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Pulsed field ablation in medicine: irreversible electroporation and electropermeabilization theory and applications

Edward J Jacobs

Edward J Jacobs

Wallace H Coulter School of Biomedical Engineering, Georgia Institute of Technology & Emory Medical SchoolAtlanta, USA
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Jacobs, Edward J
, 
Boris Rubinsky

Boris Rubinsky

Department of Bioengineering and Department of Mechanical Engineering, University of California, BerkeleyBerkeley, USA
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Rubinsky, Boris
 und 
Rafael V Davalos

Rafael V Davalos

Wallace H Coulter School of Biomedical Engineering, Georgia Institute of Technology & Emory Medical SchoolAtlanta, USA
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Davalos, Rafael V
  
27. Feb. 2025
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Artikel-Kategorie: review
Online veröffentlicht: 27. Feb. 2025
Seitenbereich: 1 - 22
Eingereicht: 21. Nov. 2024
Akzeptiert: 07. Dez. 2024
DOI: https://doi.org/10.2478/raon-2025-0011
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© 2025 Edward J Jacobs et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

FIGURE 1.

Conceptual schematic of the molecular mechanisms of electropermeabilization. (A) An intact cell membrane (B) in an exogenous electric field experiences an induced transmembrane potential. (C) Hydrophobic pores become energetically favorable as water infiltrates the bilayer. With the removal of the applied electric field, the hydrophobic pore reseals within nanoseconds. (D) If higher and longer external electric fields are applied, phospholipids invert to form small hydrophilic pores that allow the passage of ions and small molecules. Elastic forces within the membrane allow for these pores to reseal within nanoseconds to microseconds after the removal of the electric field. (E) With higher magnitude and longer duration electric fields, pores number may increase, and nucleated pores may expand or combine, allowing the transport of larger molecules and higher quantities across the membrane. Significant lipid oxidation is indicated to occur at high electric fields. (F) If excessive, the lipid bilayer may hemorrhage leading to lytic (necrotic) cell death. (G) After cessation of the applied electric field, the cell membrane may remain permeable due to the presence of lipid oxidation, which, in return, also allows for easier pore formation upon the introduction of another electric field. (H) As significant mass transport occurs over the cell membrane, the cell may lose homeostasis and die through regulated cell death, or (G) the cell may repair the permeable and damaged cell membrane to regain homeostasis.
Conceptual schematic of the molecular mechanisms of electropermeabilization. (A) An intact cell membrane (B) in an exogenous electric field experiences an induced transmembrane potential. (C) Hydrophobic pores become energetically favorable as water infiltrates the bilayer. With the removal of the applied electric field, the hydrophobic pore reseals within nanoseconds. (D) If higher and longer external electric fields are applied, phospholipids invert to form small hydrophilic pores that allow the passage of ions and small molecules. Elastic forces within the membrane allow for these pores to reseal within nanoseconds to microseconds after the removal of the electric field. (E) With higher magnitude and longer duration electric fields, pores number may increase, and nucleated pores may expand or combine, allowing the transport of larger molecules and higher quantities across the membrane. Significant lipid oxidation is indicated to occur at high electric fields. (F) If excessive, the lipid bilayer may hemorrhage leading to lytic (necrotic) cell death. (G) After cessation of the applied electric field, the cell membrane may remain permeable due to the presence of lipid oxidation, which, in return, also allows for easier pore formation upon the introduction of another electric field. (H) As significant mass transport occurs over the cell membrane, the cell may lose homeostasis and die through regulated cell death, or (G) the cell may repair the permeable and damaged cell membrane to regain homeostasis.

Figure 2.

Electric field and current through heterogeneous tissue. (A) Without electroporation, current (green arrows) passes around the cells (pink) through the extracellular space (blue). (B) Electroporation allows for current to pass through the cells, but it is still influenced by tissue heterogeneity.
Electric field and current through heterogeneous tissue. (A) Without electroporation, current (green arrows) passes around the cells (pink) through the extracellular space (blue). (B) Electroporation allows for current to pass through the cells, but it is still influenced by tissue heterogeneity.

FIGURE 3.

(A) cumulative registered patient and trial numbers for IRE and PFA on ClinicalTrials.gov. (B) Breakdown of trials and (C) patient populations by tissue type. Other contains renal, lung, stomach, esophageal, gallbladder, hilus pulmonis, extremity, lymph node, intestinal, rectal, laryngeal, head and neck, and breast cancers; benign prostate hyperplasia; chronic bronchitis; tonsillar hypertrophy.
(A) cumulative registered patient and trial numbers for IRE and PFA on ClinicalTrials.gov. (B) Breakdown of trials and (C) patient populations by tissue type. Other contains renal, lung, stomach, esophageal, gallbladder, hilus pulmonis, extremity, lymph node, intestinal, rectal, laryngeal, head and neck, and breast cancers; benign prostate hyperplasia; chronic bronchitis; tonsillar hypertrophy.

FIGURE 4.

(A) Monophasic IRE waveform and (B) Biphasic H-FIRE waveform. (1) Magnitude (voltage or current), (2) pulse width, (3) interphase delay, (4) interpulse / intercycle delay, (5) burst repitition interval.
(A) Monophasic IRE waveform and (B) Biphasic H-FIRE waveform. (1) Magnitude (voltage or current), (2) pulse width, (3) interphase delay, (4) interpulse / intercycle delay, (5) burst repitition interval.

FIGURE 5.

Pulsed field ablation treatment planning pipeline. (A) Images of the region of interest are taken through CT, MRI, US, or other modalities. Typically, segmentation is performed to define individual tissue regions before computational modeling, as the dynamic electric field, temperature, and conductivity distributions are tissue dependent. Numerical modeling is performed with the intent to maximize targeted tissue coverage with a critical electric field while minimizing deleterious effects on nearby structures. Following, the protocol is implemented for the treatment of the target tissue. While computational modeling can inform treatments, the exact application of PFA can often differ from a priori computational modeling. Post-treatment imaging is frequently used to assess acute and long-term ablation success. (B) Tissue electroporation modeling is multifaceted and requires knowledge about multiple electroporation-dependent and electroporation-independent tissue properties. The local electric potential depends on the local electrical conductivity and temperature. The electrical conductivity also depends on the local temperature and the electric field, as pore formation due to the local electric field allows for current to flow through cells. Subsequently, temperature generation depends on the electric field magnitude and the local conductivity. Images in panel A were adapted from various sources for instructional purposes.100,235
Pulsed field ablation treatment planning pipeline. (A) Images of the region of interest are taken through CT, MRI, US, or other modalities. Typically, segmentation is performed to define individual tissue regions before computational modeling, as the dynamic electric field, temperature, and conductivity distributions are tissue dependent. Numerical modeling is performed with the intent to maximize targeted tissue coverage with a critical electric field while minimizing deleterious effects on nearby structures. Following, the protocol is implemented for the treatment of the target tissue. While computational modeling can inform treatments, the exact application of PFA can often differ from a priori computational modeling. Post-treatment imaging is frequently used to assess acute and long-term ablation success. (B) Tissue electroporation modeling is multifaceted and requires knowledge about multiple electroporation-dependent and electroporation-independent tissue properties. The local electric potential depends on the local electrical conductivity and temperature. The electrical conductivity also depends on the local temperature and the electric field, as pore formation due to the local electric field allows for current to flow through cells. Subsequently, temperature generation depends on the electric field magnitude and the local conductivity. Images in panel A were adapted from various sources for instructional purposes.100,235

FIGURE 6.

Immune response following pulsed field ablation. The tumor microenvironment (TME) evolved through all stages of cancer progression and protects itself through reprogramming immune cells (T regulatory cells [T-reg], myeloid-derived suppressor cells [MDSCs], and tumor-associated macrophages [TAMs]), attracting stromal cells (endothelial cells and fibroblasts) that help deposit a dense extracellular matrix (ECM). This produces an immunosuppressive “cold” tumor that excludes normal immune cells from infiltrating. Pulsed-field ablation indiscriminately kills tumor cells, stromal cells, and immunosuppressive immune cells within the ablation and restructures the ECM. The removal of active immunosuppression, permeabilization of mature blood vessels, and release of Damage Associated Molecular patterns (DAMPs) by IRE entices innate immune cell infiltration. Tumor antigens are released by treated cells, which are either taken up by dendritic cells or drained directly into lymph nodes for antigen presentation. Tumor-specific T- and B-cells mature within the lymph nodes, then antigen-specific T- and B-cells leave the lymph node to potentially remove residual cancer or target distant metastatic disease.
Immune response following pulsed field ablation. The tumor microenvironment (TME) evolved through all stages of cancer progression and protects itself through reprogramming immune cells (T regulatory cells [T-reg], myeloid-derived suppressor cells [MDSCs], and tumor-associated macrophages [TAMs]), attracting stromal cells (endothelial cells and fibroblasts) that help deposit a dense extracellular matrix (ECM). This produces an immunosuppressive “cold” tumor that excludes normal immune cells from infiltrating. Pulsed-field ablation indiscriminately kills tumor cells, stromal cells, and immunosuppressive immune cells within the ablation and restructures the ECM. The removal of active immunosuppression, permeabilization of mature blood vessels, and release of Damage Associated Molecular patterns (DAMPs) by IRE entices innate immune cell infiltration. Tumor antigens are released by treated cells, which are either taken up by dendritic cells or drained directly into lymph nodes for antigen presentation. Tumor-specific T- and B-cells mature within the lymph nodes, then antigen-specific T- and B-cells leave the lymph node to potentially remove residual cancer or target distant metastatic disease.
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