Abstract
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. A series of short electric pulses create nanoscale defects in the cell membrane, eventually leading to cell death. Typical IRE protocols deliver a series of 50–100 µs monopolar pulses. High frequency IRE (H-FIRE) aims to replace these monopolar pulses with integrated bursts of 0.25–10 µs bipolar pulses. Here, we examine ablations created using a broad array of IRE and H-FIRE protocols in a potato tissue phantom model. Our results show that H-FIRE pulses require a higher energy dose to create equivalent lesions to standard IRE treatment protocols. We show that ablations in potato do not increase when more than 40 H-FIRE bursts are delivered. These results show that H-FIRE treatment protocols can be optimized to produce clinically relevant lesions while maintaining the benefits of a non-thermal ablation technique.
Similar content being viewed by others
References
Heller, L. C., and R. Heller. In vivo electroporation for gene therapy. Hum. Gene Ther. 17:890–897, 2006.
Ivorra, A., L. M. Mir, and B. Rubinsky. Electric field redistribution due to conductivity changes during tissue electroporation: experiments with a simple vegetal model. IFMBE Proc. 25:59–62, 2009.
Miklavcic, D., B. Mali, B. Kos, R. Heller, and G. Sersa. Electrochemotherapy: from the drawing board into medical practice. Biomed. Eng. Online 2014. doi:10.1186/1475-925X-13-29.
Yarmush, M. L., A. Golberg, G. Sersa, T. Kotnik, and D. Miklavcic. Electroporation-based technologies for medicine: principles, applications, and challenges. Annu. Rev. Biomed. Eng. 16:295–320, 2014.
Jaroszeski, M. J., et al. Toxicity of anticancer agents mediated by electroporation in vitro. Anti-cancer Drug 11:201–208, 2000.
Dean, D. A. Nonviral gene transfer to skeletal, smooth, and cardiac muscle in living animals. Am. J. Physiol. Cell Physiol. 289:C233–C245, 2005.
Davalos, R. V., L. M. Mir, and B. Rubinsky. Tissue ablation with irreversible electroporation. Ann. Biomed. Eng. 33:223–231, 2005.
Jiang, C. L., R. V. Davalos, and J. C. Bischof. A review of basic to clinical studies of irreversible electroporation therapy. IEEE Trans. Biomed. Eng. 62:4–20, 2015.
Chu, K. F., and D. E. Dupuy. Thermal ablation of tumours: biological mechanisms and advances in therapy. Nat. Rev. Cancer 14:199–208, 2014.
Siddiqui, I. A., et al. High-frequency irreversible electroporation: safety and efficacy of next-generation irreversible electroporation adjacent to critical hepatic structures. Surg. Innov. 2017. doi:10.1177/1553350617692202.
Scheffer, H. J., et al. Irreversible electroporation for nonthermal tumor ablation in the clinical setting: a systematic review of safety and efficacy. J. Vasc. Interv. Radiol. 25:997–1011, 2014.
Garcia, P. A., et al. Non-thermal irreversible electroporation (N-TIRE) and adjuvant fractionated radiotherapeutic multimodal therapy for intracranial malignant glioma in a canine patient. Technol. Cancer Res. Treat. 10:73–83, 2011.
Garcia, P. A., J. H. Rossmeisl Jr., T. L. Ellis, and R. V. Davalos. Nonthermal irreversible electroporation as a focal ablation treatment for brain cancer. In: Tumors of the Central Nervous System, Volume 12. Dordrecht: Springer, pp. 171–182, 2014.
Martin, R. C., E. Schwartz, J. Adams, I. Farah, and B. M. Derhake. Intra-operative anesthesia management in patients undergoing surgical irreversible electroporation of the pancreas, liver, kidney, and retroperitoneal tumors. Anesthesiol. Pain Med. 5:e22786, 2015.
Bower, M., L. Sherwood, Y. Li, and R. Martin. Irreversible electroporation of the pancreas: definitive local therapy without systemic effects. J. Surg. Oncol. 104:22–28, 2011.
Scheffer, H. J., et al. Irreversible electroporation for nonthermal tumor ablation in the clinical setting: a systematic review of safety and efficacy. J. Vasc. Interv. Radiol. 2014. doi:10.1016/j.jvir.2014.01.028.
Cheung, W., et al. Irreversible electroporation for unresectable hepatocellular carcinoma: initial experience and review of safety and outcomes. Technol. Cancer Res. Treat. 12:233, 2013.
Cannon, R., S. Ellis, D. Hayes, G. Narayanan, and R. C. Martin. Safety and early efficacy of irreversible electroporation for hepatic tumors in proximity to vital structures. J. Surg. Oncol. 107:544–549, 2013.
Martin, II, R. C., K. McFarland, S. Ellis, and V. Velanovich. Irreversible electroporation in locally advanced pancreatic cancer: potential improved overall survival. Ann. Surg. Oncol. 20:443–449, 2013.
Martin, II, R. C., K. McFarland, S. Ellis, and V. Velanovich. Irreversible electroporation therapy in the management of locally advanced pancreatic adenocarcinoma. J. Am. Coll. Surg. 215:361–369, 2012.
Usman, M., W. Moore, R. Talati, K. Watkins, and T. V. Bilfinger. Irreversible electroporation of lung neoplasm: a case series. Med. Sci. Monit. Int. Med. J. Exp. Clin. Res. 18:CS43, 2012.
Garcia, P. A., et al. Intracranial nonthermal irreversible electroporation: in vivo analysis. J. Membr. Biol. 236:127–136, 2010.
Pech, M., et al. Irreversible electroporation of renal cell carcinoma: a first-in-man phase I clinical study. Cardiovasc. Interv. Radiol. 34:132–138, 2011.
Wendler, J. J., et al. Angiography in the isolated perfused kidney: radiological evaluation of vascular protection in tissue ablation by nonthermal irreversible electroporation. Cardiovasc. Interv. Radiol. 35:383–390, 2012.
Wendler, J. J., et al. Urinary tract effects after multifocal nonthermal irreversible electroporation of the kidney: acute and chronic monitoring by magnetic resonance imaging, intravenous urography and urinary cytology. Cardiovasc. Interv. Radiol. 35:921–926, 2012.
Wendler, J., et al. Short- and mid-term effects of irreversible electroporation on normal renal tissue: an animal model. Cardiovasc. Interv. Radiol. 36:512–520, 2013.
Olweny, E. O., et al. Irreversible electroporation: evaluation of nonthermal and thermal ablative capabilities in the porcine kidney. Urology 81:679–684, 2013.
Kingham, T. P., et al. Ablation of perivascular hepatic malignant tumors with irreversible electroporation. J. Am. Coll. Surg. 215:379–387, 2012.
Charpentier, K. P. Irreversible electroporation for the ablation of liver tumors: are we there yet? Arch. Surg. 147:1053–1061, 2012.
Lee, E. W., C. T. Loh, and S. T. Kee. Imaging guided percutaneous irreversible electroporation: ultrasound and immunohistological correlation. Technol. Cancer Res. Treat. 6:287–293, 2007.
Rubinsky, B., G. Onik, and P. Mikus. Irreversible electroporation: a new ablation modality—clinical implications. Technol. Cancer Res. Treat. 6:37–48, 2007.
Lee, E. W., et al. Advanced hepatic ablation technique for creating complete cell death: irreversible electroporation. Radiology 255:426–433, 2010.
Ricke, J., et al. Irreversible electroporation (IRE) fails to demonstrate efficacy in a prospective multicenter phase II trial on lung malignancies: The ALICE trial. Cardiovasc. Interv. Radiol. 38:401–408, 2015.
Daniels, C., and B. Rubinsky. Electrical field and temperature model of nonthermal irreversible electroporation in heterogeneous tissues. J. Biomech. Eng. Trans. ASME 2009. doi:10.1115/1.3156808.
Arena, C. B., M. B. Sano, M. N. Rylander, and R. V. Davalos. Theoretical considerations of tissue electroporation with high-frequency bipolar pulses. IEEE Trans. Biomed. Eng. 58:1474–1482, 2011.
Golberg, A., B. G. Bruinsma, B. E. Uygun, and M. L. Yarmush. Tissue heterogeneity in structure and conductivity contribute to cell survival during irreversible electroporation ablation by “electric field sinks”. Sci. Rep. 5:8485, 2015.
Gabriel, S., R. Lau, and C. Gabriel. The dielectric properties of biological tissues: II. Measurements in the frequency range 10 Hz to 20 GHz. Phys. Med. Biol. 41:2251, 1996.
Bhonsle, S. P., C. B. Arena, D. C. Sweeney, and R. V. Davalos. Mitigation of impedance changes due to electroporation therapy using bursts of high-frequency bipolar pulses. Biomed. Eng. Online 2015. doi:10.1186/1475-925X-14-S3-S3.
Arena, C. B., et al. High-frequency irreversible electroporation (H-FIRE) for non-thermal ablation without muscle contraction. Biomed. Eng. Online 2011. doi:10.1186/1475-925X-10-102.
Weaver, J. C., K. C. Smith, A. T. Esser, R. S. Son, and T. Gowrishankar. A brief overview of electroporation pulse strength-duration space: a region where additional intracellular effects are expected. Bioelectrochemistry 2012. doi:10.1016/j.bioelechem.2012.02.007.
Sano, M. B., C. B. Arena, M. R. DeWitt, D. Saur, and R. V. Davalos. In-vitro bipolar nano- and microsecond electro-pulse bursts for irreversible electroporation therapies. Bioelectrochemistry 100:69–79, 2014.
Kotnik, T., and D. Miklavčič. Theoretical evaluation of voltage inducement on internal membranes of biological cells exposed to electric fields. Biophys. J. 90:480–491, 2006.
Tsong, T. Y. On electroporation of cell membranes and some related phenomena. J. Electroanal. Chem. Interfacial Electrochem. 299:271–295, 1990.
Arena, C. B., C. S. Szot, P. A. Garcia, M. N. Rylander, and R. V. Davalos. A three-dimensional in vitro tumor platform for modeling therapeutic irreversible electroporation. Biophys. J. 103:2033–2042, 2012.
Sano, M. B., et al. Bursts of bipolar microsecond pulses inhibit tumor growth. Sci. Rep. 2015. doi:10.1038/srep14999.
Sano, M. B., et al. Towards the creation of decellularized organ constructs using irreversible electroporation and active mechanical perfusion. Biomed. Eng. Online 9:83, 2010.
Edd, J. F., L. Horowitz, R. V. Davalos, L. M. Mir, and B. Rubinsky. In vivo results of a new focal tissue ablation technique: irreversible electroporation. IEEE Trans. Biomed. Eng. 53:1409–1415, 2006.
Miklavčič, D., D. Šemrov, H. Mekid, and L. M. Mir. A validated model of in vivo electric field distribution in tissues for electrochemotherapy and for DNA electrotransfer for gene therapy. Biochim. Biophys. Acta Gen. Subj. 1523:73–83, 2000.
Hjouj, M., and B. Rubinsky. Magnetic resonance imaging characteristics of nonthermal irreversible electroporation in vegetable tissue. J. Membr. Biol. 236:137–146, 2010.
Neal, R. E., et al. In vivo irreversible electroporation kidney ablation: experimentally correlated numerical models. IEEE Trans. Biomed. Eng. 62:561–569, 2015.
Neal, R. E., et al. In vivo characterization and numerical simulation of prostate properties for non-thermal irreversible electroporation ablation. Prostate 74:458–468, 2014.
Makower, R., and S. Schwimmer. Inhibition of enzymic color formation in potato by adenosine triphosphate. Biochem. Biophys. Acta 14:156–157, 1954.
Ivorra, A., L. Mir, and B. Rubinsky. Electric field redistribution due to conductivity changes during tissue electroporation: experiments with a simple vegetal model. In: World Congress on Medical Physics and Biomedical Engineering, 7–12 September 2009, Munich, Germany. Berlin: Springer, 2010, pp. 59–62.
Edd, J. F., and R. V. Davalos. Mathematical modeling of irreversible electroporation for treatment planning. Technol. Cancer Res. Treat. 6:275–286, 2007.
Bonakdar, M., E. L. Latouche, R. L. Mahajan, and R. V. Davalos. The feasibility of a smart surgical probe for verification of IRE treatments using electrical impedance spectroscopy. IEEE Trans. Biomed. Eng. 62:2674–2684, 2015.
Yao, C., et al. Bipolar microsecond pulses and insulated needle electrodes for reducing muscle contractions during irreversible electroporation. IEEE Trans. Biomed. Eng. 2017. doi:10.1109/TBME.2017.2690624.
Deodhar, A., et al. Irreversible electroporation near the heart: ventricular arrhythmias can be prevented with ECG synchronization. Am. J. Roentgenol. 196:W330–W335, 2011.
Dunki-Jacobs, E., P. Philips, and I. Martin. Evaluation of thermal injury to liver, pancreas and kidney during irreversible electroporation in an in vivo experimental model. Br. J. Surg. 101:1113–1121, 2014.
Acknowledgments
This work was supported in part by the NSF through GRFP, STTR 1346343 and IIP 12655105, the Virginia Center for Innovative Technology (VA-CIT) through MF13-034-LS, the NIH through R21 CA192042-01, and the DOD through the Prostate Cancer Research Program (PCRP) Postdoctoral Training Award W81XWH-15-1-0137. The authors would also like to thank the Virginia Tech Institute for Critical Technologies and Applied Sciences (ICTAS), the Virginia Tech-Knowledge Works, and the Virginia Tech Corporate Research Center (VT-CRC) for their support of this Project.
Conflicts of interest
MBS, ELL, MRD, and RVD have accepted/pending patents on IRE based technologies. All other authors have no conflicts to report.
Author information
Authors and Affiliations
Corresponding author
Additional information
Associate Editor Leonidas D. Iasemidis oversaw the review of this article.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Miklovic, T., Latouche, E.L., DeWitt, M.R. et al. A Comprehensive Characterization of Parameters Affecting High-Frequency Irreversible Electroporation Lesions. Ann Biomed Eng 45, 2524–2534 (2017). https://doi.org/10.1007/s10439-017-1889-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10439-017-1889-2