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Defined as materials that interface with biological systems, biomaterials have been categorized based on their chemical and physical composition, biodegradability, origin, and modification generations.¹ Throughout the past decade, their use has increased in tissue engineering, regenerative medicine, and yes, dentistry.

Yet, despite a plethora of articles and arguments regarding what qualifies a material to carry the promising and powerful "bio" prefix, confusion reigns. Partially compounding the problem is the manner in which some manufacturers describe the capabilities of their respective materials using terms such as "bioactive," "biorestorative," and "biomimetic."

Fortunately, a consensus was reached last year when 50 dentists, scientists, clinicians, and other key opinion leaders (eg, teachers, manufacturers, editors) from Europe and North America met for 3 days to discuss exactly what is meant when the term "bioactive" is used to describe restorative materials.² Their consensus states that when applied to a dental restorative material, the term "bioactivity" should describe an active and beneficial biological process.² Therefore, dental restorative materials may be called bioactive if-in addition to primarily restoring or replacing missing tooth structure-they can actively stimulate or direct specific cellular or tissue responses or control interactions with microbiologic species.² In the consensus statement, the experts suggest that these effects should be characterized by the field of application, effect, and how the effect was scientifically proven.²

Not surprisingly, dental materials carrying a descriptor with the prefix "bio" (eg, bioacceptable, biocompatible, biorestorative) are not multipurpose by virtue of their biocompatibility. Rather, their applications are limited based on their classification and composition.¹

"I think of bioactive materials in three categories: restoratives, liners, and cements," says Nathaniel Lawson, DMD, PhD, assistant professor and director of the Division of Biomaterials in the Department of Clinical and Community Sciences at the University of Alabama at Birmingham School of Dentistry. "Bioactive liners have been available for a long time. Calcium hydroxide and mineral trioxide aggregate could both be considered bioactive because they cause the release of growth factors from tooth structure and result in the eventual deposition of reparative dentin."

Newer bioactive liners with modified formulations (eg, those combined with a light-cured resin) that make them easier to use have become popular, Lawson observes.

The bioactive components of these materials allow ionic exchange and seal improvement over time, and the rubberized resins and glass-ionomer particles combine the self-bonding advantages of resin ionomers with the improved strength and surface characteristics of composites, adds Allen Ali Nasseh, DDS, MMSc, a clinical instructor in the Department of Restorative Dentistry and Biomaterial Sciences at Harvard University School of Dental Medicine and the president of RealWorldEndo^®.

"Bioactive liners release fluoride and exchange a number of important ions, such as calcium and phosphate, throughout their lifespans. This exchange with the normal components of saliva allows these materials to act as reservoirs, and the release of these ions further helps to improve the seal and protect against microleakage through the production of appetite crystals where they interact with dentin," Nasseh explains.

Lawson notes that bioactive restoratives have mostly been marketed as materials that release calcium-a major component of hydroxyapatite. Calcium release is thought to prevent secondary caries by facilitating the remineralization of the tooth structure surrounding a bioactive restoration. In this regard, glass-ionomer materials would be considered bioactive as well because they also release fluoride that helps to remineralize the tooth structure surrounding a restoration, he adds.

"Today, many manufacturers are jumping on the ‘bioactive bandwagon,' and by bioactive, they mean ‘able to be remineralized,'" observes John Frachella, DMD, a pediatric dentist in Oregon who works in private practices across the country, is on staff at the Oregon Health and Science University Dental School, and lectures for New York University Lutheran Medical College dental residency programs. "However, not all bioactive materials can do what a glass ionomer does with its mineral-releasing reservoir effect, such as prevent caries on adjacent tooth surfaces, at cavosurface margins, and interproximally.³ Composites and resin-based sealants are incapable of that."

According to Frachella, systematic review demonstrates that the fluorine and strontium ions released from a glass-ionomer penetrate deeply into underlying demineralized dentin and that this pattern is consistent with the science that supports the concept of remineralization. Glass ionomer is the only source of these tooth-penetrating ions. It is important to note that at every stage in the development of the caries process-even when there is cavitation-it is still possible for remineralization cycles to return via the same pathways they left.

"This cannot happen with composite resin because of its anhydrous nature and the fact that mineral ion transfer requires moisture," Frachella elaborates. "This concept is not foreign; the desire for mineral ionic transfer is why dentists have always painted topical fluoride onto moist teeth."

Hydroxyapatite becomes fluorapatite as a result of fluoride ions displacing hydrogen ions in the apatite matrix of teeth, explains Frachella. When fluoride is present, hydrogen ions spin off of carbon atoms because fluoride insists on sharing the electrons-but only in the presence of moisture. Mineral ionic transfer is the mechanism by which remineralization occurs. Composites are used in dry-field conditions; therefore, they do not transfer ions or remineralize tooth structures, he says.

"Another claim of bioactive restoratives is that they can precipitate hydroxyapatite from their surfaces," Lawson says. "This hydroxyapatite could fill in the space between the restoration and the tooth in the same way as the corrosion byproducts produced by amalgam."

Bioactive cements can also release ions and grow hydroxyapatite in the space between the cement and the tooth. A potential benefit of bioactive cement is its ability to precipitate hydroxyapatite into a possible cement gap at a crown margin, Lawson explains.

"Bioceramics are known for being the first hydrophilic, antimicrobial, self-bonding cements that have incredible biocompatibility relative to all other endodontic cements," says Nasseh. "Bioactive restorative materials are recognized for their class improvements in self bonding, fracture resistance from the incorporation of rubberized resins, fluoride release, and other active ion exchanges after placement, which help to improve the seal over time."

Nasseh has observed that during the past decade, bioceramic materials and bioactive hybrid restorative cements have gained traction. The use of bioceramic materials has grown exponentially in endodontics, and bioactive hybrid restorative cements are now being used routinely in restorative dentistry, he says.

"Today, the gap between these two materials is being filled by a new generation of endodontic liners that allow interaction between the pure bioceramic material, which is placed first for the best biocompatibility, and the bioactive material that is placed on top of the bioceramic as a second layer in a sandwich technique," notes Nasseh. "This enables clinicians to take advantage of the convenience of a dual-cure material while preserving the best possible biocompatibility afforded by pure bioceramics."

In 1998, the World Health Organization recommended atraumatic restorative treatment (ART) (ie, placement of glass ionomer over partially excavated caries) as the first line of defense for saving primary teeth worldwide. In silver-modified atraumatic restorative treatment (SMART), the fluoride and silver ions in silver diammine fluoride (SDF) work with the fluoride and many other minerals in a glass ionomer to remineralize faster and more powerfully than anything else used in dentistry, Frachella says.

SMART combines three clinically proven procedures: application of silver diammine fluoride to arrest the development of caries and remineralize; partial removal of caries to remain minimally invasive, which now has international consensus as a best practice; and placement of a glass ionomer to remineralize and deter microbes. According to Frachella, all three are supported by high levels of evidence and when used together, maintain their individual advantages. In fact, when used together, they work better than when used alone and their advantages are enhanced. All studies show that SDF alone, glass ionomer alone, and fluoride varnish alone are insufficient to arrest multiple-surface caries, he explains.

"Class I and II SMART stops food impaction, remineralizes, desensitizes, fills cavitation, is antibacterial, and arrests all surface caries, including those on adjacent teeth, due to the silver/fluoride reservoir effect of SDF and glass ionomer combined," elaborates Frachella. "Although SDF alone for class I lesions can arrest caries, it can also leave a food trap if there is cavitation, and class II lesions treated with SDF alone leave many patients with a ‘toothache' that is really a ‘gum ache' resulting from food impaction."

Another significant application for bioactive materials is their use as a liner, deep base, or bulk fill for long-term provisionalization to improve the coronal seal following root canal therapy. According to Nasseh, historically, endodontists have placed cotton and a temporary filling material to provisionally seal endodontic restorations, but the poor quality of the seal and potential for coronal leakage associated with this technique has long been acknowledged in the literature.

"To date, we have not had a practical solution to this problem," admits Nasseh. "My hope is that by using this new generation of inexpensive, bioactive liners to bulk fill the access preparation immediately after endodontic therapy, clinicians can once and for all eliminate the techniques that have long been a weak link in the endodontic/restorative chain."

SMART is nontraumatic, can be delivered immediately, can quickly reduce any backlog of patients with active caries and pain, can help special needs patients of all ages with rampant tooth decay (especially difficult-to-treat root caries), and can be provided at a very low cost in a variety of settings," observes Frachella. "Furthermore, the silver ions in SDF form a squamous layer of silver protein conjugates that increases resistance to acid dissolution. This limits lesion growth while increasing lesion mineral density and hardness, which is the very definition of remineralization."

Frachella elaborates that once inside bacteria, the silver ions in SDF attack cellular respiration and attach to DNA where the silver stops cell replication in a bacteria-killing domino effect. This greatly outperforms other anticaries agents, he says.

"Also, patients who repeatedly miss scheduled appointments may benefit from SMART, which can help fearful adults and kids to eventually become more willing to accept traditional dental treatment later," Frachella adds.

According to David Alleman, DDS, co-director of the Alleman-Deliperi Centers for Biomimetic Dentistry, biorestorative materials provide a much greater value to patients in delaying or preventing the need for future retreatments when used with the proper techniques. In fact, the use of biorestorative materials according to biomimetic protocols has resulted in an increase in the average life span of large composite restorations from approximately 5 years to between 15 and 20 years, he says.

"That is a 300% to 400% improvement," Alleman observes. "This essentially eliminates more than 70% of future retreatments."

However, more than 20 years of experience using biorestorative materials has confirmed that success is predicated on specific material and protocol characteristics, Alleman cautions. For example, biorestorative materials should bond to a "gold standard" dentin bonding system that achieves a microtensile bond strength in the range of 40 MPa to 60 MPa in a low C-Factor test as well as demonstrates a modulus of elasticity of 12 GPa for deep dentin replacement and between 12 GPa and 20 GPa for intermediate and superficial dentin replacements. In addition, Alleman says enamel replacements with biorestorative materials should wear at a rate of less than 50 microns per year, whereas the cohesive/tensile strength of biorestorative restorations should fall in the range of 30 MPa to 40 MPa.⁴

To realize these standards, Alleman notes that biorestorative dental treatments must be completed in ways that increase bond strengths by decreasing polymerization stresses in the first 5 to 30 minutes of hybrid dentin formation.

Other benefits of a biorestorative approach are more practical, such as the improved efficiency and predictability of endodontic root repair procedures when bioceramic materials are combined with the new generation of bioactive liners that are optimized to work with them, says Nasseh, who plans to share several techniques that he has developed for repairing endodontic perforations during access procedures using this combination.

Patient comfort and convenience are other advantages. For example, when bioceramic materials and bioactive hybrid restorative cements are used in combination as two, distinct layers (ie, sandwich technique), clinicians may be able to maximize the unique advantages of each material, Nasseh suggests. Clinicians would use a pure bioceramic material wherever there is direct contact with cells and greater biocompatibility is required (eg, perforation, direct pulp capping). In these situations, a layer of bioceramic material would be applied to the site, followed by a layer of bioactive liner placed directly on top to capitalize on the latter's dual-cure capability.

"Historically, either the patient would have to return for a second visit or the clinician would have to struggle with less biocompatible materials because biocompatibility and dual-curing capability were mutually exclusive," Nasseh explains. "Today, we can apply a bioceramic material to create the most biocompatible tissue interface layer, immediately follow that with a dual-cure liner that is optimized for restorative qualities, and then cure it to prevent the underlying bioceramic-which demonstrates a long setting time-from washing out."

Such a technique affords clinicians the best of both worlds, Nasseh notes. The bioceramic is protected by the dual-cure bioactive cement while it sets, allowing the dentist to continue working on the site.

Dentists need to remember that tooth decay is a process of demineralization, and demineralization and remineralization are in a constant battle in the mouth," Frachella advises. "Cavitation occurs when demineralization overpowers the remineralizing ability of saliva and serum fluids, but those same pathways that enable minerals to leave teeth are reversible, even when cavitation has already occurred."

That reversal is best achieved in a minimally invasive, highly effective, low-cost way, such as when SDF and glass ionomers are combined together for SMART, says Frachella. However, many of the new bioactive materials comprised mostly of composite resin do not work for SMART because they only release trace amounts of minerals, if any at all, he adds. SMART is about sealing silver ions into partially excavated decay with a highly bioactive mineral-releasing glass.

"Resin-modified glass ionomer (RMGI) is OK to use for SMART, provided it contains at least 80% pure glass-ionomer cement. In other words, 20% resin is OK for SMART, but after light-curing RMGI-which is necessary even with ‘dual-cure' RMGI products to prevent unpolymerized resin-the restoration may have a darker appearance," Frachella notes, adding that most of the darkness is only on the outer surface of the restoration and will wear off in a week or two, leaving a light yellow to light brown end result that is much less dark than an amalgam. "The resin in RMGI contains light-sensitive particles that make the material light-curable, but when performing SMART with RMGI, the light oxidizes the silver, drawing it up through the glass and resin."

As a result, SMART with RMGI is not recommended for anterior teeth, but clinicians would not use amalgam on anterior teeth either, Frachella says.

Of course, research and development efforts to enhance the bioactivity, biocompatibility, and biorestorative nature of dental materials are not limited to those that replace hard tissue in traditional "restorative" applications. Investigations continue to pursue advancements that will improve gingival and periodontal tissue healing as well as the osseointegration of dental implants, including extracellular matrix components (eg, collagen, hyaluronic acid) and platelet-derived growth factor (PDGF).

For example, acellular dermal matrices, which have been used successfully to achieve the same goals and purposes as subepithelial connective tissue grafts (ie, the gold standard for predictably enhancing root coverage), afford greater ease and convenience for patients and dentists.^5,6 Derived from donated human skin that undergoes a multistep process to remove both the epidermis and cells that can lead to tissue rejection, an acellular dermal matrix is used for gingival tissue grafting.

"We want to provide optimal results for our patients, and currently, that requires using our better judgment to decide between using connective tissue grafts or an acellular matrix," says Paul S. Rosen, DMD, MS, who maintains full-time private practices limited to periodontics, surgical implant placements, and regenerative therapy in both Pennsylvania and New York City. "The previously available, cell-based gingival grafting technologies were not very good and did not produce impressive results."

A clinical professor of periodontics at the University of Maryland School of Dentistry, Baltimore, Maryland, Rosen explains that researchers are still trying to achieve results with newer materials and construction matrices that will match what is possible with autogenous tissue and produce an equal amount of predictively successful outcomes. The safety of new materials that are in development is of primary importance, followed by other requisites, including easy handling, a short learning curve, and ready incorporation.

"Newer grafting materials must act as a scaffold for the patient's own cells to integrate into the area and form new tissues," Rosen explains. "Because these materials are utilized in areas where there is an absence of gingival tissue or a minimal zone of tissue that will not withstand inflammation or function, we need a biomaterial that will increase the quantity and quality of tissue."

According to Rosen, the availability of a biologic material capable of restoring highly recessed gingival margins could have implications for esthetic restorative dentistry. In such cases, dentists oftentimes opt to use restorative materials rather than tissue grafts because they feel that masking or protecting the root is a more benign approach than the surgeries involved. A predictable biomaterial that is able to produce esthetic results and be preferred by patients could change the way dentists approach these cases, he says.

"The optimal biomaterial for gingival grafting would facilitate regrowth of the entire attachment apparatus, including any lost bone, cementum, and periodontal ligament. A biomaterial capable of predictably regenerating these tissues would be more universally accepted by patients than connective tissue grafts because nobody wants a donor site," Rosen says. "A minimally invasive approach is the most preferred by patients."

Interestingly, leukocyte- and platelet-rich fibrin (L-PRF)-a 3-
dimensional, autogenous biomaterial obtained from a patient's peripheral blood samples without including anti-coagulants or other additives-is a biomimetic/bioactive growth factor that has been shown to be effective in a variety of systematic reviews for soft-tissue wound healing and periodontal regeneration when compared with hard tissues. Michael A. Pikos, DDS, an oral and maxillofacial surgeon in Palm Harbor, Florida, notes that since 2011, several studies have demonstrated that the adjunctive use of L-PRF for intrabony defect regeneration led to significantly elevated clinical attachment levels as well as reduced probing depths.⁷

"L-PRF is composed of a supraphysiologic dose of platelets and leukocytes capable of stimulating tissue regeneration through the release of growth factors derived from blood (eg, PDGF, vascular endothelial growth factor [VEGF], transforming growth factor beta [TGF-β])," explains Pikos. "Its main function is to stimulate new vascularization, which is a process essential for optimal wound healing. However, because it contains a large proportion of leukocytes, it may also protect the regenerating tissue from potential pathogen invasion."

In addition, although L-PRF is primarily used as an outer "barrier" during flap closure for many indications because of its ability to rapidly stimulate soft-tissue regeneration, it has also been effective for correcting Miller class I and II gingival recessions. The addition of L-PRF to common periodontal regenerative strategies is thought to only benefit the current protocols, Pikos adds.

"It is well-known that autologous tissues are the gold standard materials for tissue regeneration based on their ability to bypass the ‘foreign body response.' Therefore, autologous materials such as L-PRF may promote a more natural wound healing response because they are 100% derived from human tissues from the same patient," Pikos elaborates. "In general, wound healing occurs faster as a result, especially when compared with common biomaterials derived from allograft or xenograft tissues."

However, among L-PRF's limiting factors is its gel-like consistency. Its use alone may not always prevent flap collapse or hold sufficient volume to protect against tissue collapse in larger intrabony defects, Pikos cautions. Therefore, the use of L-PRF in the absence of other interventions has not been viewed to be as effective as a barrier membrane or bone grafting material for large-sized intrabony defects. Studies investigating combination approaches (eg, L-PRF plus barrier membrane, L-PRF plus bone graft) for various-sized intrabony defects are still lacking.

Furthermore, to date, no preclinical or clinical studies have evaluated the effect of L-PRF on periodontal regeneration histologically, Pikos adds. Although L-PRF has been shown to significantly reduce probing depths and improve clinical attachment levels, it remains to be seen if it is actually promoting periodontal regeneration that is characterized by a regenerated periodontal ligament with insertion of Sharpey's fibers spanning from alveolar bone into cementum.

"Unlike collagen barrier membranes, L-PRF has an extremely short biodegradation rate, and in the majority of cases, it is replaced by host tissues within 14 days. Therefore, it is important to utilize L-PRF correctly for each clinical indication presented," advises Pikos, noting that L-PRF cannot act as a true barrier membrane as defined in the literature because it cannot function as a "barrier" after a 10- to 14-day period. "The treating clinician must be fully aware of the biological activity, potential, and limitations of L-PRF for tissue regeneration prior to introducing it into the practice."

Pikos performs guided bone regeneration with a standard barrier membrane (eg, collagen, high-density polytetrafluoroethylene [d-PTFE], or titanium-mesh, depending on the clinical situation) and recommends adding L-PRF to the outer layer of standard barriers to further improve soft-tissue wound healing. The incorporation of leukocytes from L-PRF also provides additional host defenses against potential incoming pathogens, especially when a large procedure is performed, he says. This is especially helpful for smokers and diabetic patients for whom vascularization and increased chance of infection are known issues.

In recent years, the search for enhanced bioactive, biorestorative, and biomimetic qualities has led research into exploring the use of other materials to promote improved restoration, healing, and integration. For example, the use of treated dentin matrix as a scaffolding material in tissue engineering has proven its odontogenic induction ability on dental-derived stem cells. Unfortunately, the sources of such cells are limited, making it necessary to identify new, easily obtained seed cells. For example, although jawbone marrow mesenchymal stem cells are not dental-derived stem cells, they hold promise as seed cells in tooth root tissue engineering.⁸

In addition, innovative hydroxyapatite biomaterials (ie, inorganic materials generally accepted for enhancing dental implant osseointegration¹) that exhibit a trabecular structure similar to natural bone have demonstrated a unique, controlled micro- and macroporosity of almost 90% as well as interconnectivity that supports rapid bone ingrowth and formation. These characteristics promote easy access to cells, biological fluids, and signaling molecules throughout the bone substitute, which contributes to the material's suitability as a bone grafting material. Despite its porosity, the material resists compression forces similar to natural cancellous bone, making it appropriate for dentistry. The biological processes necessary for effective bone regeneration are instigated once the material is placed and begins rapidly absorbing bioactive proteins, growth factors, and bone precursor cells.⁹

Furthermore, synthetic hydroxyapatite could be used as a biomimetic preventive material because of its biocompatibility and similarity to biologically formed hydroxyapatite in natural teeth. The material's efficiency in occluding open dentin tubules as a means of protecting sensitive teeth has been well-documented in clinical studies, and its effects against caries, use in biofilm management, and ability to protect against erosion further support its use in dentistry.¹⁰

Also on the horizon and in development are dental material technologies incorporating antibacterial molecules, Lawson says. Quaternary ammonium compounds, which can repel bacteria based on their net negative electromagnetic charge, are one group of molecules that show promise in this area. There are also some alkasite dental materials that produce a high pH for an antibacterial effect, he adds.

Although the majority of bio-innovations in materials for dentistry have focused on direct application, as new biomaterials and compositions are introduced, 3D printing shows increasing promise for fabricating the scaffolds that are required in dental hard- and soft-tissue engineering. Researchers have developed novel biomaterials and compositions that are able to be used in 3D printing methods, which, in particular, could have applications for periodontal tissue regeneration.