Janus piezoelectric adhesives regulate macrophage TRPV1/Ca2+/cAMP axis to stimulate tendon-to-bone healing by multi-omics analysis

Piezoelectric stimulation has garnered substantial interest as a promising strategy for tissue regeneration. However, studies investigating its impact on tendon-to-bone healing characterized by fibrocartilage remain scarce. Moreover, there are considerable technical challenges in achieving minimally invasive application of piezoelectric stimulation on the irregular tendon-to-bone interface. Herein, we developed Janus asymmetric piezoelectric adhesives by assembling adhesive hydrogel (GAN) and non-adhesive hydrogel (GM) on each side of piezoelectric poly (L-lactic acid) nanofiber. Piezoelectric adhesives exhibited superior anti-inflammatory effects both <i>in vitro</i> and <i>ex vivo</i>. Notably, the transient receptor potential (TRP) ion channels, a class of versatile signaling molecules, are closely associated with the regulation of inflammation. This study demonstrated that piezoelectric stimulation promoted Ca²⁺ influx through the activation of transient receptor potential vanilloid 1 (TRPV1), further enhancing cAMP signaling pathway in macrophages by RNA sequencing. Additionally, <i>in vivo</i> proteomic analysis revealed Arachidonic acid metabolism and TNF-α signaling pathway downregulation and VEGF signaling pathway upregulation in a rat rotator cuff repair model. Piezoelectric adhesives ultimately achieved inflammation alleviation, angiogenesis enhancement, and fibrocartilage regeneration promotion, improving the biomechanical strength of the enthesis. This study elucidated the mechanism by which piezoelectric stimulation regulated tendon-to-bone healing through multi-omics analysis. The piezoelectric adhesives hold promise as a convenient and effective strategy for enhancing tendon-to-bone healing in clinical practice.