Micromotion‐Driven “Mechanical‐Electrical‐Pharmaceutical Coupling” Bone‐Guiding Membrane Modulates Stress‐Concentrating Inflammation Under Diabetic Fractures

The use of piezoelectric materials to convert micromechanical energy at the fracture site into electrical signals, thereby modulating stress-concentrated inflammation, has emerged as a promising treatment strategy for diabetic fractures. However, traditional bone-guiding membranes often face challenges in diabetic fracture repair due to their passive and imprecise drug release profiles. Herein, a piezoelectric polyvinylidene fluoride (PVDF) fibrous membrane is fabricated through electrospinning and oxidative polymerization to load metformin (Met) into a polypyrrole (PPy) coating (Met-PF@PPy), creating a "mechanical-electrical-pharmaceutical coupling" system. In a micromotion mechanical environment, Met-PF@PPy converts mechanical energy into electrical signals, activating the electrochemical reduction of PPy and triggering stress-responsive Met release. The generated electrical signals suppress inflammation through M1-to-M2 macrophage polarization and simultaneously enhance osteogenesis. Simultaneously, Met inhibits the NF-κB pathway to reduce pro-inflammatory cytokines while activating the AMPK pathway to promote osteogenesis and angiogenesis. In a diabetic mouse femoral fracture model, Met-PF@PPy significantly reduces inflammatory markers, enhances vascularization, and increases bone mineral density and bone volume fraction by over 30%. This "force-electric-drug coupling" strategy provides an innovative approach for active regulation in diabetic fracture repair and offers a versatile platform for advancing piezoelectric materials in regenerative medicine.