Abstract
Electric permeabilization of cell membranes is the main mechanism of irreversible electroporation (IRE), an ablation technique for treatment of unresectable cancers, but the pulses also induce a significant temperature increase in the treated volume. To investigate the therapeutically thermal contribution, a preclinical setup is required to apply IRE at desired temperatures while maintaining stable temperatures. This study’s aim was to develop and test an electroporation device capable of maintaining a pre-specified stable and spatially homogeneous temperatures and electric field in a tumor cell suspension for several clinical-IRE-settings. A hydraulically controllable heat exchange electroporation device (HyCHEED) was developed and validated at 37 °C and 46 °C. Through plate electrodes, HyCHEED achieved both a homogeneous electric field and homogenous-stable temperatures; IRE heat was removed through hydraulic cooling. IRE was applied to 300 μL of pancreatic carcinoma cell suspension (Mia PaCa-2), after which cell viability and specific conductivity were determined. HyCHEED maintained stable temperatures within ±1.5 °C with respect to the target temperature for multiple IRE-settings at the selected temperature levels. An increase of cell death and specific conductivity, including post-treatment, was found to depend on electric-field strength and temperature. HyCHEED is capable of maintaining stable temperatures during IRE-experiments. This provides an excellent basis to assess the contribution of thermal effects to IRE and other bio-electromagnetic techniques.
Highlights
Irreversible electroporation (IRE) is a relatively new focal ablation technique for the treatment of unresectable solid tumors at challenging anatomical sites including the liver, kidney, and pancreas [1,2,3].irreversible electroporation (IRE) is a modality in which short but high-voltage pulses are applied between electrodes implanted in the target volume to cause nanopores in the cell membranes
A hydraulically controllable heat exchange electroporation device (HyCHEED) was developed to maintain a stable temperature level in a target volume (TV) during electroporation by removing the heat generated by the electric pulses
For the treatment of the cells with 1250 V·cm−1, a total ablation of 100% was obtained for both 37 ◦ C and 46 ◦ C. These results show that, at relatively low electric-field strengths, temperature plays a significant role in the increase of the electrical specific conductivity of the target volume, and in the increase of the cell death in the target tissue
Summary
Irreversible electroporation (IRE) is a relatively new focal ablation technique for the treatment of unresectable solid tumors at challenging anatomical sites including the liver, kidney, and pancreas [1,2,3].IRE is a modality in which short but high-voltage pulses are applied between electrodes implanted in the target volume to cause nanopores in the cell membranes. Mild hyperthermic temperatures (T ≤ 45 ◦ C) enhance the therapeutic effects of chemotherapy and radiotherapy, depending on the temperature and the duration of heating, i.e., the thermal dose [3,12,13,14,15,16] These enhancements are achieved through a variety of molecular and physiological mechanisms, including inhibition of DNA damage repair for T > ~41 ◦ C, increase of blood flow and reoxygenation for 39 ◦ C < T < 44 ◦ C, decrease of tumor pH, and stimulation of the immune response [15,17,18,19]. The temperature increase during traditional mild hyperthermia and thermal ablation is produced using invasive or external techniques, such as electromagnetic, capacitive, conductive heating, or focused ultrasound techniques [3,22,23,24,25,26]
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