Non-thermal Tissue Ablation Research Articles

Modeling methods in overlapping electroporation treatments: Pulse number effects on tissue conductivity and ablation area

Irreversible electroporation (IRE) is a non-thermal tissue ablation technique that utilizes high-voltage pulses between electrode pairs to destroy tissue. Numerical models are essential for predicting treatment outcomes and aiding in treatment planning. This paper studies a nonlinear conductivity model (NC) and a multiparametric nonlinear conductivity model (MPNC) to investigate overlapping electroporation treatments using a three-needle electrode configuration. The NC model accounts for the effects of the electric field and temperature on tissue conductivity during multiple pulsed electric field applications. The MPNC model incorporates the influence of pulse number, alongside electric field and temperature, on tissue conductivity. Results indicate that in the MPNC model, tissue conductivity is significantly higher in regions where the electric field intensity is below the threshold for irreversible electroporation, with the maximum difference reaching 0.4S/m. In contrast, tissue conductivity is slightly lower in regions where the electric field intensity exceeds the IRE threshold. Additionally, the MPNC model predicts a smaller area of irreversible electroporation and a larger area of reversible electroporation, with these differences becoming more pronounced as the distance between electrode needles increases. These findings underscore the importance of considering pulse number effects in numerical models to enhance the accuracy of treatment planning for irreversible electroporation-based therapies.

Burst sine wave electroporation (B-SWE) for expansive blood-brain barrier disruption and controlled non-thermal tissue ablation for neurological disease.

The blood-brain barrier (BBB) limits the efficacy of treatments for malignant brain tumors, necessitating innovative approaches to breach the barrier. This study introduces burst sine wave electroporation (B-SWE) as a strategic modality for controlled BBB disruption without extensive tissue ablation and compares it against conventional pulsed square wave electroporation-based technologies such as high-frequency irreversible electroporation (H-FIRE). Using an in vivo rodent model, B-SWE and H-FIRE effects on BBB disruption, tissue ablation, and neuromuscular contractions are compared. Equivalent waveforms were designed for direct comparison between the two pulsing schemes, revealing that B-SWE induces larger BBB disruption volumes while minimizing tissue ablation. While B-SWE exhibited heightened neuromuscular contractions when compared to equivalent H-FIRE waveforms, an additional low-dose B-SWE group demonstrated that a reduced potential can achieve similar levels of BBB disruption while minimizing neuromuscular contractions. Repair kinetics indicated faster closure post B-SWE-induced BBB disruption when compared to equivalent H-FIRE protocols, emphasizing B-SWE's transient and controllable nature. Additionally, finite element modeling illustrated the potential for extensive BBB disruption while reducing ablation using B-SWE. B-SWE presents a promising avenue for tailored BBB disruption with minimal tissue ablation, offering a nuanced approach for glioblastoma treatment and beyond.

Advances in Tumor Management: Harnessing the Potential of Histotripsy.

Tissue ablation techniques have long been used in clinical settings to treat various oncologic diseases. However, many of these techniques are invasive and can cause substantial adverse effects. Histotripsy is a noninvasive, nonionizing, nonthermal tissue ablation technique that has the potential to replace surgical interventions in various clinical settings. Histotripsy works by delivering high-intensity focused ultrasound waves to target tissue. These waves create cavitation bubbles within tissues that rapidly expand and collapse, thereby mechanically fractionating the tissue into acellular debris that is subsequently absorbed by the body's immune system. Preclinical and clinical studies have demonstrated the efficacy of histotripsy in treating a range of diseases, including liver, pancreatic, renal, and prostate tumors. Safety outcomes of histotripsy have been generally favorable, with minimal adverse effects reported. However, further studies are needed to optimize the technique and understand its long-term effects. This review aims to discuss the importance of histotripsy as a noninvasive tissue ablation technique, the preclinical and clinical literature on histotripsy and its safety, and the potential applications of histotripsy in clinical practice. Keywords: Tumor Microenvironment, Ultrasound-High-Intensity Focused (HIFU), Ablation Techniques, Abdomen/GI, Genital/Reproductive, Nonthermal Tissue Ablation, Histotripsy, Clinical Trials, Preclinical Applications, Focused Ultrasound © RSNA, 2024.

Modeling Methods for Treatment Planning in Overlapping Electroporation Treatments.

Irreversible electroporation (IRE) is a non-thermal tissue ablation therapy which is induced by applying high voltage waveforms across electrode pairs. When multiple electrode pairs are sequentially used, the treatment volume (TV) is typically computed as the geometric union of the TVs of individual pairs. However, this method neglects that some regions are exposed to overlapping treatments. Recently, a model describing cell survival probability was introduced which effectively predicted TV with overlapping fields in vivo. However, treatment overlap has yet to be quantified. This study characterizes TV overlap in a controlled in vitro setup with the two existing methods which are compared to an adapted logistic model proposed here. CHO cells were immobilized in agarose gel. Initially, we characterized the electric field threshold and the cell survival probability for overlapping treatments. Subsequently, we created a 2D setup where we compared and validated the accuracy of the different methods in predicting the TV. Overlap can reduce the electric field threshold required to induce cell death, particularly for treatments with low pulse number. However, it does not have a major impact on TV in the models assayed here, and all the studied methods predict TV with similar accuracy. Treatment overlap has a minor influence in the TV for typical protocols found in IRE therapies. This study provides evidence that the modeling method used in most pre-clinical and clinical studies seems adequate.

High-frequency irreversible electroporation brain tumor ablation: exploring the dynamics of cell death and recovery

Improved therapeutics for malignant brain tumors are urgently needed. High-frequency irreversible electroporation (H-FIRE) is a minimally invasive, nonthermal tissue ablation technique, which utilizes high-frequency, bipolar electric pulses to precisely kill tumor cells. The mechanisms of H-FIRE-induced tumor cell death and potential for cellular recovery are incompletely characterized. We hypothesized that tumor cells treated with specific H-FIRE electric field doses can survive and retain proliferative capacity. F98 glioma and LL/2 Lewis lung carcinoma cell suspensions were treated with H-FIRE to model primary and metastatic brain cancer, respectively. Cell membrane permeability, apoptosis, metabolic viability, and proliferative capacity were temporally measured using exclusion dyes, condensed chromatin staining, WST-8 fluorescence, and clonogenic assays, respectively. Both tumor cell lines exhibited dose-dependent permeabilization, with 1,500 V/cm permitting and 3,000 V/cm inhibiting membrane recovery 24 h post-treatment. Cells treated with 1,500 V/cm demonstrated significant and progressive recovery of apoptosis and metabolic activity, in contrast to cells treated with higher H-FIRE doses. Cancer cells treated with recovery-permitting doses of H-FIRE maintained while those treated with recovery-inhibiting doses lost proliferative capacity. Taken together, our data suggest that H-FIRE induces reversible and irreversible cellular damage in a dose-dependent manner, and the presence of dose-dependent recovery mechanisms permits tumor cell proliferation.

A Theoretical Argument for Extended Interpulse Delays in Therapeutic High-Frequency Irreversible Electroporation Treatments.

We sought to determine whether modifications to the delays within H-FIRE bursts could yield a more desirable clinical outcome in terms of ablation volume versus extent of tissue excitation. We used a modified spatially extended nonlinear node (SENN) nerve fiber model to evaluate excitation thresholds for H-FIRE bursts with varying delays. We then calculated non-thermal tissue ablation, thermal damage, and excitation in a clinically relevant numerical model. Excitation thresholds were maximized by shortening d1, and extension of d2 up to 1,000 μs increased excitation thresholds by at least 60% versus symmetric bursts. In the ablation model, long interpulse delays lowered the effective frequency of burst waveforms, modulating field redistribution and reducing heat production. Finally, we demonstrate mathematically that variable delays allow for increased voltages and larger ablations with similar extents of excitation as symmetric waveforms. Interphase and interpulse delays play a significant role in outcomes resulting from H-FIRE treatment. Waveforms with short interphase delays (d1) and extended interpulse delays (d2) may improve therapeutic efficacy of H-FIRE as it emerges as a clinical tissue ablation modality.

Abstract PR8: Irreversible electroporation is an effective tumor-ablation strategy that induces immunologic cell death and promotes systemic antitumor immunity

Abstract New therapeutic strategies are direly needed to treat pancreatic cancer. Over the last decade, tumor-ablation strategies, such as radiofrequency ablation, have emerged as promising therapeutic options. However, these strategies are associated with significant complications and treatment limitations. To circumvent these limitations, members of our research team developed a nonthermal tissue ablation modality, termed irreversible electroporation (IRE), for treating solid tumors. IRE delivers a series of low-energy, unipolar electric pulses through electrodes inserted directly into the tumor to produce structural defects in the target cell membrane and cell death. While the effectiveness of IRE in inducing targeted tumor ablation is well established, there is a paucity of data pertaining to immune system activation following IRE. Here, we hypothesize that IRE treatment will elicit robust proinflammatory cell death signaling and a strong anticancer immune response, ultimately leading to decreased disease burden. To evaluate this hypothesis, we utilized healthy pancreatic tissue, patient-derived xenograft (PDX) models, in vivo studies using immunocompetent mouse models, and studies in human patients. In healthy ex vivo pancreatic tissue, IRE induces predominately apoptotic cell death with limited proinflammatory effects. However, in ex vivo PDX tumors and in vivo murine pancreatic tumors, IRE induced voltage-dependent inflammatory cell death signaling, marked by the release of defined damage-associated molecular patterns (DAMPs). Mice treated with IRE exhibited 40% or more ablation of pancreatic tumors, significantly increased progression-free survival, and lower overall disease burden. IRE treatment also reduced local and systemic immunosuppressive cell populations, such as tumor-associated macrophages and T-regulatory cells, and increased proinflammatory signaling weeks after treatment. The increased proinflammatory signaling was, in part, associated with the generation of specific DAMPs and robust activation of the innate immune system. Additionally, we observed increased evidence of improved antigen presentation, altered immune checkpoint signaling pathways, and engagement of the adaptive immune system. Together, our data support a model whereby the unique cell death and tumor ablation following IRE treatment stimulate the local innate immune system, which shifts the tumor microenvironment from an anti-inflammatory state to a proinflammatory state. Likewise, the nonthermal nature of the ablation improves tumor antigen availability. Together, these mechanisms result in robust engagement of the adaptive immune system and improved systemic antitumor immune responses. We anticipate that IRE will be highly capable of improving conventional pancreatic cancer treatment strategies and complement emerging immunomodulatory approaches targeting primary tumors, metastatic lesions, and preventing recurrence. This abstract is also being presented as Poster A11. Citation Format: Rebecca M. Brock, Natalie Beitel-White, Melvin F. Lorenzo, Veronica M. Ringel-Scaia, Sheryl Coutermarsh-Ott, Navid Manuchehrabadi, Rafael V. Davalos, Irving C. Allen. Irreversible electroporation is an effective tumor-ablation strategy that induces immunologic cell death and promotes systemic antitumor immunity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR8.

Ultrafast three-dimensional microbubble imaging in vivo predicts tissue damage volume distributions during nonthermal brain ablation.

Transcranial magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) thermal ablation is under clinical investigation for non-invasive neurosurgery, though its use is restricted to central brain targets due primarily to skull heating effects. The combination of FUS and contrast agent microbubbles greatly reduces the ultrasound exposure levels needed to ablate brain tissue and may help facilitate the use of transcranial FUS ablation throughout the brain. However, sources of variability exist during microbubble-mediated FUS procedures that necessitate the continued development of systems and methods for online treatment monitoring and control, to ensure that excessive and/or off-target bioeffects are not induced from the exposures.Methods: Megahertz-rate three-dimensional (3D) microbubble imaging in vivo was performed during nonthermal ablation in rabbit brain using a clinical-scale prototype transmit/receive hemispherical phased array system.Results: In-vivo volumetric acoustic imaging over microsecond timescales uncovered spatiotemporal microbubble dynamics hidden by conventional whole-burst temporal averaging. Sonication-aggregate ultrafast 3D source field intensity data were predictive of microbubble-mediated tissue damage volume distributions measured post-treatment using MRI and confirmed via histopathology. Temporal under-sampling of acoustic emissions, which is common practice in the field, was found to impede performance and highlighted the importance of capturing adequate data for treatment monitoring and control purposes.Conclusion: The predictive capability of ultrafast 3D microbubble imaging, reported here for the first time, will enable future microbubble-mediated FUS treatments with unparalleled precision and accuracy, and will accelerate the clinical translation of nonthermal tissue ablation procedures both in the brain and throughout the body.

Transcatheter intra-arterial perfusion (TRIP)-MRI biomarkers help detect immediate response to irreversible electroporation of rabbit VX2 liver tumor.

Irreversible electroporation (IRE) is a nonthermal tissue ablation technique that represents a promising treatment option for unresectable liver tumors, but the effectively treated zone cannot be reliably predicted. We investigate the potential benefit of transcatheter intra-arterial perfusion (TRIP) -MRI for the early noninvasive differentiation of IRE zone from surrounding reversibly electroporated (RE) zone. Seventeen rabbits with VX2 liver tumors were scanned with morphological and contrast-enhanced MRI sequences approximately 30 min after IRE tumor ablation. Quantitative TRIP-MRI perfusion parameters were evaluated in IRE zone and RE zone, defined according to histology. MRI and histology results were compared among zones using Wilcoxon rank-sum tests and correlations were evaluated by Pearson's correlation coefficient. There were significant differences in area under the curve, time to peak, maximum and late enhancement, wash-in and wash-out rates in the tumor IRE zones compared with the boundary tumor RE zones and untreated tumors. Histology showed significantly fewer tumor cells, microvessels and significantly more apoptosis in tumor IRE zones compared with tumor RE zones (-51%, -66% and +185%, respectively) and untreated tumors (-60%, -67%, and +228%, respectively). A strong correlation was observed between MRI and histology measurements of IRE zones (r = 0.948) and RE zones (r = 0.951). TRIP-MRI demonstrated the potential to detect immediate perfusion changes following IRE liver tumor ablation and effectively differentiate the IRE zone from the surrounding tumor RE zone.

Simplified Non-Thermal Tissue Ablation With a Single Insertion Device Enabled by Bipolar High-Frequency Pulses.

To demonstrate the feasibility of a single electrode and grounding pad approach for delivering high frequency irreversible electroporation treatments (H-FIRE) in in-vivo hepatic tissue. Ablations were created in porcine liver under surgical anesthesia by adminstereing high frequency bursts of 0.5-5.0μs pulses with amplitudes between 1.1-1.7 kV in the absence of cardiac synchronization or intraoperative paralytics. Finite element simulations were used to determine the electric field strength associated with the ablation margins (ELethal) and predict the ablations feasible with next generation electronics. All animals survived the procedures for the protocol duration without adverse events. ELethal of 2550, 1650, and 875V/cm were found for treatments consisting of 100x bursts containing 0.5μs pulses and 25, 50, and 75μs of energized-time per burst, respectively. Treatments with 1μs pulses consisting of 100 bursts with 100μs energized-time per burst resulted in ELethal of 650V/cm. A single electrode and grounding pad approach was successfully used to create ablations in hepatic tissue. This technique has the potential to reduce challenges associated with placing multiple electrodes in anatomically challenging environments. H-FIRE is an in situ tumor ablation approach in which electrodes are placed within or around a targeted region to deliver high voltage electrical pulses. Electric fields generated around the electrodes induce irrecoverable cell membrane damage leading to predictable cell death in the relative absence of thermal damage. The sparing of architectural integrity means H-FIRE offers potential advantages compared to thermal ablation modalities for ablating tumors near critical structures.

A Conceivable Mechanism Responsible for the Synergy of High and Low Voltage Irreversible Electroporation Pulses.

Irreversible electroporation (IRE), is a new non-thermal tissue ablation technology in which brief high electric field pulses are delivered across the target tissue to induce cell death by irreversible permeabilization of the cell membrane. A deficiency of conventional IRE is that the ablation zone is relatively small, bounded by the irreversible electroporation isoelectric field margin. In the previous studies we have introduced a new treatment protocol that combines few short high voltage (SHV) pulses with long low-voltage (LLV) pulses. In the previous studies, we also have shown that the addition of few SHV pulses increases by almost a factor of two the area ablated by a protocol that employs only the LLV pulses. This study employs potato and gel phantom to generate a plausible explanation for the mechanism. The study provides circumstantial evidence that the mechanism involved is the production of electrolytic compounds by the LLV pulse sequence, which causes tissue ablation beyond the margin of the irreversible electroporation isoelectric field generated by the SHV pulses, presumable to the reversible electroporation isoelectric field margin generated by the SHV pulses.

Electrical Membrane Breakdown (EMB): Preliminary Findings of a New Method of Non-thermal Tissue Ablation

Electrical membrane breakdown (EMB) is a novel form of non-thermal treatment that has not, to our knowledge, been previously evaluated for its potential utility as an ablation mechanism. The findings with EMB immediately after treatment were compared with other forms of ablation (cryoablation and IRE (irreversible electroporation)) in the porcine liver clinically, ultrasonographically, and by light microscopy and ultrastructural analysis. Clinically, EMB did not induce muscular contractions, in contrast with IRE. By ultrasound, all lesions were hypoechoic when compared to the untreated liver. EMB created a consistent pattern of immediate tissue destruction at the light microscopic and ultrastructural level, characterized by pulse-dose-related coagulative necrosis and nuclear pyknosis, preserved blood vessels and adjacent structures, and sharply demarcated margins. We conclude that the profile of EMB ablation is distinctive and unique, inducing necrosis by immediate electrical rupture of cell membranes non-thermally while preserving proteins and adjacent vessels with potentially superior stimulation of the immune system than other ablation modalities.

Nonthermal Ablation by Using Intravascular Oxygen Radical Generation with WST11: Dynamic Tissue Effects and Implications for Focal Therapy

Purpose To examine the hypothesis that vascular-targeted photodynamic therapy (VTP) with WST11 and clinically relevant parameters can be used to ablate target tissues in a non-tumor-bearing large-animal model while selectively sparing blood vessels and collagen. Materials and Methods By using an institutional animal care and use committee-approved protocol, 68 ablations were performed in the kidneys (cortex and medulla) and livers of 27 adult pigs. Posttreatment evaluation was conducted with contrast material-enhanced computed tomography in the live animals at 24 hours. Immunohistochemistry was evaluated and histologic examination with hematoxylin-eosin staining was performed at 4 hours, 24 hours, and 7 days. Intravenous infusion of WST11 (4 mg per kilogram of body weight) was followed by using near-infrared illumination (753 nm for 20 minutes) through optical fibers prepositioned in target tissues by using a fixed template. Treated areas were scanned, measured, and statistically analyzed by using the Student t test and two-way analysis of variance. Results Focal WST11 VTP treatment in the liver and kidney by using a single optical fiber resulted in well-demarcated cylindrical zones of nonthermal necrosis concentrically oriented around the light-emitting diffuser, with no intervening viable parenchymal cells. The radius of ablated tissue increased from approximately 5 mm at 150 mW to approximately 7 mm at 415 mW (P < .01). Illumination through fiber triads at 1-cm separation resulted in confluent homogeneous necrosis. Patterns of acute injury within 24 hours were consistent with microcirculatory flow arrest and collagen preservation (demonstrated with trichrome staining). In the peripheral ablation zone, blood vessels at least 40 μm in diameter were selectively preserved and remained functional at 7 days. Ablated tissues exhibited progressive fibrosis and chronic inflammatory cell infiltrates. No histologic changes consistent with thermal injury were observed in blood vessels or collagen. The renal hilum and collecting system did not show treatment effect, despite treatment proximity. Conclusion WST11 VTP induces nonthermal tissue ablation in target tissue while preserving critical organ structures and bystander blood vessels within solid organs. (©) RSNA, 2016 Online supplemental material is available for this article.

Synergistic Combination of Electrolysis and Electroporation for Tissue Ablation.

Electrolysis, electrochemotherapy with reversible electroporation, nanosecond pulsed electric fields and irreversible electroporation are valuable non-thermal electricity based tissue ablation technologies. This paper reports results from the first large animal study of a new non-thermal tissue ablation technology that employs “Synergistic electrolysis and electroporation” (SEE). The goal of this pre-clinical study is to expand on earlier studies with small animals and use the pig liver to establish SEE treatment parameters of clinical utility. We examined two SEE methods. One of the methods employs multiple electrochemotherapy-type reversible electroporation magnitude pulses, designed in such a way that the charge delivered during the electroporation pulses generates the electrolytic products. The second SEE method combines the delivery of a small number of electrochemotherapy magnitude electroporation pulses with a low voltage electrolysis generating DC current in three different ways. We show that both methods can produce lesion with dimensions of clinical utility, without the need to inject drugs as in electrochemotherapy, faster than with conventional electrolysis and with lower electric fields than irreversible electroporation and nanosecond pulsed ablation.

Minimally Invasive, Non-Thermal Tissue Ablation with a Single Exponential Decay Electrolytic Electroporation Waveform

A new minimally invasive tissue ablation technique, that combines the biophysical processes of electroporation and electrolysis, is introduced. The technology employs electrode needles inserted in the target tissue to deliver an Electrolytic Electroporation Waveform (EEW) in the form of an exponential decay voltage, several tens of microsecond long. A case study in a large animal model demonstrates that clinically significant size lesions can be achieved with a single, milliseconds long EEW. Ablation with EEW has major advantages over the comparable tissue ablation techniques of electrolysis, reversible electroporation and irreversible electroporation. EEW is orders of magnitude faster than conventional electrolytic ablation. EEW does not require the use of muscle relaxant as irreversible electroporation and EEW does not require injection of drugs as reversible electroporation. This new technology is simple to use and may become an important addition to the minimally invasive surgery armamentarium.

Nonthermal Irreversible Electroporation: Fundamentals, Applications, and Challenges

Tissue ablation is an essential procedure for the treatment of many diseases. In the last decade, a nonthermal tissue ablation using intensive pulsed electric fields, called nonthermal irreversible electroporation (NTIRE), has rapidly emerged. The exact mechanisms responsible for cell death by NTIRE, however, are currently unknown. Nevertheless, the technique's remarkable ability to ablate tissue in the proximity of larger blood vessels, to preserve tissue architecture, short procedure duration, and shortened postoperative recovery period rapidly moved NTIRE from bench to bed side. This work provides an overview on the development of NTIRE, its current state-of-the-art, challenges, and future needs.

Irreversible Electroporation of a Hepatocellular Carcinoma Lesion Adjacent to a Transjugular Intrahepatic Portosystemic Shunt Stent Graft

We report in a 65-year-old man hepatocellular carcinoma adjacent to a transjugular intrahepatic portosystemic shunt stent-graft which was successfully treated with irreversible electroporation (IRE). IRE is a new non-thermal tissue ablation technique which uses electrical pulses to induce cell necrosis by irreversible membrane poration. IRE proved to be more advantageous in the ablation of perivascular tumor with little injury to the surrounding structures.

Short- and Mid-term Effects of Irreversible Electroporation on Normal Renal Tissue: An Animal Model

Irreversible electroporation (IRE) is a novel nonthermal tissue ablation technique by high current application leading to apoptosis without affecting extracellular matrix. Previous results of renal IRE shall be supplemented by functional MRI and differentiated histological analysis of renal parenchyma in a chronic treatment setting. Three swine were treated with two to three multifocal percutaneous IRE of the right kidney. MRI was performed before, 30 min (immediate-term), 7 days (short-term), and 28 days (mid-term) after IRE. A statistical analysis of the lesion surrounded renal parenchyma intensities was made to analyze functional differences depending on renal part, side and posttreatment time. Histological follow-up of cortex and medulla was performed after 28 days. A total of eight ablations were created. MRI showed no collateral damage of surrounded tissue. The highest visual contrast between lesions and normal parenchyma was obtained by T2-HR-SPIR-TSE-w sequence of DCE-MRI. Ablation zones showed inhomogeneous necroses with small perifocal edema in the short-term and sharp delimitable scars in the mid-term. MRI showed no significant differences between adjoined renal parenchyma around ablations and parenchyma of untreated kidney. Histological analysis demonstrated complete destruction of cortical glomeruli and tubules, while collecting ducts, renal calyxes, and pelvis of medulla were preserved. Adjoined kidney parenchyma around IRE lesions showed no qualitative differences to normal parenchyma of untreated kidney. This porcine IRE study reveals a multifocal renal ablation, while protecting surrounded renal parenchyma and collecting system over a mid-term period. That offers prevention of renal function ablating centrally located or multifocal renal masses.

Therapeutic potential of irreversible electroporation in sarcoma

Irreversible electroporation is a newly developed nonthermal tissue ablation technique in which certain short-duration electrical fields are used to permanently permeabilize the cell membrane to disrupt cellular homeostasis. This disruption of cellular homeostasis initiates apoptosis, which leads to permanent cell death. Sarcomas are generally divided into soft-tissue and bone sarcomas based on their different mesenchymal origins and anatomical locations. Each of these sarcomas present in different ways, exhibit different behaviors and prognoses, and present unique therapeutic challenges. In this article, a series of recently conducted irreversible electroporation treatment for sarcomas based on local nonthermal ablation are summarized, and the therapeutic potential of this newly developed technique is assessed.

High-frequency irreversible electroporation (H-FIRE) for non-thermal ablation without muscle contraction

BackgroundTherapeutic 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.MethodsA 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.ResultsNo 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.ConclusionsH-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.