Bioactive Having an effect on or eliciting a response from living tissue, an organism, or a cell, especially in inducing the formation of superficial hydroxyapatite.
Bioinductive Capable of inducing a response in a biological system.
Biomaterial Any matter, surface, or construct that interacts with biological systems.
Biomimetics Study of the formation, structure, or function of biologically produced substances and materials (e.g., silk or nacre) and biological mechanisms and processes (e.g., protein synthesis or mineralization) for the purpose of synthesizing similar products by artificial mechanisms that mimic natural structures.
CAD-CAM CAD refers to computer-aided design technology, based on the use of computer software and systems to assist in the creation, modification, analysis, and optimization of two-dimensional or three-dimensional models of objects. Any computer program that embodies computer graphics and an application program that facilitates engineering functions in the design process can be classified as CAD software. The term CAM refers to computer-aided manufacturing of a restorative device using the CAD input file. CAM may be additive (buildup) or subtractive (machining of a device from a larger starting piece of material).
Cytology The harvesting of disaggregated cells and related microscopic material for analysis of disease.
Nanotechnology Technology that focuses on the atomic and molecular scale (<100 nm) of materials, devices, and other structures. On this scale, in which at least one dimension must be below 100 nm, quantum mechanics (quantum theory) controls material properties or behavior.
Osteoconductive Capable of acting as a matrix or scaffold to facilitate new bone growth on its surface.
Self-assembling materials Disordered materials that form an organized structure or pattern as a consequence of specific, local interactions among the components, without external direction.
Smart materials Synthetic materials that interact with external stimuli, such as light, temperature, stress, moisture, pH, and electric/magnetic fields, in such a way as to alter specific properties in a controlled fashion and return to the original state after the stimulus has been removed.
Voxel Volumetric picture element that represents a single sample, or data point, on a regularly spaced three-dimensional grid. It is analogous to how pixel defines a point in two-dimensional space.
The materials and devices in current use are effective, but improvements in performance are always needed. For instance, caries-prevention treatments have reduced the need for initial restorations, replacement restorations, and removable dentures. Minimally invasive dentistry concepts have led to the removal of less tooth structure and the sealing of leaking defective margins of restorations. Nonetheless, because of the promotion of higher-cost esthetic restorations, sometimes at the expense of durability, the need for both repair and replacement of restorations will continue because resin restorative materials fail and degrade over time. Thus the choice of materials for a given clinical situation will continue to be based on a comparative analysis that balances cost, benefits, and risks. Until caries is considered truly “curable,” there will be a need for novel solutions, such as remineralizing agents, smart materials, and durable repair and replacement materials that avoid the need to repeatedly restore teeth. The focus of emerging applications of dental materials is primarily on the prevention, detection, and treatment of caries, periodontal disease, and oral cancer. These materials are often called dental biomaterials because of the increase of interaction with the biological systems.
New dental biomaterials must satisfy the following requirements: (1) be nontoxic to human cells, (2) not support the growth of microbes and fungi, (3) be able to form an excellent seal between the oral cavity and underlying tooth structure, (4) be sufficiently bioactive to stimulate in vivo repair of tissues, (5) have properties similar to the tissue that is to be repaired or replaced, (6) exhibit handling properties that allow ease of manipulation and promote optimal clinical performance, (7) exhibit an esthetically pleasing appearance, and (8) are cost-effective.
In the following subsections, research and technologies are discussed for their relevance to solving oral health–related problems. Figure 20-1 depicts a flowchart of basic, translational, and clinical research representing stages in the development of emerging technologies and products. The farther to the right of the chart a technology or material is, the higher the probability that this material will have a desirable clinical outcome. The discussion is divided into three sections: biomaterials, biological materials, and instruments and processes.
Any matter, surface, or construct that interacts with biological systems is considered to be a biomaterial. In the present context, only synthetically derived or highly processed nonsynthetic materials (materials of biological origin) are discussed. In dentistry, these are also preferably known as dental materials.
In which ways will nanotechnology provide products or processes that can improve oral health outcomes?
Nanotechnology uses nanosized particles and surface features with very high ratios of surface area to volume that are usually different in their bioactivity, solubility, and antimicrobial effects compared with larger particles of the same composition. Thus changes in properties cannot be extrapolated by an inverse linear analysis of particle size but must be determined through in vitro and in vivo testing of the nanomaterials. In dentistry, nanotechnology had been focused on the development of nanoparticle fillers to improve dental composite esthetics. The use of nanotechnology today is more diverse.
In biomimetics, nanotechnology is being used to develop materials that promote hard tissue remineralization. Biomimetic materials and processes mimic those that occur in nature, particularly self-assembly of components to form, replace, or repair oral tissues. These concepts are discussed further later in this chapter.
For dental implants and related devices, nanoparticles are used to modify dental implant surfaces to influence the host response at the cellular and tissue levels. Electrophoretic sol-gel fabrication, pulsed laser deposition, sputter coating, and ion-beam–assisted deposition are among the approaches used to develop nanotextured, thin-film, biocompatible coatings for implant surfaces. These technologies reduce the thickness of the coating layer and increase the specific surface area and reactivity to improve the interaction with the surrounding apical tissue.
Important nanoparticles include metals, such as silver, and ceramic powders, such as silica and titanium dioxide. In situ–generated silver nanoparticles have been reported to be highly effective in restorative resins, bonding resins, and prosthetic resins for inhibiting a variety of biofilm-forming bacteria while not interfering with manipulation, curing, mechanical properties, or other performance properties. Silica nanoparticles already have wide use in dentistry, from toothpastes to composites. Titania nanoparticles are widely used for pigments in dental materials but lack the stronger antimicrobial effects of Ag.
Another recently introduced nanotechnology kills bacteria on contact on restoration surfaces. Infinix flowable composite (Nobio Ltd., Israel), which contains quaternary ammonium bound to silica (also known as QASi ) was reported to significantly reduce Enterococcus faecalis on the surface of the material without affecting composite flexural strength, radiopacity, depth of cure, water sorption, or water solubility. After 6 and 12 months of use in vivo, there was a 50% reduction of live bacteria on Nobio QASi composites compared with control composites. An added advantage of the QASi-containing surfaces is that no “recharging” is needed, unlike the fluoride in glass ionomers that confers microbial resistance. Prevention of bacterial biofilm protects the integrity of the dental product restorations.
Resin Restorative Materials
Despite the recent innovations in increasing the service life of contemporary resin composites (see “Innovations in Dental Composites” in Chapter 5, Classification of Composites by Unique Properties ), significant uncertainty exists regarding the interactions of bacterial biofilms, wear, and fatigue leading to recurrent caries. Thus further improvements are needed in order to greatly increase the clinical life of resin-based restorations to match and even surpass the durability of amalgam, the gold standard, and eliminate the need to repair the restored teeth. To this end, major goals for restorative materials continue to be the reduction of composite shrinkage during curing, porosity, wear and attrition, improvement of the composite–dentin interface, and increasing the degree of conversion of resin monomers.
One factor that influences restorative longevity is operator error. Materials with many steps, the requirements for a dry field, difficult handling, or long curing times are inherently prone to mistakes that often lead to material defects, such as voids and inadequate curing, which hasten the onset of fatigue, fracture, and abrasion. Thus more technique insensitive (“forgiving”), operator-friendly, esthetic, and long-lived composites are being developed.
As discussed in Chapter 5, Classification of Composites by Manipulation Characteristics , two novel flowable composites marketed as “bulk-fill, universal restorative resins,” G-aenial Universal Flo (GC America, Alsip, IL) and Surefil-SDR flow (DENTSPLY International, York, PA), among others, exemplify operator-friendly materials that are translucent and have flowable rheology, easy handling properties, and a large depth and degree of conversion. Both exhibit low shrinkage and shrinkage stress, which allow the composite to be placed in large increments instead of the prescribed 2-mm layers, further contributing to their technique insensitivity. Because these highly flowable composites contain reinforcing filler on a par with the highly loaded, nonflowable, and “packable” hybrids, such as those described in Chapter 5, Classification of Composites by Manipulation Characteristics , their performance is similar to those of current posterior resins, raising expectations of high durability and long clinical life. Early-stage wear resistance and durability tests have validated the benefits of their high filler loading, low curing stress, and high level and depth of cure.
Filtek Universal (3M ESPE, St. Paul, MN) is a recent addition (2019) to the category of operator-friendly composites. The nanoparticle fillers in this composite provide superior shade matching and wear resistance. This composite contains two unique monomers: addition-fragmentation monomer ( AFM) and aromatic urethane dimethacrylate (AUDMA). The AFM fragments and repolymerizes during curing, reducing curing stress and enhancing marginal integrity. The AUDMA decreases the number of reactive groups in the resin and increases polymer flexibility. Fewer reactive groups moderate the volumetric shrinkage, and the increased polymer flexibility reduces the stiffness of the polymer matrix before the matrix reaches the gelation point. Both of these contribute to decreased curing stress, improved marginal integrity, and ultimately, improved abrasive wear resistance.
Omnichroma (Tokuyama Dental America) is a single-shade, universal composite that matches every tooth shade, from A1 to D4. The innovative material contains 260-nm spherical nanoparticles that can scatter red-to-yellow colors as ambient light impinges on and is reflected from the composite. The red-to-yellow scattering blends with the scattered light of the adjacent dentition to produce an esthetic color match and reduces operator sensitivity.
Most present-day dental materials do not induce dental tissue responses and are not bioactive. Bioactivity is defined in ISO 23317 as a property that elicits a specific biological response at the interface of the material, which results in the formation of a bond between tissue and material. As such, bioactivity incorporates antimicrobial, remineralizing, and bone-forming materials, as discussed in this section. Bioactive materials implanted in a living body form a thin layer rich in Ca and P on their surface. The material then connects to the living tissue through this apatite layer without a distinct boundary. Bioactive materials are useful for the healing of tissues, especially pulp and periapical tissues, and for supporting root development in immature teeth.
Bioactive materials available now include calcium hydroxide, bone grafts, bioglass particulates, and hydraulic (water-setting) ceramic powders. The calcium–silicate powders are considered the gold standard for endodontic surgical procedures, pulpotomy, revascularization, and apexification procedures. The calcium aluminate–based powders, being more acid-resistant, are being used with glass ionomers for supragingival cement for prosthodontics and have found limited use for restorative applications. Their acid resistance makes them useful for infected sites, which are generally acidic; as such, the aluminates may be used for the same indications as mineral trioxide aggregate (MTA) materials. Calcium phosphate cements are generally slower-setting than the hydraulic cements but are being used for scaffolding purposes where the formation of hydroxyapatite is necessary and porosity is acceptable.
Theobromine, a xanthine found in cocoa, promotes the formation of hydroxyapatite mineral and increases the size of hydroxyapatite crystals by upregulating osteogenesis, which would have numerous benefits. For instance, theobromine may remineralize adjacent tooth enamel and have the potential to close gaps between restoration and tooth, improve bond-strength durability associated with reduced bond degradation, and enhance bone integration with implant surfaces. The large crystallite size leads to resistance to dissolution via the decreased specific surface area available for acid dissolution. New bioactive materials are under development that, in general, will create a biomimetic “presence” in vivo that induces healing superior to those of many present-day dental materials.
Dental resins have been combined with bioactive TiO 2 nanoparticles to promote hydroxyapatite formation, enhance mechanical strength, and act photo-catalytically as a bactericidal agent. A dentin bonding adhesive with TiO 2 nanoparticles can provide on-demand, photo-induced microbial inhibition and simultaneously fill marginal gaps via remineralization of adjacent dentin and enamel. This technology may reduce recurrent caries, improve tissue integration with implant surfaces, and prevent peri-implantitis or other infections at the tissue–implant interface. These results are intriguing and highly promising, but they have not yet been tested clinically.
The surface of materials is often what makes them bioactive. Titanium as an implant material is an example. Like chromium, titanium spontaneously reacts with oxygen to form a self-repairing, protective oxide layer (TiO 2 ), which makes the implant surface largely corrosion-resistant, inert, and biocompatible. However, surface roughness and other aspects of surface topography, together with surface chemistry, are also known to strongly influence the early events in healing and osseointegration that follow implant placement. Interactions between proteins, cells, tissues, and implant surfaces play a role in determining the success or failure of all implanted materials and devices. The surface chemistry and topography-related mechanisms that control these events are poorly understood. Nevertheless, substantial research effort in dental implantology is currently directed at developing surfaces with controlled topography and chemistry at the nanoscale level to optimally promote protein adsorption and cell adhesion. Biomimetic calcium phosphate coatings for implants are under development to enhance osteoconductive properties and incorporate biological agents to accelerate bone healing in the peri-implant area. Overall, these research efforts to understand and control surfaces are showing great promise, and some are likely to lead to materials, processes, and/or procedures to enhance the reliability of placement, indications for use, and the success rate of dental implants.
Preventing and removing biofilms is important for pediatric dentistry and especially periodontics and endodontics. Adjunctive liquids are needed that can quickly kill and remove bacterial colonies in biofilms during periodontal scaling. In endodontics, new irrigants are needed to better remove and deactivate smear layers containing remnant bacteria after root canal preparation, which is never complete. Some endodontic irrigation liquids are combined with acids or surfactant to dissolve the dentinal smear layer created by endodontic instruments in a root canal. Combination devices containing a drug, bone morphogenetic protein (BMP), or amino acids are envisioned for endodontic and periodontal uses. Two such combinations, QMIX and MTAD (DENTSPLY Inc.), are irrigants in endodontics.
Endodontics has been dramatically changed by the introduction of hydraulic ceramic (water-setting) cements that create high-pH environments and thereby have antimicrobial properties. For example, the tricalcium silicates and calcium aluminates have enhanced endodontic and pulpal treatment with their antimicrobial properties and dimensional stability.
Although the clinical performance of dental resins has improved remarkably in durability, bond strength, and esthetics, most still lack antimicrobial properties and allow bacterial colonization and biofilm formation. Antimicrobial monomers are being investigated and developed to prevent recurrent caries better than composites that release fluoride ions. Ideally, the polymerized resins would have sustained antimicrobial characteristics. Examples include modified (chlorinated) polyethylene or other polymers that may provide antimicrobial activity.
What stages of research will lead to the adoption of new remineralizing materials and processes for dental practice?
Remineralizing Agents and Materials
The dental literature reflects a strong demand for preventive and “healing” therapies for individuals at moderate risk for caries to prevent a shift to a high level of risk. Thus low concentrations of fluoride are included in toothpaste, well water, and other fluoridated sources to have beneficial effects on enamel and dentin remineralization.
Other remineralizing agents include the use of nanoparticles of hydroxyapatite because they are on the same crystalline scale as naturally occurring hydroxyapatite crystals in enamel or dentin. A promising example of this approach was reported by Li et al. in 2008, who found that 20-nm nanohydroxyapatite particles had a superior anticaries repair effect compared with that of larger hydroxyapatite particles.
Liquid remineralizing dentin bonding agents, which should wet, flow, and completely fill the demineralized zone created by etching prior to or simultaneous with bonding to the restorative material, are also being developed. For instance, a tricalcium silicate product was tested with polyacrylic acid and sodium tripolyphosphate for remineralization. When these materials were applied under a restorative material, the combined material infiltrated the demineralized collagen fibrils with precursors that restored the calcium phosphate at the interfaces of the dentin and the restorative material. Incorporation of some of these technologies into primers and dentin bonding agents are expected to both inhibit caries activity and increase the service life of composite restorations.
Theobromine, a bioactive agent discussed earlier, is an alternative to fluoride as a remineralization agent. Theobromine is currently used in Theodent toothpaste products (Theodent LLC, New Orleans).
Emerging technologies and materials that promote remineralization at early and moderately advanced stages of caries are being developed more rapidly now that highly sensitive imaging and measurement processes are available ( Chapter 15, Diagnostic Systems ).
In addition to remineralizing small lesions, gross remineralizing treatments and bone grafts are increasingly needed for dentistry. Bone-grafting materials are necessary for various oral surgeries, such as alveolar ridge augmentation and sinus augmentation, and for the placement of implants or to improve mandibular denture stability. Extraction socket grafting materials are gaining popularity to prevent the collapse of cortical bone and enable the placement of an implant. Also, patients prefer faster treatment and fewer surgeries, which drives research and development toward single-stage implant procedures with immediate functional loading (IFL). Implants with nanotechnology coatings may increase the success and acceptability of the single-stage and IFL procedures, but before implant placement, grafts are often needed.
Graft materials are available containing allogeneic, xenogeneic, or synthetic hydroxyapatite particles to act as a scaffold for gradual replacement by the patient’s bone. These current bone grafts slowly resorb, and the replacement bone densifies over months until a restorative denture or implant can be made. More rapid resorption and bone-growth-stimulating materials are needed to meet the demand for faster implant placement after tooth extraction, even immediate placement. Some available grafting materials are designed for faster resorption and bone growth. For instance, PepGen P-15 (DENTSPLY Friadent, Mannheim, Germany), a hydroxyapatite product with an amino acid, is available for accelerating natural bone regeneration. Infuse (Medtronic, Minneapolis, MN), a collagen sponge with recombinant human bone morphogenetic protein-2 (rhBMP-2), is indicated for sinus augmentation and localized alveolar ridge augmentation. BMPs, also known as cytokines, represent a group of growth factors that can affect cell interactions and cell behavior. PerioGlas and NovaBone Dental Putty (NovaBone Products, Jacksonville, FL) contain coarse (>100 μm) bioglass particles for implantation as a resorbable scaffold for bone growth and periodontal grafting. Ostim-Paste (aap Biomaterials GmbH, Dieburg, Germany) is a nanocrystalline hydroxyapatite paste that can be used to repair the intraoral bony defects that may result from cystectomies (a surgical procedure to remove a cyst), root tip resections, extractions, and surgical tooth removal; for augmentations in the areas of the alveolar processes and maxillary sinuses (sinus lift); and for filling periodontal defects. Clinical trials are needed to determine the success of each of these approaches and guide the development of future products.
New bioactive glasses are under development that contain more boron and silica than the original formulas of 45S5 bioglass (45 wt% SiO 2 and a 5:1 ratio of CaO to P 2 O 5 ) for osteogenesis , and the new formulas may be resorbed more quickly, with faster bone replacement. Copper or silver in these glasses may also enhance soft tissue deposition in other applications. Powders, fibers, or foams of the bioactive glasses may be used as scaffolds for use in the rapid replacement of bone or soft tissue. Scaffolds of bioactive glass are used for osteoconduction, and they may also initiate the development of cartilage ( chondrogenesis ). The latter could be useful for temporomandibular joint (TMJ) treatments. Combinations of biodegradable polymers with bioactive glass particles may also enhance tissue replacement and serve as the basis for new grafting materials.
In which ways does the use of smart materials lead to improvements in the quality of oral health care?
Stimulus-Responsive “Smart” Materials
“Smart” materials are designed for interaction with external stimuli, such as light, temperature change, stress, moisture, pH, or electric/magnetic fields. Examples of such dental materials include zirconia ceramics that transform from a tetragonal to monoclinic crystal form when tensile stress is induced at crack tips, leading to an increase in crystal volume and compressive stress to prevent the propagation of cracks. Light-curing composites begin curing when irradiated with particular wavelengths of blue light, and others change color when irradiated (for use in orthodontics). Glass-ionomer cements will weaken when desiccated, making orthodontic bands easier to remove. Other glass-ionomer restoratives increase the release of fluoride when the pH in plaque fluid decreases (becomes acidic). Nickel-titanium wires are designed to soften when chilled below body temperature for bending and threading through orthodontic brackets. Smart cements have been envisioned to soften and allow debonding by a temperature change or irradiation process for the removal of orthodontic devices, indirect restoratives, and some implant components.
Secondary caries and the unnecessary replacement of defective restorations can be prevented and adjacent enamel remineralized through one of the following preservative treatments: (1) sealing of marginal crevices adjacent to defective restorations with a hydrophilic resin, (2) sealing crevices with a smart resin capable of the controlled release of chlorhexidine or another antibacterial agent, (3) sealing crevices with a smart resin capable of the controlled release of fluoride, and (4) applying a sealing resin or varnish that can release xylitol or other caries-management agents at specified concentrations over a specific period of time. Emerging technologies and materials for sealing may include smart hydrophilic resins that release fluoride and/or other mineralizing agents when the pH of oral fluids decreases to a range of 4.0 to 5.5 to seal moist microscopic crevices adjacent to defective restorations and reduce enamel demineralization. Improved, smarter sealants, varnishes, and composites that release fluoride would be beneficial. Concomitant studies of composition, particle size, and particle-size distribution for smarter release of fluoride (on-demand release) would make them “smart sealants.” The rapid induction or reversal of anesthesia may be another future application for smart materials. For instance, particles or substances applied in the sulcus could start or stop the anesthetic reaction. Smart material concepts can provide the clinician with better control, which will certainly suggest approaches for new products.
Self-assembling materials automatically construct prespecified assemblies. Viruses, cells, tissues, and whole organisms are examples of biological self-assemblies, whereas crystals are an example of nonbiological self-assemblies. The latter can be derived from polymers, metals, ceramics, or combinations of components. Self-assembly occurs by orchestrated stages of initiation, propagation, and termination. Control systems for initiation and/or propagation may be templates (e.g., template polymerization of proteins, patterning of silica templates for electrical circuits), or they might depend simply on natural rules corresponding to energetically favorable physical, chemical, mechanical, and/or biological events (e.g . , capillary forces, heterogeneous nucleation of crystallization, surface-energy reduction, phase separation, micelle formation, and steric probabilities for molecular folding).
Bone or soft tissue scaffolding of graft materials can be considered as self-assembling. The coarse porous particulate or spongy bone graft materials are designed to encourage biological tissue to respond and replace the scaffold. Templates of proteins may be used to encourage biological events, such as specific tissue growth. For example, a broad class of self-assembling peptide derivatives offers exciting novel therapies of broad potential impact in regenerative medicine. These peptide amphiphiles (PAs) incorporate a short hydrophobic domain on one end of a hydrophilic oligopeptide sequence that also contains bioactive signaling sequences. Nanostructures can be designed from these peptides through self-assembly strategies and supramolecular chemistry, having the potential to combine biocompatibility with bioactivity. Such structures offer engineering design flexibility for biomedical and biomaterials applications. This type of research is nearing clinical application. However, for the regeneration of teeth, translation remains a distant but achievable target. Possibilities involve tissue engineering, biomimetics, and stem cell biology, which are discussed in greater detail in the following sections.
Self-Healing (Self-Repairing) Materials
Self-healing is an autonomically initiated response to damage or failure. Nature continually remodels bone, which can heal itself (self-repair) even after a major fracture. Nature’s mechanisms of repair have inspired efforts to develop self-healing capabilities in synthetic materials that may well appear in dental products within a few years. To achieve self-healing, a material must be capable of identifying and repairing failures.
Restorative materials are subject to aging in vivo and have a limited lifetime; they gradually degrade because of physical, chemical, and biological phenomena such as creep, fatigue, internal stresses, dissolution, erosion, or biodegradation. An epoxy system has been developed that is self-healing, consisting of microencapsulated dicyclopentadiene and Grubb’s metathesis catalyst. If a crack occurs in the epoxy composite, some of the microcapsules are ruptured near the crack and release dicyclopentadiene, which subsequently fills the crack and reacts with the catalyst, causing polymerization of the dicyclopentadiene and repairing the crack. These materials improve the recovery of composite fracture toughness after stress in laboratory tests. Similar systems have exhibited a significantly longer service life under mechanical stress in situ compared with those without the ability for self-repair. A self-healing dental resin would be extremely important for lengthening service life.
Biomaterials science is exploring new technologies and is increasingly shifting to natural tissue repair or replacement therapies. Biological biomaterials can lead to natural tissue restoration but rely heavily on tissue engineering, biomimetics, self-assembling systems, cell biology, and regenerative dentistry.
Some biological mechanisms and processes (e.g., protein synthesis, silk and seashell formation) can be mimicked by synthesizing similar products by artificial mechanisms. Of particular interest here are those that involve self-assembly of components to form, replace, or repair oral tissues. An intriguing prospect for this approach is the use of self-assembling PAs that contain both a photopolymerizable group and the arginine-glycine-aspartic acid-serine (RGDS) cell-adhesion sequence. The self-assembling nature of the PAs causes the formation of networks of prealigned nanofibers, mimicking natural fibers. These nanofibers can be formed into tissue scaffolds as substrates for mesenchymal stem cell (MSC) cultures. Topographical patterns produced from aligned PA nanofibers were found to promote the alignment of MSCs, which indicated that the cells sensed and responded to the nanoscale features of the scaffold surfaces. The aligned MSCs then differentiated to form bone-like tissue.
Biomimetic technologies are under intense investigation for translation into clinically useful materials and treatments. These and other biomimetic approaches and the use of tissue engineering scaffolds are discussed further in the sections headed “Tissue Engineering” and “Regenerative Dentistry.”
Tissue engineering has emerged in the past 30 years as a multidisciplinary field recognized by the National Institutes of Health involving biology, medicine, and engineering. Experts hope that tissue engineering will revolutionize health care and improve quality of life for people worldwide by maintaining, restoring, and enhancing tissue and organ repair, regeneration, and function. The main requirements for engineered tissues are the appropriate levels and sequencing of regulatory signals, the presence of responsive progenitor cells, an appropriate extracellular matrix or carrier construct (i.e., scaffold), and an adequate blood supply for oxygen and nutrients. Either biological or synthetic polymers are used to form the tissue engineering scaffolds. Recent advances in understanding growth factors and biodegradable polymer scaffolds have made possible the successful tissue engineering of cartilage, bone, and related tissues. have summarized the remaining achievements required to develop the clinical techniques needed for the creation, substitution, and/or replacement of dental tissues. Among the many potential applications are fracture repair, dentin and periodontal ligament replacement, alveolar ridge augmentation, temporomandibular joint reconstruction, preosseointegration of dental implants, pulp regeneration, and partial or whole tooth regeneration.
Tooth loss is the most common organ failure. The regeneration of a tooth can include not only regrowth of the entire tooth complex as a complete biological organ but also the regeneration of individual components, including enamel, dentin, pulp, cementum, and periodontal tissues. Two lines of investigation deal with restoration of partial tooth damage using tooth-related stem cells for the repair or whole-tooth regeneration by using stem cells or tissue-engineering techniques. The first successful bioengineering of entire tooth structures was reported in 2002 using cells from dissociated porcine third molar tooth buds seeded on biodegradable polymer scaffolds that were implanted in rat hosts for 20 to 30 weeks.
Osteonecrosis is a new and serious dental disease that arises from receiving bisphosphonates intravenously or orally to treat other medical conditions. Conventional debridement is ineffective in treating osteonecrosis, so biological solutions are being developed to treat the condition and to prevent the onset of other dental events, such as surgeries or extractions.
Chronic periodontitis is one of the most common oral diseases worldwide, after caries. In periodontics, tissue-engineering strategies are being developed to serve as periodontal regenerative therapies for the restoration of lost alveolar bone, periodontal ligament, and root cementum. These strategies are based on the growth of new functional tissue rather than replacement of the periodontium. These studies have shown that regeneration is feasible for small to moderate-sized periodontal defects using cell-scaffold constructs for future clinical use. Yet even though tissue engineering has created the means for predictable and optimal periodontal tissue regeneration, routine clinical periodontal regenerative medicine and clinical use remain in an early stage.
Still greater challenges are major bone reconstruction after trauma or cancer and augmentation following implants. Formidable challenges exist for regenerating normal bone structure and restoring the functionality of tooth-supporting tissues. Possibilities depend on an understanding of the cellular and molecular mechanisms involved in periodontal tissue regeneration, the differentiation potential of stem cells, and the interactions among stem cells, scaffolds, and host tissues. Intense research and development activities in these areas indicate that placing implants may soon be possible, even under adverse anatomical or biological circumstances. Tissue engineering may soon lead to the reconstruction of lost bone in bone deformities more effectively and less traumatically than the traditional autogenous bone-transplantation approach.
Predicting the full impact of tissue engineering on the future of dentistry is difficult. However, tissue engineering brings together advances in disparate areas of materials science, genetics, molecular biology, and cell biology. Researchers in these disciplines may develop new alternatives for the regeneration of soft tissues, bone, and enamel. An important consideration will be the cost of these procedures, at least initially. Not only is the cost of treatment important, but the costs are significant for such projects to develop the technology, demonstrate clinical efficacy, meet regulatory requirements, commercialize the technology, and train clinicians in these innovative techniques.
Delivery Systems for Biologicals
Tissue-engineering approaches that combine biomaterials with biological materials, such as proteins (growth factors, etc.), genes, and cells (both differentiated and stem cells), are promising routes to the therapies discussed previously. Thus biological materials are a source of active, ongoing research directed in part toward developing competent scaffolding materials capable of fulfilling application-specific requirements for biodegradation, biocompatibility, mechanical stability, biofunctionality, and processability. The key attributes of any biological delivery system are controlled, sustained, and targeted release of drugs and bioactive factors. Each of these attributes is fundamentally dependent on the ability to predictably generate a functionalized material.
An example of a promising biological delivery strategy is to increase osseointegration of titanium implants by coating them to improve healing, induce peri-implant bone formation, and enhance osteointegration. Coatings may include extracellular matrix components, such as collagen, BMPs, or other proteins. Further developments are required to orchestrate the release pattern, optimize the time that the active components remain bioactive, control degradation, optimize the extracellular matrix that forms on the implant surfaces, and achieve maximum bone formation at minimal concentrations of the biological material.
A regenerative approach for diseased or necrotic pulp tissue includes tissue removal and replacement with healthy tissue, including melanocortin peptides (melanocyte-stimulating hormone, α-MSH), which possess antiinflammatory properties. A nanostructured and functionalized multilayered film containing α-MSH was reported for endodontic regeneration. Applied as a gel or strip, MSH films were placed adjacent to the damaged tooth to encourage the growth and regeneration of cells. In tests performed on cavity-filled mice teeth, researchers saw extremely positive results; after a month, the cavities had disappeared. This technology is in its formative stages.
Many approaches may be viable for biological materials in dentistry, but several more years will be required before a version is available for general use in dental practice.