Multifunctional piezoelectric hydrogels under ultrasound stimulation boost chondrogenesis by recruiting autologous stem cells and activating the Ca(2+)/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 in situ cartilage regeneration. Here, our study investigated the potential of a piezoelectric hydrogel (Hyd(6)) for enhancing cartilage regeneration through ultrasound (US) stimulation. Hyd(6) has multiple properties including injectability, self-healing capabilities, and piezoelectric characteristics. These properties synergistically promote stem cell chondrogenesis. The fabrication and characterization of Hyd(6) revealed its excellent biocompatibility, biodegradability, and electromechanical conversion capabilities. In vitro and in vivo experiments revealed that Hyd(6), 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 Ca(2+), activating downstream CaM/CaN signaling pathways and accelerating cartilage formation. An in vivo study in a rabbit model of chondral defects revealed that Hyd(6) 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 Hyd(6) as a novel therapeutic approach for treating cartilage injuries, offering a self-powered, noninvasive, and effective strategy for tissue engineering and regenerative medicine.