Engineering the Host‐Graft Interface Stabilizes Vascular Integration and Improves Endocrine Function of Transplanted Ovarian Tissue

Ovarian tissue cryopreservation and transplantation (OTCT) restores fertility and ovarian endocrine function in patients exposed to gonadotoxic cancer therapies but graft outcomes remain variable due to the avascular nature of the transplantation procedure. Here, the host-graft interface is engineered using a synthetic microporous annealed particle (MAP) hydrogel transplantation strategy to support vascular integration of human ovarian tissue cubes. In a xenograft model of primary ovarian insufficiency (POI), non-encapsulated ovarian tissue strips exhibit early but transient and disorganized host vascular infiltration. In contrast, tissue cubes encapsulated within MAP hydrogels (OvaMAPs) demonstrate sustained host vascular integration with significantly greater mouse vessel area and length at 3 and 6 weeks post-transplantation. By 20 weeks, both non-encapsulated grafts and OvaMAPs restore circulating estradiol and suppress follicle-stimulating hormone, confirming integration of the grafts with the host hypothalamic-pituitary axis. Notably, OvaMAP recipients exhibit reduced variability in estradiol levels, suggesting consistent, predictable graft function. These findings identify stabilization of vascular remodeling at the host-graft interface as a key determinant of ovarian graft performance and demonstrate that a fully synthetic microporous biomaterial can improve the durability and predictability of endocrine function restoration after OTCT for patients at risk of POI.