Quest for the development of tooth root/periodontal ligament complex by tissue engineering

The life-span of the tooth is intimately-associated with healthiness of periodontal ligament (PDL) which is a connective tissue situated between bone and cementum that covers tooth root surface. However, once this tissue is severely damaged by deep caries, periodontitis, and trauma, this leads to severe difficulty in its regeneration, resulting in tooth loss and decreased quality of life. The development of the therapy for generation and regeneration of the periodontal tissue is an urgent issue. Therefore, researchers have tried to improve efficiently-generative and regenerative medicine using stem cells, signal molecules, and scaffolds, requisite for tissue regeneration. In recent studies, a dental follicle tissue that is composed of stem cell population potentially differentiating into PDL tissue, cementum, and alveolar bone is of current interest. More recently a revolutionary and attractive study reporting the development of bio-hybrid implant that reserved newly-formed cementum/ PDL tissue complex on its surface was introduced. In this review, we describe comprehensive reports that tried to develop the cementum/PDL complex by tissue engineering and future prospects. Structure and function of the periodontal tissue The periodontal tissue is composed of four major tissues: periodontal ligament (PDL) tissue, cementum, alveolar bone, and gingival tissue. PDL tissue is composed of heterogeneous cell populations, various extracellular proteins including collagens, elastic system fibers, fibronectin, osteocalcin, proteoglycans, vitronectin, and matricellular proteins, nerve fibers, and blood vessels [1]. PDL cell population includes fibroblasts that are principal cells in PDL tissue [2,3], PDL stem cells (PDLSCs), epithelial cell rests of Malassez that are descendants of the Hertwig’s epithelial root sheath (HERS), endothelial cells, and others. Especially, PDLSCs have the potentials to differentiate into PDL fibroblasts, cementoblasts and osteoblasts [4-6]. Aged PDLSCs decrease tissue regenerative potential, but they can be restored by the extrinsic microenvironment, suggesting the retention of their plasticity [7]. Thus researchers have tried to characterize PDLSCs for generation and regeneration of the periodontal tissue in the last decade. The central role of PDL tissue is to connect tooth root through cementum to the bone socket by forming the Sharpey’s fibers, which are composed of collagen bundles that insert their terminus into cementum and bone surfaces. This function is essentially maintained by three dimensional structure of collagens and elastic system fibers. Other functions involve cushioning mechanical stresses such as compressive and tensile forces arisen by mastication, and adjusting bite force depending on food hardness via sensory nerve located in the PDL tissue. Thus, it is not an exaggeration to say that PDL tissue determines the life-span of tooth. Origin of PDL tissue The Cephalic neural crest (CNC) cells are principal in fabricating many mesenchymal structures during craniofacial development, including teeth, bones, muscles, and neurons [8,9]. Some reports described a hierarchy of periodontal lineage segregated from migratory CNC cells through intermediate dental follicle (DF) cells [10-12]. Approaches to construct cementum/PDL structure Dental tissue-derived mesenchymal stem cells, such as PDLSCs and dental follicle progenitor cells (DFPCs) were characterized with respect to their feasibility of PDL-like and cementum-like formations [13]. Cementogenesis is indispensable in PDL tissue formation and reformation. Sonoyama et al. developed the ‘bio-root’ by using PDLSCs and stem cells from apical papilla with tooth root-shaped hydroxyapatite tricalcium phosphate (HA/TCP), and showed the formation of PDL tissue on the surface of the ‘bio-root’ when transplanted in swine [14]. Although they did not show apparent cementum deposition on the HA/TCP, this group improved the ‘bio-root’ by utilizing the PDLSC sheet, showing the defined periodontal tissue structure including cementum-like formation [15]. In addition, PDLSC pellet, PDL cell sheet, PDLSCs cultured with conditioned medium from developing apical tooth germ cells have been introduced to construct cementum/PDL complex in vivo [1618]. A recent study described the pivotal role of HERS that guides root formation in cementogenesis as well as root formation [19]. Correspondence to: Hidefumi Maeda DDS, Ph.D, Associate Professor, Department of Endodontology and Operative Dentistry, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, Tel: +8192-642-6432; Fax: +81-92-642-6366, E-mail: [email protected]