Abstract
Electroporation-based therapies are powerful biotechnological tools for enhancing the delivery of exogeneous agents or killing tissue with pulsed electric fields (PEFs). Electrochemotherapy (ECT) and gene therapy based on gene electrotransfer (EGT) both use reversible electroporation to deliver chemotherapeutics or plasmid DNA into cells, respectively. In both ECT and EGT, the goal is to permeabilize the cell membrane while maintaining high cell viability in order to facilitate drug or gene transport into the cell cytoplasm and induce a therapeutic response. Irreversible electroporation (IRE) results in cell kill due to exposure to PEFs without drugs and is under clinical evaluation for treating otherwise unresectable tumors. These PEF therapies rely mainly on the electric field distributions and do not require changes in tissue temperature for their effectiveness. However, in immediate vicinity of the electrodes the treatment may results in cell kill due to thermal damage because of the inhomogeneous electric field distribution and high current density during the electroporation-based therapies. Therefore, the main objective of this numerical study is to evaluate the influence of pulse number and electrical conductivity in the predicted cell kill zone due to irreversible electroporation and thermal damage. Specifically, we simulated a typical IRE protocol that employs ninety 100-µs PEFs. Our results confirm that it is possible to achieve predominant cell kill due to electroporation if the PEF parameters are chosen carefully. However, if either the pulse number and/or the tissue conductivity are too high, there is also potential to achieve cell kill due to thermal damage in the immediate vicinity of the electrodes. Therefore, it is critical for physicians to be mindful of placement of electrodes with respect to critical tissue structures and treatment parameters in order to maintain the non-thermal benefits of electroporation and prevent unnecessary damage to surrounding healthy tissue, critical vascular structures, and/or adjacent organs.
Highlights
Electroporation is a phenomenon resulting from an increase in the transmembrane potential (TMP) of a cell above a critical value leading to pore formation [1,2,3]
The pulsed electric fields (PEFs) themselves are administered so as to not kill cells directly but instead aid in the uptake of molecules with lethal or therapeutic potential – this combined approach being named electrochemotherapy (ECT) or gene therapy based on gene electrotransfer (EGT), respectively [16,17]
The electric field distribution, one of the main factors determining the outcome of irreversible electroporation [40,50], as well as for other electroporation-based treatments [49,57] shows that regions surrounding the electrodes experience the highest electric fields (Figure 2A)
Summary
Electroporation is a phenomenon resulting from an increase in the transmembrane potential (TMP) of a cell above a critical value leading to pore formation [1,2,3]. Prior to IRE, biotechnological and therapeutic applications of electroporation in tissue have avoided the irreversible regime in order to maintain high cell viability This process of reversible electroporation has been used to successfully treat cancer when the PEFs are combined with chemotherapeutic agents or plasmid DNA [11,12,13,14,15,16]. The non-thermal mode of cell death (unlike in microwave or radiofrequency ablation) in IRE is unique in that it does not rely on thermal damage from Joule heating to kill tumor cells It allows for successful treatment even in close proximity to critical structures and without being affected by the heat sink effect due to the presence of large vessels [8,26,29,30]
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