The regeneration of diabetic bone defects remains challenging as the innate healing process is impaired by glucose fluctuation, reactive oxygen species (ROS), and overexpression of proteinases (such as matrix metalloproteinases, MMPs). A “diagnostic” and therapeutic dual‐logic‐based hydrogel for diabetic bone regeneration is therefore developed through the design of a double‐network hydrogel consisting of phenylboronic‐acid‐crosslinked poly(vinyl alcohol) and gelatin colloids. It exhibits a “diagnostic” logic to interpret pathological cues (glucose fluctuation, ROS, MMPs) and determines when to release drug in a diabetic microenvironment and a therapeutic logic to program different cargo release to match immune‐osteo cascade for better tissue regeneration. The hydrogel is also shown to be mechanically adaptable to the local complexity at the bone defect. Furthermore, the underlying therapeutic mechanism is elucidated, whereby the logic‐based cargo release enables the regulation of macrophage polarization by remodeling the mitochondria‐related antioxidative system, resulting in enhanced osteogenesis in diabetic bone defects. This study provides critical insight into the design and biological mechanism of dual‐logic‐based tissue‐engineering strategies for diabetic bone regeneration.

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Risk of implant failure increases profoundly in patients with pre‐existing conditions (e.g., diabetes). Current therapies adopt a one‐sided focus on the direct antibacterial properties of biomaterials and osteogenesis stimulation. However, in this study it is demonstrated that a “chain armor” structure (Ce‐TA) that mainly targets the regulation of the local pathological microenvironment, provides a novel solution to scavenge reactive oxygen species (ROS) by simulating superoxide dismutase and catalase and significantly improving osteointegration under diabetic conditions. Ce‐TA based on a metal phenolic network biological functional interface is successfully constructed. Ce‐TA, an ultrathin armor structure, is biocompatible and facile. Through in vitro assays it is demonstrated that Ce‐TA reshapes the diabetic microenvironment into a regenerative one in a microenvironment‐responsive manner, where Ce‐TA regulates hypoxia‐inducible factor 1α (HIF‐1α) activity by reducing the level of mitochondrial ROS, and effectively alleviates mitochondrial dysfunction and reprogrammes macrophages to a pro‐healing state. Furthermore, it is confirmed that Ce‐TA shows excellent therapeutic effects on the reducing postoperative infection and enhances osteointegration of intra‐osseous implants in diabetic rat models. The proposed strategy opens up a promising opportunity for repurposing metals with intrinsic enzyme‐like activity for the goal of enhancing the osteointegration of devices with orthopedic and dental applications among diabetic patients.

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The regeneration of bone defects in patients with diabetes mellitus (DM) is remarkably impaired by hyperglycemia and over-expressed proinflammatory cytokines, proteinases (such as matrix metalloproteinases, MMPs), etc. In view of the fact that exosomes represent a promising nanomaterial, herein, we reported the excellent capacity of stem cells from apical papilla-derived exosomes (SCAP-Exo) to facilitate angiogenesis and osteogenesis whether in normal or diabetic conditions in vitro. Then, a bioresponsive polyethylene glycol (PEG)/DNA hybrid hydrogel was developed to support a controllable release of SCAP-Exo for diabetic bone defects. This system could be triggered by the elevated pathological cue (MMP-9) in response to the dynamic diabetic microenvironment. It was further confirmed that the administration of the injectable SCAP-Exo-loaded PEG/DNA hybrid hydrogel into the mandibular bone defect of diabetic rats demonstrated a great therapeutic effect on promoting vascularized bone regeneration. In addition, the miRNA sequencing suggested that the mechanism of dual-functional SCAP-Exo might be related to highly expressed miRNA-126-5p and miRNA-150-5p. Consequently, our study provides valuable insights into the design of promising bioresponsive exosome-delivery systems to improve bone regeneration in diabetic patients.

Objective To develop an in vivo model to simulate the complex internal environment of diabetic peri‐implantitis (T2DM‐PI) model for a better understanding of peri‐implantitis in type 2 diabetic patients. Materials and methods Maxillary first molars were extracted in Sprague‐Dawley (SD) rats, and customized cone‐shaped titanium implants were installed in the extraction sites. Thereafter, implants were uncovered and customized abutments were screwed into implants. A high‐fat diet and a low‐dose injection of streptozotocin were utilized to induce T2DM. Finally, LPS was locally injected in implant sulcus to induce peri‐implantitis. Results In the present study, T2DM‐PI model has been successfully established. Imaging analysis revealed that abundant inflammatory cells infiltrated in the soft tissue in T2DM‐PI group with concomitant excessive secretion of inflammatory cytokines. Moreover, higher expression of MMP and increased number of osteoclasts led to collagen disintegration and bone resorption in T2DM‐PI group. Conclusions These results describe a novel rat model which stimulate T2DM‐PI in vivo, characterized by overwhelming inflammatory response and bone resorption. This model has a potential to be used for investigation of initiation, progression and interventional therapy of T2DM‐PI.

Aim: To explore the relationship between long non-coding RNAs (lncRNAs) and immune response and to construct an immune-related competing endogenous RNA (ceRNA) network in periodontitis.Materials and methods: Gene expression profiles in gingival tissues were acquired from the Gene Expression Omnibus database. Bioinformatic analysis was performed to establish an immune-related ceRNA network. Subsequently, functional enrichment analysis was performed to detect the biological processes in which the ceRNA network might be involved.Results: A combined classification model involving seven lncRNAs was constructed.Receiver operating characteristic curve analysis showed satisfactory classification ability of the established model. Further analysis revealed that the screened lncRNAs were significantly correlated with patient immunity. Finally, an immune-related ceRNA network was constructed based on the lncRNA MIAT, miR-1246, miR-1260b, miR-3652, miR-4286, and 27 mRNAs. Accordingly, functional enrichment analysis demonstrated that this network is closely related to the proliferation, differentiation, and activation of B cells. Conclusions:The lncRNA MIAT and the MIAT-based ceRNA network may be instrumental in regulating the immune response, especially of B cells, during the progression of periodontitis.

Extrusible biomaterials have recently attracted increasing attention due to the desirable injectability and printability to allow minimally invasive administration and precise construction of tissue mimics. Specifically, self-healing colloidal gels are a novel class of candidate materials as injectables or printable inks considering their fascinating viscoelastic behavior and high degree of freedom on tailoring their compositional and mechanical properties. Herein, we developed a novel class of adaptable and osteogenic composite colloidal gels via electrostatic assembly of gelatin nanoparticles and nanoclay particles. These composite gels exhibited excellent injectability and printability, and remarkable mechanical properties reflected by the maximal elastic modulus reaching ~150 kPa combined with high self-healing efficiency, outperforming most previously reported self-healing hydrogels. Moreover, the cytocompatibility and the osteogenic capacity of the colloidal gels were demonstrated by inductive culture of MC3T3 cells seeded on the 3D-printed colloidal scaffolds. Besides, the biocompatibility and biodegradability of the colloidal gels was proved in vivo by subcutaneous implantation of the 3D-printed scaffolds. Furthermore, we investigated the therapeutic capacity of the colloidal gels, either in form of injectable gels or 3D-printed bone substitutes, using rat sinus bone augmentation model or critical-sized cranial defect model. The results confirmed that the composite gels were able to adapt to the local complexity including irregular or customized defect shapes and continuous on-site mechanical stimuli, but also to realize osteointegrity with the surrounding bone tissues and eventually be replaced by newly formed bones.