Tooth Formation: Are the Hardest Tissues of Human Body Hard to Regenerate?

Abstract

With increasing life expectancy, demands for dental tissue and whole-tooth regeneration are becoming more significant. Despite great progress in medicine, including regenerative therapies, the complex structure of dental tissues introduces several challenges to the field of regenerative dentistry. Interdisciplinary efforts from cellular biologists, material scientists, and clinical odontologists are being made to establish strategies and find the solutions for dental tissue regeneration and/or whole-tooth regeneration. In recent years, many significant discoveries were done regarding signaling pathways and factors shaping calcified tissue genesis, including those of tooth. Novel biocompatible scaffolds and polymer-based drug release systems are under development and may soon result in clinically applicable biomaterials with the potential to modulate signaling cascades involved in dental tissue genesis and regeneration. Approaches for whole-tooth regeneration utilizing adult stem cells, induced pluripotent stem cells, or tooth germ cells transplantation are emerging as promising alternatives to overcome existing in vitro tissue generation hurdles. In this interdisciplinary review, most recent advances in cellular signaling guiding dental tissue genesis, novel functionalized scaffolds and drug release material, various odontogenic cell sources, and methods for tooth regeneration are discussed thus providing a multi-faceted, up-to-date, and illustrative overview on the tooth regeneration matter, alongside hints for future directions in the challenging field of regenerative dentistry.

Keywords: amelogenesis; cementogenesis; dentinogenesis; dentogenesis; drug release materials; odontogenic cells; scaffolds; stem cells; whole-tooth regeneration.

Figure 1

Tooth structure and dental tissues with the respective stem cell populations. (A) The odontoblast niche is bordering dental pulp beneath the dentin with odontoblast processes projecting towards enamel. (B) Diverse cell populations are found in dental pulp, DPSCs, which can give rise to odontoblasts. (C) Cementocytes are residing in the lacunae of cellular cementum at the root apex with their cellular processes projecting towards the periodontal ligament.

Figure 2

Major signaling cascades involved in amelogenesis, odontogenesis, and cementogenesis. (A) Signaling pathways modulating amelogenesis with TGF-β superfamily ligands (BMP2 and TGF-β1/2/3) playing the major role in matrix protein and metalloproteinases feedback-regulation and Runx2 being an important transcription factor. (B) Central signaling cascades of odontogenesis are depicted. The TGF-β superfamily ligands (BMP2/4 and TGFβs) regulate many odontogenic genes with ERK1/2 as convergence point and Klk4-Osx as important transcription factor tandem. (C) Major cementogenesis-related signaling cascades with Osx as the central transcription factor being regulated via Wnt/β-catenin in a feedback-loop. Ameloblast-derived products (LRAP and amelogenin) were shown modulate key cementogenic gene expression in vitro.

Figure 3

SEM images of agarose lyophilized (LYO) (a–c) and supercritically-dried (SCD) (d–f) and agarose/hydroxyapatite (33/76 w%) composite LYO (g–i) and SCD (k–m) at three different magnifications. The scale bars are 10 μm (left), 1 μm (middle), and 0.2 μm (right), respectively. Reproduced from Witzler et al., 2019 [171]. Open Access Copyright Permission (Creative Commons CC BY license).

Figure 4

Release data of (a) adenosin triphosphate (ATP) and (b) suramin from agarose/hydroxyapatite (AG100HA0) (black), AG50HA50 (orange), and AG33HA67 (blue) scaffolds. Data fit: Weibull equation. Reproduced from Witzler et al., 2019 [171]. Open Access Copyright Permission (Creative Commons CC BY license).