Lu Liu, Xiaodan Liu, Ting Liu, Haibin Ma, Dongmei Chen, Shudan Liu
Chronic diabetic wounds represent a significant clinical challenge due to impaired healing processes characterized by persistent inflammation, compromised angiogenesis, and a hostile microenvironment. Despite the therapeutic potential of mesenchymal stem cells (MSCs), their post-transplantation survival remains suboptimal in such pathological conditions. Here, we developed a sustained-release oxymatrine-loaded hyaluronic acid methacryloyl (HAMA) hydrogel to enhance placental mesenchymal stem cell (PMSC)-mediated repair in diabetic wounds. In a streptozotocin-induced diabetic mouse model with full-thickness dorsal skin defects, photo-crosslinked HAMA-OMT hydrogels were fabricated and evaluated for their effects on PMSC survival and wound healing outcomes. Comprehensive assessments included wound closure rates, histological analysis, angiogenesis, collagen remodeling, macrophage polarization, and the activation status of Nrf2/HO-1 and TLR4/NF-κB signaling pathways. The porous HAMA matrix provided structural support for PMSC adhesion and survival, while OMT incorporation improved hypoxia resistance and mitigated burst release kinetics. In diabetic wounds, the HAMA-OMT+PMSCs combination treatment significantly accelerated re-epithelialization, enhanced regeneration of hair follicles and sweat glands, promoted angiogenesis, and improved collagen organization compared to single-treatment groups. Mechanistically, OMT exerted dual regulatory effects by suppressing TLR4/NF-κB-driven inflammatory responses, promoting CD206+M2 macrophage polarization, and activating Nrf2/HO-1-mediated antioxidant defenses, thereby protecting PMSCs from oxidative stress-induced apoptosis. Collectively, these findings demonstrate that OMT-loaded HAMA hydrogel synergizes with PMSCs to reconstruct a pro-regenerative microenvironment, offering a promising cell, material, and small-molecule combinatorial strategy for the effective treatment of chronic diabetic wounds.