Actively Infiltrative Micro/Nanochannels Propel Cell Migration-to-Mechanoactivation Transition for Centralized Osteogenesis

The insufficient cellular infiltration and cell activity are the main challenges for bone regeneration in the central region. Here, actively infiltrative micro/nanochannels were engineered within the filaments of 3D printed scaffolds using supercritical CO 2 foaming and particles leaching. This structure facilitated cell and protein migration, enabling deep infiltration within the filaments. These hierarchical micro/nanochannels induced cellular deformation, thereby enhancing mitochondrial activity. Transcriptomic analysis revealed that cytoskeletal stretching, triggered by actively infiltrative micro/nanochannels, activated the Wnt/β-catenin pathway via YAP-mediated mechanotransduction, significantly enhancing the tricarboxylic acid cycle to boost mitochondrial ATP production. By leveraging capillary forces for long-distance cell migration and activating a high-energy cellular state through mechanotransduction, this strategy enables rapid bone regeneration in the central region of large-scale rabbit cranial defects. Our findings overcome diffusion-limited osteogenesis and promote endogenous bone regeneration.