Background: Therapeutic irreversible electroporation (IRE) is an emerging technology for the non-thermal ablation of tumors. The technique involves delivering a series of unipolar electric pulses to permanently destabilize the plasma membrane of cancer cells through an increase in transmembrane potential, which leads to the development of a tissue lesion. Clinically, IRE requires the administration of paralytic agents to prevent muscle contractions during treatment that are associated with the delivery of electric pulses. This study shows that by applying high-frequency, bipolar bursts, muscle contractions can be eliminated during IRE without compromising the non-thermal mechanism of cell death. Methods: A combination of analytical, numerical, and experimental techniques were performed to investigate high-frequency irreversible electroporation (H-FIRE). A theoretical model for determining transmembrane potential in response to arbitrary electric fields was used to identify optimal burst frequencies and amplitudes for in vivo treatments. A finite element model for predicting thermal damage based on the electric field distribution was used to design non-thermal protocols for in vivo experiments. H-FIRE was applied to the brain of rats, and muscle contractions were quantified via accelerometers placed at the cervicothoracic junction. MRI and histological evaluation was performed post-operatively to assess ablation. Results: No visual or tactile evidence of muscle contraction was seen during H-FIRE at 250 kHz or 500 kHz, while all IRE protocols resulted in detectable muscle contractions at the cervicothoracic junction. H-FIRE produced ablative lesions in brain tissue that were characteristic in cellular morphology of non-thermal IRE treatments. Specifically, there was complete uniformity of tissue death within targeted areas, and a sharp transition zone was present between lesioned and normal brain. Conclusions: H-FIRE is a feasible technique for non-thermal tissue ablation that eliminates muscle contractions seen in IRE treatments performed with unipolar electric pulses. Therefore, it has the potential to be performed clinically without the administration of paralytic agents.

This study introduces the use of high-frequency pulsed electric fields for tissue electroporation. Through the development of finite element models and the use of analytical techniques, electroporation with rectangular, bipolar pulses is investigated. The electric field and temperature distribution along with the associated transmembrane potential development are considered in a heterogeneous skin fold geometry. Results indicate that switching polarity on the nanosecond scale near the charging time of plasma membranes can greatly improve treatment outcomes in heterogeneous tissues. Specifically, high-frequency fields ranging from 500 kHz to 1 MHz are best suited to penetrate epithelial layers without inducing significant Joule heating, and cause electroporation in underlying cells.

Electroporation based treatments consist in applying one or multiple high voltage pulses to the tissues to be treated. As an undesired side effect, these pulses cause electrical stimulation of excitable tissues such as nerves and muscles. This increases the complexity of the treatments and may pose a risk to the patient. To minimize electrical stimulation during electroporation based treatments, it has been proposed to replace the commonly used monopolar pulses by bursts of short bipolar pulses. In the present study, we have numerically analyzed the rationale for such approach. We have compared different pulsing protocols in terms of their electroporation efficacy and their capability of triggering action potentials in nerves. For that, we have developed a modeling framework that combines numerical models of nerve fibers and experimental data on irreversible electroporation. Our results indicate that, by replacing the conventional relatively long monopolar pulses by bursts of short bipolar pulses, it is possible to ablate a large tissue region without triggering action potentials in a nearby nerve. Our models indicate that this is possible because, as the pulse length of these bipolar pulses is reduced, the stimulation thresholds raise faster than the irreversible electroporation thresholds. We propose that this different dependence on the pulse length is due to the fact that transmembrane charging for nerve fibers is much slower than that of cells treated by electroporation because of their geometrical differences.

Objective: Electroporation-based therapies (EBTs) employ high voltage pulsed electric fields (PEFs) to permeabilize tumor tissue; this results in changes in electrical properties detectable using electrical impedance spectroscopy (EIS). Currently, commercial potentiostats for EIS are limited by impedance spectrum acquisition time ( ~ 10 s); this timeframe is much larger than pulse periods used with EBTs ( ~ 1 s). In this study, we utilize rapid EIS techniques to develop a methodology for characterizing electroporation (EP) and thermal effects associated with high-frequency irreversible EP (H-FIRE) in real-time by monitoring inter-burst impedance changes. Methods: A charge-balanced, bipolar rectangular chirp signal is proposed for rapid EIS. Validation of rapid EIS measurements against a commercial potentiostat was conducted in potato tissue using flat-plate electrodes and thereafter for the measurement of impedance changes throughout IRE treatment. Flat-plate electrodes were then utilized to uniformly heat potato tissue; throughout high-voltage H-FIRE treatment, low-voltage inter-burst impedance measurements were used to continually monitor impedance change and to identify a frequency at which thermal effects are delineated from EP effects. Results: Inter-burst impedance measurements (1.8 kHz - 4.93 MHz) were accomplished at 216 discrete frequencies. Impedance measurements at frequencies above ~ 1 MHz served to delineate thermal and EP effects in measured impedance. Conclusion: We demonstrate rapid-capture (<; <; 1 s) EIS which enables monitoring of inter-burst impedance in real-time. For the first time, we show impedance analysis at high frequencies can delineate thermal effects from EP effects in measured impedance. Significance: The proposed waveform demonstrates the potential to perform inter-burst EIS using PEFs compatible with existing pulse generator topologies.

Irreversible electroporation (IRE) is an emerging cancer treatment that utilizes non-thermal electric pulses for tumor ablation. The pulses are delivered through minimally invasive needle electrodes inserted into the target tissue and lead to cell death through the creation of nanoscale membrane defects. IRE has been shown to be safe and effective when performed on tumors in the brain, liver, kidneys, pancreas, and prostate that are located near critical blood vessels and nerves. Accurate treatment planning and prediction of the ablation volume require a priori knowledge of the tissue-specific electric field threshold for cell death. This study addresses the challenge of defining an electric field threshold for human prostate cancer tissue. Three-dimensional reconstructions of the ablation volumes were created from one week post-treatment magnetic resonance imaging (MRIs) of ten patients who completed a clinical trial. The ablation volumes were incorporated into a finite element modeling software that was used to simulate patient-specific treatments, and the electric field threshold was calculated by matching the ablation volume to the field contour encompassing the equivalent volume. Solutions were obtained for static tissue electrical properties and dynamic properties that accounted for electroporation. According to the dynamic model, the electric field threshold was 506 ± 66 V/cm. Additionally, a potentially strong correlation (r = −0.624) was discovered between the electric field threshold and pre-treatment prostate-specific antigen levels, which needs to be validated in higher enrollment studies. Taken together, these findings can be used to guide the development of future IRE protocols.

Irreversible electroporation (IRE) is a new technology for ablating aberrant tissue that utilizes pulsed electric fields (PEFs) to kill cells by destabilizing their plasma membrane. When treatments are planned correctly, the pulse parameters and location of the electrodes for delivering the pulses are selected to permit destruction of the target tissue without causing thermal damage to the surrounding structures. This allows for the treatment of surgically inoperable masses that are located near major blood vessels and nerves. In select cases of high-dose IRE, where a large ablation volume is desired without increasing the number of electrode insertions, it can become challenging to design a pulse protocol that is inherently nonthermal. To solve this problem we have developed a new electrosurgical device that requires no external equipment or protocol modifications. The design incorporates a phase change material (PCM) into the electrode core that melts during treatment and absorbs heat out of the surrounding tissue. Here, this idea is reduced to practice by testing hollow electrodes filled with gallium on tissue phantoms and monitoring temperature in real time. Additionally, the experimental data generated are used to validate a numerical model of the heat transfer problem, which is then applied to investigate the cooling performance of other classes of PCMs. The results indicate that metallic PCMs, such as gallium, are better suited than organics or salt hydrates for thermal management, because their comparatively higher thermal conductivity aids in heat dissipation. However, the melting point of the metallic PCM must be properly adjusted to ensure that the phase transition is not completed before the end of treatment. When translated clinically, phase change electrodes have the potential to continue to allow IRE to be performed safely near critical structures, even in high-dose cases.