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.

Automated summary

This study develops a bone microenvironment-mimicking scaffold with microchannel networks and nanofibrous structures using 3D printing and thermally induced phase separation techniques. The scaffold promotes cells migration and nutrient transportation. Cell experiments show that the scaffold promotes angiogenesis and osteogenesis, and enhances the angiogenic activity of osteoblasts through the activation of specific pathways.