A 3D-printed composite scaffold with sequential delivery of QK and osteogenic growth peptides promotes diabetic bone regeneration through angiogenic and osteogenic modulation

Diabetic bone defects heal poorly due to hyperglycemia-induced impairments in osteogenesis and angiogenesis, which may lead to delayed regeneration if left untreated. To address these challenges, we developed a composite 3D-printed poly(lactic-co-glycolic acid)/hydroxyapatite (HA) scaffold functionalized with the orchestrated release of vascular endothelial growth factor-mimetic peptide (QK) and osteogenic growth peptide (OGP). The unique triphasic release profile of the scaffold was engineered to mimic natural bone-healing cascades: (1) the initial rapid release of QK peptides resulting from degradation of the dextran methacrylate coating initiates angiogenesis, thereby addressing the critical vascular deficiency; (2) the subsequent sustained release of OGP stimulates osteoblast differentiation and bone formation; and (3) the prolonged release of Ca 2+ and PO 4 3− from nano-HA particles supports matrix mineralization and structural integrity. This spatiotemporally coordinated delivery system surpasses conventional single-factor approaches by simultaneously addressing the multiple pathological features of diabetic bone abnormalities. In-vitro and in-vivo evaluations validated the sequential release kinetics of the scaffold that effectively couple vascularization and osteogenesis, establishing a regenerative milieu that mitigates diabetes-impaired healing deficiencies. The coordinated actions of these components not only offer an alternate therapeutic strategy for diabetic bone defects but also hold potential for application in other complex tissue-regeneration scenarios requiring coordinated multicellular responses.