Endometrial ECM Modified Hemispherical Hydrogels Delivering MenSCs Promote the Regeneration of Thin Endometrium

Abstract Thin endometrium (TE), a major cause of embryo implantation failure, increases the risk of early miscarriage, ectopic pregnancy, and perinatal complications. Owing to the poor utilization and short‐term effectiveness of current stem cell therapies, their efficacy in improving reproductive outcomes in patients with TE is limited. Endometrial extracellular matrix (EMECM) modified hemispherical hydrogels (ECMHPs) are developed to deliver menstrual blood‐derived stem cells (MenSCs) to promote TE repair. The irregular porous structure on one side of the hemispherical hydrogel microspheres significantly enhances their retention capability on the uterine wall, whereas the bioactive decellularized EMECM promotes MenSCs proliferation and paracrine function. In vitro experiments demonstrate that ECMHPs@MenSCs promote the proliferation of damaged human endometrial stromal cells (HESCs) while inhibiting their fibrosis and apoptosis. In TE rat models, intrauterine transplantation of the ECMHPs delivering MenSCs system (ECMHPs@MenSCs) extends retention time, promotes endometrial thickness by 2.3‐fold, increases glandular number by 3.7‐fold, inhibits endometrial fibrosis. Additionally, this system improves endometrial regeneration markers and uterine receptivity, and restores fertility, with a mean gestational sac number of 11.0 ± 2.8 compared with only 2.3 ± 2.1 in the untreated group. This study provides an efficient and convenient therapeutic strategy for TE repair and fertility restoration.