JODE Biomineralization and Biomaterial Considerations10.5005/jp-journals-10047-0004 in Dentin Remineralization INVITED REVIEW Biomineralization and Biomaterial Considerations in Dentin Remineralization 1Xu Zhang, 2Zuohui Xiao, 3Haorong Wang, 4Anil Kishen ABSTRACT during the demineralization process. From a clinical Dentin is a composite hard tissue, comprising of inorganic standpoint, optimal remineralization of a demineralized and organic matrices, and regulated by many proteins during dentin layer will aid in preventing/treating dentin caries, development. The demineralization of dentin results from the root caries, and dentin hypersensitivity.3 These strategies loss of inorganic matrix [mainly hydroxyapatite (HAP)], but the would serve as the foundation for minimally invasive organic matrix (mainly type I collagen) will sustain for a period approaches in the management of early dental caries. of time after demineralization. Over the past decade, there has Dentin remineralization is a complex process and been a growing interest on the remineralization of demineralized dentin, primarily in connection with minimally invasive caries most relevant research in dentin remineralization management. More and more biomaterials and methods are involves the understanding of the property of dentin currently being evaluated to achieve newer approaches for matrix, the composition of remineralization solution and the remineralization of demineralized dentin. These strategies the interaction between the matrix and solution. In dentin are mostly based on biomimetic approaches and aim to matrix, besides inorganic fraction [mainly hydroxyapatite achieve the characteristics of natural hard tissue. This article (HAP)], it also consists of significant levels of organic matrix will present a complete review on the basic compositions and properties of dentin, which formed the basis for the biomimetic that comprises of type I collagen and noncollagenous remineralization of demineralized dentin. proteins (NCPs), such as dentin matrix protein (DMP1) and dentin phosphoprotein (DPP), also known as DMP2 Keywords: Biomineralization, Collagen, Dentin, Non- collagenous proteins, Remineralization. or phosphophoryn, with highly phosphorylated serine and threonine residues.4 The NCPs has an important How to cite this article: Zhang X, Xiao Z, Wang H, Kishen role in the mineralization of collagen fibrils. According A. Biomineralization and Biomaterial Considerations in Dentin Remineralization. J Oper Dent Endod 2016;1(1):7-12. to the location within the collagen fibrils, the apatite crystallites are classified into extrafibrillar minerals Source of support: Nil and intrafibrillar minerals. Extrafibrillar minerals are Conflict of interest: None located in spaces separating the collagen fibrils, while the intrafibrillar minerals are largely in the gap regions of INTRODUCTION the fibrils extending between tropocollagen molecules.5-7 Management of demineralized dentin is an important It is suggested that remineralization mechanisms in 8-11 issue in dentistry. Clinicians routinely favor removing enamel and dentin are similar. Many studies have the softened dentin completely based on the hypothesis demonstrated that methods used in enamel remineraliza- that softened dentin is typically infected dentin.1 It is tion would also work in case of dentin remineralization. established that softening of dentin always precedes A typical example for this is the application of fluoride. bacterial invasion and leaves a layer that is soft but not Currently, an accepted notion is that dentin remineraliza- infected. This layer of demineralized dentin is thick in tion occurs neither by spontaneous precipitation nor by acute caries.2 The term remineralization of dental tissue nucleation of mineral on the organic matrix but by the 3 refers to the replacement of the mineral fraction lost growth of residual crystals in the lesions. However, the role of organic matrix in association with the residual crystals (inorganic matrix) on dentin remineralization is 1Associate Professor, 2,3Graduate Student, 4Professor and Head debated. It has been indicated that if NCPs, as inhibitors of 1-3Department of Endodontics, School and Hospital of mineralization are removed, mineralization would occur 3 Stomatology, Tianjin Medical University, Tianjin, PR China on the completely demineralized dentin substrate. On 12 4Discipline of Endodontics, Faculty of Dentistry, University of the other hand, Saito et al reported that if completely Toronto, Toronto, Canada demineralized dentin collagen (by EDTA treatment) Corresponding Author: Anil Kishen, Professor and Head contains a higher content of ester phosphate, it would 3 Discipline of Endodontics, Faculty of Dentistry, University of induce remineralization. In addition, Kawasaki et al have Toronto, 124 Edward Street, Toronto, Ontario, Canada, e-mail: reported that the presence of fluoride could overcome the [email protected] inhibitory effect of NCPs on mineralization. Journal of Operative Dentistry and Endodontics, January-June 2016;1(1):7-12 7 Xu Zhang et al In dentin remineralization, the role of (a) inorganic matrix, (b) organic matrix, and (c) inorganic/organic additives in remineralization solution, needs to be further clarified. This knowledge would form the basis for newer methodologies for the remineralization of dentin or enamel. With improved understanding on the biomin- eralization of dentin and functions of NCPs, biomimetic strategies that are based on the interaction between organ- ic macromolecules and inorganic/organic matrix could be developed for the remineralization of dental hard tissue. The advantage of biomimetic mineralization is that it simulates the natural process of formation of mineral crystals without using special equipment and strict conditions.13 Some biomimetic remineralizing agents have been developed, such as nanocomplexes Fig. 1: Schematic drawing of the odontoblast-predentin region of stabilizer and amorphous calcium phosphate (ACP). during dentinogenesis. Macromolecules are synthesized within 14 the odontoblast cell bodies (below). The constituents of predentin, These nanocomplexes can remineralize enamel lesions, collagen, and proteoglycan (PG) are secreted close to the and when combined with a phosphorylated collagen, odontoblast cell bodies to form the extracellular, nonmineralized these nanocomplexes can remineralize dentin collagen predentin matrix. Some of this proteoglycan fraction is metabolized as well15 These strategies would provide the foundation in predentin. It should be noted that the ‘mineralization front’ is just an operative term, denoting that part of predentin where mineral for the nondestructive and more efficient methodologies formation is initiated17 for the minimally invasive management of dental caries. This review will focus on the biomineralization of dentin Dentin collagen fibrils show a high degree of and the role of inorganic/organic matrix constituents on organization, a strong crystalline character and ability to dentin remineralization. interlock, which might be related to the specific type of NCPs that induced mineralization.24,30,31 In the beginning BIOMINERALIZATION OF DENTIN of the mineralization, the HAP crystals start in gap regions The process of biomineralization of dentin involves the or attach to the collagen fibrils that work as a scaffold. On interaction of NCPs with collagen fibrils and minerals.16 The the other hand, the body fluid composed of extracellular formation of dentin is a tissue-specific biomineralization and intracellular fluid is known as a source of calcium process, which occurs at spatially independent sites and phosphate in biomineralization,32 but the roles of throughout the organic extracellular matrices, mostly other inorganic ions and organic macromolecules in body type I collagen fibrils and NCPs. The schematic drawing fluid and their synergism are not completely elucidated. in Figure 1 depicts the highly polarized odontoblast with its It is considered that calcium ions are transported to the 17 process extending through the predentin into the dentin. mineralization front by a transcellular route, where Ca2+– The mineralization front follows the cell movement activated ATPase, in concert with Na+/Ca2+– exchangers, at the same rate, maintaining an essentially constant calcium channels and intracellular calcium binding 18 width of the unmineralized predentin. In predentin zone, proteins, maintain a delicate calcium ion homeostasis the odontoblast actively secretes collagen to form collagen in odontoblasts.33-37 Phosphate ions are nonspecifically network and proteoglycan (PG). Several noncollagenous cleaved from compounds by alkaline phosphatase to components, such as DPP, γ-carboxyglutamate-containing support mineralization. Activity of alkaline phosphatase proteins of the osteocalcin type (Gla-protein) and a second has been shown to increase at the mineralization front pool of PG, are transported within the odontoblast process when crystal growth is occurring.38 and secreted just in front of the advancing mineralized Understanding the function of body fluid in dentin. In the mineralization front, NCPs interacts with the collagen fibrils and inorganic ions to specifically trap biomineralization is significant for remineralization. Up calcium and phosphate ions to initialize mineralization.19-21 to now, simulated body fluid has widely been used in Furthermore, a second pool of PGs appeared to be the in vitro study of mimetic mineralization. What