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

ABSTRACT 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 V 1.3 amplifies intracellular calcium (Ca 2+ ) influx during subsequent stimulation. ES delivered through a skin‐conformal ITO‐based wearable device similarly increases Ca V 1.3 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 V 1.3 upregulation and attenuates these regenerative responses, supporting a functional contribution of VGCC‐mediated Ca 2+ signaling to ES‐assisted wound repair. Human skin cells further exhibit enhanced Ca 2+ responsiveness and coordinated transcriptional and proteomic remodeling following sustained ES. These findings identify adaptive VGCC‐associated Ca 2+ signaling as a key cellular mechanism underlying sustained ES responses at the bioelectronic interface.