A Periosteum‐Inspired Janus Piezoelectric Scaffold Using Bioenergetic‐Driven H‐Type Vascularization for Diabetic Bone Regeneration

An imbalance in the bone-vessel-coupled regeneration process is one of the key factors hindering the effective treatment of diabetic bone defects, which are rooted in the impaired function of mitochondria. Inspired by the bilayered heterogeneous structure of the periosteum, a bilayered, biomimetic, Janus piezoelectric scaffold (JPS) with endogenous piezoelectric effects was developed to regulate energy metabolism. JPS comprises a zinc-doped apatite-gelatin-poly-L-lactic acid membrane fabricated using electrospinning and integrated with a resveratrol-loaded microsphere composite hydrogel. Without requiring an external power source, JPS is designed to respond to local micromechanical stimulation and generate electroactive cues, while synergizing with the controlled release of resveratrol to regulate angiogenesis-related signaling and endothelial metabolic reprogramming. Single-cell sequencing indicated that bone microenvironment remodeling may be associated with H-type vessels, which are bone-specific microvasculatures. JPS provides a continuous power source in a high-sugar environment, thereby reconstructing the bone-vessel coupled regeneration process. JPS treatment stimulated the vascular features associated with H-type vessel-mediated bone regeneration in vascular organoids. The JPS group showed a substantially enhanced bone volume of 21.1% vs. 8.5% in the control in a diabetic calvarial defect model. This study presents an efficient material platform for addressing clinical challenges associated with diabetic bone regeneration.