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Garchitorena Ferreira, María Inés

Bioactive materials in remineralization Garchitorena Ferreira, María Inés*

Abstract The focus of the treatment of carious lesions affecting dentin tissue has changed dramatically in recent decades. Knowledge about the etiology of dental caries, dentin pathophysiology and the development of dental biomaterials and adhesive techniques have resulted in minimal intervention treatments. Given this new alternative for treating dentin lesions, it is necessary to evaluate the potential recovery of dentin through mineralization treatments and the development of bioactive materials that facilitate the repair or regeneration of this tissue by imitating the physiological mechanisms of mineralization and recomposing the tissue’s original mechanical properties. This is done to obtain successful clinical results based on biomimetic treatments.

Keywords: Dentin, Remineralization, .

* Assistant Prof. Operative Dentistry 1, Universidad de la República. Uruguay

Received on: 15 Mar 16 – Accepted on: 17 Aug 16

Odontoestomatología / Vol. XVIII. Nº 28 / November 2016 11 Introduction mechanisms of tissue mineralization. Therefore, knowing how these processes Several studies have been conducted to have naturally occur in odontogenesis and a better understanding of the biological and understanding cellular signaling by bio-active microstructural changes in dentin tissue components released from the dentin matrix regarding caries lesions and the possibility of during injury may help develop techniques remineralizing the tissue involved (1-5). and materials to facilitate the biomechanical Dentin is altered on account of produced recovery of the dentin affected by pathological by , both in its inorganic and organic processes, surgical procedures and restorative constituents. These acids lead to dentin tissue materials (8). demineralization, with the subsequent loss of Caries-affected dentin regeneration is a crystals. They also alter the organic desirable clinical approach which is opposed matrix, that is to say, the fibers. to traditional practice whereby the tissue is Caries-affected dentin which is preserved in fully removed from the dental preparation. the preparation after eliminating the infected The partial removal of carious dentin, when tissue is potentially repairable (6). However, health condition and pulp response are it must be noted that the structure of this correctly diagnosed, allows for the necessary residual dentin has specific histologic features biological conditions to prevent the lesion on account of the lesion. from progressing and to promote pulp A detailed review of the studies conducted to defense mechanisms. The hermetic seal of date into dentin remineralization sheds light the restoration is essential for a conservative on several aspects and illustrates the need to treatment to be successful, within continue developing materials with clinical comprehensive planning based on minimal applications that can complement minimal intervention principles (9-12). intervention treatment plans. However, dentin tissue recovery is a complex process as it involves the reconstitution Development of two different phases: type-I organic collagen and inorganic , which have The modern treatment of carious lesions a specific spatial connection. This composite involves the removal of only the infected structure of dentin is denatured on account external dentin, while internal dentin that of demineralization and the subsequent can be remineralized is preserved (7). breakdown of collagen polymerization Therefore, after excavation of the carious when facing the conditions of carious lesions, it is likely that the substrate for lesions. This means that remineralization on clinical bonding to restorative materials will its own is insufficient for the full recovery be a combination of normal dentin on the of demineralized carious dentin. It is also periphery and of affected dentin in the center necessary to regenerate the structure of the of the lesion. The mineral distribution of the collagen matrix, and both stages must be caries-affected dentin is highly variable, and connected in a specific way. The recovery the depth of the lesion can extend hundreds of denatured collagen can be crucial to re- of microns below the excavated surface. establish the micromechanical properties The biomimetics treatment of caries-affected of carious dentin through intrafibrillar tissues involves guiding remineralization, remineralization (13). following or imitating the physiological Some studies show that the deeper sites

12 Garchitorena Ferreira, María Inés need to contain residual for the included in oral health products. For instance, dentin affected by carious lesions to be these can be mouthwashes and toothpastes remineralized. This should be intrafibrillar containing nano- that interact with mineral to allow for nucleation and growth and precipitate on the surface. during remineralization (1, 4). It has been They can also be products containing determined that remineralization occurs nanomaterials to remineralize early enamel through the growth of crystals that tend to sub-micrometric lesions. However, research increase in size and eventually bond, thus on the use of nanomaterials in larger cavities forming tissue that is more homogeneously is still under way (15). remineralized (1). Conventional remineralization of the carious Remineralized tissue that has restored dentin often involves using solutions with mechanical properties under physiological and in various fluoride conditions indicates that mineral crystallites concentrations. It has been well established are closely linked or even chemically bound to that conventional remineralization does the collagen matrix. The quality of the dentin not occur through spontaneous nucleation will depend on the tissue’s characteristics: of the mineral in the organic matrix, but microstructure, mineral density and location rather through the growth of residual apatite of minerals in the organic matrix (1, 14). crystals in partially demineralized dentin. Biomaterials are elements used to repair or The conventional remineralization strategy replace damaged organs or tissues. Research relies on epitaxial growth on existing apatite on biomaterials began in the 1960s, as the crystals. If there are none or very few residual discipline started to develop as a science. At crystals, there is no remineralization. The first they were inert materials, and as of the mineral content of the surface layer of the 1980s a second generation began: bioactive lesion impacts the characteristics of the materials. These materials can replace tissues. resulting remineralization, including its Nowadays scientific research develops location and mineral deposition density (2). cells and tissues, that is to say, regenerating In turn, guided tissue remineralization resorts biomaterials. These promote cell activation to biomimetic analogs of dentin matrix and aid the regeneration of specific tissues. phosphoproteins to induce amorphous This is how biomaterials science intersects (ACP) nanoprecursors with tissue engineering, an area of bio- in the internal compartments of collagen engineering that focuses on the recovery of fibrils (16). This strategy is independent from biological functions, as these materials require apatite crystallites that may have remained. or gel-based supports or scaffolds to This biomimetic remineralization process guide cell proliferation. To do this, supports is a bottom-up approach used to create must be porous and biodegradable. nanocrystals that are small enough to fit in or supports, or polymer-ceramic the gaps between adjacent collagen molecules supports are used, and research currently and establish a hierarchical order regarding focuses on developing nanoscale supports. mineralized collagen (Fig. 1). Both totally Their ceramic phase is formed by bioactive and partially demineralized dentin, with , containing (SiO2), calcium reconstituted type-I collagen fibrils that are oxide (CaO) and oxide (P2O5). completely devoid of matrix phosphoproteins In recent years, biomimetic approaches have have been successfully remineralized with this been adopted to develop nanomaterials to be strategy (2).

Bioactive materials in dentin remineralization 13 industries. Polyvinylphosphonic acid (PVPA) is a polyelectrolyte that has been used as a biomimetic analog for phosphoproteins like Dentin matrix acidic phosphoprotein 1 (DMP1) and dentin phosphoprotein (DPP) (20).

Fig. 1 ACP nanoprecursors are indicated with arrows (Tay 2008)

Some people are working on the experimental stages, and, in some cases, selling various dental materials used to recompose dentin tissue. Bioactive are surface-active materials which minerals can bind to. The basic components of bioactive glasses are calcium oxide, sodium, phosphorus and silica (17). Although most information has been acquired through research, this material has also been used in dentistry, and Fig. 2 TEM image of a bioactive glass nanoparticle there is growing interest in this area, especially for (Vollenweider 2007) dentin mineralization or remineralization (18). Amorphous calcium phosphate (ACP) is Bioactive glasses are thought to form a an HA precursor, this being the final and bioactive layer at the interface in contact stable product in the precipitation of calcium with live tissue called (HCA), and phosphate ions in neutral or alkaline which is equivalent to the mineral phase of solutions. Regarding the large scope of hard human tissues (19). solution conditions in which precipitation A significantly higher remineralization rate occurs spontaneously, amorphous calcium has been observed with the use of bioactive phosphate precedes the occurrence of HA. glass nanoparticles as opposed to micrometric This is why they have been studied as a filler glass particles. This confirms the importance phase in polymeric materials, stimulated by of particle size in the clinical applications of its excellent biocompatibility and the release bioglasses (Fig. 2). of calcium and phosphate ions (21). Polyelectrolytes are whose repeating However, in their application for dental units bear an electrolyte group. These groups materials, the relatively high solubility dissociate in aqueous solutions, making the of ACP and its quick conversion to polymers charged. Charged molecular chains, ACP in an aqueous environment might commonly present in several soft matter entail limitations regarding structural, systems, play a key role in determining the mechanical and chemical stability (21). The structure, stability and interactions of various nanocomplex casein amorphous calcium molecular assemblies. Both natural and phosphate (RecaldentTM (CPP-ACP) is synthetic polyelectrolytes are used in a variety of technology based on ACP stabilized by casein

14 Garchitorena Ferreira, María Inés phosphopeptides (CPP), making them a apatite formation. Additionally, the hydroxyl metastable complex. This technology has ions that are released during hydration can shown anticariogenic activity in both in create unfavorable conditions for bacteria situ studies and clinical trials. Additionally, survival and proliferation. Antibacterial a significant increase has been observed in properties are necessary mainly in the dentin- the levels of calcium and phosphate ions on restoration interfacial area. supragingival plaque when mouthwash is used. Although glass-ionomer contain Also, the in situ remineralization of enamel calcium and phosphate, they show no subsuperficial lesions is promoted (22). These bioactivity. Besides, there is a wealth of properties might make ACP an effective information on the positive effects of fluoride mineralizing agent (21). ACP bioactivity on the enamel, but there is no data proving may prove particularly useful when included the efficacy of fluoride ions to induce in composite resins, sealants and adhesives mineralization in demineralized dentin or to in order to prevent tooth demineralization contribute to the nucleation of new apatite and to actively promote remineralization. crystallites in dentin with no residual apatite, According to a study published in 2003, the with the use of classic glass ionomers (24). inclusion of silica (Si) and/or zirconia (Zr) in It would be beneficial if glass-ionomer the ACP improves the duration of the release had bioactivity, as nowadays biomaterials of mineral ions through the slower conversion with therapeutic or bioactive functions tend to HAP observed in the composite (23). to be developed, which add to its inherent Calcium silicate cements, called mineral properties (18). trioxide aggregate cements (MTA, such Recently a technique that involves the guided as ProRoot MTA, MTA Angelus, Tech formation of a layer of fluorapatite that Biosealer) are derivatives. resembles enamel has been developed. This They are used as dentistry materials for is done on a mineral substrate and has the different clinical applications, particularly potential to enhance the remineralization in endodontics. Calcium silicate cements of superficial enamel and/or exposed are hydrophilic materials that can tolerate dentin defects. This technique, Biomimetic humidity and that harden with biofluids Mineralization (BIMIN), uses calcium ions (blood, plasma, saliva, dentinal fluid). These diffusion from a solution in a glycerin-enriched materials can release calcium and hydroxyl gel with phosphate and fluoride ions. When ions (alkalizing activity) into surrounding the conditioned gel is in direct contact with fluids, thus creating the conditions necessary the tooth’s exposed surface, a mineral layer for apatite formation (24). firmly adhered to the tooth’s surface is formed An in vitro study published in 2011 showed within eight hours. The recent application of the bioactivity of experimental composite BIMIN in a clinical feasibility study showed resins containing calcium-silicate powder the formation of a fluorapatite deposit on (24). Selecting the correct hydrophilic resin . Biomimetic mineralization is to prepare experimental compounds was based on the principle of crystallization essential to provide the absorbing from oversaturated solutions and involves the capacity and bioactivity properties: the controlled diffusion of calcium, phosphate absorption of small amounts of water leads and fluoride ions onto the tooth’s surface. It to the hydration of calcium-silicate filling has been proven that this technique generates materials, which allows for calcium release and fluorapatite on enamel prisms, which was

Bioactive materials in dentin remineralization 15 confirmed by X-ray diffraction. More recently, affected dentin that remains after the partial the in vivo biomimetic mineralization effect removal of the carious lesions. on human enamel has been reported. In this Mineral formation is a necessary, but may not case, night application led to the formation of be a sufficient, condition for reestablishing a layer that resembled enamel on the tooth’s dentin functionality after remineralization surface. (25) A possible BIMIN application treatments (14). Mineral concentration is the precipitation of minerals on dentin in itself is insufficient to evaluate the surfaces, thus obstructing open tubules. This success of current remineralization makes it possible for this method to have a strategies. Mechanical recovery seems to clinical application for treating sensitivity, be partially reestablished when the mineral erosion and other conditions (25). is incorporated into the structure, but its connection with the matrix is different from physiological recovery (1). Re-establishment Discussion of functionality requires both the formation Several studies have reported, in the last few of extrafibrillar and intrafibrillar minerals in decades, scientists’ efforts to remineralize the gap regions of the collagen fibrils (14). dentin, including the use of phosphoproteins Therefore, intrafibrillar remineralization in (26), casein amorphous calcium phosphate particular is essential to restore the mechanical phosphopeptides (21, 27), bioactive glass properties of dentin (2, 3, 14, 29). particles (28), colloidal nano-beta-tricalcium It is still difficult for new advances in phosphate (13) and polyelectrolytes containing remineralizing biomaterials to be translated carboxylic acids (20). These studies have reported into materials that are available on the market. relative success in the mineral formation where However, research is promising and predicts a the dentin lesion is located (1). not so distant future where clinicians can have The ideal biomaterial should promote reactive a large range of bioactive materials at their dentin deposition and also remineralize the disposal to help them in their conservative treatments in restorative dentistry (Table 1).

IN VITRO IN VIVO VEHICLE/ BIOACTIVE ELEMENT BIOACTIVITY STUDIES STUDIES BIOMATERIAL OSTEINDUCTION NANOSCALE BIOGLASSES YES NO GLASS IONOMERS OSTEOCONDUCTION ANALOGS. MEDIA CONTAINING CALCIUM POLYELECTROLYTES INTRAFIBRILLAR REMIN. IN THE YES NO PRESENCE OF PHOSPHATES GLASS IONOMERS. COMMERCIAL PRECIPITATES WITH CALCIUM AND FLUORIDE YES YES PRODUCT: FUJI TRIAGE, FUJI GP PHOSPAHTE AS FLUORAPATITE AND BIMIN SYSTEM PROMOTES REPAIRING DENTIN ON CALCIUM ACCOUNT OF PULP NECROSIS. NO YES YES COMPOSITE RESINS REMINERALIZING EFFECT COMPOSITE RESINS, ADHESIVE RELEASE OF CALCIUM AND CPP-ACP YES YES SYSTEMS. COMMERCIAL PHOSPHATE IONS PRODUCT: RIVA PROTECT COLLOIDAL NANO-BETA- INTRAFIBRILLAR YES NO COMPOSITE RESINS TRICALCIUM PHOSPHATE REMINERALIZATION COMPOSITE RESINSCOMMERCIAL HYDROXYAPATITE. PROMOTES CALCIUM SILICATE YES NO PRODUCT: MTA, PRO ROOT AND DENTIN REGENERARTION AS BIODENTINE Table 1. Table comparing materials being developed and sold

16 Garchitorena Ferreira, María Inés Final remarks 82 (12): 941-43. 6. Bresciani E, Wagner WC, Navarro There is currently no clinical product MFL, Dickens SH, Peters MC. In vivo available on the market to achieve biomimetic dentin microhardness beneath a calcium remineralization (25). However, great phosphate cement. J Dent Res. 2010 progress is being made into biomaterials, 89(8) 836- 41. especially by applying and 7. Mehdawi I, Abou Neel EA, Valappil SP, tissue engineering. Palmer G, Salih V, Pratten J, Spratt DA, Nanotechnology has made it possible to develop Young AM. Development of remineralizing, materials with bioactive properties that can act antibacterial dental materials. Acta at nanoscale levels, activating cells and tissues to Biomater. 2009; 5: 2525-39. promote tissue regeneration (30). 8. Smith AJ, Tobias RS, Murray PE. The development of dentin regenerating Transdentinal stimulation of reactionary biomaterials will make it possible to dentinogenesis in ferrets by dentine matrix recompose the complex structure of this components. J Dent. 2001; 29: 341-46. tissue, and it will also be able to recover 9. Bjorndal L, Reit C, Bruun G, Markvart M, when facing the masticatory effort. This will Kjaldgaard M, Nasman P et al. Treatment contribute to improving restorative dentistry, of deep caries lesions in adults: randomized regarding both the maximum conservation of clinical trials comparing stepwise vs. direct healthy tissue and tissue regeneration. complete excavation, and direct pulp capping vs. partial pulpotomy. Eur J Oral References Sci. 2010; 118: 290-7. 10. Alves L, Fontanella V, Damo A, Ferreira 1. Bertassoni LE, Habelitz S, Marshall SJ, de Oliveira E, Maltz M. Qualitative and Marshall GW. Mechanical recovery of quantitative radiographic assessment dentin following remineralization in of sealed carious dentin: a 10-year vitro- an indentation study. J Biomech. prospective study. Oral Surg Oral Med Jan 2011; 44 (1): 176-81 Oral Pathol Oral Radiol Endod. 2010 2. Dai L, Liu Y, Salameh Z, Khan S, Mao J, Jan;109(1):135-41. Pashley DH, Tay FR. Can caries-affected 11. Schwendicke F. Incomplete Caries dentin be completely remineralized by Removal: A Systematic Review and Meta- guided tissue remineralization? Dent analysis. J Dent Res 2013; 92 (4): 306-14. Hypotheses. Jan 2011; 2 (2): 74-82 12. Maltz M, Oliveira EF, Fontanella V, 3. Kinney JH, Habelitz S, Marshall SJ, Carminatti G. Deep caries Lesions after Marshall GW. The importance of incomplete dentine caries removal: intrafibrillar mineralization of collagen 40-month follow-up study. Caries Res on the mechanical properties of dentin. J 2007; 41(6):493-6. Dent Res. 2003; 82 (12) 957-61 13. Shibata Y, He LH, Kataoka Y, Miyazaki 4. Ten Cate JM. Remineralization of caries T, Swain MV. Micromechanical property lesions extending into dentin. J Dent Res. recovery of human carious dentin 2001; 80 (5): 1407-11. achieved with colloidal nano-beta- 5. Veis A. : on the trail of tricalcium phosphate. J Dent Res. 2008; the phosphate. Part I: Chance encounters 87:233-7 and the path to dentin. J Dent Res. 2003; 14. Bertassoni LE, Habelitz S, Kinney JH,

Bioactive materials in dentin remineralization 17 Marshall SJ, Marshall GW. Biomechanical evidence? Austr Dent J 2008; 53:268-73. perspective on the remineralization of 23. Dickens SH, Flaim GM, Takagi dentin. Caries Res. 2009; 43: 70-7. S. Mechanical properties and 15. Hannig M, Hannig C. Nanomaterials in biochemical activity of remineralizing preventive dentistry. Nat Nanotechnol resin-based Ca-PO4 cements. Dent 2010; 5:565–9. Mater.2003;19:558-66. 16. Gu L, Kim YK, Liu Y, Ryou H, Wimmer 24. Gandolfi MG, Taddei P, Siboni F, Modena CE, Dai L, Arola DD, Looney SW, E, De Stefano ED, Prati C. Biomimetic Pachley DH, Tay FR. Biomimetic analogs remineralization of human dentin using for collagen biomineralization. J Dent promising innovative calcium silicate Res.2011; 90 (1): 82-7. hybrid “smart” materials. Dent Mater. 17. Yli-Urpo H, Narhi M, Narhi T. Compound 2011. 27. 1055 69. changes and tooth mineralization effects 25. Guentsch A, Seidler K, Nietzsche S, Hefti of glass ionomer cements containing AF, Preshaw PM, Watts DC, Jandt KD, bioactive glass (S53P4), an in vivo study. Sigusch BW. Biomimetc mineralization: Biomater. 2005; 26: 5934-41. long-term observations in patients with 18. Prabhakar AR, Paul J, Besappa dentin sensitivity. Dent Mater. 2012; 28: N. Comparative evaluation of the 457-64. remineralizing effects and surface26. Saito T, Yamauchi M, Crenshaw MA. microhardness of glass ionomer cements Apatite induction by insoluble dentin containing bioactive glass (S53P4): an in collagen. J Bone Miner Res. 1998; 13(2): vitro study. Int J Clin Ped Dent. 2010; 3 265-70. (2): 69-77. 27. Rahiotis C, Vougiouklakis G. Effect of a 19. Salonen JI, Arjasamaa M, Tuominen U, CPP-ACP agent on the demineralization Behbehani MJ, Zaatar EI. Bioactive glass and remineralization of dentine in vitro. J in dentistry. J Minim Interv Dent. 2009; Dent. 2007; 35: 695-98. 2(4): 208-18. 28. Vollenweider M, Brunner TJ, Knecht S, 20. Tay FR, Pashley DH. Guided tissue Grass RN, Zehnder M, Imfeld T, Stark remineralization of partially demineralized WJ. Remineralization of human dentin human dentin. Biomater. 2008; 29: using ultrafine bioactive glass particles. 1127-37. Acta Biomater. 2007; 3: 936-43. 21. Skrtic D, Antonucci JM, Eanes ED. 29. Kim YK, Yiu CKY, Kim JR, Gu L, Kim Amorphous calcium phosphate-based SK, Weller RN, Pashley DH, Tay FR. bioactive polymeric composites for Failure of a glass ionomer to remineralize mineralized tissue regeneration. J Res Natl apatite depleted dentin. J Dent Res. 2010. Inst Stand Technol. 2003; 108: 167-82. 89(3) 230 35. 22. Reynolds EC. Calcium phosphate-based 30. Mantri SS, Mantri SP. The nano era remineralization systems: Scientific in dentistry. Sci Biol Med. 2013 Jan- Jun; 4(1): 39-44.

María Inés Garchitorena: [email protected]

18 Garchitorena Ferreira, María Inés