A Triple‐Integrated 3D‐Printed Composite Scaffold of High‐Activity Peptide‐Metal Ion‐Bone Cement Facilitates Osteo‐Vascular Regenerative Repair of Diabetic Bone Defects

Abstract Hyperglycemia and its induced oxidative stress microenvironment present formidable challenges to the repair of diabetic bone defects. Herein, a novel TZGP (α‐TCP/ZnO/GM@P2) composite scaffold for diabetic bone defect repair is developed. Characterization results demonstrate that the α‐TCP cement scaffold, ZnO nanoparticles, and gelatin microspheres loaded with and protecting P2 (a novel parathyroid hormone‐related peptide) achieve complementary advantages. The TZGP scaffold, while meeting the mechanical strength requirements of cancellous bone, compensates for the deficiency of bioactive peptides in inorganic scaffolds. Its biocompatibility is enhanced, and the scaffold is endowed with antibacterial and antioxidant properties. The in vitro and in vivo results reveal that the TZGP scaffold releases active factors P2 and Zn 2+ , promotes cell proliferation and recruitment in a high‐glucose microenvironment, reduces cellular reactive oxygen species accumulation, improves DNA injury and mitochondrial homeostasis, and induces osteogenic‐angiogenic differentiation. Compared with the conventional α‐TCP scaffold, the TZGP scaffold exhibits more excellent biodegradability, accelerates local tissue filling, and promotes bone accumulation and vascular reconstruction in diabetic bone defects. Consequently, the novel design strategy of the TZGP scaffold offers a promising approach to repairing diabetic bone defects.