Piezoelectric Gel/Bat-Met/Mx Enhances Diabetic Craniomaxillofacial Bone Regeneration

A piezoelectric hydrogel with low-intensity pulsed ultrasound and photothermal dual response was developed to target mitochondria and promote bone regeneration in diabetic bone defects. A mitochondria-targeted Gel/BaT-Met/MX hydrogel was synthesized by modifying barium titanate with triphenylphosphine and metformin-zinc complex, then integrating it into GelMA with MXene for enhanced conductivity. The hydrogel was characterized using FTIR and SEM, alongside assessments of photothermal and piezoelectric properties. Biocompatibility was evaluated via CCK-8 assays, while osteogenic potential was tested through co-culture with rat BMSCs, using ARS and ALP staining. In vivo efficacy was assessed in a diabetic rat bone defect model using male Sprague-Dawley rats (4–6 weeks old) via micro-CT and HE staining, with ethical approval from the institutional committee. Mechanisms were explored using transcriptomic sequencing, immunofluorescence, and Western blot analysis. The hydrogel was successfully synthesized and exhibited excellent photothermal and piezoelectric properties. It significantly enhanced bone regeneration in diabetic microenvironment defects, restoring diabetes-induced mitochondrial membrane potential dysfunction and effectively clearing mitochondrial reactive oxygen species. Mechanistically, it promoted bone regeneration by targeting mitochondria through the PI3K-Akt signaling pathway, as confirmed by molecular analyses. The Gel/BaT-Met/MX hydrogel, with its dual ultrasound/NIR responsiveness, effectively targets mitochondrial dysfunction, regulates glucose metabolism, and enhances osteogenesis via the PI3K-Akt pathway, offering a promising therapeutic strategy for diabetic craninomaxillofacial bone defect repair with potential clinical translational value.