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 0.1 s. The resulting treatment zones were quantified using viability staining and lethal electric field intensities were determined numerically. Computational modeling was then used to determine parameters necessary for INSPIRE treatments to achieve equivalent treatment zones to clinical electroporation treatments and evaluate the potential for these treatments to induce deleterious thermal damage. RESULTS: Lethal thresholds between 1109 and 709 V/cm were found for nominal 0.01 s treatments with pulses between 350 ns and 2000 ns at physiological temperatures. Further increases in dose resulted in significant decreases in lethal thresholds. Given these experimental results, treatment zones comparable to clinical electroporation are possible by increasing the dose and voltage used with nanosecond duration pulses. Temperature-controlled simulations indicate minimal thermal cell death while achieving equivalent treatment volumes to clinical electroporation. CONCLUSION: Nanosecond electrical pulses can achieve comparable outcomes to traditional electroporation provided sufficient electrical doses or voltages are applied. The use of temperature-controlled delivery may minimize thermal damage during treatment. SIGNIFICANCE: Intense muscle stimulation and the need for cardiac gating have limited irreversible electroporation. Nanosecond pulses can alleviate these challenges, but traditionally have produced significantly smaller treatment zones. This study suggests that larger ablation volumes may be possible with the INSPIRE approach and that future in vivo studies are warranted.

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. Treatments consisted of integrated energized times (doses) of 0.01 or 0.1 s. Pulse width, electrical dose, and initial temperature were all found to significantly affect the size of ablations and the resulting lethal electric field strength. The smallest ablations were created at 10 °C and ELethal were calculated to be 1729, 1359, 929, 777, 483 V/cm for 0.01 s treatments with 1, 2, 4, 8, and 100 µs pulses, respectively. At 37 °C these values decreased to 773, 614, 507, 462, and 394 V/cm, respectively. Increasing the dose from 0.01 to 0.1 s at 37 °C resulted in statistically significant decreases (p < 0.001) in ELethal for all treatments except for the 100 µs group. This study found that IRE is a thermally mediated, dose-dependent ablation modality for pulses on the order of one microsecond. Tissue temperatures are not accounted for when determining ablative boundaries in treatment planning algorithms. This work demonstrates that data generated at room temperature may not be predictive of ablation volumes in-vivo and that local temperatures should be accounted for in treatment planning.

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. RESULTS: The temperature controlled ablation diameters were conditionally different than the open-loop treatments and closed-loop treatments generally produced smaller ablations. Closed-loop control enabled the investigation of treatments with steady state 42 °C hyperthermic conditions which were not feasible without active feedback. Baseline closed-loop treatments at 20 °C resulted in ablations measuring 9.9 ± 0.3 mm in diameter while 37 °C treatments were 20% larger (p < 0.0001) measuring 11.8 ± 0.3 mm indicating that this protocol induces a thermally mediated biological response. CONCLUSION: A closed-loop control algorithm which modulated the delay between successive pulse waveforms to achieve stable target temperatures was demonstrated. Algorithmic control enabled the evaluation of specific treatment parameters at physiological temperatures not possible with open-loop systems due to excessive Joule heating. SIGNIFICANCE: Irreversible electroporation is generally considered to be a non-thermal ablation modality and temperature monitoring is not part of the standard clinical practice. The results of this study indicate ablative outcomes due to exposure to pulses on the order of one microsecond may be thermally mediated and dependent on local tissue temperatures. The results of this study set the foundation for experiments in vivo utilizing temperature control algorithms.