Coaxial printing of slow-release heparin-binding epidermal growth factor scaffold to avoid the occurrence of intrauterine adhesions.

Abstract

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.