Hierarchical periosteum-bone composite scaffold with staged release of dexamethasone and endothelial cell derivatives for efficient critical-sized bone defect repair

Bone tissue engineering represents a promising approach for developing multifunctional biomaterials to facilitate bone regeneration. In this study, we designed a hierarchically composite scaffold that mimics both the periosteum and bone to investigate its effectiveness in repairing critical-sized bone defects. The periosteal layer of the bionic bilayered scaffold was created using a nonwoven mat of core-shell structured nanofibers. The fiber core consisted of a methylpropionylated gelatin (GelMA) hydrogel that encapsulated endothelial cell derivatives (ECd), while the shell was composed of a blend of poly(L-lactide-co-ε-caprolactone), bioactive glass (BG), and dexamethasone (DEX), enabling the staged release of the payloads. Then, a bulk of GelMA/BG/DEX hydrogel was integrated with the periosteal layer to construct a hierarchical periosteum-bone composite scaffold. Such a scaffold facilitated revascularization, anti-inflammation, and the promotion of mature bone formation through the biomimetic properties of organic-inorganic hybrid components and a three-dimensional porous structure, as well as the dual effects of staged release of DEX and ECd. In vivo, the scaffold significantly promoted repair of a 6-mm rat calvarial defect, accompanied by up-regulated expression of CD31, OPN, and type I collagen. Transcriptome sequencing analysis also revealed that the repair process is closely associated with the JAK2-STAT signaling pathway. Collectively, this bionic hierarchical scaffold enhanced critical-sized bone defect repair through synergistic multifunctional regulation, including enhanced angiogenesis, modulation of inflammation, and efficient osteogenic differentiation, demonstrating broad and promising clinical translation potential.