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.

The two major causes for implant failure are postoperative infection and poor osteogenesis. Initial period of osteointegration is regulated by immunocytes and osteogenic‐related cells resulting in inflammatory response and tissue healing. The healing phase can be influenced by various environmental factors and biological cascade effect. To synthetically orchestrate bone‐promoting factors on biomaterial surface, built is a dual delivery system coated on a titanium surface (abbreviated as AH‐Sr‐AgNPs). The results show that this programmed delivery system can release Ag+ and Sr2+ in a temporal‐spatial manner to clear pathogens and activate preosteoblast differentiation partially through manipulating the polarization of macrophages. Both in vitro and in vivo assays show that AH‐Sr‐AgNPs‐modified surface renders a microenvironment adverse for bacterial survival and favorable for macrophage polarization (M2), which further promotes the differentiation of preosteoblasts. Infected New Zealand rabbit femoral metaphysis defect model is used to confirm the osteogenic property of AH‐Sr‐AgNPs implants through micro‐CT, histological, and histomorphometric analyses. These findings demonstrate that the programmed surface with dual delivery of Sr2+ and Ag+ has the potential of achieving an enhanced osteogenic outcome through favorable immunoregulation.

Objectives Bone defects caused by diseases and trauma are usually accompanied by inflammation, and the implantation of biomaterials as a common repair method has also been found to cause inflammatory reactions, which affect bone metabolism and new bone formation. This study investigated whether exosomes from adipose-derived stem cells (ADSC-Exos) plays an immunomodulatory role in traumatic bone defects and elucidated the underlying mechanisms. Methods ADSC-Exos were loaded by a biomaterial named gelatine nanoparticles (GNPs), physical and chemical properties were analysed by zeta potential, surface topography and rheology. A rat model of skull defect was used for our in vivo studies, and micro-CT and histological staining were used to analyse histological changes in the bone defect area. RT-qPCR and western blotting were performed to verify that ADSC-Exos could regulate M1/M2 macrophage polarization. MicroRNA (miRNA) array analysis was conducted to determine the miRNA expression profiles of ADSC-Exos. After macrophages were treated with a miR-451a mimic, miR-451a inhibitor and ISO-1, the relative expression of genes and proteins was measured by RT-qPCR and western blotting. Results In vivo, micro-CT and histological staining showed that exosome-loaded GNPs (GNP-Exos) hydrogel, with good biocompatibility and strong mechanical adaptability, exhibited immunomodulatory effect mainly by regulating macrophage immunity and promoting bone tissue healing. Immunofluorescence further indicated that ADSC-Exos reduced M1 marker (iNOS) expression and increased M2 marker (CD206) expression. Moreover, in vitro studies, western blotting and RT-qPCR showed that ADSC-Exos inhibited M1 macrophage marker expression and upregulated M2 macrophage marker expression. MiR-451a was enriched in ADSC-Exos and targeted macrophage migration inhibitory factor (MIF). Macrophages treated with the miR-451a mimic showed lower expression of M1 markers. In contrast, miR-451a inhibitor treatment upregulated the expression of M1 markers and downregulated the expression of M2 markers, while ISO-1 (a MIF inhibitor) treatment upregulated miR-451a expression and downregulated M1 macrophage marker expression. Conclusion GNP-Exos can effectively regulate bone immune metabolism and further promote bone healing partly through immune regulation of miR-451a, which may provide a therapeutic direction for bone repair.

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.

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.

Osteoporosis is a wide-range disease with a negative impact on bone defect healing. Strontium ranelate (SR) has promising osteogenic potential for its dual function on stimulating osteoblasts and inhibiting osteoclast activity. However, it has limitations for its dose-dependent effect and side effects on systemic applications. Here, a sequentially cross-linking strategy including enzyme-cross-linking through tyrosinase from mushroom and physical folding is acquired to create SR loaded gelatin nanoparticle/silk fibroin aerogel (abbreviated as S/G-Sr-MT) with drug release controlling capacity. The results showed successful enzyme-cross-linking, excellent spatial structure, and enhanced mechanical properties of S/G-Sr-MT. Even Sr2+ loading and stable release with markedly inhibited initial burst release were detected. The biomineralization investigation showed rapid deposition of hydroxyapatite on the surface of S/G-Sr-MT. In vitro, spreading morphology and higher osteogenic gene expression of MC3T3-E1 seeded on S/G-Sr-MT were observed compared to other groups after 7 day culturing. In vivo, S/G-Sr-MT showed an obvious osteogenic capacity in calvaria defects of ovariectomized rats in which high Runx2 expression and inhibited TRAP activity were observed. Such results suggested the S/G-Sr-MT scaffold could stimulate osteogenic differentiation of osteoblasts while inhibiting osteoclast behaviors in vivo. These findings highlight the potential osteogenic ability and clinical application of SR incorporated enzyme-cross-linked scaffold in ovariectomized (OVX) bone healing.

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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.