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Endodontic therapy is performed to prevent or treat apical periodontitis and consists of the total or partial removal of dental pulp. To a certain extent, vital functioning pulp serves as the most efficient barrier against bacterial invasion.1 However, numerous studies have proven that direct pulp capping in cariously exposed teeth provides unpredictable results and is less successful than complete pulpectomy.2 This could be related to remnant bacteria in surrounding dentin despite excavation of clinical caries and the inflammatory response to the carious exposure extending to the pulp tissue.3 In addition, it may be related to an inadequate long-term seal resulting in microorganism microleakage or to materials that fail to achieve pulp repair and dentin bridge formation.4 The success of pulp capping therapy depends on complete disinfection through chemomechanical debridement of the pathological or necrotic pulp tissue, followed by hermetically sealing the root canal system from the oral and periapical environment.
Despite the progress made in improving the performance of root canal preparation and filling techniques, clinicians are still confronted with two problems. The first issue is the complexity of the pulp root canal and its ramifications, which creates major difficulties for complete disinfection, shaping, and filling to prevent bacterial infiltration and ingress. The other problem is that root canal filling materials do not meet all the requirements of an ideal material, including adhesion to dentin, maintaining a sufficient seal, insolubility in tissue fluids, dimensional stability, resorbability, radiopacity, antibacterial activity, and biocompatibility.5 In addition, while sealers and filling materials used for endodontic practice have previously proven their biocompatibility in several in vitro and in vivo tests, controversy still remains regarding the acceptable biocompatibility of primary endodontic filling materials, potentially hindering the healing process in cases involving extrusion beyond the canal.6
In recent decades, new biomaterials have been used in endodontic therapies, particularly mineral trioxide aggregate (MTA)- and calcium phosphate-based materials. These materials promote pulpal and periapical healing because of their biocompatibility and bioactive properties, thereby improving the prognosis for endodontic treatments. The question that needs to be addressed has to do with determining the kind of biomaterials and the conditioning that can be used going forward. Progress in biomedical research has provided new directions for the design of biologically effective pulp therapies. Thus, this article reviews the various bioactive materials used in endodontics.
Methods
The search strategy followed the indications of the National Health Service’s Centre for Reviews and Dissemination in the United Kingdom, and researchers used the Medline database for articles. The key MeSH terms used were: bioactive and bioactive materials in endodontics. The search was later expanded to gather more information by including the following databases: Scopus, EBSCOHost, Scirus, and Cochrane. The keywords used were: bioactive materials and bioactive materials in endodontics. Selected article references were reviewed to extend the search for relevant articles.
Biocompatibility of Current Endodontic Filling Materials
Biocompatibility tests have shown that all of the currently used filling materials, including gutta percha (GP), cause local adverse effects on vital tissues.7 GP has been the most widely used root canal filling material because findings from animal studies showed it to be well tolerated and the formation of a fibrous tissue capsule surrounding pieces of GP has been reported.8 However, the inertness of GP has been an issue, with in vivo tissue experiments showing cytotoxic reactions being caused to varying extents depending on the size, surface characteristics, formulation, and type of GP. Fine particles of GP (eg, those resulting from thermocompaction) can cause an intense, localized tissue response that may be a significant factor in the impairment of healing of periapical lesions in the case of overfilling.9
Certain endodontic sealers can cause local and systemic adverse effects. Numerous commonly used root canals sealers, such as epoxy resin-based, calcium hydroxide-based, and zinc oxide–eugenol-based sealers, possess a marked cytotoxic and tissue-irritating potency, notably for periodontal ligament cells.10 Eugenol, zinc, or formaldehyde products of root canal sealers have significant potential toxicity for periapical tissues.11
In addition, root canal sealers dissolve when exposed to an aqueous environment for extended periods, possibly causing moderate or severe cytotoxic reactions and contributing to endodontic treatment failure. Sealers even induce necrosis of bone or cementum.12 Histologic investigations on monkeys have demonstrated that root canal sealers can induce mild-to-severe periapical inflammation, especially when teeth were overfilled.13
Mutagenic and genotoxic effects have also been observed with sealers releasing formaldehyde or generating this substance during their setting reaction, as well as with sealers containing bisphenol-A-diglycidylether or its derivatives.14 The use of epoxy resin-based sealers induced the highest level of DNA damage.15 Furthermore, the obvious carcinogenicity of the formaldehyde-releasing and epoxy resin-based root canal sealers on human osteoblastic cells should be taken into consideration.
Although the presence of pathogens in the root canal system and preoperative periradicular lesions are the primary causes of endodontic failure, it is widely assumed that the tissue response to root canal filling materials becomes significant in the event of overfilling and may influence the outcome of endodontic treatment. Thus, use of materials with potential risks for cytotoxicity, genotoxicity, mutagenicity, or carcinogenicity should be avoided in practice because safer alternatives are available.
Calcium Hydroxide
Calcium hydroxide, or Ca(OH)2, has good antibacterial properties. It has an alkaline pH (a level of approximately 12) that helps reduce osteoclastic activity and induce bone formation. The alkaline pH level causes activation of alkaline phosphatise enzyme that induces osteoblastic activity.16 However, calcium hydroxide also acts by other mechanisms.17 When used as a pulp capping agent, it induces dentin bridge formation.18 The alkaline pH concentration may be responsible for the formation of dentin bridge.19
Pulpal fibroblast-like cells differentiate and may lead to dentinogenesis. When placed in contact with connective tissue, these cells promote the formation of a cementoid barrier. In vitro studies have demonstrated the fibroblast-like cells, when in direct contact with the calcium hydroxide, exhibit dramatic alteration in the morphology, growth rate, protein synthesis, and alkaline phosphatase activity.20 However, because calcium hydroxide is soluble and degrades with time, it may not provide a permanent long-term bacteriometic seal if the restoration eventually fails.21
In other endodontic procedures, calcium hydroxide allows clinical control of infection and may improve the prognosis for apical periodontitis. Some authors report a success rate of approximately 81% after 5 years of treatment with the use of calcium hydroxide in infected teeth.22 However, the main disadvantage of calcium hydroxide is that it must be replaced many times in apexification and foraminal closure, which are consequently long-term procedures, requiring 6 to 18 months to obtain an apical barrier,23 and a reduction in microhardness of root dentin has been shown after applying long-term calcium hydroxide therapy.
Calcium Silicate-Based Bioactive Materials
Mineral Trioxide Aggregate
MTA was developed by Torabinejad and White in the early 1990s as a potential root-end filling material or for use as a repair material for lateral root perforations.24 It is composed mainly of tricalcium silicate, dicalcium silicate, tricalcium aluminate, and tetracalcium aluminoferrite. Initially available only in gray, white MTA was subsequently introduced due to the discoloration potential associated with gray MTA.25 White MTA lacks the aluminoferrite phase that imparts grayness.26
Nontoxic and biocompatible, the material induces the formation of mineralized tissues.27 The mechanism of formation of hard tissues is the calcium oxides of MTA reacting with tissue fluids to form calcium hydroxide. Some authors believe the high alkaline nature of MTA is mainly due to the calcium hydroxide that is formed and is also responsible for its biological properties.28 Antibacterial and antifungal activities have also been studied.29 The antibacterial effect of MTA was less than that of calcium hydroxide. Its sealing ability has been extensively evaluated using various methods and was found to be superior to conventional reterograde filling materials.30
Studies of MTA as an apexification material have found it to provide a good apical seal. A 5-mm apical barrier of MTA followed by GP condensation after 24 hours has been advocated.31 MTA has shown to resist compaction forces of GP condensation. The sealing ability, biocompatibility, and dentinogenic activity of MTA are attributed to the production of an adherent interfacial layer that resembles hydroxyapatite in composition. It was concluded that calcium ions released from MTA react with the phosphate ions in tissue fluid, yielding hydroxyapatite.32 MTA supports cellular adhesion and cellular growth.33 There is an increase of osteoblastic activity markers (interleukin [IL]-1α, IL-1β, osteocalcin, and alkaline phosphatase) in contact with MTA.34 A study investigating the effects of MTA on cementoblast growth and osteocalcin production in tissue culture has shown that this biomaterial could be considered cementoconductive.35
Bioactive Dentin Substitute
A calcium silicate-based product specifically designed as a dentin replacement material became commercially available in 2009. This bioactive dentin substrate has a wide range of applications, including endodontic repair (root perforations, apexification, resorptive lesions, and retrograde filling material in endodontic surgery) and pulp capping and as a dentin replacement material in restorative dentistry. The material is formulated using MTA-based cement technology and improves on some properties of these types of cements, such as physical qualities and handling. With potential for managing a deep carious cavity in operative dentistry whether or not the pulp is exposed, the material is able to stimulate tissue regeneration and has good pulp response. Its dentin-like mechanical properties have a beneficial effect on living cells and act in a biocompatible manner.36
Comprised mainly of tricalcium silicate, dicalcium silicate, calcium carbonate, calcium oxide, iron oxide, and zirconium dioxide as a radiopacifier, the liquid portion of the product contains calcium chloride and a hydrosoluble polymer. Once mixed, it has a setting time of 12 minutes. The material induces mineralization in the form of osteodentine by expressing markers of odontoblasts and increases transforming growth factor (TGF)-beta 1 secretion from pulpal cells, enabling early mineralization. During the setting of the cement, calcium hydroxide is formed. Due to its high pH level, calcium hydroxide causes irritation at the area of exposure. This zone of coagulation necrosis has been suggested to cause division and migration of precursor cells to the substrate surface—the addition and cytodifferentiation into odontoblast-like cells.37 Therefore, this material induces apposition of reactionary dentin by odontoblast stimulation and reparative dentin by cell differentiation.
Biocompatibility has been investigated by various authors. Laurent et al tested the calcium silicate-based material to evaluate its genotoxicity, cytoxicity, and effects on the target cell’s specific function. The study concluded that it is biocompatible. Also, the material was not found to affect the specific functions of the target cells and, thus, could safely be used. Further, it does not impact human pulp fibroblast functions, expression of alpha type 1 collagen, dentine sialoprotein, and Nestin.36,38
The marginal adaptation of the bioactive substrate has been observed to be micromechanical. The high pH level causes organic tissues to dissolve from the dentin tubule. The alkaline environment at the boundary area of contact between the material and hard tooth substance opens a path through which the dentin substitute mass can enter the exposed opening of the dentin canaliculi.39 The material is used as a pulp capping agent, inducing the formation of a dentin bridge. Histologic studies comparing the dentin bridge formed between MTA and the bioactive substrate have concluded that the material induces complete dentin bridge without any evidence of pulpal inflammation.40 Due to excellent sealing properties and bioactivity, the bioactive substrate material has also been advocated as a root-end filling material or for root perforations.41 Other clinical applications include apexification and primary tooth pulpotomy.
Calcium Phosphate Biomaterials
Calcium phosphate biomaterials are biocompatible and nontoxic and can induce mineralized tissue formation. Partial dissolution of calcium phosphate ceramics leads to precipitation of apatite microcrystals in the center and on the surfaces of the biomaterial. These biomaterials also sustain cellular degradations (phagocytosis and osteoclasis) and are replaced by new hard, calcified tissue. The biomaterial can favor osteoconduction by its porosity, allowing colonization of either bone or the dental pulp implantation site by osseous cells such as osteocytes and osteoblasts.
Calcium phosphate biomaterials act as scaffold for the formation of new mineralized tissue. They are able to create a tight bond with mineralized tissues, which could serve as an effective barrier against bacterial leakage in the apical area and dentin–pulp interface.42
Calcium Phosphate Ceramics
Studies on calcium phosphate ceramics have identified their bioactivity and sealing abilities. These materials can be used in pulp capping and apexification or during endodontic surgery.43 Many in vivo studies explored the use of different types of calcium phosphate ceramics in pulp capping in efforts to induce new dentin formation without an initial necrotic fibrous layer and while avoiding pulpal cell alterations usually observed using calcium hydroxide products.
Satisfactory results were reported with hydroxyapatite (HA), tricalcium phosphate (β-TCP), biphasic calcium phosphate (BCP; an intimate mixture of HA and β-TCP), octacalcium phosphate (OCP), and dicalcium phosphate dihydrate (DCPD).44,45 HA is ideal as an inorganic component of calcified tissues. DCPD, OCP, and β-TCP are able to transform into apatites similar to biologic apatites.46
In vivo studies evaluating the dentinogenic effect of calcium phosphate ceramics on animal models reported three types of mineralization: dentin bridge formation, dystrophic calcification, and mineralization. Microparticles of β-TCP, HA, and BCP are responsible for the formation of a calcified bridge similar to that observed with calcium hydroxide, although success was more frequently obtained with HA and BCP.47 OCP and DCPD evaluated in various animal models caused extensive dystrophic mineralized tissue in the pulp chamber and also along the root canal walls. Using macroparticles of β-TCP, HA, or BCP in animal models, homogenous mineralization was observed around the biomaterials.48
These histologic observations have suggested calcium phosphate ceramics may be useful for specific applications in endodontics, including microparticles of HA, TCP, and BCP for pulp capping, and macroparticles of HA, OCP, and DCPD for pulpotomy and apexification.
Calcium Phosphate Cements
The concept of apatitic calcium phosphate cement (CPC) was first introduced by LeGeros in 1982. CPCs have been used as bone substitutes to repair craniofacial defects and proposed for use in pulp capping, endodontic sealing, and filling.49,50 New self-setting CPCs containing calcium oxide (CaO) or calcium hydroxide have also been developed; these biomaterials may be an interesting alternative to calcium hydroxide, which is currently used in endodontics. A monocalcium phosphate-monohydrate–CaO-based cement was recently proposed for endodontic treatment with better mechanical properties than calcium hydroxide. The setting reaction produced a mixture of calcium-deficient hydroxyapatite (CDHA) and calcium hydroxide. The presence of calcium hydroxide would confer antibacterial properties to this CPC. Similarly, by mixing DCPD and CaO, a CPC with better mechanical and physical properties for dental applications was obtained. This DCPD–CaO-based cement provided a better seal than the one obtained using zinc oxide-eugenol cement with or without a GP point. In addition, this cement also presented antibacterial effects due to the presence of calcium hydroxide.51
Another composite material consisting of MTA with a CPC matrix was also developed as a root-end filling material to combine the qualities, biological properties, and sealing ability of each biomaterial and to improve its manipulation characteristics.52 Its chemical properties and biocompatibility are similar to those of MTA. In addition, chitosan-based cements, which are nonrigid cellulosic cements, were evaluated and the preliminary results on their bioactivity and biocompatibility showed that they could be promising for various dental applications such as endodontics.53
The relatively small size and lack of accessibility of the various endodontic sites have necessitated the development of injectable forms of calcium phosphate cement. However, its thick consistency is not suitable for injection purposes, and thus numerous materials have been added to improve its rheological properties. Experimental studies have been conducted with glycerine,54 silicon gel,55 polyethylene glycol, liquid paraffin, glycerol56 cellulose, and titanium dioxide.57 To promote periapical tissue healing, the addition of another gel agent, chondroitin sulfate, was also proposed in CPC formulation. Other components, such as dispersants, binders, plasticizers, or drugs, can be incorporated to modify their biological properties and injectability. Several in vivo studies58 were made with CPC used as a sealer in association with GP. CPC was more biocompatible and induced a less inflammatory reaction compared with zinc oxide-eugenol sealer.
In endodontics, a composite material of calcium phosphate and collagenic gel was first tested on monkeys in 1977 and 1978 in apexification, pulpotomy, and partial pulpectomy to induce the physiological canal space closure.58,59 This composite gel was shown to promote pulp calcification. Nontoxic and biocompatible, it was resorbed and replaced by mineralized tissues that looked like dentin or cementum.
Injectable Bone Substitutes
Injectable bone substitute (IBS) material is a ceramic consisting of biphasic calcium phosphate in a matrix of hydroxypropylmethyl cellulose.60 The main feature of this injectable biomaterial is the mineral component with various HA:β-TCP ratios, making it possible to control its kinetics of dissolution and precipitation, and, subsequently, the bioactivity of the bone substitute.61 CPCs provide dense biomaterials with irregular microporosity, whereas macroporosity is known to be an essential factor for homogeneous and early bone colonization.62
In endodontics, the difficulty in injecting a ceramic through a thin needle relates to the water used as the liquid-phase carrier. However, injectable calcium phosphate biomaterials would be able to pass through thin needles and dental root canals without alteration or demixing of the phases. Water or liquid phases without viscous consistency show Newtonian properties, and an aqueous polymer solution is a better carrier for mineral granules. Apparent viscosity measurements and extrusion tests have indicated that macromolecules are most suitable for this purpose. An injectable composite IBS (80 μm to 200 μm) consisting of a 2% aqueous cellulose ether solution and biphasic calcium phosphate granules of 80 μm to 200 μm have been tested. The cellulosic gels are pseudoplastic, and their viscosity decreases with the shearing during the extrusion from the syringe and increases after injection. To develop an injectable composite for endodontics, small calcium phosphate granules are preferable for injection in a narrow root canal. Few studies have been conducted on the role of particle size of calcium phosphate ceramic on wound healing and calcified tissue ingrowth, but the few available have shown conflicting results.63
In vivo studies have investigated the biologic effects of IBS with various particle sizes: 40 μm to 80 μm, 80 μm to 200 μm, and 200 μm to 500 μm. These studies confirmed that small calcium phosphate particles (40 μm to 80 μm) support bone ingrowth to a similar extent to larger ones. The BCP degradation and bone substitution process occurred earlier and faster for IBS 40 μm to 80 μm than for IBS 200 μm to 500 μm. Qualitatively, IBS with small BCP particle granulometry was shown to be more favorable for restoration of the initial trabecular structure IBS (40 μm to 80 μm).
These preliminary results obtained with BCP/hydrosoluble polymer composites, described as IBS, demonstrated that they could be used in endodontics as a possible root canal filling material. However, further in vivo investigations and clinical studies are needed to assess the performances of this new injectable bioactive material in everyday endodontic procedures.
Conclusion
The range of biomaterials in dental surgery, especially in endodontics, has increased in recent years. MTA and calcium phosphate biomaterials have been assessed as biocompatible and bioactive alternatives to current filling materials. They have demonstrated their efficiency in inducing some mineralized tissues. To improve their ease of use, an important evolution in this field was observed with the development of various injectable calcium phosphate biomaterials. Composite biomaterials such as injectable bone substitutes (consisting of calcium phosphate in a polymer matrix) could have the necessary qualities for root canal fillers. They combine biocompatibility, bioactivity, and the rheological properties to be injected in a narrow root canal.
About the Authors
Satyajit Mohapatra, MDS
Post Graduate
Department of Endodontics
Institute of Dental Sciences
Bhubaneswar, India
Swadheena Patro, MDS
Reader
Department of Endodontics
Institute of Dental Sciences
Bhubaneswar, India
Sumita Mishra, MDS
Senior Lecturer
Department of Orthodontics
Institute of Dental Sciences
Bhubaneswar, India
Queries to the author regarding this course may be submitted to authorqueries@aegiscomm.com.
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