Material Tissue Interaction—From Toxicity to Tissue Regeneration

Material tissue interaction has gained increasing interest over recent decades. In addition to new scientific findings and their clinical implications, this topic has attracted strong public interest (eg, the discussion of mercury in amalgam and, more recently, the controversy over bisphenol A in resin-based composites).¹  Consequently, legal regulations concerning the safety of materials used in general medicine, including those used in dentistry, have been put into force.²  Interestingly, dental research has been on the forefront of the medical field with respect to the development of tests, standards, and legal regulations related to material tissue interactions.

The basic idea behind such interactions is the fact that substances are eluted (ie, released) from the material when it comes in contact with various tissues, which then in turn influence the adjacent tissues (Figure 1). The process of release of substances from a material into the surrounding tissues is influenced by the material's bulk and surface properties, time after mixing (setting reaction), and the type of tissue. With setting materials (for example, resin-based composites) most substances (such as residual monomers) are released shortly after mixing.³  Over time, different concepts regarding the material tissue interaction of dental materials have emerged. In this review, these concepts will be discussed, together with their practical legal and clinical consequences.

The inert material concept was the initial concept for material tissue interaction. The focus of this concept has been the attempt to avoid any tissue damage after the application of a dental material.²  Since this goal is virtually impossible to achieve, the practical aim is to use biotolerable materials. Thus, biocompatibility can be regarded as the ability of a biomaterial to perform its desired function with respect to a medical therapy without eliciting any clinically significant adverse effects in the recipient.⁴ 

Local reactions occur at the site of material application. Examples are pulp inflammation after pulp capping with dental adhesives (potentially followed by pulp necrosis)⁵  and gingival inflammation after exposure to metal oxides from metal-ceramic crowns.⁶  The mechanism may be the toxicity of substances such as metal ions released in toxic amounts (direct effect), but increased growth of bacteria (eg, on or under resin-based composites; indirect effect) may also play a role.⁷  Recently, lip burning after the incorrect use of a high-power light curing unit through rubber dam has been reported.⁸ 

Systemic tissue reactions occur distant from the actual area of application. Resorption processes (passing the epithelial barrier), transportation in blood and deposition in organs, as well as metabolic transformation and excretion are the determining factors. In dentistry, systemic reactions occurred in the past if dentists polished or removed amalgam fillings with high-speed rotary instruments but without water-cooling. As a result, symptoms of neurotoxicity, such as tremors, have been observed.⁹ 

Allergic reactions to dental materials can be regarded as the combination of local exposure and the activation of the body's immune system involving the activation of local dendritic cells and T cells in local lymph nodes.⁹  Mostly type IV (delayed) and a few type I (immediate) reactions have been reported.⁹  Clinical signs can be local, such as perioral eczema after the application of nickel-containing steel appliances, or can appear also in distant areas of the body (eg, after exposure of allergic patients to relevant metals). Examples will be described below.

Methods for testing adverse material effects include cell cultures, animal experiments, and clinical studies. One of the first studies on material tissue interaction was performed in dogs and tested the pulp reaction to silicate cement as compared to that associated with zinc phosphate cement. Even then the protective influence of residual dentin was already being described (see below).¹⁰ 

Modern test methods rely on cell cultures (screening tests) to determine unspecific (not related to the dental target tissues) damaging effects to cells (cytotoxicity, mutagenicity). Small animal tests, formerly called secondary tests, are performed, for example, to test for skin/mucosa irritation and systemic toxic effects but also for the potential of type IV sensitization to materials. Finally, usage tests are carried out where materials are applied in experimental animals as they would be in patients (eg, the pulp/dentin test to evaluate the pulp response to endodontic or restorative materials).⁹ 

Recently, special cell culture methods have been developed and aimed at replacing animal models; with these new models, a material is placed on one side of a dentin disk and a three-dimensional cell culture simulating the pulp tissue is placed on the other side of the disk (dentin barrier test).^11,12  A number of these test methods have been combined to establish standards (eg, ISO standards). The goal was to improve the comparability of data generated in different test laboratories as well as to save costs and test animals by avoiding duplicate testing.^2,13 

Legal regulations regarding the safety of dental materials were promulgated in the United States in 1976, followed by the European Union in 1993, and then by virtually all countries around the world. Accordingly, dental materials are classified as medical devices and must pass a certification process before they may be marketed. Although worldwide regulations differ in their details, the main aim of this certification process is the same, namely to demonstrate safety of the medical device. In this context, safety is defined as the absence of unacceptable risks. The manufacturers are legally responsible for the safety of their materials (see also the above definition of biocompatibility). In the United States, the Food and Drug Administration (FDA) is in charge of this process and provides detailed information regarding regulations on their Web site (http://www.fda.gov). The evidence of safety (biocompatibility) can be shown using the above-mentioned standards.

Despite the application of best practice test methods in this process of premarket safety evaluation, adverse reactions in the clinic cannot be ruled out completely, since a large number of patients under a variety of clinical conditions are exposed to the materials. Therefore, a postmarket surveillance/reporting system has been installed in each country, and each dentist is obliged to report adverse effects from dental materials to the respective authorities.

The aim of such legal regulations with respect to premarket certification is to protect the consumer, in this case the patient, from adverse effects. Finally, the manufacturers are responsible for the security of their materials. However, this legislation also protects the dentists: if they follow the indications as specified in the instructions for use provided by the manufacturer, then all patient claims can be directed to the manufacturer. However, significant responsibilities remain with the dentist.

As mentioned above, the dentist is responsible (and legally liable) to follow the instructions for use and the indication, as specified by the manufacturer, for the individual patient. Adverse effects in patients from dental materials occur, in general, only seldom (<0.3%).¹⁴  Allergies in patients are even more rare, but they exist.⁹  In a group of contact dermatitis patients, 1.3% were allergic to bisphenol A diglycidyl ether dimethacryalate (Bis-GMA).¹⁵  In a group of 86 patients in whom symptoms such as a burning mouth were attributed to dental alloys, 20% had a positive patch test reaction to a tested metal; however, this test was clinically relevant in only 5% of these patients, because the respective metal was part of an intraoral alloy. In a further 5% of the patients, the relevance was questionable.⁶  Examples of allergic reactions are shown in Figures 2 through 4. However, allergies of dental personnel are more frequent. Based on a questionnaire study,¹⁶  it was estimated that up to 2% of dentists showed allergic reactions to the monomers used in resin-based composites and related adhesives (Figure 5). Furthermore, it has been suggested¹⁷  that exposure to methacrylates may induce cross reactivity to acrylates. The protection afforded against contact with relevant monomers by the use of gloves is only limited. Penetration of the monomers in commonly used solvents through latex or nitrile gloves takes place within a few minutes.^18,19  This means that any direct contact of the protected or nonprotected skin with resin materials (adhesives and resin-based materials) should be avoided (the so-called “no-touch” technique).²⁰ 

Allergies to metals such as nickel are well known. However, there is also evidence that cross reactivity exists between nickel and palladium.^6,21,22  Hence, palladium-containing alloys should not be used in patients with a nickel allergy. Less known is the fact that there are allergic reactions to fragrances, such as essential oils, which include eugenol.²³ 

Important for the dentist is to prevent any allergic reaction from occurring by conducting a correct anamnesis, at recall visits as well. In the event of clinical symptoms indicating the possibility of an allergy to dental materials, the dentist should refer the patient to a specialist for patch testing, which is the gold standard for confirming a type IV (delayed) allergy. The dentist should inform the specialist about the material that is suspected to have caused the allergic reaction and its composition. Patients may ask to have a patch test done before a dental treatment, even though they do not have symptoms indicating an allergy. This is usually not recommended, however, since there is a slight chance of sensitization by the patch test, and such a risk seems acceptable only if there are distinct clinical symptoms of an allergy. Furthermore, an allergy may develop at any time, even immediately after the test, and since no prediction is possible, patch tests do not necessarily provide any additional safety in this case.^24,25 

Localized lichenoid reactions (OLRs) have been described in the direct vicinity of amalgam, gold alloys, or composite resins (Figure 6A).^26-28  In cases with lesions restricted to the contact area with the material, 67.8% of patients showed a positive patch test reaction indicative of an allergic background. For lesions extending out of the contact area, this was the case in only 38.6% of patients.²⁹  Such lesions are normally attributed to an oral lichen planus (OLP), which is a dermatological disease (Figure 6B). Whitish lesions with striations (Wickham's striae) not related to a material are indicative of an OLP.³⁰ 

Histology of OLR shows a clear line of inflammatory cells beneath the epithelium, which cannot be distinguished from OLP histologically. The etiology of the lichen is mainly unknown. The standard therapy for persisting localized contact lesions is to replace the contacting material. A patch test for allergy confirmation may be indicated. In case of persistence of the mucosal lesion, the patient should be referred to a specialist. Topical corticosteroids are the treatment of choice for OLP, although several other medications have been studied, including retinoids, tacrolimus, and cyclosporine, as well as photodynamic therapy.³⁰  OLP and OLR may be premalignant diseases, although malignant transformation has been reported to be below 1%.^30,31  In a further study,³²  four out of 192 cases of OLP developed into a squamous cell carcinoma. In any case, constant surveillance is required if the lesion does not subside.³² 

The “off-label use” term characterizes the application of a material or medication that is not approved for the specific indications listed by the manufacturer. Dentists are allowed to conduct off-label use, but in this case, the dentist alone, not the manufacturer, is responsible and legally liable for any adverse effect. This is the case, for instance, if a dentist uses adhesives for pulp capping and the manufacturer has not specified this particular indication for the product.

Bisphenol A (BPA) has recently attracted considerable attention (“mercury of the 21st century”). Some authors^33,34  claim that BPA exposure leads to reduced fertility (male and female), irreversible changes of the developing organism (pubertal timing), neurotoxic effects, and other diseases, such as diabetes. In this context, dental resin materials such as fissure sealants are mentioned, and indeed, BPA is part of the molecular structure of commonly used dental monomers like Bis-GMA. However, BPA is not intentionally added to dental resin-based composites, and under physiological conditions conversion of the dental monomers into BPA has not been observed, with the exception of Bis-DMA, which was used in a few fissure sealants (eg, Delton®, DENSPLY Professional, York, PA, USA).^35-37  Unfortunately, the dentist is not able to determine whether a resinous material contains Bis-DMA based on the Material Safety Data Sheet, since manufacturers do not always provide such a detailed declaration of material components (see also the material related to referral for allergy testing, above).

However, BPA is used during the production process of Bis-GMA and related substances. Despite available purification processes, BPA residues (impurities) exist. Therefore, BPA is found in saliva and urine after placement of resinous materials (sealants and composite restorations).^38,39  This has only been observed shortly after placement, and values returned to normal after eight hours (saliva) or 30 hours (urine). Again, Bis-DMA products released 20 times more BPA than did Bis-GMA products.³⁸  Recent measurements of BPA release demonstrated that such levels of BPA are more than 2500 times less than the conservative BPA exposure limit, as proposed by the European Food Safety Authority, at 5000 ng per kilogram per day.⁴⁰  Therefore, according to present knowledge, the risk posed by the BPA content of dental resinous materials was rated to be negligible.¹⁴ 

Whereas the inert material concept is mainly focused on the detection and description of the phenomenon of the adverse effect, the aim of the analytical concept is to elucidate the mechanism and the modifying factors underlying the phenomenon. The ultimate aims of the analytical concept are to improve or develop materials and to find ways to avoid adverse reactions elicited by existing products.⁴¹  Test methods are generally more sophisticated than those used for the inert material concept; they include methods from microbiology as well as from biochemical and molecular cell biology, but also analytical chemical methods, in order to elucidate cellular pathways that are potentially altered by dental materials. Methods have to be chosen or tailored individually, whereas standardized test methods play only a minor role.

Dental adhesives are cytotoxic in direct contact with cells.⁴²  However, pulp reactions after the application of dental adhesives and composites in medium deep and shallow cavities do not occur if an intact dentin layer of >0.5 mm is present.⁹  This shows that dentin may be protective against material toxicity. The reason is that the permeability of dentin is exponentially related to dentin thickness (Figure 7), in which the diameter of dentinal tubules increases with decreasing distance to the pulp.⁴³  Furthermore, after cavity preparation, dentin is covered with a smear layer, which further reduces its permeability.⁴⁴  In addition, the so-called dentin sclerosis or intratubular deposition of apatite reduces the penetration of potentially toxic substances. Some of these substances, such as eugenol or zinc from amalgam, become bound to organic and inorganic dentin components.^45,46 

However, pulp reactions to resin-based composites occur even with an intact dentin layer if bacteria are on the cavity floor; these bacteria may have invaded through (micro-) gaps between the material and cavity wall.⁷  This means that dentin is not protective against bacteria and that bacterial penetration must be prevented by the correct application of an effective dental adhesive. Therefore, dental adhesives in medium deep and shallow cavities offer a means with which to prevent damage to the dental pulp and may be regarded as protective of pulpal health.

However, in deep cavities (<0.5 mm from the pulp) the situation is different. Pulp exposure is possible and difficult to diagnose when the patient is treated under local anesthesia with vasoconstrictors. In this case, direct contact of the unset material with the wet and living pulp tissue occurs. Contact with wet tissue may interfere with the material's setting process, which increases the release of substances from the material. Since there is apparently no, or only little, protection by the dentin, these cytotoxic substances from the material (eg, eluted monomers) may evoke cell necrosis, with the consequence of pulp inflammation, as seen histologically, which can occur even without any pain.⁵ 

Lower monomer concentrations do not cause cell necrosis, but rather apoptosis. Clinical studies^5,47,48  in humans provide evidence that pulp capping with dental adhesives leads to an inhibition of tertiary dentin formation (biomineralization). Such concentrations of relevant monomers, such as 2-hydroxyethyl methacrylate (HEMA) or triethylene glycol diemthacrylate (TEGDMA) cause DNA damage by the following mechanisms: cellular glutathione is consumed in the process of monomer detoxification.^49,50  As glutathione is also needed for maintaining the intracellular balance of reactive oxygen species (ROS), depletion of glutathione leads to an increase in ROS, which then results in oxidative DNA damage.⁵¹  Subsequently, a series of adaptive cellular mechanisms is activated in order to maintain cellular homeostasis of the pulp tissue (eg, leading to DNA repair or to the disposal of damaged cells through apoptosis).⁵²  As a result of these highly energy-consuming reactions, the differentiation of dental stem cells into secondary odontoblasts, and thus tertiary dentin formation, is impaired. Interestingly, the use of certain antioxidants, such as N-acetyl cysteine, counteracts these effects and may be used as a component in future dental materials.^52,53 

Further studies^54,55  have shown that low concentrations of resin monomers such as TEGDMA or HEMA may lead to a reduced defense potential against bacteria. Cells of the innate immune system (here macrophages), which are in charge of clearing bacterial invasion through activating an inflammation process, are blocked by dental monomers at low (noncytotoxic) concentrations. This may impair the immunological defense of the pulp against bacteria.

In shallow and medium cavities, dental adhesives exert a protective effect on dental pulp; additional means of protection are not necessary. In deep cavities with the potential of pulp exposure, dental adhesives should not be placed directly on the dental pulp since they impair biomineralization and defense mechanisms against bacteria. Other bioactive materials (see below) should be used instead. Another promising approach, as a consequence of the above-mentioned reactions, is the incorporation of antioxidants (eg, N-acetyl cysteine) into monomers in order to reduce adverse cellular reactions, which is presently being investigated.

The aim of the bioactive materials concept is to use a material as a therapeutic means to initiate specific biological processes, such as biomineralization or the introduction of antibacterial activity. However, the material itself stays, more or less, physically intact.

The concept of inducing biomineralization is not new, since pulp capping with Ca(OH)₂ was introduced by Herrmann as early as 1928, although on a relatively empirical basis.^56,57  Recently, the mechanisms of tertiary dentin formation have been elucidated further. Apparently, signaling molecules that induce tertiary dentin formation, such as transforming growth factor–β1, are present in dentin and can be released through the application of Ca(OH)₂ or exposed on the dentin surface by ethylenediamine tetraacetic acid (EDTA).^58-60  Signaling molecules activate responsive cells (pulpal stem cells), which are present in specific niches in the pulp tissue. These cells migrate to the site of pulp exposure, where they differentiate into secondary odontoblasts and form tertiary dentin.^61-63 

In recent years, tricalcium silicate materials such as mineral trioxide aggregate (MTA) have been marketed. They release Ca(OH)₂ and induce tertiary dentin formation in animal studies, revealing slightly better results than Ca(OH)₂.^64,65  A large randomized clinical trial⁶⁶  has provided confirming evidence that MTA performs superior to Ca(OH)₂ after direct pulp capping. This was evaluated in a practice-based research network for up to two years.⁶⁶  The major problems with such materials are high costs, long setting times of up to several hours, and possible tooth discoloration, even after use of white MTA.⁶⁷  Therefore, MTA is mainly indicated for posterior teeth and can be used in combination with self-etch adhesives.

A different formulation of tricalcium silicate cement (Biodentine, Septodont, Saint-Maur-des-Fossés, France) was developed recently with a setting time of only several minutes.⁶⁸  The material releases Ca(OH)₂ and is less cytotoxic than MTA or glass ionomer cements.^69,70  It induces an upregulation of signaling molecules involved in biomineralization, such as osteocalcin (OCN), collagen type 1 (COL1A1), dentin sialophosphoprotein (DSPP), bone sialoprotein (BSP), and dentin matrix protein (DMP-1), in cell cultures and tertiary dentin formation in animal studies.^69,71-74  Furthermore, a diffusion zone between Biodentine and the adjacent dentin has been described.⁷⁵  Clinical studies on tertiary dentin formation are rare. A clinical trial comparing Biodentine with a glass ionomer cement (GC Fuji IX GP, GC Europe N. V., Leuven, Belgium) 12 months after application for indirect pulp capping showed no statistically significant difference regarding the clinical efficacy of both materials in patients with reversible pulpitis. However, cone beam computed tomography (CBCT) showed a significant difference where most healed CBCT lesions had received Biodentine, while most that did not heal had received the glass ionomer cement.⁷⁶  Direct pulp capping in premolars and molars scheduled for extraction showed similar results for MTA and Biodentine six weeks after application.^77,78 

Recently, a new material was marketed that contains both MTA and resin monomers (up to 50%) and is light cured (TheraCal LC, Bisco Inc, Schaumburg, IL, USA). This material releases more calcium in vitro than does a classical MTA material or a Ca(OH)₂ preparation and induces an alkaline pH similarly to MTA or Ca(OH)₂.^79,80  It apparently does not release Ca(OH)₂, and calcium release was less than for Biodentine.^68,81  The light-cured MTA was reported to be cytotoxic, but more detailed data on this finding were lacking.⁸²  In animal experiments on primates, this material stimulated bridging after pulp capping and elicited only a mild inflammatory response.⁸³  However, primate studies also showed bridging for resin adhesives,⁸⁴  which could not consistently be observed in humans.^5,47,48  Therefore, more investigation is needed in this area.

The use of antibacterial substances in dental materials has a long tradition. Mainly, substances such as metals (copper, zinc, or silver), fluorides, cetylpyridiniumchloride, different chlorhexidine compounds, glutaraldehyde, triclosan, zinc oxide, eugenol, and even antibiotics have been included in dental materials. Their antibacterial effect mainly depends on the continued release of antibacterial substances from the material.⁴¹  The antibacterial monomer MDPB (12-methacryloyloxydodecylpyridinium bromide) was developed by Imazato and others.^85,86  This antibacterial moiety is tightly bound to the polymer network after polymerization. Surface inhibition of bacterial growth was shown in vitro, but the effect was masked after coverage with saliva proteins.⁸⁷  On dentin, the noncured primer in fact reduced the bacterial load.⁸⁸ 

The main problem with this approach is that antibacterial substances are often also toxic to mammalian cells. However, there are strategies to prevent this: the above-mentioned antibacterial monomer is only active before polymerization; after curing the effect is reduced, which prevents damage to dental pulp.⁸⁹  Other strategies follow a similar idea of time regulation: photodynamic inhibition of bacteria (PIB) is based on light of a defined wavelength, which activates special antibacterial substances (photosensitizers). This is not a new approach, but as a result of the limited effectiveness of the photosensitizers used to date, it has not gained large market acceptance.⁹⁰  However, new photosensitizers with a higher efficiency have been developed; these photosensitizers may stand a better chance in the market in the future.^91,92 

These examples clearly show that dentists are able to actively influence cellular reactions by their choice of material application and that material tissue interactions have not only negative aspects (possible tissue damage) but also positive effects, such as the stimulation of repair or antibacterial action as well.

The aim of the tissue regeneration concept is to stimulate or induce the regeneration of tissues (eg, parts of the tooth like the dental pulp) by using a material that, in contrast to the bioactive material concept, is eventually replaced by the newly formed tissue. Tissue regeneration can be achieved using methods of tissue engineering, as described by Langer and Vacanti,⁹⁴  with the following components: 1) a matrix/scaffold, 2) signaling molecules, and 3) responsive cells (stem cells or progenitor cells^*).

Signaling molecules, as mentioned above, are present in dentin and can be released (eg, by treatment with EDTA).⁶⁰  Furthermore, dentin surfaces can be activated and signaling molecules are exposed on the dentin surface, potentially inducing the differentiation of pulp stem (progenitor) cells contacting dentin to become secondary odontoblasts (contact differentiation).⁹⁵  Stem cells are present not only in the pulp tissue but also in periapical niches and in inflamed apical tissues as well as in the evoked intracanal blood influx from periapical tissues.^96-98  According to the tissue engineering concept, a matrix/scaffold is needed, into which signaling molecules and stem cells are incorporated. To date, two concepts have been discussed in the literature: one is the isolation of stem cells with in vitro expansion for reimplantation; the other is a primarily cell-free concept, which relies on the immigration of resident stem cells into a matrix/scaffold as a result of the presence of signaling molecules (cell homing).^96,99  Both concepts rely on a suitable matrix/scaffold that can be regarded as a dental material, which must have properties different from commonly used dental materials.

In contrast to commonly used dental materials, these matrix materials should undergo controlled degradation in order to be replaced by new tissue.¹⁰⁰  The incorporated signaling molecules should be released in a prolonged way, and heparin was shown to be able to control this process.¹⁰¹  Furthermore, not only the material itself, but also the degraded components, should not be toxic to the target cells. Specifically for pulp regeneration, the matrix material should be injectable.¹⁰⁰  A number of candidate materials are available (Table 1), most of which are hydrogels offering a tissue-like water content.¹⁰⁰ 

The possibility of pulp regeneration has been shown in several studies. One of the first was presented by the group of J. Nör,¹⁰²  who placed dentin slices filled with a solid poly-l-lactic acid matrix containing human pulp-derived stem cells and vascular endothelial growth factor subcutaneously into immunodeficient mice. After six weeks, a pulp-like tissue with odontoblast-like cells at the dentin surface had developed.¹⁰²  In addition, de novo formation of new tubular dentin was shown in this model.¹⁰³  Similar results were observed in a tooth root model after injection of a hydrogel material (self-assembling peptide) together with human pulp-derived stem cells and signaling molecules. A pulp-like tissue was generated six weeks after implantation in immunodeficient mice if the dentin had been conditioned with EDTA prior to cell seeding (Figure 8). The sole usage of sodium hypochlorite led to dentin resorption.⁹⁵  Other experiments using full-length roots of human premolars filled with Puramatrix (BD Biosciences, Bedford, MA, USA) or recombinant collagen and stem cells from primary teeth showed similar results.¹⁰⁴  Studies in dogs⁹⁹  also showed new pulp tissue formation in teeth: after extraction, apectomy, and removal of pulp tissue, the root canals of the respective teeth were filled with collagen as a matrix, cells, and signaling molecules. Fourteen days after replantation, newly formed pulp-like tissue was detectable, and odontoblast-like cells had formed on the dentin surface.

Clinical studies are under way, but results are not yet available.¹⁰⁵  Case reports^106,107  on necrotic teeth with open apices have been published and showed healing of periapical lesions with continued root formation after a so-called revascularization protocol. However, clinical success was only determined by radiographs and vitality testing. One case allowed for later histologic evaluation: a pulp revascularization protocol had been applied to an immature permanent incisor with irreversible pulpitis and without apical lesion. The tooth fractured 3.5 weeks later and had to be extracted. Histology showed a loose connective tissue similar to pulp and a layer of flattened odontoblast-like cells lined along the predentin.¹⁰⁸  One can speculate whether this new tissue was due to regeneration or was a remnant of the original pulp. In another case report¹⁰⁹  it was shown that soft connective tissue, similar to that in the periodontal ligament and cementum- or bone-like hard tissue, formed in the canal of a human revascularized/revitalized tooth.

Although some of these data are promising, a number of serious problems still exist.¹¹⁰  Infection and its control are apparently a major concern.^107,111  Furthermore, it is still unclear whether true regeneration takes place with the formation of pulp or pulp-like tissue and dentin or whether it is instead the repair and formation of connective tissue, bone, and cementum.^109,112  Additionally, it is not yet clear which of the two concepts, cell transplantation or cell homing, will ultimately be the most clinically successful. Clearly a better understanding of the characteristics of pulp-derived stem cells is necessary.¹¹³  Nonetheless, advances in this area have been rapid, and the main focus lies firmly on the development of a suitable material.

Concerning the current concepts delineated in this review, the inert material concept will be further developed in the future but will remain mainly a routine testing method. The analytical concept will continue to attract major scientific attention since the understanding of material tissue interaction will be the basis for further material improvement, as emphasized by the recent report of the European Commission on the future of restorative materials.^14,41  The bioactive concept as well as tissue engineering will play major roles in the future as regenerative medicine advances.

A main challenge will be combining these concepts (eg, the inert material concept with concepts of bioactivity or tissue engineering). Possible solutions include the following:

• 1

  Adjustment of the concentration of active substances in a material or eluted from a material to elicit the desired effect, but with concomitant avoidance of cell toxicity (window of effectivity). However, bacteria are normally more resistant than cells, and this approach may thus be problematic.

• 2

  Development of materials that release antibacterial substances into their vicinity; however, as a result of low diffusibility of such substances in the tissues, they should not reach further distant cells in toxic amounts. An example is eugenol, which, when mixed with zinc oxide, is released in high doses on the cavity floor and thus elicits an antibacterial effect. However, as a result of the restricted diffusion of this hydrophobic substance through the hydrophilic residual dentin, it does not damage dental pulp cells if the residual dentin layer is thicker than 0.5 mm.

• 3

  Controlling the time of action by adjusting a material so that the active substance is only released in the unset state or briefly after setting. This effect can, for example, be observed with an antibacterial monomer (see above). A different way to control the time of action is to apply antibacterial (and potentially cytotoxic) root canal dressings for only a limited time period of just a few days. An additional method for controlling the time of action is PIB, which was also mentioned above.

In any case, material tissue interaction is not only an important area of research and development but it also has direct influence on our daily practice. The modern patient who seeks information from many easily available sources will ask his dentist for advice. Therefore, the successful dentist of the future will not only be the expert who knows all relevant diseases and how to prevent or treat them but will also be someone who possesses the argumentative competence to effectively communicate with a well-informed patient and to participate in public discussions.

The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article.