A temperature and pH dual-responsive injectable self-healing hydrogel prepared by chitosan oligosaccharide and aldehyde hyaluronic acid for promoting diabetic foot ulcer healing.

Chronic wound, such as skin defect after burn, pressure ulcer, and diabetic foot ulcer is very difficult to cure. Its pathological process is often accompanied with local temperature rise, pH decrease, and other phenomena. Owing to their outstanding hydrophilic, biocompatibility, and responsive properties, hydrogels could accelerate the healing process. In this study, we chose chitosan oligosaccharide (COS) grafted with Pluronic F127 (F127-COS). Aldehyde hyaluronic acid (A-HA) oxidized by NaIO4. And added boric acid (BA) to prepare a thermosensitive and pH-responsive injectable self-healing F127-COS/A-HA/COS/BA (FCAB) hydrogel, loaded with drug deferoxamine (DFO) in order to have an accurate release and promote angiogenesis of diabetic foot ulcer. In vitro experiments had verified that the FCAB hydrogel system loaded with DFO (FCAB/D) could promote migration and angiogenesis of HUVEC. A diabetes rat back wound model further confirmed its role in promoting angiogenesis in wound repair process. The results showed that the FCAB/D hydrogel exhibited unique physicochemical properties, excellent biocompatibility, and significantly enhanced therapeutic effects for diabetic foot ulcer.

GelMA Hydrogel Loaded with Extracellular Vesicles Derived from Umbilical Cord Mesenchymal Stem Cells for Promoting Cutaneous Diabetic Wound Healing.

Chronic diabetic wounds have become a significant cause of disability worldwide. It is highly desired to develop effective therapies that can promote the rapid healing of diabetic wounds. Owing to the outstanding hydrophilic and water-retaining properties, hydrogels could accelerate the healing process. Extracellular vesicles (EVs) have shown the ability to promote cell regeneration and angiogenesis. In this study, we chose a gelatin methacryloyl (GelMA) hydrogel, a kind of biomaterial characteristic of good biocompatibility, to load the EVs derived from umbilical cord mesenchymal stem cells (UCMSCs) in order to have a long-lasting effect by consistent release of EVs. Then, the hydrogel with EVs was used to treat diabetic wounds in rat models. Nuclear magnetic resonance spectroscopy and scanning electron microscopy were used to characterize the synthesis of the hydrogel; cell experiments, animal experiments, and histological staining were used to evaluate the function of the hydrogel with EVs. The results show that the GelMA hydrogel incorporated with the UCMSC-derived EVs exhibits unique physicochemical properties, excellent biocompatibility, and much enhanced therapeutic effects for diabetic wounds.

Sustained Release of BMSC-EVs from 3D Printing Gel/HA/nHAP Scaffolds for Promoting Bone Regeneration in Diabetic Rats.

Extracellular vesicles (EVs) play an important role in intercellular communication, and the function of EVs mainly depends on the state of source cells. To determine the effect of diabetic microenvironment on EVs secreted by bone marrow mesenchymal stem cells (BMSCs), this work explores the effect of normal glucose (5.5 mm) cultured BMSCs derived EVs (NG-EVs) and high glucose (30 mm) cultured BMSCs derived EVs (HG-EVs) in regulating the migration, proliferation and osteoblastic differentiation of BMSCs in vitro. In order to improve the bioavailability of EVs, this work constructs a sustained release system of polydopamine (PDA) functionalized 3D printing gelatin/hyaluronic acid/nano-hydroxyapatite (Gel/HA/nHAP) scaffolds (S/PDA) and verifies its function in the calvarial defect model of diabetic rats. This work confirms that both NG-EVs and HG-EVs can promote proliferation and migration, inhibit apoptosis and promote osteogenic differentiation, but the function of HG-EVs is weaker than that of NG-EVs. Therefore, EVs secreted by autologous cells of diabetic patients are not suitable for self-repair. This work hopes that the 3D printing scaffold designed for sustained-release EVs will provide a new strategy for acellular tissue engineering bone repair in diabetic patients.

Injectable hydrogel loaded with 4-octyl itaconate enhances cartilage regeneration by regulating macrophage polarization.

Macrophages play a distinctive role in the early stage of inflammation after cartilage defects. Previous studies have shown that macrophages can express different phenotypes, among which M2 polarization is important to maintain the balance of the inflammatory microenvironment and promote cartilage regeneration. In this study, 4-octyl itaconic acid (4-OI), a derivative of the endogenous metabolite itaconic acid, was used to regulate the polarization behavior of macrophages and enhance cartilage repair. Oxidized sodium alginate (OSA) and gelatin (GEL) were selected as materials to form injectable hydrogels with the function of sustained release of 4-OI. In vivo and in vitro experiments have verified that the OSA/GEL hydrogel system loaded with 4-OI could promote M2 macrophage polarization and inhibit the inflammatory reaction. A rat knee joint cartilage defect model further confirmed its role in promoting cartilage regeneration in the later stage. In this study, the OSA/GEL hydrogel was successfully fabricated as a vehicle for delivering 4-OI, which could evidently alleviate the inflammatory reaction and thus accelerate tissue regeneration. The results of this study provide a new method for promoting subsequent tissue regeneration by regulating the early immune response.

Preparation of Recombinant Human Collagen III Protein Hydrogels with Sustained Release of Extracellular Vesicles for Skin Wound Healing.

Existing treatment methods encounter difficulties in effectively promoting skin wound healing, making this a serious challenge for clinical treatment. Extracellular vesicles (EVs) secreted by stem cells have been proven to contribute to the regeneration and repair of wound tissue, but they cannot be targeted and sustained, which seriously limits their current therapeutic potential. The recombinant human collagen III protein (rhCol III) has the advantages of good water solubility, an absence of hidden viral dangers, a low rejection rate and a stable production process. In order to achieve a site-specific sustained release of EVs, we prepared a rhCol III hydrogel by cross-linking with transglutaminase (TGase) from Streptomyces mobaraensis, which has a uniform pore size and good biocompatibility. The release profile of the rhCol III-EVs hydrogel confirmed that the rhCol III hydrogel could slowly release EVs into the external environment. Herein, the rhCol III-EVs hydrogel effectively promoted macrophage changing from type M1 to type M2, the migration ability of L929 cells and the angiogenesis of human umbilical vein endothelial cells (HUVECs). Furthermore, the rhCol III-EVs hydrogel is shown to promote wound healing by inhibiting the inflammatory response and promoting cell proliferation and angiogenesis in a diabetic rat skin injury model. The reported results indicate that the rhCol III-EVs hydrogel could be used as a new biological material for EV delivery, and has a significant application value in skin wound healing.