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

Mesenchymal stromal cells (MSCs) hold substantial clinical promise for regenerative and anti-inflammatory therapies due to their inherent capacity for tissue repair and immunomodulation. However, precise understanding and control of how microenvironmental cues influence therapeutic paracrine activities remain poorly defined. Here, we introduce a microfluidic-derived gelatin methacryloyl (GelMA) microsphere system designed for the coencapsulation of MSCs with inflammatory cytokines. This platform allows us to precisely tune the local chemomechanical microenvironment, thereby directly programming the MSC secretome. We demonstrate that the synergy between mechanical signals from a soft matrix and inflammatory biochemical cues (TNF-α and IFN-γ) profoundly enhances the immunomodulatory and regenerative capabilities of encapsulated MSCs. Mechanistic studies reveal that focal adhesion kinase and Yes-associated protein dependent pathways are involved in the mechanosensitive activation of MSCs in the presence of inflammatory factors. In a mouse model of chronic diabetic wounds, treatment with these engineered cell-laden microspheres significantly accelerates wound closure, promotes angiogenesis, and restores immune homeostasis by shifting macrophage polarization from a pro-inflammatory M1 to a pro-regenerative M2 phenotype. Our findings introduce a universal and highly potent mechanomedicine strategy for programming cellular functions, offering an efficient and promising approach for the treatment of chronic inflammatory diseases.