Hindawi Stem Cells International Volume 2020, Article ID 5734539, 15 pages https://doi.org/10.1155/2020/5734539 Review Article Tissue Engineering Approaches for Enamel, Dentin, and Pulp Regeneration: An Update Geraldine M. Ahmed ,1,2 Eman A. Abouauf,1,3 Nermeen AbuBakr ,1,4 Christof E. Dörfer,5 and Karim Fawzy El-Sayed1,5,6 1Stem Cell and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo, Egypt 2Department of Endodontics, Faculty of Dentistry, Cairo University, Cairo, Egypt 3Department of Conservative Dentistry, Faculty of Dentistry, Cairo University, Cairo, Egypt 4Oral Biology Department, Faculty of Dentistry, Cairo University, Cairo, Egypt 5Clinic for Conservative Dentistry and Periodontology, School of Dental Medicine, Christian Albrechts University, Kiel, Germany 6Oral Medicine and Periodontology Department, Faculty of Dentistry, Cairo University, Cairo, Egypt Correspondence should be addressed to Geraldine M. Ahmed; [email protected] Received 6 December 2019; Accepted 7 January 2020; Published 25 February 2020 Guest Editor: Alireza Moshaverinia Copyright © 2020 Geraldine M. Ahmed et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Stem/progenitor cells are undifferentiated cells characterized by their exclusive ability for self-renewal and multilineage differentiation potential. In recent years, researchers and investigations explored the prospect of employing stem/progenitor cell therapy in regenerative medicine, especially stem/progenitor cells originating from the oral tissues. In this context, the regeneration of the lost dental tissues including enamel, dentin, and the dental pulp are pivotal targets for stem/progenitor cell therapy. The present review elaborates on the different sources of stem/progenitor cells and their potential clinical applications to regenerate enamel, dentin, and the dental pulpal tissues. 1. Introduction Mesenchymal stem/progenitor cells (MSCs) are unspe- cialized plastic-adherent cells with the ability for self- Dental caries is globally considered among the most prev- renewal and multilineage differentiation [2] into multiple alent bacterially induced diseases, resulting in enamel and cell lineages [3]. They have been isolated from a variety of dentin destruction. If untreated, the destruction will dental tissues, including dental pulp stem cells (DPSCs), mostly lead to irreversible pulpal tissue damage [1]. Cur- stem/progenitor cells isolated from the human pulp of exfo- rently, the classical line of treatment involves the removal liated deciduous teeth (SHED), periodontal ligament stem/- of the affected dental tissues and their subsequent replace- progenitor cells (PDLSCs), stem/progenitor cells from ment with artificial filling materials, with divergent physi- apical papilla (SCAP), alveolar bone-proper-derived stem/- cal and functional properties [1]. Due to various negative progenitor cells (AB-MSCs), gingival mesenchymal stem/- consequences of the restorative techniques and inherent progenitor cells (GMSCs), and dental follicle stem/progenitor deficiencies of the restoration materials, the ideal solutions cells (DFSCs) [4, 5]. The stem/progenitor cells derived from to replace defective dental structures could be by biologi- the oral cavity express several mesenchymal markers, includ- cally restoring/regenerating the lost dental tissues. The ing CD29, CD73, CD90, and CD105, as well as embryonic development of such new alternative treatment methods markers such as Sox2, Nanog, and Oct4 [6], but lack the is currently considered as an important goal for the dental expression of hematopoietic markers, including CD34, therapeutic researches. CD45, and HLA-DR. Relying on their remarkable 2 Stem Cells International proliferative ability and differentiation potential, these stem/- protein- (BMP-) 2 was shown to induce the differentiation of progenitor cells are believed to be very promising in the dental pulp stem/progenitor cells into odontoblasts [23]. It development of future therapeutic approaches to regenerate was also demonstrated that BMP-4 mediates the differentia- the enamel, dentin, and pulpal tissues [7]. tion of human embryonic stem cells into dental epithelium with the ability for tooth formation [28]. In addition, trans- 2. The Tissue Engineering Triad forming growth factor-β (TGF-β) promotes the differentia- tion of odontoblast-like cells and stimulates dental pulp Tissue engineering is an interdisciplinary field that applies stem cell-mediated mineralization [23]. Broadly speaking, the principles of engineering and life sciences towards the these growth factor-mediated cell responses are crucial for development of biological substitutes that could restore, growth, wound healing, and angiogenesis in repair/regenera- maintain, or improve tissue and organ functions [8]. The tion processes [26]. concept of tissue engineering relies on the employment of a triad of stem/progenitor cells, scaffolds, and growth factors [8, 9] to regenerate functional biological tissues. Scaffolds 3. Enamel Regeneration have to be implemented with a suitable choice of cells and signaling molecules to initiate the formation of a new 3.1. Enamel Structure and Amelogenesis. Enamel, the hardest dental tissue that can homogenize with the surrounding tissue in the human body, is a highly organized dental tissue, tissues [10–12]. covering the outer layer of the tooth crown. It possesses Numerous stem cell sources have been identified to play unique mechanical and structural properties [29–32], relying an essential role in tissue regeneration. Stem cells are either on its high hydroxyapatite content, the arrangement of apa- embryonic or adult stem cells [13]. Embryonic stem cells tite crystals into enamel prisms, and finally, the alignment are immature, undifferentiated cells derived from the inner of these prisms in a picket-fence appearance in a tissue of cell mass of blastocysts [14, 15], with the ability to undergo high physical resilience and great hardness [33–37]. Amelo- continuous self-renewal and differentiation. Adult stem/- blasts, the enamel-forming cells, are specialized epithelial progenitor cells are undifferentiated cells that are capable of cells differentiating from the inner cells of the enamel organ differentiating into certain types of tissues [3]. They maintain [38]. They exhibit polarization and elongation with a pro- the integrity of tissues they reside in such as blood, skin, nounced Golgi apparatus and endoplasmic reticulum to form bone, and dental pulp [16]. and secrete enamel proteins and influx phosphate and cal- Scaffolds could be natural polymers (e.g., collagen, chito- cium ions into the forming enamel matrix [39, 40]. Enamel san, alginate, and hyaluronic acid) or synthetic materials proteins are necessary for enamel formation, with amelo- (e.g., polyglycolic acid, polylactic acid, and polylactic polygly- genin, ameloblastin, and enamelin being the three major pro- colic acid) and bioactive ceramics, with each category having teins observed in the developing teeth [41]. Recently, this list its merits as well as limitations in use [17]. Scaffolds could be was amended by amelotin and odontogenic ameloblast- utilized as a cell support tool, upon which cells are cultured associated protein (ODAM), which were observed in the in vitro, prior to their transplantation together with their junctional epithelium and during the maturation stage of produced matrix in vivo. Scaffolds can further be employed amelogenesis [42–45]. Once the enamel matrix is formed, as growth factor/drug delivery tools, to attract body cells to ameloblasts reabsorb water and degrade enamel proteins the scaffold site in vivo for new tissue formation [18]. In this during the maturation stage of amelogenesis [39, 40]. Finally, context, scaffolds are essential to structurally support and they undergo apoptosis and the mature enamel becomes transport growth factors, DNA, biologically active proteins, acellular. As a result, once damaged, unlike other biominera- and cells as well as provide physical signals important for bio- lized hard tissues such as dentin and bone, the enamel cannot logical repair/regeneration processes [19, 20]. Aside from regenerate by itself [37, 46]. Therefore, a reparative healing of these, the topography, architecture, and composition of destroyed enamel depends mainly, if at all, on acellular remi- scaffolds can interact and affect cell response and subsequent neralization of superficial demineralized defects [47]. tissue formation [18]. It is important for scaffolds to mimic To restore enamel defects either due to caries, trauma, or the natural extracellular matrix of the tissue to be replaced others, artificial materials were manufactured to resemble its [21, 22]. Optimum design for dental tissue regeneration hardness [48]. Unfortunately, most of the current materials should be made to achieve mechanical integrity and func- do not possess the same mechanical, physical, and esthetic tionality and to help in cell adhesion and differentiation. properties of the lost tissues [49]. Despite the urgent need As a third important factor in the tissue engineering for tooth enamel regeneration, enamel tissue engineering is triad, growth factors were suggested to be crucial for the facing many difficulties [50–53], including the complex regenerative process. They are normally released from cells posttranslational