Synergistic Chemomechanical Cues within Mesenchymal Stromal Cell-Laden Hydrogel Microspheres for Accelerated Diabetic Wound Healing

This study developed microfluidic gelatin methacryloyl (GelMA) microspheres that coencapsulated mesenchymal stromal cells with inflammatory cytokines to program a defined chemomechanical microenvironment for diabetic wound healing. By varying GelMA methacrylation, the authors produced soft and stiff microspheres with distinct mechanics and showed that the soft formulation promoted greater MSC spreading, vinculin expression, and YAP nuclear localization, consistent with enhanced mechanosensing. Under TNF-α and IFN-γ priming, MSCs in soft microspheres showed stronger upregulation of immunomodulatory and regenerative genes including TSG6, IDO, COX2, CCL2, IL-1ra, VEGF, TGFβ1, and FGF2. Conditioned media from these constructs improved fibroblast migration and endothelial tube formation, while coculture assays showed a shift in macrophages toward a pro-regenerative M2 phenotype. In a streptozotocin-induced diabetic mouse wound model, cytokine-primed MSC-laden microspheres accelerated wound closure, increased dermal thickness and collagen deposition, enhanced CD31-positive neovascularization, and improved immune balance, supporting a mechanomedicine strategy for chronic wound repair.