Ultrasound-Responsive Electroactive Polyetheretherketone Scaffold Promotes Bioenergetic Bone Regeneration by Regulating Mitochondrial Permeability Transition Pores

Abstract Mitochondrial dysfunction and energy metabolic imbalance in senescent bone marrow mesenchymal stem cells (BMSCs) are critical pathological foundations for senile bone regeneration. Existing therapeutic strategies suffer from a lack of active mitochondrial bioenergetic driving forces, failing to effectively reverse energy metabolic suppression of senescent BMSCs. Here, an ultrasound-activated electroactive scaffold was constructed by anchoring barium titanate-transition metal carbide (MXene@BaTiO3) heterojunctions on the surface of polyetheretherketone (PEEK) to reactivate mitochondrial energy metabolism and promote bone regeneration under senescence-associated bone loss conditions. These heterojunctions adhere to BMSC membranes and generate electrical stimulation upon ultrasound stimulation, which significantly inhibits abnormal opening of mitochondrial permeability transition pores (mPTP), reduces leakage of mtDNA and Cyt c, and maintains membrane potential stability. Mechanistic investigations reveal that electrical stimulation activates the PI3K/Akt/MDM2 signaling axis to promote the degradation of accumulated p53, which relieves the competitive binding of p53 to TRAP1, thereby restoring TRAP1-CypD-mediated mPTP gating and mitochondrial homeostasis. Consequently, this ultrasound-activated electroactive scaffold drives mitochondrial energy metabolism and osteogenic differentiation of senescence-like BMSCs in vitro, which is further confirmed in a rat model. These results demonstrate the potential of this electroactive scaffold as a regulator of mitochondrial energy metabolism for senescence-associated bone regeneration.