While the primary goal of focal therapy for prostate cancer (PCa) is conserving patient quality of life by reducing oncological burden, available modalities use thermal energy or whole-gland radiation which can damage critical neurovascular structures within the prostate and increase risk of genitourinary dysfunction. High-frequency irreversible electroporation (H-FIRE) is a promising alternative ablation modality that utilizes bursts of pulsed electric fields (PEFs) to destroy aberrant cells via targeted membrane damage. Due to its nonthermal mechanism, H-FIRE offers several advantages over state-of-the-art treatments, but waveforms have not been optimized for treatment of PCa. In this study, we characterize lethal electric field thresholds (EFTs) for H-FIRE waveforms with three different pulse widths as well as three interpulse delays in vitro and compare them to conventional irreversible electroporation (IRE). Experiments were performed in non-neoplastic and malignant prostate cells to determine the effect of waveforms on both targeted (malignant) and adjacent (non-neoplastic) tissue. A numerical modeling approach was developed to estimate the clinical effects of each waveform including extent of nonthermal ablation, undesired thermal damage, and nerve excitation. Our findings indicate that H-FIRE waveforms with pulse durations of 5 and 10 μs provide large ablations comparable to IRE with tolerable levels of thermal damage and minimized muscle contractions. Lower duration (2 μs) H-FIRE waveforms exhibit the least amount of muscle contractions but require increased voltages which may be accompanied by unwanted thermal damage.

Pulsed field ablation (PFA) has emerged as an alternative to thermal techniques in treating cardiac arrhythmias due to the better safety profile and similar efficacy. However, lack of deep electric field penetration has led to incomplete transmural lesions and 1-year recurrence rates of ∼30 %. Electroporation induces non-linear increases in tissue electrical conductivity, influencing the electric field distribution and subsequent ablation. Characterization of the electroporation-dependent properties across PFA waveforms would improve the accuracy of predicting the electric field distribution through tissue for different patients and catheter designs. Utilizing a neural network trained on electroporation finite element models, we characterized the first electroporation-dependent conductivity curves for the complete range of clinically relevant pulse widths (0.5-100 μs) and electric fields (100-2500 V/cm) in cardiac tissue. We then evaluated the lethal electric field thresholds of human cardiomyocytes in a tissue-mimicking hydrogel. We used both the derived conductivity curves and the lethal thresholds to simulate the non-linear electric field distribution in atrial tissue using a bipolar probe configuration and in ventricular tissue using a monopolar probe configuration, analyzing how waveforms affect ablation depth. As the pulse width increased, the bulk electrical conductivity and the electric field threshold decreased, while the electroporated conductivity remained the same. We found a strong linear correlation between the tissue and the in vitro electric field thresholds. The results provide a rationale for incorporating electroporation effects within PFA modeling, and the characterized curves provide paramount information for predicting complete transmural lesion development with different electrode and treatment designs.

To evaluate the feasibility of real-time temperature monitoring during an electroporation-based therapy procedure, a data-driven state-space model was developed. Agar phantoms mimicking low conductivity (LC) and high conductivity (HC) tissues were tested under the influences of high (HV) and low (LV) applied voltages. Real-time changes in impedance, measured by Fourier Analysis SpecTroscopy (FAST) along with the known tissue conductivity and applied voltages, were used to train the model. A theoretical finite element model was used for external validation of the model, producing model fits of 95.8, 88.4, 90.7, and 93.7% at 4 mm and 93.2, 58.9, 90.0, and 90.1% at 10 mm for the HV-HC, LV-LC, HV-LC, and LV-HC groups, respectively. The proposed model suggests that real-time temperature monitoring may be achieved with good accuracy through the use of real-time impedance monitoring.

Purpose: High-frequency irreversible electroporation (H-FIRE) is a pulsed field ablation (PFA) technique that employs a series of high-voltage, microseconds-long positive and negative pulses, separated by interphase (d1) and interpulse (d2) delays to non-thermally ablate tissue. Previous experimental and computational data suggest an impact of delays on nerve excitation and electrochemical effects. However, the impact of delays on PFA outcomes, such as change in resistance and ablation generation, has only recently started to be elucidated. Methods: While recording the applied voltage and currents, we delivered a series of increasing voltages, termed voltage ramps, into tuber and cardiac tissues using both needle electrode pairs and flat plate electrodes. Tissues were stained for metabolic activity to measure irreversible electroporation areas following treatment. Results: Our findings support previous in vitro data that delays do not significantly affect ablation areas. While there were significant differences in applied current, resistance, and conductivity between different pulse widths at sub-electroporation electric fields, we found no significant differences after inducing electroporation between different delays and pulse widths. Consequently, since delays do not affect ablation areas or local conductivity, the data suggests that delays should not affect the electric field threshold or Joule heating within the tissue. Conclusion: The findings presented here provide critical insights into electroporation-dependent tissue conductivity changes from H-FIRE with implications for improving H-FIRE parameterization and computational models for treatment planning in cancer and cardiac pulsed field ablation.

Objective: This study characterizes the effects of external conductivity on electroporation to develop methods to overcome potential patient-to-patient variability. Impact Statement: We demonstrate that constant power pulsed electric fields (PEFs) achieve consistent treatment outcomes despite variations in conductivity, thereby improving the predictability and efficacy of electroporation-based therapies. Introduction: Electropermeabilization-based therapies typically deliver static voltages between electrodes to induce cell permeabilization. However, tissue conductivity variations introduce uncertainty in treatment outcomes, as the tissue-specific electric field thresholds that induce electroporation also depend on the extracellular conductivity. Methods: Cell-laden hydrogels were fabricated with varying extracellular conductivities and treated with constant voltage PEFs. The voltages and currents were recorded to calculate the applied powers, and the reversible and irreversible electroporation thresholds were quantified using cell-impermeant and viability assays. Homogeneous and heterogeneous multi-tissue finite element models were employed to simulate the impact of tumor conductivity variability on the outcomes of reversible and irreversible electroporation for constant applied voltage, current, and power PEFs. Additionally, an in vivo murine pancreatic tumor model assessed the correlation between PEF delivery and treatment efficacy. Results: The In vitro experiments revealed that the electric field and current density thresholds were conductivity dependent, whereas the power density thresholds remained stable under variable conductivities. Computational modeling indicated that constant power PEFs best predicted tumor coverage in both homogeneous and heterogeneous multi-tissue models. Similarly, the in vivo tumor responses were also better predicted by applied power rather than voltage or current alone. Conclusions: Applying constant power PEFs enables consistent electroporation outcomes despite variations in conductivity.