Magnetic on–off manipulated matrix mechanic vibration to enhance cell clutches-reinforcement and Ca2+ influx facilitating BMSCs neural differentiation and TBI repair

Considering the feasibility of remote on–off control and deep tissue penetration, magnetic-manipulation is highly desirable to provide on-demand extracellular matrix (ECM) signaling. On the other hand, matrix dynamic mechanics can bias neural differentiation and are thus vital for neural regeneration, inspiring new strategies for ECM dynamic manipulation and a comprehensive understanding of mechanotransduction mechanisms. Herein, we developed a magnetic-manipulated platform of Fe3O4 magnetic nanoparticles (MNPs)-integrated bioactive hydrogel. MNPs respond to the magnetic field (MF) to produce strains on hydrogel networks, leading to a vibration of matrix stiffness in brain tissue-relevant range. By low-pulsed MF (0.1 T) loading, the promotion of mechanotransduction involving cell elongation, Ca2+ influx, and neural differentiation of bone marrow mesenchymal stem cells (BMSCs) was realized. Furthermore, we revealed that mechanic vibration triggered matrix resistance to cell clutches-reinforcement, which activated the TRPV4 channel to induce Ca2+ influx, finally promoting subsequent neural differentiation via PI3K-AKT and calcium signaling pathways. By remote MF on–off, the magnetic-manipulated hydrogel was applied in traumatic brain injury (TBI) repair, realizing satisfactory brain tissue regeneration and neurological functional recovery. This magnetic-manipulated hydrogel platform opens new avenues to investigate cell-matrix interactions, shedding light on new biomaterials and clinical therapy strategies for tissue regeneration and trauma treatment.