Multifunctional piezoelectric hydrogels under ultrasound stimulation boost chondrogenesis by recruiting autologous stem cells and activating the Ca2+/CaM/CaN signaling pathway

Articular cartilage, owing to the lack of undifferentiated stem cells after injury, faces significant challenges in reconstruction and repair, making it a major clinical challenge. Therefore, there is an urgent need to design a multifunctional hydrogels capable of recruiting autologous stem cells to achieve <i>in situ</i> cartilage regeneration. Here, our study investigated the potential of a piezoelectric hydrogel (Hyd₆) for enhancing cartilage regeneration through ultrasound (US) stimulation. Hyd₆ has multiple properties including injectability, self-healing capabilities, and piezoelectric characteristics. These properties synergistically promote stem cell chondrogenesis. The fabrication and characterization of Hyd₆ revealed its excellent biocompatibility, biodegradability, and electromechanical conversion capabilities. <i>In vitro</i> and <i>in vivo</i> experiments revealed that Hyd₆, when combined with US stimulation, significantly promotes the recruitment of autologous stem cells and enhances chondrogenesis by generating electrical signals that promote the influx of Ca²⁺, activating downstream CaM/CaN signaling pathways and accelerating cartilage formation. An <i>in vivo</i> study in a rabbit model of chondral defects revealed that Hyd₆ combined with US treatment significantly improved cartilage regeneration, as evidenced by better integration of the regenerated tissue with the surrounding cartilage, greater collagen type II expression, and improved mechanical properties. The results highlight the potential of Hyd₆ as a novel therapeutic approach for treating cartilage injuries, offering a self-powered, noninvasive, and effective strategy for tissue engineering and regenerative medicine.