A novel injectable gelatin gel for sustained estrogen release to promote endometrial regeneration by modulation of the Wnt/β-catenin signaling pathway

Background & Objective: Intrauterine adhesions (IUA) are complex disorders with a high recurrence rate that seriously affect the reproductive function and quality of life in women of childbearing age. Currently, effective treatment methods are lacking. In this study, we aimed to utilize the microporous structure of gelatin nanoparticles (GNPs) to fully integrate estradiol (E2) and to develop an injectable GNPs-E2 gel to explore its repair effect on endometrial injury and adhesions. Methods & Results: First, we loaded unmodified natural GNPs with E2 and prepared a new composite gelatin GNPs-E2 gel. GNPs-E2 gel had good compressive resistance, injectability, and the ability to slowly release drugs. A rat model of IUA was established using chemical injury. Rats with IUA were treated with oral estrogen, intrauterine phosphate-buffered saline (PBS) solution, GNPs gel, estrogen solution, or GNPs-E2 gel. The results showed that the GNPs-E2 gel significantly promoted endometrial thickening and glandular increase and improved endometrial fibrosis. In addition, we found that Axin2 and β-catenin were significantly upregulated in the GNPs-E2 gel group, and this upregulation trend was significantly correlated with the degree of endometrial regeneration. This further confirmed that GNPs-E2 gel promoted endometrial recovery by activating the Wnt/β-catenin pathway. Conclusion GNPs-E2 gel, as a sustained-release system of estrogen, inhibits endometrial fibrosis and improves IUA through the Wnt/β-catenin signaling pathway. The development of GNPs-E2 gel provides an innovative approach for the prevention and treatment of IUA and shows great potential for clinical application, offering a new treatment strategy for women of childbearing age.