He Jing, Gu Zeming, Wei Qianqian, Zhang Jing, Sun Yuan, Shao Huifeng, He Yong
Center for Reproductive Medicine, Department of Gynecology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; State Key Laboratory of Fluid Power and Mechatronic Systems, School of Mechanical Engineering, Zhejiang University, Hangzhou 310027, China.
State Key Laboratory of Fluid Power and Mechatronic Systems, School of Mechanical Engineering, Zhejiang University, Hangzhou 310027, China.
Acta Biomater. 2025 Jul 1;201:229-240. doi: 10.1016/j.actbio.2025.06.025. Epub 2025 Jun 13.
Intrauterine adhesions (IUAs) present a significant clinical challenge in reproductive medicine with limited effective treatments. Here, we developed an innovative bioactive scaffold using coaxial 3D printing technology to address this unmet need. The scaffold consists of a gelatin methacryloyl (GelMA)-heparin methacryloyl (HepMA) bioink that electrostatically binds and sustains controlled release of heparin-binding epidermal growth factor (HB-EGF). This unique design serves as both a physical barrier to prevent post-injury adhesions and a bioactive delivery system promoting endometrial regeneration through neovascularization. Furthermore, bone marrow-derived mesenchymal stem cells (BMSCs) were incorporated to modulate the local immune microenvironment by polarizing macrophages toward an anti-inflammatory M2 phenotype. Our results demonstrate that this combined approach successfully restored endometrial receptivity, as evidenced by recovered estrogen receptor α (ERα) and progesterone receptor (PR) expression, and ultimately enabled successful pregnancy in an animal model of uterine injury. Comprehensive safety assessments confirm the therapeutic potential of this approach. This multifunctional scaffold represents a promising therapeutic strategy for IUAs, addressing structural, regenerative, and immunological barriers to endometrial repair. STATEMENT OF SIGNIFICANCE: Intrauterine adhesions (IUAs) are a significant complication that can occur following gynecological procedures, affecting approximately 20 % of women after a miscarriage and decreasing the rates of live births. Current treatment options are insufficient, highlighting the urgent need for more effective interventions. To address this issue, we developed a bioactive scaffold using coaxial 3D bioprinting with a biodegradable hydrogel composed of GelMA and HepMA. This scaffold is loaded with stem cells (BMSCs) to help modulate the immune response and includes a sustained-release of growth factors (HB-EGF) to promote re-epithelialization. Our findings indicate that this innovative scaffold not only prevents adhesions but also has the potential to restore fertility, offering a promising strategy to improve outcomes for women at risk of developing IUAs.
宫腔粘连（IUAs）在生殖医学中是一项重大的临床挑战，有效治疗方法有限。在此，我们利用同轴3D打印技术开发了一种创新的生物活性支架，以满足这一未被满足的需求。该支架由甲基丙烯酰化明胶（GelMA）-甲基丙烯酰化肝素（HepMA）生物墨水组成，能静电结合并持续控制释放肝素结合表皮生长因子（HB-EGF）。这种独特设计既作为防止损伤后粘连的物理屏障，又作为通过新生血管形成促进子宫内膜再生的生物活性递送系统。此外，引入了骨髓间充质干细胞（BMSCs），通过将巨噬细胞极化为抗炎M2表型来调节局部免疫微环境。我们的结果表明，这种联合方法成功恢复了子宫内膜容受性，雌激素受体α（ERα）和孕激素受体（PR）表达的恢复证明了这一点，最终在子宫损伤动物模型中实现了成功妊娠。全面的安全性评估证实了该方法的治疗潜力。这种多功能支架代表了一种有前景的IUAs治疗策略，解决了子宫内膜修复的结构、再生和免疫障碍。意义声明：宫腔粘连（IUAs）是妇科手术后可能发生的重大并发症，流产后约20%的女性受其影响，降低了活产率。目前的治疗选择不足，凸显了对更有效干预措施的迫切需求。为解决这一问题，我们使用同轴3D生物打印技术，用由GelMA和HepMA组成的可生物降解水凝胶开发了一种生物活性支架。该支架负载干细胞（BMSCs）以帮助调节免疫反应，并包括生长因子（HB-EGF）的持续释放以促进再上皮化。我们的研究结果表明，这种创新支架不仅能防止粘连，还具有恢复生育能力的潜力，为改善有发生IUAs风险的女性的治疗结果提供了一种有前景的策略。
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