Treatment of Spontaneous Tumors With Algorithmically Controlled Electroporation.

Objective: To study the safety and efficacy of algorithmically controlled electroporation (ACE) against spontaneous equine melanoma.

Methods: A custom temperature sensing coaxial electrode was paired with a high voltage pulse generation system with integrated temperature feedback controls. Computational modeling and ex vivo studies were conducted to evaluate the system's ability to achieve and maintain target temperatures.

Investigation of integrated time nanosecond pulse irreversible electroporation against spontaneous equine melanoma.

Introduction: Integrated time nanosecond pulse irreversible electroporation (INSPIRE) is a novel tumor ablation modality that employs high voltage, alternating polarity waveforms to induce cell death in a well-defined volume while sparing the underlying tissue. This study aimed to demonstrate the efficacy of INSPIRE against spontaneous melanoma in standing, awake horses.

Methods: A custom applicator and a pulse generation system were utilized in a pilot study to treat horses presenting with spontaneous melanoma.

A novel in vitro model of clinical cryoablation to investigate the transition zone for focal tumor ablation.

Cryoablation (CA) of solid tumors is highly effective at reducing tumor burden and eliminating small, early stage tumors. However, complete ablation is difficult to achieve and cancer recurrence is a significant barrier to treatment of larger tumors compared to resection. In this study, we explored the relationship between temperature, ice growth, and cell death using a novel in vitro model of clinical CA with the Visual-ICE (Boston Scientific) system, a clinically approved and widely utilized device.

Integrated Time Nanosecond Pulse Irreversible Electroporation (INSPIRE): Assessment of Dose, Temperature, and Voltage on Experimental and Clinical Treatment Outcomes.

Objective: This study sought to investigate a novel strategy using temperature-controlled delivery of nanosecond pulsed electric fields as an alternative to the 50-100 microsecond pulses used for irreversible electroporation.

Methods: INSPIRE treatments were carried out at two temperatures in 3D tumor models using doses between 0.001 s and 0.

Polymer Nanoparticles Enhance Irreversible Electroporation In Vitro.

Expanding the volume of an irreversible electroporation treatment typically necessitates an increase in pulse voltage, number, duration, or repetition. This study investigates the addition of polyethylenimine nanoparticles (PEI-NP) to pulsed electric field treatments, determining their combined effect on ablation size and voltages. U118 cells in an in vitro 3D cell culture model were treated with one of three pulse parameters (with and without PEI-NPs) which are representative of irreversible electroporation (IRE), high frequency irreversible electroporation (H-FIRE), or nanosecond pulsed electric fields (nsPEF).

Thermochromic Tissue Phantoms for Evaluating Temperature Distribution in Simulated Clinical Applications of Pulsed Electric Field Therapies.

Irreversible electroporation (IRE) induces cell death through nonthermal mechanisms, however, in extreme cases, the treatments can induce deleterious thermal transients. This study utilizes a thermochromic tissue phantom to enable visualization of regions exposed to temperatures above 60°C. Poly(vinyl alcohol) hydrogels supplemented with thermochromic ink were characterized and processed to match the electrical properties of liver tissue.

Algorithmically Controlled Electroporation: A Technique for Closed Loop Temperature Regulated Pulsed Electric Field Cancer Ablation.

Objective: To evaluate the effect of a closed-loop temperature based feedback algorithm on ablative outcomes for pulsed electric field treatments.

Methods: A 3D tumor model of glioblastoma was used to assess the impact of 2 μs duration bipolar waveforms on viability following exposure to open and closed-loop protocols. Closed-loop treatments evaluated transient temperature increases of 5, 10, 15, or 22 °C above baseline.

Electro-thermal therapy: Microsecond duration pulsed electric field tissue ablation with dynamic temperature control algorithms.

Electro-thermal therapy (ETT) is a new cancer treatment modality which combines the use of high voltage pulsed electric fields, dynamic energy delivery rates, and closed loop thermal control algorithms to rapidly and reproducibly create focal ablations. This study examines the ablative potential and profile of pulsed electric field treatments delivered in conjunction with precise temperature control algorithms. An ex vivo perfused liver model was utilized to demonstrate the capability of 5000 V 2 μs duration bipolar electrical pulses and dynamic temperature control algorithms to produce ablations.

Irreversible electroporation is a thermally mediated ablation modality for pulses on the order of one microsecond.

Irreversible electroporation (IRE) is generally considered to be a non-thermal ablation modality. This study was designed to examine the relative effect of temperature on IRE ablation sizes for equivalent dose treatments with constitutive pulses between 1 and 100 µs. 3D in-vitro brain tumor models maintained at 10 °C, 20 °C, 30 °C, or 37 °C were exposed to 500 V treatments using a temperature control algorithm to limit temperature increases to 5 °C.

Electro-Thermal Therapy Algorithms and Active Internal Electrode Cooling Reduce Thermal Injury in High Frequency Pulsed Electric Field Cancer Therapies.

Thermal tissue injury is an unintended consequence in current irreversible electroporation treatments due to the induction of Joule heating during the delivery of high voltage pulsed electric fields. In this study active temperature control measures including internal electrode cooling and dynamic energy delivery were investigated as a process for mitigating thermal injury during treatment. Ex vivo liver was used to examine the extent of thermal injury induced by 5000 V treatments with delivery rates up to five times faster than current clinical practice.

Temperature Dependence of High Frequency Irreversible Electroporation Evaluated in a 3D Tumor Model.

Electroporation is a bioelectric phenomenon used to deliver target molecules into cells in vitro and irreversible electroporation (IRE) is an emerging cancer therapy used to treat inoperable tumors in situ. These phenomena are generally considered to be non-thermal in nature. In this study, a 3D tumor model was used to investigate the correlation between temperature and the effectiveness of standard clinical IRE and high frequency (H-FIRE) protocols.

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

Objective: 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.

Methods: Ablations were created in porcine liver under surgical anesthesia by adminstereing high frequency bursts of 0.5-5.

High-Frequency Irreversible Electroporation Using 5,000-V Waveforms to Create Reproducible 2- and 4-cm Ablation Zones-A Laboratory Investigation Using Mechanically Perfused Liver.

Purpose: To investigate if high-frequency irreversible electroporation (H-FIRE) treatments can be delivered at higher voltages and with greater energy delivery rates than currently implemented in clinical irreversible electroporation protocols.

Materials And Methods: Treatments using 3,000 V and 5,000 V were administered to mechanically perfused ex vivo porcine liver via a single applicator and grounding pad (A+GP) as well as a 4-applicator array (4AA). Integrated energized times (IET) 0.

Burst and continuous high frequency irreversible electroporation protocols evaluated in a 3D tumor model.

High frequency irreversible electroporation (H-FIRE) is an emerging cancer therapy which uses bursts of alternating polarity pulses to target and destroy the membranes of cells within a predictable volume. Typically, 2 µs pulses are rapidly repeated 24-50 times to create a 48-100 µs long energy burst. Bursts are repeated 100×  at 1 Hz, resulting in an integrated energized time of 0.

Synergistically Enhancing the Therapeutic Effect of Radiation Therapy with Radiation Activatable and Reactive Oxygen Species-Releasing Nanostructures.

Nanoparticle-based radio-sensitizers can amplify the effects of radiation therapy on tumor tissue even at relatively low concentrations while reducing the potential side effects to healthy surrounding tissues. In this study, we investigated a hybrid anisotropic nanostructure, composed of gold (Au) and titanium dioxide (TiO), as a radio-sensitizer for radiation therapy of triple-negative breast cancer (TNBC). In contrast to other gold-based radio sensitizers, dumbbell-like Au-TiO nanoparticles (DATs) show a synergistic therapeutic effect on radiation therapy, mainly because of strong asymmetric electric coupling between the high atomic number metals and dielectric oxides at their interfaces.

Reduction of Muscle Contractions during Irreversible Electroporation Therapy Using High-Frequency Bursts of Alternating Polarity Pulses: A Laboratory Investigation in an Ex Vivo Swine Model.

Purpose: To compare the intensity of muscle contractions in irreversible electroporation (IRE) treatments when traditional IRE and high-frequency IRE (H-FIRE) waveforms are used in combination with a single applicator and distal grounding pad (A+GP) configuration.

Materials And Methods: An ex vivo in situ porcine model was used to compare muscle contractions induced by traditional monopolar IRE waveforms vs high-frequency bipolar IRE waveforms. Pulses with voltages between 200 and 5,000 V were investigated, and muscle contractions were recorded by using accelerometers placed on or near the applicators.

Optimization of a single insertion electrode array for the creation of clinically relevant ablations using high-frequency irreversible electroporation.

High-frequency irreversible electroporation (H-FIRE) is an emerging ablation modality, delivering rapid bursts of bipolar microsecond-duration electrical pulses to non-thermally ablate tissue including tumors. With advantages over current electroporation techniques including mitigation of muscle stimulation and reduced susceptibility to heterogeneous tissue properties, H-FIRE may produce more uniform and predictable ablations and can potentially be delivered with a single applicator device. However, the resulting ablations tend to be smaller than those provided with equivalent energy monopolar pulse protocols.

Treatment of Cancer In Vitro Using Radiation and High-Frequency Bursts of Submicrosecond Electrical Pulses.

High-frequency irreversible electroporation (H-FIRE) is an emerging cancer therapy, which uses bursts of short duration, alternating polarity, high-voltage electrical pulses to focally ablate tumors. Here, we present a preliminary investigation of the combinatorial effects of H-FIRE and ionizing radiation. In vitro cell cultures were exposed to bursts of 500 ns pulses and single radiation doses of 2 or 20 Gy then analyzed for 14 days.

A Comprehensive Characterization of Parameters Affecting High-Frequency Irreversible Electroporation Lesions.

Several focal therapies are being investigated clinically to treat tumors in which surgery is contraindicated. Many of these ablation techniques, such as radiofrequency ablation and microwave ablation, rely on thermal damage mechanisms which can put critical nerves or vasculature at risk. Irreversible electroporation (IRE) is a minimally invasive, non-thermal technique to destroy tumors.

Irreversible electroporation for the ablation of pancreatic malignancies: A patient-specific methodology.

Background And Objectives: Irreversible Electroporation (IRE) is a focal ablation technique highly attractive to surgical oncologists due to its non-thermal nature that allows for eradication of unresectable tumors in a minimally invasive procedure. In this study, our group sought to address the challenge of predicting the ablation volume with IRE for pancreatic procedures.

Methods: In compliance with HIPAA and hospital IRB approval, we established a pre-treatment planning methodology for IRE procedures in pancreas, which optimized treatment protocols for individual cases of locally advanced pancreatic cancer (LAPC).

Asymmetric Waveforms Decrease Lethal Thresholds in High Frequency Irreversible Electroporation Therapies.

Irreversible electroporation (IRE) is a promising non-thermal treatment for inoperable tumors which uses short (50-100 μs) high voltage monopolar pulses to disrupt the membranes of cells within a well-defined volume. Challenges with IRE include complex treatment planning and the induction of intense muscle contractions. High frequency IRE (H-FIRE) uses bursts of ultrashort (0.

Production of Spherical Ablations Using Nonthermal Irreversible Electroporation: A Laboratory Investigation Using a Single Electrode and Grounding Pad.

Purpose: To mathematically model and test ex vivo a modified technique of irreversible electroporation (IRE) to produce large spherical ablations by using a single probe.

Materials And Methods: Computed simulations were performed by using varying voltages, electrode exposure lengths, and tissue types. A vegetable (potato) tissue model was then used to compare ablations created by conventional and high-frequency IRE protocols by using 2 probe configurations: a single probe with two collinear electrodes (2EP) or a single electrode configured with a grounding pad (P+GP).

Targeted cellular ablation based on the morphology of malignant cells.

Treatment of glioblastoma multiforme (GBM) is especially challenging due to a shortage of methods to preferentially target diffuse infiltrative cells, and therapy-resistant glioma stem cell populations. Here we report a physical treatment method based on electrical disruption of cells, whose action depends strongly on cellular morphology. Interestingly, numerical modeling suggests that while outer lipid bilayer disruption induced by long pulses (~100 μs) is enhanced for larger cells, short pulses (~1 μs) preferentially result in high fields within the cell interior, which scale in magnitude with nucleus size.

Bursts of Bipolar Microsecond Pulses Inhibit Tumor Growth.

Irreversible electroporation (IRE) is an emerging focal therapy which is demonstrating utility in the treatment of unresectable tumors where thermal ablation techniques are contraindicated. IRE uses ultra-short duration, high-intensity monopolar pulsed electric fields to permanently disrupt cell membranes within a well-defined volume. Though preliminary clinical results for IRE are promising, implementing IRE can be challenging due to the heterogeneous nature of tumor tissue and the unintended induction of muscle contractions.

In-vitro bipolar nano- and microsecond electro-pulse bursts for irreversible electroporation therapies.

Under the influence of external electric fields, cells experience a rapid potential buildup across the cell membrane. Above a critical threshold of electric field strength, permanent cell damage can occur, resulting in cell death. Typical investigations of electroporation effects focus on two distinct regimes.