Adaptive Cellular Responsiveness to Electrical Stimulation at the Skin-Electrode Interface

Wearable electrical stimulation (ES) devices are emerging platforms for wound healing, where cellular responses at the skin-electrode interface critically influence therapeutic outcomes. Here, we demonstrate that skin cells dynamically adapt to sustained ES by upregulating voltage-gated calcium channels (VGCCs) and enhancing their sensitivity to electrical cues. Using a transparent indium tin oxide (ITO)-based bioelectronic platform, we find that ES-induced upregulation of the L-type VGCC Ca_V1.3 amplifies intracellular calcium (Ca²⁺) influx during subsequent stimulation. ES delivered through a skin-conformal ITO-based wearable device similarly increases Ca_V1.3 expression in mouse wound tissue, accompanied by accelerated wound healing, enhanced collagen deposition, vascular remodeling, and changes in the CD206/iNOS macrophage-associated marker balance. Pharmacological inhibition of L-type VGCCs with nifedipine suppresses Ca_V1.3 upregulation and attenuates these regenerative responses, supporting a functional contribution of VGCC-mediated Ca²⁺ signaling to ES-assisted wound repair. Human skin cells further exhibit enhanced Ca²⁺ responsiveness and coordinated transcriptional and proteomic remodeling following sustained ES. These findings identify adaptive VGCC-associated Ca²⁺ signaling as a key cellular mechanism underlying sustained ES responses at the bioelectronic interface.