Improving Prediction of the Potential Distribution Induced by Cylindrical Electrodes within a Homogeneous Rectangular Grid during Irreversible Electroporation

Background: Irreversible electroporation (IRE) is an ablation technique based on the application of short, high-voltage pulses between needle electrodes (diameter: ~1.0 × 10−3 m). A Finite Difference-based software simulating IRE treatment generally uses rectangular grids, yielding discretization issues when modeling cylindrical electrodes and potentially affecting the validity of treatment planning simulations. Aim: Develop an Electric-Potential Estimation (EPE) method for accurate prediction of the electric-potential distribution in the vicinity of cylindrical electrodes. Methods: The electric-potential values in the voxels neighboring the cylindrical electrode voxels were corrected based on analytical solutions derived for coaxial/cylindrical electrodes. Simulations at varying grid resolutions were validated using analytical models. Low-resolution heterogeneous simulations at 2.0 × 10−3 m excluding/including EPE were compared with high-resolution results at 0.25 × 10−3 m. Results: EPE significantly reduced maximal errors compared to analytical results for the electric-potential distributions (26.6–71.8%→0.4%) and for the electrical resistance (30%→1–6%) at 3.0 × 10−3 m voxel-size. EPE significantly improved the mean-deviation (43.1–52.8%→13.0–24.3%) and the calculation-time gain (>15,000×) of low-resolution compared to high-resolution heterogeneous simulations. Conclusions: EPE can accurately predict the potential distribution of neighboring cylindrical electrodes, regardless of size, position, and orientation in a rectangular grid. The simulation time of treatment planning can therefore be shortened by using large voxel-sized models without affecting accuracy of the electric-field distribution, enabling real-time clinical IRE treatment planning

Preclinical studies in small animals for advanced drug delivery using hyperthermia and intravital microscopy

This paper presents three devices suitable for the preclinical application of hyperthermia via the simultaneous high-resolution imaging of intratumoral events. (Pre)clinical studies have con-firmed that the tumor micro-environment is sensitive to the application of local mild hyperthermia. Therefore, heating is a promising adjuvant to aid the efficacy of radiotherapy or chemotherapy. More so, the application of mild hyperthermia is a useful stimulus for triggered drug release from heat-sensitive nanocarriers. The response of thermosensitive nanoparticles to hyperthermia and en-suing intratumoral kinetics are considerably complex in both space and time. To obtain better insight into intratumoral processes, longitudinal imaging (preferable in high spatial and temporal resolution) is highly informative. Our devices are based on (i) an external electric heating adaptor for the dorsal skinfold model, (ii) targeted radiofrequency application, and (iii) a microwave an-tenna for heating of internal tumors. These models, while of some technical complexity, significantly add to the understanding of effects of mild hyperthermia warranting implementation in research on hyperthermia

Preclinical Studies in Small Animals for Advanced Drug Delivery Using Hyperthermia and Intravital Microscopy

This paper presents three devices suitable for the preclinical application of hyperthermia via the simultaneous high-resolution imaging of intratumoral events. (Pre)clinical studies have confirmed that the tumor micro-environment is sensitive to the application of local mild hyperthermia. Therefore, heating is a promising adjuvant to aid the efficacy of radiotherapy or chemotherapy. More so, the application of mild hyperthermia is a useful stimulus for triggered drug release from heat-sensitive nanocarriers. The response of thermosensitive nanoparticles to hyperthermia and ensuing intratumoral kinetics are considerably complex in both space and time. To obtain better insight into intratumoral processes, longitudinal imaging (preferable in high spatial and temporal resolution) is highly informative. Our devices are based on (i) an external electric heating adaptor for the dorsal skinfold model, (ii) targeted radiofrequency application, and (iii) a microwave antenna for heating of internal tumors. These models, while of some technical complexity, significantly add to the understanding of effects of mild hyperthermia warranting implementation in research on hyperthermia

Preclinical studies in small animals for advanced drug delivery using hyperthermia and intravital microscopy

This paper presents three devices suitable for the preclinical application of hyperthermia via the simultaneous high-resolution imaging of intratumoral events. (Pre)clinical studies have con-firmed that the tumor micro-environment is sensitive to the application of local mild hyperthermia. Therefore, heating is a promising adjuvant to aid the efficacy of radiotherapy or chemotherapy. More so, the application of mild hyperthermia is a useful stimulus for triggered drug release from heat-sensitive nanocarriers. The response of thermosensitive nanoparticles to hyperthermia and en-suing intratumoral kinetics are considerably complex in both space and time. To obtain better insight into intratumoral processes, longitudinal imaging (preferable in high spatial and temporal resolution) is highly informative. Our devices are based on (i) an external electric heating adaptor for the dorsal skinfold model, (ii) targeted radiofrequency application, and (iii) a microwave an-tenna for heating of internal tumors. These models, while of some technical complexity, significantly add to the understanding of effects of mild hyperthermia warranting implementation in research on hyperthermia.</p

Mathematical modeling of the thermal effects of irreversible electroporation for in vitro, in vivo, and clinical use: a systematic review

Introduction: Irreversible electroporation (IRE) is a relatively new ablation method for the treatment of unresectable cancers. Although the main mechanism of IRE is electric permeabilization of cell membranes, the question is to what extent thermal effects of IRE contribute to tissue ablation. Aim: This systematic review reviews the mathematical models used to numerically simulate the heat-generating effects of IRE, and uses the obtained data to assess the degree of mild-hyperthermic (temperatures between 40 °C and 50 °C) and thermally ablative (TA) effects (temperatures exceeding 50 °C) caused by IRE within the IRE-treated region (IRE-TR). Methods: A systematic search was performed in medical and technical databases for original studies reporting on numerical simulations of IRE. Data on used equations, study design, tissue models, maximum temperature increase, and surface areas of IRE-TR, mild-hyperthermic, and ablative temperatures were extracted. Results: Several identified models, including Laplace equation for calculation of electric field distribution, Pennes Bioheat Equation for heat transfer, and Arrhenius model for thermal damage, were applied on various electrode and tissue models. Median duration of combined mild-hyperthermic and TA effects is 20% of the treatment time. Based on the included studies, mild-hyperthermic temperatures occurred in 30% and temperatures ≥50 °C in 5% of the IRE-TR. Conclusions: Simulation results in this review show that significant mild-hyperthermic effects occur in a large part of the IRE-TR, and direct thermal ablation in comparatively small regions. Future studies should aim to optimize clinical IRE protocols, maintaining a maximum irreversible permeabilized region with minimal TA effects

Thermodynamic profiling during irreversible electroporation in porcine liver and pancreas: a case study series

Aims: First, the aim of the study was to determine whether irreversible electroporation (IRE) is associated with heat generation in the liver and pancreas at clinical (≤1,500 V/cm) and supraclinical (>1,500 V/cm) electroporation settings; second, to assess the risk of thermal tissue damage in and adjacent to the treated volume in highly perfused versus moderately perfused parts of both organs; third, to investigate the influence of perfusion and of the presence and the orientation of a metal stent on the maximal thermal elevation (ΔTSession,max) in the tissue during an IRE session at fixed IRE settings, and finally, to determine whether the maximum temperature elevation within the IRE-subjected organ during an IRE treatment (single or multiple sessions) is reflected in the organ's surface temperature. Methods: The aims were investigated in 12 case studies conducted in five female Landrace pigs. Several IRE settings were applied for lateral (2), triangular (3), and rectangular (4) electrode configurations in the liver hilum, liver periphery, pancreas head, and pancreas tail. IRE series of 10-90 pulses were applied with pulse durations that varied from 70 μs to 90 μs and electric field strengths between 1,200 V/cm and 3,000 V/cm. In select cases, a metal stent was positioned in the bile duct at the level of the liver hilum. Temperatures were measured before, during, and after IRE in and adjacent to the treatment volumes using fiber optical temperature probes (temperature at the nucleation centers) and digital thermography (surface temperature). The occurrence of thermal damage was assumed to be at temperatures above 50 °C (ΔTSession,max ≥ 13 °C relative to body temperature of 37 °C). The temperature fluctuations at the organ surface (ΔTLocSurf) were compared to the maximum temperature elevation during an IRE treatment in the electroporation zone. In select cases, IRE was applied to tissue volumes encompassing the portal vein (PV) and a constricted and patent superior mesenteric vein (SMV) to determine the influence of the heatsink effect of PV and SMV on ΔTSession,max. Results: The median baseline temperature was 31.6 °C-36.3 °C. ΔTSession,max ranged from -1.7 °C to 25.5 °C in moderately perfused parts of the liver and pancreas, and from 0.0 °C to 5.8 °C in highly perfused parts. The median ΔTLocSurf of the liver and pancreas was 1.0 °C and 10.3 °C, respectively. Constricting the SMV in the pancreas head yielded a 0.8 °C higher ΔTSession,max. The presence of a metal stent in the liver hilum resulted in a ΔTSession,max of 19.8 °C. Stents parallel to the electrodes caused a ΔTSession,max difference of 4.2 °C relative to the perpendicular orientation. Conclusions: Depending on IRE settings and tissue type, IRE is capable of inducing considerable heating in the liver and pancreas that is sufficient to cause thermal tissue damage. More significant temperature elevations are positively correlated with increasing number of electrode pairs, electric field strength, and pulse number. Temperature elevations can be further exacerbated by the presence and orientation of metal stents. Temperature elevations at the nucleation centers are not always reflected in the organ's surface temperature. Heat sink effects caused by large vessels were minimal in some instances, possibly due to reduced blood flow caused by anesthesia. Relevance for patients: Appropriate IRE settings must be chosen based on the tissue type and the presence of stents to avoid thermal damage in healthy peritumoral tissue and to protect anatomical structures [Table: see text]

Thermodynamic profiling during irreversible electroporation in porcine liver and pancreas: a case study series

Aims: First, the aim of the study was to determine whether irreversible electroporation (IRE) is associated with heat generation in the liver and pancreas at clinical (≤1,500 V/cm) and supraclinical (>1,500 V/cm) electroporation settings; second, to assess the risk of thermal tissue damage in and adjacent to the treated volume in highly perfused versus moderately perfused parts of both organs; third, to investigate the influence of perfusion and of the presence and the orientation of a metal stent on the maximal thermal elevation (ΔTSession,max) in the tissue during an IRE session at fixed IRE settings, and finally, to determine whether the maximum temperature elevation within the IRE-subjected organ during an IRE treatment (single or multiple sessions) is reflected in the organ's surface temperature. Methods: The aims were investigated in 12 case studies conducted in five female Landrace pigs. Several IRE settings were applied for lateral (2), triangular (3), and rectangular (4) electrode configurations in the liver hilum, liver periphery, pancreas head, and pancreas tail. IRE series of 10-90 pulses were applied with pulse durations that varied from 70 μs to 90 μs and electric field strengths between 1,200 V/cm and 3,000 V/cm. In select cases, a metal stent was positioned in the bile duct at the level of the liver hilum. Temperatures were measured before, during, and after IRE in and adjacent to the treatment volumes using fiber optical temperature probes (temperature at the nucleation centers) and digital thermography (surface temperature). The occurrence of thermal damage was assumed to be at temperatures above 50 °C (ΔTSession,max ≥ 13 °C relative to body temperature of 37 °C). The temperature fluctuations at the organ surface (ΔTLocSurf) were compared to the maximum temperature elevation during an IRE treatment in the electroporation zone. In select cases, IRE was applied to tissue volumes encompassing the portal vein (PV) and a constricted and patent superior mesenteric vein (SMV) to determine the influence of the heatsink effect of PV and SMV on ΔTSession,max. Results: The median baseline temperature was 31.6 °C-36.3 °C. ΔTSession,max ranged from -1.7 °C to 25.5 °C in moderately perfused parts of the liver and pancreas, and from 0.0 °C to 5.8 °C in highly perfused parts. The median ΔTLocSurf of the liver and pancreas was 1.0 °C and 10.3 °C, respectively. Constricting the SMV in the pancreas head yielded a 0.8 °C higher ΔTSession,max. The presence of a metal stent in the liver hilum resulted in a ΔTSession,max of 19.8 °C. Stents parallel to the electrodes caused a ΔTSession,max difference of 4.2 °C relative to the perpendicular orientation. Conclusions: Depending on IRE settings and tissue type, IRE is capable of inducing considerable heating in the liver and pancreas that is sufficient to cause thermal tissue damage. More significant temperature elevations are positively correlated with increasing number of electrode pairs, electric field strength, and pulse number. Temperature elevations can be further exacerbated by the presence and orientation of metal stents. Temperature elevations at the nucleation centers are not always reflected in the organ's surface temperature. Heat sink effects caused by large vessels were minimal in some instances, possibly due to reduced blood flow caused by anesthesia. Relevance for patients: Appropriate IRE settings must be chosen based on the tissue type and the presence of stents to avoid thermal damage in healthy peritumoral tissue and to protect anatomical structures [Table: see text]

Mathematical modeling of the thermal effects of irreversible electroporation for in vitro, in vivo, and clinical use: a systematic review

Irreversible electroporation (IRE) is a relatively new ablation method for the treatment of unresectable cancers. Although the main mechanism of IRE is electric permeabilization of cell membranes, the question is to what extent thermal effects of IRE contribute to tissue ablation. This systematic review reviews the mathematical models used to numerically simulate the heat-generating effects of IRE, and uses the obtained data to assess the degree of mild-hyperthermic (temperatures between 40 °C and 50 °C) and thermally ablative (TA) effects (temperatures exceeding 50 °C) caused by IRE within the IRE-treated region (IRE-TR). A systematic search was performed in medical and technical databases for original studies reporting on numerical simulations of IRE. Data on used equations, study design, tissue models, maximum temperature increase, and surface areas of IRE-TR, mild-hyperthermic, and ablative temperatures were extracted. Several identified models, including Laplace equation for calculation of electric field distribution, Pennes Bioheat Equation for heat transfer, and Arrhenius model for thermal damage, were applied on various electrode and tissue models. Median duration of combined mild-hyperthermic and TA effects is 20% of the treatment time. Based on the included studies, mild-hyperthermic temperatures occurred in 30% and temperatures ≥50 °C in 5% of the IRE-TR. Simulation results in this review show that significant mild-hyperthermic effects occur in a large part of the IRE-TR, and direct thermal ablation in comparatively small regions. Future studies should aim to optimize clinical IRE protocols, maintaining a maximum irreversible permeabilized region with minimal TA effects