Exposure of biological cells to high-voltage, short-duration electric pulses causes a transient increase in their plasma membrane permeability, allowing transmembrane transport of otherwise impermeant molecules. In recent years, large steps were made in the understanding of underlying events. Formation of aqueous pores in the lipid bilayer is now a widely recognized mechanism, but evidence is growing that changes to individual membrane lipids and proteins also contribute, substantiating the need for terminological distinction between electroporation and electropermeabilization. We first revisit experimental evidence for electrically induced membrane permeability, its correlation with transmembrane voltage, and continuum models of electropermeabilization that disregard the molecular-level structure and events. We then present insights from molecular-level modeling, particularly atomistic simulations that enhance understanding of pore formation, and evidence of chemical modifications of membrane lipids and functional modulation of membrane proteins affecting membrane permeability. Finally, we discuss the remaining challenges to our full understanding of electroporation and electropermeabilization.

Exposure of cells to high voltage electric pulses increases transiently membrane permeability through membrane electroporation. Electroporation can be reversible and is used in gene transfer and enhanced drug delivery but can also lead to cell death. Electroporation resulting in cell death (termed as irreversible electroporation) has been successfully used as a new non-thermal ablation method of soft tissue such as tumours or arrhythmogenic heart tissue. Even though the mechanisms of cell death can influence the outcome of electroporation-based treatments due to use of different electric pulse parameters and conditions, these are not elucidated yet. We review the mechanisms of cell death after electroporation reported in literature, cell injuries that may lead to cell death after electroporation and membrane repair mechanisms involved. The knowledge of membrane repair and cell death mechanisms after cell exposure to electric pulses, targets of electric field in cells need to be identified to optimize existing and develop of new electroporation-based techniques used in medicine, biotechnology, and food technology.

Each biological cell, trillions of which build our bodies, is enveloped by its plasma membrane. Composed largely of a bilayer (double layer) of lipids just two molecules thick (about 5 nm), and behaving partly as a liquid and partly as a gel, the cell plasma membrane nonetheless separates and protects the cell from its surrounding environment very reliably and stably. Embedded within the lipid bilayer, also quite stably, are a number of different proteins, some of which act as channels and pumps, providing a pathway for transporting specific molecules across the membrane. Without these proteins, the membrane would be a largely impenetrable barrier. Electrically, the cell plasma membrane can be viewed as a thin insulating sheet surrounded on both sides by aqueous electrolyte solutions. When exposed to a sufficiently strong electric field, the membrane will undergo electrical breakdown, which renders it permeable to molecules that are otherwise unable to cross it. The process of rendering the membrane permeable is called membrane electroporation. Unlike solid insulators, in which an electrical breakdown generally causes permanent structural change, the membrane, with its lipids behaving as a two-dimensional liquid, can spontaneously return to its prebreakdown state. If the exposure is sufficiently short and the membrane recovery sufficiently rapid for the cell to remain viable, electroporation is termed reversible; otherwise, it is termed irreversible. Since its discovery [1]–[3], electroporation has steadily gained ground as a useful tool in various areas of medicine and biotechnology. Today, reversible electroporation is an established method for introducing chemotherapeutic drugs into tumor cells (electrochemotherapy) [4]. It also offers great promise as a technique for gene therapy without the risks caused by viral vectors (DNA electrotransfer) [5]. In clinical medicine, irreversible electroporation is being investigated as a method for tissue ablation (nonthermal electroablation) [6], whereas in biotechnology, it is useful for extraction of biomolecules [7] and for microbial deactivation, particularly in food preservation [8]. This article, the first in a series of three focusing on electroporation, describes the phenomenon at the molecular level of the lipid bilayer, and then proceeds to the cellular level, explaining how exposure of a cell as a whole to an external electric field results in an inducement of voltage on its plasma membrane, its electroporation, and transport thorough the electroporated membrane. The second article will review the most important and promising applications of electroporation, and the third article will focus on the hardware for electroporation (pulse generators and electrodes) and on the need for standards, safety, and certification.