BMSCs-targeting piezoelectric stimulation and immunomodulatory dual-functional hydrogel for promoting diabetic bone regeneration
Jintao Dong, Wengang Dong, Huijie Ran, Ding Wen Wu, Xinli Wang, Hongli Chen, Jiahao Cao, Xu Wang, Xinsen Lin, Wei Lei, Tianji Wang, Yafei Feng
Abstract
Bone regeneration in diabetic patients poses a significant clinical challenge due to persistent hyperglycemia and chronic inflammation, which disrupt the crucial interaction between the immune microenvironment and bone marrow-derived mesenchymal stem cells (BMSCs), thereby impairing osteogenesis. To address this limitation, ultrasonic-responsive barium titanate (BTO) nanoparticles were coated with BMSC membranes (B-TNs) and subsequently integrated into a carboxylated modified silk fibroin (CMS) hydrogel. This resulted in a dual-functional B-TNs@CMS composite hydrogel designed to combine targeted BMSC stimulation with immunomodulatory properties. Under diabetic conditions, the composite hydrogel facilitated macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Proteomic analysis and validation assays demonstrated that CMS reprograms macrophages through the PI3K-Akt-mTORC1 signaling axis, thereby restoring an osteogenesis-supportive immune microenvironment conducive to osteogenesis. Simultaneously, the degradation of CMS released B-TNs, which produced a moderate level of reactive oxygen species (ROS) under optimized extracorporeal ultrasound (US) stimulation. This process activated Wnt/β-catenin signaling, enhancing BMSC proliferation and osteogenic differentiation. This study highlights the significant potential of a dual-modular strategy integrating immune modulation with spatially targeted osteogenic stimulation, offering a promising therapeutic approach for diabetic bone regeneration.