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

  • Adv Healthc Mater. 2026 Apr;15(15):e04360. doi: 10.1002/adhm.202504360.
Yixin Zhang  1  2  3 ,  Lin Liang  1 ,  Kaichi Ma  1 ,  Fan Li  1 ,  Lijing Kong  1 ,  Ruiting He  1 ,  Jiawei Cai  1 ,  Yuan Jiang  1 ,  Hongjie Zou  2 ,  Pei Xu  1 ,  Zhonghai Wang  2 ,  Jihui Du  2  3 ,  Mingxing Liu  1 ,  Zhiyong Zhang  1
Affiliations
  • 1. Translational Research Centre of Regenerative Medicine and 3D Printing, Department of Orthopedic Surgery, Guangzhou Key Laboratory of Spine Disease Prevention and Treatment, Guangdong Province Engineering Research Center For Biomedical Engineering, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center For Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, P. R. China.
  • 2. Research Center for Clinical and Translational Medicine, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen Nanshan People's Hospital, and the Sixth Affiliated Hospital of Shenzhen University Medical School, Shenzhen, P. R. China.
  • 3. Guangdong Key Laboratory For Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory For Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, P. R. China.
PMID: 41660804 DOI: 10.1002/adhm.202504360
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.

Keywords
extracellular vesicles; fibrin hydrogel; intrauterine adhesion; mesenchymal stem cells; tissue regeneration.
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