Hard tissue repair and regeneration cost hundreds of billions of dollars annually worldwide, and the need has substantially increased as the population has aged. Hard tissues include bone and tooth structures that contain calcium phosphate minerals. Smart biomaterial-based tissue engineering and regenerative medicine methods have the exciting potential to meet this urgent need. Smart biomaterials and constructs refer to biomaterials and constructs that possess instructive/inductive or triggering/stimulating effects on cells and tissues by engineering the material’s responsiveness to internal or external stimuli or have intelligently tailored properties and functions that can promote tissue repair and regeneration. The smart material-based approaches include smart scaffolds and stem cell constructs for bone tissue engineering; smart drug delivery systems to enhance bone regeneration; smart dental resins that respond to pH to protect tooth structures; smart pH-sensitive dental materials to selectively inhibit acid-producing bacteria; smart polymers to modulate biofilm species away from a pathogenic composition and shift towards a healthy composition; and smart materials to suppress biofilms and avoid drug resistance. These smart biomaterials can not only deliver and guide stem cells to improve tissue regeneration and deliver drugs and bioactive agents with spatially and temporarily controlled releases but can also modulate/suppress biofilms and combat infections in wound sites. The new generation of smart biomaterials provides exciting potential and is a promising opportunity to substantially enhance hard tissue engineering and regenerative medicine efficacy.

Periodontitis is initiated by the infection of periodontal bacteria and subsequent tissue inflammation due to immunoreaction, eventually leading to periodontal apparatus loss. Stem cells from human exfoliated deciduous teeth (SHEDs) have exhibited beneficial characteristics in dental tissue regeneration. However, the immunomodulatory functions of SHEDs have not been elucidated in the context of periodontitis treatment. In this study, we investigated the potential immunomodulatory effects of SHEDs on experimental periodontitis and demonstrated that multidose delivery of SHEDs led to periodontal tissue regeneration. SHEDs and monocytes/macrophages were cocultured in transwell systems and SHEDs were found to be capable of promoting monocyte/macrophage conversion to CD206 M2-like phenotype. Bioluminescence imaging (BLI) was employed to assess the survival and distribution of SHEDs after delivery in periodontal tissues in an induced periodontitis model, and BLI revealed that SHEDs survived for ∼7 days in periodontal tissues with little tissue diffusion. Then, multidose SHED delivery was applied to treat periodontitis at 7-day intervals. Results showed that mutidose SHEDs altered the cytokine expression profile in gingival crevicular fluid, reduced gum bleeding, increased new attachment of periodontal ligament, and decreased osteoclast differentiation. Micro-computed tomography analysis showed SHED administration significantly increased periodontal regeneration and alveolar bone volume, and decreased distance of cementoenamel junction to alveolar bone crest. Furthermore, an increase in the number of CD206 M2 macrophages was observed in periodontal tissues following the delivery of SHEDs, which aligned well with the promoted conversion to CD206 M2-like cells from monocytes/macrophages in vitro after stimulation by SHEDs. This study demonstrated in a rat periodontitis model that local delivery of SHEDs attributed to the induction of M2 macrophage polarization, reduction of periodontal tissue inflammation, and enhancement of periodontal regeneration.

This study shows that metformin can induce DPC differentiation and mineralization in an AMPK-dependent manner and that this well-tolerated antidiabetic drug has potential in regenerative endodontics as well as in other regenerative applications.