Mineralized cellulose nanofibers reinforced bioactive hydrogel remodels the osteogenic and angiogenic microenvironment for enhancing bone regeneration

Slow osteogenesis and insufficient vascularization remain significant challenges in achieving effective bone repair and functional restoration with tissue-engineered scaffolds. Herein, a novel mineralized nanofibers reinforced bioactive hydrogel was designed to enhance bone regeneration inspired from the structural and functional properties of the bone tissue extracellular matrix (ECM). This bioactive hydrogel integrated enzymatically mineralized TEMPO-oxidized bacterial cellulose (m-TOBC) nanofibers and mesoporous silica nanoparticles (MSNs) loaded with the angiogenic drug dimethyloxalylglycine (DMOG) into gelatin methacryloyl (GelMA). The m-TOBC nanofibers achieved one stone, three birds: improving the printability of GelMA ink, mechanical properties, and osteoconduction of the hydrogel. The incorporation of MSNs loaded with DMOG fostered an angiogenic microenvironment through the release of DMOG. Results indicated that the bioactive hydrogel significantly enhanced in vitro mineralized matrix deposition and osteoblastic alkaline phosphatase expression. Additionally, the bioactive hydrogel had good ability to promote angiogenesis in terms of enhanced endothelial cell migration, tube formation, and upregulated angiogenic genes expression levels. In a critical-sized rat cranial defect model, the bioactive hydrogel significantly enhanced bone regeneration. Overall, this research offered a promising strategy to design nanofibers enhanced hydrogel to remodel osteogenic and angiogenic microenvironment for enhancing bone repair.