Calcium Signaling Hacking by MILD Electroporation: A Novel Approach for Bioelectronic Medicine

Electrical stimulation has expanded beyond excitable tissues, with bioelectronic medicine exploring new therapeutic avenues. We propose a novel paradigm: continuously repeated electroporation to induce controlled Ca²⁺ influx and modulate cellular functions. Given the central role of Ca²⁺ as a second messenger tightly regulated by homeostatic mechanisms, transient permeabilization via electric fields enables perturbation of intracellular Ca²⁺ dynamics, influencing processes such as proliferation, differentiation, metabolism, and cell death. We define "MILD electroporation" as a process involving prolonged or repetitive mild membrane permeabilization induced by electric fields that facilitates calcium entry without causing direct cell death. At 5^th World Congress on Electroporation and Pulsed Electric Fields in Biology, Medicine, and Food & Environmental Technologies, we presented in vitro evidence showing that specific electric field waveforms elicit Ca²⁺ oscillations in stem cells, modulating gene expression and promoting proliferation. We also presented preliminary results suggesting that burst-modulated alternating fields may slow cancer cell proliferation.