Biomimetic Thermo‐Sensitive Hydrogel Encapsulating Hemangiomas Stem Cell Derived Extracellular Vesicles Promotes Microcirculation Reconstruction in Diabetic Wounds

Abstract Tissue repair and regeneration in ischemic areas require effective strategies for angiogenesis and microcirculation reconstruction. In this research, extracellular vesicles (EVs) derived from hemangioma stem cells (HemSC) are used as bio‐functional materials for angiogenesis. In addition, a novel thermo‐sensitive hydrogel based on chitosan (CS) and modified with hyaluronic oligosaccharides (oHA), is specially developed as an ideal carrier of HemSC‐EVs. The oHA/CS gel provides a sustained‐release delivery system for EVs, enhances the angiogenic function of HemSC‐EVs, and exerts other bio‐functions to comprehensively accelerate tissue repair. The physical properties of EVs@oHA/CS gel proved to be soft, highly elastic deformable, biocompatible, and can maintain the shape and structure of EVs. In vitro co‐culture assay verifies the angiogenic effect of EVs@oHA/CS gel , and this effect is also evaluated in a diabetic wound model. Compared to untreated group, the EVs@oHA/CS gel group has only 26.9% wound area on day 14, and 226.8% blood flux mark on day 17. Pharmacological mechanisms of HemSC‐EVs are predicted by RNA‐seq, and cluster analysis of miRNAs predicted targets presents several up‐regulated biological processes involving in angiogenesis and wound healing. In conclusion, it is suggested that EVs@oHA/CS gel as a satisfying therapeutic system for microcirculation reconstruction in tissue repair.