Scaffold‐Hydrogel Synergy with OPC‐Crosslinked dUECM and VEGF‐Nanocomposite Hydrogel Achieves Dual “Structural‐Vascular” Regeneration in Rats

Absolute uterine factor infertility (AUFI) remains untreatable with current assisted reproduction techniques. Although decellularized uterine extracellular matrix (dUECM) holds promise for uterine reconstruction, its clinical translation is limited by rapid degradation and poor angiogenic capacity. Herein, a dual-component system was developed by combining oligomeric proanthocyanidin (OPC)-crosslinked dUECM with an injectable VEGF-loaded nanocomposite hydrogel. The OPC-dUECM scaffold (1 mg/mL OPC solution) restored native-like tensile strength, reduced collagenase-induced degradation to 52%, and facilitated cellular infiltration. The VEGF-EPL-HP nanocomposite hydrogel was fabricated by encapsulating VEGF (350 ng/mL) in ε-polylysine/heparin-poloxamer (EPL-HP) nanoparticles dispersed within a thermosensitive hydrogel. The hydrogel exhibited a gelation temperature of 23.2°C, provided sustained VEGF release over 7 days, and showed negligible hemolytic toxicity. In vitro, this hydrogel significantly enhanced the migration and tube formation of human umbilical vein endothelial cells. At 90 days post-surgery in a rat uterine defect model, the combined OPC-dUECM + VEGF-EPL-HP group achieved full endometrial and myometrial regeneration, accompanied by elevated microvessel density, attenuated inflammation, and negligible fibrotic lesions. Collectively, this study validated a synergistic scaffold-hydrogel platform enabling concurrent structural reconstruction and vascularization of the injured uterus, offering a clinically translatable strategy for AUFI patients.