PCL-HAMA-Sema3A scaffold promotes bone regeneration

Abstract A 3D-printed polycaprolactone (PCL) scaffold was combined with hyaluronic acid methacrylate (HAMA) hydrogel carrying Semaphorin-3A (Sema 3A) to create an implantable PCL-HAMA-Sema 3A construct for critical-size bone defects. PCL provided robust mechanical support and interconnected macropores, while HAMA overcame PCL’s hydrophobicity and enabled sustained Sema 3A release. Sema3A orchestrates bone homeostasis via the neuropilin-1/plexin-A holoreceptor. It simultaneously drives osteoblast differentiation through Wnt/β-catenin activation and suppresses osteoclastogenesis by disrupting RANKL/RANK signaling. Sema3A scavenges reactive oxygen species (ROS) and shifts macrophages from the M1 to the M2 phenotype, thereby mitigating inflammation and preventing oxidative and inflammatory bone loss. Additionally, it enhances angiogenesis by up-regulating VEGF. Collectively, Sema3A couples osteogenesis, anti-resorption, anti-oxidation and vascularization, offering a multi-target therapeutic strategy for critical bone defects.