Bioactive ion engineered 3D printed TCP scaffolds promote vascularized bone regeneration in diabetic bone defects by restoring mitochondrial homeostasis

Diabetes mellitus (DM)-associated hyperglycemia disrupts vascularized bone regeneration through mitochondrial dysfunction in repair-related cells and hindering scaffold-mediated bone defect repair. To overcome this challenge, we developed an innovative 3D-printed β-tricalcium phosphate scaffold co-doped with zinc and silicon ions (Zn/Si-TCP). In vitro evaluations revealed that Zn/Si-TCP significantly enhanced cellular viability of both endothelial cells and osteoblasts under hyperglycemic conditions, achieving this through dual mechanisms: (1) effective reactive oxygen species (ROS) scavenging (35 % reduction), and (2) restoration of mitochondrial homeostasis, as demonstrated by 1.5-fold upregulation of mitochondrial fusion protein Mfn1 and 0.6-fold downregulation of fission protein Drp1. The scaffold notably improved mitochondrial function, enhancing membrane potential by 1.4-fold and boosting ATP generation by 1.2-fold. These synergistic effects translated to superior biological performance, with 1.5-fold enhancement in angiogenic capacity (tube formation assay) and 1.9-fold increase in osteogenic activity (ALP assay). In vivo studies in a diabetic rat calvarial defect model demonstrated the remarkable efficacy of Zn/Si-TCP scaffolds, which achieved a 4.6-fold increase in vascular density and a 2.0-fold improvement in bone volume fraction (BV/TV) compared to undoped TCP controls at 8 weeks post-implantation, indicating successful vascularized bone reconstruction facilitated by Zn/Si-TCP scaffolds. This study establishes a new paradigm in diabetic bone repair by developing a dual-functional scaffold that coordinately promotes angiogenesis and osteogenesis through mitochondrial homeostasis regulation.