Keywords

11.1 Introduction

Biomaterials, be they metal or polymer, ceramic or glass, or some combination of all of these, when placed inside the human body are not normally rejected. The term rejection in this context generally refers to an adverse immunological response analogous to that seen when patients reject an organ transplant. For the most part, nonbiological materials when placed in contact with human tissue, either upon or beneath the skin, are well tolerated and may become “accepted” by the body. In these circumstances, if the implant is then able to effectively carry out its function for the required period of time, it may be described as expressing biocompatibility.

However, every implant material, no matter how “biocompatible,” stimulates a response by the tissues of the body. This response may be such that the recipient (the patient) is unaware of any problem and the implant effectively carries out its function. Or the response may be so severe that the patient’s life is compromised. When placed subcutaneously within the body, a biomaterial will induce an inflammatory response. This is the opening gambit in the body’s defense mechanism and the commencement of the wound healing response.

How our body responds to a wound, and the surgical implantation of a medical device such as vascular prosthesis or a hip joint replacement clearly produces a wound, is well understood. How the presence of a biomaterial modifies that response is somewhat less well defined.

11.2 Granulation Tissue

Granulation tissue defines inflammation during wound healing. Once healing has initiated following injury, granulation tissue will be initiated at the site within a few days. It is characterized by specific cell and tissue activities which can be highlighted using microscopic histological evaluation. Histologists and pathologists have over many years developed staining techniques which can be applied to very thin sections of tissue and permit an accurate examination of the tissue. Four significant components have been identified:

  1. 1.

    Active macrophage cells: these cells are employed in phagocytosis. Phagocytic cells act as mini-vacuum cleaners and clear up tissue debris.

  2. 2.

    Neutrophil activity: these cells are also employed in a phagocytic role, specifically in the removal of bacterial and other foreign proteins.

  3. 3.

    Angiogenesis: this describes the formation of new blood capillaries infiltrating the site of injury. A new blood supply will provide an effective access route for the wound healing cells and nutrition for the regenerating tissue.

  4. 4.

    Fibroblast cell activity: these cells are employed in the production and deposition of new connective tissue [1, 2].

Wound healing in the absence of an implant, following a clean surgical incision and effective suturing where the wound edges are brought into apposition, will progress with minimal loss of tissue and minimal scar tissue formation. Wound healing in the presence of an implanted biomaterial will lead to a modification of this progression, and the extent of this modification will be determined by factors related to the implant and the site of implantation. These factors will include the size and shape of the biomaterial device, the chemical nature of the material, and the physical form of the implant. In particular the nature of the biomaterial surface will influence the inflammatory response and the new tissue development. Factors such as porosity and surface topography have been demonstrated to influence significantly this response. A material may be selected for implantation because of its stable, nonreactive nature; nevertheless, its presence will fundamentally disrupt the formation of connective tissue, alter the network of new blood capillaries (angiogenesis), and may stimulate an enhanced phagocytic cell activity leading to continued inflammation.

11.3 Foreign Body Response

“The foreign body reaction is neither a single event nor a simple process, but a broad concept and multi-factorial phenomenon” [3]. This definition, true of almost every event associated with the inflammatory response, identifies the foreign body response as a part of the body’s initial defense mechanism against any invading agent from bacteria to biomaterial. This may be a relatively short-term response or part of a long-lasting or chronic reaction. It may stimulate a specific (antibody related) or a nonspecific immune response. In simple terms the foreign body response may be considered as that part of the inflammatory process which is activated by the presence of a foreign agent, e.g., bacterial and biomaterial, and will continue to be active until the foreign agent is removed. A foreign body reaction will involve the components of granulation tissue and phagocytic cells such as neutrophils and macrophages and will further see the introduction of another cell type, that is, the formation of giant cells or multinucleated cells. The foreign body giant cell is by definition a large cell, up to 100 μm in diameter (Fig. 11.1). It is formed when a foreign agent stimulates a phagocytic activity which cannot be effectively completed by the cell. This may be due to the large size of the agent (a very realistic factor when considering phagocytic cell activity in contact with biomaterials) or to some chemical effect of the foreign agent which inhibits the phagocytic process. The outcome is the formation of large, multinucleated cells. The nature of the agent which stimulates the response will effectively determine the nature of the response, the activity of the cells at the site, and for what length of time the response will remain active. For example, a simple wound with no infection or implant present may heal with very little evidence of a foreign body response. The attendance of invading bacteria and therefore foreign protein will stimulate an increase in granulation and phagocytic activity. The presence of an implanted biomaterial will further modify this response. This may lead to a process termed “frustrated phagocytosis” where the phagocytic cell is unable to encapsulate the stimulating material. It has been postulated that this is the trigger for the development of foreign body giant cells in contact with implanted biomaterials [4].

Fig. 11.1
figure 1

Foreign body giant cell. An implanted material will always stimulate a foreign body response. A sustained macrophage activity in the presence of a degrading or corroding implant material may result in the formation of foreign body giant or multinucleated giant cells. The image above details a giant cell formed in response to a bacterial toxin. (Image from Public Health Image Library)

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11.4 Repair

Repair and remodeling of new tissue are the final stage in the wound healing response and, if the injury is slight, will lead to the regeneration of normal tissue and a return to the “status quo.” However, if the injury is more severe, and this is the more common scenario, the process will lead to the generation of normal tissue and also scar tissue. Scar tissue can be defined as tissue that is the result of wound healing. It is composed of fibers of collagen and will often lead to a restricted elasticity of the tissue concerned. Most importantly, scar tissue generally is less able to carry out the function of the tissue it is replacing. The extent of scar tissue formation is highly dependent on the severity of the initial injury. In the presence of an implanted biomaterial, it may take the form of fibrosis or fibrous encapsulation where the active fibroblast cells lay down protein (collagen) which is physically wrapped around the implant device, thus sealing it from the rest of the tissue. This encapsulating tissue will be primarily composed of fibroblast cells and collagen. In an ideal scenario, the implanted material will then be ignored by the body, subsequent wound healing will continue uninterrupted, and the implanted device will function effectively. However, local and systemic factors may be involved in the progression of the tissue response in these circumstances [2]. Local factors will include the physical and chemical nature of the implant material, the nature of the local blood supply, and the effects of any invading microorganisms. Systemic factors will include the health of the patient and the effect of the release of any leachable or degrading or corroding products from the implant itself.

11.5 Acute and Chronic Inflammation

An acute inflammation is usually a short, highly active period which persists for a limited time and is resolved within a few days. It is characterized by the action of neutrophils, the first cells to be recruited to the damaged site, and other white blood cells. The rapid recruitment of neutrophils to the site of injury will result in effective phagocytosis of microorganisms and any other foreign materials. Acute inflammation is further characterized by the accumulation of plasma proteins at the injured site, leading to swelling (edema). These plasma proteins are in fluid phase, and this leads to a buildup and retention of fluid at the site. The subsequent swelling can result in perceived pain for the patient. Recruitment of neutrophils is triggered by chemical signals (chemotactic factors) which stimulate only those cells which have the means to recognize these factors to move towards the site. This triggering process relies on the action of cell surface proteins or receptors. Interactions between chemical signals (generally protein) and cell surface receptors (protein) are highly specific, and a cell will only be stimulated or activated if it carries the receptor to a specific signal. In this way neutrophils are activated to pass through the blood vessel wall following appropriate stimulation and migrate towards the source of the chemotactic agent. There are a very large number of proteins which have been identified as having chemotactic properties at inflammatory sites, and we are only beginning to understand the mode of action and relevance of a small proportion of these.

The phagocytic potential of the recruited neutrophil is then enhanced by a process known as opsonization. This is a process by which the body identifies the materials/agents to be phagocytozed by coating or labeling them with specific proteins (opsonins). Opsonins occur naturally in blood plasma and have receptors which are recognized by the neutrophils. The most significant opsonins (i.e., those factors which have been most researched and are best understood) are immunoglobulin G (IgG) and a complement related protein fragment termed activated C3 (C3b) [5]. These proteins have been shown to attach to foreign material at the site of injury (usually they attach to bacterial proteins, but they have been shown to attach to implanted materials) and enhance the subsequent attachment and activation of neutrophils and macrophages leading to phagocytosis. In normal circumstances this would lead to effective removal of the foreign agent from the site. However, when an implant is present, it is highly likely that the phagocytic cell will be unable to engulf and remove the phagocytic stimulus. As stated previously, this may lead to “frustrated phagocytosis” during which the enzyme contents of the phagocytic cell are released, further phagocytic cell recruitment is stimulated, and foreign body giant cells may arise.

A biomaterial which is effectively sealed within a fibrous capsule may permit the acute inflammatory phase to progress to completion as would be expected in a wound healing environment. However, a biomaterial which is degrading or corroding or in some other way disturbing, the surrounding tissue may stimulate a chronic inflammatory response. The presence of the macrophage is probably the most significant factor in any chronic inflammatory response associated with implanted biomaterials. Macrophage is a large phagocytic white blood cell, derived from the monocyte. The monocyte migrates from the blood to the site of stimulus (injury) where it is changed or transformed. The macrophage is present in most tissues and has a scavenging role in the body. When activated at the site of an implanted biomaterial, it plays a highly significant role in the inflammatory response (Fig. 11.2). The chronic response is characterized by the presence of large numbers of different cell types at the site of injury or implantation. These cells can include all or any of the following: monocytes, macrophages, lymphocytes, fibroblasts, endothelial cells, and foreign body giant cells. There is also likely to be a highly vascularized connective tissue mass. A chronic inflammatory response to implanted materials is generally highly localized around the tissue-material interface and is usually of fairly short duration (2–3 weeks). However, persistent chronic inflammation has been demonstrated with a number of implant materials and devices. It is likely that an inflammatory response which persists for long time periods (months to years) may also be associated with an infection which is implant related [2].

Fig. 11.2
figure 2

Macrophage activity. This response is indicative of an aggressive tissue reaction to an adverse stimulus. There are numerous macrophages present. The image details the histopathologic changes detected in a lung biopsy tissue. Necrotic changes are indicated by the breakdown of the alveolar walls resulting in pulmonary edema. (Image from Public Health Image Library)

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Characterizing a chronic inflammation to an implanted material is notoriously difficult. There will be a mixed cell population and possibly evidence of cell necrosis (cell death). Necrosis may be stimulated by an over-activated inflammation or may be due to the presence of a cytotoxic biomaterial (Fig. 11.3).

Fig. 11.3
figure 3

Chronic inflammation. The image details a fibrotic granulation tissue which is indicative of a chronic inflammatory response. The area details a mass of inflammatory cells stimulated as a result of a pulmonary infection. (Image from Public Health Image Library)

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11.6 Infection

Infection occurs in up to 10% of patients who have received an implanted medical device [6]. Nosocomial infection rates, i.e., hospital-acquired infection, can be very much higher and pose a serious risk to patients who have received implants. Such infections are extremely resistant to antibiotic therapies. Infections which become problematic shortly after implant surgery are often acquired during the surgical procedure or within the hospital environment. These infections will massively exacerbate the inflammatory process and may contribute to early failure and removal of the medical device. This is not only disadvantageous for the patient but very costly for the health-care provider and a significant contributing factor to the huge problems associated with nosocomial infection. However, it is also true that the very presence of the implant may be a contributing factor to the virulence of the microorganism, i.e., the ability of the organism to exert a toxic effect on the body. The implant may provide a convenient means of transport for the invading organism, carrying it to tissues normally inaccessible, where it is more likely to become pathogenic. The presence of the device may inhibit the natural defense mechanisms of the body and compromise the functioning of the immune system. Increasingly there is concern that the physical presence of the implant may provide a substrate upon which a resistant, pathogenic biofilm may flourish.

11.7 Local and Systemic Responses

It is not uncommon to read in the medical device or materials literature of references to “inert” biomaterials. These references are generally alluding to the older generation of implant materials, i.e., stainless steel and polyethylene, which were selected because it was considered that they would have no interaction with or effect upon the tissues with which they came into contact. Notwithstanding the success these and other biomaterials have had as surgical implants, we are now aware that these materials are not inert. Indeed they not only stimulate a response that may well have adverse consequences for the interfacing tissues but with time the biological environment will have a deleterious effect on the materials themselves. It is now accepted that no material placed within the body is inert; indeed such an effect would be contrary to the purpose of the majority of implanted medical devices. Most materials used in implant surgery today are designed to have an active role when in contact with tissue and will in due time stimulate a tissue response. In most cases this response will be a simple modification of the normal wound healing process the body will undergo following any traumatic injury. As indicated previously, the nature of the modification will be determined by factors which are related not only to the chemical nature of the implant (e.g., metal, polymer, ceramic) but also to the size and shape of the implant, the surface topography, the porosity, the wettability of the material surface, and the propensity for the material to degrade or corrode in the biological environment.

The nature of any systemic response associated with an implant is more difficult to determine than the local response. In most cases the local response is immediate and by definition located at the site of the implantation. A systemic response may arise months or years following implantation and may be manifest at a site distant from the original implant. Many of the concerns surrounding systemic toxicity are linked with the potential for carcinogenic or mutagenic changes or the ability for the implant material to stimulate a hypersensitive response.

11.8 Soft and Hard Tissue Responses

The presence of an implant may provide an ongoing stimulus to inflammation. This may be as a result of interaction of the implant with the soft tissues or through the production of leachable or degradation products from the implant. We may assume that an implant material which is stable and does not produce leachable components will not have a significant effect on the wound healing process other than to provide a physical barrier and a substrate for the deposition of protein and the development of a collagenous capsule (Fig. 11.4). In this situation the implant material is effectively sealed off from the body and plays no other active role. If the implant can maintain its function, then it may remain successfully within the body indefinitely. If the implant material continues to stimulate a response, i.e., by the production of leachable components or corrosion/degradation products, then the fibrous encapsulation may be enhanced. A greater level of material interaction will stimulate a greater cellular activity and consequently a progressively thicker fibrous capsule. In early animal studies, the thickness of this capsule was often equated to the “biocompatibility” of the implant material. The thicker the capsule, the more irritating and therefore less “biocompatible” was the biomaterial considered. However, an aggressive implant material may never allow the tissue response to stabilize. Continued stimulus from the implant will lead to a persistent and chronic inflammation. This inflammatory environment will mean a more active and aggressive cellular response, thus further stimulating greater and greater degradation.

Fig. 11.4
figure 4

Fibrous capsule. The image details a fibrous tissue which has formed in response to an implanted biomaterial. The biomaterial, in particulate form, was placed within a muscle pocket in an experimental animal (rat). The tissue section shown was prepared after an implantation period of 4 weeks. In many studies using such implantation techniques, the thickness of the fibrous capsule has been used as a “measure” of the biocompatibility of the materials

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Implantation of a biomaterial into bone tissue will stimulate a wound healing response analogous to that encountered following fracture or other hard tissue injury. This follows a well-recognized developmental pattern, involving an initial wound healing inflammation, bone remodeling, and bone maturation. The success of a biomaterial implanted into the bone may be determined by its ability to permit this process to occur and itself to become integrated into the healing process, leading to a stable fixation of the implant at the hard tissue site. The search for new and better endosseous implants focuses primarily on the development of materials which demonstrate osteogenesis, i.e., materials which actively participate in and/or stimulate the production of new bone tissue during the healing phase and are actively incorporated within this new tissue. There is a huge number of factors which may influence this process. However, in simplistic terms, biomaterials have been attributed with the properties of contact osteogenesis (bone formation occurs directly in contact with the implant surface and “grows” out towards the surrounding bone) and distance osteogenesis (the surrounding bone is the focus of osteogenesis which may be stimulated by the presence of the implant). However, contact and distance osteogenesis are generally identified by microscopic “snapshot” evaluation of recovered tissue-material interfaces and have become convenient descriptive terms and may not be accurate descriptions of what is occurring during a complex healing process. Roberts [7] has postulated a hard tissue healing timetable based on a rat dental implant study. In agreement with most studies on hard tissue wound healing, the process is categorized into four stages. It is worth noting that these are not distinctly different processes and the wound healing process in both soft and hard tissue healing is a fluid, dynamic process.

The four stages are (1) development of a woven callous by 6 weeks, (2) lamellar compaction by 18 weeks, (3) interface remodeling by 18 weeks, and (4) development of mature compact bone by 54 weeks. The initial inflammatory phase may be considered completed by the 6-week stage, and it is during this period that the presence of an implanted material will have the most significant effect on the long-term fate of the bone-biomaterial interface.

11.9 Blood-Material Interactions

When blood contacts a surface that is not the endothelial lining of blood vessels, it undergoes a complex series of interdependent reactions which may lead to platelet activation and adhesion, coagulation, and the formation of thrombosis. These mechanisms have evolved as part of a sophisticated defense process designed to limit blood loss following injury and facilitate the wound healing process. Unfortunately the introduction of artificial materials into the body via surgical intervention leads to the contact of blood with the biomaterial substrate, with inevitable adverse consequences. These interactions primarily involve the biomaterial substrate, platelets, clotting proteins, and the eventual breakdown of the resultant clot or thrombosis by the fibrinolytic process [8]. The body has evolved a number of mechanisms for dealing with thrombus formation once it has been initiated. Therefore, although all biomaterials in contact with blood will stimulate an adverse response, a number of materials can be tolerated and will function effectively. These mechanisms include the physical/mechanical action of flowing blood to prevent the buildup of thrombosis and naturally occurring inhibitors of coagulation to inactivate thrombin. Platelets, coagulation, and blood vessel cell lining (endothelial) systems interact to promote local hemostasis but prevent generalized blood clotting and thrombosis [8]. Determination of the hemocompatibility of biomaterials is complex because these factors are not effective during in vitro evaluation of biomaterials. Yet it is by using in vitro testing methods that researchers and manufacturers garner most of the biological information. And these are the methods used to pass judgment on the potential for an implant material to function effectively within a blood-contacting environment or on its likelihood to lead to adverse or possible fatal biological consequences. The relative merits of cell culture (in vitro) and animal testing (in vivo) are an ongoing argument in biomaterial evaluation. Many researchers will argue that the test environment encountered within the in vitro test is so far removed from the clinical experience as to be meaningless and produce misleading data. Notwithstanding the moral/ethical arguments associated with the use of animals in biomaterial testing, many others will argue that in vivo or animal studies can only be interpreted effectively if we have already garnered the fundamentals of the cell-material interactions using cell culture. The argument is particularly focused in blood-biomaterial interactions where blood cells and blood components introduced to the in vitro environment have already been exposed to adverse conditions before ever meeting the material or device under consideration. But it remains an argument that rages without effective resolution in all areas of the biological evaluation of implant materials and the determination of what is termed biocompatibility .

11.10 Biocompatibility

The term biocompatibility is often associated with cell culture testing of biomaterials. In many cases simple in vitro test methods are employed with a potential biomaterial as the test sample. If a positive result is obtained, i.e., the cells remain viable, then the material is labeled “biocompatible.” If the cells die or are significantly adversely affected, the material is labeled “non-biocompatible.” This is a serious misuse of the term biocompatibility and a misuse of the in vitro test. Biocompatibility is not the result of a single event or phenomenon. It refers to a collection of processes involving different but independent mechanisms of reaction between a material and its host tissue. Biocompatibility refers to the ability of a material to perform a function. The ability to perform and to continue to perform this function depends not only on its interaction with tissue but also on the intrinsic mechanical and physical properties of the material. The definition of biocompatibility refers to appropriate host response [9]:

The ability of a material to perform with appropriate host response in a specific application.

It does not stipulate that there should be no response. This may be a minimal response or indeed a more aggressive response. The definition refers to specific application. Biocompatibility should always be described with reference to the situation in which a material or device will be used. No material should be described as “biocompatible” without further qualification. Biocompatibility is therefore not an intrinsic property of any material [10]. The majority of in vitro tests employed in biomaterial evaluation measure cytotoxicity. However, the lack of toxicity cannot be equated with biocompatibility. Cell culture assays are not biocompatibility assays. The safety evaluation of medical devices is generally based on in vivo testing which evaluates acute and chronic toxicity and inflammation, irritation and sensitivity, carcinogenicity and mutagenicity, allergic responses, hemocompatibility, and systemic toxicity. It is not possible to assess all of these factors using in vitro assays; however, test models have now become established which permit the in vitro evaluation of acute toxicity, genotoxicity [11], hemocompatibility [12], necrotic cell death, and apoptosis [13].

The introduction and development of in vitro testing have raised many concerns with respect to reproducibility and proper regulatory control. The establishment of new in vitro assays requires three steps, development, validation, and acceptance. Acceptance of in vitro assays involves satisfying the regulatory bodies, the manufacturers, and the users. At present there are few, if any, properly validated in vitro tests [14].

International standard ISO 10993 part 5 [15] was developed as the result of a harmonization of various existing standard procedures and the outcome reports of working groups. The standard acknowledges the widespread use of in vitro cytotoxicity testing and defines a scheme for testing which will allow the user to identify the most appropriate test procedures. These tests specify the incubation of cultures of mammalian cells with the medical device or component part of the device (i.e., the direct test method) or with an extract derived from the device (i.e., the indirect test method). Information is provided on appropriate test sample preparation for the direct testing, and in some detail, the most appropriate means of producing extracts for indirect testing are presented. The standard provides details on a number of recommended established cell lines, although these are not exclusive. The standard further provides details on how cytotoxicity may be most appropriately determined. This evaluation is categorized as follows:

  1. 1.

    Assessment of cell damage by morphological means

  2. 2.

    Measurements of cell damage

  3. 3.

    Measurements of cell growth

  4. 4.

    Measurement of specific aspects of cell metabolism

It is noted that evaluation may be by qualitative or quantitative means. It should also be noted that the standard does not present a single in vitro method for cytotoxicity evaluation but allows the user to select an appropriate range of tests. Furthermore, at no point does the standard use the term biocompatibility in connection with this type of test. Another important aspect of the standard is the reference made to negative and positive control materials that should be employed in all test systems.

Replacement of animal testing is not the objective of in vitro assays and an appropriate use of both in vitro and in vivo is the most sensible approach to biomaterial evaluation. Simple in vitro assays can provide screening information and play a significant role in the early phase of investigation. Subsequent studies should employ more specific in vitro models alongside animal studies. This level of testing should include the use of human cell lines.

The test procedures identified in ISO 10993 part 5 are designed to evaluate cytotoxicity. The primary goal of such tests is to determine safety. As such these can be considered screening tests for use in the development and research of novel materials and for the quality control of medical devices (both component parts and final products). Even at this simple level of testing, relevant information can be garnered with respect to the final use of the test material. However, the user must be careful to appreciate the simplicity of such testing. For example, it is prudent that any cytotoxicity evaluation should employ more than one cell line and where appropriate and possible should make use of human primary cell lines. Even simple screening tests can benefit from some level of quantification where this can be sensibly applied. Although ISO 10993 does make reference to the use of subjective, semiquantitative grading systems, these will rarely produce any meaningful data and do not easily allow for the comparison of data between different laboratories or indeed different users. Qualitative assessment of cell morphological changes by an appropriately trained individual remains a more meaningful technique. However, quantification using measurements of cell metabolic functions is readily employed and can provide accurate and reproducible data easily transferred between researchers. These includes cell-counting procedures, both manual and automatic [16], assessment of DNA levels [17], or the determination of cell activity by MTT assay [18].

11.11 Carcinogenicity

The potential for biomaterials or their degradation products to induce the growth of malignant cells is an area of increasing concern as we strive to develop and manufacture materials which will spend longer and longer times in contact with the tissues of the human body. Sarcomas associated with implant materials have been cited in the literature following procedures with a number of animal models (almost always rats and mice). However, biomaterial-induced sarcomas are rare in humans. In experimental animals there has been evidence produced of the carcinogenicity of a wide range of implanted materials (polymers and metals) generally when presented with smooth surfaces. Some metallic powders have also been implicated when placed in contact with connective tissues. In contrast there is little evidence of carcinogenicity with polymeric powders or with the metals primarily used in orthopedic surgery. ISO 10993 part 3 [19] describes carcinogenicity testing as the means to determine the tumorigenicity potential of devices, materials, and/or extracts to either a single or multiple exposures over a period of the total lifespan of the test animal. As the animal is generally a rodent and the maximum experimental time is around 12 months, there remains considerable concern as to how relevant such a procedure may be in identifying potential problems with materials which may be implanted within human tissues for periods in excess of 30 or 40 years. The standard further states that although any implant remaining within the body in excess of 30 days should be considered to have long-term or permanent contact, it is only necessary to conduct carcinogenicity testing if there is evidence from other sources which suggest a problem. Consequently, few implant materials have been subjected to animal testing which is specifically designed to identify carcinogenic potential.

Most carcinogenicity concerns are associated with the physical presence of the biomaterial in direct contact with the tissue. There are a number of factors which may influence the potential for such an implant to trigger an adverse response. Most significant of these appears to be the size, shape, and surface finish of the implant material. A highly polished, smooth surface has been most significantly associated with tumors, particularly in the animal model. Indeed materials lose their carcinogenic potential if the smooth nature of the substrate is disrupted. This is often referred to as the “Oppenheimer effect,” a reference to the research group who identified this phenomenon in a large animal study. However, there are also concerns that chemicals which leach from implanted materials, either by design or otherwise, may stimulate a toxicity that has an adverse effect on the genetic material of the host cells. We can perhaps take some comfort in the fact that there is now a large population of patients who have been recipients to long-term implantations (joint replacements, breast prostheses, etc.) with little evidence that carcinogenicity is a problem. Nevertheless, carcinogenicity concerns are real, and it is incumbent upon the biomaterials’ community to research and develop test methods which will effectively highlight potentially carcinogenic materials.

11.12 Hypersensitivity

Sensitization or hypersensitivity reactions to biomaterials are usually associated with a prolonged or repeated contact with a chemical substance, normally a substance which leaches from the biomaterial and stimulates the body’s immune system. The majority of such biomaterial-induced reactions have been associated with skin-contacting devices; however, increasing concerns are being expressed over the potential for implanted materials to stimulate both the cell-mediated and antibody-mediated immune responses. Degradation products from biomaterials which act as antigens within the body are known as allergens and may stimulate an exaggerated immune response which will lead to damaging effects on the host. Metal hypersensitivity is well established in areas outside implantation; however, corrosion of metal implants and the formation of metal ion-protein complexes may mediate metal hypersensitivity following implantation. The most significant chemical allergens associated with biomaterials and the degradation products of biomaterials are low-molecular-weight entities, i.e., metal ions. They are referred to as haptens and only become allergens when complexed with another biological molecule. It is important therefore that appropriate means of assessing the potential allergenicity of an implant material are employed before materials can be considered for long-term implantation. At present there is no effective means of predicting the potential for an implanted material or leachable chemical to generate an allergic effect.