Functional restoration of uterine architecture and fertility via a 3D-printed biomimetic scaffold: The role of macrophage-driven immunomodulation

The structural complexity of the uterus makes identifying biomaterials and scaffold designs for supporting functional tissue regeneration challenging. Poly(L-lactide-co-caprolactone) (PLCL) has gained attention due to its biocompatibility and tunable degradation profile. In this study, a three-layered PLCL scaffold was fabricated via melt electrowriting (MEW) 3D printing to mimic the mechanical properties of the native uterine matrix. Using a mouse model of severe uterine injury, we demonstrated that the PLCL scaffold markedly promoted structural repair and functional recovery, as evidenced by improved pregnancy outcomes. Mechanistically, the scaffold enhanced macrophage recruitment and skewed their polarization toward an M2 phenotype, accompanied by upregulation of the hallmark genes <i>SPP1</i>, <i>LGALS3</i>, and <i>TREM2</i>. Furthermore, the scaffold stimulated parenchymal cell proliferation and migration and activated the JAK-STAT3 and YAP-Hippo signaling pathways, thereby establishing a pro-regenerative niche. Collectively, these findings highlight a scaffold-driven immunomodulatory mechanism that promotes uterine regeneration through macrophage polarization and activation of key signaling pathways.