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Research article
First published online July 10, 2015

Animal Models for Evaluation of Bone Implants and Devices: Comparative Bone Structure and Common Model Uses

L. M. Wancket [email protected]View all authors and affiliations
Volume 52, Issue 5
https://doi.org/10.1177/0300985815593124

Abstract

Bone implants and devices are a rapidly growing field within biomedical research, and implants have the potential to significantly improve human and animal health. Animal models play a key role in initial product development and are important components of nonclinical data included in applications for regulatory approval. Pathologists are increasingly being asked to evaluate these models at the initial developmental and nonclinical biocompatibility testing stages, and it is important to understand the relative merits and deficiencies of various species when evaluating a new material or device. This article summarizes characteristics of the most commonly used species in studies of bone implant materials, including detailed information about the relevance of a particular model to human bone physiology and pathology. Species reviewed include mice, rats, rabbits, guinea pigs, dogs, sheep, goats, and nonhuman primates. Ultimately, a comprehensive understanding of the benefits and limitations of different model species will aid in rigorously evaluating a novel bone implant material or device.
Bone and joint implants and devices are a rapidly growing portion of the health care industry, with an estimated $9 billion in Medicare expenditures spent on implantable orthopedic devices in 2009.17 Considerable research continues toward developing novel devices to improve bone and joint function and health. The implant and device field contains diverse classes, including tissue-engineered constructs, combination products (ie, antimicrobial coatings for devices), and biomaterials (synthetic or natural nondrug substance(s) used as a whole or as a part of a system to treat, augment, or replace any tissue, organ, or function11). For the purpose of this review, the term implant will be used to refer to this wide variety of products.
Animal models are a key component of many nonclinical implant studies, and the ideal species varies by the specific implant and its intended use. This review outlines how bone and joint implants are evaluated in models of human diseases and the advantages and limitations of species commonly used in implant studies.

Evaluating Implants In Vivo: Biological Relevance, Biofunctionality, Biocompatibility/Safety, and Clinical Relevance/Efficacy

Bone and joint implants can have a variety of effects on the host, from providing basic mechanical support to initiating local and systemic host responses. To evaluate both intended and unintended effects, several stages are used to evaluate implants, including biological relevance, biofunctionality, biocompatibility/safety, and clinical relevance/efficacy.

Biological Relevance

Initial laboratory testing is used to demonstrate fundamental biological relevance of an implant’s structure and material composition53 (biological relevance defined here as effects likely to be relevant and meaningful for humans and/or animals). This stage uses a combination of in vitro, ex vivo (ie, tissue explants), and in vivo models. Ex vivo tissue and in vivo animal models provide initial insights into how an implant may alter the physiological, biomechanical, and hormonal functions of bone. This stage of study often uses smaller animal models (rabbits, rodents), including animals that mimic specific human conditions (ie, transgenic or knockout mice, guinea pigs with spontaneous degenerative joint disease).

Biofunctionality

A related testing stage that can be separate from or combined with biological relevance is biofunctionality (defined here as the ability of an implant to alter tissue function in a desired way). Unique bone and joint properties often measured include the following:53,78
•
Chondrogenesis: the ability of an implant to induce or support regrowth of cartilage
•
Osteointegration: growth of tissue into or along the surface of implanted material (Figs. 1–3)
•
Osteoconductivity: ability of a scaffold to promote/support osteogenic cells within a defined space
•
Osteoinduction: soluble or matrix-bound signals that interact with and drive local uncommitted host stem cells/progenitors toward an osteoblastic phenotype; osteoinductive implants can induce bone formation at heterotopic sites (ie, muscle; Fig. 4)9
Figure 1. Local cortical tissue response to implant, femur cortical bone, rabbit. Local tissue response to implantation of high-density plastic (*) at 26 weeks prior, showing no significant osteointegration or immune response. New bone has been deposited (osteointegration) along the marrow surface (black arrow) and the endosteal surface (white arrows). Exakt processed fully mineralized section. Hematoxylin and eosin (HE). Figure 2. Local periosteal reaction without significant osteointegration in response to stainless steel implant, femur cortical bone, rabbit. Fibrous connective tissue directly lines the implant surface (*) with minimal giant cell response along the implant surface (arrow). Woven and plexiform bone has formed adjacent to the fibrous connective tissue. Exakt processed fully mineralized section. HE. Figure 3. (a) Woven bone response to alveolar bone resection, oral cavity, dog. Proliferation of woven bone in response to resection of alveolar bone to depth of a reference notch created in the tooth at the time of surgery (vertical black line). Red staining predominates on the surface (newer bone, thin arrow) adjacent to deeper blue-stained bone (older bone, thick arrow). Implanted bone void filler (asterisk) is surrounded by macrophages and giant cells (shown in Fig. 3b) and shows no osteointegration. Decalcified, modified Masson’s trichrome. (b) Immune response to bone void filler, oral cavity, dog. A serial section of the region indicated by the asterisk in Figure 3a at higher magnification, showing the presence of giant cells (thick arrow) and macrophages (thin arrow) adjacent to bone void filler (*). Decalcified, HE.
Figure 4. Osteoinduction within xenograft, skeletal muscle, athymic mouse. Demineralized human bone implanted within skeletal muscle for 35 days facilitated production of hyaline cartilage within preexisting osteonal canals (thin black arrow) and appositional woven bone deposition (thick black arrows indicating osteocytes) along the surface of the decellularized implant (white arrows indicating empty lacunae). Decalcified, hematoxylin and eosin.
As with evaluating biological relevance, biofunctionality is often tested in rodents and rabbits if the implant can be scaled to a small size and placed in a bone with similar physiology to that of the intended human site. If small animal models are not appropriate, larger species are used (dogs, pigs, small ruminants).

Biocompatibility/Safety

While biofunctionality tests if the implant has the desired effects (ie, osteoinduction when implanted in muscle), biocompatibility/safety studies can identify undesirable local or systemic effects (ie, immune reaction to osteoinductive material).30 Biocompatible implants (and any breakdown or leachable derivatives) should be nontoxic, nonthrombogenic, noncarcinogenic, nonantigenic, and nonmutagenic.30 Safety studies often use rodents and rabbits to detect local tissue damage (often including histiocytic and multinucleated cell infiltrates; Fig. 3b)47,80 and systemic toxicities (often from breakdown or leachable derivatives). While tissue reactions to specific materials are not discussed here, recent reviews30,47 provide detailed information about host reactions to different materials.

Clinical Relevance/Efficacy

Finally, while functionality and safety can be established in smaller species, it may be necessary to demonstrate efficacy in larger animals (dogs, small ruminants, pigs, nonhuman primates [NHPs]), where local blood flow and mechanical loading can be critical to implant success.53,78

Diseases/Conditions Commonly Modeled

Enhancing Osteoinductive and Chondrogenic Potential After Injury

Implants that initiate or enhance bone or cartilage growth are highly desirable for injured tissues, especially those that have limited vascular or marrow supply to support intrinsic repair (ie, membranous craniofacial bone79). Osteoinductive and/or chondrogenic potential is often measured in athymic mice and rats.65,79 Chondrogenic implants are used in an attempt to repair synovial joints16,65 and intervertebral disks. Osteoinductive implants are used as interventions to repair vertebral fractures,10,79 during dental and craniofacial bone surgery,18,79 and in segmental defects/nonunions (discussed in detail below).

Large Bone Defects and Nonunions

Large bone defects occur secondary to a pathologic event (ie, trauma, inflammation, surgical resection64) that causes extensive bone loss. In human clinical settings, critical-size defects are defined as those that do not heal within ∼6 months postinjury in otherwise healthy adults.12 Affected sites (ie, anteromedial tibia20) often have limited adjacent muscle that could provide physical coverage and an auxiliary blood supply. Critical-size defects in animal models are defined as “the smallest size intraosseous wound in a particular bone and species of animal that will not heal spontaneously during the lifetime of the animal”27,67 or a defect with <10% bone regeneration over the animal’s lifetime.27 Surgically created critical defects are a gap in length >2.25 times the diameter of the affected bone26,46 or large cylindrical defects in femoral condyles or tibial metaphysis. Rats, rabbits, and increasingly small ruminants are used in defect models.59 One advantage of small ruminants is that their repair rate is more comparable to humans than rodents (a large tibial defect can fully repair within 12 weeks in rats but may take 32–52 weeks in goats or sheep32).

Implant-Related Complications

Finally, while implants have an overall positive impact on human health, individuals may have implant-related complications (usually modeled in rodents and rabbits). Negative responses to implants can include reactions to wear debris, osteolytic bone resorption, anatomic malalignment, implant instability/breakage, heterotopic ossification, pain, and immunologic reactions/hypersensitivity.80 Over 100 000 cases of implant-associated infection and osteomyelitis are reported annually in the United States.55 On average, 2% to 5% of internal fixation devices become infected19,74 and may require surgical removal to eliminate the infection. Up to 70% of organisms isolated in prosthetic joint infections are Gram-positive agents, including Staphylococcus epidermidis, Staphylococcus aureus, and β-hemolytic streptococci.55,80

Human Bone: Terminology, Organization, and Development

Terminology

Understanding how human bone is organized and develops is important when selecting an appropriate model species. Since there are multiple anatomic and histologic terms for some bone structures, in this review, a single term is used for each feature, with alternate terms listed in parentheses. Microscopically, bone is generally organized into woven (type I collagen fibers arranged haphazardly) or lamellar (collagen in parallel layers or concentric rings) patterns. Additionally, plexiform (or laminar or fibrolamellar) bone is produced within the periosteum when significant bone strength and rapid deposition are required. Plexiform bone is lamellar bone deposited on brick-like cores of nonlamellar bone (Fig. 2).60 Plexiform, woven, primary lamellar, and primary osteons are forms of primary bone (formed during initial bone modeling on a substrate of bone or cartilage without resorption of preexisting bone). Secondary bone includes secondary osteons (Haversian systems) that replace primary bone through remodeling (coordinated deposition of new bone with resorption of preexisting bone). Macroscopically, bone is generally organized into cortical (or compact, referring to filling in spaces in plexiform bone) and cancellous bone (or trabecular or spongy or medullary). Structural differences between the 2 forms include bone density (cortical > cancellous), vascular access (cancellous > cortical), and presence of full osteons (cortical) or hemiosteons (cancellous).

Organization

All normal adult human cortical bone is lamellar with extensive secondary osteonal remodeling.28,36 Plexiform bone is rarely present in humans, and in adults, woven bone is only formed during rapid bone formation (ie, fracture callus, hyperparathyroidism).45,64 Macroscopically, approximately 80% of the adult human skeleton comprises cortical bone (by weight), and the remaining 20% is trabecular.24,34 Load-bearing long bones are 80% to 100% cortical bone, while vertebrae are 80% cancellous and 20% cortical.69 Subchondral plate bone adjacent to articular cartilage is generally thin36 with minimal regenerative capabilities.

Development

Ossification in humans begins early in the neonatal period and continues throughout early adulthood, with fusion of the proximal and distal femoral epiphyses completed by 19 to 20 years in males and 2 to 3 years earlier in females.15,53,84 Human remodeling rates range from 10% to 55% (average whole-body trabecular bone turnover per year64), with age-associated cortical bone loss occurring primarily at the endocortical endosteum.10 Bone adjacent to red marrow generally has higher rates of remodeling (eg, 10%–15% per year in ilium trabecular bone) compared with sites adjacent to yellow (fatty) marrow.63

Factors to Consider When Selecting a Model

Certain characteristics are desirable when selecting any animal model, including low intra- and interanimal variation, the availability of sensitive methods to assess a biological parameter, and the use of treatment conditions that most closely match human clinical disease.53 Additional factors should be considered in bone and joint models (Table 1). First, since implants may be intended for use in either cortical or cancellous bone, it is important to identify which sites and at what age a model species’ macro- and microstructure best matches human bone. Second, blood supplies that support bone healing can differ markedly between species84 and by macroscopic structure (cancellous > cortical). Third, control groups or sites (ie, sham-operated, autologous cancellous bone graft78) can aid in differentiating implant effects on bone repair from intrinsic bone-healing abilities (which can be significant in rodents and rabbits). Next, repair responses in skeletally immature animals can be more rapid than in mature adults.65 For example, femoral fractures have been shown to heal within 4 weeks in 6-week-old rats but may take up to 26 weeks in 52-week-old rats.51 These age-related changes can be further complicated by sexual dimorphism, which has been well documented in rodents and is influenced by sex hormones.40 Finally, implants that cannot be scaled down (ie, joint replacement) require a large animal model.53
Table 1. Species Factors to Consider When Selecting a Bone/Joint Implant Model.
Factor Implications for Model
Implant site Cancellous vs cortical vs specialized (ie, alveolar bone in oral cavity)
  Microstructure at implant site
  Bone large enough to accept human-sized implant
  Vascular supply to bone
  Adjacent soft tissue that will be disturbed during implantation/provide vascular support
Control groups and materials Autologous graft availability (gold standard for bone repair material)
  Sham-operated sites
Nutrition Reduced healing under food restriction or reduced ability to eat postimplant28,76
Age Greater bone and cartilage healing ability in younger animals15,57
Genetic background Strain variability, inbred vs outbred34,43
The following sections outline common model uses and comparative bone pathology for the most common preclinical species (summarized in Table 2).
Table 2. Summary of Human and Animal Bone Properties.
Species Secondary Centers of Ossification Present at Birth28 Macroscopic Similarity to Human Bone37,52–53,60 Microscopic Structure45,60,62,64,81 Osteonal Remodeling10,28,48,56,66 Age of Skeletal Maturity3,11,15,52 Average Cartilage Thickness (Femur, mm)16
Human Yes, limited to distal femur and proximal tibia NA Circumferential lamellar bone with extensive remodeling Yes (in utero) 16–20 y15,84 2.2–2.523
NHP No Very similar Similar to human Yes (age varies by species) 5 y (baboon), 7 y (rhesus) 0.57–0.72 (cynomolgus)7,13
Rodent No Not similar Primary bone predominates over life span Minimal, advanced age ∼26 wk, with potential for continuous growth68 0.030–0.1 (mouse), 0.17 (rat)73
Rabbit No Minimally similar Primary bone predominates, secondary osteons develop with age Minimal, advanced age 8–11 mo 0.2–0.44
Dog No Moderately similar Plexiform bone, some remodeling to small secondary osteons Yes (<1 y) 10–18 mo83 0.6–1.3
Pig Yes Moderately similar Plexiform with transition to dense secondary osteonal Yes (>6 m) 18–24 mo (mini),75 2–4 y (conventional) 1.5
Small ruminant Yes Very similar Plexiform until 7–9 y (sheep), heterogeneous secondary osteonal with age (goat) Yes (>1 y) 15–18 mo (sheep), 2–3 y (goat) 0.4–0.5 (sheep), 0.6–1.7 (goat)57
NA, not applicable; NHP, nonhuman primate.

Rodents

Model Uses

Knockout and transgenic rodent models (ie, senescence accelerated mice) are a key resource in the biological relevance stage of implant studies.12,48 Athymic nude mice and rats are also commonly used to test osteoinductive and cartilage regenerative potential of allogenic and xenogeneic materials.16 Rats are used to model bone infection55 and extraoral surgical approaches.18 While rodents have limited cortical remodeling or secondary osteon formation, they can model cancellous bone responses in lumbar vertebral bodies and the distal femoral and proximal tibial metaphyses.4,28,63

Relevance to Human Bone and Joint Conditions

There are significant limitations to consider when extrapolating implant findings from rodents to humans, including differences in bone micro- and macrostructure, rates of growth, and size. Unlike the secondary bone present in the adult human long bone cortices, rodent long bone cortices are predominantly primary bone and have minimal cancellous bone available to harvest for autografts.53 Bone growth in rats continues much longer after sexual maturity than in humans.39 Bone-healing capacity is higher in rodents than in humans at sites such as craniofacial bones,71 and the retention of open physes in adults may enhance intrinsic articular cartilage healing potential.16 Finally, some implants cannot be scaled down to a rodent size to test clinical equivalency.12

Guinea Pig

While guinea pigs are not a common model for bone implants, strains that develop spontaneous degenerative joint disease, like the Dunkin-Hartley, are used to evaluate cartilage regeneration and joint support implants. Dunkin-Hartley male guinea pigs develop histologic lesions by 3 months of age, which progress within 6 months to lesions that closely resemble human joint changes.38,76

Rabbit

Model Uses

Rabbit hindlimbs are commonly used for cortical and cancellous bone implant studies. The tibia is easily accessible due to minimal associated soft tissue, and the femur has sufficient medullary space for many internal fixation studies.14 Mature rabbit condyles can support 3- to 4-mm defects to test biocompatibility and osteoinduction in cancellous bone.16 Rabbits are also used to model vertebral fracture repair, methods to control common implant-associated pathogens (ie, Staphylococcus epidermidis14,22), effects of wear debris particles,12 and extraoral surgical approaches.18

Relevance to Human Bone and Joint Conditions

Rabbits offer advantages over large animal models by reaching skeletal maturity at a relatively early age and advantages over rodents by undergoing more secondary osteonal remodeling.53 Despite these positive characteristics, there are significant differences between rabbit and human bone. The rate of cortical bone remodeling is rapid in the young rabbits often used in studies, which can be less representative of the healing response in adult humans.78 Rabbits also have relatively fatty bone marrow, which is not ideal for autogenous bone grafts.53 Rabbit femoral condyle cartilage is relatively thin,5,65 and articular cartilage in young, 3- to 9-month-old rabbits has rapid healing potential that can be a confounding factor in long-term studies.16,82

Dog

Model Uses

Dogs are commonly used in dental studies60 and are a valuable model of peri-implantitis (inflammation of tissue adjacent to dental implants), due to their susceptibility to biofilm accumulation and spontaneous periodontitis.18 Large-breed dogs can often support human-sized implants,60 and their large synovial joints, such as the stifle, can be monitored via arthroscopy.16 Additionally, sufficient material for autogenous bone grafts can be harvested from the proximal humerus.53 Finally, dogs are also amenable to studies that evaluate how rehabilitation activities affect implant function.16

Relevance to Human Bone and Joint Conditions

Canine and human bone have many similarities, including formation of secondary osteons, epiphyseal fusion after maturity, comparable intracortical remodeling activity,28 and age-associated bone loss.10 The 2 species also have similar bone weight, density, and composition of bone organic, inorganic, and water fractions.1,64 Humans and dogs also both lack substantial intrinsic healing ability for cartilage defects.16 Key differences include the retention of plexiform bone on canine cortical periosteal and endosteal surfaces45,81 and thinner articular cartilage in dogs.16 Dogs have higher annual total-body trabecular bone turnover rates (averaging 94%–101% in male and female canine trabecular bone compared with an estimated 10%–55% in adult humans41,60,64), which may partially explain the high rate of solid bony fusion and low rates of nonunion in canine models.64 One important limitation of using dogs is that remodeling and apposition rates can vary significantly both within and between dogs.25 For example, individual ribs in a single-purpose-bred Beagle may have statistically different bone remodeling parameters.6

Pig (Conventional and Minipig)

Model Uses

Conventional pigs and minipigs are used to evaluate bone osteogenic material in craniomaxillary facial surgery models,12 extra- and intraoral surgical approaches for dental implants,18 interventions for femoral head osteonecrosis, and repair of cartilage and bone fractures.60 Sufficient material for autogenous cancellous bone grafts can be harvested from the proximal humerus.53 Skeletally mature conventional pig articular cartilage is also thick enough (∼1.5 mm) to create both full- and partial-thickness cartilage defects that can be monitored via arthroscopy.16

Relevance to Human Bone and Joint Conditions

Bone mineral density, anatomy, morphology, remodeling rate, and healing of pigs are similar to humans.64 Pigs have both growing and adult skeletal phases5 with well-developed Haversian systems in mature bone.10 Swine intra-articular cartilage and associated ligaments in synovial joints are similar to the conformation in human joints.75 Disadvantages include high growth rates, excessive body weight, and difficulty in being handled compared with other species.64 Pig tibial and femoral length is also relatively short, which can prevent direct testing of human-sized implants64 or creation of stable, critical-size defects.53

Sheep and Goats

Model Uses

Use of small ruminant orthopedic models is increasing, with reports of sheep and goat models growing from ∼5% of bone papers in the 1980s to 11% to 15% in the 2000s.50,59 Small ruminants are used to model defect repair in long bones, bone filler materials in cranial defects, fracture repair devices, tissue response to wear debris, extraoral surgical approaches, and intervertebral disk replacements.12,18 The relatively vertical alignment of the cervical vertebrae in small ruminants undergoes some of the same axial compression and rotation forces as the human spine.53

Relevance to Human Bone and Joint Conditions

Small ruminants and humans have a comparable body weight, bone size, and bone-healing potential, as well as tibial blood supply (young sheep) and bone composition and remodeling rates (goats).64 Additionally, the ratio of cartilage to subchondral bone, subchondral bone consistency, joint size, accessibility for arthroscopy, and limited intrinsic healing capacity in goats are similar to human joints.2,16,33 Autogenous cancellous grafts can also be performed in small ruminants.53 Despite these similarities, there are several important differences between small ruminant and human bone. Sheep cortical bone remains predominantly plexiform through 7 to 9 years of age.64,66 Sheep undergo seasonal bone loss, and if a study occurs during winter (when bone formation is depressed), control animals may spontaneously lose and regain bone.10 While in mature sheep, trabecular bone is more dense and stronger than human bone, immature sheep have weaker, low-density trabecular bone that is highly flexible (due to higher collagen content54).

NHPs

NHPs and humans share significant genetic homology, have comparable osteonal remodeling in skeletally mature individuals, and develop similar diseases, including osteoarthritis and age-associated bone loss.37 Comparable bone biopsy sites are also available in both species, such as vertebral bodies, the cortex of the seventh rib, proximal femur, and ilium.4,63 NHPs are generally used in bone implant studies when other large animal models do not adequately represent human bone biomechanics and loading, including dental implants and vertebral repair products. The tooth and jaw structure of NHPs provide relevant information about stress responses to mechanical loading of dental implants.18 Baboons are also used to evaluate specialized intervertebral artificial disks.12 While NHPs have key advantages as a model for these specialized implant sites, implants for other sites such as long bones are sometimes better suited for other large animal models. NHP long bones can be too small to support adult human implants. For example, a mature male rhesus has a ∼16.5-cm-long femur with a 1.25-cm mid-shaft diameter while mature hounds can have a 20-cm-long femur with a 2.5- to 3-cm mid-shaft diameter.53

Study Design, Nomenclature, and Scoring Criteria for Bone/Joint Implants

While many factors used to design effective toxicology studies of small and large molecules are also applicable to bone implant studies, there are several additional criteria to consider. Reactions to implants are generally time, not dose, dependent.72 Implants designed to promote bone growth may require studies lasting longer than 6 months to allow sufficient time for bone regeneration, remodeling, and detection of implant absorption or degradation.64 Also, implant placement almost always incites a significant nonspecific localized tissue reaction, secondary to surgical/implantation trauma.72 It is therefore important to include sham surgery and/or control implants to differentiate reactions that are implant induced from those that are primarily implantation induced.
Histologic processing of bone and joint implant samples can be uniquely challenging, and variations in implants are too numerous to be addressed here. Readers interested in processing specific implant materials and common bone-staining methods are referred to recent publications.4,70 Additional analytic techniques (macroscopic evaluation, radiographs, computed tomography [CT], micro-CT8) can also provide key information on 3D structure and device surface-tissue interactions, factors that can be difficult to appreciate with histology alone.
Excellent resources are available for both the design and interpretation of in vivo studies, including guidances that are the basis for implant regulations in several countries (Table 3). Clinical and basic bone researchers have developed standardized histomorphometry terms and evaluation methods to provide consistency across studies.21,63 Cartilage scoring criteria are recommended by the International Cartilage Repair Society (ICRS, preferred for implant studies31,49) and the Osteoarthritis Research Society International Histopathology Initiative (OARSI, preferred for drug-related effects42,43,61). Finally, standard nomenclature and image resources for spontaneous bone and joint lesions are available in the forthcoming bone, cartilage, and tooth INHAND manuscript (http://goreni.org/index.php) and National Toxicology Program Non-neoplastic Lesion Atlas (http://ntp.niehs.nih.gov/nnl/guide/index.htm).
Table 3. International Standards for Biological Evaluation of Bone and Joint Implants.
Issuing Organization Primary Category Standard No. Standard Name
International Organization for Standardization (ISO) Biocompatibility 10993-6 Tests for local effects after implantation
  10993-11 Tests for systemic toxicity
ASTM (formerly American Society for Testing and Materials) Biocompatibility F748—06 (2010) Standard Practice for Selecting Generic Biological Test Methods for Materials and Devices
F763—04 (2010) Standard Practice for Short-Term Screening of Implant Materials
F981—04 (2010) Standard Practice for Assessment of Compatibility of Biomaterials for Surgical Implants with Respect to Effect of Materials on Muscle and Bone
F1027—86 (2012) Standard Practice for Assessment of Tissue and Cell Compatibility of Orofacial Prosthetic Materials and Devices
F1408—97 (2013) Standard Practice for Subcutaneous Screening Test for Implant Materials
F1439—03 (2013) Standard Guide for Performance of Lifetime Bioassay for the Tumorigenic Potential of Implant Materials
F1904—14 Standard Practice for Testing the Biological Responses to Particles In Vivo
  F1983—99 (2008) Standard Practice for Assessment of Compatibility of Absorbable/Resorbable Biomaterials for Implant Applications
Biofunctionality F2721-09 Standard Guide for Preclinical In Vivo Evaluation in Critical Sized Segmental Bone Defects
F2451—05 (2010) Standard Guide for In Vivo Assessment of Implantable Devices Intended to Repair or Regenerate Articular Cartilage
F2529—13 Standard Guide for In Vivo Evaluation of Osteoinductive Potential for Materials Containing Demineralized Bone (DBM)
F2721—09 Standard Guide for Preclinical In Vivo Evaluation in Critical Size Segmental Bone Defects
F2884—12 Standard Guide for Preclinical In Vivo Evaluation of Spinal Fusion

Concluding Thoughts

As implant development and clinical use continues to expand, it is important for pathologists evaluating bone and joint implant studies to understand the basics of bone structure and the advantages and disadvantages of different animal models. While no single animal model completely recapitulates human bone and joint development and repair, various species can provide key support when developing implants.

Acknowledgements

Dr David H. Johnson provided assistance with reference formatting and figure preparation.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

1. Aerssens J, Boonen S, Lowet G, et al. Interspecies differences in bone composition, density, and quality: potential implications for in vivo bone research. Endocrinology. 1998;139(2):663–670.
Crossref
PubMed
ISI
Google Scholar
2. Ahern BJ, Parvizi J, Boston R, et al. Preclinical animal models in single site cartilage defect testing: a systematic review. Osteoarthritis Cartilage. 2009;17(6):705–713.
Crossref
PubMed
ISI
Google Scholar
3. Aigner T, Cook JL, Gerwin N, et al. Histopathology atlas of animal model systems—overview of guiding principles. Osteoarthritis Cartilage. 2010;18(suppl 3):S2–S6.
Crossref
PubMed
ISI
Google Scholar
4. Allen MR, Burr DB. Techniques in histomorphometry. In: Burr DB, Allen MR eds. Basic and Applied Bone Biology. Amsterdam, the Netherlands: Academic Press; 2014:131–148.
Crossref
Google Scholar
5. An YH, Freidman RJ. Animal selections in orthopaedic research. In: An YH, Freidman RJ, eds. Animal Models in Orthopaedic Research. Boca Raton, FL: CRC Press; 1999:39–57.
Google Scholar
6. Anderson C, Danylchuk KD. Bone-remodeling rates of the Beagle: a comparison between different sites on the same rib. Am J Vet Res. 1978;39(11):1763–1765.
PubMed
ISI
Google Scholar
7. Athanasiou KA, Rosenwasser MP, Buckwalter JA, et al. Interspecies comparisons of in situ intrinsic mechanical properties of distal femoral cartilage. J Orthop Res. 1991;9(3):330–340.
Crossref
PubMed
ISI
Google Scholar
8. Bagi CM, Berryman E, Moalli MR. Comparative bone anatomy of commonly used laboratory animals: implications for drug discovery. Comp Med. 2011;61(1):76–85.
PubMed
ISI
Google Scholar
9. Barradas AM, Yuan H, van Blitterswijk CA, et al. Osteoinductive biomaterials: current knowledge of properties, experimental models and biological mechanisms. Eur Cell Mater. 2011;21:407–429.
Crossref
PubMed
ISI
Google Scholar
10. Bonucci E, Ballanti P. Osteoporosis—bone remodeling and animal models. Toxicol Pathol. 2014;42(6):957–969.
Crossref
PubMed
ISI
Google Scholar
11. Boretos JW, Eden M. Contemporary Biomaterials, Material and Host Response, Clinical Applications, New Technology and Legal Aspects. Park Ridge, NJ: Noyes Publications; 1984.
Crossref
Google Scholar
12. Boutrand J. Methods and interpretation of performance studies for bone implants. In: Boutrand J, ed. Biocompatibility and Performance of Medical Devices. Oxford, UK: Woodhead Publishing Limited; 2012:272–279.
Crossref
Google Scholar
13. Buckwalter JA, Martin JA, Olmstead M, et al. Osteochondral repair of primate knee femoral and patellar articular surfaces: implications for preventing post-traumatic osteoarthritis. Iowa Orthop J. 2003;23:66–74.
PubMed
Google Scholar
14. Burkholder TH, Linton G, Hoyt RF Jr, et al. The rabbit as an experimental model. In: Suckow MA, Stevens KA, Wilson RP, eds. The Laboratory Rabbit, Guinea Pig, Hamster, and Other Rodents. Amsterdam, the Netherlands: Academic Press; 2012:548–550.
Crossref
Google Scholar
15. Cardoso HF. Epiphyseal union at the innominate and lower limb in a modern Portuguese skeletal sample, and age estimation in adolescent and young adult male and female skeletons. Am J Phys Anthropol. 2008;135(2):161–170.
Crossref
PubMed
ISI
Google Scholar
16. Chu CR, Szczodry M, Bruno S. Animal models for cartilage regeneration and repair. Tissue Eng Part B Rev. 2010;16(1):105–115.
Crossref
PubMed
ISI
Google Scholar
17. Cosgrove J. MEDICARE: Lack of Price Transparency May Hamper Hospitals’ Ability to Be Prudent Purchasers of Implantable Medical Devices. 2012;GAO-12-126 Implantable Medical Devices, St. Louis.
Google Scholar
18. Dard M. Methods and interpretation of performance studies for dental implants. In: Boutrand J, ed. Biocompatibility and Performance of Medical Devices. Oxford, UK: Woodhead Publishing Limited; 2012:308–344.
Crossref
Google Scholar
19. Darouiche RO. Treatment of infections associated with surgical implants. N Engl J Med. 2004;350(14):1422–1429.
Crossref
PubMed
ISI
Google Scholar
20. DeCoster TA, Gehlert RJ, Mikola EA, et al. Management of posttraumatic segmental bone defects. J Am Acad Orthop Surg. 2004;12(1):28–38.
Crossref
PubMed
ISI
Google Scholar
21. Dempster DW, Compston JE, Drezner MK, et al. Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 2013;28(1):2–17.
Crossref
PubMed
ISI
Google Scholar
22. Donlan RM. Biofilm formation: a clinically relevant microbiological process. Clin Infect Dis. 2001;33(8):1387–1392.
Crossref
PubMed
ISI
Google Scholar
23. Frisbie DD, Cross MW, McIlwraith CW. A comparative study of articular cartilage thickness in the stifle of animal species used in human pre-clinical studies compared to articular cartilage thickness in the human knee. Vet Comp Orthop Traumatol. 2006;19(3):142–146.
Crossref
PubMed
ISI
Google Scholar
24. Frost HM. Introduction to a New Skeletal Physiology. 2 vols. Pueblo, CO: Pajaro Group; 1995.
Google Scholar
25. Greaves P. Histopathology of Preclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation. Amsterdam, the Netherlands: Academic Press; 2012.
Google Scholar
26. Gugala Z, Lindsey RW, Gogolewski S. New approaches in the treatment of critical-size segmental defects in long bones. Macromol Symp. 2007;253:147–161.
Crossref
Google Scholar
27. Gugala Z, Gogolewski S. Regeneration of segmental diaphyseal defects in sheep tibiae using resorbable polymeric membranes: a preliminary study. J Orthop Trauma. 1999;13(3):187–195.
Crossref
PubMed
ISI
Google Scholar
28. Haschek WM, Rousseaux CG, Wallig MA. Bones and joints. In: Haschek WM, Rousseaux CG, Wallig MA eds. Fundamentals of Toxicologic Pathology. 2nd ed. Amsterdam, the Netherlands: Academic Press; 2010:416–417.
Crossref
Google Scholar
29. Heinrichs C, Colli M, Yanovski JA, et al. Effects of fasting on the growth plate: systemic and local mechanisms. Endocrinology. 1997;138(12):5359–5365.
Crossref
PubMed
ISI
Google Scholar
30. Helmus MN, Gibbons DF, Cebon D. Biocompatibility: meeting a key functional requirement of next-generation medical devices. Toxicol Pathol. 2008;36(1):70–80.
Crossref
PubMed
ISI
Google Scholar
31. Hoemann C, Kandel R, Roberts S, et al. International Cartilage Repair Society (ICRS) recommended guidelines for histological endpoints for cartilage repair studies in animal models and clinical trials. Cartilage. 2011;2(2):153–172.
Crossref
PubMed
ISI
Google Scholar
32. Horner EA, Kirkham J, Wood D, et al. Long bone defect models for tissue engineering applications: criteria for choice. Tissue Eng Part B Rev. 2010;16(2):263–271.
Crossref
PubMed
ISI
Google Scholar
33. Jackson DW, Lalor PA, Aberman HM, et al. Spontaneous repair of full-thickness defects of articular cartilage in a goat model: a preliminary study. J Bone Joint Surg Am. 2001;83(1):53–64.
Crossref
PubMed
ISI
Google Scholar
34. Jee WSS. Structure and function of bone tissue. In: Bronner F, Worrell RV, eds. Orthopaedics: Principles of Basic and Clinical Science. Boca Raton, FL: CRS Press; 1999:5–25.
Google Scholar
35. Jepsen KJ, Price C, Silkman LJ, et al. Genetic variation in the patterns of skeletal progenitor cell differentiation and progression during endochondral bone formation affects the rate of fracture healing. J Bone Miner Res. 2008;23(8):1204–1216.
Crossref
PubMed
ISI
Google Scholar
36. Jerome C, Hoch B. Skeletal system. In: Treuting PM, Dintzis SM, eds. Comparative Anatomy and Histology: A Mouse and Human Atlas. Amsterdam, the Netherlands: Academic Press; 2012:53–64.
Crossref
Google Scholar
37. Jerome CP, Peterson PE. Nonhuman primate models in skeletal research. Bone. 2001;29(1):1–6.
Crossref
PubMed
ISI
Google Scholar
38. Jimenez PA, Glasson SS, Trubetskoy OV, et al. Spontaneous osteoarthritis in Dunkin Hartley guinea pigs: histologic, radiologic, and biochemical changes. Lab Anim Sci. 1997;47(6):598–601.
PubMed
Google Scholar
39. Kilborn SH, Trudel G, Uhthoff H. Review of growth plate closure compared with age at sexual maturity and lifespan in laboratory animals. Contemp Top Lab Anim Sci. 2002;41(5):21–26.
PubMed
Google Scholar
40. Kim BT, Mosekilde L, Duan Y, et al. The structural and hormonal basis of sex differences in peak appendicular bone strength in rats. J Bone Miner Res. 2003;18(1):150–155.
Crossref
PubMed
ISI
Google Scholar
41. Kimmel DB, Jee WS. A quantitative histologic study of bone turnover in young adult beagles. Anat Rec. 1982;203(1):31–45.
Crossref
PubMed
Google Scholar
42. Kraus VB, Huebner JL, DeGroot J, et al. The OARSI histopathology initiative—recommendations for histological assessments of osteoarthritis in the guinea pig. Osteoarthritis Cartilage. 2010;18(suppl 3):S35–S52.
Crossref
PubMed
ISI
Google Scholar
43. Laverty S, Girard CA, Williams JM, et al. The OARSI histopathology initiative—recommendations for histological assessments of osteoarthritis in the rabbit. Osteoarthritis Cartilage. 2010;18(suppl 3):S53–S65.
Crossref
PubMed
ISI
Google Scholar
44. Li X, Gu W, Masinde G, et al. Genetic variation in bone-regenerative capacity among inbred strains of mice. Bone. 2001;29(2):134–140.
Crossref
PubMed
ISI
Google Scholar
45. Liebschner MA. Biomechanical considerations of animal models used in tissue engineering of bone. Biomaterials. 2004;25(9):1697–1714.
Crossref
PubMed
ISI
Google Scholar
46. Lindsey RW, Gugala Z, Milne E, et al. The efficacy of cylindrical titanium mesh cage for the reconstruction of a critical-size canine segmental femoral diaphyseal defect. J Orthop Res. 2006;24(7):1438–1453.
Crossref
PubMed
ISI
Google Scholar
47. Long PH. Medical devices in orthopedic applications. Toxicol Pathol. 2008;36(1):85–91.
Crossref
PubMed
ISI
Google Scholar
48. Long PH, Leininger JR. Bones, joints, and synovia. In: Maronpot RR, Boorman GA, Gaul BW, eds. Pathology of the Mouse. St Louis, MO: Cache River Press; 1999:645–652.
Google Scholar
49. Mainil-Varlet P, Van Damme B, Nesic D, et al. A new histology scoring system for the assessment of the quality of human cartilage repair: ICRS II. Am J Sports Med. 2010;38(5):880–890.
Crossref
PubMed
ISI
Google Scholar
50. Martini L, Fini M, Giavaresi G, et al. Sheep model in orthopedic research: a literature review. Comp Med. 2001;51(4):292–299.
PubMed
ISI
Google Scholar
51. Meyer RA Jr, Tsahakis PJ, Martin DF, et al. Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats. J Orthop Res. 2001;19(3):428–435.
Crossref
PubMed
ISI
Google Scholar
52. Mosekilde L, Weisbrode SE, Safron JA, et al. Calcium-restricted ovariectomized Sinclair S-1 minipigs: an animal model of osteopenia and trabecular plate perforation. Bone. 1993;14(3):379–382.
Crossref
PubMed
ISI
Google Scholar
53. Muschler GF, Raut VP, Patterson TE, et al. The design and use of animal models for translational research in bone tissue engineering and regenerative medicine. Tissue Eng Part B Rev. 2010;16(1):123–145.
Crossref
PubMed
ISI
Google Scholar
54. Nafei A, Danielsen CC, Linde F, et al. Properties of growing trabecular ovine bone, part I: mechanical and physical properties. J Bone Joint Surg Br. 2000;82(6):910–920.
Crossref
PubMed
Google Scholar
55. Nair MB, Kretlow JD, Mikos AG, et al. Infection and tissue engineering in segmental bone defects—a mini review. Curr Opin Biotechnol. 2011;22(5):721–725.
Crossref
PubMed
ISI
Google Scholar
56. Newman E, Turner AS, Wark JD. The potential of sheep for the study of osteopenia: current status and comparison with other animal models. Bone. 1995;16(4)(suppl):277S–284S.
Crossref
PubMed
ISI
Google Scholar
57. Niederauer GG, Niederauer GM, Cullen LC Jr, et al. Correlation of cartilage stiffness to thickness and level of degeneration using a handheld indentation probe. Ann Biomed Eng. 2004;32(3):352–359.
Crossref
PubMed
ISI
Google Scholar
58. O’Driscoll SW, Saris DB, Ito Y, et al. The chondrogenic potential of periosteum decreases with age. J Orthop Res. 2001;19(1):95–103.
Crossref
PubMed
ISI
Google Scholar
59. O’Loughlin PF, Morr S, Bogunovic L, et al. Selection and development of preclinical models in fracture-healing research. J Bone Joint Surg Am. 2008;90(suppl 1):79–84.
Crossref
PubMed
ISI
Google Scholar
60. Pearce AI, Richards RG, Milz S, et al. Animal models for implant biomaterial research in bone: a review. Eur Cell Mater. 2007;13:1–10.
Crossref
PubMed
ISI
Google Scholar
61. Pritzker KP, Gay S, Jimenez SA, et al. Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis Cartilage. 2006;14(1):13–29.
Crossref
PubMed
ISI
Google Scholar
62. Qin L, Mak AT, Cheng CW, et al. Histomorphological study on pattern of fluid movement in cortical bone in goats. Anat Rec. 1999;255(4):380–387.
Crossref
PubMed
Google Scholar
63. Recker RR, Kimmel DB, Dempster D, et al. Issues in modern bone histomorphometry. Bone. 2011;49(5):955–964.
Crossref
PubMed
ISI
Google Scholar
64. Reichert JC, Saifzadeh S, Wullschleger ME, et al. The challenge of establishing preclinical models for segmental bone defect research. Biomaterials. 2009;30(12):2149–2163.
Crossref
PubMed
ISI
Google Scholar
65. Reinholz GG, Lu L, Saris DB, et al. Animal models for cartilage reconstruction. Biomaterials. 2004;25(9):1511–1521.
Crossref
PubMed
ISI
Google Scholar
66. Reinwald S, Burr D. Review of nonprimate, large animal models for osteoporosis research. J Bone Miner Res. 2008;23(9):1353–1368.
Crossref
PubMed
ISI
Google Scholar
67. Rimondini L, Nicoli-Aldini N, Fini M, et al. In vivo experimental study on bone regeneration in critical bone defects using an injectable biodegradable PLA/PGA copolymer. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;99(2):148–154.
Crossref
PubMed
Google Scholar
68. Roach HI, Mehta G, Oreffo RO, et al. Temporal analysis of rat growth plates: cessation of growth with age despite presence of a physis. J Histochem Cytochem. 2003;51(3):373–383.
Crossref
PubMed
ISI
Google Scholar
69. Rosenberg AE, Roth SI. Bone. In: Mills SE, ed. Histology for Pathologists. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012:85–106.
Google Scholar
70. Rousselle S, Wicks J. Preparation of medical devices for evaluation. Toxicol Pathol. 2008;36(1):81–84.
Crossref
PubMed
ISI
Google Scholar
71. Schmitz JP, Hollinger JO. The critical size defect as an experimental model for craniomandibulofacial nonunions. Clin Orthop Relat Res. 1986;205:299–308.
Crossref
Google Scholar
72. Schuh JC. Medical device regulations and testing for toxicologic pathologists. Toxicol Pathol. 2008;36(1):63–69.
Crossref
PubMed
ISI
Google Scholar
73. Simon WH. Scale effects in animal joints, I: articular cartilage thickness and compressive stress. Arthritis Rheum. 1970;13(3):244–256.
Crossref
PubMed
Google Scholar
74. Stinner DJ, Keeney JA, Hsu JR, et al. Outcomes of internal fixation in a combat environment. J Surg Orthop Adv. 2010;19(1):49–53.
PubMed
Google Scholar
75. Swindle MM, Makin A, Herron AJ, et al. Swine as models in biomedical research and toxicology testing. Vet Pathol. 2012;49(2):344–356.
Crossref
PubMed
ISI
Google Scholar
76. Taylor DK, Lee VK. Guinea pigs as experimental models. In: Suckow MA, Stevens KA, Wilson RP, eds. The Laboratory Rabbit, Guinea Pig, Hamster, and Other Rodents. Amsterdam, the Netherlands: Academic Press; 2012:709–710.
Crossref
Google Scholar
77. van Leeuwen BL, Hartel RM, Jansen HW, et al. The effect of chemotherapy on the morphology of the growth plate and metaphysis of the growing skeleton. Eur J Surg Oncol. 2003;29(1):49–58.
Crossref
PubMed
ISI
Google Scholar
78. Viateau V Guillemin G. Experimental animal models for tissue-engineered bone regeneration. In: Petite H, Quarto R, eds. Engineered Bone. Georgetown, TX: Eurekah.com/Landes Bioscience; 2005:89–91.
Google Scholar
79. Viateau V, Guillemin G. Experimental animal models for tissue-engineered bone regeneration In: Petite H, Quarto R, eds. Engineered Bone. Georgetown, TX: Eurekah.com/Landes Bioscience; 2005:94.
Google Scholar
80. Vigorita VJ, Ghelman B, Mintz D. Orthopaedic Pathology. Philadelphia, PA: Lippincott Williams &Wilkins; 2008.
Google Scholar
81. Wang X, Mabrey JD, Agrawal CM. An interspecies comparison of bone fracture properties. Biomed Mater Eng. 1998;8(1):1–9.
PubMed
ISI
Google Scholar
82. Wei X, Gao J, Messner K. Maturation-dependent repair of untreated osteochondral defects in the rabbit knee joint. J Biomed Mater Res. 1997;34(1):63–72.
Crossref
PubMed
ISI
Google Scholar
83. Yamasaki K. Histologic study of the femoral growth plate in beagle dogs. Toxicol Pathol. 1995;23(5):612–616.
Crossref
PubMed
ISI
Google Scholar
84. Zoetis T, Tassinari MS, Bagi C, et al. Species comparison of postnatal bone growth and development. Birth Defects Res B Dev Reprod Toxicol. 2003;68(2):86–110.
Crossref
PubMed
ISI
Google Scholar

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Published In

Volume 52, Issue 5
Pages: 842 - 850
Article first published online: July 10, 2015
Issue published: September 2015

Keywords

  1. animal models
  2. biocompatibility
  3. bone implants
  4. bone remodeling
  5. dental implants
  6. medical device
  7. peri-implantitis
  8. safety assessment

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© The Author(s) 2015.
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PubMed: 26163303

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L. M. Wancket
Biocompatibility, NAMSA, Northwood, OH, USA
[email protected]
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Notes

L. M. Wancket, Biocompatibility, NAMSA, 6750 Wales Road, Northwood, OH 43619, USA. Email: [email protected]

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    Go to citation Crossref Google Scholar
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