Bioinspired Silk and Human Amniotic Membrane-Based MSC-sEV-Functionalized Wound Dressing Enhances Skin Regeneration: A Cell-Free Therapeutic Modality for Wound Care

Full-thickness wounds pose significant healing challenges due to their impaired regenerative capacity, persistent inflammation, and oxidative stress. Enhancing the bioactivity of silk fibroin (SF) and the mechanical strength of the human amniotic membrane (hAM) can improve wound healing outcomes. Mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) offer promising anti-inflammatory and antioxidant benefits, but their poor retention and painful application limits their clinical utility. To overcome these challenges, we developed a composite scaffold of SF and hAM (Sh), loaded with sEVs (ShE), designed to accelerate wound healing by modulating inflammation, oxidative stress, and tissue regeneration. ShE exhibited excellent physical stability, optimal swelling, degradation kinetics, hemocompatibility, and sustained sEV release. <i>In vitro</i>, it enhanced keratinocyte and fibroblast proliferation and migration, reduced oxidative stress, and provided immunomodulatory and pro-angiogenic effects. ShE significantly lowered ROS levels, suppressed PHA-activated PBMNC proliferation, facilitated macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, and promoted angiogenesis. <i>In vivo</i>, ShE accelerated wound closure within 21 days, outperforming DuoDERM, a commercial dressing. Histopathological analysis demonstrated improved epidermal maturation, dermal regeneration, and reduced scarring in ShE-treated wounds, confirming the superior tissue regeneration capacity. Additionally, its fabrication from medical waste and indigenous raw materials ensures cost-effectiveness and sustainability in healthcare applications. By synergistically regulating cell physiology for skin regeneration, ShE emerges as a promising, clinically viable, and affordable wound dressing for enhanced wound care management.