Injectable Piezoelectric Hydrogel Promotes Tendon–Bone Healing via Reshaping the Electrophysiological Microenvironment and M2 Macrophage Polarization

Rotator cuff tear (RCT) is a common musculoskeletal disease that poses challenges for functional regeneration of the tendon-bone interface (TBI). The transition of TBI between soft and hard tissues determines its structural and physiological environment complexity. Here, we present an injectable biopiezoelectric material PVA/CNF/BTO@PDA (Piezoelectric) hydrogel based on three-dimensional (3D) printing inspired by the "muscle-electrical coupling". This Piezoelectric hydrogel indicated desirable piezoelectric and mechanical properties, excellent biodegradability, and biosafety. In vitro, electrical stimulation from Piezoelectric hydrogel by the Flexcell Tissue Train system promoted the polarization of macrophages to the M2 phenotype, directing the targeted aggregation and zonal-specific differentiation of bone mesenchymal stem cells (BMSCs) for TBI formation. Also, optimal piezoelectric stimulation of the Piezoelectric hydrogel could alleviate inflammatory factor expression and regulate the osteotendinogenic differentiation of BMSCs under an H2O2/IL-1β inflammation environment. Furthermore, in vivo application of injectable Piezoelectric hydrogel demonstrates its regenerative potential, indicating that physiological repair with Piezoelectric hydrogel significantly accelerates and promotes TBI healing in a chronic RCT model. Therefore, our findings propose a new therapeutic strategy for functional TBI regeneration and enhance the treatment outcomes for RCT.