Membrane Electroporation and Electropermeabilization: Mechanisms and Models

Abstract

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.

Simulation of the influence of voltage level and pulse spacing on the efficiency, aggressiveness and uniformity of the electroporation process in tissues using meshless techniques

“…Consequently, the closer the pulses are to each other, the lower the pore resealing and the recovery of physiological level of the impermeability of the cell (shorter cycles of pore expansion and contraction), which could lead to greater fatigue of the cellular membrane because it experiences significant deformations for a longer period of time. Even when the pulse spacing allows for full membrane resealing, a cell can exhibit alterations in its physiological processes for hours before returning to its normal state (memory effects) . Accordingly, comparing two electroporation protocols with the same applied voltage, which theoretically cause irreversible electroporation in the same amount of tissue, that with closer pulses can be considered more aggressive since it induces greater fatigue in the cellular membranes of the reversibly electroporated cells.…”

“…Even when the pulse spacing allows for full membrane resealing, a cell can exhibit alterations in its physiological processes for hours before returning to its normal state (memory effects). 29 Accordingly, comparing two electroporation protocols with the same applied voltage, which theoretically cause irreversible electroporation in the same amount of tissue, that with closer pulses can be considered more aggressive since it induces greater fatigue in the cellular membranes of the reversibly electroporated cells.…”

“…In treatment planning, both at experimental and clinical levels, numerical modeling of the electric field distribution has become an important tool; the increment of electric conductivity due to electroporation and its effects on drug uptake have been simulated by Corovic et al 24 Electrochemotherapy and irreversible electroporation are successfully used today to treat deep tumors, assuring total covering of tumors with electric fields and assisting the cutting of affected tissues. 12 As mentioned by Kotnik et al, 29 pore formation due to electroporation is not strictly a threshold phenomenon in the sense that the process does not occur only when the magnitude of the electric field, E, exceeds the reversible limit, E rev . Strictly speaking, pore formation in cells is possible for lower values than E rev , but there may be a defined a limit, E rev , above which the pore size and duration become important to favor detectable molecule transport from the extracellular to the intracellular space.…”

“…As mentioned by Kotnik et al, pore formation due to electroporation is not strictly a threshold phenomenon in the sense that the process does not occur only when the magnitude of the electric field, E , exceeds the reversible limit, E rev . Strictly speaking, pore formation in cells is possible for lower values than E rev , but there may be a defined a limit, E rev , above which the pore size and duration become important to favor detectable molecule transport from the extracellular to the intracellular space.…”

Pulsed electric fields create pores in the voltage sensors of voltage-gated ion channels

“…However, experimental evidence suggests that membrane proteins are affected as well. Particularly voltage-gated ion channels (VGICs) have been identified as targets of the electric field (4). VGICs are a class of transmembrane proteins that respond to changes in the transmembrane voltage (TMV) with conformational rearrangements that lead to opening or closure of an ion-selective pore.…”