Artificial implant devices comprise a variety of metallic alloys, polymers, ceramics, hydrogels or composites for a large number of purposes and with widely different properties. With the exception of drug delivery systems, sutures, and other degradable biomaterial systems (Chapter II.2.5), the implant devices are intended to resist chemical and biochemical degradation, and to have minimal leaching of structural components or additives. However, synthetic devices are influenced by chemical, and in some cases enzymatic, processes resulting in the release of biomaterials-associated components. Since there are no natural repair mechanisms parallel to natural tissues, degradation (biodegradation) is a “one-way” process that brings about microscopic and macroscopic surface and bulk changes of the devices, sometimes enhanced by the biomechanical and bioelectrical conditions that the devices are intended to resist. With the exception of pathologic calcification of certain polymer implants, the surface changes may not be significant for the mechanical strength of the implant, whereas in contrast the released substances very often have biological effects on the surrounding tissues or, possibly, at other remote locations. Inflammatory, foreign body, or other local host reactions, and tumorigenesis are discussed in Chapters II.4.1, II.4.2, and II.4.6. The following discussion is concerned with the possibility of systemic toxic reactions and/or hypersensitive reactions caused by biomaterials-derived xenobiotics.
Xenobiotic components derived from in vivo medical devices have parenteral contact with connective tissue or other specialized tissues such as bone, dentin, vascular or ocular tissue, whereas leachables from skin and mucosa contacting devices have to pass the epithelial lining of the oral mucosa, the skin, the gastrointestinal tract, or – for volatiles – the lung alveoli to get “inside” the body. In any of these cases, further distribution of foreign substances to other tissues and organs is dependent on membrane diffusion into blood capillaries and lymph vessels. The transport may be facilitated by reversible binding to plasma proteins, globulins (metal, metal compounds), and chylomicrons (lipophilic substances). Storage – and later release – may take place for certain components in tissues such as fat and bone.
In addition to particulate matter, the released components consist of chemical substances of different atomic and molecular size, solubility, and other chemical characteristics, depending on the mother material. Examples are metal ions from orthopedic implants or prosthodontic materials, or residual monomers, chemical initiators, inhibitors, plasticizers, antioxidants, etc., from polymer implants and dental materials. Other degradation products from inorganic, organic, and composite devices also “rub off” to the surrounding tissues. The kinetic mechanisms for biomaterials components are in part the same as those of xenobiotics introduced by food or environmental exposure, i.e., the released components are subject to oxidation, reduction, and hydrolysis, followed by conjugation mechanisms. All metabolic changes are, by their nature, intended to eliminate them by way of the urine, bile, lungs, and to a certain degree in salivary-, sweat-, and mammary glands, and hair (deBruin, 1981).
A key question is, do the released components or their metabolites have any systemic toxic effect on the host, and/or could they induce unwanted immunological reactions?
Systemic toxicity depends on toxic substances hitting a target organ with high sensitivity to a specific toxicant. Target organs are the central nervous system, the circulatory system, the hematopoietic system, and visceral organs such as liver, kidney, and lungs, in that order. The toxicity is based on interference with key cell functions, and depends on the dose, and the duration, of the exposure. Serious effects may be incompatible with continued life, but most effects cause local and reversible cell damage. However, some sublethal effects may include somatic cell mutation expressed as carcinogenesis, or germinal cell mutation, resulting in reproductive toxicity.
The key word in the evaluation of general toxicity is the dose, defined as the amount of substance an organism is exposed to, usually expressed as mg per kg bodyweight. Adverse effects of foreign substances are often the result of repeated, chronic exposure to small doses that, over a prolonged period of time, may have deleterious effects similar to one large, short-term exposure, provided that the repeated doses exceed a certain threshold level. This level is determined by the capacity for metabolism and elimination. Another important factor is the possibility of synergistic potentiating effects when several toxicants are present simultanously. Whatever mechanism is involved, the principle of systemic toxicity presupposes a dose-dependent reaction that may be measured and described, and that may be explained by specific reactions at distinct molecular sites (Eaton and Gilbert, 2008).
The components derived from biomaterials represent a large series of widely different foreign substances with few characteristics in common, and with a largely unknown concentration. Most of them have to be characterized as toxic per se, with large variations as regards their place on a ranking list of potential toxicity. This statement is relevant for metal ions and salts, as well as for polymeric components derived from biomaterials devices. Local inflammatory and other host reactions towards biomaterial implants are well known (Chapter II.4.2), whereas the significance of individual implant components is difficult to assess.
However, many studies have provided information on the presence of wear and corrosion debris from metallic orthopedic implants, often initiated by the aseptic loosening of total hip replacements. Oxides or hydroxides of cobalt, titanium, aluminium, iron, nickel, and chromium are found in the periprosthetic tissues, depending on the alloys used. Post-mortem data also indicate accumulation in regional lymph nodes and liver. Further vascular distribution of ions and extremely small particles has made it possible to estimate concentration of some of these components in whole blood. Such findings open up the possibility of evaluating the potential effect on different organs. Information in this area is growing by sophisticated cytotoxicity research, by experimental animal studies, and by extrapolation of occupational and environmental data. So far, the risk of systemic toxicity caused by metallic implant components is considered to be negligible, although it is recommended that the orthopedic research community pay attention to the basic functions of kidneys, reproductive organs, and the central nervous system among arthroplastic patients (Keegan et al., 2007).
Metallic dental material is another source of exposure. In vitro experiments have shown that chromium and nickel are released from base metal orthodontic appliances, although the amounts are not comparable with the amounts calculated in food intake (Park and Shearer, 1983). As witnessed by hypersensitive reactions, uptake of metal components by mucosa from fillings and prosthodontic devices does take place, but on a scale too low to be of interest in the systemic toxicity context.
An exception is the release and pulmonary uptake of volatile metallic mercury from dental amalgam fillings. Many studies have been able to quantify the concentration of mercury in plasma and urine depending on the burden of dental amalgam (Mackert and Berglund, 1997), and occupational studies have demonstrated that mercury accumulates in tissues belonging to the central nervous system (Nylander et al., 1989). Reproductive toxicity has been of specific concern for dental personnel.
However, similar to other metals such as chromium and nickel, mercury exposure also takes place in food and respiratory air. Careful scrutiny by national and international scientific committees of the large amount of (partly controversial) data has not resulted in a consensus conclusion that the application of mercury dental amalgam should be discontinued, although the environmental concern of mercury is recognized. The European Commission (2008), by its Scientific Committee of Emerging and Newly Identified Health Risks (SCENIHR), has recently investigated possible adverse effects of mercury dental amalgam on urinary, neurological, immunological, psychological, reproductive, and other systems, and concludes that there is little epidemiological evidence to show that mercury released by dental amalgam fillings contributes to the etiology of systemic diseases.
Non-metallic dental materials comprise numerous composite polymeric materials based on a variety of methacrylate monomers polymerized by specific chemical additives. Numerous elution experiments have demonstrated the release of monomers and additives, particularly during the first hours after polymerization (Michelsen et al., 2007). Degradation and erosion of the dental filling and prosthodontic materials over time is another source of released components. Most released substances have proven to be cytotoxic in vitro (Geurtsen et al., 1998). Some components have been of specific interest for their toxicity to the reproductive system. Examples are the UV-absorber oxybenzone, Bisphenol A, and phtalates, all released from different polymeric materials. Oxybenzone has an estrogenic potential, Bisphenol A binds estrogen receptors in vitro with the potential of impairing the reproductive system, and phtalates have antiandrogenic characteristics as judged by environmental research. Since Bisphenol A is released from fissure sealants, mainly applied in children, this issue has been of specific interest in the toxicological discussion of dental materials. However, current literature does not support any risk associated with these materials (Azarpazhooh and Main, 2008).
Minute quantities of phtalates and degradation products of chemical additives derived from freshly made (poly)methylmethacrylate dental prostheses have been demonstrated in saliva (Lygre et al., 1993). Larger amounts of plastiziser phtalates are released from temporary biomaterials such as PVC tubing; therefore the risk of deleterious effects on specific patient groups such as dialysis patients or premature neonatates has been discussed (Calafat et al., 2004). Another point in this context is the observation that (poly)methylmethacrylate monomer from setting bone cement may cause transient cardiovascular reactions. The dose applied in hip arthroplasty is large enough to cause hypotension, whereas the smaller dose associated with percutaneous vertebroplasty is not (Kaufmann et al., 2002).
Other clinically relevant data on the systemic toxicity of degradation products from dental polymeric materials and non-metallic implants are scarce. On this background a fair conclusion would be that there is no data indicating long-standing systemic toxicity caused by biomaterials-derived xenobiotics. However, current cytotoxic and animal research may reveal toxic mechanisms on the intracellular level that may prove relevant for released biomaterials components. In addition, the biomaterials field is characterized by the increasing number of synthetic materials on the market. Despite the premarketing testing programs, it is difficult to predict single or synergistic toxic effects of leachable components and degradation products in the future.
The low probability of direct systemic adverse effects on target organs caused by biomaterials products does not rule out deleterious effects by other mechanisms requiring only minute amounts of the foreign material. All substances not recognized as natural components of the tissues are subject to possible clearance by several mechanisms, e.g., phagocytic cells such as polymorphonuclear leucocytes, macrophages, and monocytes attempting to degrade and export the components. Larger foreign components are subject to more aggressive reactions by giant cells causing an inflammatory foreign-body reaction. Enzymes and other bioactive molecules associated with phagocytosis and foreign-body reaction may cause severe local tissue damage. In addition, phagocytic cell contact, and contact with the circulatory system of lymph and blood, opens up another way of neutralizing foreign substances by way of the immune system, introducing a biologic memory of previously encountered foreign substances, and an enhancement system for their neutralization.
The immune system is an indispensable biological mechanism to fight potentially adverse invaders, most commonly of microbial origin. However, the immune system occasionally strikes invading molecules – adverse or not – with an intensity that stands in contrast to their modest concentration, and with the ability to cause host tissue damage. This phenomenon is called hypersensitivity. The resulting injury is part of a group of adverse reactions classified as immunotoxic.
In principle, immunologic hypersensitivity comprises two different mechanisms: allergy and intolerance. Allergy is an acquired condition resulting in an over-reaction upon contact with a foreign substance, provided there is a genetic disposition and previous exposure to the substance. Allergic reactions may include asthma, rhinitis, urticaria, intraoral and systemic symptoms, and eczema. Intolerance is an inherited reaction that resembles allergy and has common mediators and potentiating factors, such as complement activation, histamine release, etc., but is not dependent on a previous sensitization process. Intolerance reactions have been associated with drugs such as acetyl-salicylic acid, whereas intolerance to leachable biomaterial components such as benzoic acid is conceivable but not known.
A foreign substance able to induce an allergic reaction is called an allergen. There is no acceptable way of predicting whether a substance or a compound is potentially allergenic on the basis of its chemical composition and/or structure alone. However, experimental evidence, and years of empirical results after testing substances causing allergic reactions, has given some leads, e.g., large foreign molecules such as proteins and nucleoproteins are strong allergens, whereas lipids are not. However, the strongest chemical allergens associated with biomaterials are often chemically active substances of low molecular weight, often less than 500 Da, such as lipid-soluble organic substances derived from polymer materials or metal ions and metal salts. These are called haptens, i.e., they become full allergens only after reaction or combination with proteins that may be present in macrophages and Langerhans cells of the host.
Allergies are most often categorized into four main groups (Type I–IV) according to the reaction mechanisms. Types I to III are associated with humoral antibodies initiated by B-lymphocytes that develop into immunoglobulin-producing plasma cells. The immunoglobulins are classified into five different classes, IgE, A, D, G, and M, according to their basic structure and size. A variable portion of the immmunoglobulin is specific for the antigen that induced its production. The Type IV reaction is a cell-mediated reaction caused by T lymphocytes.
Types II and III allergies comprise antigen–antibody encounters including complement activation, cell lysis, release of vasoactive substances, inflammatory reaction, and tissue damage. Necrosis of peri-implant tissue with histologic appearance and serum complement analyses consistent with Type III hypersensitivity has been observed in cases of atypical loosening of total hip prostheses (Hensten-Pettersen, 1993). However, according to the appropriate ISO and FDA documents for immunotoxicological testing of medical devices (ISO 10993-20, 2006, and FDA Immunotoxicity Testing Guidance, 1999) Type II and III reactions are omitted because they are relatively rare, and are less likely to occur with medical devices/materials, leaving Types I and IV relevant in the present context.
The Type I reaction is based on an interaction between an intruding allergen and IgE immunoglobulins located in mast cells, basophils, eosinophils, and platelets, resulting in release of active mediators such as histamine and other vasoactive substances. The results are local or systemic reactions seen within a short time (minutes). The symptoms depend on the tissue or organ subject to sensitization, e.g., inhaled allergens such as pollen, residual proteins associated with surgical latex gloves or other natural latex products may result in asthmatic seizures, swelling of the mucosa of the throat or worse: decreased blood pressure and anaphylactic shock. Food allergies may also give systemic symptoms. This type of host reaction is usually associated with full antigens. Since the potential allergens associated with biomaterials are small molecular haptens, the probablility of IgE-based allergic reactions is low, although IgE antibodies to chromium and nickel have been reported (Hensten-Pettersen, 1993). Reports on adverse reactions to orthopedic devices describe patients with urticarial reactions. Contact urticaria is a wheal and flare response to compounds applied on intact skin. The role of immunological contact urticaria in relation to medical devices is not clear.
Cell-mediated hypersensitivity is referred to as “delayed,” because it takes more than 12 hours to develop, often 24–72 hours. The T lymphocytes producing the response have been sensitized by a previous encounter with an allergen, and act in concert with other lymphocytes and mononuclear phagocytes to create three histologically different types, characterized by skin-related tissue reactions. The reactions are elicited by interaction of cells and mediators which comprise: (1) induration (the granulomatous type); (2) swelling and induration, and possibly fever (the tuberculin type); and (3) eczema (the contact type) (Britton, 2001).
Prolonged challenges of macrophage-resistant allergens, usually of microbial origin, may result in persistant immunological granuloma formation. Such reactions have been associated with occupational beryllium and zirconium exposure, but the main form of delayed hypersensitivity in relation to biomaterials is the contact form.
Allergic contact dermatitis is acquired through previous sensitization with a foreign substance. The hapten is absorbed by the skin or mucosa, and binds to certain proteins associated with the Langerhans cells, forming a complete antigen. The antigen stimulates the formation of activated, specialized T cells. Upon new exposure, the allergen–T cell encounter releases inflammatory mediators resulting in further production and attraction of T cells, causing tissue damage. The reactions are not necessarily limited to the exposure site.
The presence of allergic contact dermatitis is evaluated by epidermal or intradermal skin tests. A vast amount of information on the allergenic characteristics of biomaterials-related substances has been obtained in this way, especially as regards dental materials (Kanerva et al., 1995). However, many biomaterials employed in dentistry, such as metal alloys and resin-based materials, have medical counterparts which are encountered in everyday life. The sensitization process, therefore, often has taken place before the biomaterials contact.
Atopic individuals have a constitutional predisposition for IgE-based hypersensitive reactions caused by environmental and food allergens. The reaction includes histamine-mediated hay fever, asthma, gastrointestinal symptoms or skin rashes, and is more pronounced at an early age. Atopics have an increased risk of acquiring irritant contact dermatitis to external biomaterial devices, such as orthodontic appliances. The relation to allergic contact dermatitis is unclear (Lindsten and Kurol, 1997), so also is the relationship between atopy and allergens or haptens from biomaterials exposed parenterally.
Biomaterial immunology includes reactions associated with oral rehabilitation, as well as medical devices. Of these, dental materials are by far the most common, and represent a large variety of metallic and polymer products. With the exception of some extraoral orthodontic equipment and latex utensils, the exposure site of these materials is oral tissues. The local immunological reactions include gingivitis or gingival lichenoids, mucosal inflammation and blistering or perioral dermal reactions, all of the delayed contact reaction type. In addition, dermal reactions may occur at remote locations. Occasionally IgE-based immediate reactions, such as angioedema, contact urticaria or anaphylaxis are seen, mostly related to temporary biomaterials, such as natural rubber latex.
Considering the vast number of dental patients, the incidence of immunotoxicity reactions is extremely low. In contrast to medical implants, such reactions are easily observed in the dental clinic, but determination of the eliciting allergen is not easy. In Table II.2.5.1 some allergenic components associated with dental biomaterials are listed on the basis of empirical findings by epidermal patch tests. Some of these items have their counterparts in orthopedic implants or other medical devices.
Information on immunological adverse effects in dental medicine has been obtained by case reports, questionnaire studies, and reports from adverse reaction registry units and dermatological units. In some cases the cause–effect relationship has been assessed by clinical experience only. For these and other reasons, there are no reliable epidemiological statistics on adverse effects in terms of incidence data. The prevalence in published reports varies from 1:100 to 1:10,000 (Schedle et al., 2007), and comprises both local and remote hypersensitivity reactions. However, all reports indicate salts of nickel, gold, cobalt, palladium, mercury, and chromium as the main metallic allergens. Of the polymer alternatives, the monomers of HEMA, EGDMA, TEGDMA, and MMA, together with polymerization chemicals, such as benzoyl peroxide and dimethylparatoluidin, are prevalent. It is argued that the sensitization may have taken place by exposure to parallell allergens in everyday life, and that the oral encounter elicits the reaction. It is also accepted that, for anatomical reasons, oral tissues develop hypersensitive reactions less easily than dermal tissues.
The exact progress of hypersensitivity reactions associated with implants is not clear. It might include both the sensitization and the elicitation process, or just the latter. Reactions of this type are difficult to recognize unless they have dermal or systemic expressions, such as eczemas or fistulas. In addition, such reactions may be part of local atoxic and/or mechanically induced inflammation using similar mediators for tissue response. Because of a lack of more distinct descriptions, such reactions have been referred to as “deep tissue” reactions of Type IV hypersensitivity. Immunological toxicity to surface medical devices and external communicating devices (dialyzers, laparoscopes, etc.) may represent mechanisms of sensitization and hypersensitivity reactions similar to those of orally exposed biomaterials.
A vast battery of in vitro and in vivo experimental studies have been performed to study potential adverse effects of biomaterial devices, such as artificial joints, heart valves, and breast prostheses (Rodgers et al., 1997). Aseptic loosening of metallic hip prostheses has been associated with “biologic” causes, in addition to biomechanical factors and wear debris. However, it is unclear whether metal sensitivity is a contributing factor to implant failure (Hallab et al., 2001). In fact, it is argued that the loosening process enhances immunological sensitization, indicating that the cause–effect relation may be the reverse (Milavec-Puretic et al., 1998). German orthopedists and immunologists, discussing the complicated relationship between potential allergens and the presence of implant failures, fistulas, and dermal reactions, underline the value of an allergological anamnesis (Thomas et al., 2008). However, similar to dental medicine, there is no strict contraindication for using a biomaterial containing a known allergen for a particular patient. Such decisions have to be taken on the basis of individual evaluation. What is clear, however, is that local and general eczematous reactions have been observed following the insertion of metallic implants in patients subsequently shown to be allergic to cobalt, chromium, and nickel.
Many case reports also describe the immediate healing of dermal reactions after the removal of metal implants (Al-Saffar and Revell, 1999). In addition, metal allergy has been discussed as a contributing factor in the development of in-stent coronary restenosis, although there is little evidence for this effect (Hillen et al., 2002). However, established metal allergy in a patient does not as a rule seem to be accompanied by clinical reactions to implant alloys containing the metal. If this statement is true, it is in line with clinical observations made in surveys on the use of metallic alloys in prosthodontics and orthodontics. Inhomogeneiety or a mixture of alloys appears to determine the efflux of potentially hypersensitive metal ions, and hence increases the possibility of eliciting a hypersensitive reaction (Grimsdottir et al., 1992).
Methyl-methacrylate bone cement is another potential allergenic factor in orthopedic surgery, as is their counterpart in dentistry and cosmetic dentistry (Kaplan et al., 2002). As indicated in Table II.2.5.1, prime elicitors are monomers of MMA and HEMA, and additives such as benzoyl peroxide, N,N-dimethyl-p-toluidine, and hydroquinone (Thomas et al., 2006).
TABLE II.2.5.1 Some Allergens in Dental Materials Based on Epicutaneous Testing
∗Sensitizers in orthopedic surgery. Other orthopedic metals are manganese, vanadium, molybdenum, aluminum, and zirconium, all with undecided allergen characteristics (Thomas et al., 2008; Geier et al., 2008). In addition, protein in natural rubber latex is a Type I allergen in dental and general medicine.
An extensive literature reflects clinical surveys and research activities related to natural latex used as a barrier material by the health professions. It is accepted that residual latex proteins and chemicals associated with the production process may cause immediate and delayed reactions in patients and health personnel (Turjanmaa et al., 1996).
The FDA testing guidance referred to above (FDA, 1999) also lists other interactions of medical devices, extracts of medical devices or adjuvants with the immune system, such as impairment of the normal immunologic protective mechanisms (immunosuppression), and long-term immmunological activity (immunostimulation) that may lead to harmful autoimmune responses. The autoimmune reaction is explained by the biomaterial-associated agent acting as an adjuvant that is stimulating to antibody–complement-based tissue damage by cross-reactions with human protein. Chronic inflammatory, immune-related granuloma may take part in the development of autoimmune reactions.
Biocompatibility issues related to medical devices form a multidimensional crossroads of technology and biology. One component is the various classes of biomaterials, such as plastics and other polymers, metals, ceramics, glasses, etc., depending on expert design to obtain maximal mechanical properties and minimal chemical dissolution. Another is the mode of application, ranging from skin and mucosal contact to totally submerged implants, with external communicating devices in-between. A third dimension is the duration of contact, ranging from minutes to the expected lifetime, and the fourth, and decisive component, is the biological reactions that can be expected. These circumstances prevent general statements on biomaterials. The present overview is aimed at students, and limited to a focus on collective mechanisms determining systemic toxicity and discussion of hypersensitivity reactions documented by clinical reports.
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