Autocatalytic Hydrolysis of Degradable Polyester Microspheres for Long-Lasting Release of BMP-2 Immunomodulates Bone Regeneration In Vitro

Degradable polyester microspheres are commonly utilized in bone tissue engineering due to their excellent biocompatibility and controlled drug-release profiles. While poly(lactic-<i>co</i>-glycolic acid) (PLGA) microspheres offer rapid degradation but lack sufficient mechanical strength for prolonged implantation, polycaprolactone (PCL) microspheres, with their slower degradation rate and hydrophobic nature, are less suitable for short-term drug-release applications. In this study, PLGA-based degradable polyester microspheres were modified by introducing mesoporous calcium silicate (MCS) with a high specific surface area of 623.59 m²/g and a pore volume of 1.81 cm³/g and PCL and loaded with bone morphogenetic protein-2 (BMP-2). The self-catalytic hydrolysis of composite microspheres (BMGACL) enables sustained and controlled BMP-2 release over 98 days, supporting the entire bone regeneration process. Additionally, mesoporous calcium silicate enhances the microspheres' mechanical properties, providing effective structural support for bone defects. Compared to other groups, BMGACL microspheres significantly promoted the proliferation and osteogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs). Notably, the BMP-2 released by composite microspheres can regulate macrophage polarization to M2 phenotype through multiple signaling pathways including cGMP-PKG and TGF-β. In an immune microenvironment enriched with M2-associated macrophages, this process induces BMSCs to express osteogenic genes. Simultaneously, it enhances the deposition of bone formation markers such as alkaline phosphatase (AP) and calcium nodules, with levels reaching 3.7 times and 20.5 times higher than those in the control group, respectively. In summary, this study proposes an efficient biodegradable polyester drug-loaded microsphere system that holds promise for advancing clinical translation of bone defect repair materials.