CHEMICAL BIOLOGY

Biocompatibility of Materials Used in Medical Devices, Methods For Evaluating

 

Frederick Silver, Robert Wood Johnson Medical School, Piscataway, New Jersey

doi: 10.1002/9780470048672.wecb042

 

Medical devices are used for a variety of functions in humans. This review elaborates on the types of tests used to evaluate biocompatibility of the interactions between man-made medical devices and host tissues and organs. The outcome of the response depends on the site of implantation, the species of the host, the genetic makeup of the host, the sterility of the implant, and the effect the device has on biological processes. Biological processes involved in host tissue responses to implantable medical devices reflect activation of a series of cascades that require blood proteins or other components found in the blood.

 

Two types of regulatory approvals for medical devices exist in the United States, 510(k) notification and premarket approval (PMA). The specific tests required prior to regulatory approval vary with the type of device and application; however, some general testing is usually recommended. Normally, animal testing is conducted to demonstrate that a medical device is safe, and when implanted in humans the device will reduce, alleviate, or eliminate the possibility of adverse medical reactions or conditions. The American Society for Testing and Materials (ASTM) as well as the International Organization for Standardization (ISO) publishes standards for testing medical devices. The recommended tests include culture cytotoxicity, skin irritation, short-term intramuscular implantation, short-term subcutaneous implantation, blood coagulation, long-term implantation, mucous membrane irritation, systemic injection, sensitization assays, and mutagenicity testing.

 

Introduction—What Are Medical Devices?

Medical devices are used for a variety of functions from promoting the healing of small wounds using adhesive bandages to maintaining the flow of blood through arteries narrowed by atherosclerosis using metallic vascular stents. The purpose of this article is not to give an overview of the many devices used in medicine to promote wellness and homeostasis but to elaborate on the types of tests used to evaluate the interactions between man-made devices and host tissues and organs. These man-made devices are called medical devices in the United States and are regulated for interstate distribution by the Federal Food and Drug Administration (FDA). In many cases, medical devices consist of assemblies of polymers, metals, ceramics, and composites that are used in diagnostic procedures and as implants in animals and in humans. In the United States, extensive biocompatibility testing occurs before the devices are marketed to the general public. Prior to 1976, no federal regulations existed to oversee the sale and uses of medical devices in the United States. In 1976, the U.S. Congress enacted the Medical Device Amendments to the Federal, Food, Drug, and Cosmetic Act of 1938, which called for the establishment of three classes of medical devices (Table 1a). Class 1 devices are those that present little or no risk to the user, whereas Class 2 and 3 devices present some risk and a high degree of risk to the user, respectively. These devices are regulated by requiring limited animal testing (Class 2) and extensive animal and human testing (Class 3). The European Union has a system of device classification similar to the United States as recognized by the Medical Device Directive (Table 1b).

The term biocompatible is used widely to infer that an implant is safe for use in the general population. Although this term is used broadly, it may be a misnomer because only materials that are found in living tissues are truly biocompatible. Below, we examine what methods are used to evaluate the biocompatibility of materials used in medical devices.

 

Table 1a. Classifications of medical devices marketed in the united states

 

Class

Type of device

FDA filing required

I

Crutches, bedpans, depressors, adhesive bandages, hospital beds

PMN/510K

II

Hearing aids, blood pumps, catheters contact lens, electrodes

510(k)

III

Cardiac pacemakers, intrauterine devices, intraocular lens, heart valves, orthopedic devices

PMA

PMN, premarket notification.

 

Table 1b. Classifications of medical devices of the european union

 

Class

Type of device

Regulatory requirements

I

Stethoscopes, hospital beds, wheelchairs

Technical file, other assurances

IIa

Hearing aids, electrographs, ultrasound assessment equipment

Technical file, conformity

IIb

Surgical lasers, infusion pumps, ventilators

Technical file, type examination

 

Intensive care monitoring equipment

 

III

Balloon catheters, heart valves

Audit of quality assurance examination of design

 

Biocompatibility—What Is Does it Mean?

The word biocompatibility is a relative term that means that the materials used in a medical device do not elicit a reaction that either 1) makes the device not perform its intended use or 2) causes reactions that affect the functioning and health of the host. All materials used in devices will elicit a response from the host; it could be an immediate response, one that is prolonged, or even a delayed reaction that occurs sometime after contact with the device. The outcome of the response depends on the site of implantation, the species of the host, the genetic makeup of the host, and the sterility of the implant. All implants have a significantly greater rate of infection when compared with the background rate associated with the surgical procedure performed in the absence of the device. At the very least, an implant should not interfere with biological processes that are required for normal homeostasis of the host.

 

Biological Systems—Which Ones Are Important for Normal Homeostasis and Survival?

Devices in contact with the external tissues such as skin typically are considered separately from a biocompatibility perspective from devices implanted internally. Implantable devices affect biological processes that involve blood; therefore, the testing of these devices is somewhat more complicated. Many skin contact devices are used short term, and therefore biocompatibility testing is limited. However, for permanent internal implants, the required testing can be as long as several years and require analysis of the effects of the device on cells and tissues as well as on healing responses that occur at the interface between the tissue and the device. For this reason, it is important to understand which biological systems may be affected when permanent implants are to be used.

Biological processes involved in host-tissue responses to implantable medical devices reflect the activation of a series of cascades that require blood proteins or other components found in blood. Biological systems activated by implants include blood clotting, platelet aggregation, complement activation, kinin formation, fibrinolysis, phagocytosis, immune responses, and wound healing (1) (Table 2). Wound healing involves several biological processes, including blood clotting, inflammation, dilation of neighboring blood vessels, accumulation of blood cells and fluid at the point of contact, and finally deposition of fibrous tissue around an implant. Vasodilation of blood vessels and accumulation of interstitial fluid around an implant can occur through activation of the kinin and complement pathways (1). Phagocytosis of dead tissue occurs by attraction and migration of inflammatory cells to the site of injury near an implant. The inflammatory cells attracted include neutrophils and monocytes that are present to digest dead tissue and implant materials. Once phagocytosis occurs, it may lead to digestion of implant remnants and formation of fibrous scar tissue around the implant. If a large blood clot surrounds an implant, then fibrinolysis must proceed to remove the clotted blood before the healing process can be completed (1).

 

Table 2. Biological systems affected by medical devices (1)

 

System

Function

Device effect

Blood clotting

Maintains blood fluidity

Clot formation-occlusion

Complement

Prevents bacterial invasion

Depletes complement

Fibrinolysis

Degrades blood clots

Degrades tissue grafts

Immune responses

Limits infection

Prolongs inflammation

Kinin formation

Causes vasodilation

Prolongs inflammation

Platelet aggregation

Limits bleeding

Shortens platelet life

Phagocytosis

Limits infection

Prolongs inflammation

Wound healing

Repairs tissue defects

Promotes fibrous scar Tissue

 

Blood proteins are involved in the lysis of foreign cells via the complement pathway (1). This mechanism involves activation of complement proteins in the presence of an antibody-antigen complex attached to the surface of a foreign cell. Components of the complement pathway are sometimes compromised by activation and/or adsorption onto the surface of a medical device. This action leads to complement component depletion that causes the patient to be at risk for bacterial infection and makes evaluation of complement depletion an important aspect of the design of cardiovascular devices. Activated complement components also prolong inflammation by generating C3a and C5a, which are agents that cause vasodilation. Complement activation is associated with and contributes to whole-body inflammation, which is observed as a complication to cardiopulmonary bypass. Complement activation is responsible for hyperacute rejection of animal tissue grafts (2) and is important in reactions to implants (3-5).

Most foreign surfaces cause blood to clot as a result of direct contact with a foreign surface. This clotting occurs via the intrinsic clotting cascade or from injury to tissue that develops during implantation as result of activation of Hageman factor and factor IX, which are two proteins found in blood (Table 2). Platelets, which are enucleated cells, are also found in blood; they release factors that contribute to formation of blood clots. Devices used in the cardiovascular system normally are designed to limit their propensity to clot blood. In the case of cardiovascular devices, excessive blood clotting will cause the device to occlude; in these applications, blood clotting is minimized. Because foreign materials typically cause blood clots, they are only used to replace large and medium-sized vessels. Host vessels are used to replace the function of small-diameter vessels. Several tests are used to measure blood clotting and platelet aggregation caused by contact with a medical device (6-8).

In addition to activating blood clotting (9), activated Hageman factor activates prekallikrein of the kinin system, which leads to bradykinin that causes vascular vasodilation. Activation of Hageman factor and blood clotting also leads to the conversion of plasminogen to plasmin which initiates the degradation of fibrin formed during clotting by a process termed fibrinolysis (1).

Phagocytic cells including neutrophils and macrophages, coat medical devices either from direct blood contact or via inflammation and extravascular movement of these cells into the tissue fluids that surround a device. In either situation, first neutrophils and then monocytes arrive in the area around the device and attempt to degrade the implant. If the implant is biodegradable, then these cells remain until the device is totally removed. If the device is nondegradable, then the number of cells surrounding an implant will depend on the how reactive the implant is. For example, although Dacron vascular grafts are permanent devices, monocytes can be observed surrounding the implant for months and years. In some patients, continued reactivity can cause peri-implant fluid accumulation, which if left uncorrected can require implant removal. In other cases where contact of tissue with the implant causes a prolonged inflammatory response, other white blood cells including eosinophils, B cells, and T cells can be observed in the vicinity of the device. These cells are an indication of either an allergic reaction or the formation of antibodies that stimulate prolonged inflammation. Measurement of inflammatory cells surrounding an implant is usually accomplished by direct histological evaluation (10-12).

As phagocytic cells accumulate near the implant, they elaborate hydrolytic enzymes that degrade both the implant and the surrounding tissues; fibroblasts and endothelial cells are also migrating into the area around the device and begin to lay down new extracellular matrix with capillaries and collagen fibrils (1). Thus, the wound healing process involves inflammation, removal of the implant and tissue components, as well as the deposition of new extracellular matrix. If the implant is nondegradable and nonporous, then a fibrous capsule forms around it. The thickness of the fibrous capsule depends on the degree of inflammation caused by the device. If the implant is porous, the device may biodegrade and lead to the formation of a small amount of fibrous scar tissue in the defect when the implant is removed. In some cases, however, after the implant biodegrades, an abundance of scar tissue can be deposited where the implant was previously observed. The thickness of the fibrous capsule formed around an implant is usually measured histologically.

Wear particles generated by a moving device can lead to prolonged inflammation and even implant failure in the case of hip and knee implants. Small polymeric or metallic particles, which are about 1 pm in diameter, are ingested by neutrophils and monocytes and may lead to necrosis of these cells and the release of inflammatory mediators into the wound area. Large particles are surrounded by monocytes, which form multinucleated giant cells that can in many cases be tolerated by tissues without leading to implant failure. However, once wear particles are released from the implant, they can migrate to other tissues or even to local lymph nodes causing swelling and systemic problems. Implant wear particles are quantitatively determined from histological and electron-microscopic studies (13-15).

 

Types of Tests—What Types of Tests Are Used?

Two types of regulatory approvals exist for medical devices in the United States, 510(k) notification and premarket approval (PMA). The types of tests required for approval depend on the classification of the medical device. 510(k) notification involves marketing a device that is substantially equivalent to a device on the market prior to 1976. All devices introduced after 1976 that are not substantially equivalent to devices on the market before 1976 are automatically classified as Class 3 devices and require PMA (16). For a device to be considered substantially equivalent to a device on the market before 1976, it must have the same intended use, no new technological characteristics, and have the same performance as one or more devices on the market prior to 1976. In addition, all medical devices must be sterilized either by end-sterilization or by some other acceptable means that can be validated, which means that any test done in cell culture or in an animal model must be conducted on a device that has been validated to be sterile. Sterility validation is conducted on all medical devices as described in the literature (17).

The testing conducted on biomaterials intended for use in medical devices must address safety and effectiveness criteria that depend on the intended use as described above as discussed in depth the literature (18, 19). The specific tests required vary with the type of device and application; however, some general testing is usually recommended. Normally, animal testing is conducted to demonstrate that a medical device is safe, and when implanted in humans that the device will reduce, alleviate, or eliminate the possibility of adverse medical reactions or conditions (17).

According to the American Society of Testing Materials (ASTM) Medical Devices Standards (Annual Book of ASTM Standards, Section 13, Medical Devices, ASTM 1916 Race Street, Philadelphia, PA 19103; available at: www.astm.org), the type of generic biological test methods for materials and devices depends on the end-use application. The ASTM as well as the International Organization for Standardization (ISO) publishes standards for testing medical devices as listed in Tables 3 and 4. Biological reactions that are detrimental to the successful use of a material in one device application may not be applicable to the success of a material in a different end use. A list of potentially applicable biocompatibility tests that are related to the end use of a material and/or a device is given in Table 3 as a starting point. These tests are as follows:

 

Cell culture cytotoxicity

This test is used to evaluate the toxicity of a material in vitro or an extract of a material used in a device. Several different tests have been used and have produced a spectrum of biocompatibility assessments on the same material (20-22). The tests used measure the viability of cells in contact with a material or an extract of a material. A variety of cell lines can be used; however, a modified fibroblast line is usually the gold standard. Some tests used include 1) direct cell culture, 2) agar diffusion testing, 3) filter diffusion testing, and 4) barrier testing (22).

As pointed out by Learmonth (23), although the intact implant may not be cytotoxic to cells, any material and mechanical flexural mismatch may lead to release of wear particles that can excite a cytochemical reaction that culminates in inflammation and cell cytotoxicity. The generation of wear particles and their size is of particular importance to the failure of joint implants through a process termed osteolysis (23).

 

Table 3. Biological tests used to evaluate biocompatibility based on ASTM medical device standards, section 13

 

Test

ASTM standard

Cell culture cytotoxicity

F748

Skin irritation

F719

Intramuscular and subcutaneous implant

F748

Blood compatibility

F748

Hemolysis

F756

Carcinogenesis

F748

Long-term implantation

F748

Mucous membrane irritation

F748

Systemic injection acute toxicity

F750

Intracutaneous injection

F749

Sensitization

F720

Mutagenicity

F748

Pyrogenicity

F748

 

Table 4. Biological evaluation of medical devices based on ISO standards

 

Test

ISO standard

Part 1: Evaluation and testing

Part 2: Animal welfare requirements

Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity

Part 4: Selection of tests for interactions with blood

Part 5: Tests for in vitro cytotoxicity

Part 6: Tests for local effects after implantation

Part 10: Tests for irritation and delayed-type hypersensitivity

Part 11: Tests for systemic toxicity

10993-1:2003

10993-2:2006

10993-3:2003

10993-4:2002

10993-5:1999

10993-6:2007

10993-10:2002

10993-11:2006

 

Skin irritation assay

This test involves applying a patch of the material (or an extract of the material) to an area of an animal that has been shaved; in some cases the skin is abraded before the test material is applied. After 24 hours of contact, the patch is removed, and the skin is graded for redness and swelling. The grading scale can vary from 0 to 4: 0 means no redness and/or swelling and 4 means extensive redness and/or swelling. Standard test materials are used to evaluate skin irritation (24).

 

Short-term intramuscular implantation

This test is designed to evaluate the reaction of tissue to a device for periods of 7 to 30 days. This test can be conducted in the muscle below the skin in rabbits or rodents including mice, rats, and guinea pigs. At the conclusion of the test period, the samples are graded both visually and based on analysis of histological sections. A test described in the United States Pharmacopia (USP) is widely used. The purpose of this test is to evaluate the inflammatory potential (e.g., redness and swelling) grossly. In some cases, histological evaluation of the tissue is performed at the light and electron microscopic levels to look for phagocytic and immune cells. Some investigators use an intramuscular implantation site because the blood supply and hence the inflammatory potential may be easily evaluated. In addition, the results of short-term implantation tests may not reflect material-mediated inflammatory responses that may also occur (25).

 

Short-term subcutaneous implantation

This test is an alternative for studying the reaction of tissue to a device for a period of days to weeks. In this test, a tissue pocket is made in the skin above the muscle layer, the device is inserted into the pocket, and the pocket is sutured or stapled closed. Normally the device is placed deep into the pocket away from the site of insertion of the device so that reactions at the suture or clip site do not affect the evaluation of biocompatibility. Although short-term implantation studies do give an analysis of the biocompatibility of a material at a local site; systemic effects can also be observed from corrosion products that develop from vascular implants that migrate to other sites (26).

 

Blood coagulation

Blood coagulation is normally assessed by determination of clotting times and extent of platelet aggregation initiated by the device surface in either static or dynamic systems. In a dynamic test, blood flows through the device or over a test surface made of the materials used in the device. This test is normally conducted on blood-contacting devices to ensure that the blood-coagulation and platelet-aggregation pathways are not modified. The tests are conducted in vitro using human or animal blood, ex-vivo in a flow chamber using animal blood, or in vivo in an animal model. It has been noted that variability in the results using standard materials is noted in ex-vivo tests of blood compatibility; this finding is attributed to the type of animal model used, the flow velocity, the time of exposure, and the method used to measure blood cell adhesion (27). Studies of stents used in the cardiovascular system illustrate that clot or thrombus formation is dependent on the type and design of the device (28, 29) and may be influenced by the corrosion of metallic implants (30).

 

Hemolysis

Hemolysis is determined by placing powder, rods, or extracts of a material in contact with human or animal plasma for about 90 minutes at 37°C (31). The amount of hemoglobin released into solution after lysis of the red cells in contact with the device is measured. When red cells undergo lysis, hemoglobin is released from the cells, and the absorbance from released hemoglobin is proportional to the amount of cell lysis. Extensive red-cell lysis is not desirable for devices that are to be implanted in the cardiovascular system. The measurement of hemolysis and its relevance is a question that should be addressed it each device application.

 

Carcinogenicity

Carcinogenicity testing involves long-term implantation (up to 2 years) in an animal model usually under the skin to look for tumor formation (32). This test is required for devices that employ materials that have not been extensively tested. Typically these tests are conducted in rodents, although rodents do form tumors to most solid implants (1).

 

Long-term implantation tests

These tests are covered by ASTM specifications F361 and F469 for muscle and bone, respectively. Implant materials are placed in the muscle as a soft-tissue model and in bone as a hard-tissue model. The implantation site is evaluated grossly and histologically for inflammation, giant cell formation, signs of implant movement, and for tissue necrosis. Although long-term implantation gives some indication of biocompatibility, it does not consider issues such as biofilm formation, infection, and encrustation associated with use of devices such as urologic implants (33). It is recommended that long-term implantation tests be conducted on a model relevant to the intended end use. In addition, the effect of wear particles is an important consideration with long-term implantation (23).

 

Mucous membrane irritation

Mucous membrane irritation is evaluated by placing a material in close proximity to a mucous membrane such as the oral mucosa. The test evaluates the amount of irritation and inflammation from gross and histological measurements. The hamster cheek pouch or oral mucosa is a model frequently used for this test (34).

 

Systemic injection

Systemic injection (acute toxicity) is designed to determine the biological response to a single intravenous or intraperitoneal injection of an extract (50mg/kg) of a material over a 72-hour time period (35). Extracts are prepared using saline or other solutions that simulate body fluids. Animals are monitored for signs of toxicity immediately after injection and at various time intervals (1).

 

Intracutaneous injection

Intracutaneous injection involves the reaction of an animal to a single injection of a saline or vegetable oil extract of a material. Rabbits are commonly used, and they are studied for signs of inflammation (redness and swelling) at the injection site for a period of 72 hours (36).

 

Sensitization assays

Sensitization assays involve mixing the material or extract that has been in contact with a device with Freund’s complete adjuvant and injection of the test sample into the subcutaneous tissue during a 2-week induction period (37). After 2 weeks, the material or extract is placed on the skin near the injection site for 24 hours, and then the skin is evaluated for redness and swelling.

 

Mutagenicity

Mutagenicity is evaluated using the Ames test or an equivalent test. This test employs genetically altered bacteria (bacteria with altered nutritional characteristics), which are placed in contact with an extract of a material. Mutations are observed that lead to a reversion back to the “wild-type” phenotype that grows only under the original nutritional conditions and not under conditions that allows mutant growth. It has been reported many very small-wear particles are released from metal-on-metal contact in joint replacements, and these particles may cause mutagenic damage in bone cells (23). However, many of these wear particles may also be of concern as carcinogens.

 

Pyrogenicity

Pyrogenicity is used to evaluate fever-producing substances that may contaminate a medical device. They are components of gram-negative bacterial cell membranes (endotoxins) or are materials of chemical origin. The presence of endotoxins is determined by injecting an extract of the device into the circulatory system of a rabbit and measuring temperature in the rabbit’s ear. Another method to measure endotoxins involves contact of the material with cells that are lysed specifically by endotoxins (Limulus Amebocyte Lysate Test). Chemical pyrogens are determined by the rabbit test (38).

 

Animal Models—A Variety of Animal Models Are Used

A variety of animal models is used to evaluate the biocompatibility of medical devices. They include dog, sheep, goat, rabbit, mouse, rat, ferret, and pig. Pearse et al. (39) and Murray et al. (22) give a recent review of animal models in bone and dental device testing, respectively. Factors that lead to choice of a particular animal model include housing requirements as well as cost, maintenance, and care factors, resistance to disease, interanimal uniformity, tolerance to surgery, animal lifespan, the number and size of the implant (39-41). International standards (ISO 10993) provide guidance to determine the number of animals and the species that should be tested for each treatment and time point. Although the rat is one of the most widely used species in medical research because of its size and tissue structure, it is not a good model for testing some medical devices. Although the dog may not be a good model for bone implants because of differences in size and shape of canine bone in comparison with human bone, it is sometimes used because commercially available implants and instruments are available for canine surgery (39). Tissue microstructure, composition, wound healing, and remodeling differences with the human play an important role in animal model selection.

 

Summary

The word biocompatible is perhaps a misnomer; it refers to the ability of materials used in medical devices not to the illicit adverse reactions that occur when implanted in humans. To assess biocompatibility, several tests have been developed to study the interactions of materials and biological tissues. The biocompatibility of a material or a device requires that it not activate any biological homeostatic systems including blood coagulation, platelet aggregation, inflammation, complement, or fibrinolysis.

Biocompatibility testing of medical devices depends on many criteria. Devices that contact only the skin and are for short-term use require less-stringent testing. These devices do not require long-term testing prior to human use. In contrast, implantable devices require more safety and effectiveness testing before they can be used in humans. The type of testing required depends on the end-use application. Although the term biocompatible is relative, because all devices will lead to some reactions by cells and tissues, it is important that the reactions caused at the device-tissue interface do not lead to implant failure or interfere with the functioning of any biological systems.

Biocompatibility tests vary for short-term versus long-term contact with tissue. Depending on whether the contact is with skin or internally, many standard tests have been developed for biocompatibility screening. Although many tests are predictive of the responses observed during use of devices in humans, biocompatibility of a device is ultimately only verified after extensive human clinical trials and general use in the population.

 

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Further Reading

Ratner BD, Hoffman AS, Schoen FJ, Lemons JE, eds. An Introduction to Materials in Medicine, 2nd ed. 2004. Elsevier, San Diego, CA.

Silver FH, Christiansen DL. Biomaterials Science and Biocompatibility. 1999. Springer, New York.