Diabetes mellitus (DM) aggravates periodontitis, resulting in accelerated periodontal bone resorption. Disordered glucose metabolism in DM causes reactive oxygen species (ROS) overproduction resulting in compromised bone healing, which makes diabetic periodontal bone regeneration a major challenge. Inspired by the natural bone healing cascade, a mesoporous silica nanoparticle (MSN)-incorporated PDLLA (poly(dl-lactide))-PEG-PDLLA (PPP) thermosensitive hydrogel with stepwise cargo release is designed to emulate the mesenchymal stem cell “recruitment-osteogenesis” cascade for diabetic periodontal bone regeneration. During therapy, SDF-1 quickly escapes from the hydrogel due to diffusion for early rat bone marrow stem cell (rBMSC) recruitment. Simultaneously, slow degradation of the hydrogel starts to gradually expose the MSNs for sustained release of metformin, which can scavenge the overproduced ROS under high glucose conditions to reverse the inhibited osteogenesis of rBMSCs by reactivating the AMPK/β-catenin pathway, resulting in regulation of the diabetic microenvironment and facilitation of osteogenesis. In vitro experiments indicate that the hydrogel markedly restores the inhibited migration and osteogenic capacities of rBMSCs under high glucose conditions. In vivo results suggest that it can effectively recruit rBMSCs to the periodontal defect and significantly promote periodontal bone regeneration under type 2 DM. In conclusion, our work provides a novel therapeutic strategy of a bioinspired drug-delivery system emulating the natural bone healing cascade for diabetic periodontal bone regeneration.

Mesenchymal stromal/stem cells (MSCs) are the most promising stem cells for the treatment of multiple inflammatory and immune diseases due to their easy acquisition and potent immuno-regulatory capacities. These immune functions mainly depend on the MSC secretion of soluble factors. Recent studies have shown that the metabolism of MSCs plays critical roles in immunomodulation, which not only provides energy and building blocks for macromolecule synthesis but is also involved in the signaling pathway regulation. A thorough understanding of metabolic regulation in MSC immunomodulatory properties can provide new sights to the enhancement of MSC-based therapy. MSC immune regulation can be affected by cellular metabolism (glucose, adenosine triphosphate, lipid and amino acid metabolism), which further mediates MSC therapy efficiency in inflammatory and immune diseases. The enhancement of glycolysis of MSCs, such as signaling molecule activation, inflammatory cytokines priming, or environmental control can promote MSC immune functions and therapeutic potential. Besides glucose metabolism, inflammatory stimuli also alter the lipid molecular profile of MSCs, but the direct link with immunomodulatory properties remains to be further explored. Arginine metabolism, glutamine-glutamate metabolism and tryptophan-kynurenine via indoleamine 2,3-dioxygenase (IDO) metabolism all contribute to the immune regulation of MSCs. In addition to the metabolism dictating the MSC immune functions, MSCs also influence the metabolism of immune cells and thus determine their behaviors. However, more direct evidence of the metabolism in MSC immune abilities as well as the underlying mechanism requires to be uncovered.

Periodontitis is a widespread oral disease that results in the loss of alveolar bone. Low-intensity pulsed ultrasound (LIPUS), which is a new therapeutic option, promotes alveolar bone regeneration in periodontal bone injury models. This study investigated the protective effect of LIPUS on oxidative stress in periodontitis and the mechanism underlying this process.

Through loss‐ and gain‐of‐function experiments in knockout and transgenic mice, Forkhead box O (FOXO) family transcription factors have been demonstrated to play essential roles in many biological processes, including cellular proliferation, apoptosis and differentiation. Osteogenic differentiation from mesenchymal stem cells (MSCs) into osteoblasts is a well‐organized process that is carefully guided and characterized by various factors, such as runt‐related transcription factor 2 (Runx2), β‐catenin, osteocalcin (OCN), alkaline phosphatase (ALP) and activating transcription factor 4 (ATF4). Accumulating evidence suggests multiple interactions among FOXO members and the differentiation regulatory factors listed above, resulting in an enhancement or inhibition of osteogenesis in different stages of osteogenic differentiation. To systematically and integrally understand the role of FOXOs in osteogenic differentiation and explain the contrary phenomena observed in vitro and in vivo, we herein summarized FOXO‐interacting differentiation regulatory genes/factors and following alterations in differentiation. The underlying mechanism was further discussed on the basis of binding types, sites, phases and the consequent downstream transcriptional alterations of interactions among FOXOs and differentiation regulatory factors. Interestingly, a bidirectional effect of FOXOs on balancing osteogenic differentiation was discovered in MSCs. Moreover, FOXO factors are reported to be activated or suppressed by several context‐dependent signalling inputs during differentiation, and the underlying molecular basis may offer new drug development targets for treatments of bone formation defect diseases.