Mesenchymal Stem Cell Spheroids Induced by Supramolecular Nanofibers for Diabetic Wound Healing

Abstract Diabetic wounds, which are a serious complication of diabetes, are a threat to most diabetic patients and there is a lack of satisfactory therapeutic strategies. Mesenchymal stem cell (MSC) spheroids are under intensive investigation and have emerged as a particularly promising clinical therapy to induce wound healing; however, clinical applications of MSC spheroids have lagged because of the difficulties related to proper preparation, in situ instruction and insufficient efficacy. Herein, a novel Biotin‐^DFYIGSR supramolecular hydrogel is designed for three‐dimensional (3D) culture of MSCs, which enables monodispersed MSCs to form cell spheroids with high efficacy and is fairly suitable for quick spheroid harvest. MSC spheroids are demonstrated with enhanced paracrine function, which exhibited increased cell survival and promoted three overlapping stages of wound healing through the integrin α2β1 subunits. These spheroids not only accelerated the wound transition from the inflammatory phase to proliferation phase by inhibiting neutrophils and inducing M2 macrophage transition, but also promoted cell proliferation and neovascularization at wound sites to motivate skin regeneration. Ultimately, MSC spheroids achieved re‐epithelialization and collagen deposition for desirable wound closure. MSC spheroids induced by Biotin‐^DFYIGSR are a facile solution for the safe and efficient treatment of diabetic wounds, with great potential for clinical application.