Bone Microenvironment‐Mimetic Scaffolds with Hierarchical Microstructure for Enhanced Vascularization and Bone Regeneration

Microchannel networks within engineered 3D scaffold can allow nutrient exchange and rapid blood vessels formation. However, fabrication of a bone microenvironment-mimicking scaffold with hierarchical micro/nanofibrous and microchannel structures is still a challenge. Herein, inspired by structural and functional cues of bone remodeling, a microchannel networks-enriched nanofibrous scaffold by using 3D printing and thermally induced phase separation techniques, which can facilitate cells migration and nutrients transportation, is developed. The customizable vascular-like structure of polycaprolactone within the nanofibrous gelatin-silica scaffold is fabricated using 3D-printed sacrificial templates, while dimethyloxalylglycine (DMOG)-loaded mesoporous silica nanoparticles (MSNs) located on the scaffold surface and bone forming peptide-1 (BFP)-loaded MSNs embedded in the scaffold are implemented for sequential release of DMOG and BFP. The cell experiments show that dual-drug delivery scaffold (DBM/GP) promotes angiogenesis by stimulating migration, tube formation, and angiogenesis-related genes/protein expression of endothelial cells, and osteogenesis by promoting osteo-related genes expression and mineral deposition of osteoblasts. Additionally, DBM/GP scaffold facilitates the angiogenic activity of osteoblasts by activating phosphatidylinositol 3-kinase/protein kinase B/hypoxia inducible factor-1 alpha pathway. Furthermore, enhanced vascularization and bone regeneration of DBM/GP scaffold are demonstrated via subcutaneous and skull defect models. Overall, this study reveals that the bone microenvironment-mimetic dual-drug delivery scaffold provides a promising strategy for bone defects treatment.