Signal Converter‐Based Therapy Platform Promoting Aging Bone Healing by Improving Permeability of the Mitochondrial Membrane

The aging microenvironment promotes persistent inflammation and loss of intrinsic regenerative capacity. These are major obstacles to effective bone tissue repair in older adults. This study aims to explore how physical thermal stimulation can effectively delay the bone marrow mesenchymal stem cells (BMSCs) aging process. Based on this, an implantable physical signal-converter platform is designed as a therapeutic system that enables stable heat signals at the bone injury site under ultrasound stimulation (US). It is found that the therapeutic platform controllably reduces the mitochondrial outer membrane permeabilization of aging BMSCs, bidirectionally inhibiting mitochondrial reactive oxygen species and mitochondrial DNA (mtDNA) leakage. The leakage ratio of mtDNA decreases by 22.7%. This effectively mitigates the activation of the cGAS-STING pathway and its downstream NF-κB signaling induced by oxidative stress in aging BMSCs, thereby attenuating the pathological advancement of chronic inflammation. Thus, it effectively restores the metabolism and osteogenic differentiation of aging BMSCs in vitro, which is further confirmed in a rat model. In the GMPG/US group, the bone mineral density increases 2-3 times at 4 weeks in the rats femoral defect model. Therefore, this ultrasound-based signal-conversion platform provides a promising strategy for aging bone defect repair.