Hierarchical Composite Scaffold That Synergistically Combines Orderly Active Factor Release with Scaffold Degradation for Enhanced Bone Repair

Effective bone regeneration requires biodegradable scaffolds to provide temporary mechanical support while progressively creating space and delivering bioactive cues in step with tissue healing. However, achieving synergy between orderly active particle release and scaffold degradation remains a major challenge. This study aimed to develop a hierarchical scaffold for sustained bioactive-ion delivery and bone-defect repair. The scaffold consisted of a 3D-printed poly(p-dioxanone) (PPDO) framework and a freeze-dried gelatin network. Magnesium oxide-coated chitosan microspheres (MgO@CS) were incorporated into gelatin to support early cell recruitment and angiogenesis, whereas citrate-functionalized amorphous calcium phosphate (Cit-ACP) was embedded in PPDO to provide sustained osteogenic stimulation. During in vitro degradation, gelatin was largely removed within 5 weeks, progressively opening space for tissue infiltration. PPDO fibers showed morphological erosion at weeks 7–8 but persisted as the principal structural framework. The scaffold continuously released Mg2+, Ca2+, and citrate during the 14-day observation period. Cell experiments demonstrated enhanced cellular recruitment, vascularization, and osteogenic differentiation. In a rat calvarial defect model, the scaffold enhanced bone formation and improved BV/TV. These results demonstrate that coupling stage-matched scaffold degradation with compartmentalized bioactive-ion delivery provides a promising strategy for coordinating vascularized bone regeneration.