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/CSgel 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/CSgel 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/CSgel, and this effect is also evaluated in a diabetic wound model. Compared to untreated group, the EVs@oHA/CSgel 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/CSgel as a satisfying therapeutic system for microcirculation reconstruction in tissue repair.

Beyond Traditional Medicine: EVs-Loaded Hydrogels as a Game Changer in Disease Therapeutics

“…The in situ polymerization method involves the co-mixing of a gel precursor solution and an EVs solution. The polymerization conditions must be mild, e.g., 365 nm UV irradiation for 1 min [ 52 ], and polymerization at room temperature [ 53 ] or 37 °C [ 54 ]. Alternatively, hydrogels can also be prepared first, and then mixed with the EVs solution to allow the adsorption of EVs into hydrogels [ 55 ].…”

“…Alternatively, hydrogels can also be prepared first, and then mixed with the EVs solution to allow the adsorption of EVs into hydrogels [ 55 ]. The most often used hydrogel materials for EVs delivery include calcium alginate (Ca-Alg) [ 53 , 56 ], arginine-glycine-aspartate (RGD) [ 57 , 58 , 59 ], hyaluronic acid (HA) [ 55 , 60 , 61 , 62 ], chitosan (CS) [ 54 , 63 , 64 , 65 , 66 ], and gelatin methacrylate (GelMA) [ 34 , 52 , 67 , 68 ]. The synthesis of the hydrogel has been well documented in many reviews [ 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ], and is not described in the current work.…”

“…Based on the pathological features of abnormal hyperplasia of vascular endothelial cells in infantile hemangioma (IH) [ 152 ], Sha et al [ 54 ] isolated CD133-positive Hemangioma stem cells (HemSCs) from IH and obtained the EVs from culture supernatants. They modified CS with hyaluronic oligosaccharides (oHA) to synthesize a thermosensitive hydrogel that served as a carrier for the EVs.…”

“… miR-7/21/221-EVs-oHA/CS accelerated wound healing of diabetic wounds. ( a ) Wound images on days 0, 7, 14, 21 after the first treatment; ( b ) schematic diagram of wound healing [ 54 ]. …”

Visible-Light Cross-Linkable Multifunctional Hydrogels Loaded with Exosomes Facilitate Full-Thickness Skin Defect Wound Healing through Participating in the Entire Healing Process

“…Exosomes are extracellular vesicles released by various types of cells that can regulate intercellular communication by delivering their biologically active molecules (nucleic acids, proteins, and lipids) . Compared to stem cell therapies, exosomes exhibit lower immunogenicity, greater stability, and easier storage. , Furthermore, exosomes possess the ability to participate in immune regulation, inhibit apoptosis, and promote tissue regeneration, making them a treatment alternative with a favorable performance-risk ratio compared to whole cells. , The conventional approach involves direct injection of exosomes into the wound site.…”