Stem cell-driven biomedical technologies for tooth regeneration: engineering scaffolds, organoid models, and molecular targeted strategies

Abstract

Tooth loss remains a major unmet clinical challenge, and current prosthetic approaches cannot restore the biological complexity, sensory function, or regenerative capacity of natural teeth. Recent progress in stem cell biology, developmental engineering, and regenerative biomaterials has opened new possibilities for biological tooth regeneration. This review integrates advances across three major research domains that together define the current landscape of translational regenerative dentistry. First, we discuss stem cell-based, scaffold-guided strategies for tooth regeneration. These approaches combine dental and nondental stem cells, including DPSCs, SCAPs, PDLSCs, SHED, and iPSC-derived lineages, with bioactive materials such as HA/TCP ceramics, dentin-derived extracellular matrix scaffolds, and natural or synthetic polymers to promote odontogenic differentiation, vascularization, and periodontal attachment. Second, we summarize emerging tooth organoid and bioengineered tooth germ technologies that recapitulate epithelial–mesenchymal interactions and enable controlled reconstruction of dentin–pulp and periodontal compartments for modeling human odontogenesis. Third, we highlight molecular regulation-driven therapeutic strategies, focusing on the modulation of Wnt, BMP, FGF, TGF-β, and USAG-1 pathways to stimulate endogenous tooth regeneration and correct developmental defects. Despite marked progress, challenges remain, including stable neurovascular integration, optimization of stem cell–material crosstalk, precise control of spatiotemporal signaling, and long-term functional stability in vivo. Finally, we outline future directions involving smart biomaterials, gene- and protein-based molecular targeting, organoid-guided regeneration, and iPSC-enabled personalized therapies, which may further accelerate the clinical translation of stem cell-based tooth regeneration.

1. Introduction

Tooth development in humans is a highly orchestrated process involving sequential epithelial–mesenchymal interactions, tightly regulated molecular signaling pathways (e.g., BMP, FGF, and Wnt), and coordinated cellular differentiation events. During embryogenesis, the initiation of the dental lamina gives rise to the tooth germ, which progresses through the bud, cap, and bell stages, ultimately forming enamel, dentin, and periodontal structures. This developmental cascade ensures structural integrity and functional integration of the dentition within the craniofacial system. From an evolutionary perspective, human dentition is thecodont, heterodont, and diphyodont. Teeth are anchored in alveolar sockets, exhibit morphological specialization, and undergo only a single natural cycle of replacement. Consequently, once permanent teeth are lost, no endogenous mechanism exists for regeneration, underscoring the clinical importance of restorative and regenerative strategies.

Tooth loss arises from diverse etiologies, including developmental anomalies, dental caries, periodontal disease, and traumatic injury [1–3]. Regardless of the cause, tooth loss disrupts oral homeostasis and exerts far-reaching functional, aesthetic, and psychological consequences. Epidemiological studies confirm its widespread prevalence, with a global pooled estimate of edentulism reaching approximately 22%, and as high as 32% in economically disadvantaged regions [4, 5]. In elderly populations, tooth loss is directly associated with frailty, impaired mastication, and malnutrition, contributing to systemic conditions such as sarcopenia and cardiovascular disease.