The Coupling of Gradient Mechano-Electrical Microenvironments Promotes Interface Regeneration via Ca2⁺ Signaling Activation

The natural tendon-bone interface achieves stress dispersion through its gradient arrangement of collagen fibers and mineralization; however, surgical repair often leads to stress concentration and regeneration failure. To address this issue, an implantable, magnetically responsive gradient piezoelectric hydrogel system is developed that mimics the natural interface by aligning short fibers (CMSFs) using a static magnetic field, thereby creating a dynamic mechanical microenvironment for cell differentiation. Under a dynamic magnetic field, gradient mechanical vibrations enhance differentiation through cellular mechanosensing, while piezoelectric signals further promote tissue regeneration. The GelMA-based hydrogel integrates CMSFs and BaTiO₃ nanoparticles through electrospinning and magnetic regulation, thereby maintaining stem cell homeostasis via the Calcr pathway and activating Ca²⁺ signaling to drive multilineage differentiation. In the rat Achilles tendon-bone injury model, the system successfully regenerates a continuous four-layer tissue structure, restoring 80% of the native tensile strength and outperforming control groups histologically. This study pioneers 1) gradient mechanical programming in implants and 2) the synergy of “magnetic-force-electric” multi-physical fields for interface regeneration, offering an innovative strategy for complex tissue repair.