A sequential and synergistic release sacrificial microgels scaffold for endometrial niche reprogramming and fertility restoration

Intrauterine adhesions (IUA) remain a therapeutic challenge, necessitating advanced regenerative strategies. Herein, we propose a "programmed endometrial niche" strategy, a 3D-printed adipose-derived stem cells (ADSCs) hydrogel scaffold is constructed via microfluidic technology, incorporating platelet-rich plasma (PRP)-loaded thermosensitive gelatin microgels (PMS@AH) for sequential and synergistic delivery of PRP and ADSCs to restore the endometrial immune microenvironment and niche. In vitro assays demonstrate that PMS@AH possesses excellent biocompatibility and significantly promoted cell proliferation, migration, and angiogenesis, accompanied by potent anti-inflammatory activity. In both rat and cynomolgus macaque IUA models, it effectively restored endometrial structure, reduced fibrosis and inflammation, and successfully restored fertility. Mechanistically, RNA-sequencing analysis reveals that PMS@AH involves suppressing the IL-17/nuclear factor-κB (NF-κB) pathway to modulate the immune microenvironment and inhibiting the Wnt/β-catenin pathway to program the endometrial niche. This sequentially releasing scaffold presents a promising platform for treating IUA and broader applications in reproductive medicine.