Irreversible electroporation

Irreversible electroporation (IRE or NTIRE for non-thermal irreversible electroporation) is a soft tissue ablation technique using ultra short but strong electrical fields to create permanent and hence lethal nanopores in the cell membrane, to disrupt the cellular homeostasis. The resulting cell death results from apoptosis and not necrosis as in all other thermal or radiation based ablation techniques. The main use of IRE lies in tumor ablation in regions where precision and conservation of the extracellular matrix, blood flow and nerves are of importance. The technique is in an experimental stage and has not been approved for use outside of clinical trials. IRE is used in the NanoKnife System.

First observations of IRE effects go back to 1898. Nollet reported the first systematic observations of the appearance of red spots on animal and human skin that was exposed to electric sparks. However, its use for modern medicine began in 1982 with the seminal work of Neumann and colleagues. Pulsed electric fields were used to temporarily permeabilize cell membranes to deliver foreign DNA into cells. In the following decade, the combination of high-voltage pulsed electric fields with the chemotherapeutic drug bleomycin and with DNA yielded novel clinical applications: electrochemotherapy and gene electrotransfer respectively.

In these treatment modalities IRE was an unwanted side effect to reversible electroporation. In 2005, Davalos et al. described the first study of a potential use of IRE.

Utilizing ultra short pulsed but very strong electrical fields, micropores and nanopores are induced in the phospholipid bilayers which form the outer cell membranes. Two kinds of damage can occur:

It should be stated that even though the ablation method is generally accepted to be apoptosis, some findings seem to contradict a pure apoptotic cell death, making the exact process by which IRE causes cell death unclear.

The mechanism of IRE is not completely understood. The current theory is as follows:

When an electrical field of more than 0.5 V/nm is applied to the resting trans-membrane potential, it is proposed that water enters the cell during this dielectric breakdown. Hydrophilic pores are formed. A molecular dynamics simulation by Tarek illustrates this proposed pore formation in two steps:

It is proposed that as the applied electrical field increases, the greater is the perturbation of the phospholipid head groups, which in turn increases the number of water filled pores. This entire process can occur within a few nanoseconds. Average sizes of nanopores are likely cell-type specific. In swine livers, they average around 340-360 nm, as found using SEM.

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