With the long history of use of many materials in dental surgery, biocompatibility concerns are not as great a concern as other issues, such as long-term degradation, mechanical strength problems, and prevention of secondary caries. It is important, however, not to forget that the potential exists for adverse tissue responses to synthetic materials used in repair, augmentation, and repair of natural tissue structures. As new materials and repair techniques become available and the sophistication of cell-level and subcellular response evaluations increases, the concerns to be addressed and the methods to be used may change. The advent of tissue-engineered medical products may mean that new questions must be addressed.
For more than 2000 years, humans have attempted to improve life through the use of materials and devices of nonhuman origin as prosthetic devices and restorative materials in contact with tissues in the oral and maxillofacial environments . Initially, the patient or someone providing care might use whatever materials were close at hand to make repairs and prosthetics. Before 400 bc , the Etruscans were fabricating bridges and partial dentures using gold combined with animal or extracted human teeth. As communications improved and humans became more mobile and more urbanized, dentists and health care providers realized that some materials were more successful than others when used in contact with oral and maxillofacial tissues. At about the same time, researchers in other fields of medicine were also realizing that the tissue response to some materials was more favorable than the response to other materials. Some of the first publications to look at the evaluation of the tissue response to dental materials were those of Autian and his colleagues in the early 1970s, and an early review article was published in 1971 .
Depending on how biocompatibility is defined, the term may include adverse effects of a material on tissues and physiologic systems, adverse effects of the physiologic environment on the material, or a combination of the two, such as an adverse tissue response to the products of material degradation caused by physiologic exposure. The biocompatibility of a material depends upon the type of material, where it is placed, and the function it is expected to perform. Therefore, a material cannot be biocompatible but it does elicit an acceptable tissue response when tested or used in a specific tissue or category of tissue under certain conditions, including the health status of the patient [8].
Areas of biocompatibility concern
The oral and maxillofacial environment is complex and varied, with different requirements and different biocompatibility issues depending on the specific use. Other than fully implanted materials, exposure includes exposure to saliva, foodstuffs, bacteria, and the products of interactions between components of the environment. These exposures place severe requirements on the performance of the device components and may have requirements unique to this environment. Although most sites in the body in which biomedical materials may be placed have a relatively constant temperature and chemical composition (in the absence of infection or inflammation), the oral environment exhibits extremes of temperature, pH, and chemical composition of food. The extremes of temperature from that of ice cream (0°C) to hot coffee (90°C) may lead to compatibility problems, such as thermal expansion, changes in mechanical properties, or failure of bonding. The pH in the microenvironment around dental caries–causing bacteria may be as low as 2.2 . The pH of gastric secretions is 1.0 to 3.5 , and the pH of the acid produced in the stomach is 0.8. . The exposure of intraoral materials to gastric contents because of reflux or regurgitation as a result of medical conditions or bulimia presents a special biocompatibility challenge that, although not the normal physiologic condition, may require consideration under some circumstances.
When caries are removed from a tooth, the cavity created may provide the opportunity for chemical components or degradation products of dental materials to migrate to the pulp chamber of the tooth, meaning that it is necessary to be concerned about the possible toxic effects on blood, capillary tissues, and neurons and potential problems with the tissues in the mouth. If there is a possible problem with the contact of certain materials with the contacts of the pulp chamber, then appropriate precautions must be taken to isolate the restorative material, such as the use of cavity liners.
In general, the most benign tissue response seen to materials placed within living tissues is the formation of a fibrous tissue capsule around the material, walling it off from the physiologic environment. The thickness of this capsule is sometimes used as one indicator of the acceptability of the material, because a thicker capsule suggests that the body is continuing to produce additional fibrous tissue in response to a continuing irritant that has not yet been minimized by the capsule that has formed. There are exceptions to the formation of a fibrous tissue capsule, in which bone may be formed directly on the surface of a material without any capsule. Certain metals and ceramics exhibit this characteristic.
Restorative materials
Restorative materials include those used for replacing carious tissue within the tooth structure, such as inlays and onlays, crowns, bridges, partial dentures, and full dentures. Many of the materials used to fill cavities are normally not placed into direct contact with tissues other than dentin and enamel. They are subject to corrosion, wear, and leaching of constituent chemicals . If a curing reaction is involved in placement, an exotherm may occur, monomers or other chemicals may be released, or the raw materials may leach through the dentin tubules and into the pulp chamber and come into contact with blood and nerve tissue. Additionally, materials used in endodontic therapy must come into contact with the pulp space and its contents, and it may leak into periapical tissues, creating additional concerns beyond those for materials intended to restore the crown morphology . When used in contact with gingiva or the tissue lining the mouth, additional testing for tissue response may be necessary, and the possibilities for problems caused by direct contact increase.
Amalgam
The biocompatibility of amalgam, a product of the reaction of liquid mercury with silver and other metals, has been the subject of controversy for many years. There has been a concern that the mercury used in the reaction may leach out of the restoration as a result of unreacted material, dissolution in saliva, or corrosion reactions. It is known that mercury exists inorganically as the metal or in one of two charge states and in an organic form (methyl mercury). When present as methyl mercury, it is known to be highly toxic. Methyl mercury has been responsible for toxic reactions in the hat industry, in environmental disasters, and through consumption of seafood. Mercury in vapor form is easily taken up by the body. The mercury present in an amalgam reaction exists in the metallic form and is not easily absorbed from the digestive system if swallowed. It is completely bound up with the other metals present in the amalgam because the reaction is a chemical one that combines it with the metals to form an alloy.
Studies reviewed by the US Public Health Service and the Food and Drug Administration suggest that based on available evidence, there is no proof of any mercury toxicity from dental amalgam to the patient, other than in cases of allergy . A study published in the New England Journal of Medicine concluded that there is no clear evidence for the removal of amalgams and that the evidence is open to wide interpretation. The authors of two reviews published in Europe concluded, “According to the conclusions of independent evaluations from different state health agencies, the release of mercury from dental amalgam does not present any non-acceptable risk to the general population” and “…there is little evidence of a correlation between amalgam restorations and adverse neurological or neuropsychological effects…That said, additional studies are needed to strengthen the case” . Two studies reported on amalgam use in children and examined a total of 520 children who received amalgam randomly matched against 521 who received composite restorations. One study concluded that “…there is no reason to discontinue the use of mercury amalgam as the standard of care for caries in posterior teeth” . The other concluded that “…amalgam should remain a viable clinical option in dental restorative treatment” .
Polymeric materials and composites
Many restorative materials other than amalgam are compounds that are polymerized or otherwise reacted in the prepared tooth cavity at the time of placement . These materials consist of monomers, fillers, initiators, accelerators, and additives that are combined through some type of a curing reaction . If the proportions of the different components are not correct or if the curing reactions are not carried to completion, some or all of the components may be available to become dissolved in saliva, pass through tubules into the pulp chamber, or otherwise be released. Some monomer also may be released before curing occurs or during curing. Initiators and accelerators, depending on the type of curing reaction, may cause polymerization to occur or be accelerated without actually becoming a part of the polymer chain, which leads to the possibility that they may be free to diffuse out of the material and come into contact with tissues. In the same way, additives such as plasticizers act to change the mechanical properties of the final product but are not necessarily bound up in the constituent polymers.
Metallic materials
When metals and alloys are used in dentistry, there is the opportunity for adverse reactions caused by the release of metal ions or other products of the interaction between the physiologic environment and the metals . Except for certain noble metals, pure metals and alloys used in dentistry derive biocompatibility from the formation of a protective layer on the surface called a passive film, which is an oxide of one or more of the components of the alloy . These films are products of an oxidative (corrosive) reaction that reduces the corrosion rate by several orders of magnitude and essentially prevents further corrosion once the passive layer is formed. Because this layer is protective, anything that disturbs the layer can lead to either a brief period of repassivation or, under the wrong conditions, failure to protect the underlying metal from corrosion. Contact between two different metals in the mouth or changes in the temperature or pH in the mouth can cause breakdown in protection and can, in the case of dissimilar metals, lead to galvanic corrosion. Even when the passive film is intact, the corrosion rate is not zero—just very small. Metal ions are being released at slow rates, but the body can have adverse reactions to those ions. There may be local toxic responses, systemic changes in metabolic processes, or an allergic response to certain metal ions . Although uncommon, the metal most frequently responsible for an allergic response is nickel, which is present in most stainless steels, most cobalt/chromium alloys, nickel-titanium alloys, and nickel-chromium alloys. If an adverse allergic response occurs, little can be done other than to exchange the metal component for one that does not contain nickel.
Another way that an adverse response can occur is if corrosion produces particles of corrosive product, which can induce the same type of tissue response that may result from the formation of wear particles (see later discussion).
One positive aspect of the use of metals in implant surgery is that titanium and its alloys (and potentially other metals) have caused bone to attach directly to the metal without any intervening soft tissue capsule . This occurrence is considered to be evidence of superior biocompatibility of titanium and is the basis for many of the applications of titanium in dentistry. It is likely that the favorable response may be to the TiO 2 passive film that is present on the surface and not to the titanium itself. Recently, there has been some caution expressed that, under certain conditions of chemical exposure and pH in the oral environment, titanium and its alloys may not exhibit the high corrosion resistance and stable passive film that has been reported previously .
Ceramic materials
The tissue response to ceramic materials used in surgery falls into two basic categories: (1) porcelains and other hard ceramics used in crowns, inlays, and onlays and (2) ceramics that are intended to react with surrounding tissues. It is also important to note that the passive films that form on metals to protect them from corrosion are ceramic in nature and are the actual interface being presented to tissue on metals. Ceramics of the first type would seem to be insoluble and, with (theoretically) little or no chemical being released from them and little opportunity for tissue to respond, there should be little concern with their biocompatibility. Not as much attention has been applied to their testing . Some researchers have found that this assumption may not be true . In cell culture experiments, some ceramics were found to cause little suppression of mitochondria activity, some were found to be initially toxic, but that toxicity declined after an artificial aging process, one was extremely cytotoxic and became toxic again after repolishing, and one did not regain its toxicity with repolishing. The conclusion was that the aging process was removing cytotoxic chemicals from the ceramics but that the leaching was only from the surface in some cases while being from the bulk of the material in others. In reviewing reports of biocompatibility testing, it is important to review the condition of the materials being tested. In the referenced study, the ceramics that were not cytotoxic (feldspathic veneer porcelains) were fired before testing, but the other three materials tested were processed by pressing into molds according to manufacturer’s instructions but had not been subjected to the final sintering treatment. It is possible that the sintering process would have bound up the toxic species into the bulk and prevented a tissue response.
The other class of tissue responses to ceramics concerns ceramics that are intended to interact with the surrounding tissues. In general, these materials do not have the necessary mechanical properties for use in crowns and other restorations but undergo at least a small amount of dissolution at the surface and are composed of compounds that contain calcium and phosphorus, two of the elements that comprise the mineral content of bone. Bioglass and calcium phosphate ceramics, such as hydroxyapatite and tricalcium phosphate, interact with surrounding bone to form a bond between the material and the tissue that can be stronger than either the bone or the material itself . In a process called osteointegration, the materials become integrated into the bone as it repairs itself and may reside permanently within the healed bone, although some are dissolved or resorbed and replaced by new bone . These materials are intentionally reactive with bone but are recognized and incorporated as if they were bone.
Wear
Whenever two surfaces experience relative movement, there is the opportunity for wear and the formation of wear particles surrounding the site where wear is occurring. The tissue response to small particles of a material can be different to that for the bulk material. Particles small enough to be phagocytized by cells can induce a cascade of tissue responses and the release of cellular mediators, which may then act as positive reinforcers to the process and result in significant tissue responses . Although not exactly the result of wear, particles of material may be released into tissues because of corrosion, polishing and finishing operations, or inadvertent loss of a small piece of the material during other dental procedures, such as placement or removal of a dental dam or removal of impression material from the mouth. As a particle is phagocytized, it enters the same defensive process that the body would use to defend itself from a cellular attacker, such as a bacterium. Although the engulfment of a bacterium can result in the death of the attacker and the defender cell, in the case of biomaterials the defender cell may die and release the offending particle back into the surrounding tissue intact. These cells may release chemical signaling compounds to cause recruiting of additional defender cells. If the particles are not dissolved in the process or otherwise removed from the tissues, the same particles can be repeatedly phagocytized and released, increasing the levels of chemical mediators in the tissues. These chemicals themselves can have an adverse effect on the tissues by activating or deactivating cells, such as fibroblasts, osteoblasts, and osteoclasts .
Most of the research that examines the physiologic consequences of wear has centered on orthopedic devices because the wear occurs within an enclosed space and clinical failures have been seen in that environment. In dental and maxillofacial applications, the wear of restorative materials has less potential for the particles to enter the tissues, because wear particles and particles produced during placement and finishing are more likely to be ingested or removed by rinsing and suction. The potential exists for particles to enter periodontal pockets, and the wear of temporomandibular joint prostheses has been shown to produce problems similar to those from the wear of total joint prostheses in orthopedic surgery .
The amount of wear that may occur between two surfaces subjected to loads while undergoing relative motion can be related to several different factors, but the amount of frictional forces applied at the interface is directly proportional to the load being applied perpendicular to the wearing surfaces. The forces present at occlusal surfaces during chewing and the forces present at the temporomandibular joint can be high. The force on molars can be as high as 800 to 900 N , so wear forces being generated can be significant. Because of the lever action of the temporomandibular joint, the forces dissipated through the joint can be different than forces experienced at the occlusal surfaces.
Restorative materials
Restorative materials include those used for replacing carious tissue within the tooth structure, such as inlays and onlays, crowns, bridges, partial dentures, and full dentures. Many of the materials used to fill cavities are normally not placed into direct contact with tissues other than dentin and enamel. They are subject to corrosion, wear, and leaching of constituent chemicals . If a curing reaction is involved in placement, an exotherm may occur, monomers or other chemicals may be released, or the raw materials may leach through the dentin tubules and into the pulp chamber and come into contact with blood and nerve tissue. Additionally, materials used in endodontic therapy must come into contact with the pulp space and its contents, and it may leak into periapical tissues, creating additional concerns beyond those for materials intended to restore the crown morphology . When used in contact with gingiva or the tissue lining the mouth, additional testing for tissue response may be necessary, and the possibilities for problems caused by direct contact increase.
Amalgam
The biocompatibility of amalgam, a product of the reaction of liquid mercury with silver and other metals, has been the subject of controversy for many years. There has been a concern that the mercury used in the reaction may leach out of the restoration as a result of unreacted material, dissolution in saliva, or corrosion reactions. It is known that mercury exists inorganically as the metal or in one of two charge states and in an organic form (methyl mercury). When present as methyl mercury, it is known to be highly toxic. Methyl mercury has been responsible for toxic reactions in the hat industry, in environmental disasters, and through consumption of seafood. Mercury in vapor form is easily taken up by the body. The mercury present in an amalgam reaction exists in the metallic form and is not easily absorbed from the digestive system if swallowed. It is completely bound up with the other metals present in the amalgam because the reaction is a chemical one that combines it with the metals to form an alloy.
Studies reviewed by the US Public Health Service and the Food and Drug Administration suggest that based on available evidence, there is no proof of any mercury toxicity from dental amalgam to the patient, other than in cases of allergy . A study published in the New England Journal of Medicine concluded that there is no clear evidence for the removal of amalgams and that the evidence is open to wide interpretation. The authors of two reviews published in Europe concluded, “According to the conclusions of independent evaluations from different state health agencies, the release of mercury from dental amalgam does not present any non-acceptable risk to the general population” and “…there is little evidence of a correlation between amalgam restorations and adverse neurological or neuropsychological effects…That said, additional studies are needed to strengthen the case” . Two studies reported on amalgam use in children and examined a total of 520 children who received amalgam randomly matched against 521 who received composite restorations. One study concluded that “…there is no reason to discontinue the use of mercury amalgam as the standard of care for caries in posterior teeth” . The other concluded that “…amalgam should remain a viable clinical option in dental restorative treatment” .
Polymeric materials and composites
Many restorative materials other than amalgam are compounds that are polymerized or otherwise reacted in the prepared tooth cavity at the time of placement . These materials consist of monomers, fillers, initiators, accelerators, and additives that are combined through some type of a curing reaction . If the proportions of the different components are not correct or if the curing reactions are not carried to completion, some or all of the components may be available to become dissolved in saliva, pass through tubules into the pulp chamber, or otherwise be released. Some monomer also may be released before curing occurs or during curing. Initiators and accelerators, depending on the type of curing reaction, may cause polymerization to occur or be accelerated without actually becoming a part of the polymer chain, which leads to the possibility that they may be free to diffuse out of the material and come into contact with tissues. In the same way, additives such as plasticizers act to change the mechanical properties of the final product but are not necessarily bound up in the constituent polymers.
Metallic materials
When metals and alloys are used in dentistry, there is the opportunity for adverse reactions caused by the release of metal ions or other products of the interaction between the physiologic environment and the metals . Except for certain noble metals, pure metals and alloys used in dentistry derive biocompatibility from the formation of a protective layer on the surface called a passive film, which is an oxide of one or more of the components of the alloy . These films are products of an oxidative (corrosive) reaction that reduces the corrosion rate by several orders of magnitude and essentially prevents further corrosion once the passive layer is formed. Because this layer is protective, anything that disturbs the layer can lead to either a brief period of repassivation or, under the wrong conditions, failure to protect the underlying metal from corrosion. Contact between two different metals in the mouth or changes in the temperature or pH in the mouth can cause breakdown in protection and can, in the case of dissimilar metals, lead to galvanic corrosion. Even when the passive film is intact, the corrosion rate is not zero—just very small. Metal ions are being released at slow rates, but the body can have adverse reactions to those ions. There may be local toxic responses, systemic changes in metabolic processes, or an allergic response to certain metal ions . Although uncommon, the metal most frequently responsible for an allergic response is nickel, which is present in most stainless steels, most cobalt/chromium alloys, nickel-titanium alloys, and nickel-chromium alloys. If an adverse allergic response occurs, little can be done other than to exchange the metal component for one that does not contain nickel.
Another way that an adverse response can occur is if corrosion produces particles of corrosive product, which can induce the same type of tissue response that may result from the formation of wear particles (see later discussion).
One positive aspect of the use of metals in implant surgery is that titanium and its alloys (and potentially other metals) have caused bone to attach directly to the metal without any intervening soft tissue capsule . This occurrence is considered to be evidence of superior biocompatibility of titanium and is the basis for many of the applications of titanium in dentistry. It is likely that the favorable response may be to the TiO 2 passive film that is present on the surface and not to the titanium itself. Recently, there has been some caution expressed that, under certain conditions of chemical exposure and pH in the oral environment, titanium and its alloys may not exhibit the high corrosion resistance and stable passive film that has been reported previously .
Ceramic materials
The tissue response to ceramic materials used in surgery falls into two basic categories: (1) porcelains and other hard ceramics used in crowns, inlays, and onlays and (2) ceramics that are intended to react with surrounding tissues. It is also important to note that the passive films that form on metals to protect them from corrosion are ceramic in nature and are the actual interface being presented to tissue on metals. Ceramics of the first type would seem to be insoluble and, with (theoretically) little or no chemical being released from them and little opportunity for tissue to respond, there should be little concern with their biocompatibility. Not as much attention has been applied to their testing . Some researchers have found that this assumption may not be true . In cell culture experiments, some ceramics were found to cause little suppression of mitochondria activity, some were found to be initially toxic, but that toxicity declined after an artificial aging process, one was extremely cytotoxic and became toxic again after repolishing, and one did not regain its toxicity with repolishing. The conclusion was that the aging process was removing cytotoxic chemicals from the ceramics but that the leaching was only from the surface in some cases while being from the bulk of the material in others. In reviewing reports of biocompatibility testing, it is important to review the condition of the materials being tested. In the referenced study, the ceramics that were not cytotoxic (feldspathic veneer porcelains) were fired before testing, but the other three materials tested were processed by pressing into molds according to manufacturer’s instructions but had not been subjected to the final sintering treatment. It is possible that the sintering process would have bound up the toxic species into the bulk and prevented a tissue response.
The other class of tissue responses to ceramics concerns ceramics that are intended to interact with the surrounding tissues. In general, these materials do not have the necessary mechanical properties for use in crowns and other restorations but undergo at least a small amount of dissolution at the surface and are composed of compounds that contain calcium and phosphorus, two of the elements that comprise the mineral content of bone. Bioglass and calcium phosphate ceramics, such as hydroxyapatite and tricalcium phosphate, interact with surrounding bone to form a bond between the material and the tissue that can be stronger than either the bone or the material itself . In a process called osteointegration, the materials become integrated into the bone as it repairs itself and may reside permanently within the healed bone, although some are dissolved or resorbed and replaced by new bone . These materials are intentionally reactive with bone but are recognized and incorporated as if they were bone.
Wear
Whenever two surfaces experience relative movement, there is the opportunity for wear and the formation of wear particles surrounding the site where wear is occurring. The tissue response to small particles of a material can be different to that for the bulk material. Particles small enough to be phagocytized by cells can induce a cascade of tissue responses and the release of cellular mediators, which may then act as positive reinforcers to the process and result in significant tissue responses . Although not exactly the result of wear, particles of material may be released into tissues because of corrosion, polishing and finishing operations, or inadvertent loss of a small piece of the material during other dental procedures, such as placement or removal of a dental dam or removal of impression material from the mouth. As a particle is phagocytized, it enters the same defensive process that the body would use to defend itself from a cellular attacker, such as a bacterium. Although the engulfment of a bacterium can result in the death of the attacker and the defender cell, in the case of biomaterials the defender cell may die and release the offending particle back into the surrounding tissue intact. These cells may release chemical signaling compounds to cause recruiting of additional defender cells. If the particles are not dissolved in the process or otherwise removed from the tissues, the same particles can be repeatedly phagocytized and released, increasing the levels of chemical mediators in the tissues. These chemicals themselves can have an adverse effect on the tissues by activating or deactivating cells, such as fibroblasts, osteoblasts, and osteoclasts .
Most of the research that examines the physiologic consequences of wear has centered on orthopedic devices because the wear occurs within an enclosed space and clinical failures have been seen in that environment. In dental and maxillofacial applications, the wear of restorative materials has less potential for the particles to enter the tissues, because wear particles and particles produced during placement and finishing are more likely to be ingested or removed by rinsing and suction. The potential exists for particles to enter periodontal pockets, and the wear of temporomandibular joint prostheses has been shown to produce problems similar to those from the wear of total joint prostheses in orthopedic surgery .
The amount of wear that may occur between two surfaces subjected to loads while undergoing relative motion can be related to several different factors, but the amount of frictional forces applied at the interface is directly proportional to the load being applied perpendicular to the wearing surfaces. The forces present at occlusal surfaces during chewing and the forces present at the temporomandibular joint can be high. The force on molars can be as high as 800 to 900 N , so wear forces being generated can be significant. Because of the lever action of the temporomandibular joint, the forces dissipated through the joint can be different than forces experienced at the occlusal surfaces.
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