Natural regeneration-inspired sequential delivery of synergistic growth factors for structural and functional endometrial regeneration.

Abstract

Large-scale deep endometrial injury has a serious impact on the reproductive health of women, necessitating the development of novel therapeutic approaches. Treatment strategies using single factor may not perfectly match the intricate and dynamic process of endometrial regeneration. In light of the sequential progression of vascularization and endometrial remodeling observed during the regeneration of injured endometrium, a dual growth factor sequential delivery system is prepared by loading IGF-1 onto hydrogel microspheres and blending with an outer bulk hydrogel containing VEGF. The controlled degradation of hydrogel facilitates the sequential release of the two factors, thereby fostering the vascularization, migration and proliferation of endometrial cells in vitro. Animal experiments have proved that the hydrogel system can promote the regeneration of endometrial structure through vascular remodeling, glandular regeneration, and proliferation of endometrial cells, and simultaneously improve the rate of embryo implantation and live birth, which further indicates the functional reconstruction of the injured endometrium. Consequently, drawing inspiration from the sequential process of endometrial regeneration, this study provides innovative strategies for structural and functional restoration of the endometrium. STATEMENT OF SIGNIFICANCE: This research presents an innovative approach to the treatment of injured endometrium through a sequential dual growth factor delivery system. The system involves the incorporation of IGF-1 onto hydrogel microspheres, which are subsequently embedded within a GelMA hydrogel matrix containing VEGF. Unlike conventional hydrogel-based therapeutic strategies that involve the loading of growth factors, the developed delivery system is engineered in accordance with the vascularization and endometrial remodeling processes inherent to the regeneration of injured endometrial tissue. It facilitates the initial release of VEGF to stimulate the formation of blood vessels, followed by a gradual release of IGF-1 during the intermediate phase of endometrial regeneration to promote tissue remodeling. Pre-clinical animal studies have demonstrated that this innovative delivery strategy effectively restores the structure and function of the endometrium, suggesting significant potential for clinical application.