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 in vitro and ex vivo . 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 Ca 2+ influx through the activation of transient receptor potential vanilloid 1 (TRPV1), further enhancing cAMP signaling pathway in macrophages by RNA sequencing . Additionally, in vivo 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.