Leonard, S.; Battelli, L.; Schwegler-Berry, D.; Friend, S.; Andrew, M.; Chen, B. T.; Tsuruoka, S.; Endo, M.; Castranova, V. Toxicology 2010, 269, 136There is no corresponding record for this reference.
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80Nagai, H.; Okazaki, Y.; Chew, S. H.; Misawa, N.; Yamashita, Y.; Akatsuka, S.; Ishihara, T.; Yamashita, K.; Yoshikawa, Y.; Yasui, H.; Jiang, L.; Ohara, H.; Takahashi, T.; Ichihara, G.; Kostarelos, K.; Miyata, Y.; Shinohara, H.; Toyokuni, S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, E1330There is no corresponding record for this reference.
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81Oyabu, T.; Myojo, T.; Morimoto, Y.; Ogami, A.; Hirohashi, M.; Yamamoto, M.; Todoroki, M.; Mizuguchi, Y.; Hashiba, M.; Lee, B. W.; Shimada, M.; Wang, W. N.; Uchida, K.; Endoh, S.; Kobayashi, N.; Yamamoto, K.; Fujita, K.; Mizuno, K.; Inada, M.; Nakazato, T.; Nakanishi, J.; Tanaka, I. Inhalation Toxicol. 2011, 23, 78481https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlyjsb7F&md5=cddb6a34ef5d1fddf9700805d4d7013dBiopersistence of inhaled MWCNT in rat lungs in a 4-week well-characterized exposureOyabu, Takako; Myojo, Toshihiko; Morimoto, Yasuo; Ogami, Akira; Hirohashi, Masami; Yamamoto, Makoto; Todoroki, Motoi; Mizuguchi, Yohei; Hashiba, Masayoshi; Lee, Byeong Woo; Shimada, Manabu; Wang, Wei-Ning; Uchida, Kunio; Endoh, Shigehisa; Kobayashi, Norihiro; Yamamoto, Kazuhiro; Fujita, Katsuhide; Mizuno, Kohei; Inada, Masaharu; Nakazato, Tetsuya; Nakanishi, Junko; Tanaka, IsamuInhalation Toxicology (2011), 23 (13), 784-791CODEN: INHTE5; ISSN:0895-8378. (Informa Healthcare)It is important to conduct a risk assessment that includes hazard assessment and exposure assessment for the safe prodn. and handling of newly developed nanomaterials. We conducted an inhalation study of a multi-wall carbon nanotube (MWCNT) as a hazard assessment. Male Wistar rats were exposed to well-dispersed MWCNT for 4 wk by whole body inhalation. The exposure concn. in the chamber was 0.37 ± 0.18 mg/m3. About 70% of the MWCNTs in the chamber were single fiber. The geometric mean diam. (geometric std. deviation, GSD) and geometric mean length (GSD) of the aerosolized MWCNTs in the chamber were 63 nm (1.5) and 1.1 μm (2.7), resp. The amts. of MWCNT deposited in the rat lungs were detd. by the x-ray diffraction method and elemental C anal. The av. deposited amts. at 3 days after the inhalation were 68 μg/lung by the x-ray diffraction method and 76 μg/lung by elemental C anal. The calcd. deposition fractions were 18% and 20% in each anal. The amt. of retained MWCNT in the lungs until 3 mo after the inhalation decreased exponentially and the calcd. biol. half times of MWCNT were 51 days and 54 days, resp. The clearance was not delayed, but a slight increase in lung wt. at 3 days after the inhalation was obsd.
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82Delorme, M. P.; Muro, Y.; Arai, T.; Banas, D. A.; Frame, S. R.; Reed, K. L.; Warheit, D. B. Toxicol. Sci. 2012, 128, 44982https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1enurbL&md5=c658cc064f3366f3c60081f58bf98563Ninety-Day Inhalation Toxicity Study With A Vapor Grown Carbon Nanofiber in RatsDeLorme, Michael P.; Muro, Yukihiro; Arai, Toshihiro; Banas, Deborah A.; Frame, Steven R.; Reed, Kenneth L.; Warheit, David B.Toxicological Sciences (2012), 128 (2), 449-460CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)A subchronic inhalation toxicity study of inhaled vapor grown carbon nanofibers (CNF) (VGCF-H) was conducted in male and female Sprague Dawley rats. The CNF test sample was composed of > 99.5% carbon with virtually no catalyst metals; Brunauer, Emmett, and Teller (BET) surface area measurements of 13.8 m2/g; and mean lengths and diams. of 5.8 μm and 158 nm, resp. Four groups of rats per sex were exposed nose-only, 6 h/day, for 5 days/wk to target concns. of 0, 0.50, 2.5, or 25 mg/m3 VGCF-H over a 90-day period and evaluated 1 day later. Assessments included conventional clin. and histopathol. methods, bronchoalveolar lavage fluid (BALF) anal., and cell proliferation (CP) studies of the terminal bronchiole (TB), alveolar duct (AD), and subpleural regions of the respiratory tract. In addn., groups of 0 and 25 mg/m3 exposed rats were evaluated at 3 mo postexposure (PE). Aerosol exposures of rats to 0.54 (4.9 f/cc), 2.5 (56 f/cc), and 25 (252 f/cc) mg/m3 of VGCF-H CNFs produced concn.-related small, detectable accumulation of extrapulmonary fibers with no adverse tissue effects. At the two highest concns., inflammation of the TB and AD regions of the respiratory tract was noted wherein fiber-laden alveolar macrophages had accumulated. This finding was characterized by minimal infiltrates of inflammatory cells in rats exposed to 2.5mg/m3 CNF, inflammation along with some thickening of interstitial walls, and hypertrophy/hyperplasia of type II epithelial cells, graded as slight for the 25mg/m3 concn. At 3 mo PE, the inflammation in the high dose was reduced. No adverse effects were obsd. at 0.54mg/m3. BALF and CP endpoint increases vs. controls were noted at 25mg/m3 VGCF-H but not different from control values at 0.54 or 2.5mg/m3. After 90 days PE, BALF biomarkers were still increased at 25mg/m3, indicating that the inflammatory response was not fully resolved. Greater than 90% of CNF-exposed, BALF-recovered alveolar macrophages from the 25 and 2.5mg/m3 exposure groups contained nanofibers (> 60% for 0.5mg/m3). A nonspecific inflammatory response was also noted in the nasal passages. The no-obsd.-adverse-effect level for VGCF-H nanofibers was considered to be 0.54mg/m3 (4.9 fibers/cc) for male and female rats, based on the minimal inflammation in the terminal bronchiole and alveolar duct areas of the lungs at 2.5mg/m3 exposures. It is noteworthy that the histopathol. observations at the 2.5mg/m3 exposure level did not correlate with the CP or BALF data at that exposure concn. In addn., the results with CNF are compared with published findings of 90-day inhalation studies in rats with carbon nanotubes, and hypotheses are presented for potency differences based on CNT physicochem. characteristics. Finally, the (lack of) relevance of CNF for the high aspect ratio nanomaterials/fiber paradigm is discussed.
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83Xu, J.; Futakuchi, M.; Shimizu, H.; Alexander, D. B.; Yanagihara, K.; Fukamachi, K.; Suzui, M.; Kanno, J.; Hirose, A.; Ogata, A.; Sakamoto, Y.; Nakae, D.; Omori, T.; Tsuda, H. Cancer Sci. 2012, 103, 204583https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslOlsrbL&md5=feb9bff89dd33afca838221fe46b4b39Multi-walled carbon nanotubes translocate into the pleural cavity and induce visceral mesothelial proliferation in ratsXu, Jiegou; Futakuchi, Mitsuru; Shimizu, Hideo; Alexander, David B.; Yanagihara, Kazuyoshi; Fukamachi, Katsumi; Suzui, Masumi; Kanno, Jun; Hirose, Akihiko; Ogata, Akio; Sakamoto, Yoshimitsu; Nakae, Dai; Omori, Toyonori; Tsuda, HiroyukiCancer Science (2012), 103 (12), 2045-2050CODEN: CSACCM; ISSN:1349-7006. (Wiley-Blackwell)Multi-walled C nanotubes have a fibrous structure similar to asbestos and induce mesothelioma when injected into the peritoneal cavity. In the present study, we investigated whether C nanotubes administered into the lung through the trachea induce mesothelial lesions. Male F344 rats were treated with 0.5 mL of 500 μg/mL suspensions of multi-walled C nanotubes or crocidolite 5 times over a 9-day period by intrapulmonary spraying. Pleural cavity lavage fluid, lung and chest wall were then collected. Multi-walled carbon nanotubes and crocidolite were found mainly in alveolar macrophages and mediastinal lymph nodes. Importantly, the fibers were also found in the cell pellets of the pleural cavity lavage, mostly in macrophages. Both multi-walled C nanotube and crocidolite treatment induced hyperplastic proliferative lesions of the visceral mesothelium, with their proliferating cell nuclear antigen indexes approx. 10-fold that of the vehicle control. The hyperplastic lesions were assocd. with inflammatory cell infiltration and inflammation-induced fibrotic lesions of the pleural tissues. The fibers were not found in the mesothelial proliferative lesions themselves. In the pleural cavity, abundant inflammatory cell infiltration, mainly composed of macrophages, was obsd. Conditioned cell culture media of macrophages treated with multi-walled carbon nanotubes and crocidolite and the supernatants of pleural cavity lavage fluid from the dosed rats increased mesothelial cell proliferation in vitro, suggesting that mesothelial proliferative lesions were induced by inflammatory events in the lung and pleural cavity and likely mediated by macrophages. In conclusion, intrapulmonary administration of multi-walled carbon nanotubes, like asbestos, induced mesothelial proliferation potentially assocd. with mesothelioma development.
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84Usui, Y.; Haniu, H.; Tsuruoka, S.; Saito, N. Med. Chem. 2012, 2, 105There is no corresponding record for this reference.
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85Fiorito, S.; Serafino, A.; Andreola, F.; Togna, A.; Togna, G. J. Nanosci. Nanotechnol. 2006, 6, 591There is no corresponding record for this reference.
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86Liu, Z.; Davis, C.; Cai, W.; He, L.; Chen, X.; Dai, H. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 1410There is no corresponding record for this reference.
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87Schipper, M. L.; Nakayama-Ratchford, N.; Davis, C. R.; Kam, N. W.; Chu, P.; Liu, Z.; Sun, X.; Dai, H.; Gambhir, S. S. Nat. Nanotechnol. 2008, 3, 21687https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXkt1Slu7w%253D&md5=814b1f01559c4f5071a5b81c4e94c64aA pilot toxicology study of single-walled carbon nanotubes in a small sample of miceSchipper, Meike L.; Nakayama-Ratchford, Nozomi; Davis, Corrine R.; Kam, Nadine Wong Shi; Chu, Pauline; Liu, Zhuang; Sun, Xiaoming; Dai, Hongjie; Gambhir, Sanjiv S.Nature Nanotechnology (2008), 3 (4), 216-221CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Single-walled carbon nanotubes are currently under evaluation in biomedical applications, including in vivo delivery of drugs, proteins, peptides, and nucleic acids (for gene transfer or gene silencing), in vivo tumor imaging, and tumor targeting of single-walled carbon nanotubes as an antineoplastic treatment. However, concerns about the potential toxicity of single-walled carbon nanotubes have been raised. Here the authors examine the acute and chronic toxicity of functionalized single-walled carbon nanotubes when injected into the bloodstream of mice. Survival, clin., and lab. parameters reveal no evidence of toxicity over 4 mo. Upon killing, careful necropsy and tissue histol. show age-related changes only. Histol. and Raman microscopic mapping demonstrate that functionalized single-walled carbon nanotubes persisted within liver and spleen macrophages for 4 mo without apparent toxicity. Although this is a preliminary study with a small group of animals, the results encourage further confirmation studies with larger groups of animals.
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88Lee, Y.; Geckeler, K. E. Adv. Mater. 2010, 22, 4076There is no corresponding record for this reference.
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89Beg, S.; Rizwan, M.; Sheikh, A. M.; Hasnain, M. S.; Anwer, K.; Kohli, K. J. Pharm. Pharmacol. 2011, 63, 14189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsl2qsb8%253D&md5=f800be62875197edd899cef00929df25Advancement in carbon nanotubes: basics, biomedical applications and toxicityBeg, Sarwar; Rizwan, Mohammad; Sheikh, Asif M.; Hasnain, M. Saquib; Anwer, Khalid; Kohli, KanchanJournal of Pharmacy and Pharmacology (2011), 63 (2), 141-163CODEN: JPPMAB; ISSN:0022-3573. (John Wiley & Sons Ltd.)A review. Objectives Carbon nanotubes (CNTs) have attracted much attention by researchers worldwide in recent years for their small dimensions and unique architecture, and for having immense potential in nanomedicine as biocompatible and supportive substrates, as a novel tool for the delivery of therapeutic mols. including peptides, RNA and DNA, and also as sensors, actuators and composites. Key findings CNTs have been employed in the development of mol. electronic, composite materials and others due to their unique at. structure, high surface area-to-vol. ratio and excellent electronic, mech. and thermal properties. Recently they have been exploited as novel nanocarriers in drug delivery systems and biomedical applications. Their larger inner vol. as compared with the dimensions of the tube and easy immobilization of their outer surface with biocompatible materials make CNTs a superior nanomaterial for drug delivery. Literature reveals that CNTs are versatile carriers for controlled and targeted drug delivery, esp. for cancer cells, because of their cell membrane penetrability. Summary This review enlightens the biomedical application of CNTs with special emphasis on utilization in controlled and targeted drug delivery, as a diagnostics tool and other possible uses in therapeutic systems. The review also focuses on the toxicity aspects of CNTs, and revealed that genotoxic potential, mutagenic and carcinogenic effects of different types of CNTs must be explored and overcome by formulating safe biomaterial for drug delivery. The review also describes the regulatory aspects and clin. and market status of CNTs.
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90Lanone, S.; Boczkowski, J. Curr. Mol. Med. 2006, 6, 65190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XosVeksbo%253D&md5=0358c92e1516daa1f126c10e6c44fbc1Biomedical applications and potential health risks of nanomaterials: molecular mechanismsLanone, Sophie; Boczkowski, JorgeCurrent Molecular Medicine (2006), 6 (6), 651-663CODEN: CMMUBP; ISSN:1566-5240. (Bentham Science Publishers Ltd.)A review. Nanotechnologies, defined as techniques aimed to conceive, characterize and produce material at the nanometer scale, represent a fully expanding domain, and one can predict without risk that prodn. and utilization of nanomaterials will increase exponentially in the coming years. Applications of nanotechnologies are numerous, in const. development, and their potential use in the medical field as diagnosis and therapeutics tools is very attractive. The size particularity of these nanomaterials gives them novel properties, allowing them to adopt new comportments because of the laws of quantum physics that exist at this scale. However, worries are expressed regarding the exact properties that make these nanomaterials attractive, and questions are raised regarding their potential toxicity, their long-term secondary effects or their biodegradability, particularly when thinking of their use in the (nano)medical field. These questions are justified by the knowledge of the toxic effects of atm. pollution micrometric particles on health, and the fear to get an amplification of these effects because of the size of the materials blamed. In this paper, the authors first expose the sensed medical applications of nanomaterials, and the physicochem. and mol. determinants potentially responsible for nanomaterials biol. effects. Finally, the authors present a synthesis of the actual knowledge regarding toxicol. effects of nanomaterials. It is clear that, in regard to the almost empty field of what is known on the subject, there's an urge to better understand biol. effects of nanomaterials, which will allow their safe use, in particular in the nanomedicine field.
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91Firme, C. P., III; Bandaru, P. R. Nanomedicine 2010, 6, 245There is no corresponding record for this reference.
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92Alberts, B.; Bray, D.; Hopkin, K.; Johnson, A.; Lewis, J.; Raff, M.; Roberts, K.; Walter, P. Essential Cell Biology, 3rd ed.; Garland Science: New York, 2010.There is no corresponding record for this reference.
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93Cook, S. D.; Beckenbaugh, R. D.; Redondo, J.; Popich, L. S.; Klawitter, J. J.; Linscheid, R. L. J. Bone Jt. Surg., Am. Vol. 1999, 81, 63593https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1M3oslCgtQ%253D%253D&md5=4014804b9b5cdbae2a6ee0257da571d1Long-term follow-up of pyrolytic carbon metacarpophalangeal implantsCook S D; Beckenbaugh R D; Redondo J; Popich L S; Klawitter J J; Linscheid R LThe Journal of bone and joint surgery. American volume (1999), 81 (5), 635-48 ISSN:0021-9355.BACKGROUND: The metacarpophalangeal joint is the most commonly involved joint when rheumatoid arthritis affects the hand. Many prosthetic implants have been designed for the replacement of this joint. Although studies of these implants have shown relief of pain, they have generally demonstrated a poor range of motion, progression of ulnar drift, and bone loss, as well as failure, fracture, and dislocation of the implant. METHODS: From December 1979 to February 1987, 151 pyrolytic carbon metacarpophalangeal implants were inserted in fifty-three patients. The implants had an articulating, unconstrained design with a hemispherical head and grooved, offset stems. Forty-four patients had rheumatoid arthritis; five, posttraumatic arthritis; three, osteoarthritis; and one, systemic lupus erythematosus. Three patients (eleven implants) were lost to long-term follow-up, and twenty patients (fifty-one functioning implants) died after the implant had been in situ for an average of 7.2 years. Eighteen implants (12 percent) in eleven patients were revised. Fourteen of the eighteen implants were replaced with a silicone-elastomer or another type of implant, and the remaining four were removed and a pyrolytic carbon implant was reinserted with the addition of bone cement or bone graft, or both. Twenty-six patients (seventy-one implants) were available for long-term review at an average of 11.7 years (range, 10.1 to 16.0 years) after implantation. RESULTS: The implants improved the arc of motion of the fingers by an average of 13 degrees and elevated the arc by an average of 16 degrees. As a result, fingers were in a more functional, extended position. A complete set of preoperative, postoperative, and follow-up radiographs was available for fifty-three of the seventy-one implants that were followed long term. There was a high prevalence of joint stability: fifty (94 percent) of the fifty-three implants were in a reduced position postoperatively, and forty-one (82 percent) of those fifty implants were still in the postoperative reduced position at the time of long-term follow-up. Ulnar deviation averaged 20 degrees preoperatively and 19 degrees at the time of follow-up, with only the long finger having an increase in deviation. No adverse remodeling or resorption of bone was seen. Fifty (94 percent) of the fifty-three implants had evidence of osseointegration, with sclerosis around the end and shaft of the prosthetic stems. Radiolucent changes were seen adjacent to twelve implants. There was minimum-to-moderate subsidence (four millimeters or less) of thirty-four implants; most of the subsidence occurred immediately postoperatively. Survivorship analysis demonstrated an average annual failure rate of 2.1 percent and a sixteen-year survival rate of 70.3 percent. The five and ten-year survival rates were 82.3 percent (95 percent confidence interval, 74.6 to 88.2 percent) and 81.4 percent (95 percent confidence interval, 73.0 to 87.8 percent), respectively. None of the revised implants had any visible changes of wear or deformity of the surfaces or stems. Four instances of chronic inflammatory tissue and three instances of proliferative synovitis were noted histologically. Focal pigment deposits were seen in three fingers, one of which had removal of the implant two months after a fracture. No evidence of intracellular particles or particulate synovitis was found. CONCLUSIONS: The results of this study demonstrate that pyrolytic carbon is a biologically and biomechanically compatible, wear-resistant, and durable material for arthroplasty of the metacarpophalangeal joint.
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94Brantigan, J. W.; Neidre, A.; Toohey, J. S. Spine J. 2004, 4, 68194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2crntVOjtA%253D%253D&md5=ac224c6e85b634603638f3a4adeb4a00The Lumbar I/F Cage for posterior lumbar interbody fusion with the variable screw placement system: 10-year results of a Food and Drug Administration clinical trialBrantigan John W; Neidre Arvo; Toohey John SThe spine journal : official journal of the North American Spine Society (2004), 4 (6), 681-8 ISSN:1529-9430.BACKGROUND CONTEXT: The Lumbar I/F Cage is a carbon fiber reinforced polymer (CFRP) device designed to separate the mechanical and device functions of interbody fusion. A Investigational Device Exemption (IDE) clinical study of the CFRP cage was conducted during an enrollment period from 1991 to 1993. Based on the 2-year results of this study, the cage was approved by the US Food and Drug Administration (FDA) in February 1999. Since then, the Lumbar I/F Cage device has become widely used in the United States. PURPOSE: This study was designed to determine the long-term results of patients who received this device during the 1991-1993 enrollments. STUDY DESIGN/SETTING: Investigators from the original study were asked to evaluate their original patients according to FDA-reviewed case report forms. Although many of the centers were unable to provide significant follow-up, two centers that enrolled almost half of the original study group provided reports on a high percentage of their original patients. This paper reviews the results in those patients. PATIENT SAMPLE: Inclusion criteria included patients with degenerative disc disease who had at least one failed lumbar discectomy or decompression procedure at one or more levels. OUTCOME MEASURES: Clinical success was defined by a modified Prolo score evaluating pain, function, medication usage and economic status. Fusion success, determined by evaluation of plain radiographs, was defined by continuous bone bridging the fusion area with no lucencies. Flexion-extension X-rays were done on patients who had previous removal of pedicle screw implants. Any motion on flexion-extension films indicated pseudarthrosis. METHODS: All patients were contacted at their last known address. Internet search services were used to locate additional patients. Thirty-three of 43 eligible patients (77%) were evaluated, including 31 patients who reported for examination and X-ray and 2 additional patients by telephone survey and written questionnaire. RESULTS: Clinical success was achieved in 32 of 37 patients (86.5%) at 24 months and in 29 of 33 patients (87.8%) at 10 years. This included 61% excellent, 27% good, and 12% fair results. Fusion success was reported in 37 of 37 patients (100%) at 24 months and in 29 of 30 patients (96.7%) at 10 years. Patient satisfaction was reported in 31 of 33 (93.9%). Further lumbar surgery was done in 23 patients: in 18 patients for elective removal of pedicle screws and in 5 patients to extend the fusion to adjacent levels. Adjacent segment degeneration occurred in 61% of patients but was clinically significant in only 20%. Smokers had equal clinical and fusion success with nonsmokers at 24 months and 10 years and had adjacent segment degeneration in 37%, a rate significantly lower than nonsmokers at 87%. CONCLUSIONS: The high rate of clinical success, fusion success, and patient satisfaction at 24 months was maintained at 10-year follow-up. Adjacent segment degeneration was common but was usually not clinically significant.
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95Williams, M. A.; van Riet, S. J. Heart Valve Dis. 2006, 15, 8095https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28%252FptlygsA%253D%253D&md5=70933f3c42f7500a89970a60b0352055The On-X heart valve: mid-term results in a poorly anticoagulated populationWilliams Mervyn A; van Riet SoniaThe Journal of heart valve disease (2006), 15 (1), 80-6 ISSN:0966-8519.BACKGROUND AND AIM OF THE STUDY: The study aim was to evaluate the clinical performance of the On-X heart valve in a socioeconomically disadvantaged population. Most patients were from an indigenous, poorly educated and geographically dispersed segment of the population where anticoagulation therapy was generally erratic. METHODS: Between 1999 and 2004, a total of 530 valves (242 mitral valves, 104 aortic valves, 92 double valves) was implanted in 438 patients (average age 33 years; range: 3-78 years). The most common reason for surgery was rheumatic valve disease (57%), followed by degenerative valve disease (11%) and infective endocarditis (9%). Follow up was 95% complete for a total of 746 patient-years (pt-yr). Among the patient population, 40% were either not anticoagulated or were unsatisfactorily anticoagulated. RESULTS: Hospital mortality was 2.3%, and none of the hospital deaths was valve-related. Mean (+/- SE) actuarial survival (including hospital deaths) at four years was: AVR 73.8 +/- 8.1%, MVR 83.4 +/- 5.7% and DVR 60.9 +/- 10.3%. Linearized rates (for AVR, MVR and DVR, respectively) for late complications (%/ pt-yr) were: bleeding events 0.6, 1.0, and 2.3; thrombosis 0.0, 0.2, and 0.0; endocarditis 0.6, 1.0, and 2.3; paravalvular leak 0.6, 0.2, and 0.0; systemic embolism 1.1, 1.5, and 3.5. Most systemic emboli were related to infective endocarditis. Among patients there were seven uncomplicated, full-term pregnancies. CONCLUSION: Bearing in mind the erratic anticoagulation coverage and high incidence of infective endocarditis, the results of this study may be regarded as encouraging. The low incidence of valve thrombosis (one case) was noteworthy. These data also suggest that the On-X valve may be implanted with relative safety in women wishing to have children.
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96Saito, N.; Aoki, K.; Usui, Y.; Shimizu, M.; Hara, K.; Narita, N.; Ogihara, N.; Nakamura, K.; Ishigaki, N.; Kato, H.; Haniu, H.; Taruta, S.; Kim, Y. A.; Endo, M. Chem. Soc. Rev. 2011, 40, 3824There is no corresponding record for this reference.
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97Hara, K.; Aoki, K.; Usui, Y.; Shimizu, M.; Narita, N.; Ogihara, N.; Nakamura, K.; Ishigaki, N.; Sano, K.; Haniu, H.; Kato, H.; Nishimura, N.; Kim, Y. A.; Taruta, S.; Saito, N. Mater. Today 2011, 14, 43497https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFWjs7nP&md5=f59f6ab06c9cda4b62396a40c86175dbEvaluation of CNT toxicity by comparison to tattoo inkHara, Kazuo; Aoki, Kaoru; Usui, Yuki; Shimizu, Masayuki; Narita, Nobuyo; Ogihara, Nobuhide; Nakamura, Koichi; Ishigaki, Norio; Sano, Kenji; Haniu, Hisao; Kato, Hiroyuki; Nishimura, Naoyuki; Kim, Yoong Ahm; Taruta, Seiichi; Saito, NaotoMaterials Today (Oxford, United Kingdom) (2011), 14 (9), 434-440CODEN: MTOUAN; ISSN:1369-7021. (Elsevier Ltd.)The absence of an optimal nano-sized ref. material has been the biggest obstacle in evaluating the safety of carbon nanotubes as biomaterials. In this study, black tattoo inks, which have a long history of use by humans, are shown to be suitable ref. materials composed of nano-sized carbon black particles. We have also demonstrated that multi-walled carbon nanotubes have comparable basic safety properties to those of tattoo inks when used as biomaterials.
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98Takanashi, S.; Hara, K.; Aoki, K.; Usui, Y.; Shimizu, M.; Haniu, H.; Ogihara, N.; Ishigaki, N.; Nakamura, K.; Okamoto, M.; Kobayashi, S.; Kato, H.; Sano, K.; Nishimura, N.; Tsutsumi, H.; Machida, K.; Saito, N. Sci. Rep. 2012, 2, 49898https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs12rur7F&md5=df21786aac7ee347c7868d24dfae5754Carcinogenicity evaluation for the application of carbon nanotubes as biomaterials in rasH2 miceTakanashi, Seiji; Hara, Kazuo; Aoki, Kaoru; Usui, Yuki; Shimizu, Masayuki; Haniu, Hisao; Ogihara, Nobuhide; Ishigaki, Norio; Nakamura, Koichi; Okamoto, Masanori; Kobayashi, Shinsuke; Kato, Hiroyuki; Sano, Kenji; Nishimura, Naoyuki; Tsutsumi, Hideki; Machida, Kazuhiko; Saito, NaotoScientific Reports (2012), 2 (), srep00498, 7 pp.CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)The application of carbon nanotubes (CNTs) as biomaterials is of wide interest, and studies examg. their application in medicine have had considerable significance. Biol. safety is the most important factor when considering the clin. application of CNTs as biomaterials, and various toxicity evaluations are required. Among these evaluations, carcinogenicity should be examd. with the highest priority; however, no report using transgenic mice to evaluate the carcinogenicity of CNTs has been published to date. Here, we performed a carcinogenicity test by implanting multi-walled CNTs (MWCNTs) into the s.c. tissue of rasH2 mice, using the carbon black present in black tattoo ink as a ref. material for safety. The rasH2 mice did not develop neoplasms after being injected with MWCNTs; instead, MWCNTs showed lower carcinogenicity than carbon black. Such evaluations should facilitate the clin. application and development of CNTs for use in important medical fields.
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99Wang, J.; Sun, P.; Bao, Y.; Liu, J.; An, L. Toxicol. In Vitro 2011, 25, 242There is no corresponding record for this reference.
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100Devadasu, V. R.; Bhardwaj, V.; Kumar, M. N. Chem. Rev. 2013, 113, 1686There is no corresponding record for this reference.
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101Iannazzo, D.; Piperno, A.; Pistone, A.; Grassi, G.; Galvagno, S. Curr. Med. Chem. 2013, 20, 1333101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmt1yns7Y%253D&md5=527a93e973edaa5af5a588f65c907382Recent advances in carbon nanotubes as delivery systems for anticancer drugsIannazzo, Daniela; Piperno, Anna; Pistone, Alessandro; Grassi, Giovanni; Galvagno, SignorinoCurrent Medicinal Chemistry (2013), 20 (11), 1333-1354CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. Problems assocd. with the administration of anticancer drugs, such as limited soly., poor biodistribution, lack of selectivity, and healthy tissue damage, can be overcome by the implementation of drug delivery systems. A wide range of materials, including liposomes, microspheres, polymers and recently, carbon nanotubes (CNTs), were investigated for delivering anticancer drugs on the purpose of reducing the no. of necessary administrations, providing more localized and better use of the active agents, and increasing patient compliance. Carbon nanotubes (CNTs) have attracted particular attention as carriers of biol. relevant mols. due to their unique phys., chem. and physiol. properties. The exact relationship between the phys.-chem. properties of carbon nanotubes, their cell-to-cell interactions, reactivity, and biol./systemic consequences are relevant issues and it is important to know such inter-relationships beforehand to employ the benefits of these nanomaterials without the hazardous consequences. The purpose of this review is to present highlight of recent developments in the application of carbon nanotubes as cargoes for anticancer drugs and in the diagnosis of cancer diseases.
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102Veetil, J. V.; Ye, K. Biotechnol. Prog. 2009, 25, 709102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXotlWltrs%253D&md5=f3bd6f9f80418fccddc610d170f0f90dTailored carbon nanotubes for tissue engineering applicationsVeetil, Jithesh V.; Ye, KaimingBiotechnology Progress (2009), 25 (3), 709-721CODEN: BIPRET; ISSN:8756-7938. (Wiley-Blackwell)A review. A decade of aggressive researches on carbon nanotubes (CNTs) has paved way for extending these unique nanomaterials into a wide range of applications. In the relatively new arena of nanobiotechnol., a vast majority of applications are based on CNTs, ranging from miniaturized biosensors to organ regeneration. Nevertheless, the complexity of biol. systems poses a significant challenge in developing CNT-based tissue engineering applications. This review focuses on the recent developments of CNT-based tissue engineering, where the interaction between living cells/tissues and the nanotubes were transformed into a variety of novel techniques. This integration has already resulted in a revaluation of tissue engineering and organ regeneration techniques. Some of the new treatments that were not possible previously become reachable now. Because of the advent of surface chem., the CNT's biocompatibility was significantly improved, making it possible to serve as tissue scaffolding materials to enhance the organ regeneration. The superior mechanic strength and chem. inert also makes it ideal for blood compatible applications, esp. for cardiopulmonary bypass surgery. The applications of CNTs in these cardiovascular surgeries led to a remarkable improvement in mech. strength of implanted catheters and reduced thrombogenicity after surgery. Moreover, the functionalized CNTs were extensively explored for in vivo targeted drug or gene delivery, which could potentially improve the efficiency of many cancer treatments. However, just like other nanomaterials, the cytotoxicity of CNTs was not well established. Hence, more extensive cytotoxic studies are warranted while converting the hydrophobic CNTs into biocompatible nanomaterials.
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103Watari, F.; Takashi, N.; Yokoyama, A.; Uo, M.; Akasaka, T.; Sato, Y.; Abe, S.; Totsuka, Y.; Tohji, K. J. R. Soc. Interface 2009, 6, S371There is no corresponding record for this reference.
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104Prabhu, P.; Patravale, V. J. Biomed. Nanotechnol. 2012, 8, 859104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVWgtrvP&md5=2b982dc803aba3f5c42debb083e886deThe upcoming field of theranostic nanomedicine: an overviewPrabhu, Priyanka; Patravale, VandanaJournal of Biomedical Nanotechnology (2012), 8 (6), 859-882CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)A review. Nanocarriers have drastically changed the face of health care by making a mark in diverse arenas of diagnosis, drug delivery, and gene delivery to name a few. The recent feat in nanotechnol. was the birth of nanotheranostics which aims at blending both therapeutic and diagnostic functions within a single nanoscaffold. The field of theranostic nanomedicine is a result of fruitful advances in fields of material science, imaging modalities, formulation development, and mol. biol. Theranostic nanomedicine that was at first developed for enhancing the quality of treatment meted out to cancer patients has now been explored even in atherosclerosis and infections, albeit to a lower extent. The review summarizes various types of nanocarriers that were explored with one or sometimes multiple imaging modalities for an array of applications ranging from drug delivery and gene delivery to photosensitizing agent delivery for photodynamic therapy. The article also highlights the few but significant developments made in the field of theranostic nanomedicine for atherosclerosis and infections. In conclusion, theranostic nanomedicine is a rapidly growing field. However, there are a few problems that need to be addressed before theranostic nanocarriers carve a niche for themselves in the clinic.
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105Drbohlavova, J.; Chomoucka, J.; Adam, V.; Ryvolova, M.; Eckschlager, T.; Hubalek, J.; Kizek, R. Curr. Drug Metab. 2013, 14, 547105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1yhsLvI&md5=27e03e68b3c54c38eb8cd1da0d111d9eNanocarriers for Anticancer Drugs - New Trends in NanomedicineDrbohlavova, Jana; Chomoucka, Jana; Adam, Vojtech; Ryvolova, Marketa; Eckschlager, Tomas; Hubalek, Jaromir; Kizek, ReneCurrent Drug Metabolism (2013), 14 (5), 547-564CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)This review provides a brief overview of the variety of carriers employed for targeted drug delivery used in cancer therapy and summarizes advantages and disadvantages of each approach. Particularly, the attention was paid to polymeric nanocarriers, liposomes, micelles, polyethylene glycol, poly(lactic-co-glycolic acid), dendrimers, gold and magnetic nanoparticles, quantum dots, silica nanoparticles, and carbon nanotubes. Further, this paper briefly focuses on several anticancer agents (paclitaxel, docetaxel, camptothecin, doxorubicin, daunorubicin, cisplatin, curcumin, and geldanamycin) and on the influence of their combination with nanoparticulate transporters to their properties such as cytotoxicity, short life time and/or soly.
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106Karousis, N.; Tagmatarchis, N.; Tasis, D. Chem. Rev. 2010, 110, 5366There is no corresponding record for this reference.
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107Kam, N. W.; O’Connell, M.; Wisdom, J. A.; Dai, H. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 11600There is no corresponding record for this reference.
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108Venkatesan, N.; Yoshimitsu, J.; Ito, Y.; Shibata, N.; Takada, K. Biomaterials 2005, 26, 7154There is no corresponding record for this reference.
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109Dumortier, H.; Lacotte, S.; Pastorin, G.; Marega, R.; Wu, W.; Bonifazi, D.; Briand, J. P.; Prato, M.; Muller, S.; Bianco, A. Nano Lett. 2006, 6, 1522There is no corresponding record for this reference.
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110McDevitt, M. R.; Chattopadhyay, D.; Kappel, B. J.; Jaggi, J. S.; Schiffman, S. R.; Antczak, C.; Njardarson, J. T.; Brentjens, R.; Scheinberg, D. A. J. Nucl. Med. 2007, 48, 1180There is no corresponding record for this reference.
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111Liu, Z.; Jiao, L.; Yao, Y.; Xian, X.; Zhang, J. Adv. Mater. 2010, 22, 2285There is no corresponding record for this reference.
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112Hwang, J. Y.; Shin, U. S.; Jang, W. C.; Hyun, J. K.; Wall, I. B.; Kim, H. W. Nanoscale 2013, 5, 487There is no corresponding record for this reference.
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113Ferrari, M. Nat. Rev. Cancer 2005, 5, 161113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhslSnt7o%253D&md5=b4e4a4aacb2a265e76c261c4cc4b77c7Cancer nanotechnology: opportunities and challengesFerrari, MauroNature Reviews Cancer (2005), 5 (3), 161-171CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. Nanotechnol. is a multidisciplinary field, which covers a vast and diverse array of devices derived from engineering, biol., physics and chem. These devices include nanovectors for the targeted delivery of anticancer drugs and imaging contrast agents. Nanowires and nanocantilever arrays are among the leading approaches under development for the early detection of precancerous and malignant lesions from biol. fluids. These and other nanodevices can provide essential breakthroughs in the fight against cancer.
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114Ou, Z.; Wu, B.; Xing, D.; Zhou, F.; Wang, H.; Tang, Y. Nanotechnology 2009, 20, 105102There is no corresponding record for this reference.
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115Okada, S.; Saito, S.; Oshiyama, A. Phys. Rev. Lett. 2001, 86, 3835There is no corresponding record for this reference.
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116Kavan, L.; Dunsch, L. ChemPhysChem 2003, 4, 944There is no corresponding record for this reference.
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117Foldvari, M.; Bagonluri, M. Nanomedicine 2008, 4, 183There is no corresponding record for this reference.
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118Taylor, A.; Lipert, K.; Kramer, K.; Hampel, S.; Fussel, S.; Meye, A.; Klingeler, R.; Ritschel, M.; Leonhardt, A.; Büchner, B.; Wirth, M. P. J. Nanosci. Nanotechnol. 2009, 9, 5709There is no corresponding record for this reference.
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119Hong, S. Y.; Tobias, G.; Al-Jamal, K. T.; Ballesteros, B.; Ali-Boucetta, H.; Lozano-Perez, S.; Nellist, P. D.; Sim, R. B.; Finucane, C.; Mather, S. J.; Green, M. L.; Kostarelos, K.; Davis, B. G. Nat. Mater. 2010, 9, 485There is no corresponding record for this reference.
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120Liopo, A. V.; Stewart, M. P.; Hudson, J.; Tour, J. M.; Pappas, T. C. J. Nanosci. Nanotechnol. 2006, 6, 1365There is no corresponding record for this reference.
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121Keefer, E. W.; Botterman, B. R.; Romero, M. I.; Rossi, A. F.; Gross, G. W. Nat. Nanotechnol. 2008, 3, 434121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXotFehsb8%253D&md5=698b815116aae4e8a0e229bebfe6b650Carbon nanotube coating improves neuronal recordingsKeefer, Edward W.; Botterman, Barry R.; Romero, Mario I.; Rossi, Andrew F.; Gross, Guenter W.Nature Nanotechnology (2008), 3 (7), 434-439CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Implanting elec. devices in the nervous system to treat neural diseases is becoming very common. The success of these brain-machine interfaces depends on the electrodes that come into contact with the neural tissue. Here the authors show that conventional tungsten and stainless steel wire electrodes can be coated with carbon nanotubes using electrochem. techniques under ambient conditions. The carbon nanotube coating enhanced both recording and elec. stimulation of neurons in culture, rats and monkeys by decreasing the electrode impedance and increasing charge transfer. Carbon nanotube-coated electrodes are expected to improve current electrophysiol. techniques and to facilitate the development of long-lasting brain-machine interface devices. Coating conventional tungsten and stainless steel electrodes with carbon nanotubes improves their performance in research involving the implantation of elec. devices into the nervous system. The results could have an impact on electrophysiol. and the development of brain-machine interfaces.
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122Nunes, A.; Al-Jamal, K.; Nakajima, T.; Hariz, M.; Kostarelos, K. Arch. Toxicol. 2012, 86, 1009122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmtlWnu7Y%253D&md5=1f174dbcb962424f0791944af3fb26f8Application of carbon nanotubes in neurology: clinical perspectives and toxicological risksNunes, Antonio; Al-Jamal, Khuloud; Nakajima, Takeshi; Hariz, Marwan; Kostarelos, KostasArchives of Toxicology (2012), 86 (7), 1009-1020CODEN: ARTODN; ISSN:0340-5761. (Springer)A review. Nanomedicine is an emerging field that proposes the application of precisely engineered nanomaterials for the prevention, diagnosis and therapy of certain diseases, including neurol. pathologies. Carbon nanotubes (CNT) are a new class of nanomaterials, which were shown to be promising in different areas of nanomedicine. In this review, the application of CNT interfacing with the central nervous system (CNS) will be described, and representative examples of neuroprosthetic devices, such as neuronal implants and electrodes will be discussed. Furthermore, the possible application of CNT-based materials as regenerative matrixes of neuronal tissue and as delivery systems for the therapy of CNS will be presented.
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123Baughman, R. H.; Cui, C.; Zakhidov, A. A.; Iqbal, Z.; Barisci, J. N.; Spinks, G. M.; Wallace, G. G.; Mazzoldi, A.; De Rossi, D.; Rinzler, A. G.; Jaschinski, O.; Roth, S.; Kertesz, M. Science 1999, 284, 1340123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXjs1Wjtb4%253D&md5=62360d4dbaf1c8b5f85391a246e35d05Carbon nanotube actuatorsBaughman, Ray H.; Cui, Changxing; Zakhidov, Anvar A.; Iqbal, Zafar; Barisci, Joseph N.; Spinks, Geoff M.; Wallace, Gordon G.; Mazzoldi, Alberto; De Rossi, danilo; Rinzler, Andrew G.; Jaschinski, Oliver; Roth, Siegmar; Kertesz, MiklosScience (Washington, D. C.) (1999), 284 (5418), 1340-1344CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Electromech. actuators based on sheets of single-walled carbon nanotubes were shown to generate higher stresses than natural muscle and higher strains than high-modulus ferroelecs. Like natural muscles, the macroscopic actuators are assemblies of billions of individual nanoscale actuators. The actuation mechanism (quantum chem.-based expansion due to electrochem. double-layer charging) does not require ion intercalation, which limits the life and rate of faradaic conducting polymer actuators. Unlike conventional ferroelec. actuators, low operating voltages of a few volts generate large actuator strains. Predictions based on measurements suggest that actuators using optimized nanotube sheets may eventually provide substantially higher work densities per cycle than any previously known technol.
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124Chen, L.; Liu, C.; Liu, K.; Meng, C.; Hu, C.; Wang, J.; Fan, S. ACS Nano 2011, 5, 1588There is no corresponding record for this reference.
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125Vittorio, O.; Quaranta, P.; Raffa, V.; Funel, N.; Campani, D.; Pelliccioni, S.; Longoni, B.; Mosca, F.; Pietrabissa, A.; Cuschieri, A. Nanomedicine (London, U.K.) 2011, 6, 43125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1WntbnF&md5=cd57bdc6cea971b30295502a96dac065Magnetic carbon nanotubes: a new tool for shepherding mesenchymal stem cells by magnetic fieldsVittorio, Orazio; Quaranta, Paola; Raffa, Vittoria; Funel, Niccola; Campani, Daniela; Pelliccioni, Serena; Longoni, Biancamaria; Mosca, Franco; Pietrabissa, Andrea; Cuschieri, AlfredNanomedicine (London, United Kingdom) (2011), 6 (1), 43-54CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)Aims: We investigated the interaction between magnetic carbon nanotubes (CNTs) and mesenchymal stem cells (MSCs), and their ability to guide these i.v. injected cells in living rats by using an external magnetic field. Materials & methods: Multiwalled CNTs were used to treat MSCs derived from rat bone marrow. Cytotoxicity induced by nanotubes was studied using the WST-1 proliferation and Hoechest 33258 apoptosis assays. The effects of nanotubes on MSCs were evaluated by monitoring the effects on cellular growth rates, immunophenotyping and differentiation, and on the arrangement of cytoskeletal actin. MSCs loaded with nanotubes were injected in vivo in the portal vein of rats driving their localization in the liver by magnetic field. An histol. anal. was performed on the liver, lungs and kidneys of all animals. Results: CNTs did not affect cell viability and their ability to differentiate in osteocytes and adipocytes. Both the CNTs and the magnetic field did not alter the cell growth rate, phenotype and cytoskeletal conformation. CNTs, when exposed to magnetic fields, are able to shepherd MSCs towards the magnetic source in vitro. Moreover, the application of a magnetic field alters the biodistribution of CNT-labeled MSCs after i.v. injection into rats, increasing the accumulation of cells into the target organ (liver). Conclusion: Multiwalled CNTs hold the potential for use as nanodevices to improve therapeutic protocols for transplantation and homing of stem cells in vivo. This could pave the way for the development of new strategies for the manipulation/guidance of MSCs in regenerative medicine and cell transplantation.
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126Hong, C.; Kang, J.; Kim, H.; Lee, C. J. Nanosci. Nanotechnol. 2012, 12, 4352There is no corresponding record for this reference.
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127Madani, S. Y.; Tan, A.; Naderi, N.; Seifalian, A. M. J. Nanosci. Nanotechnol. 2012, 12, 9018There is no corresponding record for this reference.
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128Wang, L.; Shi, J.; Zhang, H.; Li, H.; Gao, Y.; Wang, Z.; Wang, H.; Li, L.; Zhang, C.; Chen, C.; Zhang, Z.; Zhang, Y. Biomaterials 2013, 34, 262There is no corresponding record for this reference.
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129Bhirde, A. A.; Patel, V.; Gavard, J.; Zhang, G.; Sousa, A. A.; Masedunskas, A.; Leapman, R. D.; Weigert, R.; Gutkind, J. S.; Rusling, J. F. ACS Nano 2009, 3, 307There is no corresponding record for this reference.
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130Chaudhuri, P.; Harfouche, R.; Soni, S.; Hentschel, D. M.; Sengupta, S. ACS Nano 2010, 4, 574There is no corresponding record for this reference.
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131Ruggiero, A.; Villa, C. H.; Holland, J. P.; Sprinkle, S. R.; May, C.; Lewis, J. S.; Scheinberg, D. A.; McDevitt, M. R. Int. J. Nanomed. 2010, 5, 783131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1OiurfI&md5=9bec85125af54c54919d24166e719554Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubesRuggiero, Alessandro; Villa, Carlos H.; Holland, Jason P.; Sprinkle, Shanna R.; May, Chad; Lewis, Jason S.; Scheinberg, David A.; McDevitt, Michael R.International Journal of Nanomedicine (2010), 5 (), 783-802CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)Single wall carbon nanotube (SWCNT) constructs were covalently appended with radiometal-ion chelates (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA] or desferrioxamine B [DFO]) and the tumor neovascular-targeting antibody E4G10. The E4G10 antibody specifically targeted the monomeric vascular endothelial-cadherin (VE-cad) epitope expressed in the tumor angiogenic vessels. The construct specific activity and blood compartment clearance kinetics were significantly improved relative to corresponding antibody-alone constructs. We performed targeted radioimmunotherapy with a SWCNT-([225Ac]DOTA)(E4G10) construct directed at the tumor vasculature in a murine xenograft model of human colon adenocarcinoma (LS174T). The specific construct reduced tumor vol. and improved median survival relative to controls. We also performed positron emission tomog. (PET) radioimmunoimaging of the tumor vessels with a SWCNT-([89Zr]DFO)(E4G10) construct in the same murine LS174T xenograft model and compared the results to appropriate controls. Dynamic and longitudinal PET imaging of LS174T tumor-bearing mice demonstrated rapid blood clearance (<1 h) and specific tumor accumulation of the specific construct. Incorporation of the SWCNT scaffold into the construct design permitted us to amplify the specific activity to improve the signal-to-noise ratio without detrimentally impacting the immunoreactivity of the targeting antibody moiety. Furthermore, we were able to exploit the SWCNT pharmacokinetic (PK) profile to favorably alter the blood clearance and provide an advantage for rapid imaging. Near-IR three-dimensional fluorescent-mediated tomog. was used to image the LS174T tumor model, collect antibody-alone PK data, and calc. the no. of copies of VE-cad epitope per cell. All of these studies were performed as a single administration of construct and were found to be safe and well tolerated by the murine model. These data have implications that support further imaging and radiotherapy studies using a SWCNT-based platform and focusing on the tumor vessels as the target.
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132Singh, S. J. Nanosci. Nanotechnol. 2010, 10, 7906There is no corresponding record for this reference.
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133Elhissi, A. M.; Ahmed, W.; Hassan, I. U.; Dhanak, V. R.; D’Emanuele, A. J. Drug Delivery 2012, 2012, 837327There is no corresponding record for this reference.
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134Ding, Y.; Liu, J.; Jin, X.; Lu, H.; Shen, G.; Yu, R. Analyst 2008, 133, 184There is no corresponding record for this reference.
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135Kim, J. P.; Lee, B. Y.; Lee, J.; Hong, S.; Sim, S. J. Biosens. Bioelectron. 2009, 24, 3372There is no corresponding record for this reference.
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136Lin, J.; He, C.; Zhang, L.; Zhang, S. Anal. Biochem. 2009, 384, 130There is no corresponding record for this reference.
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137Li, Q.; Tang, D.; Tang, J.; Su, B.; Huang, J.; Chen, G. Talanta 2011, 84, 538There is no corresponding record for this reference.
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138Gul, H.; Lu, W.; Xu, P.; Xing, J.; Chen, J. Nanotechnology 2010, 21, 155101There is no corresponding record for this reference.
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139Delogu, L. G.; Vidili, G.; Venturelli, E.; Ménard-Moyon, C.; Zoroddu, M. A.; Pilo, G.; Nicolussi, P.; Ligios, C.; Bedognetti, D.; Sgarrella, F.; Manetti, R.; Bianco, A. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 16612There is no corresponding record for this reference.
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140Chang, Y. T.; Huang, J. H.; Tu, M. C.; Chang, P.; Yew, T. R. Biosens. Bioelectron. 2013, 41, 898There is no corresponding record for this reference.
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141Lu, X.; Cheng, H.; Huang, P.; Yang, L.; Yu, P.; Mao, L. Anal. Chem. 2013, 85, 4007141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktVOitbc%253D&md5=af562990a1ea60b1344ed52d582b833fHybridization of Bioelectrochemically Functional Infinite Coordination Polymer Nanoparticles with Carbon Nanotubes for Highly Sensitive and Selective In Vivo Electrochemical MonitoringLu, Xulin; Cheng, Hanjun; Huang, Pengcheng; Yang, Lifen; Yu, Ping; Mao, LanqunAnalytical Chemistry (Washington, DC, United States) (2013), 85 (8), 4007-4013CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)This study demonstrates the formation of a three-dimensional conducting framework through hybridization of bioelectrochem. active infinite coordination polymer (ICP) nanoparticles with single-walled carbon nanotubes (SWNTs) for highly sensitive and selective in vivo electrochem. monitoring with combination with in vivo microdialysis. The bioelectrochem. active ICP nanoparticles were synthesized through the self-assembly process of NAD+ and Tb3+, in which all biosensing elements including an electrocatalyst (i.e., methylene green, MG), cofactor (i.e., β-NAD, NAD+), and enzyme (i.e., glucose dehydrogenase, GDH) are adaptively encapsulated. The ICP/SWNT-based biosensors are simply prepd. by drop-coating the as-formed ICP/SWNT nanocomposite onto a glassy carbon substrate. Electrochem. studies demonstrate that the simply prepd. ICP/SWNT-based biosensors exhibit excellent biosensing properties with a higher sensitivity and stability than the ICP-based biosensors prepd. only with ICP nanoparticles (i.e., without hybridization of SWNTs). By using a GDH-based electrochem. biosensor as an example, the authors demonstrate a tech. simple yet effective online electroanal. platform for continuously monitoring glucose in the brain of guinea pigs with the ICP/SWNT-based biosensor as an online detector in a continuous-flow system combined with in vivo microdialysis. Under the exptl. conditions employed here, the dynamic linear range for glucose with the ICP/SWNT-biosensor is 50-1000 μM. Moreover, in vivo selectivity studies with the biosensors prepd. by the GDH-free ICPs reveal that ICP/SWNT-based biosensors are very selective for the measurement of glucose in the cerebral system. The basal level of glucose in the microdialyzates from the striatum of guinea pigs is 0.31 ± 0.03 mM (n = 3). The study offers a simple route to the prepn. of electrochem. biosensors, which is envisaged to be particularly useful for probing the chem. events involved in some physiol. and pathol. processes.
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142Sitharaman, B.; Van Der Zande, M.; Ananta, J. S.; Shi, X.; Veltien, A.; Walboomers, X. F.; Wilson, L. J.; Mikos, A. G.; Heerschap, A.; Jansen, J. A. J. Biomed. Mater. Res., Part A 2010, 93, 1454142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlt1Smsrw%253D&md5=d592fbf57f6022b82fb159d9745ba5d0Magnetic resonance imaging studies on gadonanotube-reinforced biodegradable polymer nanocompositesSitharaman, Balaji; Van Der Zande, Meike; Ananta, Jeyarama S.; Shi, Xinfeng; Veltien, Andor; Walboomers, X. Frank; Wilson, Lon J.; Mikos, Antonios G.; Heerschap, Arend; Jansen, John A.Journal of Biomedical Materials Research, Part A (2010), 93A (4), 1454-1462CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)We report about the in vitro cytotoxicity and MRI studies of Gd3+ions-doped ultra-short single-walled carbon nanotube (gadonanotubes), gadonanotubes-reinforced poly(lactic-co-glycolic acid) (PLGA) polymer nanocomposites and in vivo small animal MRI studies using the gadonanotubes. These studies were performed to explore the suitability of gadonanotubes-reinforced PLGA polymer nanocomposite as a model scaffold for noninvasive magnetic resonance imaging (MRI) to evaluate nanotube release during the degrdn. process of the scaffold and their biodistribution upon release from the polymer matrix in vivo. The gadonanotubes at 1-100 ppm and the gadonanotubes/PLGA nanocomposites (2 wt % gadonanotubes) did not show any cytotoxicity in vitro as demonstrated using the LIVE/DEAD viability assay. For the first time, r2 relaxivity measurements were obtained for the superparamagnetic gadonanotubes. In vitro 7T MRI of the superparamagnetic gadonanotubes ([Gd] = 0.15 mM) suspended in a biocompatible 1% Pluronic F127 soln., gave a r2 value of 578 mM-1 s-1. Upon s.c. injection of the gadonanotubes suspension into the dorsal region of rats, the high r2 value translated into excellent and prolonged neg. contrast enhancement of in vivo T2 weighted proton MRI images. The in vitro characterization of the nanocomposite disks and their degrdn. process by MRI, showed strong influence of the gadonanotube on water proton relaxations. These results indicate that the gadonanotubes/PLGA nanocomposites are suitable for further in vivo studies to track by MRI the biodegrdn. release and biodistribution of gadonanotubes. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010.
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143Minati, L.; Antonini, V.; Dalla Serra, M.; Speranza, G. Langmuir 2012, 28, 15900There is no corresponding record for this reference.
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144Avti, P. K.; Talukdar, Y.; Sirotkin, M. V.; Shroyer, K. R.; Sitharaman, B. J. Biomed. Mater. Res., Part B 2013, 101, 1039144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVyksLfI&md5=2ef391b4ac33f29bc3cd8d4ef0a071c3Toward single-walled carbon nanotube-gadolinium complex as advanced MRI contrast agents: Pharmacodynamics and global genomic response in small animalsAvti, Pramod K.; Talukdar, Yahfi; Sirotkin, Matvey V.; Shroyer, Kenneth R.; Sitharaman, BalajiJournal of Biomedical Materials Research, Part B: Applied Biomaterials (2013), 101B (6), 1039-1049CODEN: JBMRGL; ISSN:1552-4973. (John Wiley & Sons, Inc.)Gadolinium nanoparticle-catalyzed single-walled carbon nanotubes (Gd-SWCNTs) have recently shown potential in vitro as high-performance T1 magnetic resonance imaging (MRI) contrast agents (CAs). Their preclin. safety assessment at nontoxic dosages is essential for MRI applications. Herein, the in vivo (in rats) pharmacodynamics of Gd-SWCNTs (water solubilized with the amphiphilic polymer PEG-DSPE) at the organ, tissue, mol., and genetic level is reported. Gd-SWCNT, com. available iron catalyzed SWCNTs (Fe-SWCNTs, control 1) and PEG-DSPE (control 2) solns. were i.v. injected at a potential nontoxic therapeutic dose (0.5 mg/kg body wt., single bolus). Postinjection, bright-field optical microscopy showed their macroscale distribution in lung, liver, kidney, brain, and spleen up to 5 days. Raman and transmission electron microscopy (TEM) showed their presence at the nanoscale within hepatocytes. Their effects on the host organ tissue, mol., and genetic level were analyzed after 1, 5, 10, 20, and 30 days by histol., biomol. [lipid peroxidn., plasma tumor necrosis factor TNF-α assay, microarrays] assays. The results indicate that Gd-SWCNTs neither cause any inflammation, nor damage to the above organs, nor any significant change in the lipid peroxidn. or plasma proinflammatory cytokine (TNF-α) levels for all the groups at all time points. Global gene expression profile of liver (main organ for the metab.) after day 1 treatment with Gd-SWCNTs shows that the gene regulation is directed toward maintaining normal homeostasis. The results taken together indicate that PEG-DSPE water-solubilized Gd-SWCNTs at potentially nontoxic dosages have pharmacodynamics similar to other com. available Fe-SWCNTs and are suitable for future preclin. development as in vivo MRI CAs. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013.
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145Ou, Z.; Wu, B. J. Nanosci. Nanotechnol. 2013, 13, 1212There is no corresponding record for this reference.
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146Hartman, K. B.; Wilson, L. J. Adv. Exp. Med. Biol. 2007, 620, 74There is no corresponding record for this reference.
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147De la Zerda, A.; Zavaleta, C.; Keren, S.; Vaithilingam, S.; Bodapati, S.; Liu, Z.; Levi, J.; Smith, B. R.; Ma, T. J.; Oralkan, O.; Cheng, Z.; Chen, X.; Dai, H.; Khuri-Yakub, B. T.; Gambhir, S. S. Nat. Nanotechnol. 2008, 3, 557147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVOqsLvO&md5=45244da12fb9416414189428db00b06cCarbon nanotubes as photoacoustic molecular imaging agents in living miceDe La Zerda, Adam; Zavaleta, Cristina; Keren, Shay; Vaithilingam, Srikant; Bodapati, Sunil; Liu, Zhuang; Levi, Jelena; Smith, Bryan R.; Ma, Te-Jen; Oralkan, Omer; Cheng, Zhen; Chen, Xiaoyuan; Dai, Hongjie; Khuri-Yakub, Butrus T.; Gambhir, Sanjiv S.Nature Nanotechnology (2008), 3 (9), 557-562CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Photoacoustic imaging of living subjects offers higher spatial resoln. and allows deeper tissues to be imaged compared with most optical imaging techniques. As many diseases do not exhibit a natural photoacoustic contrast, esp. in their early stages, it is necessary to administer a photoacoustic contrast agent. A no. of contrast agents for photoacoustic imaging have been suggested previously, but most were not shown to target a diseased site in living subjects. Here the authors show that single-walled carbon nanotubes conjugated with cyclic Arg-Gly-Asp (RGD) peptides can be used as a contrast agent for photoacoustic imaging of tumors. I.v. administration of these targeted nanotubes to mice bearing tumors showed eight times greater photoacoustic signal in the tumor than mice injected with nontargeted nanotubes. These results were verified ex vivo using Raman microscopy. Photoacoustic imaging of targeted single-walled carbon nanotubes may contribute to noninvasive cancer imaging and monitoring of nanotherapeutics in living subjects. Photoacoustic imaging offers higher spatial resoln. than most optical imaging techniques, but contrast agents are needed because many diseases in their early stages do not display a natural photoacoustic contrast. Using single-walled carbon nanotubes conjugated with a peptide as a contrast agent allows the noninvasive photoacoustic imaging of tumors in animals.
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148Heller, D. A.; Baik, S.; Eurell, T. E.; Strano, M. S. Adv. Mater. 2005, 17, 2793There is no corresponding record for this reference.
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149Liu, Z.; Peng, R. Eur. J. Nucl. Med. Mol. Imaging 2010, 37, S147There is no corresponding record for this reference.
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150Liu, Z.; Sun, X.; Nakayama-Ratchford, N.; Dai, H. ACS Nano 2007, 1, 50There is no corresponding record for this reference.
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151Adeli, M.; Soleyman, R.; Beiranvand, Z.; Madani, F. Chem. Soc. Rev. 2013, 42, 5231There is no corresponding record for this reference.
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152Liu, H.; Xu, H.; Wang, Y.; He, Z.; Li, S. Drug Dev. Ind. Pharm. 2012, 38, 1031There is no corresponding record for this reference.
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153Chen, J.; Chen, S.; Zhao, X.; Kuznetsova, L. V.; Wong, S. S.; Ojima, I. J. Am. Chem. Soc. 2008, 130, 16778153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlyitr%252FK&md5=199a741769044f2912f270c2f71d90f2Functionalized Single-Walled Carbon Nanotubes as Rationally Designed Vehicles for Tumor-Targeted Drug DeliveryChen, Jingyi; Chen, Shuyi; Zhao, Xianrui; Kuznetsova, Larisa V.; Wong, Stanislaus S.; Ojima, IwaoJournal of the American Chemical Society (2008), 130 (49), 16778-16785CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A novel single-walled carbon nanotube (SWNT)-based tumor-targeted drug delivery system (DDS) has been developed, which consists of a functionalized SWNT linked to tumor-targeting modules as well as prodrug modules. There are three key features of this nanoscale DDS: (a) use of functionalized SWNTs as a biocompatible platform for the delivery of therapeutic drugs or diagnostics, (b) conjugation of prodrug modules of an anticancer agent (taxoid with a cleavable linker) that is activated to its cytotoxic form inside the tumor cells upon internalization and in situ drug release, and (c) attachment of tumor-recognition modules (biotin and a spacer) to the nanotube surface. To prove the efficacy of this DDS, three fluorescent and fluorogenic mol. probes were designed, synthesized, characterized, and subjected to the anal. of the receptor-mediated endocytosis and drug release inside the cancer cells (L1210FR leukemia cell line) by means of confocal fluorescence microscopy. The specificity and cytotoxicity of the conjugate have also been assessed and compared with L1210 and human noncancerous cell lines. Then, it has unambiguously been proven that this tumor-targeting DDS works exactly as designed and shows high potency toward specific cancer cell lines, thereby forming a solid foundation for further development.
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154Zhang, X.; Meng, L.; Lu, Q.; Fei, Z.; Dyson, P. J. Biomaterials 2009, 30, 6041There is no corresponding record for this reference.
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155Shvedova, A. A.; Kisin, E. R.; Porter, D.; Schulte, P.; Kagan, V. E.; Fadeel, B.; Castranova, V. Pharmacol. Ther. 2009, 121, 192155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXitVOks70%253D&md5=a81cfbe5b2f7dc6b6fff6062ae5fc309Mechanisms of pulmonary toxicity and medical applications of carbon nanotubes: Two faces of Janus?Shvedova, A. A.; Kisin, E. R.; Porter, D.; Schulte, P.; Kagan, V. E.; Fadeel, B.; Castranova, V.Pharmacology & Therapeutics (2009), 121 (2), 192-204CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)A review. Nanotechnol. is an emerging science involving manipulation of materials at the nanometer scale. There are several exciting prospects for the application of engineered nanomaterials in medicine. However, concerns over adverse and unanticipated effects on human health have also been raised. In fact, the same properties that make engineered nanomaterials attractive from a technol. and biomedical perspective could also make these novel materials harmful to human health and the environment. Carbon nanotubes are cylinders of one or several coaxial graphite layer(s) with a diam. in the order of nanometers, and serve as an instructive example of the Janus-like properties of nanomaterials. Numerous in vitro and in vivo studies have shown that carbon nanotubes and(or) assocd. contaminants or catalytic materials that arise during the prodn. process may induce oxidative stress and prominent pulmonary inflammation. Recent studies also suggest some similarities between the pathogenic properties of multi-walled carbon nanotubes and those of asbestos fibers. On the other hand, carbon nanotubes can be readily functionalized and several studies on the use of carbon nanotubes as versatile excipients for drug delivery and imaging of disease processes have been reported, suggesting that carbon nanotubes may have a place in the armamentarium for treatment and monitoring of cancer, infection, and other disease conditions. Nanomedicine is an emerging field that holds great promise; however, close attention to safety issues is required to ensure that the opportunities that carbon nanotubes and other engineered nanoparticles offer can be translated into feasible and safe constructs for the treatment of human disease.
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156Pantarotto, D.; Singh, R.; McCarthy, D.; Erhardt, M.; Briand, J. P.; Prato, M.; Kostarelos, K.; Bianco, A. Angew. Chem., Int. Ed. 2004, 43, 5242156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXos1ygt7Y%253D&md5=c675eaef7643ed0d3ae93df492b5230cFunctionalized carbon nanotubes for plasmid DNA gene deliveryPantarotto, Davide; Singh, Ravi; McCarthy, David; Erhardt, Mathieu; Briand, Jean-Paul; Prato, Maurizio; Kostarelos, Kostas; Bianco, AlbertoAngewandte Chemie, International Edition (2004), 43 (39), 5242-5246CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Genetic vaccination and gene therapy research could benefit from the application of carbon nanotubes. Functionalized, pos. charged, water-sol. carbon nanotubes are able to penetrate into cells and can transport plasmid DNA by formation of noncovalent DNA-nanotube complexes. Such nanotubes can be used as novel nonviral delivery systems for gene transfer.
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157Singh, R.; Pantarotto, D.; McCarthy, D.; Chaloin, O.; Hoebeke, J.; Partidos, C. D.; Briand, J. P.; Prato, M.; Bianco, A.; Kostarelos, K. J. Am. Chem. Soc. 2005, 127, 4388157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXitVShs7Y%253D&md5=8679d4e683e3806a94b299b5a716aadaBinding and Condensation of Plasmid DNA onto Functionalized Carbon Nanotubes: Toward the Construction of Nanotube-Based Gene Delivery VectorsSingh, Ravi; Pantarotto, Davide; McCarthy, David; Chaloin, Olivier; Hoebeke, Johan; Partidos, Charalambos D.; Briand, Jean-Paul; Prato, Maurizio; Bianco, Alberto; Kostarelos, KostasJournal of the American Chemical Society (2005), 127 (12), 4388-4396CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Carbon nanotubes (CNTs) constitute a class of nanomaterials that possess characteristics suitable for a variety of possible applications. Their compatibility with aq. environments has been made possible by the chem. functionalization of their surface, allowing for exploration of their interactions with biol. components including mammalian cells. Functionalized CNTs (f-CNTs) are being intensively explored in advanced biotechnol. applications ranging from mol. biosensors to cellular growth substrates. We have been exploring the potential of f-CNTs as delivery vehicles of biol. active mols. in view of possible biomedical applications, including vaccination and gene delivery. Recently we reported the capability of ammonium-functionalized single-walled CNTs to penetrate human and murine cells and facilitate the delivery of plasmid DNA leading to expression of marker genes. To optimize f-CNTs as gene delivery vehicles, it is essential to characterize their interactions with DNA. In the present report, we study the interactions of three types of f-CNTs, ammonium-functionalized single-walled and multiwalled carbon nanotubes (SWNT-NH3+; MWNT-NH3+), and lysine-functionalized single-walled carbon nanotubes (SWNT-Lys-NH3+), with plasmid DNA. Nanotube-DNA complexes were analyzed by SEM, surface plasmon resonance, PicoGreen dye exclusion, and agarose gel shift assay. The results indicate that all three types of cationic carbon nanotubes are able to condense DNA to varying degrees, indicating that both nanotube surface area and charge d. are crit. parameters that det. the interaction and electrostatic complex formation between f-CNTs with DNA. All three different f-CNT types in this study exhibited upregulation of marker gene expression over naked DNA using a mammalian (human) cell line. Differences in the levels of gene expression were correlated with the structural and biophys. data obtained for the f-CNT:DNA complexes to suggest that large surface area leading to very efficient DNA condensation is not necessary for effective gene transfer. However, it will require further investigation to det. whether the degree of binding and tight assocn. between DNA and nanotubes is a desirable trait to increase gene expression efficiency in vitro or in vivo. This study constitutes the first thorough investigation into the physicochem. interactions between cationic functionalized carbon nanotubes and DNA toward construction of carbon nanotube-based gene transfer vector systems.
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158Kateb, B.; Van Handel, M.; Zhang, L.; Bronikowski, M. J.; Manohara, H.; Badie, B. Neuroimage 2007, 37, S9There is no corresponding record for this reference.
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159Herrero, M. A.; Toma, F. M.; Al-Jamal, K. T.; Kostarelos, K.; Bianco, A.; Da Ros, T.; Bano, F.; Casalis, L.; Scoles, G.; Prato, M. J. Am. Chem. Soc. 2009, 131, 9843There is no corresponding record for this reference.
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160Podesta, J. E.; Al-Jamal, K. T.; Herrero, M. A.; Tian, B.; Ali-Boucetta, H.; Hegde, V.; Bianco, A.; Prato, M.; Kostarelos, K. Small 2009, 5, 1176There is no corresponding record for this reference.
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161Ji, S. R.; Liu, C.; Zhang, B.; Yang, F.; Xu, J.; Long, J.; Jin, C.; Fu, D. L.; Ni, Q. X.; Yu, X. J. Biochim. Biophys. Acta 2010, 1806, 29There is no corresponding record for this reference.
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162Patel, S.; Bhirde, A. A.; Rusling, J. F.; Chen, X.; Gutkind, J. S.; Patel, V. Pharmaceutics 2011, 3, 34There is no corresponding record for this reference.
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163Prakash, S.; Malhotra, M.; Shao, W.; Tomaro-Duchesneau, C.; Abbasi, S. Adv. Drug Delivery Rev. 2011, 63, 1340There is no corresponding record for this reference.
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164Wang, L.; Zhang, M.; Zhang, N.; Shi, J.; Zhang, H.; Li, M.; Lu, C.; Zhang, Z. Int. J. Nanomed. 2011, 6, 2641164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1entL7K&md5=013ad71c31ef75e67b3c0ebd48edfedcSynergistic enhancement of cancer therapy using a combination of docetaxel and photothermal ablation induced by single-walled carbon nanotubesWang, Lei; Zhang, Mingyue; Zhang, Nan; Shi, Jinjin; Zhang, Hongling; Li, Min; Lu, Chao; Zhang, ZhenzhongInternational Journal of Nanomedicine (2011), 6 (), 2641-2652CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)Background: Single-walled carbon nanotubes (SWNT) are poorly sol. in water, so their applications are limited. Therefore, aq. solns. of SWNT, designed by noncovalent functionalization and without toxicity, are required for biomedical applications. Methods: In this study, we conjugated docetaxel with SWNT via π-π accumulation and used a surfactant to functionalize SWNT noncovalently. The SWNT were then conjugated with docetaxel (DTX-SWNT) and linked with NGR (Asn-Gly-Arg) peptide, which targets tumor angiogenesis, to obtain a water-sol. and tumor-targeting SWNT-NGR-DTX drug delivery system. Results: SWNT-NGR-DTX showed higher efficacy than docetaxel in suppressing tumor growth in a cultured PC3 cell line in vitro and in a murine S180 cancer model. Tumor vols. in the S180 mouse model decreased considerably under near-IR radiation compared with the control group. Conclusion: The SWNT-NGR-DTX drug delivery system may be promising for high treatment efficacy with minimal side effects in future cancer therapy.
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165Mattheolabakis, G.; Rigas, B.; Constantinides, P. P. Nanomedicine (London, U.K.) 2012, 7, 1577165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1GlsLnK&md5=8d1efa760ba0be2410b25102e70c9734Nanodelivery strategies in cancer chemotherapy: biological rationale and pharmaceutical perspectivesMattheolabakis, George; Rigas, Basil; Constantinides, Panayiotis P.Nanomedicine (London, United Kingdom) (2012), 7 (10), 1577-1590CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)A review. Nanotechnol. is revolutionizing the authors' approach to drug delivery, a key determinant of drug efficacy. Here, the authors present cancer drug delivery strategies that exploit nanotechnol., providing first an overview of tumor biol. aspects that critically affect the design of drug delivery carriers, namely the enhanced permeability and retention effect, the lower tumor extracellular pH and tumor-specific antigens. In general, nanoscience-based approaches have circumvented limitations in the delivery of cancer therapeutics, related to their poor aq. soly. and toxicity issues with conventional vehicles and resulted in improved pharmacokinetics and biodistribution. Included in the discussion are promising examples and pharmaceutical perspectives on liposomes, nanoemulsions, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, carbon nanotubes and magnetic nanoparticles. As the cardinal features of the ideal multifunctional cancer drug nanocarrier are becoming clear, and drug development challenges are proactively addressed, the authors anticipate that future advances will enhance therapeutic outcomes by refining the delivery and targeting of complex payloads.
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166Cai, D.; Mataraza, J. M.; Qin, Z. H.; Huang, Z.; Huang, J.; Chiles, T. C.; Carnahan, D.; Kempa, K.; Ren, Z. Nat. Methods 2005, 2, 449166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXktlWhsrc%253D&md5=6f19e836a1f039aa6a20a0caa4b3890eHighly efficient molecular delivery into mammalian cells using carbon nanotube spearingCai, Dong; Mataraza, Jennifer M.; Qin, Zheng-Hong; Huang, Zhongping; Huang, Jianyu; Chiles, Thomas C.; Carnahan, David; Kempa, Kris; Ren, ZhifengNature Methods (2005), 2 (6), 449-454CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)Introduction of exogenous DNA into mammalian cells represents a powerful approach for manipulating signal transduction. The available techniques, however, are limited by low transduction efficiency and low cell viability after transduction. Here the authors report a highly efficient mol. delivery technique, named nanotube spearing, based on the penetration of nickel-embedded nanotubes into cell membranes by magnetic field driving. DNA plasmids contg. the enhanced green fluorescent protein (EGFP) sequence were immobilized onto the nanotubes, and subsequently speared into targeted cells. The authors have achieved an unprecedented high transduction efficiency in Bal17 B-lymphoma, ex vivo B cells and primary neurons with high viability after transduction. This technique may provide a powerful tool for highly efficient gene transfer into a variety of cells, esp. the hard-to-transfect cells.
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167Dobson, J. Gene Ther. 2006, 13, 283167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFaju78%253D&md5=6eb4f729a642c00f819ff26e849bc79bGene therapy progress and prospects: magnetic nanoparticle-based gene deliveryDobson, J.Gene Therapy (2006), 13 (4), 283-287CODEN: GETHEC; ISSN:0969-7128. (Nature Publishing Group)A review. The recent emphasis on the development of non-viral transfection agents for gene delivery has led to new physics and chem.-based techniques, which take advantage of charge interactions and energetic processes. One of these techniques which shows much promise for both in vitro and in vivo transfection involves the use of biocompatible magnetic nanoparticles for gene delivery. In these systems, therapeutic or reporter genes are attached to magnetic nanoparticles, which are then focused to the target site/cells via high-field/high-gradient magnets. The technique promotes rapid transfection and, as more recent work indicates, excellent overall transfection levels as well. The advantages and difficulties assocd. with magnetic nanoparticle-based transfection will be discussed as will the underlying phys. principles, recent studies and potential future applications.
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168Chen, M. L.; He, Y. J.; Chen, X. W.; Wang, J. H. Langmuir 2012, 28, 16469There is no corresponding record for this reference.
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169Yu, J. G.; Jiao, F. P.; Chen, X. Q.; Jiang, X. Y.; Peng, Z. G.; Zeng, D. M.; Huang, D. S. J. Cancer Res. Ther. 2012, 8, 348169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjt1ygsw%253D%253D&md5=2b632bdc1b0a2c553fbd467dd5b5671aIrradiation-mediated carbon nanotubes' use in cancer therapyYu, Jin-Gang; Jiao, Fei-Peng; Chen, Xiao-Qing; Jiang, Xin-Yu; Peng, Zhi-Guang; Zeng, Dong-Ming; Huang, Du-ShuJournal of Cancer Research and Therapeutics (2012), 8 (3), 348-354CODEN: JCRTBK; ISSN:0973-1482. (Medknow Publications and Media Pvt. Ltd.)A review. Anticancer drugs such as biol. therapeutic proteins and peptides are used for treatment of a variety of tumors. However, their wider use has been hindered by their poor bioavailability and the uncontrollable sites of action in vivo. Cancer nano-therapeutics is rapidly progressing, which is being applied for solving some limitations of conventional drug delivery systems. To improve the bio-distribution of anticancer drugs, carbon nanotubes have been used as one of the most effective drug carriers. This review discusses the carbon nanotubes-mediated methods for the delivery of anticancer drugs, with emphasis on the radiation-induced drug-targeted releasing and selective photo-thermal cancer therapy.
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170Assali, M.; Cid, J. J.; Pernía-Leal, M.; Muñoz-Bravo, M.; Fernández, I.; Wellinger, R. E.; Khiar, N. ACS Nano 2013, 7, 2145There is no corresponding record for this reference.
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171Gannon, C. J.; Cherukuri, P.; Yakobson, B. I.; Cognet, L.; Kanzius, J. S.; Kittrell, C.; Weisman, R. B.; Pasquali, M.; Schmidt, H. K.; Smalley, R. E.; Curley, S. A. Cancer 2007, 110, 2654There is no corresponding record for this reference.
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172Biris, A. S.; Boldor, D.; Palmer, J.; Monroe, W. T.; Mahmood, M.; Dervishi, E.; Xu, Y.; Li, Z.; Galanzha, E. I.; Zharov, V. P. J. Biomed. Opt. 2009, 14, 021007There is no corresponding record for this reference.
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173Vázquez, E.; Prato, M. ACS Nano 2009, 3, 3819There is no corresponding record for this reference.
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174Tan, A.; Madani, S. Y.; Rajadas, J.; Pastorin, G.; Seifalian, A. M. J. Nanobiotechnol. 2012, 10, 34174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslyisbjO&md5=c55798010160b38abcccf2ca2368357aSynergistic photothermal ablative effects of functionalizing carbon nanotubes with a POSS-PCU nanocomposite polymerTan, Aaron; Madani, Seyed Yazdan; Rajadas, Jayakumar; Pastorin, Giorgia; Seifalian, Alexander M.Journal of Nanobiotechnology (2012), 10 (), 34CODEN: JNOAAO; ISSN:1477-3155. (BioMed Central Ltd.)Background: The application of nanotechnol. in biol. and medicine represents a significant paradigm shift in the approach to the treatment of cancer. Evidence suggests that when exposed to near-IR radiation (NIR), carbon nanotubes (CNTs) dissipate a substantial amt. of heat energy. We have developed a novel nanocomposite polymer, polyhedral oligomeric silsesquioxane poly (carbonate-urea) urethane (POSS-PCU). POSS-PCU displays excellent biocompatibility and has been used in making artificial organs as well as protective coatings for medical devices. Results: Functionalizing (or "coating") CNTs with POSS-PCU confers biocompatibility and increase the amt. of heat energy generated, by enhancing dispersion. Here we demonstrate that POSS-PCU-functionalized multi-walled CNTs (MWNTs) act synergistically together when exposed to NIR to thermally ablate cancer cells. Conclusion: Given that POSS-PCU has already been used in human in first-in-man studies as trachea, lacrimal duct, bypass graft and other organs, our long-term goal is to take POSS-PCU coated CNTs to clin. studies to address the treatment of cancer by optimizing its therapeutic index and increasing its specificity via antibody conjugation.
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175Levi-Polyachenko, N. H.; Merkel, E. J.; Jones, B. T.; Carroll, D. L.; Stewart, J. H., IV. Mol. Pharmaceutics 2009, 6, 1092175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXotV2msLg%253D&md5=e2779e7a6953a4e2bf98989b7c702648Rapid Photothermal Intracellular Drug Delivery Using Multiwalled Carbon NanotubesLevi-Polyachenko, Nicole H.; Merkel, Eric J.; Jones, Bradley T.; Carroll, David L.; Stewart, John H., IVMolecular Pharmaceutics (2009), 6 (4), 1092-1099CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Carbon nanotubes are unique materials that absorb IR radiation, esp. between 700 and 1100 nm, where body tissues are most transparent. Absorbed IR promotes mol. oscillation leading to efficient heating of the surrounding environment. A method to enhance drug localization for peritoneal malignancies is perfusion of warm (40-42°) chemotherapeutic agents in the abdomen. However, all tissues in the peritoneal cavity are subjected to enhanced drug delivery due to increased cell membrane permeability at hyperthermic temps. Here we show that rapid heating (within ten seconds) of colorectal cancer cells to 42°, using IR stimulation of nanotubes as a heat source, in the presence of the drugs oxaliplatin or mitomycin C, is as effective as two hours of radiative heating at 42° for the treatment of peritoneal dissemination of colorectal cancer. We demonstrate increased cell membrane permeability due to hyperthermia from multiwalled carbon nanotubes in close proximity to cell membranes and that the amt. of drug internalized by colorectal cancer cells heated quickly using carbon nanotubes equals levels achieved during routine application of hyperthermia at 42°. This approach has the potential to be used as a rapid bench to bedside clin. therapeutic agent with significant impact for localizing chemotherapy agents during the surgical management of peritoneal dissemination of colorectal cancer.
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176Chakravarty, P.; Marches, R.; Zimmerman, N. S.; Swafford, A. D.; Bajaj, P.; Musselman, I. H.; Pantano, P.; Draper, R. K.; Vitetta, E. S. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 8697There is no corresponding record for this reference.
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177Kim, J. W.; Shashkov, E. V.; Galanzha, E. I.; Kotagiri, N.; Zharov, V. P. Lasers Surg. Med. 2007, 39, 622177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2srnt1OgtA%253D%253D&md5=80b85023b981701dde5dfb8b146e5637Photothermal antimicrobial nanotherapy and nanodiagnostics with self-assembling carbon nanotube clustersKim Jin-Woo; Shashkov Evgeny V; Galanzha Ekaterina I; Kotagiri Nalinikanth; Zharov Vladimir PLasers in surgery and medicine (2007), 39 (7), 622-34 ISSN:0196-8092.BACKGROUND AND OBJECTIVES: Unique properties of carbon nanotubes (CNTs) would open new avenues for addressing challenges to realize rapid and sensitive antimicrobial diagnostics and therapy for human pathogens. In this study, new CNTs' capabilities for photothermal (PT) antimicrobial nanotherapy were explored in vitro using Escherichia coli as a model bacterium. STUDY DESIGN/MATERIALS AND METHODS: Single-walled carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs) were incubated with E. coli K12 strain. CNTs' locations in bacteria and laser-induced thermal and accompanied effects around CNTs were estimated with TEM and PT microscopy, respectively. Multi-pulse lasers at 532 and 1064 nm with 12-ns pulse duration were used for irradiating sample mixtures at different laser fluences. Cell viability was evaluated using a bacterial viability test kit and epi-fluorescence microscopy. RESULTS: This study revealed CNTs' high binding affinity to bacteria, their capability to self-assemble as clusters at bacteria surfaces, and their inherent near-infrared (NIR) laser responsiveness. Cell viability was affected neither by CNTs alone nor by NIR irradiations alone. Notable changes in bacteria viability, caused by local thermal and accompanied bubble-formation phenomena, were observed starting at laser fluences of 0.1-0.5 J/cm(2) with complete bacteria disintegration at 2-3 J/cm(2) at both wavelengths. Furthermore, ethanol in reaction mixtures significantly (more than one order) enhanced bubble formation phenomena. CONCLUSION: This first application of laser-activated CNTs as PT contrast antimicrobial agents demonstrated its great potential to cause irreparable damages to disease-causing pathogens as well as to detect the pathogens at single bacterium level. This unique integration of laser and nanotechnology may also be used for drinking water treatment, food processing, disinfection of medical instrumentation, and purification of grafts and implants. Furthermore, the significant ethanol-induced enhancement of bubble formation provides another unique possibility to improve the efficiency of selective nanophotothermolysis for treating cancers, wounds, and vascular legions.
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178Stacey, M.; Osgood, C.; Kalluri, B. S.; Cao, W.; Elsayed-Ali, H.; Abdel-Fattah, T. Biomed. Mater. 2011, 6, 011002There is no corresponding record for this reference.
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179Kawaguchi, M.; Yamazaki, J.; Ohno, J.; Fukushima, T. Int. J. Nanomed. 2012, 7, 4363179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1SnsL7O&md5=5d82cdfcdd9e7ace3478d685d8d06917Preparation and binding study of a complex made of DNA-treated single-walled carbon nanotubes and antibody for specific delivery of a "molecular heater" platformKawaguchi, Minoru; Yamazaki, Jun; Ohno, Jun; Fukushima, TadaoInternational Journal of Nanomedicine (2012), 7 (), 4363-4372CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)Carbon nanotubes have been explored as heat-delivery vehicles for thermal ablation of tumors. To use single-walled carbon nanotubes (SWNT) as a "mol. heater" for hyperthermia therapy in cancer, stable dispersibility and smart-delivery potential will be needed, as well as lack of toxicity. This paper reports the prepn. of a model complex comprising DNA-treated SWNT and anti-human IgG antibody and the specific binding ability of this model complex with the targeted protein, i.e., human IgG. Treatment with double-stranded DNA enabled stable dispersibility of a complex composed of SWNT and the antibody under physiol. conditions. Quartz crystal microbalance results suggest that there was one immobilized IgG mol. to every 21,700 carbon atoms in the complex contg. DNA-treated SWNT and the antibody. The DNA-SWNT antibody complex showed good selectivity for binding to the targeted protein. Binding anal. revealed that treatment with DNA did not interfere with binding affinity or capacity between the immobilized antibody and the targeted protein. The results of this study demonstrate that the DNA-SWNT antibody complex is a useful tool for use as a smart "mol. heater" platform applicable to various types of antibodies targeting a specific antigen.
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180Tan, A.; Yildirimer, L.; Rajadas, J.; De La Peña, H.; Pastorin, G.; Seifalian, A. Nanomedicine (London, U.K.) 2011, 6, 1101There is no corresponding record for this reference.
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181Moon, H. K.; Lee, S. H.; Choi, H. C. ACS Nano 2009, 3, 3707181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlCkur7F&md5=1246d3a800f6cf3858f1a629fff9467bIn Vivo Near-Infrared Mediated Tumor Destruction by Photothermal Effect of Carbon NanotubesMoon, Hye-Kyung; Lee, Sang-Ho; Choi, Hee-CheulACS Nano (2009), 3 (11), 3707-3713CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)The photothermal therapy using nanomaterials has been recently attracted as an efficient strategy for the next generation of cancer treatments. Single walled carbon nanotube (SWNT) is an upcoming potent candidate for the photothermal therapeutic agent since it generates significant amts. of heat upon excitation with near-IR light (NIR, λ = 700-1100 nm) which is transparent to biol. systems including skins. Such a photothermal effect can be employed to induce thermal cell death in a noninvasive manner. Here, we demonstrate in vivo obliteration of solid malignant tumors by the combined treatments of SWNTs and NIR irradn. The photothermally treated mice displayed complete destruction of the tumors without harmful side effects or recurrence of tumors over 6 mo, while the tumors treated in other control groups were continuously grown until the death of the mice. Most of the injected SWNTs were almost completely excreted from mice bodies in about 2 mo through biliary or urinary pathway. These results suggest that SWNTs may potentially serve as an effective photothermal agent and pave the way to future cancer therapeutics.
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182Iancu, C.; Mocan, L. Int. J. Nanomed. 2011, 6, 1675182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFGkt7vO&md5=5ae1f075c68ddae65fbc481e169a7ea8Advances in cancer therapy through the use of carbon nanotube-mediated targeted hyperthermiaIancu, Cornel; Mocan, LucianInternational Journal of Nanomedicine (2011), 6 (), 1675-1684CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)A review. Carbon nanotubes (CNTs) are emerging versatile tools in nanomedicine applications, particularly in the field of cancer targeting. Due to diverse surface chem. and unique thermal properties, CNTs can act as strong optical absorbers in near IR light where biol. systems prove to be highly transparent. The process of laser-mediated ablation of cancer cells marked with biofunctionalized CNTs is frequently termed "nanophotothermolysis". This paper illustrates the potential of engineered CNTs as laser-activated photothermal agents for the selective nanophotothermolysis of cancer cells.
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183Evans, M.; Kaufman, M. Nature 1981, 292, 154There is no corresponding record for this reference.
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184Takahashi, K.; Tanabe, K.; Ohnuki, M.; Narita, M.; Ichisaka, T.; Tomoda, K.; Yamanaka, S. Cell 2007, 131, 861There is no corresponding record for this reference.
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185Harrison, B. S.; Atala, A. Biomaterials 2007, 28, 344There is no corresponding record for this reference.
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186Abarrategi, A.; Gutiérrez, M. C.; Moreno-Vicente, C.; Hortigüela, M. J.; Ramos, V.; López-Lacomba, J. L.; Ferrer, M. L.; del Monte, F. Biomaterials 2008, 29, 94There is no corresponding record for this reference.
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187Tran, P. A.; Zhang, L.; Webster, T. J. Adv. Drug Delivery Rev. 2009, 61, 1097There is no corresponding record for this reference.
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188Zhang, L.; Webster, T. J. Nano Today 2009, 4, 66– 80188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXkvFGit7k%253D&md5=c5429e83ab7d03baebe8911f1def821bNanotechnology and nanomaterials: promises for improved tissue regenerationZhang, Lijie; Webster, Thomas J.Nano Today (2009), 4 (1), 66-80CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)A review. Tissue engineering and regenerative medicine aim to develop biol. substitutes that restore, maintain, or improve damaged tissue and organ functionality. While tissue engineering and regenerative medicine have hinted at much promise in the last several decades, significant research is still required to provide exciting alternative materials to finally solve the numerous problems assocd. with traditional implants. Nanotechnol., or the use of nanomaterials (defined as those materials with constituent dimensions less than 100 nm), may have the answers since only these materials can mimic surface properties (including topog., energy, etc.) of natural tissues. For these reasons, over the last decade, nanomaterials have been highlighted as promising candidates for improving traditional tissue engineering materials. Importantly, these efforts have highlighted that nanomaterials exhibit superior cytocompatible, mech., elec., optical, catalytic and magnetic properties compared to conventional (or micron structured) materials. These unique properties of nanomaterials have helped to improve various tissue growth over what is achievable today. In this review paper, the promise of nanomaterials for bone, cartilage, vascular, neural and bladder tissue engineering applications will be reviewed. Moreover, as an important future area of research, the potential risk and toxicity of nanomaterial synthesis and use related to human health are emphasized.
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189Kubinová, S.; Syková, E. Minim. Invasive Ther. Allied Technol. 2010, 19, 144189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3czlvV2gtw%253D%253D&md5=2e2562b4c3caae1724847b88907aa739Nanotechnologies in regenerative medicineKubinova Sarka; Sykova EvaMinimally invasive therapy & allied technologies : MITAT : official journal of the Society for Minimally Invasive Therapy (2010), 19 (3), 144-56 ISSN:.Nanotechnology offers promising perspectives in biomedical research as well as in clinical practice. To cover some of the latest nanotechnology trends in regenerative medicine, this review will focus on the use of nanomaterials for tissue engineering and cell therapy. Nanofibrous materials that mimic the native extracellular matrix and promote the adhesion of various cells are being developed as tissue-engineered scaffolds for the skin, bone, vasculature, heart, cornea, nervous system, and other tissues. A range of novel materials has been developed to enhance the bioactive or therapeutic properties of these nanofibrous scaffolds via surface modifications, including the immobilization of functional cell-adhesive ligands and bioactive molecules such as drugs, enzymes and cytokines. As a new approach, nanofibers prepared by using industrial scale needleless technology have been recently introduced, and their use as scaffolds to treat spinal cord injury or as cell carriers for the regeneration of the injured cornea is the subject of much current study. Cell therapy is a modern approach of regenerative medicine for the treatment of various diseases or injuries. To follow the migration and fate of transplanted cells, superparamagnetic iron oxide nanoparticles have been developed for cell labeling and non-invasive MRI monitoring of cells in the living organism, with successful applications in, e.g, the central nervous system, heart, liver and kidney and also in pancreatic islet and stem cell transplantation.
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190Dvir, T.; Timko, B. P.; Kohane, D. S.; Langer, R. Nat. Nanotechnol. 2011, 6, 13190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1Wju73E&md5=ce31677488ed9ca2549efacac9a67c0fNanotechnological strategies for engineering complex tissuesDvir, Tal; Timko, Brian P.; Kohane, Daniel S.; Langer, RobertNature Nanotechnology (2011), 6 (1), 13-22CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)A review. Tissue engineering aims at developing functional substitutes for damaged tissues and organs. Before transplantation, cells are generally seeded on biomaterial scaffolds that recapitulate the extracellular matrix and provide cells with information that is important for tissue development. Here we review the nanocomposite nature of the extracellular matrix, describe the design considerations for different tissues and discuss the impact of nanostructures on the properties of scaffolds and their uses in monitoring the behavior of engineered tissues. We also examine the different nanodevices used to trigger certain processes for tissue development, and offer our view on the principal challenges and prospects of applying nanotechnol. in tissue engineering.
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191van der Zande, M.; Junker, R.; Walboomers, X. F.; Jansen, J. A. Tissue Eng., Part B 2011, 17, 57191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpvFSrtw%253D%253D&md5=e84c5020bbeb3f4e86478ee5967a05c6Carbon Nanotubes in Animal Models: A Systematic Review on Toxic Potentialvan der Zande, Meike; Junker, Ruediger; Walboomers, X. Frank; Jansen, John A.Tissue Engineering, Part B: Reviews (2011), 17 (1), 57-69CODEN: TEPBAB; ISSN:1937-3368. (Mary Ann Liebert, Inc.)A review. Amongst the engineered nanomaterials, esp. carbon nanotubes (CNTs) have received considerable attention for application in tissue engineering scaffolds. CNTs are considered promising on behalf of their physicochem. properties, yet such nanomaterials also have been assocd. with potentially hazardous effects on human health. To gain insight into the toxicity aspects of CNTs in vivo, the present study presents a systematic review of literature. After screening of literature through defined inclusion and exclusion criteria, and subsequent data extn., it can be concluded that pulmonary administered CNTs have the capacity to induce toxicity in the lung area. However, conclusions for other organs, or on systemic toxicity, are yet premature. In addn., the carcinogenic potential of CNTs is also still ambiguous, because contradictive results are presented. Intrinsic factors, such as material characteristics, and assocd. distribution and agglomeration patterns influence the toxic potential of CNTs. Similarly, environmental factors such as the exposure route, preexisting allergies, pathol. infections, or air pollutant exposure are significant. Despite the many reports published currently, more studies will be required to gain full understanding of the toxic potential of CNTs and esp. the underlying mechanisms. For this end, development of standardized protocols and reliable nanodetection techniques will form prerequisites.
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192MacDonald, R. A.; Laurenzi, B. F.; Viswanathan, G.; Ajayan, P. M.; Stegemann, J. P. J. Biomed. Mater. Res., Part A 2005, 74, 489192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXpsFaitr0%253D&md5=e2a959135aa3fa36b615836444b27ed3Collagen-carbon nanotube composite materials as scaffolds in tissue engineeringMacDonald, Rebecca A.; Laurenzi, Brendan F.; Viswanathan, Gunaranjan; Ajayan, Pulickel M.; Stegemann, Jan P.Journal of Biomedical Materials Research, Part A (2005), 74A (3), 489-496CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Carbon nanotubes (CNT) are attractive for use in fiber-reinforced composite materials due to their very high aspect ratio, combined with outstanding mech. and elec. properties. Composite materials comprising a collagen matrix with embedded CNT were prepd. by mixing solubilized Type I collagen with solns. of carboxylated single-walled carbon nanotubes (SWNT) at concns. of 0, 0.2, 0.4, 0.8, and 2.0 wt.%. Living smooth muscle cells were incorporated at the time of collagen gelation to produce cell-seeded collagen-CNT composite matrixes. Constructs contg. 2.0 wt.% CNT exhibited delayed gel compaction, relative to lower concns. that compacted at the same rate as pure collagen controls. Cell viability in all constructs was consistently above 85% at both day 3 and day 7, whereas cell no. in CNT-contg. constructs was lower than in control constructs at day 3, though statistically unchanged by day 7. SEM showed phys. interactions between CNT and collagen matrix. Raman spectroscopy confirmed the presence of CNT at the expected diam. (0.85-1.30 nm), but did not indicate strong mol. interactions between the collagen and CNT components. Such collagen-CNT composite matrixes may have utility as scaffolds in tissue engineering, or as components of biosensors or other medical devices.
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193Cao, Y.; Zhou, Y. M.; Shan, Y.; Ju, H. X.; Xue, X. J. J Nanosci. Nanotechnol. 2007, 7, 447There is no corresponding record for this reference.
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194Meng, J.; Kong, H.; Han, Z.; Wang, C.; Zhu, G.; Xie, S.; Xu, H. J. Biomed. Mater. Res., Part A 2009, 88, 105194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cjlsVOiug%253D%253D&md5=2eeb378f1715011ed0d303e33982b733Enhancement of nanofibrous scaffold of multiwalled carbon nanotubes/polyurethane composite to the fibroblasts growth and biosynthesisMeng Jie; Kong Hua; Han Zhaozhao; Wang Chaoying; Zhu Guangjin; Xie Sishen; Xu HaiyanJournal of biomedical materials research. Part A (2009), 88 (1), 105-16 ISSN:.In this work, the effect of nanofibrous structure and multiwalled carbon nanotubes (MWNTs) incorporation in the polyurethane (PU) on the fibroblasts growth behavior was studied. The nanofibrous scaffold of multiwalled carbon nanotubes and polyurethane composite (MWNT/PU) with an average fiber diameter of 300-500 nm was fabricated by electrospinning technique. The nanofibrous scaffold of PU, smooth film of PU, and MWNT/PU were also prepared as controls. Cell viability assay, laser confocal microscopy, and scanning electron microscopy were applied to evaluate cell adhesion, proliferation, and cytoskeletal development on the scaffolds, respectively. Cell-released protein was analyzed by Bradford protein assay, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), mass spectrometry, and transwell assay, respectively. Experimental results demonstrated that the scaffold with nanofibrous structure and MWNTs incorporation exhibited highest enhancement not only to the cell adhesion and proliferation but also to the cell migration and aggregation. Besides, cells cultured on the nanofibrous scaffold of MWNT/PU released the largest amount of proteins including collagen in comparison with those on the other substrates. Hence, the nanofibrous architecture and MWNTs incorporation provided favorite interactions to the cells, which implied the application potentials of the nanofibrous composite for tissue repair and regeneration.
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195Han, Z.; Kong, H.; Meng, J.; Wang, C.; Xie, S.; Xu, H. J. Nanosci. Nanotechnol. 2009, 9, 1400There is no corresponding record for this reference.
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196Mei, F.; Zhong, J.; Yang, X.; Ouyang, X.; Zhang, S.; Hu, X.; Ma, Q.; Lu, J.; Ryu, S.; Deng, X. Biomacromolecules 2007, 8, 3729There is no corresponding record for this reference.
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197Cho, S. Y.; Yun, Y. S.; Kim, E. S.; Kim, M. S.; Jin, H. J. J. Nanosci. Nanotechnol. 2011, 11, 801There is no corresponding record for this reference.
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198Meng, J.; Song, L.; Kong, H.; Zhu, G.; Wang, C.; Xu, L.; Xie, S.; Xu, H. J. Biomed. Mater. Res., Part A 2006, 79, 298198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFarsrfJ&md5=cedbdc432f474254ac2cd985ea30448dUsing single-walled carbon nanotubes nonwoven films as scaffolds to enhance long-term cell proliferation in vitroMeng, Jie; Song, Li; Meng, Jie; Kong, Hua; Zhu, Guangjin; Wang, Chaoying; Xu, Lianghua; Xie, Sishen; Xu, HaiyanJournal of Biomedical Materials Research, Part A (2006), 79A (2), 298-306CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Carbon nanotubes have attracted intensive interests in biomedical research in recent years. In this study, a novel type of carbon nanotubes material so called nonwoven single-walled carbon nanotubes (SWNTs) with nanotopog. structure and macroscopic vol. was used as cell growing scaffold. The morphol. and surface chem. of nonwoven SWNTs were obsd. and characterized through SEM and XPS, resp. The cells were cultivated in nonwoven SWNTs and in other types of substrate as control. The cells growth behaviors including adhesion, proliferation, and cytoskeletal development was investigated by using cell viability assay and confocal observation. The exptl. results indicated that nonwoven SWNTs exhibited significant enhancement to the cells adhesion and proliferation in at least 3 wk. Numerous and highly organized cytoskeletal structures were obsd. when the cells were cultured in nonwoven SWNTs. Furthermore, an obvious promotional influence of the cells cultivated in nonwoven SWNTs scaffold upon the proliferation of those growing in the other kind of substrate through cell-cell communication had been found. The results obtained in this work are of significance to in vitro cell amplification in large scale, tissue regeneration, or guided repair, as well as biomedical device application.
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199Antoniadou, E. V.; Cousins, B. G.; Seifalian, A. M. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2010, 2010, 815199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cbptVCitg%253D%253D&md5=009d475caaed8d23055c1d2a1581b009Development of conductive polymer with carbon nanotubes for regenerative medicine applicationsAntoniadou Eleni V; Cousins Brian G; Seifalian Alexander MConference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference (2010), 2010 (), 815-8 ISSN:1557-170X.Multi-wall carbon nanotube (MWCNT)/polymer composites are hybrid materials that combine numerous mechanical, electrical and chemical properties and thus, constitute ideal biomaterials for a wide range of regenerative medicine applications. Although, complete dispersion of MWCNT in a polymer matrix has rarely been achieved, in this study we have studied the dispersibility of MWCNT in POSS-PCU, a novel polymer based on polyprolactone and polycarbonate polyurethane (PCU) with an incorporated polyhedral oligomeric silsesquioxane (POSS). Furthermore, we developed a computational model that can visualise MWCNTs in order to predict the range of dispersibility and provide a 3-D mathematical model that can predict the chemical concentration for ideal nanocomposites.
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200Mackle, J. N.; Blond, D. J.; Mooney, E.; McDonnell, C.; Blau, W. J.; Shaw, G.; Barry, F. P.; Murphy, J. M.; Barron, V. Macromol. Biosci. 2011, 11, 1272200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFSksLzM&md5=067ccbcb0c26d7fb2d2e1374b23b5deeIn vitro Characterization of an Electroactive Carbon-Nanotube-Based Nanofiber Scaffold for Tissue EngineeringMackle, Joseph N.; Blond, David J.-P.; Mooney, Emma; McDonnell, Caitlin; Blau, Werner J.; Shaw, Georgina; Barry, Frank P.; Murphy, J. Mary; Barron, ValerieMacromolecular Bioscience (2011), 11 (9), 1272-1282CODEN: MBAIBU; ISSN:1616-5187. (Wiley-VCH Verlag GmbH & Co. KGaA)In an effort to reduce organ replacement and enhance tissue repair, there was a tremendous effort to create biomechanically optimized scaffolds for tissue engineering applications. In contrast, the development and characterization of electroactive scaffolds has attracted little attention. Consequently, the creation and characterization of a carbon nanotube based poly(lactic acid) nanofiber scaffold is described herein. After 28 d in physiol. soln. at 37 °C, a change in the mass, chem. properties and polymer morphol. is seen, while the mech. properties and phys. integrity are unaltered. No adverse cytotoxic affects are seen when mesenchymal stem cells are cultured in the presence of the scaffold. Taken together, these data auger well for electroactive tissue engineering.
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201Supronowicz, P. R.; Ajayan, P. M.; Ullmann, K. R.; Arulanandam, B. P.; Metzger, D. W.; Bizios, R. J. Biomed. Mater. Res. 2002, 59, 499There is no corresponding record for this reference.
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202Bajaj, P.; Khang, D.; Webster, T. J. Int. J. Nanomed. 2006, 1, 361202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xhtlantb%252FP&md5=297f043265bba7b9bb3b7c171a173214Control of spatial cell attachment on carbon nanofiber patterns on polycarbonate urethaneBajaj, Piyush; Khang, Dongwoo; Webster, Thomas J.International Journal of Nanomedicine (2006), 1 (3), 361-365CODEN: IJNNHQ; ISSN:1176-9114. (Dove Medical Press (NZ) Ltd.)A highly aligned pattern of carbon nanofibers (CNF) on polycarbonate urethane (PCU) for tissue engineering applications was created by placing a CNF-ethanol soln. in 30μm width copper grid grooves on top of PCU. In vitro results provided the first evidence that fibroblasts and vascular smooth muscle cells selectively adhered to the PCU regions. However, endothelial cells did not display a preference for adhesion to the CNF compared with PCU regions. Previous studies have shown selective adhesion of osteoblasts (bone-forming cells) on CNF compared with PCU regions. Thus, the present results suggest that CNF aligned on PCU may be useful substrates for the control of spatial cell attachment, criteria useful for the design of a wide range of tissue engineering materials, from orthopedic to vascular.
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203Shi, X.; Hudson, J. L.; Spicer, P. P.; Tour, J. M.; Krishnamoorti, R.; Mikos, A. G. Biomacromolecules 2006, 7, 2237There is no corresponding record for this reference.
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204Lin, C.; Wang, Y.; Lai, Y.; Yang, W.; Jiao, F.; Zhang, H.; Ye, S.; Zhang, Q. Colloids Surf., B 2011, 83, 367There is no corresponding record for this reference.
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205Zanello, L. P.; Zhao, B.; Hu, H.; Haddon, R. C. Nano Lett. 2006, 6, 562There is no corresponding record for this reference.
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206Akasaka, T.; Warari, F.; Sato, Y.; Tohji, K. Mater. Sci. Eng., C 2006, 26, 675206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjvFynsb8%253D&md5=81a8b0ac6844846de34c839bd137c595Apatite formation on carbon nanotubesAkasaka, Tsukasa; Watari, Fumio; Sato, Yoshinori; Tohji, KazuyukiMaterials Science & Engineering, C: Biomimetic and Supramolecular Systems (2006), 26 (4), 675-678CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)Apatite coating on C nanotubes (CNTs) was done with a biomimetic coating method. The multi-walled CNTs (MWNTs) of curled shape with ∼30 nm in diam. were immersed for 2 wk in the simulated body fluid. Observation by SEM showed the formation of apatite on the MWNTs surface. The clusters of spherules consisting of needle-shaped apatite crystallites were massively grown on the aggregated MWNTs. The crystallites of 100 nm in width and 200-500 nm in length were grown perpendicularly to the longitudinal direction and radially originating from a common center of a single MWNT. Thus, the architecture of cryst. apatite at nano-scale levels could be produced by simple method and the MWNT may be acting as core for initial crystn. of apatite.
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207Balani, K.; Anderson, R.; Laha, T.; Andara, M.; Tercero, J.; Crumpler, E.; Agarwal, A. Biomaterials 2007, 28, 618There is no corresponding record for this reference.
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208Giannona, S.; Firkowska, I.; Rojas-Chapana, J.; Giersig, M. J. Nanosci. Nanotechnol. 2007, 7, 1679There is no corresponding record for this reference.
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209Wang, W.; Watari, F.; Omori, M.; Liao, S.; Zhu, Y.; Yokoyama, A.; Uo, M.; Kimura, H.; Ohkubo, A. J. Biomed. Mater. Res., Part B 2007, 82, 223209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXntlykurc%253D&md5=e917710ba2a9983b8f2e90bb51ec6ec9Mechanical properties and biological behavior of carbon nanotube/polycarbosilane composites for implant materialsWang, Wei; Watari, Fumio; Omori, Mamoru; Liao, Susan; Zhu, Yuhe; Yokoyama, Atsuro; Uo, Motohiro; Kimura, Hisamichi; Ohkubo, AkiraJournal of Biomedical Materials Research, Part B: Applied Biomaterials (2007), 82B (1), 223-230CODEN: JBMRGL; ISSN:1552-4973. (John Wiley & Sons, Inc.)Multiwalled carbon nanotube/polycarbosilane (MWCNT/PCS) composites were fabricated by the spark plasma sintering (SPS) method. The MWCNT/PCS composites consisted of MWCNTs and nanosized SiC particles pyrolyzed from PCS and possessing good mech. properties for bone tissue repair or dental implantation. The MWCNT/PCS composites were implanted in the s.c. tissue and femur of rats at 1 and 4 wk after implantation. Histol. investigations showed that there was little inflammatory response in the s.c. tissue, and newly formed bone tissue was obsd. in the femur. These results indicated that the MWCNT/PCS composite had little prophlogistic effect and good osteocond. The study suggested the possibility that the MWCNT/PCS composite could be a candidate bone-substitute and dental-implant material in the future.
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210Nayak, T. R.; Jian, L.; Phua, L. C.; Ho, H. K.; Ren, Y.; Pastorin, G. ACS Nano 2010, 4, 7717There is no corresponding record for this reference.
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211Niu, L.; Kua, H.; Chua, D. H. Langmuir 2010, 26, 4069There is no corresponding record for this reference.
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212Ciapetti, G.; Granchi, D.; Devescovi, V.; Baglio, S. R.; Leonardi, E.; Martini, D.; Jurado, M. J.; Olalde, B.; Armentano, I.; Kenny, J. M.; Walboomers, F. X.; Alava, J. I.; Baldini, N. Int. J. Mol. Sci. 2012, 13, 2439212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjsFyhsbg%253D&md5=dd590fa894587de8c03e10e89b635f86Enhancing osteoconduction of PLLA-based nanocomposite scaffolds for bone regeneration using different biomimetic signals to MSCsCiapetti, Gabriela; Granchi, Donatella; Devescovi, Valentina; Baglio, Serena R.; Leonardi, Elisa; Martini, Desiree; Jurado, Maria Jesus; Olalde, Beatriz; Armentano, Ilaria; Kenny, Jose M.; Walboomers, Frank X.; Alava, Jose Inaki; Baldini, NicolaInternational Journal of Molecular Sciences (2012), 13 (), 2439-2458CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)In bone engineering, the adhesion, proliferation and differentiation of mesenchymal stromal cells rely on signaling from chemico-phys. structure of the substrate, therefore prompting the design of mimetic "extracellular matrix"-like scaffolds. In this study, three-dimensional porous poly--lactic acid (PLLA)-based scaffolds have been mixed with different components, including single walled carbon nanotubes (CNT), micro-hydroxyapatite particles (HA), and BMP2, and treated with plasma (PT), to obtain four different nanocomposites: PLLA + CNT, PLLA + CNTHA, PLLA + CNT + HA + BMP2 and PLLA + CNT + HA + PT. Adult bone marrow mesenchymal stromal cells (MSCs) were derived from the femur of orthopaedic patients, seeded on the scaffolds and cultured under osteogenic induction up to differentiation and mineralization. The release of specific metabolites and temporal gene expression profiles of marrow-derived osteoprogenitors were analyzed at definite time points, relevant to in vitro culture as well as in vivo differentiation. As a result, the role of the different biomimetic components added to the PLLA matrix was deciphered, with BMP2-added scaffolds showing the highest biomimetic activity on cells differentiating to mature osteoblasts. The modification of a polymeric scaffold with reinforcing components which also work as biomimetic cues for cells can effectively direct osteoprogenitor cells differentiation, so as to shorten the time required for mineralization.
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213Usui, Y.; Aoki, K.; Narita, N.; Murakami, N.; Nakamura, I.; Nakamura, K.; Ishigaki, N.; Yamazaki, H.; Horiuchi, H.; Kato, H.; Taruta, S.; Kim, Y. A.; Endo, M.; Saito, N. Small 2008, 4, 240There is no corresponding record for this reference.
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214Saito, N.; Okada, T.; Horiuchi, H.; Murakami, N.; Takahashi, J.; Nawata, M.; Ota, H.; Nozaki, K.; Takaoka, K. Nat. Biotechnol. 2001, 19, 332There is no corresponding record for this reference.
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215Bhattacharya, M.; Wutticharoenmongkol-Thitiwongsawet, P.; Hamamoto, D. T.; Lee, D.; Cui, T.; Prasad, H. S.; Ahmad, M. J. Biomed. Mater. Res., Part A 2011, 96, 75215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVGku7zM&md5=7e3c0d86d0b66a99725a428bbe40b226Bone formation on carbon nanotube compositeBhattacharya, Mrinal; Wutticharoenmongkol-Thitiwongsawet, Patcharaporn; Hamamoto, Darryl T.; Lee, Dongjin; Cui, Tianhong; Prasad, Hari S.; Ahmad, MansurJournal of Biomedical Materials Research, Part A (2011), 96A (1), 75-82CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)The effects of a layer-by-layer assembled carbon nanotube composite (CNT-comp) on osteoblasts in vitro and bone tissue in vivo in rats were studied. The effects of CNT-comp on osteoblasts were compared against the effects by com. pure titanium (cpTi) and tissue culture dishes. Cell proliferation on the CNT-comp and cpTi were similar. However, cell differentiation, measured by alk. phosphatase activity and matrix mineralization, was better on the CNT-comp. When implanted in crit.-sized rat calvarial defect, the CNT-comp permitted bone formation and bone repair without signs of rejection or inflammation. These data indicate that CNT-comp may be a promising substrate for use as a bone implant or as a scaffold for tissue engineering. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2010.
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216Kasai, T.; Matsumura, S.; Iizuka, T.; Shiba, K.; Kanamori, T.; Yudasaka, M.; Iijima, S.; Yokoyama, A. Nanotechnology 2011, 22, 065102There is no corresponding record for this reference.
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217Narita, N.; Kobayashi, Y.; Nakamura, H.; Maeda, K.; Ishihara, A.; Mizoguchi, T.; Usui, Y.; Aoki, K.; Simizu, M.; Kato, H.; Ozawa, H.; Udagawa, N.; Endo, M.; Takahashi, N.; Saito, N. Nano Lett. 2009, 9, 1406There is no corresponding record for this reference.
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218Shimizu, M.; Kobayashi, Y.; Mizoguchi, T.; Nakamura, H.; Kawahara, I.; Narita, N.; Usui, Y.; Aoki, K.; Hara, K.; Haniu, H.; Ogihara, N.; Ishigaki, N.; Nakamura, K.; Kato, H.; Kawakubo, M.; Dohi, Y.; Taruta, S.; Kim, Y. A.; Endo, M.; Ozawa, H.; Udagawa, N.; Takahashi, N.; Saito, N. Adv. Mater. 2012, 24, 2176There is no corresponding record for this reference.
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219Olakowska, E.; Woszczycka-Korczyńska, I.; Jędrzejowska-Szypułka, H.; Lewin-Kowalik, J. Folia Neuropathol. 2010, 48, 231219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1yqu7c%253D&md5=09e3e1a6389bbc15368feec76f6765d5Application of nanotubes and nanofibres in nerve repair. A reviewOlakowska, Edyta; Woszczycka-Korczynska, Izabella; Jedrzejowska-Szypulka, Halina; Lewin-Kowalik, JoannaFolia Neuropathologica (2010), 48 (4), 231-237CODEN: FONEEW; ISSN:1641-4640. (Termedia Publishing House)A review. Nanoscience is the science of small particles of materials on a nanometer scale in at least one dimension. Nanomaterials can interact with tissues at the mol. level with a very high degree of functional specificity and control. A large group of nanomaterials includes nanotubes, nanofibres, liposomes, nanoparticles, polymeric micelles, nanogels and dendrimers. Such materials can be tailored to react with specific biol. systems at a mol. or even supra-mol. level and respond to the cell environment while minimizing undesired side effects. Neuron injuries lead to complex cellular and mol. interactions at the lesion site in an effort to repair the damaged tissue and to regenerate the axon for reconnection with its target organ. Strategies to enhance and stimulate regeneration use various nerve conduits and synthetic guidance devices. A promising strategy for treatment of neuronal injuries is to support and promote axonal growth by means of nanotubes and nanofibres. Nanotubes can be produced from various materials, such as carbon, synthetic polymers, DNA, proteins, lipids, silicon and glass. Carbon nanotubes are not biodegradable and can be used as implants. Moreover, they serve as an extracellular scaffold to guide directed axonal growth. In the review we summarize the results of nanotube and nanofibre application in nerve repair after injury.
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220Chao, T. I.; Xiang, S.; Chen, C. S.; Chin, W. C.; Nelson, A. J.; Wang, C.; Lu, J. Biochem. Biophys. Res. Commun. 2009, 384, 426There is no corresponding record for this reference.
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221Antoniadou, E. V.; Ahmad, R. K.; Jackman, R. B.; Seifalian, A. M. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2011, 2011, 3253221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC387lsFahug%253D%253D&md5=7129e5a1869d5426e914b9fd19afc987Next generation brain implant coatings and nerve regeneration via novel conductive nanocomposite developmentAntoniadou Eleni V; Ahmad Rezal K; Jackman Richard B; Seifalian Alexander MConference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference (2011), 2011 (), 3253-7 ISSN:1557-170X.Composite materials based on the coupling of conductive organic polymers and carbon nanotubes have shown that they possess properties of the individual components with a synergistic effect. Multi-wall carbon nanotube (MWCNT)/ polymer composites are hybrid materials that combine numerous mechanical, electrical and chemical properties and thus, constitute ideal biomaterials for a wide range of regenerative medicine applications. Although, complete dispersion of CNT in a polymer matrix has rarely been achieved, in this study we have succeeded high dispersibility of CNT in POSS-PCU and POSS-PCL, novel polymers based on polyprolactone and polycarbonate polyurethane (PCU) and poly(caprolactoneurea)urethane both having incorporated polyhedral oligomeric silsesquioxane (POSS). We report the synthesis and characterization of a novel biomaterial that possesses unique properties of being electrically conducting and thus being capable of electronic interfacing with tissue. To this end, POSS-PCU/MWCNT composite can be used as a biomaterial for the development of nerve guidance channels to promote nerve regeneration and POSS-PCL/MWCNT as a substrate to increase electronic interfacing between neurons and micro-machined electrodes for potential applications in neural probes, prosthetic devices and brain implants.
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222Lee, H. J.; Park, J.; Yoon, O. J.; Kim, H. W.; Lee do, Y.; Kim do, H.; Lee, W. B.; Lee, N. E.; Bonventre, J. V.; Kim, S. S. Nat. Nanotechnol. 2011, 6, 121222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVOrurs%253D&md5=20cd429604b2e0873423799f2bf680c5Amine-modified single-walled carbon nanotubes protect neurons from injury in a rat stroke modelLee, Hyun Jung; Park, Jiae; Yoon, Ok Ja; Kim, Hyun Woo; Lee, Do Yeon; Kim, Do Hee; Lee, Won Bok; Lee, Nae-Eung; Bonventre, Joseph V.; Kim, Sung SuNature Nanotechnology (2011), 6 (2), 121-125CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Stroke results in the disruption of tissue architecture and is the third leading cause of death in the United States. Transplanting scaffolds contg. stem cells into the injured areas of the brain has been proposed as a treatment strategy, and carbon nanotubes show promise in this regard, with pos. outcomes when used as scaffolds in neural cells and brain tissues. Here, we show that pretreating rats with amine-modified single-walled carbon nanotubes can protect neurons and enhance the recovery of behavioral functions in rats with induced stroke. Treated rats showed less tissue damage than controls and took longer to fall from a rotating rod, suggesting better motor functions after injury. Low levels of apoptotic, angiogenic and inflammation markers indicated that amine-modified single-walled carbon nanotubes protected the brains of treated rats from ischemic injury.
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223Chen, C. S.; Soni, S.; Le, C.; Biasca, M.; Farr, E.; Chen, E. Y.; Chin, W. C. Nanoscale Res. Lett. 2012, 7, 126223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotFKkurk%253D&md5=c50211baecbe11fcec8bb9d7d2e34ca7Human stem cell neuronal differentiation on silk-carbon nanotube compositeChen, Chi-Shuo; Soni, Sushant; Le, Catherine; Biasca, Matthew; Farr, Erik; Chen, Eric Y.-T.; Chin, Wei-ChunNanoscale Research Letters (2012), 7 (1), 126, 7 pp.CODEN: NRLAAD; ISSN:1556-276X. (Springer)Human embryonic stem cells [hESCs] are able to differentiate into specific lineages corresponding to regulated spatial and temporal signals. This unique attribute holds great promise for regenerative medicine and cell-based therapy for many human diseases such as spinal cord injury [SCI] and multiple sclerosis [MS]. Carbon nanotubes [CNTs] have been successfully used to promote neuronal differentiation, and silk has been widely applied in tissue engineering. This study aims to build silk-CNT composite scaffolds for improved neuron differentiation efficiency from hESCs. Two neuronal markers (β-III tubulin and nestin) were utilized to det. the hESC neuronal lineage differentiation. In addn., axonal lengths were measured to evaluate the progress of neuronal development. The results demonstrated that cells on silk-CNT scaffolds have a higher β-III tubulin and nestin expression, suggesting augmented neuronal differentiation. In addn., longer axons with higher d. were found to assoc. with silk-CNT scaffolds. Our silk-CNT-based composite scaffolds can promote neuronal differentiation of hESCs. The silk-CNT composite scaffolds developed here can serve as efficient supporting matrixes for stem cell-derived neuronal transplants, offering a promising opportunity for nerve repair treatments for SCI and MS patients.
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224Kim, J. A.; Jang, E. Y.; Kang, T. J.; Yoon, S.; Ovalle-Robles, R.; Rhee, W. J.; Kim, T.; Baughman, R. H.; Kim, Y. H.; Park, T. H. Integr. Biol. 2012, 4, 587224https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnvVOqt7w%253D&md5=8aa9363c6701e264607aba898744a386Regulation of morphogenesis and neural differentiation of human mesenchymal stem cells using carbon nanotube sheetsKim, Jeong Ah; Jang, Eui Yun; Kang, Tae June; Yoon, Sungjun; Ovalle-Robles, Raquel; Rhee, Won Jong; Kim, Taewoo; Baughman, Ray H.; Kim, Yong Hyup; Park, Tai HyunIntegrative Biology (2012), 4 (6), 587-594CODEN: IBNIFL; ISSN:1757-9694. (Royal Society of Chemistry)In order to successfully utilize stem cells for therapeutic applications in regenerative medicine, efficient differentiation into a specific cell lineage and guidance of axons in a desired direction is crucial. Here, we used aligned multi-walled carbon nanotube (MWCNT) sheets to differentiate human mesenchymal stem cells (hMSCs) into neural cells. Human MSCs present a preferential adhesion to aligned CNT sheets with longitudinal stretch parallel to the CNT orientation direction. Cell elongation was 2-fold higher than the control and most of the cells were aligned on CNT sheets within 5° from the CNT orientation direction. Furthermore, a significant, synergistic enhancement of neural differentiation was obsd. in hMSCs cultured on the CNT sheets. Axon outgrowth was also controlled using nanoscale patterning of CNTs. This CNT sheet provides a new cellular scaffold platform that can regulate morphogenesis and differentiation of stem cells, which could open up a new approach for tissue and stem cell regeneration.
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225Mattson, M. P.; Haddon, R. C.; Rao, A. M. J. Mol. Neurosci. 2000, 14, 175225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmsVahtLY%253D&md5=42dc02d8b544edd825a7ca973f7e0615Molecular functionalization of carbon nanotubes and use as substrates for neuronal growthMattson, Mark P.; Haddon, Robert C.; Rao, Apparao M.Journal of Molecular Neuroscience (2000), 14 (3), 175-182CODEN: JMNEES; ISSN:0895-8696. (Humana Press Inc.)Carbon nanotubes are strong, flexible, conduct elec. current, and can be functionalized with different mols., properties that may be useful in basic and applied neuroscience research. We report the first application of carbon nanotube technol. to neuroscience research. Methods were developed for growing embryonic rat-brain neurons on multiwalled carbon nanotubes. On unmodified nanotubes, neurons extend only one or two neurites, which exhibit very few branches. In contrast, neurons grown on nanotubes coated with the bioactive mol. 4-hydroxynonenal elaborate multiple neurites, which exhibit extensive branching. These findings establish the feasibility of using nanotubes as substrates for nerve cell growth and as probes of neuronal function at the nanometer scale.
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226Dubin, R. A.; Callegari, G.; Kohn, J.; Neimark, A. IEEE Trans. Nanobiosci. 2008, 7, 11There is no corresponding record for this reference.
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227Sucapane, A.; Cellot, G.; Prato, M.; Giugliano, M.; Parpura, V.; Ballerini, L. J. Nanoneurosci. 2009, 1, 10227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlvV2qurk%253D&md5=2dcea949c8379b5b063d4107fafd9160Interactions between cultured neurons and carbon nanotubes: a nanoneuroscience vignetteSucapane, Antonietta; Cellot, Giada; Prato, Maurizio; Giugliano, Michele; Parpura, Vladimir; Ballerini, LauraJournal of Nanoneuroscience (2009), 1 (1), 10-16CODEN: JNOAFT; ISSN:1939-0637. (American Scientific Publishers)A review. Carbon nanotubes, owing to their elec., chem., mech., and thermal properties, are one of the most promising nanomaterials for the electronics, computer, and aerospace industries. More recently, these unique materials are finding their niche in neuroscience. Here, we discuss the use of carbon nanotubes as scaffolds for neuronal growth. The chem. properties of carbon nanotubes can be systematically varied by attaching different functional groups. Such functionalized carbon nanotubes can be used to control the outgrowth and branching pattern of neuronal processes. We also discuss elec. interactions between neurons and carbon nanotubes. The elec. properties of nanotubes can provide a mechanism to monitor or stimulate neurons through the scaffold itself. The ease of which carbon nanotubes can be patterned makes them attractive for studying the organization of neural networks and has the potential to develop new devices for neural prosthesis. We note that addnl. toxicity studies of carbon nanotubes are necessary so that exposure guidelines and safety regulations can be set.
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228Lee, W.; Parpura, V. Prog. Brain Res. 2009, 180, 110228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c3htlWntg%253D%253D&md5=ef2fa719aa29d7c20caeb773402cfcb0Chapter 6 - Carbon nanotubes as substrates/scaffolds for neural cell growthLee William; Parpura VladimirProgress in brain research (2009), 180 (), 110-25 ISSN:.Carbon nanotubes (CNTs) due to their unique properties have sparked interest for their use in biomedical applications in recent years. In particular, the use of CNTs as substrates/scaffolds for neural cell growth has been an area of active research over the past decade. CNTs, either native or functionalized with various chemical groups, are biocompatible with neuronal cell adhesion and growth. Functionalized CNTs can modulate the neuronal growth in graded manner; positively charged CNTs promoted neurite outgrowth of hippocampal neurons in culture to a greater extent than when these cells were grown on neutral or negatively charged CNTs. Conductivity and mechanical properties of CNTs have been shown to affect neuronal morphology as well. Other neural cells, such as stem and glial cells, can also be successfully grown on CNT substrates. While currently the acute toxicity of CNTs is considered comparable to that of other forms of carbon, the long-term exposures limits need to be established in order to use these materials as neural prosthesis. Nonetheless, accumulating data support the use of CNTs as a biocompatible and permissive substrate/scaffold for neural cells and such application holds great potential in biomedicine.
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229Matsumoto, K.; Sato, C.; Naka, Y.; Whitby, R.; Shimizu, N. Nanotechnology 2010, 21, 115101There is no corresponding record for this reference.
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230Parpura, V.; Silva, G. A.; Tass, P. A.; Bennet, K. E.; Meyyappan, M.; Koehne, J.; Lee, K. H.; Andrews, R. J. J. Neurochem. 2013, 124, 436230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVOmsrY%253D&md5=1608881c7c07addfa2214d1b06145b64Neuromodulation: selected approaches and challengesParpura, Vladimir; Silva, Gabriel A.; Tass, Peter A.; Bennet, Kevin E.; Meyyappan, M.; Koehne, Jessica; Lee, Kendall H.; Andrews, Russell J.Journal of Neurochemistry (2013), 124 (3&4), 436-453CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)A review. The brain operates through complex interactions in the flow of information and signal processing within neural networks. The 'wiring' of such networks, being neuronal or glial, can phys. and/or functionally go rogue in various pathol. states. Neuromodulation, as a multidisciplinary venture, attempts to correct such faulty nets. In this review, selected approaches and challenges in neuromodulation are discussed. The use of water-dispersible carbon nanotubes has been proven effective in the modulation of neurite outgrowth in culture and in aiding regeneration after spinal cord injury in vivo. Studying neural circuits using computational biol. and anal. engineering approaches brings to light geometrical mapping of dynamics within neural networks, much needed information for stimulation interventions in medical practice. Indeed, sophisticated desynchronization approaches used for brain stimulation have been successful in coaxing 'misfiring' neuronal circuits to resume productive firing patterns in various human disorders. Devices have been developed for the real-time measurement of various neurotransmitters as well as elec. activity in the human brain during elec. deep brain stimulation. Such devices can establish the dynamics of electrochem. changes in the brain during stimulation. With increasing application of nanomaterials in devices for elec. and chem. recording and stimulating in the brain, the era of cellular, and even intracellular, precision neuromodulation will soon be upon us.
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231Behan, B. L.; DeWitt, D. G.; Bogdanowicz, D. R.; Koppes, A. N.; Bale, S. S.; Thompson, D. M. J. Biomed. Mater. Res., Part A 2011, 96, 46231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVGku7zE&md5=841004c82c8f9ff490546c65a3a9a960Single-walled carbon nanotubes alter Schwann cell behavior differentially within 2D and 3D environmentsBehan, Brenda L.; DeWitt, Daniel G.; Bogdanowicz, Danielle R.; Koppes, Abigail N.; Bale, Shyam S.; Thompson, Deanna M.Journal of Biomedical Materials Research, Part A (2011), 96A (1), 46-57CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Both spinal cord injury (SCI) and large-gap peripheral nerve defects can be debilitating affecting a patient's long-term quality of life and presently, there is no suitable treatment for functional regeneration of these injured tissues. A no. of works have suggested the benefits of elec. stimulation to promote both glial migration and neuronal extension. In this work, an elec. conductive hydrogel contg. single-walled carbon nanotubes (SWCNT) for neural engineering applications is presented and the Schwann cell (SC) response to SWCNT is examd. in both 2D and 3D microenvironments. Results from clonogenic and alamarBlue assays in 2D indicate that SWCNT (10-50 μg mL-1) inhibit SC proliferation but do not affect cell viability. Following SWCNT exposure in 2D, changes in SC morphol. can be obsd. with the nanomaterial attached to the cell membrane at concns. as low as 10 μg mL-1. In contrast to the results gathered in 2D, SC embedded within the 3D hydrogel loaded with 10-50 μg mL-1 of SWCNT exhibited little or no measurable change in cell proliferation, viability, or morphol. as assessed using a digestion assay, alamarBlue, and confocal microscopy. Collectively, this highlights that an elec.-conductive SWCNT collagen I-Matrigel biomaterial may be suitable for neural tissue engineering and is able to sustain populations of SC. Findings suggest that 2D nanoparticle toxicity assays may not be accurate predictors of the 3D response, further motivating the examn. of these materials in a more physiol. relevant environment. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2010.
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232Khang, D.; Park, G. E.; Webster, T. J. J. Biomed. Mater. Res., Part A 2008, 86, 253232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXntFaku7s%253D&md5=93b4db83338c9b3c63144b081f3fec43Enhanced chondrocyte densities on carbon nanotube composites: the combined role of nanosurface roughness and electrical stimulationKhang, Dongwoo; Park, Grace E.; Webster, Thomas J.Journal of Biomedical Materials Research, Part A (2008), 86A (1), 253-260CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Simultaneous incorporation of intrinsic nanosurface roughness and external elec. stimulation may maximize the regeneration of articular cartilage tissue more than on nanosmooth, elec. nonstimulated biomaterials. Here, we report enhanced functions of chondrocytes (cartilage synthesizing cells) on elec. and nonelec. stimulated highly dispersed carbon nanotubes (CNT) in polycarbonate urethane (PCU) compared to, resp., stimulated pure PCU. Specifically, compared to conventional longitudinal (or vertical) elec. stimulation of chondrocytes on conducting surfaces which require high voltage, we developed a lateral elec. stimulation across CNT/PCU composite films of low voltage that enhanced chondrocyte functions. Chondrocyte adhesion and long-term cell densities (up to 2 days) were enhanced (more than 50%) on CNT/PCU composites compared to PCU alone without elec. stimulation. This study further explained why by measuring greater amts. of initial fibronectin adsorption (a key protein that mediates chondrocyte adhesion) on CNT/PCU composites which were more hydrophilic (than pure PCU) due to greater nanometer roughness. Importantly, the same trend was obsd. and was even significantly enhanced when chondrocytes were subjected to elec. stimulation (more than 200%) compared to non-stimulated CNT/PCU. For this reason, this study provided direct evidence of the pos. role that conductive CNT/PCU films can play in promoting functions of chondrocytes for cartilage regeneration.
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233Sirivisoot, S.; Harrison, B. S. Int. J. Nanomed. 2011, 6, 2483233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1ent7fP&md5=2bcecac47f09fe56f71a39023de670bcSkeletal myotube formation enhanced by electrospun polyurethane carbon nanotube scaffoldsSirivisoot, Sirinrath; Harrison, Benjamin S.International Journal of Nanomedicine (2011), 6 (), 2483-2497CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)Background: This study examd. the effects of elec. conductive materials made from electrospun single- or multi-walled carbon nanotubes with polyurethane to promote myoblast differentiation into myotubes in the presence and absence of elec. stimulation. Methods and Results: After elec. stimulation, the no. of multinucleated myotubes on the electrospun polyurethane carbon nanotube scaffolds was significantly larger than that on nonconductive electrospun polyurethane scaffolds (5% and 10% w/v polyurethane). In the absence of elec. stimulation, myoblasts also differentiated on the electrospun polyurethane carbon nanotube scaffolds, as evidenced by expression of Myf-5 and myosin heavy chains. The myotube no. and length were significantly greater on the electrospun carbon nanotubes with 10% w/v polyurethane than on those with 5% w/v polyurethane. The results suggest that, in the absence of elec. stimulation, skeletal myotube formation is dependent on the morphol. of the electrospun scaffolds, while with elec. stimulation it is dependent on the elec. cond. of the scaffolds. Conclusion: This study indicates that electrospun polyurethane carbon nanotubes can be used to modulate skeletal myotube formation with or without application of elec. stimulation.
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234Quigley, A. F.; Razal, J. M.; Kita, M.; Jalili, R.; Gelmi, A.; Penington, A.; Ovalle-Robles, R.; Baughman, R. H.; Clark, G. M.; Wallace, G. G.; Kapsa, R. M. Adv. Healthcare Mater. 2012, 1, 801234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1Sht7%252FK&md5=a630e7d045395797960a6dd18c23c7b2Electrical Stimulation of Myoblast Proliferation and Differentiation on Aligned Nanostructured Conductive Polymer PlatformsQuigley, Anita F.; Razal, Joselito M.; Kita, Magdalena; Jalili, Rohoullah; Gelmi, Amy; Penington, Anthony; Ovalle-Robles, Raquel; Baughman, Ray H.; Clark, Graeme M.; Wallace, Gordon G.; Kapsa, Robert M. I.Advanced Healthcare Materials (2012), 1 (6), 801-808CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)The current study utilizes conducting polymer (CP) templates to investigate how the effects of aligned nanotopog. in conjunction with charge-balanced biphasic influences the orientation and growth behavior of primary myoblasts in vitro.
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235Mooney, E.; Mackle, J. N.; Blond, D. J.; O’Cearbhaill, E.; Shaw, G.; Blau, W. J.; Barry, F. P.; Barron, V.; Murphy, J. M. Biomaterials 2012, 33, 6132There is no corresponding record for this reference.
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236Martinelli, V.; Cellot, G.; Toma, F. M.; Long, C. S.; Caldwell, J. H.; Zentilin, L.; Giacca, M.; Turco, A.; Prato, M.; Ballerini, L.; Mestroni, L. Nano Lett. 2012, 12, 1831There is no corresponding record for this reference.
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237Holzapfel, B. M.; Reichert, J. C.; Schantz, J. T.; Gbureck, U.; Rackwitz, L.; Noth, U.; Jakob, F.; Rudert, M.; Groll, J.; Hutmacher, D. W. Adv. Drug Delivery Rev. 2013, 65, 581There is no corresponding record for this reference.
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238Nakabayashi, N.; Ishihara, K.; Iwasaki, Y. Biomaterial; Japan Society of Medical Electronics and Biological Engineering; Corona Publishing Co., Ltd.: Tokyo, 1999.There is no corresponding record for this reference.
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239Katti, K. S. Colloids Surf., B 2004, 39, 133There is no corresponding record for this reference.
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240Del Bravo, V.; Graci, C.; Spinelli, M. S.; Muratori, F.; Maccauro, G. Int. J. Immunopathol. Pharmacol. 2011, 24, 91240https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MfmslOntQ%253D%253D&md5=513a5b0bf8ae062bd9a045d908cfaa30Histological and ultrastructural reaction to different materials for orthopaedic applicationDel Bravo V; Graci C; Spinelli M S; Muratori F; Maccauro GInternational journal of immunopathology and pharmacology (2011), 24 (1 Suppl 2), 91-4 ISSN:0394-6320.Prosthetic joints loosening in absence of infection is the most common reason for revision surgery and is known as aseptic loosening. A significant role in the pathogenesis of implant failure undoubtedly played by the generation of wear debris, mainly from the load bearing joint surfaces, and the cellular reaction through the formation of tissue membrane around implants. This article analyzes histologic, immunohistochemical ad ultrastructural aspects of periprosthetic tissue membrane collected at time of surgical revision, paying attention on cell host response to different materials: metals, polyethylene and ceramics. Dimension of particles seems to be crucial in the activation of different cell population to wear debris.
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241Wang, W.; Ouyang, Y.; Poh, C. K. Ann. Acad. Med. Singapore 2011, 40, 237241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MnhtVekuw%253D%253D&md5=c5d161bc0f782efc34c6d8ad18c48748Orthopaedic implant technology: biomaterials from past to futureWang Wilson; Ouyang Youheng; Poh Chye KhoonAnnals of the Academy of Medicine, Singapore (2011), 40 (5), 237-44 ISSN:0304-4602.Orthopaedic implant technology is heavily based on the development and use of biomaterials. These are non-living materials (e.g. metals, polymers and ceramics) that are introduced into the human body as constituents of implants that fulfill or replace some important function. Examples would be prosthetic joint replacements and fracture fixation implants. For orthopaedic biomaterials to succeed in their desired functions and outcomes in the body, a number of factors need to be considered. The most obvious mechanical properties of the implants are that they need to suit their intended function, and various classes and types of biomaterials have been developed and characterised for use in different implant components depending on their demands. Less well understood but no less important are the interactions that occur between the constituent biomaterials and the living cells and tissues, both of the human host as well as pathogens such as bacteria. Biomaterials used for orthopaedic applications are generally considered to be biocompatible. However, adverse effects arising from interactions at the implant interface can result in various modes of implant failure, such as aseptic loosening and implant infection. This review paper uses the illustrative example of total hip replacement (which has been called the operation of the century) to highlight key points in the evolution of orthopaedic biomaterials. It will also examine research strategies that seek to address some of the major problems that orthopaedic implant surgery are facing today.
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242Coventry, M. B. J. Bone Jt. Surg., Am. Vol. 1985, 67, 832242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2M3mtFCqsQ%253D%253D&md5=17d4ca9afc263171d9371ab7c89961d2Late dislocations in patients with Charnley total hip arthroplastyCoventry M BThe Journal of bone and joint surgery. American volume (1985), 67 (6), 832-41 ISSN:0021-9355.I analyzed the cases of thirty-two patients in whom a Charnley total hip arthroplasty had dislocated for the first time between five and ten years postoperatively. I evaluated the possible factors that caused the late dislocations. Most of the factors were similar to those that were also present in a control group of patients who had had an arthroplasty that had not dislocated and in a group in which dislocation had occurred at variable times postoperatively. Two significant factors did emerge. First, the patients with late dislocation had a greater range of motion, especially in flexion, than those in the two control groups. Second, the acetabular component showed radiographic evidence of loosening in more of the patients in the group with late dislocation than in either of the control groups. I postulated, but did not prove, that stretching of the pseudocapsule of the hip over time and extremes of motion may lessen soft-tissue constraints and allow for late dislocation.
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243Parvizi, J.; Wade, F. A.; Rapuri, V.; Springer, B. D.; Berry, D. J.; Hozack, W. J. Clin. Orthop. Relat. Res. 2006, 447, 66243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28zmsFSitA%253D%253D&md5=761320376c976b2997e4e592cd82f5acRevision hip arthroplasty for late instability secondary to polyethylene wearParvizi Javad; Wade Frazer A; Rapuri Venkat; Springer Bryan D; Berry Daniel J; Hozack William JClinical orthopaedics and related research (2006), 447 (), 66-9 ISSN:0009-921X.We evaluated the outcome of revision arthroplasty for polyethylene wear presenting as late dislocation. The computerized databases at two institutions were reviewed to identify all patients presenting with first time dislocation five or more years after total hip arthroplasty. Records and radiographs were then evaluated, and patients whose late dislocation occurred in the presence of greater than two millimeters of polyethylene liner wear with no other etiology for dislocation were identified. There were 22 patients with a mean age of 57.8 years at primary procedure. The average time from initial arthroplasty to dislocation was 9.0 years. Revision surgery to address polyethylene wear and instability was performed at a mean of 11.1 years (range 5.8 to 23 years). Revision surgery restored stability to eighteen patients (eighty-two percent). Polyethylene wear can and is associated with late dislocation after hip arthroplasty. Exchange of polyethylene lining of a metal backed implant or revision of the all polyethylene acetabular component can successfully address late instability in the majority of patients.
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244Tarasevicius, S.; Robertsson, O.; Kesteris, U.; Kalesinskas, R. J.; Wingstrand, H. Acta Orthop. 2008, 79, 489244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1crnslOmsg%253D%253D&md5=b1896f9e45ac423156f7cd9912040a77Effect of femoral head size on polyethylene wear and synovitis after total hip arthroplasty: a sonographic and radiographic study of 39 patientsTarasevicius Sarunas; Robertsson Otto; Kesteris Uldis; Kalesinskas Romas Jonas; Wingstrand HansActa orthopaedica (2008), 79 (4), 489-93 ISSN:.BACKGROUND AND PURPOSE: The role of synovitis and high fluid pressure in the loosening process after total hip arthroplasty has gained increasing attention. We investigated the correlation between head size, polyethylene wear, and capsular distention. PATIENTS AND METHODS: We analyzed 39 unrevised, radiographically stable hips that had been operated with 28 or 32 mm femoral heads 10 years earlier because of osteoarthritis. We evaluated radiographic signs of loosening, linear and volumetric polyethylene wear, body mass index, activity level, and age. Sonographic examination was performed to measure capsular distance i.e. the distance between the prosthetic femoral neck and the anterior capsule. RESULTS: Linear wear was 0.09 mm/year and 0.18 mm/year in the 28 mm and 32 mm groups, respectively (p < 0.001). The volumetric wear was 51 mm(3)/year and 136 mm(3)/year (p < 0.001) and the capsular distance was 13 mm and 17 mm, respectively (p < 0.001). There was a correlation between linear wear (r = 0.54), volumetric wear (r = 0.62), and capsular distance (p < 0.001). INTERPRETATION: Wear was greater for the larger femoral head and was correlated to capsular distension.
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245Goodman, S. B.; Ma, T. Biomaterials 2010, 31, 5045There is no corresponding record for this reference.
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246Krell, A.; Klimake, J. J. Am. Ceram. Soc. 2006, 89, 1985There is no corresponding record for this reference.
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247Carter, C. B.; Norton, M. G. Ceramic Materials Science and Engineering; Springer: New York, 2007; pp 619– 651.There is no corresponding record for this reference.
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248Ueda, N.; Yamakami, T.; Yamaguchi, T.; Kitajima, K.; Usui, Y.; Aoki, K.; Nakanishi, T.; Miyaji, F.; Endo, M.; Saito, N.; Taruta, S. J. Ceram. Soc. Jpn. 2010, 118, 847248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFejsr7I&md5=7c1b5e2d7cac305705b569974f2ee081Fabrication and mechanical properties of high-dispersion-treated carbon nanofiber/alumina compositesUeda, Naoki; Yamakami, Tomohiko; Yamaguchi, Tomohiro; Kitajima, Kunio; Usui, Yuki; Aoki, Kaoru; Nakanishi, Takefumi; Miyaji, Fumiaki; Endo, Morinobu; Saito, Naoto; Taruta, SeiichiJournal of the Ceramic Society of Japan (2010), 118 (Sept.), 847-854CODEN: JCSJEW; ISSN:1882-0743. (Ceramic Society of Japan)High-dispersion-treated C nanofibers (CNFs) were used to fabricate uniformly-dispersed CNFs-alumina composites with enhanced mech. properties. The treatment was effective in obtaining dense and uniform composites. The composites contg. 0.4-0.8% CNFs were densified to a relative d. of >99% by vacuum sintering and subsequent hot isostatic pressing, and those contg. 1.6-2.5% CNFs were densified to full d. by plasma activated sintering. The max. bending strength of the composites (1050 MPa) was approx. the same as the bending strength of monolithic alumina (1079 MPa). The max. fracture toughness of the composites was 5.9 MPa m0.5, which was a 69% increase compared with the fracture toughness of monolithic alumina (3.5 MPa m0.5). Fracture toughness (KIC) increased rapidly with a decrease in alumina grain size (G), and the relation could be expressed by the following equation: KIC = (k1/G2) + k2 (k1 and k2 are consts.).
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249Ogihara, N.; Usui, Y.; Aoki, K.; Shimizu, M.; Narita, N.; Hara, K.; Nakamura, K.; Ishigaki, N.; Takanashi, S.; Okamoto, M.; Kato, H.; Haniu, H.; Ogiwara, N.; Nakayama, N.; Taruta, S.; Saito, N. Nanomedicine (London, U.K.) 2012, 7, 981249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFWjsr3M&md5=9307b020d5fadabc2557048a1c3cc293Biocompatibility and bone tissue compatibility of alumina ceramics reinforced with carbon nanotubesOgihara, Nobuhide; Usui, Yuki; Aoki, Kaoru; Shimizu, Masayuki; Narita, Nobuyo; Hara, Kazuo; Nakamura, Koichi; Ishigaki, Norio; Takanashi, Seiji; Okamoto, Masanori; Kato, Hiroyuki; Haniu, Hisao; Ogiwara, Naoko; Nakayama, Noboru; Taruta, Seiichi; Saito, NaotoNanomedicine (London, United Kingdom) (2012), 7 (7), 981-993CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)The addn. of carbon nanotubes (CNTs) remarkably improves the mech. characteristics of base materials. CNT/alumina ceramic composites are expected to be highly functional biomaterials useful in a variety of medical fields. Biocompatibility and bone tissue compatibility were studied for the application of CNT/alumina composites as biomaterials. Inflammation reactions in response to the composite were as mild as those of alumina ceramic alone in a s.c. implantation study. In bone implantation testing, the composite showed good bone tissue compatibility and connected directly to new bone. An in vitro cell attachment test was performed for osteoblasts, chondrocytes, fibroblasts and smooth muscle cells, and CNT/alumina composite showed cell attachment similar to that of alumina ceramic. Owing to proven good biocompatibility and bone tissue compatibility, the application of CNT/alumina composites as biomaterials that contact bone, such as prostheses in arthroplasty and devices for bone repair, are expected. Original submitted 23 March 2011; Revised submitted 16 Nov. 2011; Published online 8 March 2012.
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250Barrack, R. L.; McClure, J. T.; Burak, C. F.; Clohisy, J. C.; Parvizi, J.; Hozack, W. Clin. Orthop. Relat. Res. 2006, 453, 173250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s7htVOmsg%253D%253D&md5=3ef463f52a805539d0bcdbb89de59f63Revision total hip arthroplasty: the patient's perspectiveBarrack Robert L; McClure J Thomas; Burak Corey F; Clohisy John C; Parvizi Javad; Hozack WilliamClinical orthopaedics and related research (2006), 453 (), 173-7 ISSN:0009-921X.We evaluated a consecutive series of patients followed for at least 1 year after revision total hip arthroplasty. We surveyed 488 patients treated at three referral centers from 1998 to 2002. An experienced medical interviewer contacted patients and rated their degree of satisfaction with the original and revision arthroplasties, the reason of original arthroplasty failure, and their expectations for revision arthroplasty longevity. Surveys were completed on 320 of the 488 patients (66%). A member of the research team reviewed patients' operative reports, clinical records, and radiographs to determine the diagnosis at revision, procedure performed, and the most likely cause of failure. Patient satisfaction with the primary procedure was directly related to the time to revision. Most patients (214 of 320; 67%) expected their revision to last longer than their primary arthroplasty regardless of revision diagnosis or how long the primary procedure lasted before revision. The surgeons' failure assessments agreed with the patients' failure assessments only 36% of the time. Although the majority of patients (262 of 320; 82%) were satisfied with the results of the revision procedure, most did not agree with their surgeon as to why the original arthroplasty failed, and most had unrealistic expectations regarding revision longevity.
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251Pape, D.; Adam, F.; Fritsch, E.; Müller, K.; Kohn, D. Spine (Philadelphia) 2000, 25, 2514251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3M%252FhslShsg%253D%253D&md5=4d4eefb2043bb9ed113f78c402e67c03Primary lumbosacral stability after open posterior and endoscopic anterior fusion with interbody implants: a roentgen stereophotogrammetric analysisPape D; Adam F; Fritsch E; Muller K; Kohn DSpine (2000), 25 (19), 2514-8 ISSN:0362-2436.STUDY DESIGN: After posterior stabilization of the spondylolytic lumbosacral level, mobility of the fused vertebrae could be studied before and after an additional anterior endoscopic interbody fusion using roentgen stereophotogrammetric analysis. OBJECTIVE: To determine the in vivo primary lumbosacral stability of additional anterior interbody fusion after transpedicular screw fixation. SUMMARY OF BACKGROUND DATA: In vitro studies indicate a significant decrease in segmental motion after pedicle screw fixation and additional anterior fusion. Roentgen stereophotogrammetric studies demonstrate the adequacy of transpedicular lumbar instrumentation in posterolateral fusions. There are no studies examining the effect of additional anterior interbody fusion after posterior instrumentation in vivo. METHODS: In this study, 15 patients with low-grade spondylolisthesis at L5-S1 underwent a two-stage open posterior and endoscopic anterior lumbar fusion using carbon fiber (Brantigan I/F) cages. At surgery, tantalum markers were implanted into the fifth lumbar (L5) and the first sacral (S1) vertebra. All the patients were examined by roentgen stereophotogrammetric analysis after the first and second surgical procedures. RESULTS: After implantation of the posterior pedicle system only, the mean intervertebral mobility determined by roentgen stereophotogrammetric analysis was 0.23 mm in the transverse (x), 0.54 mm in the vertical (y), and 1.2 mm in the sagittal (z) axes. After additional anterior endoscopic fusion with carbon cages, the remaining translation between the fused segment L5/S1 decreased to 0.17 mm in the x, 0.16 mm in the y, and 0.44 mm in the z axes. CONCLUSION: Anterior endoscopic lumbosacral fusion significantly increases the primary stability of the posterior fusion with a pedicle system in two axes of motion.
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252Rousseau, M. A.; Lazennec, J. Y.; Saillant, G. J. Spinal Disord. Tech. 2007, 20, 278252https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2szisFyluw%253D%253D&md5=8310cf4b770199603578be5528c586a1Circumferential arthrodesis using PEEK cages at the lumbar spineRousseau Marc-Antoine; Lazennec Jean-Yves; Saillant GerardJournal of spinal disorders & techniques (2007), 20 (4), 278-81 ISSN:1536-0652.Usual interbody cages at the lumbar spine are made of titanium or carbon fiber-polyetheretherketone (PEEK). Pure PEEK cages have more recently been proposed for its lower elasticity modulus. The goal of our study was to investigate a series of patients with circumferential fixation using anterior PEEK cages for degenerative lumbar spine disorders with a specific interest in the local lordosis. Fifty-seven consecutive patients aged 54.6 years (29 to 75) were reviewed. The level of arthrodesis varied from L2L3 to L5S1. The clinical status and the radiologic variations in local lordosis at the level of arthrodesis were measured. Decrease in lordosis at follow-up was tested in a multivariate analysis regarding age, obesity, spinal level, bone graft amount, type of posterior instrumentation, postoperative lordosis increase, and cage height. The average follow-up was 5.7 years (4 to 8). Clinical outcomes were excellent or good in 49 cases. Fusion was definite in 56 cases. Although 47 patients had no change in lordosis after surgery, 10 cases showed lordosis increase (8.2 degrees; 5 to 12). At follow-up, local lordosis decreased in 13 cases (5.6 degrees; 4 to 8). The linear model was significant (P<0.001; R=0.590) showing that loss in lordosis was related with postoperative lordosis increase (P=0.01), cage height (P<0.001), posterior instrumentation rigidity (P=0.026), age (P=0.047), and low level (P=0.013). Lumbar circumferential arthrodesis using PEEK cages provided good clinical results and fusion rate. However, lordosis correction was not maintained at follow-up, especially at lower levels, using high cages, in older patients, and when associated with a rigid primary posterior instrumentation. Regarding the last point, this is likely that the order of the instrumentation (posterior first, then anterior) played a role in the loss of lordosis in case of rigid posterior fixation.
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253Webster, T. J.; Waid, M. C.; McKenzie, J. L.; Price, R. L.; Ejiofor, J. U. Nanotechnology 2004, 15, 48There is no corresponding record for this reference.
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254Arnould, C.; Koranyi, T. I.; Delhalle, J.; Mekhalif, Z. J. Colloid Interface Sci. 2010, 344, 390There is no corresponding record for this reference.
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255Nayagam, D. A.; Williams, R. A.; Chen, J.; Magee, K. A.; Irwin, J.; Tan, J.; Innis, P.; Leung, R. T.; Finch, S.; Williams, C. E.; Clark, G. M.; Wallace, G. G. Small 2011, 7, 1035There is no corresponding record for this reference.
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256Li, Z.; Wu, Z.; Li, K. Anal. Biochem. 2009, 387, 267There is no corresponding record for this reference.
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257Gulati, N.; Gupta, H. Crit. Rev. Ther. Drug Carrier Syst. 2012, 29, 65257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmsFemsbY%253D&md5=316e4252a796979c5ba292683931b45eTwo faces of carbon nanotube: toxicities and pharmaceutical applicationsGulati, Neha; Gupta, HimanshuCritical Reviews in Therapeutic Drug Carrier Systems (2012), 29 (1), 65-88CODEN: CRTSEO; ISSN:0743-4863. (Begell House, Inc.)A review. In the field of nanotechnol., carbon nanotube (CNT) is gaining importance for the delivery of therapeutic agents and diagnosis of diseases. CNT is emerging as an efficient nanocarrier system with cylindrical nanostructure. Due to its nanoscale dimensions, CNTs have a high cell-penetration quality that allows its use in site-specific targeting. Another aspect of the utilization of CNT lies in its hollow structure through which an active moiety can be delivered in a controlled manner via CNTs' nano channels. Despite these pos. aspects of CNT, scientists are still working to improve its biocompatibility and soly. and eliminating toxicity in vivo, which are creating problems with the use of CNTs. Therefore, functionalization becomes an important aspect to be studied because it decreases the toxicity of CNTs and make them nonimmunogenic. In this review, different functionalization techniques of CNTs and their biomedical applications-in particular for cancer therapy to date-are reviewed in detail to present the potential of this nanovector.
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258Ilbasmis-Tamer, S.; Degim, I. T. Expert Opin. Drug Delivery 2012, 9, 991There is no corresponding record for this reference.
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259Wallace, E. J.; Sansom, M. S. Nanotechnology 2009, 20, 045101There is no corresponding record for this reference.
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260Zhang, X.; Hui, Z.; Wan, D.; Huang, H.; Huang, J.; Yuan, H.; Yu, J. Int. J. Biol. Macromol. 2010, 47, 389260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpvFWns7k%253D&md5=fe3146b8008a81192f1690772d220d56Alginate microsphere filled with carbon nanotube as drug carrierZhang, Xiao-Lan; Hui, Zhong-Ying; Wan, Da-Xin; Huang, Hai-Tao; Huang, Jin; Yuan, Hong; Yu, Jia-HuiInternational Journal of Biological Macromolecules (2010), 47 (3), 389-395CODEN: IJBMDR; ISSN:0141-8130. (Elsevier B.V.)The potential biomedical application of carbon nanotube (CNT) becomes a driving force to incorporate polymer-assisted dispersed CNT into the alginate (AL) microsphere as a drug carrier. The results of XRD and SEM showed that the addn. of CNT had no evident effect on the structures and morphologies of microspheres. As expected, the incorporation of CNT enhanced the storage modulus of the AL sol, and hence improved the mech. stability of the AL/CNT microspheres. Although the swelling degree had no obvious change after the same interval under various pH conditions, the preserving time of the AL/CNT microspheres obviously increased under the pH conditions of 6.8, 7.0 and 7.4. Furthermore, the encapsulation efficiency of drug in the AL/CNT microspheres was enhanced while the drug leakage was decreased. The results of drug release with theophylline as a drug model showed that the AL/CNT microspheres inherited the pH sensitivity of the AL microspheres while the character of sustaining release was more predominant. In virtue of the cytotoxicity of the CNT-filled AL microspheres equiv. to the neat AL microspheres proved by the tests of cell viability assay, the AL/CNT microspheres, with higher stability, less drug leakage and predominant sustaining release profile, showed the potential application as a drug delivery system to intestine and colon.
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261Chin, S. F.; Baughman, R. H.; Dalton, A. B.; Dieckmann, G. R.; Draper, R. K.; Mikoryak, C.; Musselman, I. H.; Poenitzsch, V. Z.; Xie, H.; Pantano, P. Exp. Biol. Med. (Maywood, NJ, U.S.) 2007, 232, 1236261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFKnurbN&md5=e415e17afcc999b4556289863762a2a3Amphiphilic helical peptide enhances the uptake of single-walled carbon nanotubes by living cellsChin, Shook-Fong; Baughman, Ray H.; Dalton, Alan B.; Dickmann, Gregg R.; Draper, Rockford K.; Mikoryak, Carole; Musselman, Inga H.; Poenitzsch, Vasiliki Z.; Xie, Hui; Pantano, PaulExperimental Biology and Medicine (Maywood, NJ, United States) (2007), 232 (9), 1236-1244CODEN: EBMMBE; ISSN:1535-3702. (Society for Experimental Biology and Medicine)The success of many projected applications of carbon nanotubes (CNTs) to living cells, such as intracellular sensors and nanovectors, will depend on how many CNTs are taken up by cells. Here we report the enhanced uptake by HeLa cells of single-walled CNTs coated with a designed peptide termed nano-1. At. force microscopy showed that the dispersions were composed of individual and small bundles of nano-1 CNTs with 0.7- to 32-nm diams. and 100- to 400-nm lengths. Spectroscopic characterizations revealed that nano-1 disperses CNTs in a non-covalent fashion that preserves CNT optical properties. Elemental anal. indicated that our sample prepn. protocol involving sonication and centrifugation effectively eliminated metal impurities assocd. with CNT manufg. processes. We further showed that the purified CNT dispersions are taken up by HeLa cells in a time- and temp.-dependent fashion, and that they do not affect the HeLa cell growth rate, evidence that the CNTs inside cells are not toxic under these conditions. Finally, we discovered that ∼6-fold more CNTs are taken up by cells in the presence of nano-1 compared with medium contg. serum but no peptide. The fact that coating CNTs with a peptide enhances uptake offers a strategy for improving the performance of applications that require CNTs to be inside cells.
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262Kostarelos, K.; Lacerda, L.; Pastorin, G.; Wu, W.; Wieckowski, S.; Luangsivilay, J.; Godefroy, S.; Pantarotto, D.; Briand, J. P.; Muller, S.; Prato, M.; Bianco, A. Nat. Nanotechnol. 2007, 2, 108262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXit1Wrtrs%253D&md5=030c99a00e958dd35bc1a8607c882a54Cellular uptake of functionalized carbon nanotubes is independent of functional group and cell typeKostarelos, Kostas; Lacerda, Lara; Pastorin, Giorgia; Wu, Wei; Wieckowski, Sebastien; Luangsivilay, Jacqueline; Godefroy, Sylvie; Pantarotto, Davide; Briand, Jean-Paul; Muller, Sylviane; Prato, Maurizio; Bianco, AlbertoNature Nanotechnology (2007), 2 (2), 108-113CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)The development of nanomaterials for biomedical and biotechnol. applications is an area of research that holds great promise and intense interest, and carbon-based nanostructures in particular, such as carbon nanotubes (CNTs), are attracting an increasing level of attention. One of the key advantages that CNTs offer is the possibility of effectively crossing biol. barriers, which would allow their use in the delivery of therapeutically active mols. The authors' labs. have been investigating the use of CNTs in biomedical applications, and in particular as nanovectors for therapeutic agent delivery. The interaction between cells and CNTs is a crit. issue that will det. any future biol. application of such structures. Various types of functionalized carbon nanotubes (f-CNTs) exhibit a capacity to be taken up by a wide range of cells and can intracellularly traffic through different cellular barriers.
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263Zhang, L. W.; Zeng, L.; Barron, A. R.; Monteiro-Riviere, N. A. Int. J. Toxicol. 2007, 26, 103263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlsVSrtr4%253D&md5=bf4db9db99e1086cb15fa8086439fabaBiological interactions of functionalized single-wall carbon nanotubes in human epidermal keratinocytesZhang, Leshuai W.; Zeng, Liling; Barron, Andrew R.; Monteiro-Riviere, Nancy A.International Journal of Toxicology (2007), 26 (2), 103-113CODEN: IJTOFN; ISSN:1091-5818. (Informa Healthcare USA, Inc.)Carbon nanotube-based nanovectors, esp. functionalized nanotubes, have shown potential for therapeutic drug delivery. 6-Aminohexanoic acid-derivatized single-wall carbon nanotubes (AHA-SWNTs) are sol. in aq. stock solns. over a wide range of physiol. relevant conditions; however, their interactions with cells and their biol. compatibility has not been explored. Human epidermal keratinocytes (HEKs) were dosed with AHA-SWNTs ranging in concn. from 0.00000005 to 0.05 mg/mL. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell viability decreased significantly (p < .05) from 0.00005 to 0.05 mg/mL after 24 h. The proinflammatory mediators of inflammation cytokines interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, IL-10, and IL-1β were also assessed. Cytokine anal. did not show a significant increase in IL-6 and IL-8 in the medium contg. 0.000005 mg/mL of AHA-SWNTs from 1 to 48 h. IL-6 increased in cells treated with 0.05 mg/mL of AHA-SWNTs from 1 to 48 h, whereas IL-8 showed a significant increase at 24 and 48 h. No significant difference (p < .05) was noted with TNF-α, IL-10, and IL-1β expression at any time point. Transmission electron microscopy of HEKs treated with 0.05 mg/mL AHA-SWNTs for 24 h depicted AHA-SWNTs localized within intracytoplasmic vacuoles in HEKs. Treatment with the surfactant 1% Pluronic F127 caused dispersion of the AHA-SWNT aggregates in the culture medium and less toxicity. These data showed that the lower concn. of 0.000005 mg/mL of AHA-SWNTs maintains cell viability and induces a mild cytotoxicity, but 0.05 mg/mL of AHA-SWNTs demonstrated an irritation response by the increase in IL-8.
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264Rosen, Y.; Elman, N. M. Expert Opin. Drug Delivery 2009, 6, 517There is no corresponding record for this reference.
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265Kang, S.; Pinault, M.; Pfefferle, L. D.; Elimelech, M. Langmuir 2007, 23, 8670There is no corresponding record for this reference.
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266Arias, L. R.; Yang, L. Langmuir 2009, 25, 3003There is no corresponding record for this reference.
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267Liu, S.; Ng, A. K.; Xu, R.; Wei, J.; Tan, C. M.; Yang, Y.; Chen, Y. Nanoscale 2010, 2, 2744There is no corresponding record for this reference.
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268Yang, C.; Mamouni, J.; Tang, Y.; Yang, L. Langmuir 2010, 26, 16013There is no corresponding record for this reference.
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269Pantarotto, D.; Partidos, C. D.; Hoebeke, J.; Brown, F.; Kramer, E.; Briand, J. P.; Muller, S.; Prato, M.; Bianco, A. Chem. Biol. 2003, 10, 961269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXosVyksb4%253D&md5=92a0e71f951c5658affa735ee166b05cImmunization with Peptide-Functionalized Carbon Nanotubes Enhances Virus-Specific Neutralizing Antibody ResponsesPantarotto, Davide; Partidos, Charalambos D.; Hoebeke, Johan; Brown, Fred; Kramer, Ed; Briand, Jean-Paul; Muller, Sylviane; Prato, Maurizio; Bianco, AlbertoChemistry & Biology (2003), 10 (10), 961-966CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)Functionalized carbon nanotubes (CNTs) hold a lot of promise for application in medicinal chem. Based on a method for prepn. of water-sol. CNTs, the authors covalently linked a neutralizing B cell epitope from the foot-and-mouth disease virus (FMDV) to mono- and bis-derivatized CNTs. Immunol. characterization of these conjugates revealed that the epitope was appropriately presented after conjugation to CNTs for recognition by antibodies as measured by BIAcore technol. Moreover, peptide-carbon nanotubes elicited strong anti-peptide antibody responses in mice with no detectable cross-reactivity to the carbon nanotubes. However, only the mono-derivatized CNT conjugate induced high levels of virus-neutralizing antibodies. These findings highlight for the first time the potential of CNTs to present biol. important epitopes in an appropriate conformation both in vitro and in vivo and open up the possibility for their use in vaccine delivery.
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270Zhang, B.; Chen, Q.; Tang, H.; Xie, Q.; Ma, M.; Tan, L.; Zhang, Y.; Yao, S. Colloids Surf., B 2010, 80, 18There is no corresponding record for this reference.
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271Cui, D.; Tian, F.; Coyer, S. R.; Wang, J.; Pan, B.; Gao, F.; He, R.; Zhang, Y. J. Nanosci. Nanotechnol. 2007, 7, 1639There is no corresponding record for this reference.
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272Kam, N. W.; Liu, Z.; Dai, H. J. Am. Chem. Soc. 2005, 127, 12492There is no corresponding record for this reference.
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273Krajcik, R.; Jung, A.; Hirsch, A.; Neuhuber, W.; Zolk, O. Biochem. Biophys. Res. Commun. 2008, 369, 595There is no corresponding record for this reference.
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274Giljohann, D. A.; Seferos, D. S.; Prigodich, A. E.; Patel, P. C.; Mirkin, C. A. J. Am. Chem. Soc. 2009, 131, 2072There is no corresponding record for this reference.
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275Ladeira, M. S.; Andrade, V. A.; Gomes, E. R.; Aguiar, C. J.; Moraes, E. R.; Soares, J. S.; Silva, E. E.; Lacerda, R. G.; Ladeira, L. O.; Jorio, A.; Lima, P.; Leite, M. F.; Resende, R. R.; Guatimosim, S. Nanotechnology 2010, 21, 385101There is no corresponding record for this reference.
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276Sandhiya, S.; Dkhar, S. A.; Surendiran, A. Fundam. Clin. Pharmacol. 2009, 23, 263276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnvVemur0%253D&md5=8774f48258af1455312fa2a1c2ee2c8bEmerging trends of nanomedicine - an overviewSandhiya, Selvarajan; Dkhar, Steven Aibor; Surendiran, A.Fundamental & Clinical Pharmacology (2009), 23 (3), 263-269CODEN: FCPHEZ; ISSN:0767-3981. (Wiley-Blackwell)A review. Nanotechnol. is an emerging branch of science for designing tools and devices of size 1 to 100 nm with unique function at the cellular, at. and mol. levels. The concept of using nanotechnol. in medical research and clin. practice is known as nanomedicine. Nanoparticles possess some novel properties not seen with the macro mols. and they can be manipulated by attaching therapeutic components to help in diagnosis and treatment. They can also be used to probe cellular movements and mol. changes assocd. with pathol. states. Nanodevices like carbon nanotubes to locate and deliver anticancer drugs at the specific tumor site are under research. Nanotechnol. promises construction of artificial cells, enzymes and genes. This will help in the replacement therapy of many disorders which are due to deficiency of enzymes, mutation of genes or any repair in the synthesis of proteins. Currently nanodevices like respirocytes, microbivores and probes encapsulated by biol. localized embedding have a greater application in treatment of anemia and infections. Thus in the present scenario, nanotechnol. is spreading its wings to address the key problems in the field of medicine. Hence this review discusses in detail the applications of nanotechnol. in medicine with more emphasis on drug delivery and therapy.
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277Lima, M. D.; Li, N.; Jung de Andrade, M.; Fang, S.; Oh, J.; Spinks, G. M.; Kozlov, M. E.; Haines, C. S.; Suh, D.; Foroughi, J.; Kim, S. J.; Chen, Y.; Ware, T.; Shin, M. K.; Machado, L. D.; Fonseca, A. F.; Madden, J. D.; Voit, W. E.; Galvao, D. S.; Baughman, R. H. Science 2012, 338, 928There is no corresponding record for this reference.
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278Hamdi, M. Nanotechnology 2009, 20, 485501There is no corresponding record for this reference.
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279Barone, P. W.; Baik, S.; Heller, D. A.; Strano, M. S. Nat. Mater. 2005, 4, 86279https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXksl2q&md5=42c0fd7870a1f0e11335489bfb209c5fNear-infrared optical sensors based on single-walled carbon nanotubesBarone, Paul W.; Baik, Seunghyun; Heller, Daniel A.; Strano, Michael S.Nature Materials (2005), 4 (1), 86-92CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)Mol. detection using near-IR light between 0.9 and 1.3 eV has important biomedical applications because of greater tissue penetration and reduced auto-fluorescent background in thick tissue or whole-blood media. Carbon nanotubes have a tunable near-IR emission that responds to changes in the local dielec. function but remains stable to permanent photobleaching. In this work, we report the synthesis and successful testing of soln.-phase, near-IR sensors, with β-D-glucose sensing as a model system, using single-walled carbon nanotubes that modulate their emission in response to the adsorption of specific biomols. New types of non-covalent functionalization using electron-withdrawing mols. are shown to provide sites for transferring electrons in and out of the nanotube. We also show two distinct mechanisms of signal transduction-fluorescence quenching and charge transfer. The results demonstrate new opportunities for nanoparticle optical sensors that operate in strongly absorbing media of relevance to medicine or biol.
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280Popov, A. M.; Lozovik, Y. E.; Fiorito, S.; Yahia, L. Int. J. Nanomed. 2007, 2, 361280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlektbvO&md5=4bef98215a45bad8b34be3d0604d5c61Biocompatibility and applications of carbon nanotubes in medical nanorobotsPopov, Andrei M.; Lozovik, Yurii E.; Fiorito, Silvana; Yahia, L'HocineInternational Journal of Nanomedicine (2007), 2 (3), 361-372CODEN: IJNNHQ; ISSN:1176-9114. (Dove Medical Press (NZ) Ltd.)A review. The set of nanoelectromech. systems (NEMS) based on relative motion of carbon nanotubes walls is proposed for use in medical nanorobots. This set includes electromech. nanothermometer, jet nanoengine, nanosyringe (the last can be used simultaneously as nanoprobe for individual biol. mols. and drug nanodeliver). Principal schemes of these NEMS are considered. Operational characteristics of nanothermometer are analyzed. The possible methods of these NEMS actuation are considered. The present-day progress in nanotechnol. techniques which are necessary for assembling of NEMS under consideration is discussed. Biocompatibility of carbon nanotubes is analyzed in connection with perspectives of their application in nanomedicine.
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281Poland, C. A.; Duffin, R.; Kinloch, I.; Maynard, A.; Wallace, W. A.; Seaton, A.; Stone, V.; Brown, S.; Macnee, W.; Donaldson, K. Nat. Nanotechnol. 2008, 3, 423281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXotFehs7o%253D&md5=54ae8b1abbe311ade69bb8255891b407Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot studyPoland, Craig A.; Duffin, Rodger; Kinloch, Ian; Maynard, Andrew; Wallace, William A. H.; Seaton, Anthony; Stone, Vicki; Brown, Simon; MacNee, William; Donaldson, KenNature Nanotechnology (2008), 3 (7), 423-428CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Carbon nanotubes have distinctive characteristics, but their needle-like fiber shape has been compared to asbestos, raising concerns that widespread use of carbon nanotubes may lead to mesothelioma, cancer of the lining of the lungs caused by exposure to asbestos. Exposing the mesothelial lining of the body cavity of mice, as a surrogate for the mesothelial lining of the chest cavity, to long multiwalled carbon nanotubes results in asbestos-like, length-dependent, pathogenic behavior. This includes inflammation and the formation of lesions known as granulomas. This is of considerable importance, because research and business communities continue to invest heavily in carbon nanotubes for a wide range of products under the assumption that they are no more hazardous than graphite. The authors' results suggest the need for further research and great caution before introducing such products into the market if long-term harm is to be avoided. A pilot study in a small no. of mice shows that long multiwalled carbon nanotubes introduced into the abdominal cavity can cause asbestos-like pathogenic behavior. The results suggest the need for further research and caution before introducing nanotube products into the market.
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282Takagi, A.; Hirose, A.; Nishimura, T.; Fukumori, N.; Ogata, A.; Ohashi, N.; Kitajima, S.; Kanno, J. J. Toxicol. Sci. 2008, 33, 105282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmtFKksLw%253D&md5=f437c911ffcf1d60fa4e69181553a977Induction of mesothelioma in p53+/-mouse by intraperitoneal application of multi-wall carbon nanotubeTakagi, Atsuya; Hirose, Akihiko; Nishimura, Tetsuji; Fukumori, Nobutaka; Ogata, Akio; Ohashi, Norio; Kitajima, Satoshi; Kanno, JunJournal of Toxicological Sciences (2008), 33 (1), 105-116CODEN: JTSCDR; ISSN:0388-1350. (Japanese Society of Toxicology)Nanomaterials of carbon origin tend to form various shapes of particles in micrometer dimensions. Among them, multi-wall carbon nanotubes (MWCNT) form fibrous or rod-shaped particles of length around 10 to 20 μm with an aspect ratio of more than three. Fibrous particles of this dimension including asbestos and some man-made fibers are reported to be carcinogenic, typically inducing mesothelioma. Here we report that MWCNT induces mesothelioma along with a pos. control, crocidolite (blue asbestos), when administered i.p. to p53 heterozygous mice that have been reported to be sensitive to asbestos. Our results point out the possibility that carbon-made fibrous or rod-shaped micrometer particles may share the carcinogenic mechanisms postulated for asbestos. To maintain sound activity of industrialization of nanomaterials, it would be prudent to implement strategies to keep good control of exposure to fibrous or rod-shaped carbon materials both in the workplace and in the future market until the biol./carcinogenic properties, esp. of their long-term biodurability, are fully assessed.
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283Kisin, E. R.; Murray, A. R.; Sargent, L.; Lowry, D.; Chirila, M.; Siegrist, K. J.; Schwegler-Berry, D.; Leonard, S.; Castranova, V.; Fadeel, B.; Kagan, V. E.; Shvedova, A. A. Toxicol. Appl. Pharmacol. 2011, 252, 1283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjtFGgsLo%253D&md5=bb5baaea379ecf922d3e234567033c1eGenotoxicity of carbon nanofibers: Are they potentially more or less dangerous than carbon nanotubes or asbestos?Kisin, E. R.; Murray, A. R.; Sargent, L.; Lowry, D.; Chirila, M.; Siegrist, K. J.; Schwegler-Berry, D.; Leonard, S.; Castranova, V.; Fadeel, B.; Kagan, V. E.; Shvedova, A. A.Toxicology and Applied Pharmacology (2011), 252 (1), 1-10CODEN: TXAPA9; ISSN:0041-008X. (Elsevier B.V.)The prodn. of carbon nanofibers and nanotubes (CNF/CNT) and their composite products is increasing globally. CNF are generating great interest in industrial sectors such as energy prodn. and electronics, where alternative materials may have limited performance or are produced at a much higher cost. However, despite the increasing industrial use of carbon nanofibers, information on their potential adverse health effects is limited. In the current study, we examine the cytotoxic and genotoxic potential of carbon-based nanofibers (Pyrograf-III) and compare this material with the effects of asbestos fibers (crocidolite) or single-walled carbon nanotubes (SWCNT). The genotoxic effects in the lung fibroblast (V79) cell line were examd. using two complementary assays: the comet assay and micronucleus (MN) test. In addn., we utilized fluorescence in situ hybridization to detect the chromatin pan-centromeric signals within the MN indicating their origin by aneugenic (chromosomal malsegregation) or clastogenic (chromosome breakage) mechanisms. Cytotoxicity tests revealed a concn.- and time-dependent loss of V79 cell viability after exposure to all tested materials in the following sequence: asbestos > CNF > SWCNT. Addnl., cellular uptake and generation of oxygen radicals was seen in the murine RAW264.7 macrophages following exposure to CNF or asbestos but not after administration of SWCNT. DNA damage and MN induction were found after exposure to all tested materials with the strongest effect seen for CNF. Finally, we demonstrated that CNF induced predominately centromere-pos. MN in primary human small airway epithelial cells (SAEC) indicating aneugenic events. Further investigations are warranted to elucidate the possible mechanisms involved in CNF-induced genotoxicity.
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284Osmond-McLeod, M. J.; Poland, C. A.; Murphy, F.; Waddington, L.; Morris, H.; Hawkins, S. C.; Clark, S.; Aitken, R.; McCall, M. J.; Donaldson, K. Part. Fibre Toxicol. 2011, 8, 15284https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmt1Omur4%253D&md5=a8ae6fd962c052f8b7511bc65c88bce3Durability and inflammogenic impact of carbon nanotubes compared with asbestos fibresOsmond-McLeod, Megan J.; Poland, Craig A.; Murphy, Fiona; Waddington, Lynne; Morris, Howard; Hawkins, Stephen C.; Clark, Steve; Aitken, Rob; McCall, Maxine J.; Donaldson, KenParticle and Fibre Toxicology (2011), 8 (), 15CODEN: PFTABQ; ISSN:1743-8977. (BioMed Central Ltd.)Background: It has been suggested that carbon nanotubes might conform to the fiber pathogenicity paradigm that explains the toxicities of asbestos and other fibers on a continuum based on length, aspect ratio and biopersistence. Some types of carbon nanotubes satisfy the first two aspects of the fiber paradigm but only recently has their biopersistence begun to be investigated. Biopersistence is complex and requires in vivo testing and anal. However durability, the chem. mimicking of the process of fiber dissoln. using in vitro treatment, is closely related to biopersistence and more readily detd. Here, we describe an exptl. process to det. the durability of four types of carbon nanotubes in simulated biol. fluid (Gambles soln.), and their subsequent pathogenicity in vivo using a mouse model sensitive to inflammogenic effects of fibers. The in vitro and in vivo results were compared with well-characterized glass wool and asbestos fiber controls. Results: After incubation for up to 24 wk in Gambles soln., our control fibers were recovered at percentages consistent with their known in vitro durabilities and/or in vivo persistence, and three out of the four types of carbon nanotubes tested [single walled (CNTSW) and multi walled (CNTTANG2, CNTSPIN)] showed no, or minimal, loss of mass or change in fiber length or morphol. when examd. by electron microscopy. However, the fourth type [multi walled (CNTLONG1)] lost 30% of its original mass within the first three weeks of incubation, after which there was no further loss. Electron microscopy of CNTLONG1 samples incubated for 10 wk confirmed that the proportion of long fibers had decreased compared to samples briefly exposed to the Gambles soln. This loss of mass and fiber shortening was accompanied by a loss of pathogenicity when injected into the peritoneal cavities of C57Bl/6 mice compared to fibers incubated briefly. CNTSW did not elicit an inflammogenic effect in the peritoneal cavity assay used here. Conclusions: These results support the view that carbon nanotubes are generally durable but may be subject to bio-modification in a sample-specific manner. They also suggest that pristine carbon nanotubes, either individually or in rope-like aggregates of sufficient length and aspect ratio, can induce asbestos-like responses in mice, but that the effect may be mitigated for certain types that are less durable in biol. systems. Results indicate that durable carbon nanotubes that are either short or form tightly bundled aggregates with no isolated long fibers are less inflammogenic in fiber specific assays.
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285Kim, J. S.; Song, K. S.; Lee, J. K.; Choi, Y. C.; Bang, I. S.; Kang, C. S.; Yu, I. J. Arch. Toxicol. 2012, 86, 553285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVCktr%252FF&md5=9e9de75753ed4dc11531ad8bd38f5e58Toxicogenomic comparison of multi-wall carbon nanotubes (MWCNTs) and asbestosKim, Jin Sik; Song, Kyung Seuk; Lee, Jin Kyu; Choi, Young C.; Bang, In Seok; Kang, Chang Soo; Yu, Il JeArchives of Toxicology (2012), 86 (4), 553-562CODEN: ARTODN; ISSN:0340-5761. (Springer)Carbon nanotubes (CNTs) have specific properties, including elec. and thermal cond., great strength, and rigidity, that allow them to be used in many fields. However, this increasing contact with humans and the environment is also raising health and safety concerns. Thus, research on the safety of CNTs has attracted much interest, including a comparison of the toxic effects of asbestos and carbon nanotubes, due to their phys. similarity of a high aspect ratio (length/diam.). Nonetheless, there has not yet been a toxicogenomic comparison. Therefore, to examine toxicogenomic effects, the 50% growth inhibition (GI50) concn. was detd. for multi-wall carbon nanotubes (MWCNTs) and asbestos (crocidolite) and found to be approx. 0.0135 and 0.066%, resp., in the case of 24-h treatment of normal human bronchial epithelia (NHBE) cells. Using these GI50 concns., NHBE cells were then treated with MWCNTs and asbestos for 6 and 24 h, followed by a DNA microarray anal. Among 31,647 genes, 1,201 and 1,252 were up-regulated by both asbestos and MWCNTs after 6 and 24 h of exposure, resp. Meanwhile, 1,977 and 1,542 genes were down-regulated by both asbestos and MWNCTs after 6 and 24 h of exposure, resp. In particular, the asbestos and MWCNTs both induced an over twofold up- and down-regulated expression of 12 mesothelioma-related genes and 22 lung cancer-related genes when compared with the neg. control. Plus, the genes induced by the MWCNT exposure were expressed in the brain, lungs, epithelium, liver, and colon.
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286Murray, A. R.; Kisin, E. R.; Tkach, A. V.; Yanamala, N.; Mercer, R.; Young, S. H.; Fadeel, B.; Kagan, V. E.; Shvedova, A. A. Part. Fibre Toxicol. 2012, 9, 10286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFWlsrjE&md5=85a99e97112163382f51812e9d45054cFactoring-in agglomeration of carbon nanotubes and nanofibers for better prediction of their toxicity versus asbestosMurray, Ashley R.; Kisin, Elena R.; Tkach, Alexey V.; Yanamala, Naveena; Mercer, Robert; Young, Shih-Houng; Fadeel, Bengt; Kagan, Valerian E.; Shvedova, Anna A.Particle and Fibre Toxicology (2012), 9 (), 10CODEN: PFTABQ; ISSN:1743-8977. (BioMed Central Ltd.)Background: Carbon nanotubes (CNT) and carbon nanofibers (CNF) are allotropes of carbon featuring fibrous morphol. The dimensions and high aspect ratio of CNT and CNF have prompted the comparison with naturally occurring asbestos fibers which are known to be extremely pathogenic. While the toxicity and hazardous outcomes elicited by airborne exposure to single-walled CNT or asbestos have been widely reported, very limited data are currently available describing adverse effects of respirable CNF. Results: Here, we assessed pulmonary inflammation, fibrosis, oxidative stress markers and systemic immune responses to respirable CNF in comparison to single-walled CNT (SWCNT) and asbestos. Pulmonary inflammatory and fibrogenic responses to CNF, SWCNT and asbestos varied depending upon the agglomeration state of the particles/fibers. Foci of granulomatous lesions and collagen deposition were assocd. with dense particle-like SWCNT agglomerates, while no granuloma formation was found following exposure to fiber-like CNF or asbestos. The av. thickness of the alveolar connective tissue - a marker of interstitial fibrosis - was increased 28 days post SWCNT, CNF or asbestos exposure. Exposure to SWCNT, CNF or asbestos resulted in oxidative stress evidenced by accumulations of 4-HNE and carbonylated proteins in the lung tissues. Addnl., local inflammatory and fibrogenic responses were accompanied by modified systemic immunity, as documented by decreased proliferation of splenic T cells ex vivo on day 28 post exposure. The accuracies of assessments of effective surface area for asbestos, SWCNT and CNF (based on geometrical anal. of their agglomeration) vs. ests. of mass dose and no. of particles were compared as predictors of toxicol. outcomes. Conclusions: We provide evidence that effective surface area along with mass dose rather than sp. surface area or particle no. are significantly correlated with toxicol. responses to carbonaceous fibrous nanoparticles. Therefore, they could be useful dose metrics for risk assessment and management.
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287Sharifi, S.; Behzadi, S.; Laurent, S.; Forrest, M. L.; Stroeve, P.; Mahmoudi, M. Chem. Soc. Rev. 2012, 41, 2323287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivFWlsbk%253D&md5=cc3ebec4e8ccddb05d3ad7a0a0aeff13Toxicity of nanomaterialsSharifi, Shahriar; Behzadi, Shahed; Laurent, Sophie; Laird Forrest, M.; Stroeve, Pieter; Mahmoudi, MortezaChemical Society Reviews (2012), 41 (6), 2323-2343CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Nanoscience has matured significantly during the last decade as it has transitioned from bench top science to applied technol. Presently, nanomaterials are used in a wide variety of com. products such as electronic components, sports equipment, sun creams and biomedical applications. There are few studies of the long-term consequences of nanoparticles on human health, but governmental agencies, including the United States National Institute for Occupational Safety and Health and Japan's Ministry of Health, have recently raised the question of whether seemingly innocuous materials such as carbon-based nanotubes should be treated with the same caution afforded known carcinogens such as asbestos. Since nanomaterials are increasing a part of everyday consumer products, manufg. processes, and medical products, it is imperative that both workers and end-users be protected from inhalation of potentially toxic NPs. It also suggests that NPs may need to be sequestered into products so that the NPs are not released into the atm. during the product's life or during recycling. Further, non-inhalation routes of NP absorption, including dermal and medical injectables, must be studied in order to understand possible toxic effects. Fewer studies to date have addressed whether the body can eventually eliminate nanomaterials to prevent particle build-up in tissues or organs. This crit. review discusses the biophysicochem. properties of various nanomaterials with emphasis on currently available toxicol. data and methodologies for evaluating nanoparticle toxicity (286 refs.).
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288Muller, J.; Delos, M.; Panin, N.; Rabolli, V.; Huaux, F.; Lison, D. Toxicol. Sci. 2009, 110, 442288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosFWjsb8%253D&md5=36d511744ff04804dfc2dc60ff38fd22Absence of Carcinogenic Response to Multiwall Carbon Nanotubes in a 2-Year Bioassay in the Peritoneal Cavity of the RatMuller, Julie; Delos, Monique; Panin, Nadtha; Rabolli, Virginie; Huaux, Francois; Lison, DominiqueToxicological Sciences (2009), 110 (2), 442-448CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)Toxicol. investigations of carbon nanotubes have shown that they can induce pulmonary toxicity, and similarities with asbestos fibers have been suggested. The authors previously reported that multiwall carbon nanotubes (MWCNT) induced lung inflammation, granulomas and fibrotic reactions. The same MWCNT also caused mutations in epithelial cells in vitro and in vivo. These inflammatory and genotoxic activities were related to the presence of defects in the structure of the nanotubes. In view of the strong links between inflammation, mutations and cancer, these observations prompted the authors to explore the carcinogenic potential of these MWCNT in the peritoneal cavity of rats. The incidence of mesothelioma and other tumors was recorded in three groups of 50 male Wistar rats injected i.p. with a single dose of MWCNT with defects (2 or 20 mg/animal) and MWCNT without defects (20 mg/animal). Two addnl. groups of 26 rats were used as pos. (2 mg UICC crocidolite/animal) and vehicle controls. After 24 mo, although crocidolite induced a clear carcinogenic response (34.6% animals with mesothelioma vs. 3.8% in vehicle controls), MWCNT with or without structural defects did not induce mesothelioma in this bioassay (4, 0, or 6%, resp.). The incidence of tumors other than mesothelioma was not significantly increased across the groups. The initial hypothesis of a contrasting carcinogenic activity between MWCNT with and without defects could not be verified in this bioassay. The authors discuss the possible reasons for this absence of carcinogenic response, including the length of the MWCNT tested (<1 μm on av.), the absence of a sustained inflammatory reaction to MWCNT, and the capacity of these MWCNT to quench free radicals.
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289Sakamoto, Y.; Nakae, D.; Fukumori, N.; Tayama, K.; Maekawa, A.; Imai, K.; Hirose, A.; Nishimura, T.; Ohashi, N.; Ogata, A. J. Toxicol. Sci. 2009, 34, 65289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjsVKntrY%253D&md5=0c48c36f4ccc67c8b275ca358723c4c5Induction of mesothelioma by a single intrascrotal administration of multi-wall carbon nanotube in intact male Fischer 344 ratsSakamoto, Yoshimitsu; Nakae, Dai; Fukumori, Nobutaka; Tayama, Kuniaki; Maekawa, Akihiko; Imai, Kiyoshi; Hirose, Akihiko; Nishimura, Tetsuji; Ohashi, Norio; Ogata, AkioJournal of Toxicological Sciences (2009), 34 (1), 65-76CODEN: JTSCDR; ISSN:0388-1350. (Japanese Society of Toxicology)The present study assessed a carcinogenic hazard of multi-wall carbon nanotube (MWCNT) in intact (not genetically modified) rodents. MWCNT (1 mg/kg body wt., 7 animals), crocidolite (2 mg/kg body wt., 10 animals) or vehicle (2% CM-cellulose, 5 animals) was administered to male Fischer 344 rats (12 wk old) by a single intrascrotal injection. Rats were autopsied immediately after death, when becoming moribund or at the end of the maximal observation period scheduled to be 52 wk. After 37-40 wk, however, 6 MWCNT-treated animals died or became moribund due to i.p. disseminated mesothelioma (6/7, 85.7%) with bloody ascites. Peritoneal mesothelium was generally hypertrophic, and numerous nodular or papillary lesions of mesothelioma and mesothelial hyperplasia were developed. While mesothelioid cells were predominant in relatively early stage tumors, advanced stage mesotheliomas were constituted by 2 portions occupied by mesothelioid cells on the surface and spindle-shaped sarcomatous cells in the depth. In the latter, the histol. transition was apparently obsd. between these 2 portions. Mesotheliomas were invasive to adjacent organs and tissues, and frequently metastasized into the pleura. Only 1 rat survived for 52 wk in the MWCNT-treated group, and similar findings except mesothelioma were obsd. All 10 crocidolite-treated and 5 vehicle-treated rats survived for 52 wk without any particular changes except deposition of asbestos in the former case. It is thus indicated that MWCNT possesses carcinogenicity causing mesothelioma at a high rate in intact male rats under the present exptl. conditions. The present data identifies a carcinogenic hazard of MWCNT and will serve as one of the indispensable evidences to be used for the risk assessment crucial for not only protection and improvement of human health and welfare, but also safe and acceptable development and prevalence of this and similar upcoming materials.
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290Lam, C. W.; James, J. T.; McCluskey, R.; Hunter, R. L. Toxicol. Sci. 2004, 77, 126290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXnslKk&md5=888792409ef5a908b6af59d4e8143799Pulmonary Toxicity of Single-Wall Carbon Nanotubes in Mice 7 and 90 Days After Intratracheal InstillationLam, Chiu-Wing; James, John T.; McCluskey, Richard; Hunter, Robert L.Toxicological Sciences (2004), 77 (1), 126-134CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)Nanomaterials are part of an industrial revolution to develop lightwt. but strong materials for a variety of purposes. Single-wall carbon nanotubes are an important member of this class of materials. They structurally resemble rolled-up graphite sheets, usually with one end capped; individually they are about 1 nm in diam. and several microns long, but they often pack tightly together to form rods or ropes of microscopic sizes. Carbon nanotubes possess unique elec., mech., and thermal properties and have many potential applications in the electronics, computer, and aerospace industries. Unprocessed nanotubes are very light and could become airborne and potentially reach the lungs. Because the toxicity of nanotubes in the lung is not known, their pulmonary toxicity was investigated. The three products studied were made by different methods and contained different types and amts. of residual catalytic metals. Mice were intratracheally instilled with 0, 0.1, or 0.5 mg of carbon nanotubes, a carbon black neg. control, or a quartz pos. control and euthanized 7 d or 90 d after the single treatment for histopathol. study of the lungs. All nanotube products induced dose-dependent epithelioid granulomas and, in some cases, interstitial inflammation in the animals of the 7-d groups. These lesions persisted and were more pronounced in the 90-d groups; the lungs of some animals also revealed peribronchial inflammation and necrosis that had extended into the alveolar septa. The lungs of mice treated with carbon black were normal, whereas those treated with high-dose quartz revealed mild to moderate inflammation. These results show that, for the test conditions described here and on an equal-wt. basis, if carbon nanotubes reach the lungs, they are much more toxic than carbon black and can be more toxic than quartz, which is considered a serious occupational health hazard in chronic inhalation exposures.
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291Li, Z.; Hulderman, T.; Salmen, R.; Chapman, R.; Leonard, S. S.; Young, S. H.; Shvedova, A.; Luster, M. I.; Simeonova, P. P. Environ. Health Perspect. 2007, 115, 377291https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjvFWnur4%253D&md5=584a376c89f8a589602336c05974435eCardiovascular effects of pulmonary exposure to single-wall carbon nanotubesLi, Zheng; Hulderman, Tracy; Salmen, Rebecca; Chapman, Rebecca; Leonard, Stephen S.; Young, Shih-Houng; Shvedova, Anna; Luster, Michael I.; Simeonova, Petia P.Environmental Health Perspectives (2007), 115 (3), 377-382CODEN: EVHPAZ; ISSN:0091-6765. (U. S. Department of Health and Human Services, Public Health Services)Background: Engineered nanosized materials, such as single-wall carbon nanotubes (SWCNT), are emerging as technol. important in different industries. Objective: The unique phys. characteristics and the pulmonary toxicity of SWCNTs raised concerns that respiratory exposure to these materials may be assocd. with cardiovascular adverse effects. Methods: In these studies we evaluated aortic mitochondrial alterations by oxidative stress assays, including quant. polymerase chain reaction of mitochondrial (mt) DNA and plaque formation by morphometric anal. in mice exposed to SWCNTs. Results: A single intrapharyngeal instillation of SWCNTs induced activation of heme oxygenase-1 (HO-1), a marker of oxidative insults, in lung, aorta, and heart tissue in HO-1 reporter transgenic mice. Furthermore, we found that C57BL/6 mice, exposed to SWCNT (10 and 40 μg/mouse), developed aortic mtDNA damage at 7, 28, and 60 days after exposure. MtDNA damage was accompanied by changes in aortic mitochondrial glutathione and protein carbonyl levels. Because these modifications have been related to cardiovascular diseases, we evaluated whether repeated exposure to SWCNTs (20 μg/mouse once every other week for 8 wk) stimulates the progression of atherosclerosis in ApoE-/- transgenic mice. Although SWCNT exposure did not modify the lipid profiles of these mice, it resulted in accelerated plaque formation in ApoE-/- mice fed an atherogenic diet. Plaque areas in the aortas, measured by the en face method, and in the brachiocephalic arteries, measured histopathol., were significantly increased in the SWCNT-treated mice. This response was accompanied by increased mtDNA damage but not inflammation. Conclusions: Taken together, the findings are of sufficient significance to warrant further studies to evaluate the systemic effects of SWCNT under workplace or environmental exposure paradigms.
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292Tong, H.; McGee, J. K.; Saxena, R. K.; Kodavanti, U. P.; Devlin, R. B.; Gilmour, M. I. Toxicol. Appl. Pharmacol. 2009, 239, 224292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVKku7zJ&md5=592ff72b4984e340cc01602500ecacf2Influence of acid functionalization on the cardiopulmonary toxicity of carbon nanotubes and carbon black particles in miceTong, Haiyan; McGee, John K.; Saxena, Rajiv K.; Kodavanti, Urmila P.; Devlin, Robert B.; Gilmour, M. IanToxicology and Applied Pharmacology (2009), 239 (3), 224-232CODEN: TXAPA9; ISSN:0041-008X. (Elsevier B.V.)Engineered carbon nanotubes are being developed for a wide range of industrial and medical applications. Because of their unique properties, nanotubes can impose potentially toxic effects, particularly if they have been modified to express functionally reactive chem. groups on their surface. The present study was designed to evaluate whether acid functionalization (AF) enhanced the cardiopulmonary toxicity of single-walled carbon nanotubes (SWCNT) as well as control carbon black particles. Mice were exposed by oropharyngeal aspiration to 10 or 40 μg of saline-suspended single-walled carbon nanotubes (SWCNTs), acid-functionalized SWCNTs (AF-SWCNTs), ultrafine carbon black (UFCB), AF-UFCB, or 2 μg LPS. 24 h later, pulmonary inflammatory responses and cardiac effects were assessed by bronchoalveolar lavage and isolated cardiac perfusion resp., and compared to saline or LPS-instilled animals. Addnl. mice were assessed for histol. changes in lung and heart. Instillation of 40 μg of AF-SWCNTs, UFCB and AF-UFCB increased percentage of pulmonary neutrophils. No significant effects were obsd. at the lower particle concn. Sporadic clumps of particles from each treatment group were obsd. in the small airways and interstitial areas of the lungs according to particle dose. Patches of cellular infiltration and edema in both the small airways and in the interstitium were also obsd. in the high dose group. Isolated perfused hearts from mice exposed to 40 μg of AF-SWCNTs had significantly lower cardiac functional recovery, greater infarct size, and higher coronary flow rate than other particle-exposed animals and controls, and also exhibited signs of focal cardiac myofiber degeneration. No particles were detected in heart tissue under light microscopy. This study indicates that while acid functionalization increases the pulmonary toxicity of both UFCB and SWCNTs, this treatment caused cardiac effects only with the AF-carbon nanotubes. Further expts. are needed to understand the physico-chem. processes involved in this phenomenon.
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293Kobayashi, N.; Naya, M.; Ema, M.; Endoh, S.; Maru, J.; Mizuno, K.; Nakanishi, J. Toxicology 2010, 276, 143There is no corresponding record for this reference.
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294Reddy, A. R.; Krishna, D. R.; Reddy, Y. N.; Himabindu, V. Toxicol. Mech. Methods 2010, 20, 267294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmt12mt7w%253D&md5=c658b16aa7608b9cc08195315b995857Translocation and extra pulmonary toxicities of multi wall carbon nanotubes in ratsReddy, A. Rama Narsimha; Krishna, Devarakonda R.; Reddy, Y. Narsimha; Himabindu, V.Toxicology Mechanisms and Methods (2010), 20 (5), 267-272CODEN: TMMOCP; ISSN:1537-6516. (Informa Healthcare)This study evaluated the ability of the multi wall carbon nanotubes (MWCNT) to induce extra pulmonary toxicities in rats following intra-tracheal (IT) instillation of two MWCNT. Two carbon nanoparticles were instilled into the lungs of rats (0.2, 1, and 5 mg/kg b.w.) and at different post-exposure intervals, blood and organs like liver, kidney, etc. were collected. The histopathol. examn. of liver tissues revealed a dose-dependent periportal lymphocytic infiltration, ballooning, foamy degeneration, and necrosis at all post-instillation periods. However, examn. of kidney revealed the tubular necrosis and interstitial nephritis with 5 mg/kg dose at 1 mo of post-instillation of both MWCNT. These liver and kidney toxicities were further confirmed by the elevated levels of resp. tissue damage biomarkers. These results suggest the extra pulmonary toxicities of these carbon nanoparticles might be due to the translocation into the liver and kidney.
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295Ge, C.; Meng, L.; Xu, L.; Bai, R.; Du, J.; Zhang, L.; Li, Y.; Chang, Y.; Zhao, Y.; Chen, C. Nanotoxicology 2012, 6, 526There is no corresponding record for this reference.
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296Zhang, Y.; Deng, J.; Guo, F.; Li, C.; Zou, Z.; Xi, W.; Tang, J.; Sun, Y.; Yang, P.; Han, Z.; Li, D.; Jiang, C. J. Mol. Med. (Heidelberg, Ger.) 2013, 91, 117296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlt1Ghuw%253D%253D&md5=69f9d158a7b4588594fb9e353ec3aa97Functionalized single-walled carbon nanotubes cause reversible acute lung injury and induce fibrosis in miceZhang, Yanli; Deng, Jiejie; Zhang, Yanxu; Guo, Feng; Li, Chenggang; Zou, Zhen; Xi, Wen; Tang, Jun; Sun, Yang; Yang, Peng; Han, Zongsheng; Li, Dangsheng; Jiang, ChengyuJournal of Molecular Medicine (Heidelberg, Germany) (2013), 91 (1), 117-128CODEN: JMLME8; ISSN:0946-2716. (Springer)Nanotechnol. is one of today's most promising technol. developments, but safety concerns raise questions about its development. Risk assessments of nanomaterials during occupational exposure are crucial for their development. Here, we assessed the lung toxicity of functionalized single-walled carbon nanotube (f-SWCNT) exposure in C57BL/6 mice, elucidated the underlying mol. mechanism, and evaluated the self-repair ability and lung fibrosis of the mice. Sol. f-SWCNTs were administered to mice. After 18 h or 14 days, the lung histopathol., bronchoalveolar lavage fluid, lung edema, vascular permeability, and PaO2 levels were evaluated, and biochem. and immunostaining tests were also performed. We found that some f-SWCNTs could induce acute lung injury (ALI) in mice via proinflammatory cytokine storm signaling through the NF-κB pathway in vivo. We illustrated that corticosteroid treatments could ameliorate the ALI induced by the f-SWCNTs in mice. Surprisingly, the ALI was almost completely reversed within 14 days, while mild to moderate fibrosis, granuloma, and DNA damage remained in the mice at day 14. Our studies indicate potential remedies to address the growing concerns about the safety of nanomaterials. In addn., we notify that the type of functional groups should be considered in nanomedicine application as differently functionalized SWCNTs generated different effects on the lung toxicity.
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297Erdely, A.; Liston, A.; Salmen-Muniz, R.; Hulderman, T.; Young, S. H.; Zeidler-Erdely, P. C.; Castranova, V.; Simeonova, P. P. J. Occup. Environ. Med. 2011, 53, S80There is no corresponding record for this reference.
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298Zhang, Q.; Huang, J. Q.; Zhao, M. Q.; Qian, W. Z.; Wei, F. ChemSusChem 2011, 4, 864There is no corresponding record for this reference.
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299Department of health and human services, Centers for disease control and prevention, National Institute for Occupational Safety and Health. Occupational exposure to carbon nanotubes and nanofibers. , 2013; p 65.There is no corresponding record for this reference.
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300Environment directorate joint meeting of the chemicals committee and the working party on chemicals, pesticides, and biotechnology. Inhalation toxicity testing: expert meeting on potential revisions to OECD test guidelines and guidance document. , 2012; p 35.There is no corresponding record for this reference.
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301European Commission. Communicationfrom the commission to the European parliament, thecouncil and the european economic and social committee: Second regulatoryreview on nanomaterials. COM (2012, 572 final.There is no corresponding record for this reference.
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302Nakanishi, J. Risk Assessment of Manufactured Nanomaterials: Carbon Nanotubes (CNT); Final report issued on 12 August 2011, NEDO project (P06041); New Energy and IndustrialTechnology Development Organization: Kawasaki, 2011.There is no corresponding record for this reference.
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303Pauluhn, J. Regul. Toxicol. Pharmacol. 2010, 57, 78303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXkvFCltrw%253D&md5=e0591da6e84d1534d24da31c47e346dcMulti-walled carbon nanotubes (Baytubes): Approach for derivation of occupational exposure limitPauluhn, JuergenRegulatory Toxicology and Pharmacology (2010), 57 (1), 78-89CODEN: RTOPDW; ISSN:0273-2300. (Elsevier B.V.)Carbon nanotubes come in a variety of types, but one of the most common forms is multi-walled carbon nanotubes (MWCNT). This paper focuses on the dose-response and time course of pulmonary toxicity of Baytubes, a more flexible MWCNT type with the tendency to form assemblages of nanotubes. This MWCNT has been examd. in previous single and repeated exposure 13-wk rat inhalation studies. Kinetic endpoints and the potential to translocate to extrapulmonary organs have been examd. during postexposure periods of 3 and 6 mo, resp. The focus of both studies was to compare dosimetric endpoints and the time course of pulmonary inflammation characterized by repeated bronchoalveolar lavage and histopathol. during the resp. follow-up periods. To better understand the etiopathol. of pulmonary inflammation and time-related lung remodeling, two metrics of retained lung dose were compared. The first used the mass metric based on the exposure concn. obtained by filter analyses and aerodynamic particle size of airborne MWCNT. The second was based on calcd. volumetric lung burdens of retained MWCNT. Kinetic analyses of lung burdens support the conclusion that Baytubes, in principal, act like poorly sol. agglomerated carbonaceous particulates. However, the difference in pulmonary toxic potency (mass-based) appears to be assocd. with the low-d. (≈0.1-0.3 g/m3) of the MWCNT assemblages. Of note is that assemblages of MWCNT were found predominantly both in the exposure atm. and in digested alveolar macrophages. Isolated fibers were not obsd. in exposure atmospheres or biol. specimens. All findings support the conclusion that the low specific d. of microstructures was conducive to attaining the volumetric lung overload-related inflammatory response conditions earlier than conventional particles. Evidence of extrapulmonary translocation or toxicity was not found in any study. Thus, pulmonary overload is believed to trigger the cascade of events leading to a stasis of clearance and consequently increased MWCNT doses high enough to trigger sustained pulmonary inflammation. This mechanism served as conceptual basis for the calcn. of the human equiv. concn. Accordingly, multiple interspecies adjustments were necessary which included species-specific differences in alveolar deposition, differences in ventilation, and the time-dependent particle accumulation accounting for the known species-specific differences in particle clearance half-times in rats and humans. Based on this rationale and the NOAEL (no-obsd. adverse effect level) from the 13-wk subchronic inhalation study on rats, an occupational exposure limit (OEL) of 0.05 mg Baytubes/m3 (time weighted av.) is considered to be reasonably protective to prevent lung injury to occur in the workplace environment.
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304Yang, K.; Liu, Z. Curr. Drug Metab. 2012, 13, 1057304https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVWgtbjI&md5=9c7d12acb205697ed79a3dba48143f1cIn vivo biodistribution, pharmacokinetics, and toxicology of carbon nanotubesYang, Kai; Liu, ZhuangCurrent Drug Metabolism (2012), 13 (8), 1057-1067CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)A review. Owing to their interesting phys. and chem. properties, carbon nanotubes (CNTs) have attracted wide attention in nanomedicine for applications in biol. sensing, drug delivery, as well as biomedical imaging. The in vivo behaviors and toxicol. of CNTs in biol. systems, which are important fundamental questions, although have been intensively studied in recent years, remain to be clarified as distinctive results have been reported by various teams, confusing the scientific community as well as the public. In this article, we review the research on the in vivo behaviors of CNTs, and summarize the toxicity studies of CNTs in animals by different groups. Similar to other nanomaterials, the in vivo pharmacokinetics and biodistribution of CNTs are closely assocd. with their surface coatings. The excretion of CNTs from animals may happen via renal and fecal pathways, depending on the CNT surface chem., shape, and sizes. Regarding the toxicol. of CNTs, which has been a debating topic for years, the administration routes, doses, and again the surface functionalization are crit. to the in vivo toxicity of nanotubes. Much more efforts are still required to develop functional CNT bioconjugates with improved biocompatible coatings and controllable optimal sizes to achieve fast excretion and minimal toxicity, for various applications in biomedicine.
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305Cherukuri, P.; Gannon, C. J.; Leeuw, T. K.; Schmidt, H. K.; Smalley, R. E.; Curley, S. A.; Weisman, R. B. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 18882There is no corresponding record for this reference.
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306Singh, R.; Pantarotto, D.; Lacerda, L.; Pastorin, G.; Klumpp, C.; Prato, M.; Bianco, A.; Kostarelos, K. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 3357There is no corresponding record for this reference.
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307Kawaguchi, M.; Fukushima, T.; Hayakawa, T.; Nakashima, N.; Inoue, Y.; Takeda, S.; Okamura, K.; Taniguchi, K. Dent. Mater. J. 2006, 25, 719307https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjtlylsbc%253D&md5=bc2707fe86085ffc4f06c8527d4537edPreparation of carbon nanotube-alginate nanocomposite gel for tissue engineeringKawaguchi, Minoru; Fukushima, Tadao; Hayakawa, Toru; Nakashima, Naotoshi; Inoue, Yusuke; Takeda, Shoji; Okamura, Kazuhiko; Taniguchi, KunihisaDental Materials Journal (2006), 25 (4), 719-725CODEN: DMJOD5; ISSN:0287-4547. (Japan Society for Dental Materials and Devices)A novel scaffold material based on an alginate hydrogel which contained carbon nanotubes (CNTs) was prepd., and its mech. property and biocompatibility evaluated. Sol. CNTs were prepd. with acid treatment and dispersed in sodium alginate soln. as a cross-linker. After which, the mech. property (elastic deformation), saline sorption, histol. reaction, and cell viability of the resultant nanocomposite gel (CNT-Alg gel) were evaluated. The CNT-Alg gel showed faster gelling and higher mech. strength than the conventional alginate gel. Saline sorption amt. of freeze-dried CNT-Alg gel was equal to that of the alginate gel. In terms of histol. evaluation and cell viability assay, CNT-Alg gel exhibited a mild inflammatory response and non-cytotoxicity. These results thus suggested that CNT-Alg gel could be useful as a scaffold material in tissue engineering with the sidewalls of CNTs acting as active sites for chem. functionalization.
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308Sitharaman, B.; Shi, X.; Walboomers, X. F.; Liao, H.; Cuijpers, V.; Wilson, L. J.; Mikos, A. G.; Jansen, J. A. Bone 2008, 43, 362There is no corresponding record for this reference.
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309Sato, Y.; Yokoyama, A.; Shibata, K.; Akimoto, Y.; Ogino, S.; Nodasaka, Y.; Kohgo, T.; Tamura, K.; Akasaka, T.; Uo, M.; Motomiya, K.; Jeyadevan, B.; Ishiguro, M.; Hatakeyama, R.; Watari, F.; Tohji, K. Mol. Biosyst. 2005, 1, 176309https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXntlCmtro%253D&md5=5a747eb5e70c28fb14a43106bddc85bfInfluence of length on cytotoxicity of multi-walled carbon nanotubes against human acute monocytic leukemia cell line THP-1 in vitro and subcutaneous tissue of rats in vivoSato, Yoshinori; Yokoyama, Atsuro; Shibata, Ken-ichiro; Akimoto, Yuki; Ogino, Shin-ichi; Nodasaka, Yoshinobu; Kohgo, Takao; Tamura, Kazuchika; Akasaka, Tsukasa; Uo, Motohiro; Motomiya, Kenichi; Jeyadevan, Balachandran; Ishiguro, Mikio; Hatakeyama, Rikizo; Watari, Fumio; Tohji, KazuyukiMolecular BioSystems (2005), 1 (2), 176-182CODEN: MBOIBW; ISSN:1742-206X. (Royal Society of Chemistry)Carbon nanotubes (CNTs) are single- or multi-cylindrical graphene structures that possess diams. of a few nanometers, while the length can be up to a few micrometers. These could have unusual toxicol. properties, in that they share intermediate morphol. characteristics of both fibers and nanoparticles. To date, no detailed study was carried out to det. the effect of length on CNT cytotoxicity. In this paper, the authors investigated the activation of the human acute monocytic leukemia cell line THP-1 in vitro and the response in s.c. tissue in vivo to CNTs of different lengths. The authors used 220 nm and 825 nm-long CNT samples for testing, referred to as "220-CNTs" and "825-CNTs", resp. 220-CNTs and 825-CNTs induced human monocytes in vitro, although the activity was significantly lower than that of microbial lipopeptide and lipopolysaccharide, and no activity appeared following variation in the length of CNTs. On the other hand, the degree of inflammatory response in s.c. tissue in rats around the 220-CNTs was slight in comparison with that around the 825-CNTs. These results indicated that the degree of inflammation around 825-CNTs was stronger than that around 220-CNTs since macrophages could envelop 220-CNTs more readily than 825-CNTs. However, no severe inflammatory response such as necrosis, degeneration or neutrophil infiltration in vivo was obsd. around both CNTs examd. throughout the exptl. period.
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310Deng, X.; Jia, G.; Wang, H.; Sun, H.; Wang, X.; Yang, S.; Wang, T.; Liu, Y. Carbon 2007, 45, 1419310https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmtVGktrg%253D&md5=a9ad312bc30e357ccbe8e3ece7d004c8Translocation and fate of multi-walled carbon nanotubes in vivoDeng, X.; Jia, G.; Wang, H.; Sun, H.; Wang, X.; Yang, S.; Wang, T.; Liu, Y.Carbon (2007), 45 (7), 1419-1424CODEN: CRBNAH; ISSN:0008-6223. (Elsevier Ltd.)Carbon nanotube (CNT) mediated delivery system of drugs etc. has currently aroused a large interest. Because the delivery system will be ultimately introduced into the human body, the information about the in vivo biol. behavior and consequences of CNTs becomes very important. Here, using [14C-taurine]-multi-walled CNTs (MWCNTs) as tracers, the authors show the biodistribution and translocation pathways of MWCNTs in mice by 3 different routes. After mice were exposed by i.v. injection, MWCNTs predominately accumulated in liver and retained for long time. Transmission electron micrographs clearly show the remarkable entrapment of MWCNTs in hepatic macrophages (Kupffer cells). The biol. index examns. indicate low liver acute toxicity of MWCNTs. Some favorable aspects of MWCNTs being used as a drug nanovehicle are also discussed.
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311Bai, Y.; Zhang, Y.; Zhang, J.; Mu, Q.; Zhang, W.; Butch, E. R.; Snyder, S. E.; Yan, B. Nat. Nanotechnol. 2010, 5, 683311https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFajsrbN&md5=6421c975774532fc0a532bd5f969187dRepeated administrations of carbon nanotubes in male mice cause reversible testis damage without affecting fertilityBai, Yuhong; Zhang, Yi; Zhang, Jingping; Mu, Qingxin; Zhang, Weidong; Butch, Elizabeth R.; Snyder, Scott E.; Yan, BingNature Nanotechnology (2010), 5 (9), 683-689CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Sol. carbon nanotubes show promise as materials for in vivo delivery and imaging applications. Several reports have described the in vivo toxicity of carbon nanotubes, but their effects on male reprodn. have not been examd. Here, the authors show that repeated i.v. injections of water-sol. multiwalled carbon nanotubes into male mice can cause reversible testis damage without affecting fertility. Nanotubes accumulated in the testes, generated oxidative stress and decreased the thickness of the seminiferous epithelium in the testis at day 15, but the damage was repaired at 60 and 90 days. The quantity, quality and integrity of the sperm and the levels of three major sex hormones were not significantly affected throughout the 90-day period. The fertility of treated male mice was unaffected; the pregnancy rate and delivery success of female mice that mated with the treated male mice did not differ from those that mated with untreated male mice.
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312Yang, S. T.; Wang, X.; Jia, G.; Gu, Y.; Wang, T.; Nie, H.; Ge, C.; Wang, H.; Liu, Y. Toxicol. Lett. 2008, 181, 182312https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtFekurbK&md5=7b4d62b4c86cdf155e2b447bbcc014e7Long-term accumulation and low toxicity of single-walled carbon nanotubes in intravenously exposed miceYang, Sheng-Tao; Wang, Xiang; Jia, Guang; Gu, Yiqun; Wang, Tiancheng; Nie, Haiyu; Ge, Cuicui; Wang, Haifang; Liu, YuanfangToxicology Letters (2008), 181 (3), 182-189CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)The biomedical application of single-walled carbon nanotubes (SWCNTs), such as drug delivery and cancer treatment, requires a clear understanding of their fate and toxicol. profile after i.v. administration. In this study, the long-term accumulation and toxicity of i.v. injected SWCNTs in the main organs (such as liver, lung and spleen) in mice were carefully studied. Although SWCNTs stayed in mice over 3 mo, they showed low toxicity to mice. The long-term accumulation of SWCNTs in the main organs was evidenced by using Raman spectroscopy and TEM technique. Statistically significant changes in organ indexes and serum biochem. parameters (LDH, ALT and AST) were obsd. The histol. observations demonstrate that slight inflammation and inflammatory cell infiltration occurred in lung, but the serum immunol. indicators (CH 50 level and TNF-α level) remained unchanged. No apoptosis was induced in the main organs. The decreasing glutathione (GSH) level and increasing malondialdehyde (MDA) level suggest that the toxicity of SWCNTs might be due to the oxidative stress.
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313Al Faraj, A.; Fauvelle, F.; Luciani, N.; Lacroix, G.; Levy, M.; Crémillieux, Y.; Canet-Soulas, E. Int. J. Nanomed. 2011, 6, 351313https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXislChtb8%253D&md5=e7a67b9581fc77418c80f5c494ea9a34In vivo biodistribution and biological impact of injected carbon nanotubes using magnetic resonance techniquesAl Faraj, Achraf; Fauvelle, Florence; Luciani, Nathalie; Lacroix, Ghislaine; Levy, Michael; Cremillieux, Yannick; Canet-Soulas, EmmanuelleInternational Journal of Nanomedicine (2011), 6 (), 351-361CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)Single-walled carbon nanotubes (SWCNT) hold promise for applications as contrast agents and target delivery carriers in the field of nanomedicine. When administered in vivo, their biodistribution and pharmacol. profile needs to be fully characterized. The tissue distribution of carbon nanotubes and their potential impact on metab. depend on their shape, coating, and metallic impurities. Because std. radiolabeled or fluorescently-labeled pharmaceuticals are not well suited for long-term in vivo follow-up of carbon nanotubes, alternative methods are required. In this study, noninvasive in vivo magnetic resonance imaging (MRI) investigations combined with high-resoln. magic angle spinning (HR-MAS), Raman spectroscopy, iron assays, and histol. anal. ex vivo were proposed and applied to assess the biodistribution and biol. impact of i.v. injected pristine (raw and purified) and functionalized SWCNT in a 2-wk longitudinal study. Iron impurities allowed raw detection of SWCNT in vivo by susceptibility-weighted MRI. A transitional accumulation in the spleen and liver was obsd. by MRI. Raman spectroscopy, iron assays, and histol. findings confirmed the MRI readouts. Moreover, no acute toxicol. effect on the liver metabolic profile was obsd. using the HR-MAS technique, as confirmed by quant. real-time polymerase chain reaction anal. This study illustrates the potential of noninvasive MRI protocols for longitudinal assessment of the biodistribution of SWCNT with assocd. intrinsic metal impurities. The same approach can be used for any other magnetically-labeled nanoparticles.
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314Wu, H.; Liu, G.; Zhuang, Y.; Wu, D.; Zhang, H.; Yang, H.; Hu, H.; Yang, S. Biomaterials 2011, 32, 4867There is no corresponding record for this reference.
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315Wei, Q.; Zhan, L.; Juanjuan, B.; Jing, W.; Jianjun, W.; Taoli, S.; Yi’an, G.; Wangsuo, W. Nanoscale Res. Lett. 2012, 7, 473315https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38bgsVWgsg%253D%253D&md5=78725c2234bfb35cdabca8d3c5d7e696Biodistribution of co-exposure to multi-walled carbon nanotubes and nanodiamonds in miceWei Qi; Zhan Li; Juanjuan Bi; Jing Wang; Jianjun Wang; Taoli Sun; Yi'an Guo; Wangsuo WuNanoscale research letters (2012), 7 (1), 473 ISSN:.In this work, technetium-99 (99mTc) was used as the radiolabeling isotope to study the biodistribution of oxidized multi-walled carbon nanotubes (oMWCNTs) and/or nanodiamonds (NDs) in mice after intravenous administration. The histological impact of non-radiolabeled oMWCNTs or NDs was investigated in comparison to the co-exposure groups. 99mTc-labeled nanomaterials had high stability in vivo and fast clearance from blood. After a single injection of oMWCNTs, the highest distribution was found in the lungs, with lower uptake in the liver/spleen. As for NDs injected alone, high distribution in the liver, spleen, and lungs was observed right after. However, uptake in the lungs was decreased obviously after 24 h, while high accumulation in the liver or spleen continued. After co-injection of oMWCNTs and NDs, oMWCNTs significantly affected the distribution pattern of NDs in vivo. Meanwhile, the increasing dose of oMWCNTs decreased the hepatic and splenic accumulation of NDs and gradually increased lung retention. On the contrary, the NDs had no significant effects on the distribution of oMWCNTs in mice. Histological photographs showed that oMWCNTs were mainly captured by lung macrophages, and NDs were located in the bronchi and alveoli after co-administration. oMWCNTs and NDs had different modes of micro-cells. In conclusion, the behavior and fate of NDs in mice depended strongly on oMWCNTs, but NDs had a small influence on the biodistribution and excretion pattern of oMWCNTs.
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316Simon-Deckers, A.; Gouget, B.; Mayne-L’hermite, M.; Herlin-Boime, N.; Reynaud, C.; Carriere, M. Toxicology 2008, 253, 137There is no corresponding record for this reference.
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317Gomez-Gualdrón, D. A.; Burgos, J. C.; Yu, J.; Balbuena, P. B. Prog. Mol. Biol. Transl. Sci. 2011, 104, 175317https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivFOjtL8%253D&md5=616f88b27863c5fee22069edd3b6bb59Carbon nanotubes: engineering biomedical applicationsGomez-Gualdron, Diego A.; Burgos, Juan C.; Yu, Jiamei; Balbuena, Perla B.Progress in Molecular Biology and Translational Science (2011), 104 (Nanoparticles in Translational Science and Medicine), 175-245,, 8 platesCODEN: PNARC5 ISSN:. (Elsevier Inc.)A review. Carbon nanotubes (CNTs) are cylinder-shaped allotropic forms of carbon, most widely produced under chem. vapor deposition. They possess astounding chem., electronic, mech., and optical properties. Being among the most promising materials in nanotechnol., they are also likely to revolutionize medicine. Among other biomedical applications, after proper functionalization carbon nanotubes can be transformed into sophisticated biosensing and biocompatible drug-delivery systems, for specific targeting and elimination of tumor cells. This chapter provides an introduction to the chem. and electronic structure and properties of single-walled carbon nanotubes, followed by a description of the main synthesis and post-synthesis methods. These sections allow the reader to become familiar with the specific characteristics of these materials and the manner in which these properties may be dependent on the specific synthesis and post-synthesis processes. The chapter ends with a review of the current biomedical applications of carbon nanotubes, highlighting successes and challenges.
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318Cui, D.; Tian, F.; Ozkan, C. S.; Wang, M.; Gao, H. Toxicol. Lett. 2005, 155, 73318https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVCktrjP&md5=399fb2a7692374a1a69a7e63bee35a8eEffect of single wall carbon nanotubes on human HEK293 cellsCui, Daxiang; Tian, Furong; Ozkan, Cengiz S.; Wang, Mao; Gao, HuajianToxicology Letters (2005), 155 (1), 73-85CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)The influence of single-walled carbon nanotubes (SWCNTs) on human HEK293 cells is investigated with the aim of exploring SWCNTs biocompatibility. Results showed that SWCNTs can inhibit HEK293 cell proliferation, decrease cell adhesive ability in a dose- and time-dependent manner. HEK293 cells exhibit active responses to SWCNTs such as secretion of some 20-30 kd proteins to wrap SWCNTs, aggregation of cells attached by SWCNTs and formation of nodular structures. Cell cycle anal. showed that 25 μg/mL SWCNTs in medium induced G1 arrest and cell apoptosis in HEK293 cells. Biochip anal. showed that SWCNTs can induce up-regulation expression of cell cycle-assocd. genes such as p16, bax, p57, hrk, cdc42 and cdc37, down-regulation expression of cell cycle genes such as cdk2, cdk4, cdk6 and cyclin D3, and down-regulation expression of signal transduction-assocd. genes such as mad2, jak1, ttk, pcdha9 and erk. Western blot anal. showed that SWCNTs can induce down-regulation expression of adhesion-assocd. proteins such as laminin, fibronectin, cadherin, FAK and collagen IV. These results suggest that down-regulation of G1-assocd. cdks and cyclins and upregulation of apoptosis-assocd. genes may contribute to SWCNTs induced G1 phase arrest and cell apoptosis. In conclusion, SWCNTs can inhibit HEK293 cells growth by inducing cell apoptosis and decreasing cellular adhesion ability.
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319Jain, S.; Thakare, V. S.; Das, M.; Godugu, C.; Jain, A. K.; Mathur, R.; Chuttani, K.; Mishra, A. K. Chem. Res. Toxicol. 2011, 24, 2028There is no corresponding record for this reference.
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320Oberdörster, G.; Sharp, Z.; Atudorei, V.; Elder, A.; Gelein, R.; Lunts, A.; Kreyling, W.; Cox, C. J. Toxicol. Environ. Health, Part A 2002, 65, 1531320https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XosF2lsb0%253D&md5=877963d4e9368fbf52bfc48d5acb3798Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of ratsOberdorster, Gunter; Sharp, Zachary; Atudorei, Viorel; Elder, Alison; Gelein, Robert; Lunts, Alex; Kreyling, Wolfgang; Cox, ChristopherJournal of Toxicology and Environmental Health, Part A (2002), 65 (20), 1531-1543CODEN: JTEHF8; ISSN:1528-7394. (Taylor & Francis Inc.)Studies with i.v. injected ultrafine particles have shown that the liver is the major organ of their uptake from the blood circulation. Measuring translocation of inhaled ultrafine particles to extrapulmonary organs via the blood compartment is hampered by methodol. difficulties (i.e., label may come off, partial solubilization) and anal. limitations (measurement of very small amts.). The objective of our pilot study was to det. whether ultrafine elemental carbon particles translocate to the liver and other extrapulmonary organs following inhalation as singlet particles by rats. We generated ultrafine 13C particles as an aerosol with count median diams. (CMDs) of 20-29 nm (GSD 1.7) using elec. spark discharge of 13C graphite electrodes in argon. Nine Fischer 344 rats were exposed to these particles for 6 h. in whole-body inhalation chambers at concns. of 180 and 80 μg/m3; 3 animals each were killed at 0.5, 18, and 24 h postexposure. Six unexposed rats served as controls. Lung lobes, liver, heart, brain, olfactory bulb, and kidney were excised, homogenized, and freeze-dried for anal. of the added 13C by isotope ratio mass spectrometry. Org. 13C was not detected in the 13C particles. The 13C retained in the lung at 0.5 h postexposure was about 70% less than predicted by rat deposition models for ultrafine particles, and did not change significantly during the 24-h postexposure period. Normalized to exposure concn., the added 13C per g of lung on av. in the postexposure period was ∼9 ng/g organ/μg/m3. Significant amts. of 13C had accumulated in the liver by 0.5 h postinhalation only at the high exposure concn., whereas by 18 and 24 h postexposure the 13C amt. of the livers of all exposed rats was about fivefold greater than the 13C burden retained in the lung. No significant increase in 13C was detected in the other organs which were examd. These results demonstrate effective translocation of ultrafine elemental carbon particles to the liver by 1 d after inhalation exposure. Translocation pathways include direct input into the blood compartment from ultrafine carbon particles deposited throughout the respiratory tract. However, since predictive particle deposition models indicate that respiratory tract deposits alone may not fully account for the hepatic 13C burden, input from ultrafine particles present in the GI tract needs to be considered as well. Such translocation to blood and extrapulmonary tissues may well be different between ultrafine carbon and other insol. (metal) ultrafine particles.
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321Georgin, D.; Czarny, B.; Botquin, M.; Mayne-L’hermite, M.; Pinault, M.; Bouchet-Fabre, B.; Carriere, M.; Poncy, J. L.; Chau, Q.; Maximilien, R.; Dive, V.; Taran, F. J. Am. Chem. Soc. 2009, 131, 14658There is no corresponding record for this reference.
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322Wang, H.; Wang, J.; Deng, X.; Sun, H.; Shi, Z.; Gu, Z.; Liu, Y.; Zhao, Y. J. Nanosci. Nanotechnol. 2004, 4, 1019There is no corresponding record for this reference.
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323Guo, J.; Zhang, X.; Li, Q.; Li, W. Nucl. Med. Biol. 2007, 34, 579323https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmvV2itb0%253D&md5=f3a5f0b7498a2e60e1e4870f1f83675aBiodistribution of functionalized multiwall carbon nanotubes in miceGuo, Jinxue; Zhang, Xiao; Li, Qingnuan; Li, WenxinNuclear Medicine and Biology (2007), 34 (5), 579-583CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Inc.)With the application of carbon nanotubes in biomedical and pharmaceutical sciences, its basic biol. properties in vivo have become an issue of strong concern. Water-sol. functionalized multiwall carbon nanotubes (MWNTs) were labeled with radioactive 99mTc atoms, and then a tracer was used to study the distribution of MWNTs modified with glucosamine in mice. It shows that MWNTs moved easily among the compartments and tissues of the body, behaving like active mols. although their apparent mean mol. wt. is tremendously large. In this study, water-sol. MWNTs were labeled with 99mTc for the first time, and all results on the distribution of MWNTs in animals provide useful data for their use in the biomedical field.
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324Zharov, V. P.; Galanzha, E. I.; Shashkov, E. V.; Kim, J. W.; Khlebtsov, N. G.; Tuchin, V. V. J. Biomed. Opt. 2007, 12, 051503There is no corresponding record for this reference.
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325Barrett, K. E.; Boitano, S.; Brooks, H. Immunity, Infection, & Inflammation. Ganong’s Review of Medical Physiology, 23rd ed.; The McGraw-Hill Co., Inc.: New York, 2010; pp 63– 78.There is no corresponding record for this reference.
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326Meng, J.; Yang, M.; Jia, F.; Xu, Z.; Kong, H.; Xu, H. Nanotoxicology 2011, 5, 583There is no corresponding record for this reference.
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327Pacurari, M.; Qian, Y.; Fu, W.; Schwegler-Berry, D.; Ding, M.; Castranova, V.; Guo, N. L. J. Toxicol. Environ. Health, Part A 2012, 75, 129There is no corresponding record for this reference.
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328Nimmagadda, A.; Thurston, K.; Nollert, M. U.; McFetridge, P. S. J. Biomed. Mater. Res., Part A 2006, 76, 614328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhslGisb8%253D&md5=497b0c005495c687aa0db391002436b3Chemical modification of SWNT alters in vitro cell-SWNT interactionsNimmagadda, Aditya; Thurston, Karen; Nollert, Matthias U.; McFetridge, Peter S.Journal of Biomedical Materials Research, Part A (2006), 76A (3), 614-625CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Single-walled carbon nanotubes (SWNT) have been the focus of considerable attention as a material with extraordinary mech. and elec. properties. SWNT have been proposed in a no. of biomedical applications, including neural, bone, and dental tissue engineering. In these applications, it is clear that surrounding tissues will come into surface contact with SWNT composites, and compatibility between SWNT and host cells must be addressed. This investigation describes the gross phys. and chem. effects of different SWNT prepns. on in vitro cell viability and metabolic activity. Three different SWNT prepns. were analyzed: as purchased (AP-NT), purified (PUR-NT), and functionalized with glucosamine (GA-NT), over concns. of 0.001-1.0% (wt./vol.). With the exception of the lowest SWNT concns., increasing concns. of SWNT resulted in a decrease of cell viability, which was dependent on SWNT prepn. The metabolic activity of 3T3 cells was also dependent on SWNT prepn. and concn. These investigations have shown that these SWNT prepns. have significant effects on in vitro cellular function that cannot be attributed to one factor alone, but are more likely the result of several unfavorable interactions. Effects, such as destabilizing the cell membrane, sol. toxic contaminants, and limitations in mass transfer as the SWNT coalesce into sheets, may all play a role in these interactions. Using comprehensive purifn. processes and modifying the NT-surface chem. to introduce functional groups or reduce hydrophobicity or both, these interactions can be significantly improved.
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329Balasubramanian, K.; Burghard, M. Small 2005, 1, 180There is no corresponding record for this reference.
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330Portney, N. G.; Ozkan, M. Anal. Bioanal. Chem. 2006, 384, 620330https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xhtl2msLc%253D&md5=79bd00bf33d5c66c7c7375f813ab17b0Nano-oncology: drug delivery, imaging, and sensingPortney, Nathaniel G.; Ozkan, MihrimahAnalytical and Bioanalytical Chemistry (2006), 384 (3), 620-630CODEN: ABCNBP; ISSN:1618-2642. (Springer)A review. Innovation in the last decade has endowed nanotechnol. with an assortment of tools for delivery, imaging, and sensing in cancer research-stealthy nanoparticle vectors circulating in vivo, assembled with exquisite mol. control, capable of selective tumor targeting and potent delivery of therapeutics; intense and photostable quantum dot-based tumor imaging, enabling multicolor detection of cell receptors with a single optical excitation source; arrays of semiconducting nanowire and carbon nanotube sensor elements for selective multiplexed sensing of cancer markers without the need for probe labeling. These rapidly emerging tools are indicative of a burgeoning field ready to expand into medical applications. This review attempts to outline most of the current nanoparticle toolset for therapeutic release by liposomes, dendrimers, smart polymers, and virus-based systems. Advantages of nanoparticle-based imaging and targeting by use of nanoshells and quantum dots are also explored. Finally, emerging nanoelectronics-based sensing and a global discussion on the utility of each nanoparticle system addresses their fundamental advantages and shortcomings in cancer research.
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331Heister, E.; Lamprecht, C.; Neves, V.; Tilmaciu, C.; Datas, L.; Flahaut, E.; Soula, B.; Hinterdorfer, P.; Coley, H. M.; Silva, S. R.; McFadden, J. ACS Nano 2010, 4, 2615There is no corresponding record for this reference.
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332Bottini, M.; Rosato, N.; Bottini, N. Biomacromolecules 2011, 12, 3381There is no corresponding record for this reference.
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333Liu, Z.; Chen, K.; Davis, C.; Sherlock, S.; Cao, Q.; Chen, X.; Dai, H. Cancer Res. 2008, 68, 6652There is no corresponding record for this reference.
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334Sayes, C. M.; Liang, F.; Hudson, J. L.; Mendez, J.; Guo, W.; Beach, J. M.; Moore, V. C.; Doyle, C. D.; West, J. L.; Billups, W. E.; Ausman, K. D.; Colvin, V. L. Toxicol. Lett. 2006, 161, 135334https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtlWqtLvP&md5=8b4e91a6b19335e464ddf7f744977359Functionalization density dependence of single-walled carbon nanotubes cytotoxicity in vitroSayes, Christie M.; Liang, Feng; Hudson, Jared L.; Mendez, Joe; Guo, Wenhua; Beach, Jonathan M.; Moore, Valerie C.; Doyle, Condell D.; West, Jennifer L.; Billups, W. Edward; Ausman, Kevin D.; Colvin, Vicki L.Toxicology Letters (2006), 161 (2), 135-142CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)The cytotoxic response of cells in culture is dependant on the degree of functionalization of the single-walled carbon nanotube (SWNT). After characterizing a set of water-dispersible SWNTs, the authors performed in vitro cytotoxicity screens on cultured human dermal fibroblasts (HDF). The SWNT samples used in this exposure include SWNT-phenyl-SO3H and SWNT-phenyl-SO3Na (6 samples with carbon/-phenyl-SO3X ratios of 18, 41, and 80), SWNT-phenyl-(COOH)2 (1 sample with carbon/-phenyl-(COOH)2 ratio of 23), and underivatized SWNT stabilized in 1% Pluronic F108. As the degree of sidewall functionalization increased, the SWNT sample became less cytotoxic. Further, sidewall functionalized SWNT samples are substantially less cytotoxic than surfactant stabilized SWNTs. Even though cell death did not exceed 50% for cells dosed with sidewall functionalized SWNTs, optical and at. force microscopies show direct contact between cellular membranes and water-dispersible SWNTs; i.e. the SWNTs in aq. suspension ppt. out and selectively deposit on the membrane.
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335Smith, C. J.; Shaw, B. J.; Handy, R. D. Aquat. Toxicol. 2007, 82, 94335https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjs1Kqsr4%253D&md5=d04d16f2a66b7b7e73c79a0f039834bfToxicity of single walled carbon nanotubes to rainbow trout, (Oncorhynchus mykiss): Respiratory toxicity, organ pathologies, and other physiological effectsSmith, Catherine J.; Shaw, Benjamin J.; Handy, Richard D.Aquatic Toxicology (2007), 82 (2), 94-109CODEN: AQTODG; ISSN:0166-445X. (Elsevier B.V.)Mammalian studies have raised concerns about the toxicity of carbon nanotubes (CNTs), but there is very limited data on ecotoxicity to aquatic life. The authors describe the 1st detailed report on the toxicity of single walled carbon nanotubes (SWCNT) to rainbow trout, using a body systems approach. Stock solns. of dispersed SWCNT were prepd. using a combination of solvent (sodium dodecyl sulfate, SDS) and sonication. A semi-static test system was used to expose rainbow trout to either a freshwater control, solvent control, 0.1, 0.25 or 0.5 mg l-1 SWCNT for up to 10 days. SWCNT exposure caused a dose-dependent rise in ventilation rate, gill pathologies (edema, altered mucocytes, hyperplasia), and mucus secretion with SWCNT pptn. on the gill mucus. No major haematol. or blood disturbances were obsd. in terms of red and white blood cell counts, haematocrits, whole blood Hb, and plasma Na+ or K+. Tissue metal levels (Na+, K+, Ca2+, Cu, Zn and Co) were generally unaffected. However some dose-dependent changes in brain and gill Zn or Cu were obsd. (but not tissue Ca2+), that were also partly attributed to the solvent. SWCNT exposure caused statistically significant increases in Na+K+-ATPase activity in the gills and intestine, but not in the brain. Thiobarbituric acid reactive substances (TBARS) showed dose-dependent and statistically significant decreases esp. in the gill, brain and liver during SWCNT exposure compared to controls. SWCNT exposure caused statistically significant increases in the total glutathione levels in the gills (28%) and livers (18%), compared to the solvent control. Total glutathione in the brain and intestine remained stable in all treatments. Pathologies in the brain included possible aneurisms or swellings on the ventral surface of the cerebellum. Liver cells exposed to SWCNT showed condensed nuclear bodies (apoptotic bodies) and cells in abnormal nuclear division. Overt fatty change or wide spread lipidosis was absent in the liver. Fish ingested water contg. SWCNT during exposure (presumably stress-induced drinking) which resulted in pptd. SWCNT in the gut lumen and intestinal pathol. Aggressive behavior and fin nipping caused some mortalities at the end of the expt., which may be assocd. with the gill irritation and brain injury, although the solvent may also partly contributed to aggression. Overall the authors conclude that SWCNTs are a respiratory toxicant in trout, the fish are able to manage oxidative stress and osmoregulatory disturbances, but other cellular pathologies raise concerns about cell cycle defects, neurotoxicity, and as yet unidentified blood borne factors that possibly mediate systemic pathologies.
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336Prato, M.; Kostarelos, K.; Bianco, A. Acc. Chem. Res. 2008, 41, 60There is no corresponding record for this reference.
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337Shvedova, A. A.; Kisin, E. R.; Murray, A. R.; Gorelik, O.; Arepalli, S.; Castranova, V.; Young, S. H.; Gao, F.; Tyurina, Y. Y.; Oury, T. D.; Kagan, V. E. Toxicol. Appl. Pharmacol. 2007, 221, 339337https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmtlSmtb8%253D&md5=754ced2f0d0289d41ba3b6a10a3caf96Vitamin E deficiency enhances pulmonary inflammatory response and oxidative stress induced by single-walled carbon nanotubes in C57BL/6 miceShvedova, Anna A.; Kisin, Elena R.; Murray, Ashley R.; Gorelik, Olga; Arepalli, Sivaram; Castranova, Vincent; Young, Shih-Hong; Gao, Fei; Tyurina, Yulia Y.; Oury, Tim D.; Kagan, Valerian E.Toxicology and Applied Pharmacology (2007), 221 (3), 339-348CODEN: TXAPA9; ISSN:0041-008X. (Elsevier)Exposure of mice to single-walled carbon nanotubes (SWCNTs) induces an unusually robust pulmonary inflammatory response with an early onset of fibrosis, which is accompanied by oxidative stress and antioxidant depletion. The role of specific components of the antioxidant protective system, specifically vitamin E, the major lipid-sol. antioxidant, in the SWCNT-induced reactions has not been characterized. We used C57BL/6 mice, maintained on vitamin E-sufficient or vitamin E-deficient diets, to explore and compare the pulmonary inflammatory reactions to aspired SWCNTs. The vitamin E-deficient diet caused a 90-fold depletion of α-tocopherol in the lung tissue and resulted in a significant decline of other antioxidants (GSH, ascorbate) as well as accumulation of lipid peroxidn. products. A greater decrease of pulmonary antioxidants was detected in SWCNT-treated vitamin E-deficient mice as compared to controls. Lowered levels of antioxidants in vitamin E-deficient mice were assocd. with a higher sensitivity to SWCNT-induced acute inflammation (total no. of inflammatory cells, no. of polymorphonuclear leukocytes, released LDH, total protein content and levels of pro-inflammatory cytokines, TNF-α and IL-6) and enhanced profibrotic responses (elevation of TGF-β and collagen deposition). Exposure to SWCNTs markedly shifted the ratio of cleaved to full-length extracellular superoxide dismutase (EC-SOD). Given that pulmonary levels of vitamin E can be manipulated through diet, its effects on SWCNT-induced inflammation may be of practical importance in optimizing protective strategies.
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338Han, S. G.; Andrews, R.; Gairola, C. G. Inhal. Toxicol. 2010, 22, 340338https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhvFegu78%253D&md5=d17b7b2f4d581da6dff96796f4e6cd5dAcute pulmonary response of mice to multi-wall carbon nanotubesHan, Sung Gu; Andrews, Rodney; Gairola, C. GaryInhalation Toxicology (2010), 22 (4), 340-347CODEN: INHTE5; ISSN:0895-8378. (Informa Healthcare)Widespread use of carbon nanotubes is predicted for future and concerns have been raised about their potential health effects. The present study detd. the pulmonary response of mice to multi-wall carbon nanotubes (MWCNTs). The MWCNT suspension in sterile phosphate-buffered saline (PBS) was introduced into mice lungs by oropharyngeal aspiration. Female C57Bl mice were treated with either 20 or 40 μg of MWCNTs in 40 μl PBS and control groups received equal vol. of PBS. From each group, half of the mice were euthanized at day 1 and the remaining half at day 7 post treatment. Bronchoalveolar lavage (BAL) fluids, serum, and lung tissue samples were analyzed for inflammatory and oxidative stress markers. The results showed significant cellular influx by a single exposure to MWCNTs. Yields of total cells and the no. of polymorphonuclear leukocytes in BAL cells were significantly elevated in MWCNT-treated mice post-treatment days 1 and 7. Anal. of cell-free BAL fluids showed significantly increased levels of total proteins, lactate dehydrogenase, tumor necrosis factor-α, interleukin-1β, mucin, and surfactant protein-D (SP-D) in MWCNT-treated mice at day 1 post treatment. However, these biomarkers returned to basal levels by day 7 post exposure except mucin and SP-D. An increase in the urinary level of 8-hydroxy-2'-deoxyguanosine in mice treated with MWCNT suggested systemic oxidative stress. Western anal. of lung tissue showed decreased levels of extracellular superoxide dismutase (SOD) protein in MWCNT-treated mice but copper/zinc and manganese SOD remained unchanged. It is concluded that a single treatment of MWCNT is capable of inducing cytotoxic and inflammatory response in the lungs of mice.
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339Mitchell, L. A.; Gao, J.; Wal, R. V.; Gigliotti, A.; Burchiel, S. W.; McDonald, J. D. Toxicol. Sci. 2007, 100, 203339https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFKlsLrJ&md5=a9503e582d6af05864f16d652a4aade7Pulmonary and systemic immune response to inhaled multiwalled carbon nanotubesMitchell, Leah A.; Gao, Jun; Vander Wal, Randy; Gigliotti, Andrew; Burchiel, Scott W.; McDonald, Jacob D.Toxicological Sciences (2007), 100 (1), 203-214CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)Inhalation of multiwalled carbon nanotubes (MWCNTs) at particle concns. ranging from 0.3-5 mg/m3 did not result in significant lung inflammation or tissue damage, but caused systemic immune function alterations. C57BL/6 adult (10- to 12-wk) male mice were exposed by whole-body inhalation to control air or 0.3, 1, or 5 mg/m3 respirable aggregates of MWCNTs for 7 or 14 days (6 h/day). Histopathol. of lungs from exposed animals showed alveolar macrophages contg. black particles; however, there was no inflammation or tissue damage obsd. Bronchial alveolar lavage fluid also demonstrated particle-laden macrophages; however, white blood cell counts were not increased compared to controls. MWCNT exposures to 0.3 mg/m3 and higher particle concns. caused nonmonotonic systemic immunosuppression after 14 days but not after 7 days. Immunosuppression was characterized by reduced T-cell-dependent antibody response to sheep erythrocytes as well as T-cell proliferative ability in presence of mitogen, Con A. Assessment of nonspecific natural killer (NK) cell activity showed that animals exposed to 1 mg/m3 had decreased NK cell function. Gene expression anal. of selected cytokines and an indicator of oxidative stress were assessed in lung tissue and spleen. No changes in gene expression were obsd. in lung; however, interleukin-10 (IL-10) and NAD(P)H oxidoreductase 1 mRNA levels were increased in spleen.
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340Pulskamp, K.; Diabate, S.; Krug, H. F. Toxicol. Lett. 2007, 168, 58340https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtlaltrjI&md5=a56335dc6377fd5e7000806706527a02Carbon nanotubes show no sign of acute toxicity but induce intracellular reactive oxygen species in dependence on contaminantsPulskamp, Karin; Diabate, Silvia; Krug, Harald F.Toxicology Letters (2007), 168 (1), 58-74CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)Today nanosciences are experiencing massive investment worldwide although research on toxicol. aspects of these nano-sized particles has just begun and to date, no clear guidelines exist to quantify the effects. In the present study, we focus on C nanotubes (CNTs), which represent one of the most widely investigated carbon nanoparticles. The present data indicate that CNTs are able to cross the cell membrane of rat macrophages (NR8383) and, therefore, might have an influence on cell physiol. and function. NR8383 and human A549 lung cells were incubated with com. single-walled (NT-1) and multi-walled (NT-2, NT-3) CNTs, carbon black and quartz as ref. particles as well as an acid-treated single-walled CNT prepn. (SWCNT a.t.) with reduced metal catalyst content. We did not observe any acute toxicity on cell viability (WST-1, PI-staining) upon incubation with all CNT products. None of the CNTs induced the inflammatory mediators NO, TNF-α and IL-8. A rising tendency of TNF-α release from LPS-primed cells due to CNT treatment could be obsd. We detected however, a dose- and time-dependent increase of intracellular reactive oxygen species and a decrease of the mitochondrial membrane potential with the com. CNTs in both cell types after particle treatment whereas incubation with the purified CNTs (SWCNT a.t.) had no effect. This leads us to the conclusion that metal traces assocd. with the com. nanotubes are responsible for the biol. effects.
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341Ji, Z.; Zhang, D.; Li, L.; Shen, X.; Deng, X.; Dong, L.; Wu, M.; Liu, Y. Nanotechnology 2009, 20, 445101There is no corresponding record for this reference.
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342Allen, B. L.; Kichambare, P. D.; Gou, P.; Vlasova, I. I.; Kapralov, A. A.; Konduru, N.; Kagan, V. E.; Star, A. Nano Lett. 2008, 8, 3899There is no corresponding record for this reference.
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343Allen, B. L.; Kotchey, G. P.; Chen, Y.; Yanamala, N. V.; Klein-Seetharaman, J.; Kagan, V. E.; Star, A. J. Am. Chem. Soc. 2009, 131, 17194There is no corresponding record for this reference.
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344Liu, X.; Hurt, R. H.; Kane, A. B. Carbon 2010, 48, 1961There is no corresponding record for this reference.
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345Bianco, A.; Kostarelos, K.; Prato, M. Chem. Commun. (Cambridge, U.K.) 2011, 47, 10182345https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFWqtbnO&md5=00655ac3f83f6ffdb667350fde1e6148Making carbon nanotubes biocompatible and biodegradableBianco, Alberto; Kostarelos, Kostas; Prato, MaurizioChemical Communications (Cambridge, United Kingdom) (2011), 47 (37), 10182-10188CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. Carbon nanotubes are promising nanomaterials with great potential in the field of nanomedicine for both therapeutic and diagnostic applications. Different approaches have been developed to render this material biocompatible and to modulate any ensuing toxic effects. In the context of medical use, although chem. functionalized carbon nanotubes display reduced toxicity, they are still considered with scepticism due to their perceived non-biodegradability. Recently, it has been demonstrated that functionalized carbon nanotubes can be degraded by oxidative enzymes. This finding is offering a new perspective for the development of carbon nanotubes in medicine. This article highlights recent advances that can act as paradigm-shifts towards the design of biocompatible and biodegradable functionalized carbon nanotubes and allow their translation into the clinic.
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346Zhao, Y.; Allen, B. L.; Star, A. J. Phys. Chem. A 2011, 115, 9536There is no corresponding record for this reference.
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347Kotchey, G. P.; Hasan, S. A.; Kapralov, A. A.; Ha, S. H.; Kim, K.; Shvedova, A. A.; Kagan, V. E.; Star, A. Acc. Chem. Res. 2012, 45, 1770347https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVyns77I&md5=6c8c62fc0d73ec30db3eb396be97aac5A Natural Vanishing Act: The Enzyme-Catalyzed Degradation of Carbon NanomaterialsKotchey, Gregg P.; Hasan, Saad A.; Kapralov, Alexander A.; Ha, Seung Han; Kim, Kang; Shvedova, Anna A.; Kagan, Valerian E.; Star, AlexanderAccounts of Chemical Research (2012), 45 (10), 1770-1781CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Over the past three decades, revolutionary research in nanotechnol. by the scientific, medical, and engineering communities has yielded a treasure trove of discoveries with diverse applications that promise to benefit humanity. With their unique electronic and mech. properties, carbon nanomaterials (CNMs) represent a prime example of the promise of nanotechnol. with applications in areas that include electronics, fuel cells, composites, and nanomedicine. Because of toxicol. issues assocd. with CNMs, however, their full com. potential may not be achieved. The ex vitro, in vitro, and in vivo data presented in this Account provide fundamental insights into the biopersistence of CNMs, such as carbon nanotubes and graphene, and their oxidn./biodegrdn. processes as catalyzed by peroxidase enzymes. We also communicate our current understanding of the mechanism for the enzymic oxidn. and biodegrdn. Finally, we outline potential future directions that could enhance our mechanistic understanding of the CNM oxidn. and biodegrdn. and could yield benefits in terms of human health and environmental safety. The conclusions presented in this Account may catalyze a rational rethinking of CNM incorporation in diverse applications. For example, armed with an understanding of how and why CNMs undergo enzyme-catalyzed oxidn. and biodegrdn., researchers can tailor the structure of CNMs to either promote or inhibit these processes. In nanomedical applications such as drug delivery, the incorporation of carboxylate functional groups could facilitate biodegrdn. of the nanomaterial after delivery of the cargo. On the other hand, in the construction of aircraft, a CNM composite should be stable to oxidizing conditions in the environment. Therefore, pristine, inert CNMs would be ideal for this application. Finally, the incorporation of CNMs with defect sites in consumer goods could provide a facile mechanism that promotes the degrdn. of these materials once these products reach landfills.
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348Seabra, A. B.; Paula, A. J.; Duran, N. Biotechnol. Prog. 2013, 29, 1348https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitlCqsro%253D&md5=2ab6de4e4bd59196dbb3d169cad713b9Redox-enzymes, cells and micro-organisms acting on carbon nanostructures transformation: a mini-reviewSeabra, Amedea B.; Paula, Amauri J.; Duran, NelsonBiotechnology Progress (2013), 29 (1), 1-10CODEN: BIPRET; ISSN:1520-6033. (Wiley-Blackwell)A review. Carbon nanotubes, graphene and fullerenes are actual nanomaterials with many applications in different industrial areas, with increasing potentialities in the field of nanomedicine. Recently, different proactive approaches on toxicol. and safety management have become the focus of intense interest once the industrial prodn. of these materials had a significant growth in the last years, even though their short- and long-term behaviors are not yet fully understood. The most important concerns involving these carbon-based nanomaterials are their stability and potential effects of their life cycles on animals, humans, and environment. In this context, this mini review discuss the biodegradability of these materials, particularly through redox-enzymes, microorganisms and cells, to contribute toward the design of biocompatible and biodegradable functionalized carbon nanostructures, to use these materials safely and with min. impact on the environment.
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349Oberdörster, G.; Oberdörster, E.; Oberdörster, J. Environ. Health Perspect. 2005, 113, 823There is no corresponding record for this reference.
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350Zhang, L.; Alizadeh, D.; Badie, B. Methods Mol. Biol. 2010, 625, 55350https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXoslyqtL4%253D&md5=c00ba55dbeb2b231da0e64b2a98298bcCarbon nanotube uptake and toxicity in the brainZhang, Leying; Alizadeh, Darya; Badie, BehnamMethods in Molecular Biology (Totowa, NJ, United States) (2010), 625 (Carbon Nanotubes), 55-65CODEN: MMBIED; ISSN:1064-3745. (Humana Press Inc.)The development of novel drug delivery systems is essential for the improvement of therapeutics for most human diseases. Currently used cellular delivery systems, such as viral vectors, liposomes, cationic lipids, and polymers, may have limited clin. efficacy because of safety issues, low gene transfer efficiency, or cytotoxicity. Carbon nanotubes (CNTs) have garnered much interest as possible biol. vectors after the recent discovery of their capacity to penetrate cells. Inspite of the prominence of CNT studies in the nanotechnol. literature, exploration of their application to central nervous system (CNS) therapeutics is at a very early stage. Before CNTs are used for treatment of brain and spinal cord disorders, however, several issues such as their CNS penetration and toxicity need to be addressed. Here, we discuss methods by which CNT uptake and toxicity can be assessed in animal models.
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351Nygaard, U. C.; Hansen, J. S.; Samuelsen, M.; Alberg, T.; Marioara, C. D.; Løvik, M. Toxicol. Sci. 2009, 109, 113351https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlsVGiurg%253D&md5=e2e7ec7f7f9d1c4464d78afbfe9db729Single-Walled and Multi-Walled Carbon Nanotubes Promote Allergic Immune Responses in MiceNygaard, Unni C.; Hansen, Jitka S.; Samuelsen, Mari; Alberg, Torunn; Marioara, Calin D.; Lovik, MartinusToxicological Sciences (2009), 109 (1), 113-123CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)The adjuvant effect of particles on allergic immune responses has been shown to increase with decreasing particle size and increasing particle surface area. Like ultrafine particles, carbon nanotubes (CNTs) have nano-sized dimensions and a large relative surface area and might thus increase allergic responses. Therefore, we examd. whether single-walled (sw) and multi-walled (mw) CNTs have the capacity to promote allergic responses in mice, first in an s.c. injection model and thereafter in an intranasal model. Balb/cA mice were exposed to three doses of swCNT, mwCNT, as well as ultrafine carbon black particles (ufCBPs, Printex90) during sensitization with the allergen ovalbumin (OVA). Five days after an OVA booster, OVA-specific IgE, IgG1, and IgG2a antibodies in serum and the nos. of inflammatory cells and cytokine levels in bronchoalveolar lavage fluid (BALF) were detd. Furthermore, ex vivo OVA-induced cytokine release from mediastinal lymph node (MLN) cells was measured. In sep. expts., differential cell counts were detd. in BALF 24 h after a single intranasal exposure to the particles in the absence of allergen. We demonstrate that both swCNT and mwCNT together with OVA strongly increased serum levels of OVA-specific IgE, the no. of eosinophils in BALF, and the secretion of Th2-assocd. cytokines in the MLN. On the other hand, only mwCNT and ufCBP with OVA increased IgG2a levels, neutrophil cell nos., and tumor necrosis factor-alpha and monocyte chemoattractant protein-1 levels in BALF, as well as the acute influx of neutrophils after exposure to the particles alone. This study demonstrates that CNTs promote allergic responses in mice.
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352Inoue, K.; Takano, H.; Koike, E.; Yanagisawa, R.; Sakurai, M.; Tasaka, S.; Ishizaka, A.; Shimada, A. Exp. Biol. Med. (Maywood, NJ, U.S.) 2008, 233, 1583352https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVOjtLnO&md5=bed820cf7ff8e6a35263658b00780880Effects of pulmonary exposure to carbon nanotubes on lung and systemic inflammation with coagulatory disturbance induced by lipopolysaccharide in miceInoue, Ken-ichiro; Takano, Hirohisa; Koike, Eiko; Yanagisawa, Rie; Sakurai, Miho; Tasaka, Sadatomo; Ishizaka, Akitoshi; Shimada, AkinoriExperimental Biology and Medicine (Maywood, NJ, United States) (2008), 233 (12), 1583-1590CODEN: EBMMBE; ISSN:1535-3702. (Society for Experimental Biology and Medicine)Despite intensive research as to the pathogenesis of lipopolysaccharide (LPS)-related inflammation with coagulatory disturbance, their exacerbating factors have not been well explored. This study examd. the effects of pulmonary exposure to two types of nano-sized materials (carbon nanotubes: CNT [single-wall: SWCNT, and multi-wall: MWCNT]) on lung inflammation and consequent systemic inflammation with coagulatory disturbance induced by pulmonary exposure to LPS in mice and their cellular mechanisms in vitro. ICR male mice were divided into 6 exptl. groups that intratracheally received the vehicle, two types of CNT (4 mg/kg), LPS (33 μg/kg), or LPS plus either type of CNT. Twenty-four hours after treatment, both types of CNT alone induced lung inflammation with enhanced lung expression of proinflammatory cytokines, but did not synergistically exacerbate lung inflammation elicited by LPS. SWCNT significantly induced/enhanced pulmonary permeability and hyperfibrinogenemia and reduced activated protein C in the absence or presence of LPS, whereas MWCNT did moderately. Both CNT moderately, but not significantly, elevated circulatory levels of proinflammatory cytokines and chemokines. In the presence of LPS, CNT tended to elevate the levels of the mediators with an overall trend, which was more prominent with SWCNT than with MWCNT. In vitro study showed that both CNT amplified LPS-induced cytokine prodn. from peripheral blood monocytes. These results suggest that CNT can facilitate systemic inflammation with coagulatory disturbance, at least in part, via the activation of mononuclear cells, which is accompanied by moderate enhancement of acute lung inflammation related to LPS.
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353Ryman-Rasmussen, J. P.; Tewksbury, E. W.; Moss, O. R.; Cesta, M. F.; Wong, B. A.; Bonner, J. C. Am. J. Respir. Cell Mol. Biol. 2009, 40, 349353https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXislalt70%253D&md5=6317d20bcbbd32b8ee91b11500707663Inhaled multiwalled carbon nanotubes potentiate airway fibrosis in murine allergic asthmaRyman-Rasmussen, Jessica P.; Tewksbury, Earl W.; Moss, Owen R.; Cesta, Mark F.; Wong, Brian A.; Bonner, James C.American Journal of Respiratory Cell and Molecular Biology (2009), 40 (3), 349-358CODEN: AJRBEL; ISSN:1044-1549. (American Thoracic Society)C nanotubes are gaining increasing attention due to possible health risks from occupational or environmental exposures. This study tested the hypothesis that inhaled multiwalled carbon nanotubes (MWCNT) would increase airway fibrosis in mice with allergic asthma. Normal and ovalbumin-sensitized mice were exposed to a MWCNT aerosol (100 mg/m3) or saline aerosol for 6 h. Lung injury, inflammation, and fibrosis were examd. by histopathol., clin. chem., ELISA, or RT-PCR for cytokines/chemokines, growth factors, and collagen at 1 and 14 days after inhalation. Inhaled MWCNT were distributed throughout the lung and found in macrophages by light microscopy, but were also evident in epithelial cells by electron microscopy. Quant. morphometry showed significant airway fibrosis at 14 days in mice that received a combination of ovalbumin and MWCNT, but not in mice that received ovalbumin or MWCNT only. Ovalbumin-sensitized mice that did not inhale MWCNT had elevated levels IL-13 and transforming growth factor (TGF)-β1 in lung lavage fluid, but not platelet-derived growth factor (PDGF)-AA. In contrast, unsensitized mice that inhaled MWCNT had elevated PDGF-AA, but not increased levels of TGF-β1 and IL-13. This suggested that airway fibrosis resulting from combined ovalbumin sensitization and MWCNT inhalation requires PDGF, a potent fibroblast mitogen, and TGF-β1, which stimulates collagen prodn. Combined ovalbumin sensitization and MWCNT inhalation also synergistically increased IL-5 mRNA levels, which could further contribute to airway fibrosis. These data indicate that inhaled MWCNT require pre-existing inflammation to cause airway fibrosis. These findings suggest that individuals with pre-existing allergic inflammation may be susceptible to airway fibrosis from inhaled MWCNT.
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354Bihari, P.; Holzer, M.; Praetner, M.; Fent, J.; Lerchenberger, M.; Reichel, C. A.; Rehberg, M.; Lakatos, S.; Krombach, F. Toxicology 2010, 269, 148There is no corresponding record for this reference.
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355Salvati, A.; Pitek, A. S.; Monopoli, M. P.; Prapainop, K.; Bombelli, F. B.; Hristov, D. R.; Kelly, P. M.; Åberg, C.; Mahon, E.; Dawson, K. A. Nat. Nanotechnol. 2013, 8, 137355https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFSjtLg%253D&md5=cf3fbdf4d460fc8f016bbc2337719d96Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surfaceSalvati, Anna; Pitek, Andrzej S.; Monopoli, Marco P.; Prapainop, Kanlaya; Bombelli, Francesca Baldelli; Hristov, Delyan R.; Kelly, Philip M.; Aberg, Christoffer; Mahon, Eugene; Dawson, Kenneth A.Nature Nanotechnology (2013), 8 (2), 137-143CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Nanoparticles have been proposed as carriers for drugs, genes and therapies to treat various diseases. Many strategies have been developed to target nanomaterials to specific or over-expressed receptors in diseased cells, and these typically involve functionalizing the surface of nanoparticles with proteins, antibodies or other biomols. Here, we show that the targeting ability of such functionalized nanoparticles may disappear when they are placed in a biol. environment. Using transferrin-conjugated nanoparticles, we found that proteins in the media can shield transferrin from binding to both its targeted receptors on cells and sol. transferrin receptors. Although nanoparticles continue to enter cells, the targeting specificity of transferrin is lost. Our results suggest that when nanoparticles are placed in a complex biol. environment, interaction with other proteins in the medium and the formation of a protein corona can 'screen' the targeting mols. on the surface of nanoparticles and cause loss of specificity in targeting.
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356Mirshafiee, V.; Mahmoudi, M.; Lou, K.; Cheng, J.; Kraft, M. L. Chem. Commun. (Cambridge, U.K.) 2013, 49, 2557356https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtlyjt78%253D&md5=087a2a958fb63218af984eac9f6ac415Protein corona significantly reduces active targeting yieldMirshafiee, Vahid; Mahmoudi, Morteza; Lou, Kaiyan; Cheng, Jianjun; Kraft, Mary L.Chemical Communications (Cambridge, United Kingdom) (2013), 49 (25), 2557-2559CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)When nanoparticles (NPs) are exposed to the biol. environment, their surfaces become covered with proteins and biomols. (e.g. lipids). Here, the authors report that this protein coating, or corona, reduces the targeting capability of surface engineered NPs by screening the active sites of the targeting ligands.
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357Guo, L.; Von Dem Bussche, A.; Buechner, M.; Yan, A.; Kane, A. B.; Hurt, R. H. Small 2008, 4, 721There is no corresponding record for this reference.
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358Raven, K. Nat. Med. 2012, 18, 998358https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvFGgtbo%253D&md5=c209c6caa2fc8e1c1df98a9512c5c294Rodent models of sepsis found shockingly lackingRaven, KathleenNature Medicine (New York, NY, United States) (2012), 18 (7), 998CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)Some in the field are developing new ways to fine-tune the induction system so that it better mimics the poor health that many sick people are in when they develop sepsis. For example, Robert Star and his colleagues at the US National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, recently stimulated chronic kidney disease in mice before they proceeded with traditional CLP to provoke sepsis. In a study published last year, they showed that the kidney disease worsened the sepsis severity and sepsis-induced organ damage seen in the mice, as evidenced by increased blood levels of HMGB1, vascular endothelial growth factor and other inflammatory cytokines (Kidney Int.80, 1198-1211, 2011). "Animal models have to mimic the epidemiol. causes [of sepsis]," Star says. "You have to replicate whatever you have found in humans." In the end, though, most experts agree that tweaks like these are just minor improvements and that the field really needs to radically redesign animal models of sepsis from the ground up. "Clearly, current animal models seem to be incapable of predicting results in human trials of new agents," says Mitchell Fink, a surgeon at the University of California-Los Angeles. Alas, until they do, few drug developers will be willing to move forward with a drug like Tracey's antibody to HMGB1, despite the promising preclin. results.
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359Wekerle, H.; Flugel, A.; Fugger, L.; Schett, G.; Serreze, D. Nat. Med. 2012, 18, 66359https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlsF2mug%253D%253D&md5=bf9dde20197e5fda15ead1df3898015eAutoimmunity's next top modelsWekerle, Hartmut; Fluegel, Alexander; Fugger, Lars; Schett, Georg; Serreze, DavidNature Medicine (New York, NY, United States) (2012), 18 (1), 66-70CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)A review. Animal models are indispensable for studying disease pathogenesis and discovering new treatments for human organ-specific autoimmune diseases. However, there is a need of more refined paradigms for these models. Ideally, a small-animal model should represent the clin. features of human disease in their entirety. Disease in the animals should develop spontaneously, should be followed over an extended period of time and should involve the genetic, mol. and cellular elements that contribute to human pathogenesis.
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360Seok, J.; Warren, H. S.; Cuenca, A. G.; Mindrinos, M. N.; Baker, H. V.; Xu, W.; Richards, D. R.; McDonald-Smith, G. P.; Gao, H.; Hennessy, L.; Finnerty, C. C.; López, C. M.; Honari, S.; Moore, E. E.; Minei, J. P.; Cuschieri, J.; Bankey, P. E.; Johnson, J. L.; Sperry, J.; Nathens, A. B.; Billiar, T. R.; West, M. A.; Jeschke, M. G.; Klein, M. B.; Gamelli, R. L.; Gibran, N. S.; Brownstein, B. H.; Miller-Graziano, C.; Calvano, S. E.; Mason, P. H.; Cobb, J. P.; Rahme, L. G.; Lowry, S. F.; Maier, R. V.; Moldawer, L. L.; Herndon, D. N.; Davis, R. W.; Xiao, W.; Tompkins, R. G. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 3507There is no corresponding record for this reference.
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361Muller, J.; Huaux, F.; Moreau, N.; Misson, P.; Heilier, J. F.; Delos, M.; Arras, M.; Fonseca, A.; Nagy, J. B.; Lison, D. Toxicol. Appl. Pharmacol. 2005, 207, 221361https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXpslyjtrc%253D&md5=88526aefd88c6084558b3031e71a31baRespiratory toxicity of multi-wall carbon nanotubesMuller, Julie; Huaux, Francois; Moreau, Nicolas; Misson, Pierre; Heilier, Jean-Francois; Delos, Monique; Arras, Mohammed; Fonseca, Antonio; Nagy, Janos B.; Lison, DominiqueToxicology and Applied Pharmacology (2005), 207 (3), 221-231CODEN: TXAPA9; ISSN:0041-008X. (Elsevier)Carbon nanotubes focus the attention of many scientists because of their huge potential of industrial applications, but there is a paucity of information on the toxicol. properties of this material. The aim of this exptl. study was to characterize the biol. reactivity of purified multi-wall carbon nanotubes in the rat lung and in vitro. Multi-wall carbon nanotubes (CNT) or ground CNT were administered intratracheally (0.5, 2 or 5 mg) to Sprague-Dawley rats and we estd. lung persistence, inflammation and fibrosis biochem. and histol. CNT and ground CNT were still present in the lung after 60 days (80% and 40% of the lowest dose) and both induced inflammatory and fibrotic reactions. At 2 mo, pulmonary lesions induced by CNT were characterized by the formation of collagen-rich granulomas protruding in the bronchial lumen, in assocn. with alveolitis in the surrounding tissues. These lesions were caused by the accumulation of large CNT agglomerates in the airways. Ground CNT were better dispersed in the lung parenchyma and also induced inflammatory and fibrotic responses. Both CNT and ground CNT stimulated the prodn. of TNF-α in the lung of treated animals. In vitro, ground CNT induced the overprodn. of TNF-α by macrophages. These results suggest that carbon nanotubes are potentially toxic to humans and that strict industrial hygiene measures should to be taken to limit exposure during their manipulation.
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362Fenoglio, I.; Greco, G.; Tomatis, M.; Muller, J.; Raymundo-Piñero, E.; Béguin, F.; Fonseca, A.; Nagy, J. B.; Lison, D.; Fubini, B. Chem. Res. Toxicol. 2008, 21, 1690There is no corresponding record for this reference.
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363Li, N.; Xia, T.; Nel, A. E. Free Radical Biol. Med. 2008, 44, 1689363https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXks1GmsbY%253D&md5=21f6a0d574cae45a88567530d5380464The role of oxidative stress in ambient particulate matter-induced lung diseases and its implications in the toxicity of engineered nanoparticlesLi, Ning; Xia, Tian; Nel, Andre E.Free Radical Biology & Medicine (2008), 44 (9), 1689-1699CODEN: FRBMEH; ISSN:0891-5849. (Elsevier)A review. Ambient particulate matter (PM) is an environmental factor that has been assocd. with increased respiratory morbidity and mortality. The major effect of ambient PM on the pulmonary system is the exacerbation of inflammation, esp. in susceptible people. One of the mechanisms by which ambient PM exerts its proinflammatory effects is the generation of oxidative stress by its chem. compds. and metals. Cellular responses to PM-induced oxidative stress include activation of antioxidant defense, inflammation, and toxicity. The proinflammatory effect of PM in the lung is characterized by increased cytokine/chemokine prodn. and adhesion mol. expression. Moreover, there is evidence that ambient PM can act as an adjuvant for allergic sensitization, which raises the possibility that long-term PM exposure may lead to increased prevalence of asthma. In addn. to ambient PM, rapid expansion of nanotechnol. has introduced the potential that engineered nanoparticles (NP) may also become airborne and may contribute to pulmonary diseases by novel mechanisms that could include oxidant injury. Currently, little is known about the potential adverse health effects of these particles. In this communication, the mechanisms by which particulate pollutants, including ambient PM and engineered NP, exert their adverse effects through the generation of oxidative stress and the impacts of oxidant injury in the respiratory tract will be reviewed. The importance of cellular antioxidant and detoxification pathways in protecting against particle-induced lung damage will also be discussed.
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364Mercer, R. R.; Scabilloni, J.; Wang, L.; Kisin, E.; Murray, A. R.; Schwegler-Berry, D.; Shvedova, A. A.; Castranova, V. Am. J. Physiol.: Lung Cell. Mol. Physiol. 2008, 294, L87There is no corresponding record for this reference.
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365Shvedova, A. A.; Kisin, E.; Murray, A. R.; Johnson, V. J.; Gorelik, O.; Arepalli, S.; Hubbs, A. F.; Mercer, R. R.; Keohavong, P.; Sussman, N.; Jin, J.; Yin, J.; Stone, S.; Chen, B. T.; Deye, G.; Maynard, A.; Castranova, V.; Baron, P. A.; Kagan, V. E. Am. J. Physiol.: Lung Cell. Mol. Physiol. 2008, 295, L552There is no corresponding record for this reference.
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366Foucaud, L.; Wilson, M. R.; Brown, D. M.; Stone, V. Toxicol. Lett. 2007, 174, 1366https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1anurnK&md5=50ebf2951c83f598d6c3de8496147bb5Measurement of reactive species production by nanoparticles prepared in biologically relevant mediaFoucaud, L.; Wilson, M. R.; Brown, D. M.; Stone, V.Toxicology Letters (2007), 174 (1-3), 1-9CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)Exposure to nanoparticles may pose a risk to health and this hypothesis is currently being investigated by toxicologists. Although the mechanism of nanoparticle toxicity has been shown to be mediated, in part, by oxidative stress, the precise mechanism and mols. involved are still unknown. In light of this, the evaluation of the oxidative potential of nanoparticles is an important consideration in measuring their toxicity. The aim of this study was to examine the use of a fluorogenic probe, 2',7'-dichlorofluorescin (DCFH), in a cell-free assay system and to assess the relationship between the results obtained with this method and with the reactive species formation obsd. in cells. In order to obtain a well-dispersed nanoparticle suspension, bovine serum albumin (BSA) and dipalmitoyl phosphatidyl choline (DPPC) addn. in suspension medium was investigated. Both 1% BSA and 0.025% DPPC added to the medium significantly improved the stability of the nanoparticle suspension, decreasing the extent of particle agglomeration and settling over time. In a cell-free system, reactive oxygen species (ROS) prodn. by 14 nm carbon black particles (CB) suspended in DPPC was higher than that measured with the other suspensions (saline or 1% BSA). A greater ROS prodn. was obsd. in MonoMac 6 cells (MM6) following treatment with 14 nm CB suspended in medium contg. BSA and/or DPPC compared to medium alone. In conclusion, 1% BSA and 0.025% DPPC soln. was the most efficient for the prepn. of a nanoparticle suspension and to measure their oxidative potential.
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367Bihari, P.; Vippola, M.; Schultes, S.; Praetner, M.; Khandoga, A. G.; Reichel, C. A.; Coester, C.; Tuomi, T.; Rehberg, M.; Krombach, F. Part. Fibre Toxicol. 2008, 5, 14367https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cjltFWktQ%253D%253D&md5=cc2db2c23a9b97a82794d0f4adf31234Optimized dispersion of nanoparticles for biological in vitro and in vivo studiesBihari Peter; Vippola Minnamari; Schultes Stephan; Praetner Marc; Khandoga Alexander G; Reichel Christoph A; Coester Conrad; Tuomi Timo; Rehberg Markus; Krombach FritzParticle and fibre toxicology (2008), 5 (), 14 ISSN:.BACKGROUND: The aim of this study was to establish and validate a practical method to disperse nanoparticles in physiological solutions for biological in vitro and in vivo studies. RESULTS: TiO2 (rutile) dispersions were prepared in distilled water, PBS, or RPMI 1640 cell culture medium. Different ultrasound energies, various dispersion stabilizers (human, bovine, and mouse serum albumin, Tween 80, and mouse serum), various concentrations of stabilizers, and different sequences of preparation steps were applied. The size distribution of dispersed nanoparticles was analyzed by dynamic light scattering and zeta potential was measured using phase analysis light scattering. Nanoparticle size was also verified by transmission electron microscopy. A specific ultrasound energy of 4.2 x 105 kJ/m3 was sufficient to disaggregate TiO2 (rutile) nanoparticles, whereas higher energy input did not further improve size reduction. The optimal sequence was first to sonicate the nanoparticles in water, then to add dispersion stabilizers, and finally to add buffered salt solution to the dispersion. The formation of coarse TiO2 (rutile) agglomerates in PBS or RPMI was prevented by addition of 1.5 mg/ml of human, bovine or mouse serum albumin, or mouse serum. The required concentration of albumin to stabilize the nanoparticle dispersion depended on the concentration of the nanoparticles in the dispersion. TiO2 (rutile) particle dispersions at a concentration lower than 0.2 mg/ml could be stabilized by the addition of 1.5 mg/ml albumin. TiO2 (rutile) particle dispersions prepared by this method were stable for up to at least 1 week. This method was suitable for preparing dispersions without coarse agglomerates (average diameter < 290 nm) from nanosized TiO2 (rutile), ZnO, Ag, SiOx, SWNT, MWNT, and diesel SRM2975 particulate matter. CONCLUSION: The optimized dispersion method presented here appears to be effective and practicable for preparing dispersions of nanoparticles in physiological solutions without creating coarse agglomerates.
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368Cheng, C.; Muller, K. H.; Koziol, K. K.; Skepper, J. N.; Midgley, P. A.; Welland, M. E.; Porter, A. E. Biomaterials 2009, 30, 4152There is no corresponding record for this reference.
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369Hirano, S.; Fujitani, Y.; Furuyama, A.; Kanno, S. Toxicol. Appl. Pharmacol. 2010, 249, 8369https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlSjt7jP&md5=7f5755525b7224562ba1cd8dbf8a10acUptake and cytotoxic effects of multi-walled carbon nanotubes in human bronchial epithelial cellsHirano, Seishiro; Fujitani, Yuji; Furuyama, Akiko; Kanno, SanaeToxicology and Applied Pharmacology (2010), 249 (1), 8-15CODEN: TXAPA9; ISSN:0041-008X. (Elsevier B.V.)Carbon nanotubes (CNT) are cytotoxic to several cell types. However, the mechanism of CNT toxicity has not been fully studied, and dosimetric analyses of CNT in the cell culture system are lacking. Here, we describe a novel, high throughput method to measure cellular uptake of CNT using turbimetry. BEAS-2B, a human bronchial epithelial cell line, was used to investigate cellular uptake, cytotoxicity, and inflammatory effects of multi-walled CNT (MWCNT). The cytotoxicity of MWCNT was higher than that of crocidolite asbestos in BEAS-2B cells. The IC50 of MWCNT was 12 μg/mL, whereas that of asbestos (crocidolite) was 678 μg/mL. Over the course of 5 to 8 h, BEAS-2B cells took up 17-18% of the MWCNT when they were added to the culture medium at a concn. of 10 μg/mL. BEAS-2B cells were exposed to 2, 5, or 10 μg/mL of MWCNT, and total RNA was extd. for cytokine cDNA primer array assays. The culture supernatant was collected for cytokine antibody array assays. Cytokines IL-6 and IL-8 increased in a dose dependent manner at both the mRNA and protein levels. Migration inhibitory factor (MIF) also increased in the culture supernatant in response to MWCNT. A phosphokinase array study using lysates from BEAS-2B cells exposed to MWCNT indicated that phosphorylation of p38, ERK1, and HSP27 increased significantly in response to MWCNT. Results from a reporter gene assays using the NF-κB or AP-1 promoter linked to the luciferase gene in transiently transfected CHO-KI cells revealed that NF-κB was activated following MWCNT exposure, while AP-1 was not changed. Collectively, MWCNT activated NF-κB, enhanced phosphorylation of MAP kinase pathway components, and increased prodn. of proinflammatory cytokines in human bronchial epithelial cells.
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370Holt, B. D.; Dahl, K. N.; Islam, M. F. Small 2011, 22, 2348There is no corresponding record for this reference.
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371Kim, J. S.; Song, K. S.; Lee, J. H.; Yu, I. J. Arch. Toxicol. 2011, 85, 1499371https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXntFKlsbY%253D&md5=1de6c94eed4893a5e5aa972340047d19Evaluation of biocompatible dispersants for carbon nanotube toxicity testsKim, Jin Sik; Song, Kyung Seuk; Lee, Ji Hyun; Yu, Il JeArchives of Toxicology (2011), 85 (12), 1499-1508CODEN: ARTODN; ISSN:0340-5761. (Springer)Dispersion is one of the key obstacles to evaluating the in vitro and in vivo toxicity of carbon nanotubes (CNTs), as the aggregation or agglomeration of CNTs in culture media or vehicles complicates the interpretation of the toxicity test results. Thus, to test the dispersion of CNTs in biocompatible solns., 5 known biocompatible dispersants were selected that are widely used for nanomaterial toxicity evaluation studies. Single-wall nanotubes (SWCNTs) and multi-wall nanotubes (MWCNTs) were both dispersed in these dispersants and their macrodispersion evaluated using a light absorbance method. The dispersion stability of the dispersed SWCNTs and MWCNTs was also evaluated for 16 wk, plus the dispersants were tested for their innate toxicity using trypan blue dye exclusion, lactate dehydrogenase (LDH) leakage, and neutral red assays. All the dispersants were found to be biocompatible in the cytotoxicity tests when compared with a pos. control of 2% Triton X-100. In the dispersion tests, 0.02, 0.1, and 0.5% MWCNTs and SWCNTs were dild. in the resp. dispersants. Distd. water and dimethylsulfoxide (DMSO) both showed a poor macrodispersion of only 1-13% for the various CNT concns. In 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), the 0.02 and 0.1% MWCNTs showed a macrodispersion of 11 and 74%, resp., while the 0.02 and 0.1% SWCNTs showed a macrodispersion of 15 and 16%, resp. In 0.5% bovine serum albumin (BSA), the 0.02, 0.1, and 0.5% MWCNTs showed a very good macrodispersion of 32, 53, and 70%, resp., yet the 0.02% SWCNTs only showed a macrodispersion of 17%. In 1% Tween 80, the 0.02-0.5% SWNCTs exhibited a good macrodispersion of 27-81%, whereas the 0.02-05% MWCNTs only showed a macrodispersion of 13-23%. The dispersion stability of the CNTs during 16 wk was in the following descending order of BSA, Tween 80, DPPC, and DMSO for the MWCNTs and BSA, DPPC, Tween 80, and DMSO for the SWNCTs. Thus, appropriate dispersants are proposed according to the type of CNT, expt. concn., and treatment duration. Also, it is suggested that the dispersibility, dispersion stability, and biocompatibility of the selected dispersant should all be confirmed before a toxicity evaluation.
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372Dutta, D.; Sundaram, S. K.; Teeguarden, J. G.; Riley, B. J.; Fifield, L. S.; Jacobs, J. M.; Addleman, S. R.; Kaysen, G. A.; Moudgil, B. M.; Weber, T. J. Toxicol. Sci. 2007, 100, 303372https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFKlsLvE&md5=e6f80d531350136d566a0dc0acb26376Adsorbed Proteins Influence the Biological Activity and Molecular Targeting of NanomaterialsDutta, Debamitra; Sundaram, Shanmugavelayutham Kamakshi; Teeguarden, Justin Gary; Riley, Brian Joseph; Fifield, Leonard Sheldon; Jacobs, Jon Morrell; Addleman, Shane Raymond; Kaysen, George Alan; Moudgil, Brij Mohan; Weber, Thomas JosephToxicological Sciences (2007), 100 (1), 303-315CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)The possible combination of specific physicochem. properties operating at unique sites of action within cells and tissues has led to considerable uncertainty surrounding nanomaterial toxic potential. We have investigated the importance of proteins adsorbed onto the surface of two distinct classes of nanomaterials (single-walled carbon nanotubes [SWCNTs]; 10-nm amorphous silica) in guiding nanomaterial uptake or toxicity in the RAW 264.7 macrophage-like model. Albumin was identified as the major fetal bovine or human serum/plasma protein adsorbed onto SWCNTs, while a distinct protein adsorption profile was obsd. when plasma from the Nagase analbuminemic rat was used. Damaged or structurally altered albumin is rapidly cleared from systemic circulation by scavenger receptors. We obsd. that SWCNTs inhibited the induction of cyclooxygenase-2 (Cox-2) by lipopolysaccharide (LPS; 1 ng/mL, 6 h) and this anti-inflammatory response was inhibited by fucoidan (scavenger receptor antagonist). Fucoidan also reduced the uptake of fluorescent SWCNTs (Alexa647). Precoating SWCNTs with a nonionic surfactant (Pluronic F127) inhibited albumin adsorption and anti-inflammatory properties. Albumin-coated SWCNTs reduced LPS-mediated Cox-2 induction under serum-free conditions. SWCNTs did not reduce binding of LPSAlexa488 to RAW 264.7 cells. The profile of proteins adsorbed onto amorphous silica particles (50-1000 nm) was qual. different, relative to SWCNTs, and precoating amorphous silica with Pluronic F127 dramatically reduced the adsorption of serum proteins and toxicity. Collectively, these observations suggest an important role for adsorbed proteins in modulating the uptake and toxicity of SWCNTs and nano-sized amorphous silica.
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373Porter, D. W.; Sriram, K.; Wolfarth, M. G.; Jefferson, A. M.; Schwegler-Berry, D.; Andrew, M. E.; Castranova, V. Nanotoxicology 2008, 2, 144There is no corresponding record for this reference.
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374Konduru, N. V.; Tyurina, Y. Y.; Feng, W.; Basova, L. V.; Belikova, N. A.; Bayir, H.; Clark, K.; Rubin, M.; Stolz, D.; Vallhov, H.; Scheynius, A.; Witasp, E.; Fadeel, B.; Kichambare, P. D.; Star, A.; Kisin, E. R.; Murray, A. R.; Shvedova, A. A.; Kagan, V. E. PLoS One 2009, 4, e4398There is no corresponding record for this reference.
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375Worle-Knirsch, J. M.; Pulskamp, K.; Krug, H. F. Nano Lett. 2006, 6, 1261There is no corresponding record for this reference.
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376Casey, A.; Herzog, E.; Davoren, M.; Lyng, F. M.; Byrne, H. J.; Chambers, G. Carbon 2007, 45, 1425There is no corresponding record for this reference.
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377Monteiro-Riviere, N. A.; Inman, A. O.; Zhang, L. W. Toxicol. Appl. Pharmacol. 2009, 234, 222377https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXksVentg%253D%253D&md5=c125eee54344689101cccef2d02445c3Limitations and relative utility of screening assays to assess engineered nanoparticle toxicity in a human cell lineMonteiro-Riviere, N. A.; Inman, A. O.; Zhang, L. W.Toxicology and Applied Pharmacology (2009), 234 (2), 222-235CODEN: TXAPA9; ISSN:0041-008X. (Elsevier B.V.)Single-walled carbon nanotubes (SWCNT), fullerenes (C60), carbon black (CB), nC60, and quantum dots (QD) have been studied in vitro to det. their toxicity in a no. of cell types. Here, the authors report that classical dye-based assays such as MTT and neutral red (NR) that det. cell viability produce invalid results with some NM (nanomaterials) due to NM/dye interactions and/or NM adsorption of the dye/dye products. In this study, human epidermal keratinocytes (HEK) were exposed in vitro to CB, SWCNT, C60, nC60, and QD to assess viability with calcein AM (CAM), Live/Dead (LD), NR, MTT, Celltiter 96 Aq. One (96 AQ), alamar Blue (aB), Celltiter-Blue (CTB), CytoTox One (CTO), and flow cytometry. In addn., trypan blue (TB) was quantitated by light microscopy. Assay linearity (R2 value) was detd. with HEK plated at concns. from 0 to 25,000 cells per well in 96-well plates. HEK were treated with serial dilns. of each NM for 24 h and assessed with each of the viability assays. TB, CAM and LD assays, which depend on direct staining of living and/or dead cells, were difficult to interpret due to phys. interference of the NM with cells. Results of the dye-based assays varied a great deal, depending on the interactions of the dye/dye product with the carbon nanomaterials (CNM). Results show the optimal high throughput assay for use with carbon and noncarbon NM was 96 AQ. This study shows that, unlike small mols., CNM interact with assay markers to cause variable results with classical toxicol. assays and may not be suitable for assessing nanoparticle cytotoxicity. Therefore, more than one assay may be required when detg. nanoparticle toxicity for risk assessment.
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378Shvedova, A. A.; Kisin, E. R.; Mercer, R.; Murray, A. R.; Johnson, V. J.; Potapovich, A. I.; Tyurina, Y. Y.; Gorelik, O.; Arepalli, S.; Schwegler-Berry, D.; Hubbs, A. F.; Antonini, J.; Evans, D. E.; Ku, B. K.; Ramsey, D.; Maynard, A.; Kagan, V. E.; Castranova, V.; Baron, P. Am. J. Physiol.: Lung Cell. Mol. Physiol. 2005, 289, L698378https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1Cnt73I&md5=39bb1660d513632e748b238cf4b478a0Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in miceShvedova, Anna A.; Kisin, Elena R.; Mercer, Robert; Murray, Ashley R.; Johnson, Victor J.; Potapovich, Alla I.; Tyurina, Yulia Y.; Gorelik, Olga; Arepalli, Sevaram; Schwegler-Berry, Diane; Hubbs, Ann F.; Antonini, James; Evans, Douglas E.; Ku, Bon-Ki; Ramsey, Dawn; Maynard, Andrew; Kagan, Valerian E.; Castranova, Vincent; Baron, PaulAmerican Journal of Physiology (2005), 289 (5, Pt. 1), L698-L708CODEN: AJPHAP; ISSN:0002-9513. (American Physiological Society)Single-walled carbon nanotubes (SWCNT) are new materials of emerging technol. importance. As SWCNT are introduced into the life cycle of com. products, their effects on human health and environment should be addressed. We demonstrated that pharyngeal aspiration of SWCNT elicited unusual pulmonary effects in C57BL/6 mice that combined a robust but acute inflammation with early onset yet progressive fibrosis and granulomas. A dose-dependent increase in the protein, LDH, and γ-glutamyl transferase activities in bronchoalveolar lavage were found along with accumulation of 4-hydroxynonenal (oxidative biomarker) and depletion of glutathione in lungs. An early neutrophils accumulation (day 1), followed by lymphocyte (day 3) and macrophage (day 7) influx, was accompanied by early elevation of proinflammatory cytokines (TNF-α, IL-1β; day 1) followed by fibrogenic transforming growth factor (TGF)-β1 (peaked on day 7). A rapid progressive fibrosis found in mice exhibited two distinct morphologies: 1) SWCNT-induced granulomas mainly assocd. with hypertrophied epithelial cells surrounding SWCNT aggregates and 2) diffuse interstitial fibrosis and alveolar wall thickening likely assocd. with dispersed SWCNT. In vitro exposure of murine RAW 264.7 macrophages to SWCNT triggered TGF-β1 prodn. similarly to zymosan but generated less TNF-α and IL-1β. SWCNT did not cause superoxide or NO · prodn., active SWCNT engulfment, or apoptosis in RAW 264.7 macrophages. Functional respiratory deficiencies and decreased bacterial clearance (Listeria monocytogenes) were found in mice treated with SWCNT. Equal doses of ultrafine carbon black particles or fine cryst. silica (SiO2) did not induce granulomas or alveolar wall thickening and caused a significantly weaker pulmonary inflammation and damage.
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379Mukherjee, S.; Ghosh, R. N.; Maxfield, F. R. Physiol. Rev. 1997, 77, 759379https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXltlWlurk%253D&md5=f0619efffa77bb9be8be4f220a52c0b4EndocytosisMukherjee, Sushmita; Ghosh, Richik N.; Maxfield, Frederick R.Physiological Reviews (1997), 77 (3), 759-803CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)A review, with 554 refs. Mammalian cells take up extracellular material by a variety of different mechanisms that are collectively termed endocytosis. Endocytic mechanisms serve many important cellular functions including the uptake of extracellular nutrients, regulation of cell-surface receptor expression, maintenance of cell polarity, and antigen presentation. Endocytic pathways are also utilized by viruses, toxins, and symbiotic microorganisms to gain entry into cells. One of the best-characterized endocytic mechanisms is receptor-mediated endocytosis via clathrin-coated pits. This type of endocytosis constitutes the major emphasis of this review, with a brief discussion of other endocytic mechanisms and their comparison with the receptor-mediated pathway. This review describes and evaluates critically current understanding of the mechanisms of entry of plasma membrane components such as the receptor-ligand complexes and membrane lipids as well as the extracellular fluid into cells. The intracellular sorting and trafficking of these mols. upon internalization are also described. The roles of endocytosis in physiol. and pathol. processes are discussed. These include maintenance of cell polarization, antigen presentation, glucose transport, atherosclerosis, Alzheimer's disease, and the endocytosis of toxins and viruses.
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380Marsh, M.; McMahon, H. T. Science 1999, 285, 215There is no corresponding record for this reference.
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381Cherukuri, P.; Bachilo, S. M.; Litovsky, S. H.; Weisman, R. B. J. Am. Chem. Soc. 2004, 126, 15638381https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpsFKkurc%253D&md5=6d6d1e3174ff0fb2a5a23dd86d843987Near-infrared fluorescence microscopy of single-walled carbon nanotubes in phagocytic cellsCherukuri, Paul; Bachilo, Sergei M.; Litovsky, Silvio H.; Weisman, R. BruceJournal of the American Chemical Society (2004), 126 (48), 15638-15639CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The uptake of pristine single-walled carbon nanotubes into macrophage-like cells has been studied using the nanotubes' intrinsic near-IR fluorescence. Macrophage samples that have been incubated in growth media contg. suspended single-walled nanotubes show characteristic nanotube fluorescence spectra. The fluorescence intensities increase smoothly with incubation time and external nanotube concn. Near-IR fluorescence microscopy at wavelengths above 1,100 nm provides high contrast images indicating localization of nanotubes in numerous intracellular vesicles. Nanotube uptake appears to occur through phagocytosis. Population growth of macrophage cultures is unaffected by exposure to single-walled nanotube concns. of ∼ 4 μg/mL for up to 96 h.
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382Pantarotto, D.; Briand, J. P.; Prato, M.; Bianco, A. Chem. Commun. (Cambridge, U.K.) 2004, 1, 16There is no corresponding record for this reference.
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383VanHandel, M.; Alizadeh, D.; Zhang, L.; Kateb, B.; Bronikowski, M.; Manohara, H.; Badie, B. J. Neuroimmunol. 2009, 208, 3383https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjsV2muro%253D&md5=59fdd75ddd47d8f218d83a7859120de5Selective uptake of multi-walled carbon nanotubes by tumor macrophages in a murine glioma modelVanHandel, Michelle; Alizadeh, Darya; Zhang, Leying; Kateb, Babak; Bronikowski, Michael; Manohara, Harish; Badie, BehnamJournal of Neuroimmunology (2009), 208 (1-2), 3-9CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)C nanotubes (CNTs) are emerging as a new family of nanovectors for drug and gene delivery into biol. systems. To evaluate potential application of this technol. for brain tumor therapy, we studied uptake and toxicity of multi-walled CNTs (MWCNTs) in the GL261 murine intracranial glioma model. Within 24 h of a single intratumoral injection of labeled MWCNTs (5 μg), nearly 10-20% of total cells demonstrated CNT internalization. Most CNT uptake, however, occurred by tumor-assocd. macrophages (MP), which accounted for most (75%) MWCNT-pos. cells. Within 24 h of injection, nearly 30% of tumor MP became MWCNT-pos. Despite a transient increase in inflammatory cell infiltration into both normal and tumor-bearing brains following MWCNT injection, no significant toxicity was noted in mice, and minor changes in tumor cytokine expression were obsd. This study suggests that MWCNTs could potentially be used as a novel and non-toxic vehicle for targeting MP in brain tumors.
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384Shi, X.; von dem Bussche, A.; Hurt, R. H.; Kane, A. B.; Gao, H. Nat. Nanotechnol. 2011, 6, 714384https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtF2isLnM&md5=a327a19aa89eab4a0883ce97b9c7ee3fCell entry of one-dimensional nanomaterials occurs by tip recognition and rotationShi, Xinghua; von dem Bussche, Annette; Hurt, Robert H.; Kane, Agnes B.; Gao, HuajianNature Nanotechnology (2011), 6 (11), 714-719CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Materials with high aspect ratio, such as carbon nanotubes and asbestos fibers, have been shown to cause length-dependent toxicity in certain cells because these long materials prevent complete ingestion and this frustrates the cell. Biophys. models have been proposed to explain how spheres and elliptical nanostructures enter cells, but one-dimensional nanomaterials have not been examd. Here, we show exptl. and theor. that cylindrical one-dimensional nanomaterials such as carbon nanotubes enter cells through the tip first. For nanotubes with end caps or carbon shells at their tips, uptake involves tip recognition through receptor binding, rotation that is driven by asym. elastic strain at the tube-bilayer interface, and near-vertical entry. The precise angle of entry is governed by the relative timescales for tube rotation and receptor diffusion. Nanotubes without caps or shells on their tips show a different mode of membrane interaction, posing an interesting question as to whether modifying the tips of tubes may help avoid frustrated uptake by cells.
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385Haniu, H.; Saito, N.; Matsuda, Y.; Kim, Y. A.; Park, K. C.; Tsukahara, T.; Usui, Y.; Aoki, K.; Shimizu, M.; Ogihara, N.; Hara, K.; Takanashi, S.; Okamoto, M.; Ishigaki, N.; Nakamura, K.; Kato, H. Int. J. Nanomed. 2011, 6, 3295385https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvVw%253D&md5=0d00d88c046bf1e0afe5ca1614e86c70Effect of dispersants of multi-walled carbon nanotubes on cellular uptake and biological responsesHaniu, Hisao; Saito, Naoto; Matsuda, Yoshikazu; Kim, Yoong-Ahm; Park, Ki Chul; Tsukahara, Tamotsu; Usui, Yuki; Aoki, Kaoru; Shimizu, Masayuki; Ogihara, Nobuhide; Hara, Kazuo; Takanashi, Seiji; Okamoto, Masanori; Ishigaki, Norio; Nakamura, Koichi; Kato, HiroyukiInternational Journal of Nanomedicine (2011), 6 (), 3295-3307CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)Although there have been many reports about the cytotoxicity of multi-walled carbon nanotubes (MWCNTs), the results are still controversial. To investigate one possible reason, the authors investigated the influence of MWCNT dispersants on cellular uptake and cytotoxicity. Cytotoxicity was examd. (measured by alamarBlue assay), as well as intracellular MWCNT concn. and cytokine secretion (measured by flow cytometry) in human bronchial epithelial cells (BEAS-2B) exposed to a type of highly purified MWCNT vapor grown carbon fiber (VGCF, Showa Denko Kabushiki-gaisha, Tokyo, Japan) in three different dispersants (gelatin, carboxylmethyl cellulose, and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine). The authors also researched the relationship between the intracellular concn. of MWCNTs and cytotoxicity by using two cell lines, BEAS-2B and MESO-1 human malignant pleural mesothelioma cells. The intracellular concn. of VGCF was different for each of the three dispersants, and the levels of cytotoxicity and inflammatory response were correlated with the intracellular concn. of VGCF. A relationship between the intracellular concn. of VGCF and cytotoxic effects was obsd. in both cell lines. The results indicate that dispersants affect VGCF uptake into cells and that cytotoxicity depends on the intracellular concn. of VGCF, not on the exposed dosage. Thus, toxicity appears to depend on exposure time, even at low VGCF concns., because VGCF is biopersistent.
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386Haniu, H.; Saito, N.; Matsuda, Y.; Kim, Y. A.; Park, K. C.; Tsukahara, T.; Usui, Y.; Aoki, K.; Shimizu, M.; Ogihara, N.; Hara, K.; Takanashi, S.; Okamoto, M.; Ishigaki, N.; Nakamura, K.; Kato, H. Int. J. Nanomed. 2011, 6, 3487386https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht12nsLc%253D&md5=8ba6a4f924f80ec264458c37bdd079d6Elucidation mechanism of different biological responses to multi-walled carbon nanotubes using four cell linesHaniu, Hisao; Saito, Naoto; Matsuda, Yoshikazu; Kim, Yoong-Ahm; Park, Ki Chul; Tsukahara, Tamotsu; Usui, Yuki; Aoki, Kaoru; Shimizu, Masayuki; Ogihara, Nobuhide; Hara, Kazuo; Takanashi, Seiji; Okamoto, Masanori; Ishigaki, Norio; Nakamura, Koichi; Kato, HiroyukiInternational Journal of Nanomedicine (2011), 6 (), 3487-3497CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)We examd. differences in cellular responses to multi-walled carbon nanotubes (MWCNTs) using malignant pleural mesothelioma cells (MESO-1), bronchial epithelial cells (BEAS-2B), neuroblastoma cells (IMR-32), and monoblastic cells (THP-1), before and after differentiation. MESO-1, BEAS-2B and differentiated THP-1 cells actively endocytosed MWCNTs, resulting in cytotoxicity with lysosomal injury. However, cytotoxicity did not occur in IMR-32 or undifferentiated THP-1 cells. Both differentiated and undifferentiated THP-1 cells exhibited an inflammatory response. Carbon blacks were endocytosed by the same cell types without lysosomal damage and caused cytokine secretion, but they did not cause cytotoxicity. These results indicate that the cytotoxicity of MWCNTs requires not only cellular uptake but also lysosomal injury. Furthermore, it seems that membrane permeability or cytokine secretion without cytotoxicity results from several active mechanisms. Clarification of the cellular recognition mechanism for MWCNTs is important for developing safer MWCNTs.
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387Yaron, P. N.; Holt, B. D.; Short, P. A.; Lösche, M.; Islam, M. F.; Dahl, K. N. J. Nanobiotechnol. 2011, 9, 45387https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1Khu77L&md5=cad4f77848a895bc48d8dfdac844e2d8Single wall carbon nanotubes enter cells by endocytosis and not membrane penetrationYaron, Peter N.; Holt, Brian D.; Short, Philip A.; Losche, Mathias; Islam, Mohammad F.; Dahl, Kris NoelJournal of Nanobiotechnology (2011), 9 (), 45CODEN: JNOAAO; ISSN:1477-3155. (BioMed Central Ltd.)Background: Carbon nanotubes are increasingly being tested for use in cellular applications. Detg. the mode of entry is essential to control and regulate specific interactions with cells, to understand toxicol. effects of nanotubes, and to develop nanotube-based cellular technologies. We investigated cellular uptake of Pluronic copolymer-stabilized, purified ∼145 nm long single wall carbon nanotubes (SWCNTs) through a series of complementary cellular, cell-mimetic, and in vitro model membrane expts. Results: SWCNTs localized within fluorescently labeled endosomes, and confocal Raman spectroscopy showed a dramatic redn. in SWCNT uptake into cells at 4°C compared with 37°C. These data suggest energy-dependent endocytosis, as shown previously. We also examd. the possibility for non-specific phys. penetration of SWCNTs through the plasma membrane. Electrochem. impedance spectroscopy and Langmuir monolayer film balance measurements showed that Pluronic-stabilized SWCNTs assocd. with membranes but did not possess sufficient insertion energy to penetrate through the membrane. SWCNTs assocd. with vesicles made from plasma membranes but did not rupture the vesicles. Conclusions: These measurements, combined, demonstrate that Pluronic-stabilized SWCNTs only enter cells via energy-dependent endocytosis, and assocn. of SWCNTs to membrane likely increases uptake.
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388Gao, H.; Shi, W.; Freund, L. B. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 9469There is no corresponding record for this reference.
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389Tabet, L.; Bussy, C.; Amara, N.; Setyan, A.; Grodet, A.; Rossi, M. J.; Pairon, J. C.; Boczkowski, J.; Lanone, S. J. Toxicol. Environ. Health, Part A 2009, 72, 60There is no corresponding record for this reference.
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390Raffa, V.; Gherardini, L.; Vittorio, O.; Bardi, G.; Ziaei, A.; Pizzorusso, T.; Riggio, C.; Nitodas, S.; Karachalios, T.; Al-Jamal, K. T.; Kostarelos, K.; Costa, M.; Cuschieri, A. Nanomedicine (London, U.K.) 2011, 6, 1709390https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFCms7bL&md5=e4dbb4601db6b2355e2a7cebe7c0ddb2Carbon nanotube-mediated wireless cell permeabilization: drug and gene uptakeRaffa, Vittoria; Gherardini, Lisa; Vittorio, Orazio; Bardi, Giuseppe; Ziaei, Afshin; Pizzorusso, Tommaso; Riggio, Cristina; Nitodas, Stephanos; Karachalios, Theodoros; Al-Jamal, Khuloud T.; Kostarelos, Kostas; Costa, Mario; Cuschieri, AlfredNanomedicine (London, United Kingdom) (2011), 6 (10), 1709-1718CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)This work aims to exploit the antenna properties of multiwalled carbon nanotubes (MWCNTs). They can be used to induce cell permeabilization in order to transfer drugs (normally impermeable to cell membranes) both in in vitro and in vivo models. The performance of the MWCNTs as receiver antenna was modeled by finite element modeling. Once the appropriate field has been identified, the antenna properties of MWCNTs were investigated in sequential expts. involving immortalized fibroblast cell line (drug model: doxorubicin chemothererapeutic agent) and living mice (drug model: bcl-2 antiapoptotic gene) following stereotactic injection in the cerebral motor cortex. Finite element modeling anal. predicts that our MWCNTs irradiated in the radiofrequency field resemble thin-wire dipole antennas. In vitro expts. confirmed that combination of MWCNTs and electromagnetic field treatment dramatically favors intracellular drug uptake and, most importantly, drug nuclear localization. Finally, the brain of each irradiated animal exhibits a significantly higher no. of transfected cells compared with the appropriate controls. This wireless application has the potential for MWCNT-based intracellular drug delivery and electro-stimulation therapies.
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391Al-Jamal, K. T.; Kostarelos, K. Methods Mol. Biol. 2010, 625, 123391https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXoslyqtb4%253D&md5=78741953499f91a98361af3d74038cadAssessment of cellular uptake and cytotoxicity of carbon nanotubes using flow cytometryAl-Jamal, Khuloud T.; Kostarelos, KostasMethods in Molecular Biology (Totowa, NJ, United States) (2010), 625 (Carbon Nanotubes), 123-134CODEN: MMBIED; ISSN:1064-3745. (Humana Press Inc.)The field of carbon nanotube (CNT) functionalization is increasingly growing for the purpose of enhancing the biocompatibility of CNT for medical and biol. applications. Properties of CNT such as the type of functionalization, charge d., and the dispersibility profile are expected to modulate CNT cellular uptake and toxicity profile in vitro. The assay described here allows for rapid screening of CNT cellular uptake in vitro and assessing the acute cytotoxicity simultaneously. CNT cellular uptake is measured qual. by light scattering anal. without differentiating between cell binding and internalization of the CNT by the cells. In addn., flow cytometry is used to combine light scattering anal. with flow cytometry-based Annexin V/propidium iodide assay to measure the cytotoxicity. This assay is rapid, reliable, and allows for comparative anal. between various types of CNT studied.
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392Lamm, M. H.; Ke, P. C. Methods Mol. Biol. 2010, 625, 135392https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXoslyqtbw%253D&md5=0711ff2a977dffe9a66b2021ff3937a4Cell trafficking of carbon nanotubes based on fluorescence detectionLamm, Monica H.; Ke, Pu ChunMethods in Molecular Biology (Totowa, NJ, United States) (2010), 625 (Carbon Nanotubes), 135-151CODEN: MMBIED; ISSN:1064-3745. (Humana Press Inc.)Cell trafficking of carbon nanotubes (CNTs) is an area of scientific inquiry that has great implications in medicine, biosensing, and environmental science and engineering. The essence of this inquiry resides in the interaction of carbon nanostructures and cell membranes, regulated by the laws of mol. cell biol. and the physiochem. properties of the nanostructures. Of equal importance to this inquiry is a description of cellular responses to the integration of man-made materials; yet, how cellular responses may invoke whole-organism level reaction remains unclear. In this chapter, we show three exptl. studies, which may be beneficial to obtaining such an understanding. Among the reservoir of methodologies, which have proved of merit, we focus our attention on fluorescence microscopy, one of the most powerful and yet least invasive means of probing nanoparticles in biol. systems. Esp., we present the method of fluorescence energy transfer induced between a lysophospholipid mol. and a single-walled CNT upon cellular uptake, and describe coating nanotubes with RNA and suspending fullerenes with phenolic acids for facilitating their translocation across cell membranes and shuttling between cell organelles. Finally, we comment on the perspective of using mol. simulations for facilitating and guiding such expts.
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393Schrand, A. M.; Schlager, J. J.; Dai, L.; Hussain, S. M. Nat. Protoc. 2010, 5, 744There is no corresponding record for this reference.
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394Murr, L. E.; Garza, K. M.; Soto, K. F.; Carrasco, A.; Powell, T. G.; Ramirez, D. A.; Guerrero, P. A.; Lopez, D. A.; Venzor, J., III. Int. J. Environ. Res. Public Health 2005, 2, 31There is no corresponding record for this reference.
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395Mahmoudi, M.; Laurent, S.; Shokrgozar, M. A.; Hosseinkhani, M. ACS Nano 2011, 5, 7263There is no corresponding record for this reference.
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396Mahmoudi, M.; Saeedi-Eslami, S. N.; Shokrgozar, M. A.; Azadmanesh, K.; Hassanlou, M.; Kalhor, H. R.; Burtea, C.; Rothen-Rutishauser, B.; Laurent, S.; Sheibani, S.; Vali, H. Nanoscale 2012, 4, 5461There is no corresponding record for this reference.
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397Laurent, S.; Burtea, C.; Thirifays, C.; Häfeli, U. O.; Mahmoudi, M. PLoS One 2012, 7, e29997There is no corresponding record for this reference.
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398Bianco, A.; Kostarelos, K.; Partidos, C. D.; Prato, M. Chem. Commun. (Cambridge, U.K.) 2005, 5, 571There is no corresponding record for this reference.
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399Bottini, M.; Bruckner, S.; Nika, K.; Bottini, N.; Bellucci, S.; Magrini, A.; Bergamaschi, A.; Mustelin, T. Toxicol. Lett. 2006, 160, 121399https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFOhtbjI&md5=13e974f57fc918db376466a7409cba1aMulti-walled carbon nanotubes induce T lymphocyte apoptosisBottini, Massimo; Bruckner, Shane; Nika, Konstantina; Bottini, Nunzio; Bellucci, Stefano; Magrini, Andrea; Bergamaschi, Antonio; Mustelin, TomasToxicology Letters (2006), 160 (2), 121-126CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)Carbon nanotubes are a man-made form of carbon that did not exist in the environment until very recently. Due to their unique chem., phys., optical, and magnetic properties, carbon nanotubes have found many uses in industrial products and in the field of nanotechnol., including in nanomedicine. However, very little is yet known about the toxicity of carbon nanotubes. Here, the authors compare the toxicity of pristine and oxidized multi-walled carbon nanotubes on human T cells and find that the latter are more toxic and induce massive loss of cell viability through programmed cell death at doses of 400 μg/mL, which corresponds to approx. 10 million carbon nanotubes per cell. Pristine, hydrophobic, carbon nanotubes were less toxic and a 10-fold lower concn. of either carbon nanotube type were not nearly as toxic. The authors' results suggest that carbon nanotubes indeed can be very toxic at sufficiently high concns. and that careful toxicity studies need to be undertaken particularly in conjunction with nanomedical applications of carbon nanotubes.
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400Shvedova, A. A.; Castranova, V.; Kisin, E. R.; Schwegler-Berry, D.; Murray, A. R.; Gandelsman, V. Z.; Maynard, A.; Baron, P. J. Toxicol. Environ. Health, Part A 2003, 66, 1909400https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXns1Gqsb0%253D&md5=e648e99fdcbaf6779d6ae2d29255e7f1Exposure to Carbon Nanotube Material: Assessment of Nanotube Cytotoxicity using Human Keratinocyte CellsShvedova, Anna; Castranova, Vincent; Kisin, Elena; Schwegler-Berry, Diane; Murray, Ashley; Gandelsman, Vadim; Maynard, Andrew; Baron, PaulJournal of Toxicology and Environmental Health, Part A (2003), 66 (20), 1909-1926CODEN: JTEHF8; ISSN:1528-7394. (Taylor & Francis, Inc.)Carbon nanotubes are new members of carbon allotropes similar to fullerenes and graphite. Because of their unique elec., mech., and thermal properties, carbon nanotubes are important for novel applications in the electronics, aerospace, and computer industries. Exposure to graphite and carbon materials has been assocd. with increased incidence of skin diseases, such as carbon fiber dermatitis, hyperkeratosis, and naevi. The authors investigated adverse effects of single-wall carbon nanotubes (SWCNT) using a cell culture of immortalized human epidermal keratinocytes (HaCaT). After 18 h of exposure of HaCaT to SWCNT, oxidative stress and cellular toxicity were indicated by formation of free radicals, accumulation of peroxidative products, antioxidant depletion, and loss of cell viability. Exposure to SWCNT also resulted in ultrastructural and morphol. changes in cultured skin cells. These data indicate that dermal exposure to unrefined SWCNT may lead to dermal toxicity due to accelerated oxidative stress in the skin of exposed workers.
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401Kagan, V. E.; Tyurina, Y. Y.; Tyurin, V. A.; Konduru, N. V.; Potapovich, A. I.; Osipov, A. N.; Kisin, E. R.; Schwegler-Berry, D.; Mercer, R.; Castranova, V.; Shvedova, A. A. Toxicol. Lett. 2006, 165, 88401https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XlvF2nsrY%253D&md5=1cc017a92ff6b432025cd4a8e3e85411Direct and indirect effects of single walled carbon nanotubes on RAW 264.7 macrophages: Role of ironKagan, V. E.; Tyurina, Y. Y.; Tyurin, V. A.; Konduru, N. V.; Potapovich, A. I.; Osipov, A. N.; Kisin, E. R.; Schwegler-Berry, D.; Mercer, R.; Castranova, V.; Shvedova, A. A.Toxicology Letters (2006), 165 (1), 88-100CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)Single-walled carbon nanotubes (SWCNT), nano-cylinders with an extremely small diam. (1-2 nm) and high aspect ratio, have unique physico-chem., electronic and mech. properties and may exhibit unusual interactions with cells and tissues, thus necessitating studies of their toxicity and health effects. Manufd. SWCNT usually contain significant amts. of Fe that may act as a catalyst of oxidative stress. Because macrophages are the primary responders to different particles that initiate and propagate inflammatory reactions and oxidative stress, we utilized 2 types of SWCNT: (1) Fe-rich (non-purified) SWCNT (26 wt.% of Fe) and (2) Fe-stripped (purified) SWCNT (0.23 wt.% of Fe) to study their interactions with RAW 264.7 macrophages. Ultrasonication resulted in predominantly well-dispersed and sepd. SWCNT strands as evidenced by SEM. Neither purified nor non-purified SWCNT were able to generate intracellular prodn. of superoxide radicals or NO in RAW 264.7 macrophages as documented by flow-cytometry and fluorescence microscopy. SWCNT with different Fe content displayed different redox activity in a cell-free model system as revealed by EPR-detectable formation of ascorbate radicals resulting from ascorbate oxidn. In the presence of zymosan-stimulated RAW 264.7 macrophages, non-purified Fe-rich SWCNT were more effective in generating hydroxyl radicals (documented by EPR spin-trapping with 5,5-dimethyl-1-pyrroline-N-oxide, DMPO) than purified SWCNT. Similarly, EPR spin-trapping expts. in the presence of zymosan-stimulated RAW 264.7 macrophages showed that non-purified SWCNT more effectively converted superoxide radicals generated by xanthine oxidase/xanthine into hydroxyl radicals as compared to purified SWCNT. Fe-rich SWCNT caused significant loss of intracellular low mol. wt. thiols (GSH) and accumulation of lipid hydroperoxides in both zymosan-and PMA-stimulated RAW 264.7 macrophages. Catalase was able to partially protect macrophages against SWCNT induced elevation of biomarkers of oxidative stress (enhancement of lipid peroxidn. and GSH depletion). Thus, the presence of Fe in SWCNT may be important in detg. redox-dependent responses of macrophages.
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402Herzog, E.; Casey, A.; Lyng, F. M.; Chambers, G.; Byrne, H. J.; Davoren, M. Toxicol. Lett. 2007, 174, 49402https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1anurbJ&md5=eee2bdd51f7d8c709d3c009d006ee59eA new approach to the toxicity testing of carbon-based nanomaterials-The clonogenic assayHerzog, Eva; Casey, Alan; Lyng, Fiona M.; Chambers, Gordon; Byrne, Hugh J.; Davoren, MariaToxicology Letters (2007), 174 (1-3), 49-60CODEN: TOLED5; ISSN:0378-4274. (Elsevier B.V.)The cellular toxicity of three types of carbon nanoparticles, namely HiPco single-walled carbon nanotubes (SWCNT), arc discharge SWCNT and Printex 90 carbon black nanoparticles, was studied on three different cell models including the human alveolar carcinoma epithelial cell line (A549), the normal human bronchial epithelial cell line (BEAS-2B) and the human keratinocyte cell line (HaCaT) using the clonogenic assay. Carbon nanomaterials are known to interact with colorimetric indicator dyes frequently used in cytotoxicity assays. By employing the clonogenic assay, any such interactions could be avoided, allowing a more reliable method for the in vitro toxicity assessment of carbon-based nanoparticles. It could be shown that the toxicity of as produced SWCNT samples differs between cell lines and the SWCNT prodn. method used, with HiPco SWCNT samples being more reactive compared to arc discharge produced SWCNT samples, both eliciting a stronger cytotoxic response than carbon black. Furthermore, it was possible to distinguish between effects on cell viability and cell proliferation by including colony size as an addnl. endpoint in the clonogenic assay. All three particle types were highly effective in inhibiting cell proliferation in all three cell lines, whereas only HaCaT and BEAS-2B cells also showed decreased cell viability.
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403Balavoine, F.; Schultz, P.; Richard, C.; Mallouh, V.; Ebbesen, T. W.; Mioskowski, C. Angew. Chem., Int. Ed. 1999, 38, 1912There is no corresponding record for this reference.
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404Muller, J.; Decordier, I.; Hoet, P. H.; Lombaert, N.; Thomassen, L.; Huaux, F.; Lison, D.; Kirsch-Volders, M. Carcinogenesis 2008, 29, 427There is no corresponding record for this reference.
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405Haniu, H.; Saito, N.; Matsuda, Y.; Usui, Y.; Aoki, K.; Shimizu, M.; Ogihara, N.; Hara, K.; Takanashi, S.; Okamoto, M.; Nakamura, K.; Ishigaki, N.; Tsukahara, T.; Kato, H. J. Nanotechnol. 2012, 2012, 937819There is no corresponding record for this reference.
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406Isobe, H.; Tanaka, T.; Maeda, R.; Noiri, E.; Solin, N.; Yudasaka, M.; Iijima, S.; Nakamura, E. Angew. Chem., Int. Ed. 2006, 45, 6676There is no corresponding record for this reference.
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407Pumera, M.; Miyahara, Y. Nanoscale 2009, 1, 260There is no corresponding record for this reference.
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408Ambrosi, A.; Pumera, M. Chemistry (Easton) 2010, 16, 1786408https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVKjsb8%253D&md5=c1711cbd59aa18779f107ce2e92bf631Regulatory Peptides Are Susceptible to Oxidation by Metallic Impurities within Carbon NanotubesAmbrosi, Adriano; Pumera, MartinChemistry - A European Journal (2010), 16 (6), 1786-1792CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)In this article, we show that the redox properties of the regulatory peptide L-glutathione are affected by the presence of nickel oxide impurities within single-walled carbon nanotubes (SWCNTs). Glutathione is a powerful antioxidant that protects cells from oxidative stress by removing free radicals and peroxides. We show that the L-cysteine moiety in L-glutathione is responsible for the susceptibility to oxidn. by metallic impurities present in the carbon nanotubes. These results have great significance for assessing the toxicity of carbon-nanotube materials. The SWCNTs were characterized by Raman spectroscopy, high-resoln. XPS, transmission electron microscopy, and energy dispersive X-ray spectroscopy.
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409Brown, D. M.; Donaldson, K.; Stone, V. J. Biomed. Nanotechnol. 2010, 6, 224409https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVKrt73E&md5=108482d72882579329dcfcb49174beb3Nuclear translocation of Nrf2 and expression of antioxidant defence genes in THP-1 cells exposed to carbon nanotubesBrown, David M.; Donaldson, Kenneth; Stone, VickiJournal of Biomedical Nanotechnology (2010), 6 (3), 224-233CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)Carbon nanotubes have a wide range of applications in various industries and their use is likely to rise in the future. Currently, a major concern is that with the increasing use and prodn. of these materials, there may be increased health risks to exposed workers. Long (> 15 μm) straight nanotubes may undergo frustrated phagocytosis which is likely to result in reduced clearance. We examine here the effects of multiwalled carbon nanotubes of different sizes on monocytic THP-1 cells, with regard to their ability to stimulate increased expression of the HO-1 and GST genes and their ability to produce nuclear translocation of the transcription factor, Nrf2, as well as the release of several pro-inflammatory cytokines and mediators of inflammation. Our results suggest that long (50 μm) carbon nanotubes (62.5 μg/mL for 4 h) produce increased nuclear translocation of Nrf2 and increased HO-1 gene expression compared with shorter entangled nanotubes. There was no increased gene expression for GST. The long nanotubes (NT1) caused increased release of the proinflammatory cytokine IL-1β, an effect which was diminished by the antioxidant trolox, suggesting a role of oxidative stress in the upregulation of this cytokine. Tentatively, our study suggests that long carbon nanotubes may exert their effect in THP-1 cells in part via an oxidative stress mechanism.
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410Donaldson, K.; Murphy, F. A.; Duffin, R.; Poland, C. A. Part. Fibre Toxicol. 2010, 7, 5410https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c3nsF2jtg%253D%253D&md5=49db73fee80b155964e544fd639835b8Asbestos, carbon nanotubes and the pleural mesothelium: a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesotheliomaDonaldson Ken; Murphy Fiona A; Duffin Rodger; Poland Craig AParticle and fibre toxicology (2010), 7 (), 5 ISSN:.The unique hazard posed to the pleural mesothelium by asbestos has engendered concern in potential for a similar risk from high aspect ratio nanoparticles (HARN) such as carbon nanotubes. In the course of studying the potential impact of HARN on the pleura we have utilised the existing hypothesis regarding the role of the parietal pleura in the response to long fibres. This review seeks to synthesise our new data with multi-walled carbon nanotubes (CNT) with that hypothesis for the behaviour of long fibres in the lung and their retention in the parietal pleura leading to the initiation of inflammation and pleural pathology such as mesothelioma. We describe evidence that a fraction of all deposited particles reach the pleura and that a mechanism of particle clearance from the pleura exits, through stomata in the parietal pleura. We suggest that these stomata are the site of retention of long fibres which cannot negotiate them leading to inflammation and pleural pathology including mesothelioma. We cite thoracoscopic data to support the contention, as would be anticipated from the preceding, that the parietal pleura is the site of origin of pleural mesothelioma. This mechanism, if it finds support, has important implications for future research into the mesothelioma hazard from HARN and also for our current view of the origins of asbestos-initiated pleural mesothelioma and the common use of lung parenchymal asbestos fibre burden as a correlate of this tumour, which actually arises in the parietal pleura.
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411Murphy, F. A.; Schinwald, A.; Poland, C. A.; Donaldson, K. Part. Fibre Toxicol. 2012, 9, 8411https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotFKqurg%253D&md5=85cee97a266ff604dae0a21e2ea0265eThe mechanism of pleural inflammation by long carbon nanotubes: interaction of long fibres with macrophages stimulates them to amplify pro-inflammatory responses in mesothelial cellsMurphy, Fiona A.; Schinwald, Anja; Poland, Craig A.; Donaldson, KenParticle and Fibre Toxicology (2012), 9 (), 8CODEN: PFTABQ; ISSN:1743-8977. (BioMed Central Ltd.)Carbon nanotubes (CNT) are high aspect ratio nanoparticles with diams. in the nanometer range but lengths extending up to hundreds of microns. The structural similarities between CNT and asbestos have raised concern that they may pose a similar inhalation hazard. Recently CNT have been shown to elicit a length-dependent, asbestos-like inflammatory response in the pleural cavity of mice, where long fibers caused inflammation but short fibers did not. However the cellular mechanisms governing this response have yet to be elucidated. This study examd. the in vitro effects of a range of CNT for their ability to stimulate the release of the acute phase cytokines; IL-1β, TNFα, IL-6 and the chemokine, IL-8 from both Met5a mesothelial cells and THP-1 macrophages. Results showed that direct exposure to CNT resulted in significant cytokine release from the macrophages but not mesothelial cells. This pro-inflammatory response was length dependent but modest and was shown to be a result of frustrated phagocytosis. Furthermore the indirect actions of the CNT were examd. by treating the mesothelial cells with conditioned media from CNT-treated macrophages. This resulted in a dramatic amplification of the cytokine release from the mesothelial cells, a response which could be attenuated by inhibition of phagocytosis during the initial macrophage CNT treatments. We therefore hypothesize that long fibers elicit an inflammatory response in the pleural cavity via frustrated phagocytosis in pleural macrophages. The activated macrophages then stimulate an amplified pro-inflammatory cytokine response from the adjacent pleural mesothelial cells. This mechanism for producing a pro-inflammatory environment in the pleural space exposed to long CNT has implications for the general understanding of fiber-related pleural disease and design of safe nanofibers.
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412van Berlo, D.; Clift, M. J.; Albrecht, C.; Schins, R. P. Swiss Med. Wkly. 2012, 142, w13698There is no corresponding record for this reference.
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413Petersen, E. J.; Tu, X.; Dizdaroglu, M.; Zheng, M.; Nelson, B. C. Small 2013, 9, 205There is no corresponding record for this reference.
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414Ali-Boucetta, H.; Nunes, A.; Sainz, R.; Herrero, M. A.; Tian, B.; Prato, M.; Bianco, A.; Kostarelos, K. Angew. Chem., Int. Ed. 2013, 52, 2274There is no corresponding record for this reference.
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415Chiaretti, M.; Mazzanti, G.; Bosco, S. B. S.; Cucina, A.; Le Foche, F. G.; Carru, A.; Mastrangelo, S.; Di Sotto, A.; Masciangelo, R.; Chiaretti, A. M.; Balasubramanian, C.; De Bellis, G.; Micciulla, F.; Porta, N.; Deriu, G.; Tiberia, A. J. Phys.: Condens. Matter 2008, 20, 474203415https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFahsLzE&md5=d8cbc4d128ac1d6b762b8e1a5f6b3ec8Carbon nanotubes toxicology and effects on metabolism and immunological modification in vitro and in vivoChiaretti, M.; Mazzanti, G.; Bosco, S.; Bellucci, S.; Cucina, A.; Le Foche, F.; Carru, G. A.; Mastrangelo, S.; Di Sotto, A.; Masciangelo, R.; Chiaretti, A. M.; Balasubramanian, C.; De Bellis, G.; Micciulla, F.; Porta, N.; Deriu, G.; Tiberia, A.Journal of Physics: Condensed Matter (2008), 20 (47), 474203/1-474203/10CODEN: JCOMEL; ISSN:0953-8984. (Institute of Physics Publishing)The aim of this research is focused on the biol. effects of multi wall carbon nanotubes (MWCNTs) on three different human cell types, lab. animals in vivo, and immunol. effects. Large nos. of researchers are directly involved in the handling of nanostructured materials such as MWCNTs and nanoparticles. It is important to assess the potential health risks related to their daily exposure to carbon nanotubes. The administration of sterilized nanosamples has been performed on lab. animals, in both acute and chronic administration, and the pathol. effects on the parenchymal tissues have been investigated. The authors studied the serum immunol. modifications after i.p. administration of the MWCNTs. The authors did not observe any antigenic reaction; the screening of ANA, anti-ENA, anti-cardiolipin, C-ANCA and P-ANCA was neg. No quant. modification of Igs was obsd., hence no modification of humoral immunity was documented. The authors also studied the effects of MWCNTs on the proliferation of three different cell types. MCF-7 showed a significant inhibition of proliferation for all conditions studied, whereas hSMCs demonstrated a redn. of cell growth only for the highest MWCNTs concns. after 72 h. Also, no growth modification was obsd. in the Caco-2 cell line. The authors obsd. that a low quantity of MWCNTs does not provoke any inflammatory reaction. However, for future medical applications, it is important to realize prosthesis based on MWCNTs, through studying the corresponding implantation effects. Moreover, it has to be emphasized that this investigation does not address, at the moment, the carcinogenicity of MWCNTs, which requires a detailed follow-up investigation on the specific topic. In view of the subsequent and more extensive use of MWCNTs, esp. in applications where carbon nanotubes are injected into the human body for drug delivery, as a contrast agent carrying entities for MRI, or as the basic material of a new prosthesis generation, more extended tests and expts. are necessary.
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416Palomäki, J.; Karisola, P.; Pylkkänen, L.; Savolainen, K.; Alenius, H. Toxicology 2010, 267, 125There is no corresponding record for this reference.
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417Zhang, Q.; Zhou, H.; Yan, B. Methods Mol. Biol. 2010, 625, 95417https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXoslyqtLg%253D&md5=c531c3804eb58fdf3a1ba68f688956d0Reducing nanotube cytotoxicity using a nano-combinatorial library approachZhang, Qiu; Zhou, Hongyu; Yan, BingMethods in Molecular Biology (Totowa, NJ, United States) (2010), 625 (Carbon Nanotubes), 95-107CODEN: MMBIED; ISSN:1064-3745. (Humana Press Inc.)Carbon nanotubes (CNTs) have a great potential for applications in medicine. However, their biocompatibility and toxicity cause a great concern. Due to the large surface area of CNTs, chem. modification can dramatically alter their physiochem. properties and hence biol. activity. Using a combinatorial chem. approach, we report the synthesis of an 80-member surface-modified nanotube library. Based upon screening of this library with respect to protein-binding capacity, cytotoxicity, and immune response, we were able to select highly biocompatible nanotubes with reduced protein-binding cytotoxicity and immune response.
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418Johnston, H. J.; Hutchison, G. R.; Christensen, F. M.; Peters, S.; Hankin, S.; Aschberger, K.; Stone, V. Nanotoxicology 2010, 4, 207There is no corresponding record for this reference.
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419Rauch, J.; Kolch, W.; Mahmoudi, M. Sci. Rep. 2012, 2, 868419https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVKru7nO&md5=d68aa8410a507e46e0c7cff2ab1fae2fCell type-specific activation of AKT and ERK signaling pathways by small negatively-charged magnetic nanoparticlesRauch, Jens; Kolch, Walter; Mahmoudi, MortezaScientific Reports (2012), 2 (), srep00868, 9 pp.CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)The interaction of nanoparticles (NPs) with living organisms has become a focus of public and scientific debate due to their potential wide applications in biomedicine, but also because of unwanted side effects. Here, we show that superparamagnetic iron oxide NPs (SPIONs) with different surface coatings can differentially affect signal transduction pathways. Using isogenic pairs of breast and colon derived cell lines we found that the stimulation of ERK and AKT signaling pathways by SPIONs is selectively dependent on the cell type and SPION type. In general, cells with Ras mutations respond better than their non-mutant counterparts. Small neg. charged SPIONs (snSPIONs) activated ERK to a similar extent as epidermal growth factor (EGF), and used the same upstream signaling components including activation of the EGF receptor. Importantly, snSPIONs stimulated the proliferation of Ras transformed breast epithelial cells as efficiently as EGF suggesting that NPs can mimic physiol. growth factors.
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420Pantarotto, D.; Partidos, C. D.; Graff, R.; Hoebeke, J.; Briand, J. P.; Prato, M.; Bianco, A. J. Am. Chem. Soc. 2003, 125, 6160There is no corresponding record for this reference.
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421Zhang, Y. B.; Kanungo, M.; Ho, A. J.; Freimuth, P.; van der Lelie, D.; Chen, M.; Khamis, S. M.; Datta, S. S.; Johnson, A. T.; Misewich, J. A.; Wong, S. S. Nano Lett. 2007, 7, 3086There is no corresponding record for this reference.
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422Salvador-Morales, C.; Flahaut, E.; Sim, E.; Sloan, J.; Green, M. L.; Sim, R. B. Mol. Immunol. 2006, 43, 193422https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVCltbrJ&md5=6064b0a365787301a4f5a6815730e143Complement activation and protein adsorption by carbon nanotubesSalvador-Morales, Carolina; Flahaut, Emmanuel; Sim, Edith; Sloan, Jeremy; Green, Malcolm L. H.; Sim, Robert B.Molecular Immunology (2006), 43 (3), 193-201CODEN: MOIMD5; ISSN:0161-5890. (Elsevier B.V.)As a first step to validate the use of carbon nanotubes as novel vaccine or drug delivery devices, their interaction with a part of the human immune system, complement, has been explored. Hemolytic assays were conducted to investigate the activation of the human serum complement system via the classical and alternative pathways. Western blot and SDS-PAGE techniques were used to elucidate the mechanism of activation of complement via the classical pathway, and to analyze the interaction of complement and other plasma proteins with carbon nanotubes. The authors report for the first time that carbon nanotubes activate human complement via both classical and alternative pathways. The authors conclude that complement activation by nanotubes is consistent with reported adjuvant effects, and might also in various circumstances promote damaging effects of excessive complement activation, such as inflammation and granuloma formation. C1q binds directly to carbon nanotubes. Protein binding to carbon nanotubes is highly selective, since out of the many different proteins in plasma, very few bind to the carbon nanotubes. Fibrinogen and apolipoproteins (AI, AIV and CIII) were the proteins that bound to carbon nanotubes in greatest quantity.
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423Ge, C.; Du, J.; Zhao, L.; Wang, L.; Liu, Y.; Li, D.; Yang, Y.; Zhou, R.; Zhao, Y.; Chai, Z.; Chen, C. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 16968There is no corresponding record for this reference.
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424Cedervall, T.; Lynch, I.; Lindman, S.; Berggård, T.; Thulin, E.; Nilsson, H.; Dawson, K. A.; Linse, S. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 2050424https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXisVWrsro%253D&md5=83bdd8651591208f7867d50100606285Understanding the nanoparticle-protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticlesCedervall, Tommy; Lynch, Iseult; Lindman, Stina; Berggard, Tord; Thulin, Eva; Nilsson, Hanna; Dawson, Kenneth A.; Linse, SaraProceedings of the National Academy of Sciences of the United States of America (2007), 104 (7), 2050-2055CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Due to their small size, nanoparticles have distinct properties compared with the bulk form of the same materials. These properties are rapidly revolutionizing many areas of medicine and technol. Despite the remarkable speed of development of nanoscience, relatively little is known about the interaction of nanoscale objects with living systems. In a biol. fluid, proteins assoc. with nanoparticles, and the amt. and presentation of the proteins on the surface of the particles leads to an in vivo response. Proteins compete for the nanoparticle "surface," leading to a protein "corona" that largely defines the biol. identity of the particle. Thus, knowledge of rates, affinities, and stoichiometries of protein assocn. with, and dissocn. from, nanoparticles is important for understanding the nature of the particle surface seen by the functional machinery of cells. Here the authors develop approaches to study these parameters and apply them to plasma and simple model systems, albumin and fibrinogen. A series of copolymer nanoparticles are used with variation of size and compn. (hydrophobicity). The authors show that isothermal titrn. calorimetry is suitable for studying the affinity and stoichiometry of protein binding to nanoparticles. The authors det. the rates of protein assocn. and dissocn. using surface plasmon resonance technol. with nanoparticles that are thiol-linked to gold, and through size exclusion chromatog. of protein-nanoparticle mixts. This method is less perturbing than centrifugation, and is developed into a systematic methodol. to isolate nanoparticle-assocd. proteins. The kinetic and equil. binding properties depend on protein identity as well as particle surface characteristics and size.
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425Mahmoudi, M.; Lynch, I.; Ejtehadi, M. R.; Monopoli, M. P.; Bombelli, F. B.; Laurent, S. Chem. Rev. 2011, 111, 5610There is no corresponding record for this reference.
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426Rauch, J.; Kolch, W.; Laurent, S.; Mahmoudi, M. Chem. Rev. 2013, 113, 3391There is no corresponding record for this reference.
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427Walczyk, D.; Bombelli, F. B.; Monopoli, M. P; Lynch, I.; Dawson, K. A. J. Am. Chem. Soc. 2010, 132, 5761427https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXktFeks78%253D&md5=ce9efabdf94b4cb3e40fd6826e48242eWhat the Cell "Sees" in BionanoscienceWalczyk, Dorota; Bombelli, Francesca Baldelli; Monopoli, Marco P.; Lynch, Iseult; Dawson, Kenneth A.Journal of the American Chemical Society (2010), 132 (16), 5761-5768CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)What the biol. cell, organ, or barrier actually "sees" when interacting with a nanoparticle dispersed in a biol. medium likely matters more than the bare material properties of the particle itself. Typically the bare surface of the particle is covered by several biomols., including a select group of proteins drawn from the biol. medium. Here, we apply several different methodologies, in a time-resolved manner, to follow the lifetime of such biomol. "coronas" both in situ and isolated from the excess plasma. We find that such particle-biomol. complexes can be phys. isolated from the surrounding medium and studied in some detail, without altering their structure. For several nanomaterial types, we find that blood plasma-derived coronas are sufficiently long-lived that they, rather than the nanomaterial surface, are likely to be what the cell sees. From fundamental science to regulatory safety, current efforts to classify the biol. impacts of nanomaterials (currently according to bare material type and bare surface properties) may be assisted by the methodol. and understanding reported here.
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428Monopoli, M. P.; Walczyk, D.; Campbell, A.; Elia, G.; Lynch, I.; Bombelli, F. B.; Dawson, K. A. J. Am. Chem. Soc. 2011, 133, 2525428https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVOnt7w%253D&md5=a93981208087f4c615ac8c7df33a20ddPhysical-Chemical Aspects of Protein Corona: Relevance to in Vitro and in Vivo Biological Impacts of NanoparticlesMonopoli, Marco P.; Walczyk, Dorota; Campbell, Abigail; Elia, Giuliano; Lynch, Iseult; Baldelli Bombelli, Francesca; Dawson, Kenneth A.Journal of the American Chemical Society (2011), 133 (8), 2525-2534CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)It is now clearly emerging that besides size and shape, the other primary defining element of nanoscale objects in biol. media is their long-lived protein ("hard") corona. This corona may be expressed as a durable, stabilizing coating of the bare surface of nanoparticle (NP) monomers, or it may be reflected in different subpopulations of particle assemblies, each presenting a durable protein coating. Using the approach and concepts of phys. chem., we relate studies on the compn. of the protein corona at different plasma concns. with structural data on the complexes both in situ and free from excess plasma. This enables a high degree of confidence in the meaning of the hard protein corona in a biol. context. Here, we present the protein adsorption for two compositionally different NPs, namely sulfonated polystyrene and silica NPs. NP-protein complexes are characterized by differential centrifugal sedimentation, dynamic light scattering, and zeta-potential both in situ and once isolated from plasma as a function of the protein/NP surface area ratio. We then introduce a semiquant. detn. of their hard corona compn. using one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and electrospray liq. chromatog. mass spectrometry, which allows us to follow the total binding isotherms for the particles, identifying simultaneously the nature and amt. of the most relevant proteins as a function of the plasma concn. We find that the hard corona can evolve quite significantly as one passes from protein concns. appropriate to in vitro cell studies to those present in in vivo studies, which has deep implications for in vitro-in vivo extrapolations and will require some consideration in the future.
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429Mahmoudi, M.; Abdelmonem, A. M.; Behzadi, S.; Clement, J. H.; Dutz, S.; Ejtehadi, M. R.; Hartmann, R.; Kantner, K.; Linne, U.; Maffre, P.; Metzler, S.; Moghadam, M. K.; Pfeiffer, C.; Rezaei, M.; Ruiz-Lozano, P.; Serpooshan, V.; Shokrgozar, M. A.; Nienhaus, G. U.; Parak, W. J. ACS Nano 2013, 7, 6555There is no corresponding record for this reference.
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430Shannahan, J. H.; Brown, J. M.; Chen, R.; Ke, P. C.; Lai, X.; Mitra, S.; Witzmann, F. A. Small 2013, 9, 2171There is no corresponding record for this reference.
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431Riehemann, K. Small 2012, 8, 1970There is no corresponding record for this reference.
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432Kagan, V. E.; Bayir, H.; Shvedova, A. A. Nanomedicine 2005, 1, 313There is no corresponding record for this reference.
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433Donaldson, K.; Aitken, R.; Tran, L.; Stone, V.; Duffin, R.; Forrest, G.; Alexander, A. Toxicol. Sci. 2006, 92, 5433https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmsVehtrY%253D&md5=f24ea6a94d708d8cb11d5fe862c432deCarbon Nanotubes: A Review of Their Properties in Relation to Pulmonary Toxicology and Workplace SafetyDonaldson, Ken; Aitken, Robert; Tran, Lang; Stone, Vicki; Duffin, Rodger; Forrest, Gavin; Alexander, AndrewToxicological Sciences (2006), 92 (1), 5-22CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)A review. Carbon nanotubes (CNT) are an important new class of technol. materials that have numerous novel and useful properties. The forecast increase in manuf. makes it likely that increasing human exposure will occur, and as a result, CNT are beginning to come under toxicol. scrutiny. This review seeks to set out the toxicol. paradigms applicable to the toxicity of inhaled CNT, building on the toxicol. database on nanoparticles (NP) and fibers. Relevant workplace regulation regarding exposure is also considered in the light of our knowledge of CNT. CNT could have features of both NP and conventional fibers, and so the current paradigm for fiber toxicol., which is based on mineral fibers and synthetic vitreous fibers, is discussed. The NP toxicol. paradigm is also discussed in relation to CNT. The available peer-reviewed literature suggests that CNT may have unusual toxicity properties. In particular, CNT seem to have a special ability to stimulate mesenchymal cell growth and to cause granuloma formation and fibrogenesis. In several studies, CNT have more adverse effects than the same mass of NP carbon and quartz, the latter a commonly used benchmark of particle toxicity. There is, however, no definitive inhalation study available that would avoid the potential for artifactual effects due to large mats and aggregates forming during instillation exposure procedures. Studies also show that CNT may exhibit some of their effects through oxidative stress and inflammation. CNT represent a group of particles that are growing in prodn. and use, and therefore, research into their toxicol. and safe use is warranted.
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434Roco, M. C. Ann. N. Y. Acad. Sci. 2006, 1093, 1There is no corresponding record for this reference.
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435Singh, S.; Nalwa, H. S. J. Nanosci. Nanotechnol. 2007, 7, 3048There is no corresponding record for this reference.
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436Zhu, L.; Chang, D. W.; Dai, L.; Hong, Y. Nano Lett. 2007, 7, 3592There is no corresponding record for this reference.
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437Szendi, K.; Varga, C. Anticancer Res. 2008, 28, 349437https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjslWhtbo%253D&md5=b5358db4c137fbe5ebd4586fcf4bfa61Lack of genotoxicity of carbon nanotubes in a pilot studySzendi, Katalin; Varga, CsabaAnticancer Research (2008), 28 (1A), 349-352CODEN: ANTRD4; ISSN:0250-7005. (International Institute of Anticancer Research)Background: Different types of carbon nanotubes may represent toxic hazards due to their size distribution and massive surface area. They may adsorb other toxic agents that can consequently be transported into the body. The aim of the present study was to det. the possible genotoxicity of carbon nanotubes. Materials and Methods: In vivo bacterial mutagenicity and in vitro cytogenetic studies were performed on single-walled and multi-walled carbon nanotubes. Results: Oral exposure to nanotubes did not increase urinary mutagenicity in rats as studied using Ames test. No genotoxic effect was found in the in vitro micronucleus and sister chromatid exchange assays, either. Mitotic inhibition, a possible cytotoxic effect, however, was obsd. in the human lymphocyte cultures upon treatment with single-walled tubes. Conclusion: Due to the limited toxicity data on carbon nanotubes, these results may be particularly important for risk assessment purposes.
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438Di Sotto, A.; Chiaretti, M.; Carru, G. A.; Bellucci, S.; Mazzanti, G. Toxicol. Lett. 2009, 184, 192438https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVCgtLo%253D&md5=e623333003347c238942e5b957819436Multi-walled carbon nanotubes: Lack of mutagenic activity in the bacterial reverse mutation assayDi Sotto, Antonella; Chiaretti, Massimo; Carru, Giovanna Angela; Bellucci, Stefano; Mazzanti, GabrielaToxicology Letters (2009), 184 (3), 192-197CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)The mutagenic effect of multi-walled carbon nanotubes (MWCNTs) characterized by small surface/vol. ratio, high diam. and less than 0.1% of metal contaminants was evaluated by the bacterial reverse mutation assay (Ames test) on Salmonella typhimurium TA 98 and TA 100 strains, and on Escherichia coli WP2uvrA strain, in presence and in absence of the metabolic activation system S9. A preliminary cytotoxicity assay was carried out to ensure that cytotoxicity did not interfere with response. MWCNTs resulted devoid of mutagenic effect in the bacterial cellular systems tested in that they did not significantly increase the no. of revertant colonies. The mutagenic activity did not even appear in presence of the metabolic activator, so we can exclude that MWCNTs metabolites, produced via cytochrome-based P 450 metabolic oxidn. system, may act as mutagens. Carbon nanomaterials seem to exhibit different biol. activities and different toxicities in relation to their physico-chem. characteristics, size, shape, crystallinity and presence of metal traces, so it is difficult to establish their health risk. Due to the limited background of genotoxicity studies and the increased occupational and public exposure to nanomaterials, present results appear useful to extend the knowledge on the safety of carbon nanotubes in view of their possible applications.
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439Singh, N.; Manshian, B.; Jenkins, G. J.; Griffiths, S. M.; Williams, P. M.; Maffeis, T. G.; Wright, C. J.; Doak, S. H. Biomaterials 2009, 30, 3891There is no corresponding record for this reference.
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440Naya, M.; Kobayashi, N.; Mizuno, K.; Matsumoto, K.; Ema, M.; Nakanishi, J. Regul. Toxicol. Pharmacol. 2011, 61, 192440https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1ymt7jJ&md5=1712c0e1beb1a02a0cbf9dfd1b1caf72Evaluation of the genotoxic potential of single-wall carbon nanotubes by using a battery of in vitro and in vivo genotoxicity assaysNaya, Masato; Kobayashi, Norihiro; Mizuno, Kohei; Matsumoto, Kyomu; Ema, Makoto; Nakanishi, JunkoRegulatory Toxicology and Pharmacology (2011), 61 (2), 192-198CODEN: RTOPDW; ISSN:0273-2300. (Elsevier B.V.)The genotoxic potential of a high purity sample of single-wall carbon nanotubes (SWCNTs) was evaluated using a battery of in vitro and in vivo genotoxicity assays. These comprised a bacterial reverse mutation test (Ames test), an in vitro chromosomal aberration test, and an in vivo mouse bone marrow micronucleus test. The SWCNTs exerted no genotoxicity in Salmonella typhimurium TA97, TA98, TA100, and TA1535, or in Escherichia coli WP2 uvrA/pKM101, whether in the absence or presence of metabolic activation and at concns. of 12.5-500 μg/plate. In the chromosomal aberration test, at 300-1000 μg/mL, the SWCNTs did not increase the no. of structural or numerical chromosomal aberrations, whether the test was conducted with or without metabolic activation. In the in vivo bone marrow micronucleus test, doses of 60 mg/kg and 200 mg/kg SWCNTs did not affect the proportions of immature and total erythrocytes, nor did it increase the no. of micronuclei in the immature erythrocytes of mice. The results of these studies show that the high purity and well-dispersed sample of SWCNTs are not genotoxic under the conditions of the in vitro bacterial reverse mutation assay, chromosomal aberration assay, or in vivo bone marrow micronucleus test, and thus appear not to pose a genotoxic risk to human health in vivo.
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441Thurnherr, T.; Brandenberger, C.; Fischer, K.; Diener, L.; Manser, P.; Maeder-Althaus, X.; Kaiser, J. P.; Krug, H. F.; Rothen-Rutishauser, B.; Wick, P. Toxicol. Lett. 2011, 200, 176441https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnsVWqug%253D%253D&md5=01fcc87fca2689dba1dc2fea67e34641A comparison of acute and long-term effects of industrial multiwalled carbon nanotubes on human lung and immune cells in vitroThurnherr, Tina; Brandenberger, Christina; Fischer, Kathrin; Diener, Liliane; Manser, Pius; Maeder-Althaus, Xenia; Kaiser, Jean-Pierre; Krug, Harald F.; Rothen-Rutishauser, Barbara; Wick, PeterToxicology Letters (2011), 200 (3), 176-186CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)The close resemblance of carbon nanotubes to asbestos fibers regarding their high aspect ratio, biopersistence and reactivity increases public concerns on the widespread use of these materials. The purpose of this study was not only to address the acute adverse effects of industrially produced multiwalled carbon nanotubes (MWCNTs) on human lung and immune cells in vitro but also to further understand if their accumulation and biopersistence leads to long-term consequences or induces adaptive changes in these cells. In contrast to asbestos fibers, pristine MWCNTs did not induce overt cell death in A549 lung epithelial cells and Jurkat T lymphocytes after acute exposure to high doses of this material (up to 30 μg/mL). Nevertheless, very high levels of reactive oxygen species (ROS) and decreased metabolic activity were obsd. which might affect long-term viability of these cells. However, the continuous presence of low amts. of MWCNTs (0.5 μg/mL) for 6 mo did not have major adverse long-term effects although large amts. of nanotubes accumulated at least in A549 cells. Moreover, MWCNTs did not appear to induce adaptive mechanisms against particle stress in long-term treated A549 cells. Our study demonstrates that despite the high potential for ROS formation, pristine MWCNTs can accumulate and persist within cells without having major long-term consequences or inducing adaptive mechanisms.
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442Kisin, E. R.; Murray, A. R.; Keane, M. J.; Shi, X. C.; Schwegler-Berry, D.; Gorelik, O.; Arepalli, S.; Castranova, V.; Wallace, W. E.; Kagan, V. E.; Shvedova, A. A. J. Toxicol. Environ. Health, Part A 2007, 70, 2071There is no corresponding record for this reference.
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443Jacobsen, N. R.; Pojana, G.; White, P.; Møller, P.; Cohn, C. A.; Korsholm, K. S.; Vogel, U.; Marcomini, A.; Loft, S.; Wallin, H. Environ. Mol. Mutagen. 2008, 49, 476There is no corresponding record for this reference.
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444Wirnitzer, U.; Herbold, B.; Voetz, M.; Ragot, J. Toxicol. Lett. 2009, 186, 160444https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtF2jsbs%253D&md5=99240b13f4bf2a24b4fefbe64659c4cfStudies on the in vitro genotoxicity of baytubes, agglomerates of engineered multi-walled carbon-nanotubes (MWCNT)Wirnitzer, U.; Herbold, B.; Voetz, M.; Ragot, J.Toxicology Letters (2009), 186 (3), 160-165CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)The increasing prodn. and expanding application of nanoparticles in multiple aspects of life necessitate reliable safety assessment. In this context the authors here report on the evaluation of the potential genotoxicity of baytubes, i.e., agglomerates of multi-walled carbon-nanotubes (MWCNT). Testing for chromosome aberrations was done in V79 cells and for gene mutations in the Salmonella microsome test. Baytubes were formulated in deionized water at 10 mg/mL and treated with ultrasound for 30 min at 25°. Particle size distribution was detd. under the incubation conditions in the in vitro studies. In the chromosome aberration test V79 cells (OECD TG 473) were exposed in the absence or presence of S9 mix for 4 h to concns. of 2.5, 5 and 10 μg/mL of baytubes (visible from concn. of 5 μg/mL and higher). Harvest was 18 h after the beginning of the treatment. In addn., cells treated with 10 μg/mL were harvested 30 h after the beginning of the treatment. An addnl. expt. was performed using continuous treatment at 2.5, 5 and 10 μg/mL for 18 h (no S9 mix) with subsequent harvest. Under these conditions and in the concn. range tested there were no cytotoxic and no clastogenic effects. In the Salmonella microsome (Ames) test (OECD TG 471) concns. up to 5000 μg/plate were tested in Salmonella typhimurium (strains TA 1535, TA 100, TA 1537, TA 98 and TA 102) in the absence or presence of S9 mix. Under these conditions and in the concn. range tested there were no bacteriotoxic and no mutagenic effects.
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445Asakura, M.; Sasaki, T.; Sugiyama, T.; Takaya, M.; Koda, S.; Nagano, K.; Arito, H.; Fukushima, S. J. Occup. Health 2010, 52, 155445https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovFagtL0%253D&md5=35ddeba17fa9cb4c8141f567148ded12Genotoxicity and cytotoxicity of multi-wall carbon nanotubes in cultured Chinese hamster lung cells in comparison with chrysotile A fibersAsakura, Masumi; Sasaki, Toshiaki; Sugiyama, Toshie; Takaya, Mitsutoshi; Koda, Shigeki; Nagano, Kasuke; Arito, Heihachiro; Fukushima, ShojiJournal of Occupational Health (2010), 52 (3), 155-166CODEN: JOCHFV; ISSN:1341-9145. (Japan Society for Occupational Health)Objectives: The potential applications and industrial prodn. of multi-wall carbon nanotubes (MWCNT) have raised serious concerns about their safety for human health and the environment. The present study was designed to examine the in vitro cytotoxicity and genotoxicity of MWCNT and UICC chrysotile A (chrysotile). Methods: Cytotoxicity using both colony formation and lactate dehydrogenase (LDH) assays and genotoxicity including chromosome aberration, micronucleus induction and hgprt mutagenicity were examd. by exposing cultured Chinese hamster lung (CHL/IU) cells to MWCNT or chrysotile at different concns. Results: The in vitro cytotoxicity of MWCNT depended on the solvent used for suspension of MWCNT and ultrasonication duration of the MWCNT suspension. A combination of DMSO/culture medium and 3-min ultrasonication resulted in a well-dispersed medium with dispersion and isolation of agglomerated MWCNT by ultrasonication which manifested the highest cytotoxicity. The cytotoxicity was more potent for chrysotile than MWCNT. The genotoxicity of MWCNT was characterized by the formation of polyploidy without structural chromosome aberration, and an increased no. of bi- and multi-nucleated cells without micronucleus induction, as well as neg. hgprt mutagenicity. Chrysotile exhibited essentially the same genotoxicity as MWCNT, except for marginal but significant induction of micronuclei. MWCNT and chrysotile were incompletely internalized in the cells and localized in the cytoplasm. Conclusions: MWCNT and chrysotile were cytotoxic and genotoxic in Chinese hamster lung cells, but might interact indirectly with DNA. The results suggest that both test substances interfere phys. with biol. processes during cytokinesis.
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446Lindberg, H. K.; Falck, G. C.; Suhonen, S.; Vippola, M.; Vanhala, E.; Catalan, J.; Savolainen, K.; Norppa, H. Toxicol. Lett. 2009, 186, 166446https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtF2jsbg%253D&md5=c175ba5abb584c1b20becb1509d43c41Genotoxicity of nanomaterials: DNA damage and micronuclei induced by carbon nanotubes and graphite nanofibres in human bronchial epithelial cells in vitroLindberg, Hanna K.; Falck, Ghita C.-M.; Suhonen, Satu; Vippola, Minnamari; Vanhala, Esa; Catalan, Julia; Savolainen, Kai; Norppa, HannuToxicology Letters (2009), 186 (3), 166-173CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)Despite the increasing industrial use of different nanomaterials, data on their genotoxicity are scant. In the present study, we examd. the potential genotoxic effects of carbon nanotubes (CNTs; >50% single-walled, ∼40% other CNTs; 1.1 nm × 0.5-100 μm; Sigma-Aldrich) and graphite nanofibres (GNFs; 95%; outer diam. 80-200 nm, inner diam. 30-50 nm, length 5-20 μm; Sigma-Aldrich) in vitro. Genotoxicity was assessed by the single cell gel electrophoresis (comet) assay and the micronucleus assay (cytokinesis-block method) in human bronchial epithelial BEAS 2B cells cultured for 24 h, 48 h, or 72 h with various doses (1-100 μg/cm2, corresponding to 3.8-380 μg/mL) of the carbon nanomaterials. In the comet assay, CNTs induced a dose-dependent increase in DNA damage at all treatment times, with a statistically significant effect starting at the lowest dose tested. GNFs increased DNA damage at all doses in the 24-h treatment, at two doses (40 and 100 μg/cm2) in the 48-h treatment (dose-dependent effect) and at four doses (lowest 10 μg/cm2) in the 72-h treatment. In the micronucleus assay, no increase in micronucleated cells was obsd. with either of the nanomaterials after the 24-h treatment or with CNTs after the 72-h treatment. The 48-h treatment caused a significant increase in micronucleated cells at three doses (lowest 10 μg/cm2) of CNTs and at two doses (5 and 10 μg/cm2) of GNFs. The 72-h treatment with GNFs increased micronucleated cells at four doses (lowest 10 μg/cm2). No dose-dependent effects were seen in the micronucleus assay. The presence of carbon nanomaterial on the microscopic slides disturbed the micronucleus anal. and made it impossible at levels higher than 20 μg/cm2 of GNFs in the 24-h and 48-h treatments. In conclusion, our results suggest that both CNTs and GNFs are genotoxic in human bronchial epithelial BEAS 2B cells in vitro. This activity may be due to the fibrous nature of these carbon nanomaterials with a possible contribution by catalyst metals present in the materials-Co and Mo in CNTs (<5 wt.%) and Fe (<3 wt.%) in GNFs.
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447Yang, H.; Liu, C.; Yang, D.; Zhang, H.; Xi, Z. J. Appl. Toxicol. 2009, 29, 69447https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXptV2quw%253D%253D&md5=456ad454664878fb8f2bd567340f90baComparative study of cytotoxicity, oxidative stress and genotoxicity induced by four typical nanomaterials: the role of particle size, shape and compositionYang, Hui; Liu, Chao; Yang, Danfeng; Zhang, Huashan; Xi, ZhugeJournal of Applied Toxicology (2009), 29 (1), 69-78CODEN: JJATDK; ISSN:0260-437X. (John Wiley & Sons Ltd.)Although the biol. effects of some nanomaterials have already been assessed, information on toxicity and possible mechanisms of various particle types are insufficient. Moreover, the role of particle properties in the toxic reaction remains to be fully understood. In this paper, the authors aimed to explore the interrelation between particle size, shape, chem. compn., and toxicol. effects of 4 typical nanomaterials with comparable properties: carbon black (CB), single wall carbon nanotube, silicon dioxide (SiO2) and zinc oxide (ZnO) nanoparticles. The authors investigated the cytotoxicity, genotoxicity, and oxidative effects of particles on primary mouse embryo fibroblast cells. As obsd. in the Me thiazolyl tetrazolium (MTT) and water-sol. tetrazolium (WST) assays, ZnO induced much greater cytotoxicity than non-metal nanoparticles. This was significantly in accordance with intracellular oxidative stress levels measured by glutathione depletion, malondialdehyde prodn., superoxide dismutase inhibition as well as reactive oxygen species generation. The results indicated that oxidative stress may be a key route in inducing the cytotoxicity of nanoparticles. Compared with ZnO nanoparticles, carbon nanotubes were moderately cytotoxic but induced more DNA damage detd. by the comet assay. CB and SiO2 seemed to be less effective. The comparative anal. demonstrated that particle compn. probably played a primary role in the cytotoxic effects of different nanoparticles. However, the potential genotoxicity might be mostly attributed to particle shape.
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448Cveticanin, J.; Joksic, G.; Leskovac, A.; Petrovic, S.; Sobot, A. V.; Neskovic, O. Nanotechnology 2010, 21, 015102There is no corresponding record for this reference.
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449Migliore, L.; Saracino, D.; Bonelli, A.; Colognato, R.; D’Errico, M. R.; Magrini, A.; Bergamaschi, A.; Bergamaschi, E. Environ. Mol. Mutagen. 2010, 51, 294There is no corresponding record for this reference.
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450Fadeel, B.; Kagan, V. E. Redox Rep. 2003, 8, 143450https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXntVChtrY%253D&md5=ba2ee6f6cd4f6be85133c11560b8ac51Apoptosis and macrophage clearance of neutrophils: regulation by reactive oxygen speciesFadeel, Bengt; Kagan, Valerian E.Redox Report (2003), 8 (3), 143-150CODEN: RDRPE4; ISSN:1351-0002. (Maney Publishing)A review. Inflammation is a beneficial host response to foreign challenge involving numerous sol. factors and cell types, including polymorphonuclear granulocytes or neutrophils. Programmed cell death (apoptosis) of neutrophils has been documented in vitro as well as in vivo, and is thought to be important for the resoln. of inflammation, as this process allows for engulfment and removal of senescent cells prior to their necrotic disintegration. Studies in recent years have begun to unravel the mechanism of macrophage clearance of apoptotic cells, and evidence has accrued for a crit. role of externalization and oxidn. of plasma membrane phosphatidylserine, and its subsequent recognition by macrophage receptors, in this process. Activated neutrophils generate vast amts. of reactive oxygen species for the purpose of killing ingested microorganisms, and these reactive metabolites may also modulate the life-span, as well as the clearance, of the neutrophil itself. The authors address the latter topic, and summarize current knowledge on the mol. mechanisms of neutrophil apoptosis and macrophage clearance of these cells at the site of inflammation.
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451Pacurari, M.; Yin, X. J.; Zhao, J.; Ding, M.; Leonard, S. S.; Schwegler-Berry, D.; Ducatman, B. S.; Sbarra, D.; Hoover, M. D.; Castranova, V.; Vallyathan, V. Environ. Health Perspect. 2008, 116, 1211There is no corresponding record for this reference.
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452Vittorio, O.; Raffa, V.; Cuschieri, A. Nanomedicine 2009, 5, 424There is no corresponding record for this reference.
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453Haniu, H.; Matsuda, Y.; Takeuchi, K.; Kim, Y. A.; Hayashi, T.; Endo, M. Toxicol. Appl. Pharmacol. 2010, 242, 256453https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjt12htw%253D%253D&md5=f374d7ecafb04bf36ac6a84ccacc3075Proteomics-based safety evaluation of multi-walled carbon nanotubesHaniu, Hisao; Matsuda, Yoshikazu; Takeuchi, Kenji; Kim, Yoong-Ahm; Hayashi, Takuya; Endo, MorinobuToxicology and Applied Pharmacology (2010), 242 (3), 256-262CODEN: TXAPA9; ISSN:0041-008X. (Elsevier B.V.)This study evaluated the biol. responses to multi-walled carbon nanotubes (MWCNTs). Human monoblastic leukemia cells (U937) were exposed to As-grown MWCNTs and MWCNTs that were thermally treated at 1800° (HTT1800) and 2800° (HTT2800). Cell proliferation was highly inhibited by As-grown but not HTT2800. However, both As-grown and HTT1800, which include some impurities, were cytotoxic. Proteomics anal. of MWCNT-exposed cells revealed 37 protein spots on 2-dimensional electrophoresis gels that significantly changed after exposure to HTT1800 with a little iron and 20 spots that changed after exposure to HTT2800. Peptide mass fingerprinting identified 45 proteins that included heat shock protein β-1, neutral α-glucosidase AB, and DNA mismatch repair protein Msh2. These altered proteins play roles in metab., biosynthesis, response to stress, and cell differentiation. Although HTT2800 did not inhibit cell proliferation or cause cytotoxicity in vitro, some proteins related to the response to stress were changed. Moreover, DJ-1 protein, which is a biomarker of Parkinson's disease and is related to cancer, was identified after exposure to both MWCNTs. These results show that the cytotoxicity of MWCNTs depends on their impurities, such as iron, while MWCNTs themselves cause some biol. responses directly and/or indirectly in vitro. The authors' proteomics-based approach for detecting biol. responses to nanomaterials is a promising new method for detailed safety evaluations.
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454Vinzents, P. S.; Møller, P.; Sørensen, M.; Knudsen, L. E.; Hertel, O.; Jensen, F. P.; Schibye, B.; Loft, S. Environ. Health Perspect. 2005, 113, 1485There is no corresponding record for this reference.
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455Patlolla, A. K.; Hussain, S. M.; Schlager, J. J.; Patlolla, S.; Tchounwou, P. B. Environ. Toxicol. 2010, 25, 608There is no corresponding record for this reference.
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456Sargent, L. M.; Reynolds, S. H.; Castranova, V. Nanotoxicology 2010, 4, 396There is no corresponding record for this reference.
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457Karlsson, H. L.; Cronholm, P.; Gustafsson, J.; Möller, L. Chem. Res. Toxicol. 2008, 21, 1726457https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXpvFOht7Y%253D&md5=7736cadbc686269be5ca42b28ecfe297Copper Oxide Nanoparticles Are Highly Toxic: A Comparison between Metal Oxide Nanoparticles and Carbon NanotubesKarlsson, Hanna L.; Cronholm, Pontus; Gustafsson, Johanna; Moeller, LennartChemical Research in Toxicology (2008), 21 (9), 1726-1732CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Since the manuf. and use of nanoparticles are increasing, humans are more likely to be exposed occupationally or via consumer products and the environment. However, so far toxicity data for most manufd. nanoparticles are limited. The aim of this study was to investigate and compare different nanoparticles and nanotubes regarding cytotoxicity and ability to cause DNA damage and oxidative stress. The study was focused on different metal oxide particles (CuO, TiO2, ZnO, CuZnFe2O4, Fe3O4, Fe2O3), and the toxicity was compared to that of carbon nanoparticles and multiwalled carbon nanotubes (MWCNT). The human lung epithelial cell line A549 was exposed to the particles, and cytotoxicity was analyzed using trypan blue staining. DNA damage and oxidative lesions were detd. using the comet assay, and intracellular prodn. of reactive oxygen species (ROS) was measured using the oxidn.-sensitive fluoroprobe 2',7'-dichlorofluorescin diacetate (DCFH-DA). The results showed that there was a high variation among different nanoparticles concerning their ability to cause toxic effects. CuO nanoparticles were most potent regarding cytotoxicity and DNA damage. The toxicity was likely not explained by Cu ions released to the cell medium. These particles also caused oxidative lesions and were the only particles that induced an almost significant increase (p = 0.058) in intracellular ROS. ZnO showed effects on cell viability as well as DNA damage, whereas the TiO2 particles (a mix of rutile and anatase) only caused DNA damage. For iron oxide particles (Fe3O4, Fe2O3), no or low toxicity was obsd., but CuZnFe2O4 particles were rather potent in inducing DNA lesions. Finally, the carbon nanotubes showed cytotoxic effects and caused DNA damage in the lowest dose tested. The effects were not explained by sol. metal impurities. In conclusion, this study highlights the in vitro toxicity of CuO nanoparticles.
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458Deng, Z. J.; Liang, M.; Monteiro, M.; Toth, I.; Minchin, R. F. Nat. Nanotechnol. 2011, 6, 39458https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1Wju73P&md5=de9f322b14e197e47e6b1fe034525498Nanoparticle-induced unfolding of fibrinogen promotes Mac-1 receptor activation and inflammationDeng, Zhou J.; Liang, Mingtao; Monteiro, Michael; Toth, Istvan; Minchin, Rodney F.Nature Nanotechnology (2011), 6 (1), 39-44CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)The chem. compn., size, shape and surface characteristics of nanoparticles affect the way proteins bind to these particles, and this in turn influences the way in which nanoparticles interact with cells and tissues. Nanomaterials bound with proteins can result in physiol. and pathol. changes, including macrophage uptake, blood coagulation, protein aggregation and complement activation, but the mechanisms that lead to these changes remain poorly understood. Here, we show that neg. charged poly(acrylic acid)-conjugated gold nanoparticles bind to and induce unfolding of fibrinogen, which promotes interaction with the integrin receptor, Mac-1. Activation of this receptor increases the NF-κB signalling pathway, resulting in the release of inflammatory cytokines. However, not all nanoparticles that bind to fibrinogen demonstrated this effect. Our results show that the binding of certain nanoparticles to fibrinogen in plasma offers an alternative mechanism to the more commonly described role of oxidative stress in the inflammatory response to nanomaterials.
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459Sarkar, S.; Sharma, C.; Yog, R.; Periakaruppan, A.; Jejelowo, O.; Thomas, R.; Barrera, E. V.; Rice-Ficht, A. C.; Wilson, B. L.; Ramesh, G. T. J. Nanosci. Nanotechnol. 2007, 7, 584There is no corresponding record for this reference.
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460He, X.; Young, S. H.; Schwegler-Berry, D.; Chisholm, W. P.; Fernback, J. E.; Ma, Q. Chem. Res. Toxicol. 2011, 24, 2237There is no corresponding record for this reference.
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461Witzmann, F. A.; Monteiro-Riviere, N. A. Nanomedicine 2006, 2, 158There is no corresponding record for this reference.
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462Yuan, J.; Gao, H.; Ching, C. B. Toxicol. Lett. 2011, 207, 213462https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtl2htrrL&md5=bb50a718aa915a403025a530e623f7acComparative protein profile of human hepatoma HepG2 cells treated with graphene and single-walled carbon nanotubes: An iTRAQ-coupled 2D LC-MS/MS proteome analysisYuan, Jifeng; Gao, Hongcai; Ching, Chi BunToxicology Letters (2011), 207 (3), 213-221CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)Graphitic nanomaterials are promising candidates for applications in electronics, energy, materials and biomedical areas. Nevertheless, few detailed studies related to the mechanistic understanding of these nanomaterials with the living systems have been performed to date. In the present study, the authors' group applied the iTRAQ-coupled 2D LC-MS/MS approach to analyze the protein profile change of human hepatoma HepG2 cells treated with graphene and single-walled carbon nanotubes (SWCNTs), with the purpose of characterizing the interactions between living system and these nanomaterials at mol. level. Overall 37 differentially expressed proteins involved in metabolic pathway, redox regulation, cytoskeleton formation and cell growth were identified. Based on the protein profile, the authors found SWCNTs severely interfered the intracellular metabolic routes, protein synthesis and cytoskeletal systems. Moreover, the authors' data suggested that SWCNTs might induce oxidative stress, thereby activating p53-mediated DNA damage checkpoint signals and leading to apoptosis. However, only moderate variation of protein levels for the cells treated with graphene was obsd., which indicated graphene was less toxic and might be promising candidate for biomedical applications. The authors envision that this systematic characterization of cellular response at protein expression level will be of great importance to evaluate biocompatibility of nanomaterials.
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463Haniu, H.; Matsuda, Y.; Usui, Y.; Aoki, K.; Shimizu, M.; Ogihara, N.; Hara, K.; Okamoto, M.; Takanashi, S.; Ishigaki, N.; Nakamura, K.; Kato, H.; Saito, N. J. Proteomics 2011, 74, 2703463https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVOjt77E&md5=328d0cb0fba04777b76adc8c59d2aa29Toxicoproteomic evaluation of carbon nanomaterials in vitroHaniu, Hisao; Matsuda, Yoshikazu; Usui, Yuki; Aoki, Kaoru; Shimizu, Masayuki; Ogihara, Nobuhide; Hara, Kazuo; Okamoto, Masanori; Takanashi, Seiji; Ishigaki, Norio; Nakamura, Koichi; Kato, Hiroyuki; Saito, NaotoJournal of Proteomics (2011), 74 (12), 2703-2712CODEN: JPORFQ; ISSN:1874-3919. (Elsevier B.V.)A review. Carbon nanotubes (CNTs) have already been successfully implemented in various fields, and they are anticipated to have innovative applications in medical science. However, CNTs have asbestos-like properties, such as their nanoscale size and high aspect ratio (> 100). Moreover, CNTs may persist in the body for a long time. These properties are thought to cause malignant mesothelioma and lung cancer. However, based on conventional toxicity assessment systems, the carcinogenicity of asbestos and CNTs is unclear. The reason for late countermeasures against asbestos is that reliable, long-term safety assessments have not yet been developed by toxicologists. Therefore, a new type of long-term safety assessment, different from the existing methods, is needed for carbon nanomaterials. Recently, we applied a proteomic approach to the safety assessment of carbon nanomaterials. In this review, we discuss the basic concept of our approach, the results, the problems, and the possibility of a long-term safety assessment for carbon nanomaterials using the toxicoproteomic approach.
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464Snyder-Talkington, B. N.; Pacurari, M.; Dong, C.; Leonard, S. S.; Schwegler-Berry, D.; Castranova, V.; Qian, Y.; Guo, N. L. Toxicol. Sci. 2013, 133, 79464https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmt1Ohtr0%253D&md5=ad4c2a8954f782ca23e0077edd6188aaSystematic Analysis of Multiwalled Carbon Nanotube-Induced Cellular Signaling and Gene Expression in Human Small Airway Epithelial CellsSnyder-Talkington, Brandi N.; Pacurari, Maricica; Dong, Chunlin; Leonard, Stephen S.; Schwegler-Berry, Diane; Castranova, Vincent; Qian, Yong; Guo, Nancy L.Toxicological Sciences (2013), 133 (1), 79-89CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)Multiwalled carbon nanotubes (MWCNT) are one of the most commonly produced nanomaterials, and pulmonary exposure during prodn., use, and disposal is a concern for the developing nanotechnol. field. The airway epithelium is the first line of defense against inhaled particles. In a mouse model, MWCNT were reported to reach the alveolar space of the lung after in vivo exposure, penetrate the epithelial lining, and result in inflammation and progressive fibrosis. This study sought to det. the cellular and gene expression changes in small airway epithelial cells (SAEC) after in vitro exposure to MWCNT in an effort to elucidate potential toxicity mechanisms and signaling pathways. A direct interaction between SAEC and MWCNT was confirmed by both internalization of MWCNT and interaction at the cell periphery. Following exposure, SAEC showed time-dependent increases in reactive oxygen species prodn., total protein phosphotyrosine and phosphothreonine levels, and migratory behavior. Anal. of gene and protein expression suggested altered regulation of multiple biomarkers of lung damage, carcinogenesis, and tumor progression, as well as genes involved in related signaling pathways. These results demonstrate that MWCNT exposure resulted in the activation of SAEC. Gene expression data derived from MWCNT exposure provide information that may be used to elucidate the underlying mode of action of MWCNT in the small airway and suggest potential prognostic gene signatures for risk assessment.
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465Lacerda, L.; Herrero, M. A.; Venner, K.; Bianco, A.; Prato, M.; Kostarelos, K. Small 2008, 4, 1130There is no corresponding record for this reference.
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466Helfenstein, M.; Miragoli, M.; Rohr, S.; Muller, L.; Wick, P.; Mohr, M.; Gehr, P.; Rothen-Rutishauser, B. Toxicology 2008, 253, 70There is no corresponding record for this reference.
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467ISO 10993. Biological Evaluation of Medical Devices. 2000–2012.There is no corresponding record for this reference.
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468Shi, H.; Magaye, R.; Castranova, V.; Zhao, J. Part. Fibre Toxicol. 2013, 10, 15468https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXns1Ors74%253D&md5=ba824ec86ab5bb3bd6f203acf969b3f3Titanium dioxide nanoparticles: a review of current toxicological dataShi, Hongbo; Magaye, Ruth; Castranova, Vincent; Zhao, JinshunParticle and Fibre Toxicology (2013), 10 (), 15CODEN: PFTABQ; ISSN:1743-8977. (BioMed Central Ltd.)A review. Titanium dioxide (TiO2) nanoparticles (NPs) are manufd. worldwide in large quantities for use in a wide range of applications. TiO2 NPs possess different physicochem. properties compared to their fine particle (FP) analogs, which might alter their bioactivity. Most of the literature cited here has focused on the respiratory system, showing the importance of inhalation as the primary route for TiO2 NP exposure in the workplace. TiO2 NPs may translocate to systemic organs from the lung and gastrointestinal tract (GIT) although the rate of translocation appears low. There have also been studies focusing on other potential routes of human exposure. Oral exposure mainly occurs through food products contg. TiO2 NP-additives. Most dermal exposure studies, whether in vivo or in vitro, report that TiO2 NPs do not penetrate the stratum corneum (SC). In the field of nanomedicine, I.V. injection can deliver TiO2 nanoparticulate carriers directly into the human body. Upon I.V. exposure, TiO2 NPs can induce pathol. lesions of the liver, spleen, kidneys, and brain. We have also shown here that most of these effects may be due to the use of very high doses of TiO2 NPs. There is also an enormous lack of epidemiol. data regarding TiO2 NPs in spite of its increased prodn. and use. However, long-term inhalation studies in rats have reported lung tumors. This review summarizes the current knowledge on the toxicol. of TiO2 NPs and points out areas where further information is needed.
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469Kashuk, K. B.; Haber, E. Clin. Podiatry 1984, 1, 131469https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2M3lsFGktw%253D%253D&md5=7115f04963cfe8e03ff4744772efcf38Tendon and ligament prosthesesKashuk K B; Haber EClinics in podiatry (1984), 1 (1), 131-43 ISSN:0742-0668.The topic of artificial tendons and ligaments for the foot and ankle has been investigated. Close attention has been given to three implants, the Silastic-rod implant, the carbon-fiber implant, and Marlex mesh. A brief historical background was given to the development of the lateral ankle reconstructive procedures and to the development of the individual artificial prostheses. The biologic reactions produced by the implants have been presented. Carbon-fiber implants and Marlex mesh induce a fibrous growth that produces a neotendon or neoligament, depending on their use. Silastic-rod implantation establishes a hollow tube with qualities very similar to the normal tendon sheath. Carbon fiber and Marlex mesh are directly implanted and used as a temporary tendon or ligament. During this time, they act as a scaffold on which the new tendon or ligament is formed. Silastic-rod implants are incorporated into a two-stage tendon-graft procedure. The Silastic rod is used during stage one to develop a new tendon sheath. Placement of an autologous tendon within the newly formed sheath occurs in stage two. Details of the actual procedure have been presented. Any tendon used in the transfer should be of similar strength with similar expansive qualities. These implants have many potential uses in podiatry. They are particularly useful in trauma cases and patients that present with ankle instability. Research pertaining to the development of an ideal suture and anastomosis technique is still needed.
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470Parsons, J. R.; Weiss, A. B.; Schenk, R. S.; Alexander, H.; Pavlisko, F. Foot Ankle 1989, 9, 179470https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1M3nslSrsQ%253D%253D&md5=f6d1479ec2711804b36c4e4b91530d02Long-term follow-up of achilles tendon repair with an absorbable polymer carbon fiber compositeParsons J R; Weiss A B; Schenk R S; Alexander H; Pavlisko FFoot & ankle (1989), 9 (4), 179-84 ISSN:0198-0211.In this cooperative multicenter study for surgical repair of Achilles tendon rupture using a composite implant, 48 patients underwent 52 procedures. This implant is composed of filamentous uniaxially aligned carbon fibers coated with an absorbable polymer. This highly biocompatible implant acts as a scaffold for regrowth of collagenous tissue. The early strength of this repair is provided by the composite implant and by the rapid ingrowth and attachment of new tissue, which allows for an earlier and more vigorous rehabilitation program. Patients with a minimum follow-up of 1 year form the basis of this article. The overall average follow-up is 2.1 years. Three cohort groups were observed on a temporal basis and quantitatively evaluated at 1 year (N = 29), 18 months (N = 22), and 2 years (N = 20), respectively. These three groups demonstrated continuous improvement during the first postoperative year. A high level of function was maintained throughout the second year. Repair of chronic injuries (N = 15) was compared with repair of acute injuries (N = 12) at 1 year following surgery. Both groups greatly improved. However, the acute group had more serious preoperative deficits but improved to a slightly better overall level. Of the patients having at least 1 year follow-up, 86% had a good or excellent result. There was no increased morbidity associated with the use of the carbon implant.
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471Moreira-Gonzalez, A.; Jackson, I. T.; Miyawaki, T.; DiNick, V.; Yavuzer, R. Plast. Reconstr. Surg. 2003, 111, 1808471https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s7ptlSjtA%253D%253D&md5=fef1898a74767bf3b9b4525ec9e6481eAugmentation of the craniomaxillofacial region using porous hydroxyapatite granulesMoreira-Gonzalez Andrea; Jackson Ian T; Miyawaki Takeshi; DiNick Vincent; Yavuzer RehaPlastic and reconstructive surgery (2003), 111 (6), 1808-17 ISSN:0032-1052.Augmentation of the craniomaxillofacial region is required for many aesthetic and reconstructive procedures. A variety of different materials and techniques have been used. Coralline hydroxyapatite has proved to have biocompatible properties as a bone graft substitute. This study further analyzes the use of porous coral-derived hydroxyapatite granules in craniomaxillofacial augmentation for cosmetic and reconstructive purposes and evaluates the long-term clinical result. This retrospective study reviewed the use of porous coral-derived hydroxyapatite granules over a 20-year period, between 1981 and 2001, in 180 patients, in whom 393 procedures were performed. The surgical technique is described and discussed. Statistical significance was evaluated by descriptive statistics and the correlation bivariate Spearman's test (p > 0.05). For 61.6 percent of the procedures, the surgical indication was reconstructive and in 38.4 percent, cosmetic. The maxilla was the most common site of surgery (44.3 percent), followed by the mandible (21.6 percent) and zygoma (15.4 percent). The complication rate was 5.6 percent (n = 22 of 393), with contour irregularities being responsible for 59 percent (n = 13 of 22). Both infection and granule extrusion were responsible for 1.3 percent of the complications. Good results were achieved in 96.4 percent of the procedures. Porous coral-derived hydroxyapatite granules have shown considerable efficacy and versatility in craniofacial contour refinement and augmentation. They are stable, biocompatible, and safe. A sterile technique is advised, with care taken not to tear the periosteum in the pocket design and with subperiosteal placement of the granules, compaction of the granules at the site, overcorrection of 15 percent of the required total volume, watertight closure, and postoperative taping to prevent mobilization. The correct surgical indications and adherence to the principles stated above will result in a very satisfactory long-term outcome.
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472Tamimi, F.; Torres, J.; Bassett, D.; Barralet, J.; Cabarcos, E. L. Biomaterials 2010, 31, 2762There is no corresponding record for this reference.
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473Goff, T.; Kanakaris, N. K.; Giannoudis, P. V. Injury 2013, 44, S86There is no corresponding record for this reference.
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474Ciftcioglu, N.; Aho, K. M.; McKay, D. S.; Kajander, E. O. Lancet 2007, 369, 2078There is no corresponding record for this reference.
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475Jacobsen, E.; Tønning, K.; Pedersen, E.; Serup, J.; Nielsen, E. Chemical Substances in Tattoo Ink. Survey of chemical substances in consumer products no. 116; Miljøstyrelsen: København, 2012.There is no corresponding record for this reference.
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476Lehman, J. H.; Terrones, M.; Mansfield, E.; Hurst, K.; Muenier, V. Carbon 2011, 49, 2581There is no corresponding record for this reference.
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477U.S. Department of Health and Human Services Food and Drug Administration Office of the Commissioner. Considering whether an FDA-regulated product involves the application of nanotechnology: guidance for industry. Regulatory Information, 2011.There is no corresponding record for this reference.
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478ISO/TS 27687: 2008, Nanotechnologies - Terminology and definitions for nano-objects -nanoparticle, nanofibre and nanoplatè, 2008.There is no corresponding record for this reference.
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479Chen, Z.; Mao, R.; Liu, Y. Curr. Drug Metab. 2012, 13, 1035479https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVWgtbjM&md5=4aca96cbf3b0db139368a7f9a98e75e1Fullerenes for cancer diagnosis and therapy: preparation, biological and clinical perspectivesChen, Zhiyun; Mao, Ruoqing; Liu, YingCurrent Drug Metabolism (2012), 13 (8), 1035-1045CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)A review. Cancer is a major public health problem in the world. There is a great need to apply novel technologies and drugs to revolutionize multiple aspects of cancer diagnosis and therapy. Advances in nanotechnol. and nanomaterials have the potential to achieve the objective of early diagnosis and early therapy of cancer in the future. During the past few years, fullerene and its derivs. have been considered as some of the most promising nanomaterials because of their unique properties that enable a variety of medicinal applications. They can deliver drugs or small therapeutic mols. to the cancer cells. In this review, we will discuss how fullerene derivs. have been introduced into the field of cancer diagnosis and therapy. It will be highlighted that fullerene derivs. are used as anti-tumor drugs. Furthermore, prepn., characterization, pharmacokinetics and bio-distribution of fullerene and its derivs. reported in recent years will be summarized.
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480Mao, H. Y.; Laurent, S.; Chen, W.; Akhavan, O.; Imani, M.; Ashkarran, A. A.; Mahmoudi, M. Chem. Rev. 2013, 113, 3407480https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtlWgsr4%253D&md5=60b2210538d933d20f63c16e30e365e7Graphene: Promises, Facts, Opportunities, and Challenges in NanomedicineMao, Hong Ying; Laurent, Sophie; Chen, Wei; Akhavan, Omid; Imani, Mohammad; Ashkarran, Ali Akbar; Mahmoudi, MortezaChemical Reviews (Washington, DC, United States) (2013), 113 (5), 3407-3424CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review about the synthesis, toxicity, and biomedical applications of graphene and graphene oxide.
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481Misra, R. D.; Chaudhari, P. M. J. Biomed. Mater. Res., Part A 2013, 101, 528481https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVCkt73M&md5=cac1839e1d71f75d1fae517394b61098Cellular interactions and stimulated biological functions mediated by nanostructured carbon for tissue reconstruction and tracheal tubes and suturesMisra, R. D. K.; Chaudhari, P. M.Journal of Biomedical Materials Research, Part A (2013), 101A (2), 528-536CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)Nylon 6,6 is used for biol. applications including gastrointestinal segments, tracheal tubes and sutures, vascular graft, and for hard tissue reconstruction. While it is a relatively inexpensive polymer, it is not widely acceptable as a preferred biomaterial because of bioactivity. To this end, we have discovered the exciting evidence that introduction of a novel nanostructured carbon, graphene, in the void space between the nylon chains and processing at elevated pressure favorably stimulates cellular functions and provides high degree of cytocompatibility. The cell-substrate interactions on stand alone Nylon 6,6 and Nylon 6,6-graphene oxide hybrid system were investigated in terms of cell attachment, viability, proliferation, and assessment of proteins, actin, vinculin, and fibronectin. The enhanced biol. functions in the nanostructured hybrid system are attributed to relatively superior hydrophilicity of the surface and to the presence of graphene. Furthermore, it is proposed that the neg. charged graphene interacts with the polar nature of cells and the culture medium, such that the interaction is promoted through polar forces. This is accomplished by investigating cell attachment, proliferation, and morphol., including cytomorphometry evaluation, and quant. assessment of prominent proteins, actin, vinculin, and fibronectin that are sensitive to cell-substrate interactions. Osteoblasts were studied to establish the practical viability of the hybrid nanostructured biomaterial. The study strengthens the foundation for utilizing nano- or quantum-size effects of nanostructured biomaterials. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.
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482Ando, K.; Saitoh, A.; Hino, O.; Takahashi, R.; Kimura, M.; Katsuki, M. Cancer Res. 1992, 52, 978There is no corresponding record for this reference.
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483Long, G. G.; Morton, D.; Peters, T.; Short, B.; Skydsgaard, M. Toxicol. Pathol. 2010, 38, 43483https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c7isFSqsg%253D%253D&md5=439f5af98f835038f1d63e693f74874eAlternative mouse models for carcinogenicity assessment: industry use and issues with pathology interpretationLong Gerald G; Morton Daniel; Peters Terry; Short Brian; Skydsgaard MikalaToxicologic pathology (2010), 38 (1), 43-50 ISSN:.The Carcinogenicity Alternative Mouse Models (CAMM) Working Group of the Society of Toxicologic Pathology (STP) surveyed the membership to define current practices and opinions in industry regarding the use of alternative mouse models for carcinogenicity testing. The results of the survey indicated that CAMM are used most often to fulfill a regulatory requirement (e.g., to replace the two-year mouse bioassay) and are being accepted by regulatory agencies. Alternative models are also sometimes used for internal decision making or to address a mechanistic question. The CAMM most commonly used are the p53+/- and rasH2. The rasH2 appears to be the currently accepted model for general carcinogenicity testing. Problems with study interpretation included lack of historic background data, unexpected tumor finding, and tumor identification/characterization of early lesions. Problems with implementation or conduct of the study included extent of the pathology evaluation, numbers of animals, survival, and study duration. Recommendations were developed for, frequency and type of positive control testing, extent of histopathologic examination of test article-treated and positive control animals, current use and future development of diagnostic criteria; increased availability and use of historic data, and use of other genetically modified mice in carcinogenicity testing.
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484Boverhof, D. R.; Chamberlain, M. P.; Elcombe, C. R.; Gonzalez, F. J.; Heflich, R. H.; Hernandez, L. G.; Jacobs, A. C.; Jacobson-Kram, D.; Luijten, M.; Maggi, A.; Manjanatha, M. G.; Benthem, J.; Gollapudi, B. B. Toxicol. Sci. 2011, 121, 207484https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmsVykt7c%253D&md5=bfd834146966cb6a405e173a60ee64e6Transgenic Animal Models in Toxicology: Historical Perspectives and Future OutlookBoverhof, Darrell R.; Chamberlain, Mark P.; Elcombe, Clifford R.; Gonzalez, Frank J.; Heflich, Robert H.; Hernandez, Lya G.; Jacobs, Abigail C.; Jacobson-Kram, David; Luijten, Mirjam; Maggi, Adriana; Manjanatha, Mugimane G.; van Benthem, Jan; Gollapudi, B. BhaskarToxicological Sciences (2011), 121 (2), 207-233CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)A review. Transgenic animal models are powerful tools for developing a more detailed understanding on the roles of specific genes in biol. pathways and systems. Applications of these models have been made within the field of toxicol., most notably for the screening of mutagenic and carcinogenic potential and for the characterization of toxic mechanisms of action. It has long been a goal of research toxicologists to use the data from these models to refine hazard identification and characterization to better inform human health risk assessments. This review provides an overview on the applications of transgenic animal models in the assessment of mutagenicity and carcinogenicity, their use as reporter systems, and as tools for understanding the roles of xenobiotic-metabolizing enzymes and biol. receptors in the etiol. of chem. toxicity. Perspectives are also shared on the future outlook for these models in toxicol. and risk assessment and how transgenic technologies are likely to be an integral tool for toxicity testing in the 21st century.
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485Urano, K.; Tamaoki, N.; Nomura, T. Vet. Pathol. 2012, 49, 16485https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivVejsb4%253D&md5=2dd4dbedc4c952a00922cb7f9796cacbEstablishing a laboratory animal model from a transgenic animal: RasH2 mice as a model for carcinogenicity studies in regulatory scienceUrano, K.; Tamaoki, N.; Nomura, T.Veterinary Pathology (2012), 49 (1), 16-23CODEN: VTPHAK; ISSN:0300-9858. (Sage Publications)A review. Transgenic animal models have been used in small nos. in gene function studies in vivo for a period of time, but more recently, the use of a single transgenic animal model has been approved as a second species, 6-mo alternative (to the routine 2-yr, 2-animal model) used in short-term carcinogenicity studies for generating regulatory application data of new drugs. This article addresses many of the issues assocd. with the creation and use of one of these transgenic models, the rasH2 mouse, for regulatory science. The discussion includes strategies for mass producing mice with the same stable phenotype, including constructing the transgene, choosing a founder mouse, and controlling both the transgene and background genes; strategies for developing the model for regulatory science, including measurements of carcinogen susceptibility, stability of a large-scale prodn. system, and monitoring for uniform carcinogenicity responses; and finally, efficient use of the transgenic animal model on study. Approx. 20% of mouse carcinogenicity studies for new drug applications in the United States currently use transgenic models, typically the rasH2 mouse. The rasH2 mouse could contribute to animal welfare by reducing the nos. of animals used as well as reducing the cost of carcinogenicity studies. A better understanding of the advantages and disadvantages of the transgenic rasH2 mouse will result in greater and more efficient use of this animal model in the future.
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486Urano, K.; Suzuki, S.; Machida, K.; Sawa, N.; Eguchi, N.; Kikuchi, K.; Fukasawa, K.; Taguchi, F.; Usui, T. J. Toxicol. Sci. 2006, 31, 407486https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s%252FgslWitA%253D%253D&md5=94864429ab756a7c31157cdf52312042Use of IC tags in short-term carcinogenicity study on CB6F1 TGrasH2 miceUrano Koji; Suzuki Syuzo; Machida Kazuhiko; Sawa Nobuko; Eguchi Natsuko; Kikuchi Koji; Fukasawa Kazumasa; Taguchi Fukushi; Usui ToshimiThe Journal of toxicological sciences (2006), 31 (5), 407-18 ISSN:0388-1350.We studied the effect of IC tags, subcutaneously implanted animal identification tools, on rasH2 mice. A 26-week short-term carcinogenicity study was performed on a total of 299 mice including 75 male and female rasH2 mice each, and 74 male and 75 female non-Tg mice from the same litter as the rasH2 mice divided into a non-IC tag group, the IC-tag group, acetone group, TPA group and MNU group (all of the animals except for those in the non-IC tag group) had IC tags implanted subcutaneously in their backs. The administration methods of the positive control drugs TPA (2.5 micro g/kg, 3 times/week, percutaneously) and MNU (75 mg/kg, single intraperitoneal injection) were based on the protocol of the ILSI/HESI international collaborative study. The results showed no differences in the tumorigenic incidence and organs developing tumors between the IC tag and non-IC tag groups in both rasH2 and non-Tg mice. In the positive control MNU group, the tumorigenic incidence and organs developing tumors were the same as the background data and no promotion of carcinogenesis was observed. In all IC tag groups including the TPA group and MNU group, a fibrous capsule was formed around the IC tags subcutaneously, but no inflammatory changes or neoplastic changes were observed. From these findings, it was concluded that the IC tag has no effect on a 26-week carcinogenicity test of rasH2 mice under the conditions of the present study.
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487Urano, K.; Suzuki, S.; Machida, K.; Eguchi, N.; Sawa, N.; Kikuchi, K.; Hattori, Y.; Usui, T. J. Toxicol. Sci. 2007, 32, 367487https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXitV2jtw%253D%253D&md5=c6a01ce981199fae1c30e1a378dafe63Examination of percutaneous application in a 26-week carcinogenicity test in CB6F1-TG rasH2 miceUrano, Koji; Suzuki, Shuzo; Machida, Kazuhiko; Eguchi, Natsuko; Sawa, Nobuko; Kikuchi, Koji; Hattori, Yuji; Usui, ToshimiJournal of Toxicological Sciences (2007), 32 (4), 367-375CODEN: JTSCDR; ISSN:0388-1350. (Japanese Society of Toxicology)We examd. the possibility of expanding applications of rasH2 mice, which are genetically manipulated mice for short-term carcinogenicity tests, to percutaneous application. A 26-wk short-term carcinogenicity study was performed on a total of 300 mice including 75 male and female rasH2 mice each, and 75 male and female non-Tg mice each from the same litter as the rasH2 mice divided into untreated group, an ethanol group, a white Vaseline group, an acetone group, and a phorbol 12-myristate 13-acetate (TPA) group. Only shaving of dorsal skin was performed on the untreated mice. As a pos. control, TPA was administered percutaneously at a dose of 2.5 μg/kg and 3 times/wk for 26 wk based on the protocol for Tg.AC mice in the ILSI/HESI international validation study. In the ethanol, white Vaseline, and acetone groups, no tumorous changes were obsd. on the skin at the administration site. In the TPA group, nodular changes at the administration site were obsd. from seven weeks after the start of administration in rasH2 mice, and the incidence in males and females was 50.0% (7/14) and 53.3% (8/15), resp. In a pathol. examn., nodules in 21.4% (3/14) of males and 46.7% (7/15) of females were diagnosed as skin papilloma or keratoacanthoma, and the rest as squamous cell hyperplasia. In the non-Tg mice, no nodules or tumorigenic changes were obsd. at the administration site. These findings show that percutaneous application in rasH2 mice is possible in 26-wk carcinogenicity tests.
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488Palazzi, X.; Kergozien-Framery, S. Exp. Toxicol. Pathol. 2009, 61, 433488https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MrlsVOktQ%253D%253D&md5=31809ecaa45974be189dba8edaa33c9fUse of rasH2 transgenic mice for carcinogenesis testing of medical implantsPalazzi Xavier; Kergozien-Framery SylvieExperimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie (2009), 61 (5), 433-41 ISSN:.Several transgenic mice models are accepted by regulatory agencies to determine the carcinogenic potential and predict the human response to exposure of chemicals, as an alternative to the conventional 2-year rodent bioassay. The rasH2 transgenic mouse model has been proposed to evaluate the carcinogenic potential of medical devices, but few data are currently available regarding study design--namely appropriate positive and negative controls to be used--as well as historical pathology data. BIOMATECH-NAMSA recently conducted a 26-week carcinogenicity study following subcutaneous implantation in the transgenic rasH2 mouse model. This paper describes the study design and the main results obtained in the positive and negative control groups. The survival rate statistical (Kaplan-Meier) analysis showed that the survival rate was significantly affected by the occurrence of tumors in the positive control group when compared to the negative control group, in both genders. Thymic malignant lymphomas and squamous cell papillomas were reported to occur at a higher incidence in rasH2 mice exposed to a known chemical carcinogen, for terminally sacrificed animals as well as for unscheduled and terminally sacrificed animals considered together. Background and age-related lesions were few. Taken together, these data confirmed the reliability and usefulness of the rasH2 transgenic model in the assessment of carcinogenic properties of medical devices. A major beneficial property of this animal model consisted in the ability to demonstrate chemical carcinogenesis response without the solid-state tumorigenesis response seen in traditional 2-year rodent bioassays.
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489Madani, S. Y.; Naderi, N.; Dissanayake, O.; Tan, A.; Seifalian, A. M. Int. J. Nanomed. 2011, 6, 2963489https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1entL3L&md5=5167b76f2c82fbc9c43abba3eb7b003eA new era of cancer treatment: carbon nanotubes as drug delivery toolsMadani, Seyed Yazdan; Naderi, Naghmeh; Dissanayake, Oshani; Tan, Aaron; Seifalian, Alexander M.International Journal of Nanomedicine (2011), 6 (), 2963-2979CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)A review. Cancer is a generic term that encompasses a group of diseases characterized by an uncontrolled proliferation of cells. There are over 200 different types of cancer, each of which gains its nomenclature according to the type of tissue the cell originates in. Many patients who succumb to cancer do not die as a result of the primary tumor, but because of the systemic effects of metastases on other regions away from the original site. One of the aims of cancer therapy is to prevent the metastatic process as early as possible. There are currently many therapies in clin. use and recent advances in biotechnol. lend credence to the potential of nanotechnol. in the fight against cancer. Nanomaterials such as carbon nanotubes (CNTs), quantum dots and dendrimers have unique properties that can be exploited for diagnostic purposes, thermal ablation and drug delivery in cancer. CNTs are tubular materials with nanometer-sized diams. and axial symmetry, giving them unique properties that can be exploited in the diagnosis and treatment of cancer. In addn., CNTs have the potential to deliver drugs directly to targeted cells and tissues. Alongside the rapid advances in the development of nanotechnol.-based materials, elucidating the toxicity of nanoparticles is also imperative. Hence, in this review, we seek to explore the biomedical applications of CNTs, with particular emphasis on their use as therapeutic platforms in oncol.
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490Heister, E.; Brunner, E. W.; Dieckmann, G. R.; Jurewicz, I.; Dalton, A. B. ACS Appl. Mater. Interfaces 2013, 5, 1870There is no corresponding record for this reference.
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491Madani, S. Y.; Shabani, F.; Dwek, M. V.; Seifalian, A. M. Int. J. Nanomed. 2013, 8, 941There is no corresponding record for this reference.
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492Tang, S.; Tang, Y.; Zhong, L.; Murat, K.; Asan, G.; Yu, J.; Jian, R.; Wang, C.; Zhou, P. J. Appl. Toxicol. 2012, 32, 900492https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvVektLw%253D&md5=4afc234d3aa5537d8af864b9a2225319Short- and long-term toxicities of multi-walled carbon nanotubes in vivo and in vitroTang, Shaoxian; Tang, Yuechao; Zhong, Lingling; Murat, Kumuruz; Asan, Gvlqikra; Yu, Jerry; Jian, Rongrong; Wang, Changchun; Zhou, PingJournal of Applied Toxicology (2012), 32 (11), 900-912CODEN: JJATDK; ISSN:0260-437X. (John Wiley & Sons Ltd.)As nanomaterials are developed and applied, their potential for health hazards needs to be detd. In the present study, we used com. nude multi-walled carbon nanotubes (MWCNTs) trimmed to a short length (50-200 nm; s-MWCNTs) and synthesized functionalized MWCNTs with polyethylene glycol (PEG) (s-MWCNTs-PEG). We then studied the toxic effects of s-MWCNTs and s-MWCNTs-PEG on cultured cells and in a mouse model. Peripheral haemograms and various biochem. markers of the heart, liver and kidney were measured. We found no toxicity of either type of nanotube on the viability of human SKBR-3 breast carcinoma cells or control cells. There were no differences in vivo on inflammatory responses, the coagulation system, haemograms or vital organ functions between the test and control groups. Addnl., we found no toxicity of these nanotubes on male mouse sperm prodn. or mutagenesis in the long term. In conclusion, both s-MWCNTs and s-MWCNTs-PEG displayed good in vitro and in vivo biocompatibility, making future applications in biol. and clin. therapy as a carrier for drug delivery feasible. Copyright © 2012 John Wiley & Sons, Ltd.
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493The Organisation for Economic Cooperation and Development (OECD). Six years of OECD work on the safety of manufactured nanomaterials: Achievements and future opportunities. OECD brochure: Overview, 2012.There is no corresponding record for this reference.
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494Jia, G.; Wang, H.; Yan, L.; Wang, X.; Pei, R.; Yan, T.; Zhao, Y.; Guo, X. Environ. Sci. Technol. 2005, 39, 1378494https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1Grtw%253D%253D&md5=873bc79c2ce6f8b05b5efd10dd7a2e3fCytotoxicity of Carbon Nanomaterials: Single-Wall Nanotube, Multi-Wall Nanotube, and FullereneJia, Guang; Wang, Haifang; Yan, Lei; Wang, Xiang; Pei, Rongjuan; Yan, Tao; Zhao, Yuliang; Guo, XinbiaoEnvironmental Science and Technology (2005), 39 (5), 1378-1383CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)A cytotoxicity test protocol for single-wall nanotubes (SWNTs), multi-wall nanotubes (with diams. ranging from 10 to 20 nm, MWNT10), and fullerene (C60) was tested. Profound cytotoxicity of SWNTs was obsd. in alveolar macrophage (AM) after a 6-h exposure in vitro. The cytotoxicity increases by as high as ∼35% when the dosage of SWNTs was increased by 11.30 μg/cm2. No significant toxicity was obsd. for C60 up to a dose of 226.00 μg/cm2. The cytotoxicity apparently follows a sequence order on a mass basis: SWNTs > MWNT10 > quartz > C60. SWNTs significantly impaired phagocytosis of AM at the low dose of 0.38 μg/cm2, whereas MWNT10 and C60 induced injury only at the high dose of 3.06 μg/cm2. The macrophages exposed to SWNTs or MWNT10 of 3.06 μg/cm2 showed characteristic features of necrosis and degeneration. A sign of apoptotic cell death likely existed. Carbon nanomaterials with different geometric structures exhibit quite different cytotoxicity and bioactivity in vitro, although they may not be accurately reflected in the comparative toxicity in vivo.
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495Nerl, H. C.; Cheng, C.; Goode, A. E.; Bergin, S. D.; Lich, B.; Gass, M.; Porter, A. E. Nanomedicine 2011, 6, 849There is no corresponding record for this reference.
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496Qu, G.; Bai, Y.; Zhang, Y.; Jia, Q.; Zhang, W.; Yan, B. Carbon 2009, 47, 2060There is no corresponding record for this reference.
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497Buford, M. C.; Hamilton, R. F., Jr.; Holian, A. Part. Fibre Toxicol. 2007, 4, 6497https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2svptF2iuw%253D%253D&md5=697f3404a28269d3931a563488934750A comparison of dispersing media for various engineered carbon nanoparticlesBuford Mary C; Hamilton Raymond F Jr; Holian AndrijParticle and fibre toxicology (2007), 4 (), 6 ISSN:.BACKGROUND: With the increased manufacture and use of carbon nanoparticles (CNP) there has been increasing concern about the potential toxicity of fugitive CNP in the workplace and ambient environment. To address this matter a number of investigators have conducted in vitro and in vivo toxicity assessments. However, a variety of different approaches for suspension of these particles (culture media, Tween 80, dimethyl sulfoxide, phosphate-buffered saline, fetal calf serum, and others), and different sources of materials have generated potentially conflicting outcomes. The quality of the dispersion of nanoparticles is very dependent on the medium used to suspend them, and this then will most likely affect the biological outcomes. RESULTS: In this work, the distributions of different CNP (sources and types) have been characterized in various media. Furthermore, the outcome of instilling the different agglomerates, or size distributions, was examined in mouse lungs after one and seven days. Our results demonstrated that CNP suspended in serum produced particle suspensions with the fewest large agglomerates, and the most uniform distribution in mouse lungs. In addition, no apparent clearance of instilled CNP took place from lungs even after seven days. CONCLUSION: This work demonstrates that CNP agglomerates are present in all dispersing vehicles to some degree. The vehicle that contains some protein, lipid or protein/lipid component disperses the CNP best, producing fewer large CNP agglomerates. In contrast, vehicles absent of lipid and protein produce the largest CNP agglomerates. The source of the CNP is also a factor in the degree of particle agglomeration within the same vehicle.
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498Snyder-Talkington, B. N.; Qian, Y.; Castranova, V.; Guo, N. L. J. Toxicol. Environ. Health., Part B 2012, 15, 468There is no corresponding record for this reference.
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499Donaldson, K. Nanomedicine 2006, 1, 229There is no corresponding record for this reference.
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500Lam, C. W.; James, J. T.; McCluskey, R.; Arepalli, S.; Hunter, R. L. Crit. Rev. Toxicol. 2006, 36, 189500https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xjt1Cks7Y%253D&md5=6f580f33625a1c428d79a4489b368bffA Review of Carbon Nanotube Toxicity and Assessment of Potential Occupational and Environmental Health RisksLam, Chiu-wing; James, John T.; McCluskey, Richard; Arepalli, Sivaram; Hunter, Robert L.Critical Reviews in Toxicology (2006), 36 (3), 189-217CODEN: CRTXB2; ISSN:1040-8444. (Taylor & Francis, Inc.)A review. Nanotechnol. has emerged at the forefront of science research and technol. development. Carbon nanotubes (CNTs) are major building blocks of this new technol. They possess unique elec., mech., and thermal properties, with potential wide applications in the electronics, computer, aerospace, and other industries. CNTs exist in two forms, single-wall (SWCNTs) and multi-wall (MWCNTs). They are manufd. predominately by elec. arc discharge, laser ablation and chem. vapor deposition processes; these processes involve thermally stripping carbon atoms off from carbon-bearing compds. SWCNT formation requires catalytic metals. There has been a great concern that if CNTs, which are very light, enter the working environment as suspended particulate matter (PM) of respirable sizes, they could pose an occupational inhalation exposure hazard. Very recently, MWCNTs and other carbonaceous nanoparticles in fine (<2.5 μm) PM aggregates have been found in combustion streams of methane, propane, and natural-gas flames of typical stoves; indoor and outdoor fine PM samples were reported to contain significant fractions of MWCNTs. Here we review several rodent studies in which test dusts were administered intratracheally or intrapharyngeally to assess the pulmonary toxicity of manufd. CNTs, and a few in vitro studies to assess biomarkers of toxicity released in CNT-treated skin cell cultures. The results of the rodent studies collectively showed that regardless of the process by which CNTs were synthesized and the types and amts. of metals they contained, CNTs were capable of producing inflammation, epithelioid granulomas (microscopic nodules), fibrosis, and biochem./toxicol. changes in the lungs. Comparative toxicity studies in which mice were given equal wts. of test materials showed that SWCNTs were more toxic than quartz, which is considered a serious occupational health hazard if it is chronically inhaled; ultrafine carbon black was shown to produce minimal lung responses. The differences in opinions of the investigators about the potential hazards of exposures to CNTs are discussed here. Presented here are also the possible mechanisms of CNT pathogenesis in the lung and the impact of residual metals and other impurities on the toxicol. manifestations. The toxicol. hazard assessment of potential human exposures to airborne CNTs and occupational exposure limits for these novel compds. are discussed in detail. Environmental fine PM is known to form mainly from combustion of fuels, and has been reported to be a major contributor to the induction of cardiopulmonary diseases by pollutants. Given that manufd. SWCNTs and MWCNTs were found to elicit pathol. changes in the lungs, and SWCNTs (administered to the lungs of mice) were further shown to produce respiratory function impairments, retard bacterial clearance after bacterial inoculation, damage the mitochondrial DNA in aorta, increase the percent of aortic plaque, and induce atherosclerotic lesions in the brachiocephalic artery of the heart, it is speculated that exposure to combustion-generated MWCNTs in fine PM may play a significant role in air pollution-related cardiopulmonary diseases. Therefore, CNTs from manufd. and combustion sources in the environment could have adverse effects on human health.
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501Wang, L.; Castranova, V.; Mishra, A.; Chen, B.; Mercer, R. R.; Schwegler-Berry, D.; Rojanasakul, Y. Part. Fibre Toxicol. 2010, 7, 31501https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cbktFKgtw%253D%253D&md5=7c61669935e2ac2988088745d8336c29Dispersion of single-walled carbon nanotubes by a natural lung surfactant for pulmonary in vitro and in vivo toxicity studiesWang Liying; Castranova Vincent; Mishra Anurag; Chen Bean; Mercer Robert R; Schwegler-Berry Diane; Rojanasakul YonParticle and fibre toxicology (2010), 7 (), 31 ISSN:.BACKGROUND: Accumulating evidence indicate that the degree of dispersion of nanoparticles has a strong influence on their biological activities. The aims of this study were to develop a simple and rapid method of nanoparticle dispersion using a natural lung surfactant and to evaluate the effect of dispersion status of SWCNT on cytotoxicity and fibrogenicity in vitro and in vivo. RESULTS: The natural lung surfactant Survanta® was used to disperse single-walled carbon nanotubes (SWCNT) in a biological medium. At physiologically relevant concentrations, Survanta® produced well dispersed SWCNT without causing a cytotoxic or fibrogenic effect. In vitro studies show that Survanta®-dispersed SWCNT (SD-SWCNT) stimulated proliferation of lung epithelial cells at low doses (0.04-0.12 μg/ml or 0.02-0.06 μg/cm2 exposed surface area) but had a suppressive effect at high doses. Non-dispersed SWCNT (ND-SWCNT) did not exhibit these effects, suggesting the importance of dispersion status of SWCNT on bioactivities. Studies using cultured human lung fibroblasts show that SD-SWCNT stimulated collagen production of the cells. This result is supported by a similar observation using Acetone/sonication dispersed SWCNT (AD-SWCNT), suggesting that Survanta® did not mask the bioactivity of SWCNT. Likewise, in vivo studies show that both SD-SWCNT and AD-SWCNT induced lung fibrosis in mice, whereas the dispersing agent Survanta® alone or Survanta®-dispersed control ultrafine carbon black had no effect. CONCLUSIONS: The results indicate that Survanta® was effective in dispersing SWCNT in biological media without causing cytotoxic effects at the test concentrations used in this study. SD-SWCNT stimulated collagen production of lung fibroblasts in vitro and induced lung fibrosis in vivo. Similar results were observed with AD-SWCNT, supporting the conclusion that Survanta® did not mask the bioactivities of SWCNT and thus can be used as an effective dispersing agent. Since excessive collagen production is a hallmark of lung fibrosis, the results of this study suggest that the in vitro model using lung fibroblasts may be an effective and rapid screening tool for prediction of the fibrogenic potential of SWCNT in vivo.
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502Palomäki, J.; Välimäki, E.; Sund, J.; Vippola, M.; Clausen, P. A.; Jensen, K. A.; Savolainen, K.; Matikainen, S.; Alenius, H. ACS Nano 2011, 5, 6861There is no corresponding record for this reference.
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503Patlolla, A. K.; Berry, A.; Tchounwou, P. B. Mol. Cell. Biochem. 2011, 358, 189There is no corresponding record for this reference.
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504Sanchez, V. C.; Weston, P.; Yan, A.; Hurt, R. H.; Kane, A. B. Part. Fibre Toxicol. 2011, 8, 17504https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmvVKrsrw%253D&md5=4f05f67113707d8535dadf33eaa2d858A 3-dimensional in vitro model of epithelioid granulomas induced by high aspect ratio nanomaterialsSanchez, Vanesa C.; Weston, Paula; Yan, Aihui; Hurt, Robert H.; Kane, Agnes B.Particle and Fibre Toxicology (2011), 8 (), 17CODEN: PFTABQ; ISSN:1743-8977. (BioMed Central Ltd.)Background: The most common causes of granulomatous inflammation are persistent pathogens and poorly-degradable irritating materials. A characteristic pathol. reaction to intratracheal instillation, pharyngeal aspiration, or inhalation of carbon nanotubes is formation of epithelioid granulomas accompanied by interstitial fibrosis in the lungs. In the mesothelium, a similar response is induced by high aspect ratio nanomaterials, including asbestos fibers, following i.p. injection. This asbestos-like behavior of some engineered nanomaterials is a concern for their potential adverse health effects in the lungs and mesothelium. We hypothesize that high aspect ratio nanomaterials will induce epithelioid granulomas in nonadherent macrophages in 3D cultures. Results: Carbon black particles (Printex 90) and crocidolite asbestos fibers were used as well-characterized ref. materials and compared with three com. samples of multiwalled carbon nanotubes (MWCNTs). Doses were identified in 2D and 3D cultures in order to minimize acute toxicity and to reflect realistic occupational exposures in humans and in previous inhalation studies in rodents. Under serum-free conditions, exposure of nonadherent primary murine bone marrow-derived macrophages to 0.5 μg/mL (0.38 μg/cm2) of crocidolite asbestos fibers or MWCNTs, but not carbon black, induced macrophage differentiation into epithelioid cells and formation of stable aggregates with the characteristic morphol. of granulomas. Formation of multinucleated giant cells was also induced by asbestos fibers or MWCNTs in this 3D in vitro model. After 7-14 days, macrophages exposed to high aspect ratio nanomaterials co-expressed proinflammatory (M1) as well as profibrotic (M2) phenotypic markers. Conclusions: Induction of epithelioid granulomas appears to correlate with high aspect ratio and complex 3D structure of carbon nanotubes, not with their iron content or surface area. This model offers a time- and cost-effective platform to evaluate the potential of engineered high aspect ratio nanomaterials, including carbon nanotubes, nanofibers, nanorods and metallic nanowires, to induce granulomas following inhalation.
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505Teeguarden, J. G.; Webb-Robertson, B. J.; Waters, K. M.; Murray, A. R.; Kisin, E. R.; Varnum, S. M.; Jacobs, J. M.; Pounds, J. G.; Zanger, R. C.; Shvedova, A. A. Toxicol. Sci. 2011, 120, 123505https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXis1eksLo%253D&md5=89665aea5667a223bf084a4a36b1f30fComparative Proteomics and Pulmonary Toxicity of Instilled Single-Walled Carbon Nanotubes, Crocidolite Asbestos, and Ultrafine Carbon Black in MiceTeeguarden, Justin G.; Webb-Robertson, Bobbie-Jo; Waters, Katrina M.; Murray, Ashley R.; Kisin, Elena R.; Varnum, Susan M.; Jacobs, Jon M.; Pounds, Joel G.; Zanger, Richard C.; Shvedova, Anna A.Toxicological Sciences (2011), 120 (1), 123-135CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)Reflecting their exceptional potential to advance a range of biomedical, aeronautic, and other industrial products, carbon nanotube (CNT) prodn. and the potential for human exposure to aerosolized CNTs are increasing. CNTs have toxicol. significant structural and chem. similarities to asbestos (AB) and have repeatedly been shown to cause pulmonary inflammation, granuloma formation, and fibrosis after inhalation/instillation/aspiration exposure in rodents, a pattern of effects similar to those obsd. following exposure to AB. To det. the degree to which responses to single-walled CNTs (SWCNT) and AB are similar or different, the pulmonary response of C57BL/6 mice to repeated exposures to SWCNTs, crocidolite AB, and ultrafine carbon black (UFCB) were compared using high-throughput global high-performance liq. chromatog. Fourier-transform ion cyclotron resonance mass spectrometry (HPLC-FTICR-MS) proteomics, histopathol., and bronchoalveolar lavage cytokine analyses. Mice were exposed to material suspensions (40 μg per mouse) twice a week for 3 wk by pharyngeal aspiration. Histol., the incidence and severity of inflammatory and fibrotic responses were greatest in mice treated with SWCNTs. SWCNT treatment affected the greatest changes in abundance of identified lung tissue proteins. The trend in no. of proteins affected (SWCNT [376] > AB [231] > UFCB [184]) followed the potency of these materials in 3 biochem. assays of inflammation (cytokines). SWCNT treatment uniquely affected the abundance of 109 proteins, but these proteins largely represent cellular processes affected by AB treatment as well, further evidence of broad similarity in the tissue-level response to AB and SWCNTs. Two high-sensitivity markers of inflammation, one (S100a9) obsd. in humans exposed to AB, were found and may be promising biomarkers of human response to SWCNT exposure.
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506Patlolla, A. K.; Berry, A.; May, L.; Tchounwou, P. B. Int. J. Environ. Res. Public Health 2012, 9, 1649There is no corresponding record for this reference.
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507Atkins, G. J.; Haynes, D. R.; Howie, D. W.; Findlay, D. M. World J. Orthop. 2011, 2, 93507https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38ritFOhsA%253D%253D&md5=b858f7039eef67dff81fd8f1abe998dfRole of polyethylene particles in peri-prosthetic osteolysis: A reviewAtkins Gerald J; Haynes David R; Howie Donald W; Findlay David MWorld journal of orthopedics (2011), 2 (10), 93-101 ISSN:.There is convincing evidence that particles produced by the wear of joint prostheses are causal in the peri-prosthetic loss of bone, or osteolysis, which, if it progresses, leads to the phenomenon of aseptic loosening. It is important to fully understand the biology of this bone loss because it threatens prosthesis survival, and loosened implants can result in peri-prosthetic fracture, which is disastrous for the patient and presents a difficult surgical scenario. The focus of this review is the bioactivity of polyethylene (PE) particles, since there is evidence that these are major players in the development and progression of osteolysis around prostheses which use PE as the bearing surface. The review describes the biological consequences of interaction of PE particles with macrophages, osteoclasts and cells of the osteoblast lineage, including osteocytes. It explores the possible cellular mechanisms of action of PE and seeks to use the findings to date to propose potential non-surgical treatments for osteolysis. In particular, a non-surgical approach is likely to be applicable to implants containing newer, highly cross-linked PEs (HXLPEs), for which osteolysis seems to occur with much reduced PE wear compared with conventional PEs. The caveat here is that we know little as yet about the bioactivity of HXLPE particles and addressing this constitutes our next challenge.
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508Blumenfeld, T. J.; McKellop, H. A.; Schmalzried, T. P.; Billi, F. J. Arthroplasty 2011, 26, 666 e5There is no corresponding record for this reference.
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509Furmanski, J.; Kraay, M. J.; Rimnac, C. M. J. Arthroplasty 2011, 26, 796509https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MnpvVyqtQ%253D%253D&md5=724482ba56ad8fbc1659c6841af27c23Crack initiation in retrieved cross-linked highly cross-linked ultrahigh-molecular-weight polyethylene acetabular liners: an investigation of 9 casesFurmanski Jevan; Kraay Matthew J; Rimnac Clare MThe Journal of arthroplasty (2011), 26 (5), 796-801 ISSN:.Nine cross-linked highly cross-linked ultrahigh-molecular weight polyethylene acetabular liners were retrieved at revision surgery. Eight of the liners were fully intact and functional at retrieval. Six cases contained shallow initiated cracks at the root of rim notches; 1 crack had propagated several millimeters. Optical and electron microscopic inspection of the crack surfaces revealed clam shell markings, which are characteristic of fatigue crack initiation. Crack initiation at notches has been identified in reports of catastrophic cross-linked liner failures, with crack initiation sites exhibiting similar morphology and clam shell markings. Thus, we believe that the shallow cracks identified in this case series are precursors to catastrophic rim fracture. The results of this study recommend further investigations to clarify the etiology and prevalence of crack initiation in cross-linked acetabular liners.
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510Goldstein, M. J.; Ast, M. P.; Dimaio, F. R. Orthopedics 2012, 35, e1119There is no corresponding record for this reference.
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511Waewsawangwong, W.; Goodman, S. B. J. Arthroplasty 2012, 27, 323 e1There is no corresponding record for this reference.
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512Pruitt, L. A.; Ansari, F.; Kury, M.; Mehdizah, A.; Patten, E. W.; Huddlestein, J.; Mickelson, D.; Chang, J.; Hubert, K.; Ries, M. D. J. Biomed. Mater. Res., Part B 2013, 101, 476512https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktVGhurY%253D&md5=d9a2a012250665d93dd6989a0d1b55acClinical trade-offs in cross-linked ultrahigh-molecular-weight polyethylene used in total joint arthroplastyPruitt, Lisa A.; Ansari, Farzana; Kury, Matt; Mehdizah, Amir; Patten, Elias W.; Huddlestein, James; Mickelson, Dayne; Chang, Jennifer; Hubert, Kim; Ries, Michael D.Journal of Biomedical Materials Research, Part B: Applied Biomaterials (2013), 101B (3), 476-484CODEN: JBMRGL; ISSN:1552-4973. (John Wiley & Sons, Inc.)Highly cross-linked formulations of ultrahigh-mol.-wt. polyethylene (XLPE) offer exceptional wear resistance for total joint arthroplasty but are offset with a redn. in postyield and fatigue fracture properties in comparison to conventional ultrahigh-mol.-wt. polyethylene (UHMWPE). Oxidn. resistance is also an important property for the longevity of total joint replacements (TJRs) as formulations of UHMWPE or XLPE utilizing radiation methods are susceptible to free radical generation and subsequent embrittlement. The balance of oxidn., wear, and fracture properties is an enduring concern for orthopedic polymers used as the bearing surface in total joint arthroplasty. Optimization of material properties is further challenged in designs that make use of locking mechanisms, notches, or other stress concns. that can render the polymer susceptible to fracture due to elevated local stresses. Clin. complications involving impingements, dislocations, or other biomech. overloads can exacerbate stresses and negate benefits of improved wear resistance provided by XLPE. This work examines trade-offs that factor into the use of XLPE in TJR implants. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 101B: 476-484, 2013.
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513Regis, D.; Sandri, A.; Bartolozzi, P. Orthopedics 2008, 31.There is no corresponding record for this reference.
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514Lee, Y. K.; Yoo, J. J.; Koo, K. H.; Yoon, K. S.; Kim, H. J. J. Orthop. Res. 2011, 29, 218514https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M%252FmtlSrtA%253D%253D&md5=b641bef82e5287ce5aa852727ef227efMetal neck and liner impingement in ceramic bearing total hip arthroplastyLee Young-Kyun; Yoo Jeong Joon; Koo Kyung-Hoi; Yoon Kang Sup; Kim Hee JoongJournal of orthopaedic research : official publication of the Orthopaedic Research Society (2011), 29 (2), 218-22 ISSN:.Although impingement between the neck of the metallic stem and the ceramic liner has been suspected to be the cause of ceramic liner failure in ceramic-on-ceramic total hip arthroplasty (THA), no report has directly demonstrated microscopic damage on ceramic liner. We performed 18 reoperations on 18 patients who had undergone third generation ceramic-on-ceramic THA. Considering impingement, 16 patients, who were reoperated more than 1 year after previous ceramic bearing THA, were evaluated. Retrieved alumina liners, showing evidence of impingement, were examined by means of visual inspection and scanning electron microscopy (SEM). Four of the 16 hips showed neck notching and black stained liners, evidence of metallic neck to ceramic impingement. Impinged alumina bearings had been implanted for an average of 62.5 months (range: 35-99 months) before reoperation. SEM of the black stained area demonstrated disruptive wear and loss of surface integrity. Furthermore, one liner had multiple microcracks, and its cross-sectional SEM analysis revealed one microcrack propagating into the deep portion of the ceramic liner. Our observations suggest that metal neck-to-ceramic impingement in ceramic-on-ceramic THA can cause microcrack formation in ceramic liner.
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515Lopes, R.; Philippeau, J. M.; Passuti, N.; Gouin, F. Clin. Orthop. Relat. Res. 2012, 470, 1705515https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38vltVKqsw%253D%253D&md5=0d7b839f6172944a32477af32c52526aHigh rate of ceramic sandwich liner fractureLopes Ronny; Philippeau Jean M; Passuti Norbert; Gouin FrancoisClinical orthopaedics and related research (2012), 470 (6), 1705-10 ISSN:.BACKGROUND: Ceramic bearing surfaces for THA were introduced to reduce the risk of wear. However, owing to liner fracture in some of the early series and presumption that the fractures were the result of the modulus mismatch of the implant and the bone, a ceramic sandwich liner with lower structural rigidity was introduced. Fractures of these devices also were reported subsequently, although the incidence is unclear and it is unknown whether there are any risk factors associated with the fractures. QUESTIONS/PURPOSES: We therefore determined the incidence of these fractures. METHODS: We retrospectively reviewed 298 active patients in whom we implanted 353 ceramic-polyethylene sandwich liner acetabular components between November 1999 and February 2008. The mean age of the patients was 53.6 years (range, 17-84 years). The minimum followup was 6 months (mean, 41 months; range, 6-106 months). All patients were assessed clinically and radiographically. RESULTS: Seven of the 353 (2%) ceramic sandwich liners fractured at a mean of 4.3 years (range, 1.3-7.6 years) after surgery without trauma. Neither patient-related factors nor radiographic position of the implants were risk factors for fracture. CONCLUSIONS: Owing to the high rate of fractures of the sandwich ceramic polyethylene liners in our patients, we have discontinued use of this device. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
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516Traina, F.; De Fine, M.; Bordini, B.; Toni, A. Hip Int. 2012, 22, 607516https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s3gtl2gsQ%253D%253D&md5=dc972a13c11615332f674bc02ff5ce5dRisk factors for ceramic liner fracture after total hip arthroplastyTraina Francesco; De Fine Marcello; Bordini Barbara; Toni AldoHip international : the journal of clinical and experimental research on hip pathology and therapy (2012), 22 (6), 607-14 ISSN:.The aim of this study was to detect risk factors for ceramic liner fractures. 26 cementless ceramic on ceramic (COC) total hip arthroplasties (THA) revised because of ceramic liner fracture in 24 patients were compared with 49 well-functioning COC THA performed in 49 patients. Demographic parameters, type of ceramic of the liner, size and neck length of the femoral head, cup abduction angle, cup anteversion, femoral off-set, height of the centre of rotation and the incidence of noisy hips during follow-up examination were compared. A greater number of cups placed outside the optimal range of cup anteversion was found in the fracture group (p = 0.03). An audible noise was detected in 21 cases (80.7%) in the fracture group and in 3 cases (6.1%) in the non-fracture group (p = 0.001). A cup anteversion angle out of the optimal range of 15+/-10 was found to be a risk factor for ceramic liner fracture and the presence of a noisy hip frequently anticipated the failure. In our opinion neck-to-cup impingement with head subluxation and edge loading on the liner rim could have an important role in the onset of noise and subsequent liner failure, and cup malposition contributes to this mechanism of failure.
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517Kawano, S.; Sonohata, M.; Shimazaki, T.; Kitajima, M.; Mawatari, M.; Hotokebuchi, T.J. Arthroplasty 2013.There is no corresponding record for this reference.
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518Koo, K. H.; Ha, Y. C.; Kim, S. Y.; Yoon, K. S.; Min, B. W.; Kim, S. R.J. Arthroplasty 2013.There is no corresponding record for this reference.
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519Kulkarni, A. G.; Hee, H. T.; Wong, H. K. Spine J. 2007, 7, 205519https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s7it1Srsg%253D%253D&md5=b3ca20bfb07709eb4c8a5ce87c29e75aSolis cage (PEEK) for anterior cervical fusion: preliminary radiological results with emphasis on fusion and subsidenceKulkarni Arvind G; Hee Hwan T; Wong Hee KThe spine journal : official journal of the North American Spine Society (2007), 7 (2), 205-9 ISSN:1529-9430.BACKGROUND CONTEXT: Recent literature has raised some apprehensions with regard to the usage of cervical cages. PURPOSE: Radiological review of cases performed at our institution with a novel cage made of polyetheretherketone (PEEK). STUDY DESIGN: Retrospective study. METHODS: A retrospective review of the first 15 consecutive cases of single-level anterior cervical interbody fusion using the Solis cage (PEEK material) for cervical spondylotic radiculopathy or myelopathy was performed. The follow-up ranged from 12 to 35 months (average 18 months). Anteroposterior and lateral radiographs were taken immediately after the surgery and at intervals of 3, 6, 12, and 24 months after surgery. Anterior disc height (ADH), posterior disc height (PDH), interbody height ratio (IBHR), distance between the posterior margin of the cage and the posterior wall of the vertebral body (D-CPW), and interbody angle (IBA) were measured on the lateral radiographs and compared. Fusion was assessed by examining for trabecular continuity, bridging of bone across the disc space, and sclerosis at the vertebral end plates on both sides. The parameters assessed were time for fusion, subsidence, segmental sagittal alignment of the operated segment, and presence/absence of migration of the cage. Data were analyzed using the Mann-Whitney nonparametric test. RESULTS: Fusion was evident at 3-6 months postsurgery in all cases except one (93.33% fusion rate at 6 months). At the last follow-up, fusion was maintained in all cases. The immediate postoperative ADH and PDH was significantly greater than the respective preoperative values and was maintained at the last follow-up though there was a significant amount of subsidence when the follow-up radiographs were compared with the immediate postoperative X-rays. The immediate postoperative IBHR was significantly greater than the preoperative IBHR, and was maintained at the last follow-up, but not statistically significant. The immediate postoperative IBA (lordotic angle) was greater than the preoperative IBA but was not statistically significant. The IBA at the last follow-up was lesser than the preoperative value but with no statistical significance. The IBA measured at the last follow-up was less than the value at the immediate postoperative period, but not statistically significant. There was no migration or extrusion of the cage at latest follow-up. CONCLUSIONS: The high fusion rate, low subsidence, stability provided by the cage, and facilitation of radiological assessment are the result of the physical properties of the PEEK material as well as the design of the cage.
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520Kurtz, S. M.; Devine, J. N. Biomaterials 2007, 28, 4845There is no corresponding record for this reference.
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521Yang, J. J.; Yu, C. H.; Chang, B. S.; Yeom, J. S.; Lee, J. H.; Lee, C. K. Clin. Orthop. Surg. 2011, 3, 16521https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M3jsVOisQ%253D%253D&md5=302da002ae21615c855cb9ea6710265bSubsidence and nonunion after anterior cervical interbody fusion using a stand-alone polyetheretherketone (PEEK) cageYang Jae Jun; Yu Chang Hun; Chang Bong-Soon; Yeom Jin Sup; Lee Jae Hyup; Lee Choon-KiClinics in orthopedic surgery (2011), 3 (1), 16-23 ISSN:.BACKGROUND: The purposes of the present study are to evaluate the subsidence and nonunion that occurred after anterior cervical discectomy and fusion using a stand-alone intervertebral cage and to analyze the risk factors for the complications. METHODS: Thirty-eight patients (47 segments) who underwent anterior cervical fusion using a stand-alone polyetheretherketone (PEEK) cage and an autologous cancellous iliac bone graft from June 2003 to August 2008 were enrolled in this study. The anterior and posterior segmental heights and the distance from the anterior edge of the upper vertebra to the anterior margin of the cage were measured on the plain radiographs. Subsidence was defined as ≥ a 2 mm (minor) or 3 mm (major) decrease of the segmental height at the final follow-up compared to that measured at the immediate postoperative period. Nonunion was evaluated according to the instability being ≥ 2 mm in the interspinous distance on the flexion-extension lateral radiographs. RESULTS: The anterior and posterior segmental heights decreased from the immediate postoperative period to the final follow-up at 1.33 ± 1.46 mm and 0.81 ± 1.27 mm, respectively. Subsidence ≥ 2 mm and 3 mm were observed in 12 segments (25.5%) and 7 segments (14.9%), respectively. Among the expected risk factors for subsidence, a smaller anteroposterior (AP) diameter (14 mm vs. 12 mm) of cages (p = 0.034; odds ratio [OR], 0.017) and larger intraoperative distraction (p = 0.041; OR, 3.988) had a significantly higher risk of subsidence. Intervertebral nonunion was observed in 7 segments (7/47, 14.9%). Compared with the union group, the nonunion group had a significantly higher ratio of two-level fusion to one-level fusions (p = 0.001). CONCLUSIONS: Anterior cervical fusion using a stand-alone cage with a large AP diameter while preventing anterior intraoperative over-distraction will be helpful to prevent the subsidence of cages. Two-level cervical fusion might require more careful attention for avoiding nonunion.
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522Le, T. V.; Baaj, A. A.; Dakwar, E.; Burkett, C. J.; Murray, G.; Smith, D. A.; Uribe, J. S. Spine (Philadelphia) 2012, 37, 1268522https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38jhsVyqsw%253D%253D&md5=2eafcac870d73fe197a08e8faa56ee63Subsidence of polyetheretherketone intervertebral cages in minimally invasive lateral retroperitoneal transpsoas lumbar interbody fusionLe Tien V; Baaj Ali A; Dakwar Elias; Burkett Clinton J; Murray Gisela; Smith Donald A; Uribe Juan SSpine (2012), 37 (14), 1268-73 ISSN:.STUDY DESIGN: A retrospective review. OBJECTIVE: The objective is to evaluate subsidence related to minimally invasive lateral retroperitoneal lumbar interbody fusion by reviewing our experience with this procedure. SUMMARY OF BACKGROUND DATA: Polyetheretherketone intervertebral cages of different lengths, widths, and heights filled with various allograft types are commonly used as spacers in lumbar fusions. Subsidence is a potential complication. To date, there are no published reports specifically addressing subsidence, because it relates to a series of patients undergoing minimally invasive lateral retroperitoneal transpsoas lumbar interbody fusion. METHODS: An institutional review board-approved, retrospective review of a prospectively collected database was conducted. One hundred forty consecutive patients who underwent this procedure between L1 and L5 during a 2-year period were included. All patients had T scores of -2.5 or more. Postoperative radiographs during routine follow-ups were reviewed for subsidence, defined as any violation of the vertebral end plate. RESULTS: Radiographical subsidence occurred in 14.3% (20 of 140), whereas clinical subsidence occurred in 2.1%. Subsidence occurred in 8.8% (21 of 238) of levels fused. Construct length had a significant positive correlation with increasing subsidence rates. Subsidence rates decreased progressively with lower levels in the lumbar spine, but had a higher than expected rate at L4-L5. Subsidence rates of 14.1% (19 of 135) and 1.9% (2 of 103) were associated with 18-and 22-mm-wide cages, respectively. No significant trends were observed with cage lengths. Supplemental lateral plates had a higher rate of subsidence than bilateral pedicle screws. Subsidence occurred at the superior end plate 70% of the time. CONCLUSION: The use of wider intervertebral cages leads to a significantly lower rate of subsidence, but a longer cage does not necessarily offer a similar advantage. Wide cages are protective against subsidence, and the widest cages should be used whenever feasible for interbody fusion in the lumbar spine to protect indirect compression and promote arthrodesis.
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523Olivares-Navarrete, R.; Gittens, R. A.; Schneider, J. M.; Hyzy, S. L.; Haithcock, D. A.; Ullrich, P. F.; Schwartz, Z.; Boyan, B. D. Spine J. 2012, 12, 265523https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38vnt1Ciug%253D%253D&md5=569445d9bb1d1087c27107b352559a11Osteoblasts exhibit a more differentiated phenotype and increased bone morphogenetic protein production on titanium alloy substrates than on poly-ether-ether-ketoneOlivares-Navarrete Rene; Gittens Rolando A; Schneider Jennifer M; Hyzy Sharon L; Haithcock David A; Ullrich Peter F; Schwartz Zvi; Boyan Barbara DThe spine journal : official journal of the North American Spine Society (2012), 12 (3), 265-72 ISSN:.BACKGROUND CONTEXT: Multiple biomaterials are clinically available to spine surgeons for performing interbody fusion. Poly-ether-ether-ketone (PEEK) is used frequently for lumbar spine interbody fusion, but alternative materials are also used, including titanium (Ti) alloys. Previously, we showed that osteoblasts exhibit a more differentiated phenotype when grown on machined or grit-blasted titanium aluminum vanadium (Ti6Al4V) alloys with micron-scale roughened surfaces than when grown on smoother Ti6Al4V surfaces or on tissue culture polystyrene (TCPS). We hypothesized that osteoblasts cultured on rough Ti alloy substrates would present a more mature osteoblast phenotype than cells cultured on PEEK, suggesting that textured Ti6Al4V implants may provide a more osteogenic surface for interbody fusion devices. PURPOSE: The aim of the present study was to compare osteoblast response to smooth Ti6Al4V (sTiAlV) and roughened Ti6Al4V (rTiAlV) with their response to PEEK with respect to differentiation and production of factors associated with osteogenesis. STUDY DESIGN: This in vitro study compared the phenotype of human MG63 osteoblast-like cells cultured on PEEK, sTiAlV, or rTiAlV surfaces and their production of bone morphogenetic proteins (BMPs). METHODS: Surface properties of PEEK, sTiAlV, and rTiAlV discs were determined. Human MG63 cells were grown on TCPS and the discs. Confluent cultures were harvested, and cell number, alkaline phosphatase-specific activity, and osteocalcin were measured as indicators of osteoblast maturation. Expression of messenger RNA (mRNA) for BMP2 and BMP4 was measured by real-time polymerase chain reaction. Levels of BMP2, BMP4, and BMP7 proteins were also measured in the conditioned media of the cell cultures. RESULTS: Although roughness measurements for sTiAlV (S(a)=0.09±0.01), PEEK (S(a)=0.43±0.07), and rTiAlV (S(a)=1.81±0.51) varied, substrates had similar contact angles, indicating comparable wettability. Cell morphology differed depending on the surface. Cells cultured on Ti6Al4V had lower cell number and increased alkaline phosphatase specific activity, osteocalcin, BMP2, BMP4, and BMP7 levels in comparison to PEEK. In particular, roughness significantly increased the mRNA levels of BMP2 and BMP4 and secreted levels of BMP4. CONCLUSIONS: These data demonstrate that rTiAlV substrates increase osteoblast maturation and produce an osteogenic environment that contains BMP2, BMP4, and BMP7. The results show that modifying surface structure is sufficient to create an osteogenic environment without addition of exogenous factors, which may induce better and faster bone during interbody fusion.
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524Barz, T.; Lange, J.; Melloh, M.; Staub, L. P.; Merk, H. R.; Kloting, I.; Follak, N. Spine (Philadelphia) 2013, 38, E263There is no corresponding record for this reference.
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525Chen, L.; Hu, J.; Shen, X.; Tong, H. J. Mater. Sci.: Mater. Med. 2013, 24, 1843525https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFWjurvP&md5=8155a487731f2cbe84529045185ca2deSynthesis and characterization of chitosan-multiwalled carbon nanotubes/hydroxyapatite nanocomposites for bone tissue engineeringChen, Li; Hu, Jingxiao; Shen, Xinyu; Tong, HuaJournal of Materials Science: Materials in Medicine (2013), 24 (8), 1843-1851CODEN: JSMMEL; ISSN:0957-4530. (Springer)Chitosan-multiwalled carbon nanotubes/hydroxyapatite nanocomposites were synthesized by a novel in situ pptn. method. The electrostatic adsorption between multiwalled carbon nanotubes and chitosan was investigated and explained by Fourier transform IR spectroscopy anal. Morphol. studies showed that uniform distribution of hydroxyapatite particles and multiwalled carbon nanotubes in the polymer matrix was obsd. In chitosan-multiwalled carbon nanotubes/hydroxyapatite nanocomposites, the diams. of multiwalled carbon nanotubes were about 10 nm. The mech. properties of the composites were evaluated by measuring their compressive strength and elastic modulus. The elastic modulus and compressive strength increased sharply from 509.9 to 1089.1 MPa and from 33.2 to 105.5 MPa with an increase of multiwalled carbon/chitosan wt. ratios from 0 to 5 %, resp. Finally, the cell biocompatibility of the composites was tested in vitro, which showed that they have good biocompatibility. These results suggest that the chitosan-multiwalled carbon nanotubes/hydroxyapatite nanocomposites are promising biomaterials for bone tissue engineering.
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526Gupta, A.; Woods, M. D.; Illingworth, K. D.; Niemeier, R.; Schafer, I.; Cady, C.; Filip, P.; El-Amin, S. F., III. J. Orthop. Res. 2013, 31, 1374526https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFGms73P&md5=9742a9f8a36ecd7bef2ae394cac29cdaSingle walled carbon nanotube composites for bone tissue engineeringGupta, Ashim; Woods, Mia D.; Illingworth, Kenneth David; Niemeier, Ryan; Schafer, Isaac; Cady, Craig; Filip, Peter; El-Amin, Saadiq F., IIIJournal of Orthopaedic Research (2013), 31 (9), 1374-1381CODEN: JOREDR; ISSN:0736-0266. (John Wiley & Sons, Inc.)The purpose of this study was to develop single walled carbon nanotubes (SWCNT) and poly lactic-co-glycolic acid (PLAGA) composites for orthopedic applications and to evaluate the interaction of human stem cells (hBMSCs) and osteoblasts (MC3T3-E1 cells) via cell growth, proliferation, gene expression, extracellular matrix prodn. and mineralization. PLAGA and SWCNT/PLAGA composites were fabricated with various amts. of SWCNT (5, 10, 20, 40, and 100 mg), characterized and degrdn. studies were performed. Cells were seeded and cell adhesion/morphol., growth/survival, proliferation and gene expression anal. were performed to evaluate biocompatibility. Imaging studies demonstrated uniform incorporation of SWCNT into the PLAGA matrix and addn. of SWCNT did not affect the degrdn. rate. Imaging studies revealed that MC3T3-E1 and hBMSCs cells exhibited normal, non-stressed morphol. on the composites and all were biocompatible. Composites with 10 mg SWCNT resulted in highest rate of cell proliferation (p < 0.05) among all composites. Gene expression of alk. phosphatase, collagen I, osteocalcin, osteopontin, Runx-2, and Bone Sialoprotein was obsd. on all composites. In conclusion, SWCNT/PLAGA composites imparted beneficial cellular growth capabilities and gene expression, and mineralization abilities were well established. These results demonstrate the potential of SWCNT/PLAGA composites for musculoskeletal regeneration and bone tissue engineering (BTE) and are promising for orthopedic applications. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1374-1381, 2013.
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527European Commission. Proposal for a regulation of the european parliament and of thecouncil on medical devices, and amending directive 2001/83/ec, regulation(ec) no 178/2002 and regulation (EC) No 1223/2009. COM 2012, 542 final.There is no corresponding record for this reference.
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528Vardharajula, S.; Ali, S. Z.; Tiwari, P. M.; Eroğlu, E.; Vig, K.; Dennis, V. A.; Singh, S. R. Int. J. Nanomed. 2012, 7, 5361528https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFylu7zI&md5=d6d34474594e1d54ad95459386f814e7Functionalized carbon nanotubes: biomedical applicationsVardharajula, Sandhya; Ali, Sk. Z.; Tiwari, Pooja M.; Eroglu, Erdal; Vig, Komal; Dennis, Vida A.; Singh, Shree R.International Journal of Nanomedicine (2012), 7 (), 5361-5374CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)A review. Carbon nanotubes (CNTs) are emerging as novel nanomaterials for various biomedical applications. CNTs can be used to deliver a variety of therapeutic agents, including biomols., to the target disease sites. In addn., their unparalleled optical and elec. properties make them excellent candidates for bioimaging and other biomedical applications. However, the high cytotoxicity of CNTs limits their use in humans and many biol. systems. The biocompatibility and low cytotoxicity of CNTs are attributed to size, dose, duration, testing systems, and surface functionalization. The functionalization of CNTs improves their soly. and biocompatibility and alters their cellular interaction pathways, resulting in much-reduced cytotoxic effects. Functionalized CNTs are promising novel materials for a variety of biomedical applications. These potential applications are particularly enhanced by their ability to penetrate biol. membranes with relatively low cytotoxicity. This review is directed towards the overview of CNTs and their functionalization for biomedical applications with minimal cytotoxicity.
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