Bioprinted Human Umbilical Cord Mesenchymal Stem Cell-laden Microfiber-derived Extracellular Vesicles Promote Endometrial Repair and Fertility Recovery in Intrauterine Adhesions.

Intrauterine adhesions (IUAs) pose a significant reproductive health challenge, often leading to infertility and complications in pregnancy owing to endometrial damage and fibrosis. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) therapy has emerged as a potential strategy for endometrial repair. However, traditional EVs production methods yield low quantities with limited efficacy, hindering their widespread application. In this study, we proposed an innovative approach that integrates three-dimensional (3D) bioprinted human umbilical cord MSC microfiber-derived EVs (3D-EVs) with gelatin methacrylate hydrogels for in situ delivery. Our platform achieved a 1,000-fold increase in 3D-EV particles production and superior cargo quality compared with conventional 2D cultures. In a rat endometrial organoid injury model, 3D-EVs and 2D-EVs exhibited equivalent therapeutic efficacy. 3D-EVs promoted cell activity and inhibited cell damage by transferring decorin, which inhibited LPS-induced p38 phosphorylation. In vivo, 3D-EVs improved pregnancy outcomes by reducing endometrial fibrosis and promoting endometrial proliferation. Our findings suggest that 3D-EVs derived from bioprinted human umbilical cord MSC-laden microfibers mitigate endometrial injury and fibrosis, improving pregnancy outcomes in IUAs. This study opens new avenues for the development of effective EV-based therapies for the treatment of IUAs.