3D ‐Cultured Mesenchymal Stem Cell‐Derived Exosomes Embedded in a Hybrid Scaffold Enhance Diabetic Wound Healing by Promoting Angiogenesis

Wound healing in patients with diabetes remains a notable clinical challenge, arising from mitochondrial dysfunction in endothelial cells, which in turn leads to insufficient neovascularization. An effective approach to treating diabetic wounds involves administering exosomes that promote angiogenesis. Exosomes derived from adipose-derived mesenchymal stem cells cultured in a three-dimensional environment (3D-Exo) surpass conventional exosomes in yield, quality, and functionality, offering promising potential for diabetic wound healing. The synergistic promotion of wound repair by a multifunctional 3D-Exo-loaded hybrid scaffold has rarely been reported, and the mechanism underlying their combinatorial effect remains unclear. Herein, direct-writing melt electrospinning (DME) was employed to fabricate a novel polycaprolactone (PCL) microfiber scaffold (DME scaffold, DMEs), integrated with gelatin methacryloyl (GelMA) and 3D-Exo. Characterization of DMEs + GelMA@3D-Exo was subsequently performed. In vitro, the hybrid scaffold demonstrated biocompatibility with human umbilical vein endothelial cells and showed potential to facilitate angiogenesis and collagen formation. In vivo, the application of DMEs + GelMA@3D-Exo improved collagen deposition, stimulated angiogenesis, and increased wound closure rates, surpassing those observed in the DMEs and DMEs + GelMA groups. The underlying mechanism may involve 3D-Exo promoting angiogenesis by enhancing mitochondrial function in endothelial cells. Our research highlights that DMEs + GelMA@3D-Exo enhances angiogenesis and may be a viable candidate for future diabetic wound-healing therapy.