pulsed electric field ablation

Thus, catheter electrode designs for PEF therapies should aim to minimize the necessary activated electrode contact area to maximize the therapeutic effect for a given PEF protocol. Radical Prostatectomy versus Observation for Localized Prostate Cancer. The https:// ensures that you are connecting to the This series of pulses, or the "waveform", makes a long-lasting lesion in a manner of seconds. The temperature rise for each protocol was also evaluated, including blood flow simulated at 3 cm/s43 flow velocity from the distal vein into the antral region. The ability of a microbubble to impair blood flow is based on bubble size, number and total volume of bubbles, and dissolution time. This study represents the best modeling information that is available for evaluating PFA. Furthermore, PEF therapy has a promising safety profile and may be useful in other cardiac ablation indications such as posterior wall box formation, cavotricuspid isthmus lines for atrial flutter, and possibly ventricular tachycardia. If the mechanism of microbubbles is gaseous, and the volume of microbubbles is small, there may be no detectable occurrence of silent or symptomatic cerebral emboli detected by cerebral magnetic resonance imaging. The site is secure. A digital oscilloscope (TDA3044B, Tektronix, Beaverton, OR, USA) was utilized to measure the electric current, and a hole-type current probe (TCP305A, Tektronix) was clamped to a cord to connect the pulse generator and the electrodes. In vitro analysis of the origin and characteristics of gaseous microemboli during catheter electroporation ablation. Despite previous studies on IRE with PEF, no studies have investigated the efficacy of IRE with HF-PEF consisting of several monophasic pulses in the beagle prostate, except for one study with a short period of observation [21]. The slides were incubated in 3% H2O2 for 10 min to block endogenous peroxidase activity, 10% normal serum albumin for 30 min to block non-specific immunoglobulin binding, and primary antibody diluted in phosphate-buffered saline (PBS) for 60 min. RBC also developed requirements for first generation commercialization. The project required designing to specific characteristics for energy pulse waveform, frequency, duration and field strength. These findings have been consistently observed with internally tested preclinical studies, where transmural focal cardiac lesions were generated without observable off-target ablative effects beyond the epicardium. In the recent, H-FIRE consisting of several bi-phasic pulses was proposed for prostate cancer ablation to reduce muscle contraction and prevent arrhythmias [20]. Until now, catheter ablations to treat AF have mostly used thermal energy, by either burning or freezing problematic heart tissue. Pulsed field ablation vs radiofrequency ablation: esophageal injury in a Novel Porcine Model. Briefly, a 70 mm midline incision was made on the abdomen of each anesthetized dog from the xiphoid process down to expose the urinary bladder and urethra. Here we demonstrate the impact of dose dependence and the need for maintaining tissue contact during ablation. Before In this study, High-frequency PEF (HF-PEF) with monophasic pulses of 1.8 kV, 500 Hz was designed to ablate beagle prostate tissue. Prostate cancer is the most frequently diagnosed cancer in the USA, with approximately 248,530 cases in 2021 [1]. Electrical pulses can be delivered in various forms, including but not limited to. CK-MB level in the IRE-treated beagles did not significantly increase after IRE with HF-PEF compared with that in the control beagles. Thus, effective electrode designs should aim to minimize current losses to the blood to get sufficiently strong treatment effects without inducing undesirable collateral effects. Cerqueira J.A., Restan W.A.Z., Fonseca M.G., Catananti L.A., de Almeida M.L.M., Junior W.H.F., Pereira G.T., Carciofi A., Ferraz G.D.C. The IRE with PEF has many advantages to treat LAPRC by sparing the extracellular matrix, such as the neurovascular bundles, ducts, and major vasculatures in the target tissues, rapidly regenerating the tissues [23]. collected and analyzed the data and prepared the manuscript. Small blood vessel sparing is observed (outlined). 7,8 More recently, investigators have demonstrated a unique safety profile and ablative efficacy related to its ability to selectively target cardiomyocytes while sparing collateral tissue. Courtnee Lin Madsen, California Polytechnic State University, San Luis ObispoFollow, Christopher Heylman, College of Engineering, PFA promises to potentially revolutionize catheter ablation with suggestions of improved safety and efficacy. Reversible atrioventricular conduction impairment following bipolar nanosecond electroporation of the interventricular septum. PEF ablation certainly has the potential to dramatically improve the efficiency of atrial fibrillation ablation. From Figure 8, it can be seen that both monopolar configurations are able to reach 6 mm treatment depth with less than 30 J of delivered energy and no tissue reaching 50C. In particular, this study was performed at two centers and reported data regarding 15 endocardial and 7 epicardial AF ablations. Therefore, although lesions can be generated from PEF treatments without direct electrode contact in monopolar configurations, the treatment depth increases markedly when electrode contact is established. No abnormality in the ECG was noted before and after the procedure (Figure 3c). These physical and electrical characteristics must be titrated carefully to balance target tissue effects with collateral implications (muscle contraction, temperature rise, risk of electrical arcing events). When multiple packets are delivered to tissue, the accumulated injury to the cell increases. Accessibility Our study aimed to assess the safety and efficacy of high-frequency pulsed electric field (HF-PEF) in a beagle model for the treatment of prostate cancer. Deodhar A., Dickfeld T., Single G.W., Hamilton W.C., Thornton R.H., Sofocleous C.T., Maybody M., Gnen M., Rubinsky B., Solomon S.B. The load is the electrode system that include the 4-needle electrodes and the biological materials that the electrodes are in contact with. Gross and histopathological appearances of HF-PEF-induced wounds of the extracted urethra, prostate, and urinary bladder were evaluated. Differences between the groups were analyzed using two-sample t-test and MannWhitney U test, as appropriate. A stationary study solver was adopted for electric field strength evaluation, while a time-dependent study solver was used for thermal distribution around the monopolar electrodes in the prostate. Email. The global Pulsed Electric Field Ablation System market was valued at million in 2021 and is projected to reach US$ million by 2028, at a CAGR of % during the forecast period 2022-2028. Induction of cell death mechanisms and apoptosis by Nanosecond Pulsed Electric Fields (nsPEFs). In heterogeneous tissue environments, the electric field intensity from a given PEF delivery can vary greatly within the environment,41 and regions with low conductivity (high impedance) can absorb voltage drops along the current flow pathway, insulating downstream tissues from stronger treatment effects.24 There is a paucity of data on how scar tissue within the atrium or ventricle could affect PEF delivery. Non thermal irreversible electroporation: novel technology for vascular smooth muscle cells ablation. > 368 Changes in ph and not temperature significantly contributes to cell death during IRE performed at low-voltage and high pulse numbers. The electric conductivities for each of the tissues were either set identically (homogeneous system) or to relevant values extracted from literature for a representative biphasic waveform (heterogeneous system, Table I in the Data Supplement). This document comprises the steps taken by the senior project team to create a Proof-of-Concept Review for a Variable Pulsed Electric Field Ablation Catheter. Elimination of purkinje fibers by electroporation reduces ventricular fibrillation vulnerability. Rubinsky J., Onik G., Mikus P., Rubinsky B. Optimal Parameters for the Destruction of Prostate Cancer Using Irreversible Electroporation. Conversely, in a monopolar electrode arrangement, the active electrode(s) are placed near the targeted tissue with a return path to a distant, body dispersive electrode. However, relatively high voltages ranging 3500~5000 V were required to cause sufficient ablation area for H-FIRE. This model incorporated blood-filled myocardium chambers, pericardium, lungs, and esophagus in their respective locations, among the other relevant thoracic structures. The degree of inflammatory cell infiltration was revealed by H&E staining and subjectively classified into 1, mild; 2, mild to moderate; 3, moderate; 4, moderate to severe; and 5, severe, according to inflammatory cell distribution. The minimum applied voltage of PFA required to create a lesion deeper than 1 mm is 300 volts. A finite element analysis was performed to validate optimal electrical field strength for the procedure. Circulation. Various frequencies from 1 Hz to 2.5 kHz provided different apoptotic rates [13]. and J.-H.P. Galaxy Medical, Inc, San Carlos, CA (Q.C., R.E.N.). Tissue planes between different various types will have an important effect on the localization (selectivity), distribution, and ablation penetration depth. The slides were stained with hematoxylin and eosin (H&E) and Massons trichrome (MT) for histological analysis. A key component to successful cardiac ablation procedures is ensuring the generation of transmural, contiguous ablation zones, which requires in-depth knowledge regarding treatment sizes for a given therapeutic . A previous study show that electrical conductivity in the prostate increased from 0.284 to 0.927 S/m, which is 3.26-fold higher than that required to sufficiently ablate the targeted area [25]. In this article, the key aspects that need to be considered for safe and effective PEF delivery are reviewed, and their impact on clinical feasibility is discussed. It is desirable to eliminate or significantly reduce muscle contraction during cardiac ablation to minimize the risk of perforation, endocardial tissue disruption, loss of contact, and loss of catheter positioning. The maximum increase in current was approximately 10 A (Figure 3a). Germane to the current study, PEF energy could ablate epicardial GPs while sparing sensitive surrounding structures. frequency exposure than many existing common household electronic devices, particularly cell phones and microwave ovens." "Health Impacts of Radio Frequency from Smart Meters". The governing equation for the 2-point charge scenario is identified below: The 2-point charge calculation and the computer model show distinct similarities when evaluating the resulting electric field displacement and strength. A total of 90 pulses were divided into 9 cycles of 10 pulses each to avoid thermal damage from intense electrical current. For simplicity, only characteristics associated with square waveform shapes will be discussed in this review since they are most commonly used in commercial PEF ablation systems. These findings have important implications for the use of PFA as an energy source and the appropriate design of delivery systems to ensure adequate tissue contact. Despite of the enhanced cytotoxic effect in nsPEF, PEF of 1 kHz is estimated to cause less temperature rise than nsPEF, which causes thermal damage in the tissues [18,19]. Student Research However, the prostate glands almost recovered 28 d after IRE with HF-PEF, which was similar to that in the control (Figure 5c). Global Pulsed Electric Field Ablation System Market: Market segmentation Pulsed Electric Field Ablation System market is split by Type and by Application. Pulsed-field ablation (PFA) is an emerging nonthermal ablation technology. Two monopolar electrodes with 3D-printed spacer of 10 mm distance were penetrated the randomized side of the prostate under ultrasound guidance (Figure 1b,c). Voltage, electric field, and current density distributions for homogeneous (center) and heterogeneous (bottom) tissue electrical properties from a clinically relevant pulsed electrical field delivered protocol, demonstrating the distributive nature of the pericardial fluid surrounded by the pericardial sac. Figure 3 provides histological examples of lesion chronology following PEF treatment. Galaxy Medical (Galaxy) and Japan Lifeline (JLL) have announced an exclusive distribution agreement for the ALPHA1 ablation catheter in the USA, developed by Japan Lifeline for use with the Galaxy Centauri pulsed electric field (PEF) system. IRE with HF-PEF has therapeutic potential to treat prostate cancer while minimizing damage to the surrounding tissues. However, high Joule monophasic deliveries can generate very large volumes of microbubbles,25 and these have been associated with phenomena that could be considered embolic in nature such as transient ST-segment elevation and appearance of punctate ischemic lesions on postprocedural cerebral magnetic resonance imaging using diffusion-weighted and fluid-attenuated inversion recovery imaging.48 In a clinical study by Loh et al,48 bubble generation with a monophasic PEF system was shown to be dependent on the amount of charge delivered (100200 J) and whether it was delivered in an anodal or cathodal manner. Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (S.J.A.). The lesion depth was evaluated for 2 variables, applied voltage and catheter-tissue contact. These days, PFA generally involves high-voltage electric pulses from a catheter-delivered electrode or electrodes, each delivered at a tiny fraction of a second. In vivo irreversible electroporation kidney ablation: experimentally correlated numerical models. (d) Temperature changes at the midpoint between the electrodes. PFA is an emerging revolutionary technology that has been proposed to have several benefits over currently available thermal energy sources for cardiac ablation. G, Fourteen-day subgross photography of treatments in the superior vena cava with trichrome stain. We elected to use gold electrodes to resemble one of the available catheters in the market. There is evidence that cellular-specific characteristics may affect their response to PEF. Electrodes are elevated above the tissue at 1-mm intervals from 1 to 5 mm above the tissue. Our computational model has shown a correlation between PFA doses and lesion depth, higher doses being associated with the deeper irreversible lesions. If more significant energy deliveries are required, there is a chance for recruitment of skeletal muscle and potential heat generation. Irreversible Electroporation Near the Heart: Ventricular Arrhythmias Can Be Prevented With ECG Synchronization. Rapid decellularization preserving acellular tissues is essential for accurate treatment and regeneration in affected areas. contractile studies within isolated tissue baths: Translational research from Visible Heart 8600 Rockville Pike Currently, there is very little published data using systematically comparable PEF protocols to determine cell-based differences in lethal electric field threshold, so comparisons of lethal cell thresholds performed between different studies should be interpreted with caution. Intracardiac pulsed field ablation: Proof of feasibility in a chronic porcine model. ions via pulsed laser ablation using 355 nm wavelength and 5 ns long laser pulses . (c) Electrocardiogram of the beagle before and after IRE with HF-PEF (red box). C, Acute histology (trichrome) of treated tissue demonstrating a clear demarcation between dead and viable cells (dashed line). Emerging technologies for pulmonary vein isolation. Electric field maps having a 700 volt load. PEF therapy, by its nature, generates heating in tissue due to Joule heating from the delivery of electric fields and resulting current flow through a resistive tissue load. The ImageJ 1.53c software was used to measure the ablation area stained with TUNEL. The system set an electric field intensity up to 3000 V with 1001000 s pulse widths at 1002000 s pulse intervals. and B.L. The phrenic nerve threshold test was then immediately repeated, and the threshold remained consistent with the preablation threshold. and J.-H.P. Lim B., Kim H.B., Jeong S., Kim S.H., Kang J.M., Park Y., Won D.-S., Kim J.W., Ryu D.S., Kim Y., et al. The different layers of the esophagus are also delineated. In our system, the electric pulses generated by a high voltage pulse generator is delivered to the load through a low-loss transmission line. and J.-H.P. The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers14204987/s1, Figure S1. Intrapulmonary vein ablation without stenosis: a novel balloon-based direct current electroporation approach. Lattice-tip focal ablation catheter that toggles between radiofrequency and pulsed field energy to treat atrial fibrillation: a first-in-human trial. However, insulation or portioning of the electrical field using different techniques can mitigate muscle contraction. This can be advantageous by helping to bridge electrode contact gaps with tissue but is also detrimental as it diverts PEF electric current through the blood rather than the tissue. Pulsed electric field (PEF) cardiac ablation has been proposed as a nonthermal technology to cause cell death by irreversible electroporation (IRE). All beagles showed mild hematuria and erection with stiff surrounding prostate tissue immediately after the procedure but resolved spontaneously within 7 days. The successful myocardial ablation using thermal energies is dependent mostly on adequate catheter-tissue contact. Careers. Tissue sampling and gross findings. The information provided in this proof-of-concept can be used by future groups to both manufacture an actual physical prototype as well as continue to augment the PEF COMSOL simulation presented. Endocardial ventricular pulsed field ablation: a proof-of-concept preclinical evaluation. Division of Cardiology, Rhon-Klinikum Campus Bad Neustadt, Bad Neustadt, Germany (T.D.). It is important to appreciate that any combination of parameters may have its own intensity of effects and should be tested for its beneficial and unwanted effects. Preclinical evaluation of pulsed field ablation: electrophysiological and histological assessment of thoracic vein isolation. For cycles of biphasic pulse waveforms where the electric field polarity is alternated (Figure 1), the addition of multiple cycles in quick succession, comprising a packet, will alter the effective electric field threshold to induce a desired outcome. This model demonstrates that electric fields are significantly affected by tissue interfaces where conductivity discontinuities occur. Through a process called irreversible electroporation, cardiac tissue . When 1800 V/cm was applied, the cross-sectional and longitudinal electric field between the two electrodes were oval and dumbbell-shaped, respectively. 3D indicates 3-dimensional; and PFA, pulsed field ablation. E, Higher magnification of phrenic nerve section, demonstrating normal structure. Data generated or analyzed during the study are available from the corresponding author on request. The confidence intervals were calculated based on the number of animals in each study. Future work may continue to build the body of evidence for safety of biphasic waveforms to eliminate cardiac synchronization of PEF delivery. Minimal coronary artery damage by myocardial electroporation ablation. PMC legacy view We use cookies to help provide and enhance our service and tailor content. Intense exercise and endurance-training program influence serum kinetics of muscle and cardiac biomarkers in dogs. The focal electrode was only used to simulate a monopolar configuration, as bipolar activation would focus energy delivery in the blood and not tissue. In the short term (13 days), regions of necrotic cardiomyocytes are beginning to be replaced by inflammatory infiltrate, including fibroblast infiltration. Treatment titration. The MT fibrotic areas were evaluated using the ImageJ 1.53c software (Wayne Ribband, National Institutes of Health; Bethesda, MD, USA). In this work, the dark titania powder was prepared by pulsed laser ablation (Nd:YAG laser, 1064 nm, 7 ns) in water and dried in air. Some factors affecting bubble formation with catheter-mediated defibrillator pulses. Wilt T.J., Brawer M.K., Jones K.M., Barry M.J., Aronson W.J., Fox S., Gingrich J.R., Wei J.T., Gilhooly P., Grob B.M., et al. In the heterogeneous environment, the delivered energy is able to induce an electric field over the appropriate ablation threshold for a basic biphasic pulse protocol (1500 V/cm, red) across the entire cardiac wall thickness. The IRE with HF-PEF pulses were successfully delivered to the prostate. Dr Deneke reports advisory board for Imricor, InHeart, and Biotronik. First, the team did a significant amount of background research on related literature to better understand the current status of the project topic. The urothelium cells around the urethra experienced apoptosis 4 h after IRE with HF-PEF. Histopathologic results of the control and treatment groups at different time points after irreversible electroporation with high-frequency pulsed electric field. Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer. A consistent electric field threshold (600 V/cm) was used to evaluate effective treatment depth for each configuration and voltage. It has been used previously in other medical fields, such as oncology, but is now being investigated as an alternate energy source for catheter ablation of cardiac arrhythmias. The tubes were pre-chilled, and samples were centrifuged at 3500 rpm for 10 min at 4 C. The IRE with HF-PEF procedures were technically successful in all beagles. 1 Key Resources Product Specification Sheet Clinical Compendium SIGN UP FOR NEWSLETTER Request a Sales Rep Different groups have provided data on PFA use in preclinical and clinical settings. Average treatment time was 420 190 s. *** p < 0.001, compared with before IRE with HF-PEF. Regeneration by cell proliferation was assessed by immunofluorescence (IF) staining of Ki-67 (Thermo Fisher Scientific, Waltham, MA, USA). Experimental and numerical investigation of parameters affecting high-frequency irreversible electroporation for prostate cancer ablation. Biomedical Engineering Summary of clinical pulsed electrical field systems currently under evaluation or approved for human cardiac ablation. conducted the experimental work. Monophasic waveforms result in the greatest charging capacity of the cell membrane, creating the strongest treatment effects. Bill-Axelson A., Holmberg L., Garmo H., Rider J.R., Taari K., Busch C., Nordling S., Hggman M., Andersson S.-O., Spngberg A., et al. (c) Thermal distribution at the axial- and longitudinal-sections when 1800 V/cm and 100 s width of 10 pulses were applied between the two electrodes. PFA is an important new technology that is proposed to be more efficacious and safer than currently used thermal ablation. We claim: 1. FARAPULSE Pulsed Field Ablation (PFA) is a novel, non-thermal method for cardiac ablation that is fundamentally different from traditional modalities: . B, Right superior pulmonary vein treatment site mural fibrosis where nerve sparing is observed (outlined). MSIT: Ministry of Science and ICT. Dose-dependent ATP depletion and cancer cell death following calcium electroporation, relative effect of calcium concentration and electric field strength. MENLO PARK, California, October 9, 2020 Galaxy Medical, (Galaxy), a developer of Pulsed Electric Field (PEF) technology for the treatment of cardiac arrhythmias, today announced that the first patients were successfully treated with the proprietary CENTAURI System by Dr. Ante Ani in Split, Croatia as part of the ECLIPSE-AF study. Increasing voltage will directly increase treatment magnitude. HF-PEF of 1800 V was delivered in 9 groups of 10 pulses each (total 90 pulses) using two monopolar electrodes according to the electrical condition reported previously [25]. Pulsed field ablation (PFA) is a nonthermal energy modality that has been utilized for both gene electrotransfer and solid organ tumor ablation for many years. Overall, the cardiac safety of IRE with HF-PEF was verified in beagles. Finally, close examination 28 days following PEF therapy to durably isolate superior vena cava and RPV demonstrated intact phrenic nerves in all 3 pigs (Figure 4). Calcium electroporation induces tumor eradication, long-lasting immunity and cytokine responses in the CT26 colon cancer mouse model. The techniques of the IRE with HF-PEF has been described in detail previously [21]. will also be available for a limited time. The mean (SD) degree of inflammatory cell infiltration did not differ 4 h after IRE treatment from that in the control (1.40 0.52 vs. 1.11 0.33, p = 0.164). In a bipolar arrangement, the active electrodes are placed in close proximity to each other at the targeted tissue and activated simultaneously, resulting in one or more electrode pairs that deliver the therapy. Electroporation has a graded effect, and the cell injury caused by electroporation ranges from reversible electroporation with temporary pore formation in the cell membrane to irreversible electroporation (IRE) associated with cell death by apoptosis. Approximately 3 mL blood was collected and transferred into Vacutainer SST Tubes. However, higher voltages also increase associated tissue heating, potentially resulting in undesirable thermal effects. We acknowledge the inherent limitation of validating a computational model against published data, including differences in catheter design and configuration and the differences in PFA pulse duration and pulse numbers. Cardiac safety after IRE with HF-PEF was investigated through ECG and cardiac markers, Troponin I and CK-MB, in this study. After sufficient background information was obtained, project objectives and deliverables were finalized. The following voltages are evaluated under the above conditions: https://doi.org/10.1016/j.hroo.2022.05.009, Pulsed-field ablation: Computational modeling of electric fields for lesion depth analysis, View Large Overall, this proofof-concept document includes details about a pulsed electric field (PEF) ablation catheter that utilize electric waves to provide simultaneous delivery of variable electrical pulses to the heart tissue. Validation results were obtained from available literature reporting lesion depth due to pulsed-field ablation delivery in porcine models. Of note, it may take at least 1 to 2 hours before the dying cells stop metabolizing the 2,3,5-triphenyltetrazolium chloride formazan salt sufficiently to where the lesion is grossly visible.18 Cellular apoptotic markers may be helpful in the future to help determine when the majority of cells have started to permanently die. D, Acute high magnification histology (trichrome) demonstrating contraction band necrosis and myocyte fragmentation and shrinkage indicative of acute cell death. Disclosures Dr Verma reports grants from Medtronic, Biosense Webster, Abbott, and Bayer; advisory board for Medtronic, Biosense Webster, Adagio Medical, Thermedical, Kardium, and Boston Scientific; speaking fees from Medtronic and Biosense Webster. In the recent in vitro study, nanoseconds PEF (nsPEF) of 1 MHz frequency significantly enhanced cytotoxic effect of the prostate cancer cells in the presence of extracellular Ca2+ [17]. official website and that any information you provide is encrypted S.J., S.H.K., B.L., J.H.C. A computational model was developed and validated based on extracted data from invivo studies to examine the effect of different applied voltages and the impact of distance between the catheter and endocardial surface on the depth of irreversible myocardial injury using PFA.

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