3D Bioprinted Endometrial Patch Enhances Regeneration and Fertility through Organotypic Endometrial Architecture

Intrauterine adhesions (IUA), a severe condition of endometrial injury, remains a major cause of female infertility due to the lack of effective long-term regenerative therapies. To address this unmet clinical need, we develop an engineered endometrial patch (EEP) fabricated by three-dimensional bioprinting of a porcine endometrium-derived decellularized extracellular matrix bioink loaded with endometrial epithelial organoids, stromal-immune populations, and endothelial cells. The spatially organized, tri-layered construct recapitulates the native architecture of the endometrium and supports epithelial polarity, vascularization, immune modulation, and hormone responsiveness. In a rat model of IUA, EEP transplantation markedly reduced fibrosis and rescued fertility with healthy offspring across generation by restoring endometrial receptivity and tissue integrity. Transcriptomic analysis revealed activation of stem cell proliferation, epithelial development and angiogenesis pathways, highlighting a mechanistic alignment with native tissue repair. Scalable fabrication of human cell-based patches which was administered into the cavity of the endometrium of IUA rabbit model further demonstrated translational adaptability. Together, our findings establish the EEP as a clinically applicable and customizable therapeutic strategy for endometrial regeneration for patients with infertility.宫腔粘连（Intrauterine adhesions, IUA）作为一类严重的子宫内膜损伤性疾病，因缺乏有效的长期再生治疗手段，仍是女性不孕的主要诱因。为解决这一未被满足的临床需求，我们开发了一款工程化子宫内膜贴片（engineered endometrial patch, EEP）：该贴片以负载子宫内膜上皮类器官、基质免疫细胞群及内皮细胞的猪源子宫内膜脱细胞细胞外基质生物墨水为原料，通过三维生物打印制备而成。该空间结构化的三层构建体可复现子宫内膜的天然组织结构，并可支持上皮极性维持、血管生成、免疫调控及激素响应。在IUA大鼠模型中，EEP移植可显著减轻纤维化程度，通过恢复子宫内膜容受性与组织完整性，挽救了大鼠的生育能力，且子代健康可跨代繁育。转录组学分析显示，该治疗策略可激活干细胞增殖、上皮发育及血管生成通路，印证了其与天然组织修复的机制契合性。我们进一步完成了基于人源细胞的贴片的规模化制备，并将其应用于IUA兔模型的宫腔内给药，进一步验证了其临床转化适应性。综上，本研究确立了EEP作为一款可临床应用、可定制化的治疗策略，用于不孕患者的子宫内膜再生修复。