Electrical Stimulation of Cells: Drivers, Technology, and Effects

Abstract

Exposure of cells to electric fields is used in applications as diverse as deep brain stimulation to treat the symptoms of Parkinson's disease, tumor-treating fields to delay the progression of hard-to-treat cancers, and electroporation to deliver genetic materials to cells. It is also used to study the fundamental properties of electrically active cells and to induce changes in cell behavior, such as the directed outgrowth of neurites, that may one day find applications in the clinic. This review discusses some of the effects elicited on cells upon exposure to electric fields, both acutely and at longer time scales, and considers the underlying mechanisms proposed. It also provides an overview of the technology used to study the effects of exposure of cell to electric fields, including the different types of metal/electrolyte interfaces and the electrode materials used in in vitro and in vivo applications. The aim is to bring together concepts from different communities to highlight similarities, identify potential synergies, and create common ground that may lead to cross-fertilization and advances in the field.

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A historical overview of the uses of electrical stimulation in medicine, highlighting neuromodulation, cancer treatment and membrane manipulation to showcase diverse mechanisms and applications. Created in https://BioRender.com.

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Schematic representation of setups used for in vitro electric field stimulation. (a) Low-frequency stimulation using metal electrodes, leading to Faradaic reactions, including the generation of hydrogen peroxide and other electrochemical byproducts. (b) High-frequency stimulation using metal electrodes. (c) DC stimulation with Ag/AgCl electrodes and salt bridges to minimize Faradaic reactions, enabling more controlled DC field application in the biological media. Created in https://BioRender.com.

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Examples of different stimulation parameters used in literature. The inset shows a typical voltage profile used in monopolar pulsed stimulation. Frequency in this context refers to number of pulses per second (inverse of repetition period), the numbers next to the blue dots refers to the references cited in this review paper. Created in https://BioRender.com.

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Common polymer-based materials used for electrostimulation: poly­(3,4-ethylenedioxythiophene) (PEDOT), polypyrrole (PPy), and polyaniline (PANI). Carbon-based materials for electrostimulation: carbon nanotubes (CNTs), diamond, and graphene.

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(a) Key stages: Depolarization, Repolarization, (b) Illustration of the action of ion channels during depolarization and repolarization. These processes are central to understanding how cells, particularly excitable cells like neurons and muscle cells, respond to electrical stimulation. Created in https://BioRender.com.

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(a) Diagram illustrating the process of electroporation, where an externally applied electric field induces the formation of transient pores in the cell membrane, enabling the transport of molecules across the lipid bilayer. Created in https://BioRender.com. (b) An idealized representation (top) highlights the conceptual steps, while an atomic-level simulation (bottom) reveals molecular interactions and structural changes in the bilayer under an electric field oriented perpendicular to the bilayer. Reproduced with permission from ref . Copyright 2014 Annual Reviews.

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Mechanisms underlying the action of tumor treating fields (TTFs): Molecular polarization disrupts microtubule assembly during mitosis, while dielectrophoresis exerts forces on polar molecules, leading to their redistribution within the cleavage furrow. Reproduced with permission from ref . Copyright 2016 Oxford University Press.

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Key cellular responses to electrical stimulation. (a) Endothelial cells show different adhesion when cultured on negatively (A) and positively (B) biased polypyrrole films. Reproduced from ref . Copyright 1994 National Academy of Sciences, U.S.A. (b) An applied electric field (EF) directs cell migration toward the cathode. Reproduced with permission from ref . Copyright 2013 EMBO Press (Springer Nature). (c) Fluorescence microscopy images of immunostained mouse neural stem and progenitor cells (mNPCs) shows the application of DC pulses inducing differentiation. Cell labeling included GFAP (red), a predominantly astrocytic marker, as well as Tuj1 (blue), a predominantly neural marker. Scale bar: 75 μm. Adapted from ref under the Creative Commons Attribution License (CC BY). Copyright 2016. (d) Alignment of cell structure in response to electrical fields: Neurites (TUJ1+, magenta) align with astrocyte processes (Vimentin+, green; GFAP+, red). Reproduced from with permission from ref . Copyright 2006 Cambridge University Press.

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Schematic representation of electrical stimulation at the cellular level. Key effects include cell adhesion, directed cell migration (galvanotaxis), differentiation, neurite outgrowth, pro- and anti-inflammatory responses, protein transport and adsorption, calcium signaling pathways, and cytoskeletal structure reorganization. Created in https://BioRender.com.