Synergistic Bone Regeneration Through Sequential Dual-drug Delivery

The global aging population has raised concerns regarding age-related health issues like osteoporosis and bone fractures. To address these conditions, bone-like scaffolds containing bioactive molecules and biomaterials have been widely studied. However, uncontrolled burst release and delivery of drugs can incur negative side effects. To overcome this issue, a collagen-hydroxyapatite scaffold (COHAS) that can sequentially deliver Bone morphogenetic protein-2 (BMP-2) and Osteoprotegerin fused to the Fc region of immunoglobulin (OPG-Fc) is synthesized. The COHAS comprises a collagen-hydroxyapatite matrix containing BMP-2 and numerous poly-lactic glycolic acid (PLGA) microspheres with OPG-Fc, dispersed in the matrix. The dispersion of PLGA microspheres enables the retardation of OPG-Fc release compared to BMP-2 release. The controlled sequential delivery of BMP-2 and OPG-Fc exhibits synergistic potential in promoting new bone formation by simultaneously activating osteoblasts and deactivating osteoclasts. This investigation revealed that the COHAS co-loaded with BMP-2 and OPG-Fc possesses excellent cell viability and enhanced osteogenic properties in vitro. In vivo assessment via implantation of the drug-loaded COHAS using an 8 mm-calvarial defect rat model demonstrated high efficacy of new bone formation with good biocompatibility. Hence, these findings provide valuable insights for developing therapeutic scaffolds capable of sequential release of multiple drugs, with the potential to extend a cell-free treatment system for bone regeneration.