An Injectable Clinical-Grade Fibrin Hydrogel Restores Fertility in Intrauterine Adhesions via MSC-Mediated Immune and Regenerative Modulation, Unlocking an Equivalent Cell-Free EV-Based Therapy.

Abstract

While mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) hold therapeutic potential, their clinical translation is hindered by suboptimal delivery systems. This study presents a directly translatable strategy for treating intrauterine adhesions (IUA) using a clinical-grade, injectable fibrin hydrogel (Porcine Fibrin Sealant, PFS) to deliver MSCs/EVs. This platform not only ensures biocompatibility and surgical handling but also provides a protective niche. In rat models of mechanically- and ethanol-induced IUA, optimal-dose PFS-MSCs injected into the uterine cavity promote endometrial regeneration, as shown by increased endometrial thickness, gland number, and reduced fibrosis. This treatment further restores reproductive function, as evidenced by the enhanced secretion of fertility-related factors, improved embryo implantation, and the live birth of healthy offspring. Mechanistically, transcriptomic and histological analyses of the PFS-MSCs treated group revealed dual repair mechanisms: (1) immune remodeling, characterized by decreased M1 macrophages, enhanced M2 macrophage polarization, expanded Treg populations, and upregulated IL-4 level, and (2) tissue regeneration, marked by upregulated bFGF level, increased angiogenesis, and enhanced cell proliferation. Crucially, the cell-free PFS-EVs strategy achieved therapeutic equivalence to the PFS-MSCs strategy, fully reversing ethanol-induced IUA damage and enabling fertility recovery. This safe and effective platform presents a directly translatable strategy for IUA treatment.