Medical Device Regulations and Testing for Toxicologic Pathologists

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Keywords: Biocompatibility testing; ISO 10993; Global Harmonization Task Force; medical device; preclinical; device safety; biomaterials; immuno- toxicology.
Toxicologic Pathology, 36:63-69, 2008 Copyright © 2008 by Society of Toxicologic Pathology ISSN: 0192-6233 print / 1533-1601 online DOI: 10.1177/0192623307309926

Medical Device Regulations and Testing for Toxicologic Pathologists JOANN C. L. SCHUH From Applied Veterinary Pathobiology PLLC, Bainbridge Island, Washington, USA. ABSTRACT Awareness of the regulatory environment is fundamental to understanding the biological assessment of biomaterials and medical devices. Medical devices are a diverse and heterogenous group of medical products and technologies defined by the lack of chemical action or requirement for metabolism. Regional activity and the Global Harmonization Task Force are now working on harmonizing the categorization and testing of medical devices. The International Organization for Standardization (ISO) has published 19 standards for biological evaluation. ISO 10993 standards are generally accepted outright or as an alternative to most national regulatory directives or acts, although Japan and the United States require more stringency in some tests. Type of materials, intended use, and risk are the basis for drafting testing programs for biomaterials and medical devices. With growth of the medical device industry and advent of new biomaterials and technologies, the need for toxicologic pathologists in safety (biocompatibility) and efficacy (conditions of use) evaluation of moderate- to high-risk devices is expanding. Preclinical evaluation of biomaterials and medical devices increasingly requires a basic understanding of materials science and bioengineering to facilitate interpretation of complex interface reactions between biomaterials, cellular and secretory factors, and vascular and tissue responses that modulate success or failure of medical devices. Keywords: Biocompatibility testing; ISO 10993; Global Harmonization Task Force; medical device; preclinical; device safety; biomaterials; immunotoxicology.

IINTRODUCTION

DEFINITION OF MEDICAL DEVICES

Medical devices have been part of medicine since antiquity (Lyons and Petrucelli, 1987) but only have been highlighted as a separate therapeutic category since fraudulent devices drove the need for regulations (Rados, 2006). Economically, in recent years, biotechnology and medical device companies have been more productive per dollar of research and development cost than traditional pharmaceutical companies (Moses et al., 2005). Medical expenditures for devices are increasing along with aging of human populations and are reflected by a shift in venture capital funding into medical device technology (Richtel, 2007). Despite the importance of medical devices to most therapeutic indications, toxicologic pathologists have played a limited role in evaluation of the safety and efficacy of devices. Pivotal to toxicologic pathology evaluation of medical devices are a basic understanding of the development and regulatory environment and an understanding of biocompatibility testing and evaluation.

The definition of medical devices is complex as they consist of a variety of products and technologies. These can be instruments, apparatuses, appliances, materials, or other articles including software used alone or in combination for diagnosis, monitoring, cure, mitigation, treatment, compensation, and prevention of diseases or other conditions or for altering structure or function in humans and animals as determined by the Food and Drug Administration (FDA) Center for Devices and Radiation Health (CDRH; FDA Center for Devices and Radiologic Health, 2007b) and the European Commission Medical Device Directive 93/42/EEC (European Commission, 2007). Contrasted to pharmaceuticals or biologics, medical devices lack chemical action and do not depend on being metabolized. REGULATORY ENVIRONMENT The variety of types and forms of medical devices results in difficult categorization for testing. In general, medical devices are progressively regulated based on complexity and associated risk factors of invasiveness, duration of contact, affected body system, or local versus systemic effects. The major international agencies that govern food, drugs, and biologics also have offices specific to regulation and accreditation of medical devices, and their Web sites should be consulted for the most recent versions of the relevant documents (Table 1). The European Union (EU) regulations specified by directives 93/42/CEE (Medical Devices Directive [MDD] 1993), 90/385/EEC (Active Implantable Medical Devices [AIMDD]), 98/79/EC (In Vitro Diagnostic Directive [IVDD], European Commission, 2007), United States Code of Federal Regulations (21 CFR 800-900, FDA Center

Address correspondence to: JoAnn C. L. Schuh, Applied Veterinary Pathobiology PLLC, 1752 Lewis Place NW, Bainbridge Island, WA 98110-3663; e-mail: [email protected]. Abbreviations: AIMD, active implantable medical device; AIMDD, AIMD directive; CDRH, Center for Devices and Radiation Health; DHP, drugs and health products; EU, European Union; FDA, Food and Drug Administration; GHTF, Global Harmonization Task Force; GCP, good clinical practice; GLP, good laboratory practice; GMP, good manufacturing practice; ICH, International Conference of Harmonization; ISO, International Organization for Standardization; IVDD, in vitro device directive; MDD, medical devices directive; PMA, premarketing approval; PMDA, Pharmaceutical and Medical Device Agency; TGA, Therapeutic Goods Act; USP, U.S. Pharmacopeia. 63

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TABLE 1.—Web site links for major international agencies regulating medical devices. Location

Agency

Web site URL

European Union

European Commission (EC)

United Kingdom

Medicines and Healthcare Products Regulatory Agency (MHRA) Center for Devices and Radiologic Health (CDRH) Health Canada—Drugs and Health Products (DHP) Pharmaceutical and Medical Device Agency (PMDA) Therapeutic Goods Administration (TGA) New Zealand Medicines and Medical Devices Safety Authority (MedSafe)

United States of America Canada Japan Australia New Zealand

http://ec.europa.eu/enterprise/medical_devices/ index_en.htm www.mhra.gov.uk www.fda.gov/cdrh www.hc-sc.gc.ca/dhp-mps/index_e.html http://www.pmda.go.jp/english/about.html www.tga.gov.au www.medsafe.govt.nz

TABLE 2.—Comparison of the broad classification of medical devices by founding members of the Global Harmonization Task Force. EU Class I Class Ila Class Ilb Class III AIMD

FDA

PMDA

DHP

TGA

GHRF

GHRF risk

GHRF examples

Class I Class II — Class III —

Class I Class II Class III Class IV —

Class I Class II Class III Class IV —

Class I Class Ila Class Ilb Class III AIMD

Class A Class B Class C Class D —

Low Low-moderate Moderate-high High —

Tongue depressor, surgical retractor Needles, suction equipment Ventilator, bone fixation plate Heart valves, defibrillator —

EU = European Union; FDA = Food and Drug Administration (USA); PMDA = Pharmaceuticals and Medical Devices Agency (Japan); DHP = Drugs and Health Products (Canada); TGA = Therapeutic Goods Act (Australia); GHRF = Global Harmonization Task Force; AIMD = active implantable medical device (generally treated as class III devices).

for Devices and Radiologic Health, 2007d) and Pharmaceutical and Medical Device Agency (PMDA) of the Japanese Ministry of Health, Labor and Welfare (Pharmaceuticals and Medical Devices Agency, 2007) determine procedures for the majority of medical devices. Risk to the user or patient determines the amount of testing required for approval. Whereas Class I and II devices claim substantial equivalence to similar marketed devices, limited testing may be required. Class I devices (e.g., examination gloves) have minimal potential for harm and are generally simpler than Class II devices (e.g., infusion devices). Class I or II devices, depending on contact with tissue, would be subject to variable amounts of biocompatibility, physical, functional, packaging, and sterility testing but no or limited clinical testing. In the United States, a 510K application of premarket notification is generally required for approval of Class II but not Class I devices. Class III or surgically implantable devices have the highest risk and are subject to the most extensive testing and highly regulated premarketing approval (PMA in the United States) or equivalent. Once marketed, devices can be reclassified into lower or higher categories based on positive or negative clinical experiences (FDA, 2001). Similar to the International Conference of Harmonization (ICH), the Global Harmonization Task Force (GHTF, 2007) was formed in 1992 to harmonize medical device regulations. Thus far, the GHTF has begun to integrate regulations that govern the classification and risk assessment of medical devices (Table 2) and electronic reporting (study group 2), but there is no reporting from the other three study groups. Regional harmonization and

improved enforcement is also occurring within the EU (EN 30993), Australia and New Zealand (Australia New Zealand Therapeutic Products Authority), Asia, Eastern Europe, and Central and Latin America. Outside of members participating in the GHTF, medical device importations and approval are based on reciprocity (e.g., Mexico via the FDA), individual country regulations on a case-by-case basis (e.g., Argentina and several Asian countries), and lack of or limited enforcement (e.g., Peru, India, and the Middle East). Safety assessment of medical devices is guided by toxicology studies recommended by the Biological Evaluation of Medical Devices technical committee of the International Organization for Standardization (ISO) documents 10993 (ISO 10993 Technical Committee, 2007). Titles of these ISO 10993 standards and their revision status are presented in Table 3. At present, 19 parts are accepted. The first addresses general principles, and subsequent parts address specific testing standards; Part 8 has been withdrawn. Test methods for dental materials are covered by ISO 7405, Preclinical Evaluation of Biocompatibility of Medical Devices Used in Dentistry (1997). Two standards for clinical testing are covered by ISO 14155 (2003) and A Guidance on a Risk-Management Process, issued as ISO 20993 (2006), and multiple standards cover manufacturing of medical devices. These documents are available for purchase through the ISO or multiple international organizations that distribute standards, such as the British Standards Institute or American National Standards Institute. The ISO standards are widely accepted for the biological evaluation of medical devices. The complexity of the medical device

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TABLE 3.—Status of International Organization of Standardization (ISO) 10993 standards that regulate biological evaluation of medical devices. Part 1 2 3 4

Title

Publication year

Evaluation and testing Evaluation and testing within a risk management system Animal welfare requirements Tests for genotoxicity, carcinogenicity, and reproductive toxicity

5

Selection of tests for interactions with blood Amendment 1 Tests for in vitro cytotoxicity

6 7

Tests for local effects after implantation Ethylene oxide sterilization residuals

8 9

Withdrawn standard Framework for identification and quantification of potential degradation products

10

Tests for irritation and delayed-type hypersensitivity and Amendment 1

11 12

Tests for systemic toxicity Sample preparation and reference materials

13

Identification and quantification of degradation products from polymeric medical devices

14 15 16

Identification and quantification of degradation products from ceramics Identification and quantification of degradation products from metals and alloys Toxicokinetic study design for degradation products and leachables

17 18 19 20

Establishment of allowable limits for leachable substances Chemical characterization of materials Physicochemical, morphological, and topographical characterization of materials Principles and methods for immunotoxicology testing of medical devices

arena has resulted in the development of flow charts for testing procedures (ISO 10993-1) that have been modified by the FDA (Blue Book Memorandum #G95-1; FDA Center for Devices and Radiologic Health, 2007c) and more stringent testing and sample preparation required by the PMDA. These worksheets do not dictate but provide a general framework for designing a testing program in consultation with the appropriate regulatory agency. In general, good manufacturing practices, good laboratory practices, and good clinical practices (GMP, GLP, and GCP, respectively) apply to production and testing of most moderate- to high-risk medical devices by regulatory agencies. Combination products such as drug-eluting vascular stents, devices with signaling molecules causing positive interactions with tissue, and tissue engineering products are becoming more common. These combinations of medical devices and drugs or biologics are regulated under authorities for both categories as combination products (FDA Center for Devices and Radiologic Health, 2007a). Despite the long history of medical devices, highly functional and esthetic replacement and reconstruction of the body (regenerative medicine) is a relatively new direction for the industry and generally requires testing as combination products. DEVELOPMENT ENVIRONMENT Safety of medical devices requires attention to materials, procedures required to place the device, risk from design failure

2003 Under revision 2006 2003 To be revised 2002 2006 1999 Under revision 2007 1995 Under revision — 1999 Under revision 2002/2006 To be revised 2006 2002 Under revision 1998 Under revision 2001 2000 1997 To be revised 2002 2005 2006 2006

or biological incompatibility, and patient and external factors (Jayabalan, 1993). These elements also affect efficacy and longevity of medical devices. Improvements in all areas of medical device development have contributed to enhanced functionality and longevity of devices and quality of life for patients, most familiarly in orthopedic and cardiovascular indications. However, increasing longevity of patients with concurrent and chronic health problems, altered healing processes, and age-related tissue changes also affect usefulness of devices with longer service times. Traditionally, preclinical testing of biomaterials has relied on weak in vitro screening assays and limited in vivo screening and clinical trials of the components of final products. Unlike testing of drugs and biologics, several years of postmarketing data of medical devices in patients is often the first major indication of increased risks or adverse outcomes. Testing stages usually cover individual biomaterial ingredients, final biomaterial, and the final device according to standards of risk covered by ISO 10993. Time of contact is important to the required testing and is identified in ISO 10993 as limited contact (30 days). Biocompatibility testing seeks to evaluate risk of interaction between tissues and components or final device. The full testing program may include general toxicity, local tissue irritation, and preclinical and clinical evaluations (Baldrick, 2003; Bollen, 2000; Park et al., 1999; Schmalz, 2002).

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As with general toxicology safety testing procedures, cytotoxicity, genotoxicity, skin sensitization, pyrogenicity, irritation (dermal or ocular), intracutaneous reactivity, hemocompatibility, acute, subchronic, and chronic toxicity, carcinogenicity, and reproductive toxicity may be required for testing of medical devices. Implantation, most frequently in but not limited to intramuscular sites, represents the disproportionate amount of biological testing of biomaterials and devices. Rabbits are standard test subjects, although rats or other species may also be used (Gad, 2002). Traditional 2-year carcinogenicity assays are infrequently necessary with medical device extracts or solid materials, although the use of the transgenic rasH2 mouse model is a potential candidate assay for a compressed testing schedule (Tamaoki, 2001). Efficacy (conditions of use) testing of medical devices often requires animals larger than rodents to accommodate humansized devices. Consequently, efficacy test species often include guinea pigs, rabbits, dog breeds larger than beagles, sheep, goats, cattle, and full-sized pigs. Anatomical differences and horizontal orientation in animals may also require parallel development of a modified device similar to that proposed for humans to accommodate testing in animals. Testing of devices under use may also require use of spontaneous or induced diseases in animal models (e.g., bone or wound healing, osteoinduction in nude mice, and cardiac arrest, pacing, or failure models), although selection of test species and models is often limited for testing of large devices. Testing under realistic disease conditions may be vital to predicting adverse events (Rivard et al., 2007) but may not be obtainable in an animal model. Special testing, particularly immunotoxicology (ISO-10993-20), is becoming an important component of testing medical devices and will be discussed in the next section. TOXICOLOGIC PATHOLOGY EVALUATION OF MEDICAL DEVICES Biocompatibility determination of materials, composite prototypes, and final products evaluated macroscopically and usually microscopically are the foundation of evaluation of medical devices by toxicologic pathologists. Unlike toxicologic pathology of drugs, chemicals, or biopharmaceuticals, in which no significant tissue reaction may occur, biomaterials or devices interfacing with tissues or body compartments invariably induce a reaction. This interface reaction of variable severity may be limited to or confounded by tissue trauma from surgery or the implant procedure. Tissue reactions to sutures used to position the material or device or close access sites and responses to pyogenic or manufacturing contaminants need to be considered during histopathology. Evaluation of the control of the interface reaction is important for biodegradable and nonbiodegradable materials as eventual normalization is the ultimate outcome sought. A major difference with chemically or pharmacologically active compounds is that the response to medical materials and devices is time dependent rather than dose dependent. Biocompatibility generally implies a state whereby the material or device, often thought to be inert, does not cause

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toxicity or injury in a biological system. The emphasis of biocompatibility testing has been on effects of the material or device on host inflammatory and reparative systems. More recently, immunologic reaction of the host to the material or device and the accidental introduction of biofilms (Donlan and Costerton, 2002) are being recognized as important modifiers of success and failure of medical devices. Medical devices are frequently the result of bioengineering and materials science research and development of device technology (Schmalz, 2002). Thus, preliminary information emphasizing analytical characterization including physicochemical properties, infrared spectroscopy, extraction studies, and chromatography may be unfamiliar documentation provided to toxicologic pathologists by bioengineers or material scientists. Input is generally sought from pathologists to provide semiquantitative or morphometric data and photographic documentation of the biological response or biocompatibility. As a general rule, histopathology evaluation of biomaterials or medical implants will emphasize intramuscular implantation of polymers. Metal, wires, fabric, or composite materials may also need to be evaluated in a variety of other surgically accessible tissues, blood vessels, or body cavities, depending on the intended use of the biomaterial or device. Implantation tests are designed to assess localized effects of devices in contact with tissues or body fluids. Implantation procedures target paravertebral or hind-limb muscle of rabbits, or infrequently rats, by surgical dissection or insertion by transcutaneous cannula (Gad, 2002). Implantation testing guidelines for polymeric materials are found in ISO 10993-6 and the U.S. Pharmacopoeia (USP) and National Formulary (USP, 2000). The USP specifies reference standards for control plastics and provides specifications for the most widely used implantation test. Implantation testing has significant sampling issues including multiple test sites in a few animals (usually three rabbits) so that biological variability between animals can be an important issue in interpretation of the results. Furthermore, samples of normal musculature are not included for comparative purposes. Although migration of test materials has been cited as a cause of abnormal placement of materials (Gad, 2002), inappropriate initial placement into subcutaneous or intermuscular rather than intramuscular sites or completely missing the target muscle is more probable. There are no reports appropriately documenting migration of implanted materials under conditions of the standard implantation test. Removal of implant materials before histological evaluation may remove all or the majority of reactive tissue and distort the implant space, particularly with substantive ingrowth of the inflammatory reaction into the implant. Histologic embedment in resins for materials that cannot be easily sectioned is preferred to disturbing the implantation site. Evaluation of compatibility may also be problematic because of inherent disparity between control and test implant-material properties such as control materials that are more reactive than test articles, protective or highly reactive coatings on test articles, and different type and shape of control and test articles. The nature of medical devices may also result in unique problems

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TABLE 4.—Histopathology evaluation format and scoring for biocompatibility. Test

Control

Animal number Inflammation polymorphonuclear Lymphocytes Plasma cells Macrophages Giant cells Necrosis Subtotal (×2) Fibroplasia Fibrosis Fatty infiltrate Subtotal Total Group total Average* Test (–) Control = *Used to determine irritant ranking score shown below as the conclusion. A negative difference was recorded as zero. Traumatic necrosis Foreign debris Number of sites examined Conclusion Under the conditions of this study, the test article was considered a _____ Nonirritant (0.0–2.9) _____ Slight irritant (3.0–8.9) _____ Moderate irritant (9.0–15.0) _____ Severe irritant (> –15.1) to the tissue as compared to the high density polyethylene Negative Control Plastic Comments: Pathologist ____________________ Date ____________________

if the in vivo reaction is related to byproducts generated during manufacturing and complications of surgical procedures for placement. A typical histopathology evaluation format for implant material scoring (Table 4) is an improvement over historical evaluations (Laing et al., 1967; Turner et al., 1973) but still does not reflect current scientific knowledge of inflammation and pathology. For instance, the term fatty change is preferable to fatty infiltration based on the pathogenesis of adaptive metaplasia that results in adipocytes’ replacing other tissues. Although fat in muscle tissue sections is usually assumed to be replacing myofibers, hyperplastic or hypertrophied intermuscular fat responding to an implant placed in an intermuscular space should also be

considered as a possible source of an apparent increase in fat. Nerves and blood vessels in conjunction with fat are an indicator of expected intermuscular fat rather than fatty change within a muscle bundle (Schuh, 2004). Scoring protocols do not account separately for inflammatory cells such as eosinophils or mast cells and do not prescribe scoring for hemorrhage, edema, and collateral damage to nerves, fat, tendons, aponeuroses, and blood vessels. These changes, along with misplaced implants, need to be carefully documented as a comment. Average scores of the control implant reaction are subtracted from the scores of the test implant reaction to generate an irritancy score of the test article relative to the control article. Unusual reactivity in a single test animal or test site or negative

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irritancy scores caused by enhanced control-article reactivity and/or suppressed test-article activity complicates semi-quantitative evaluations. Thus, a detailed interpretive summary of the totality of the tissue implant interface is often warranted in addition to semi-quantitative scores. INFLAMMATION, IMMUNITY, AND TISSUE RESPONSES (IMMUNOTOXICOLOGY) INDUCED BY BIOMATERIALS AND MEDICAL DEVICES Preclinical biocompatibility testing of medical devices has emphasized interaction of materials with the in vivo environment rather than effects of the host and external factors on the implant. The cellular and molecular aspects of biocompatibility have not been sufficiently investigated, and as summarized above, typical scoring methodology for biocompatibility does not completely reflect the state of the art of generally known cellular or tissue responses to medical implants and devices. Primary biological responses to biomaterials and medical devices involve activation of the immune and vascular systems (cellular and secretory inflammatory responses and activation of complement and coagulation cascades) typical of a response to any foreign body. This includes a progression that may include acute, subacute, and chronic or chronic-active inflammation and reparative processes (phagocytosis, fibrosis, and cellular debris). The response is further modulated by type of biomaterials, testing site, shape of the material, and degree of expected and unexpected biodegradation. Degeneration and necrosis may be directly induced by the biomaterial or implant or by uncontrolled host inflammatory or immune responses. Such a superficial overview does not address the complex interaction of cells, cellular and tissue secretions, tissue proliferation, and vascular activity that underlie a typical inflammatory or reparative response. The role of cytokines, chemokines, complement, tissue growth factors, and appropriate and inappropriate intracellular signaling molecules are generally unappreciated in biocompatibility evaluations. Similarly, antigen-presenting dendritic cells that have a common lineage with macrophages (and hence, multinucleated giant cells) have all but been ignored in the assessment of biomaterials (Babensee and Paranjpe, 2005). Multinucleated giant cells, common inflammatory cells responding to biomaterials, are fused macrophages responding to a specific altered cytokine and chemokine milieu (McNally and Anderson, 1995), partially resulting from the inability of macrophages to phagocytize large particulates in test implants. Investigation of these giant cells as a major factor in device failure is disproportionate to the role of these cells as an end-stage component of the inflammatory response. A few studies are now being undertaken to more completely document biocompatibility and immunobiology. Localized elution of anti-inflammatory corticosteroids and vascular growth factor at implants has recently been shown to downregulate the foreign body response but also delay the reparative phase and negatively affect device function (Patil et al., 2007). The chronic response to some implanted materials is histologically consistent with a typical delayed-type hypersensitivity

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reaction, implying an immune response that harms the host. Therefore, it is not surprising that other dysfunctional states of the immune response, such as anaphylaxis, anaphylactoid reactions, allergy, or autoimmunity, may need to be investigated during development of a medical device (ISO 10993-10 and -20). The ability of medical devices (e.g., latex products) to stimulate classic allergy is known, but less clear is whether medical implants (e.g., silicone gel implants and dental amalgams) stimulate chronic immune dysfunction that can revert to normal function with implant removal. Presumably, idiosyncratic reactions within a heterogenous population account for some of the conflicting data. Less well documented but reported in silicone (Abbondanzo et al., 1999) and gold (Iwatsuki et al., 1987) implants is the formation of ectopic lymphoid follicles at sites of chronic inflammation around the materials. Formation of organized lymphoid tissue outside of typical lymphoid tissue has been associated with several autoimmune diseases but is not pathognomonic for autoimmunity. Organization of immunoregulatory cells in any chronic inflammatory focus, irrespective of causation, is to be expected when the appropriate cells and signaling molecules are present (Hjelmstrom, 2001). Inclusion of ISO 10993-20 on immunotoxicology assessment of biomaterials and medical devices confirms the interest and need to more fully evaluate the immune response to and induced by medical devices. As well as in vitro testing, typical toxicologic pathology evaluations for the biological assessment of biomaterials and medical devices should more frequently include evaluation of hematopoietic and lymphoid tissues. In particular, evaluation of lymph nodes draining the area of implant sites, histologic evaluation of distant lymph nodes, the spleen, mucosal-associated lymphoid tissues, and bone marrow, and phenotyping of circulating white blood cells are potentially useful supplemental investigations to maximize information from implantation studies. CONCLUSION AND OPPORTUNITIES Although toxicologic pathologists generally have limited training and involvement with medical device safety, efficacy, and risk assessment, opportunities exist to interact with bioengineers and materials scientists to provide robust biocompatibility evaluations of medical devices and their native components. Advances in materials and process technology are providing novel polymeric, metal, ceramic, and composite materials and tissue-engineered products for esthetic and functional regenerative medicine. Increased involvement of toxicologic pathologists in improving and setting semi-quantitative and interpretive standards for the biological evaluation of biomaterials and medical devices is recommended. Immunotoxicology testing is becoming an important component of biocompatibility testing, with mounting evidence that the host immune response to and induced by biomaterials may result in adverse immunologic events and implant failure. To improve risk assessment, histopathology evaluations of immunologically active tissues in the region of and distant to implants should be considered a part of biocompatibility testing rather than restricting analysis solely to the biomaterial and tissue interface.

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