Irreversible electroporation (IRE) is a non-thermal tissue ablation modality in which electrical pulses are used to generate targeted disruption of cellular membranes. Clinically, IRE is administered by inserting one or more needles within or around a region of interest, then applying a series of short, high amplitude pulsed electric fields (PEFs). The treatment effect is dictated by the local field magnitude, which is quite high near the electrodes but dissipates exponentially. When cells are exposed to fields of sufficient strength, nanoscale "pores" form in the membrane, allowing ions and macromolecules to rapidly travel into and out of the cell. If enough pores are generated for a substantial amount of time, cell homeostasis is disrupted beyond recovery and cells eventually die. Due to this unique non-thermal mechanism, IRE generates targeted cell death without injury to extracellular proteins, preserving tissue integrity. Thus, IRE can be used to treat tumors precariously positioned near major vessels, ducts, and nerves. Since its introduction in the late 2000s, IRE has been used successfully to treat thousands of patients with focal, unresectable malignancies of the pancreas, prostate, liver, and kidney. It has also been used to decellularize tissue and is gaining attention as a cardiac ablation technique.
Though IRE opened the door to treating previously inoperable tumors, it is not without limitation. One drawback of IRE is that pulse delivery results in intense muscle contractions, which can be painful for patients and causes electrodes to move during treatment. To prevent contractions in the clinic, patients must undergo general anesthesia and temporary pharmacological paralysis. To alleviate these concerns, high-frequency irreversible electroporation (H-FIRE) was introduced. H-FIRE improves upon IRE by substituting the long (~100 µs) monopolar pulses with bursts of short (~1 µs) bipolar pulses. These pulse waveforms substantially reduce the extent of muscle excitation and electrochemical effects. Within a burst, each pulse is separated from its neighboring pulses by a short delay, generally between 1 and 5 µs. Since its introduction, H-FIRE burst waveforms have generally been constructed simply by choosing the duration of constitutive pulses within the burst, with little attention given to this delay. This is quite reasonable, as it has been well documented that pulse duration plays a critical role in determining ablation size. In this dissertation, we explore the role of these latent periods within burst waveforms as well as their interaction with other pulse parameters. Our central hypothesis is that tuning the latent periods will allow for improved ablation size with reduced muscle contractions over traditional waveforms.
After gaining a simple understanding of how pulse width and delay interact in vitro, we demonstrate theoretically that careful tuning of the delay within (interphase) and between (interpulse) bipolar pulses in a burst can substantially reduce nerve excitation. We then analyze how pulse duration, polarity, and delays affect the lethality of burst waveforms toward determining the most optimal parameters from a clinical perspective. Knowing that even the most ideal waveform will require slightly increased voltages over what is currently used clinically, we compare the clinical efficacy of two engineered thermal mitigation strategies to determine what probe design modifications will be needed to successfully translate H-FIRE to the clinic while maintaining large, non-thermal ablation volumes. Finally, we translate these findings in two studies. First, we demonstrate that burst waveforms with an improved delay structure allow for enhanced safety and larger ablation volumes in vivo. And finally, we examine the efficacy of H-FIRE in spontaneous canine liver tumors while also comparing the ablative effect of H-FIRE in tumor and non-neoplastic tissue in a veterinary clinical setting. / Doctor of Philosophy / Cancer is soon to become the most common cause of death in the United States. In 2023, approximately 2 million new cases of cancer will be diagnosed, leading to roughly 650 thousand lost lives. Interestingly, about half of newly diagnosed cancers are caught in the early stages before the disease has spread throughout the body. With effective local intervention, these patients could potentially be cured of their malignancy. Surgical removal of the tumor is the gold standard, but it is often not possible due to tumor location, patient comorbidities, or organ health status. In some instances, focal thermal ablation with radiofrequency or microwave energy can be performed when resection is not possible. These treatments entail the delivery of thermal energy through a needle electrode, which causes local tissue damage through coagulation (cooking) of the tissue. However, thermal ablation destroys tissue indiscriminately, meaning that any nearby blood vessels or neural components will also be damaged, which precludes thousands of patients from treatment each year.
Irreversible electroporation (IRE) was introduced to overcome these challenges and provide a treatment option for patients diagnosed with otherwise untreatable tumors. IRE uses pulsed electric fields to generate nanoscale pores in cell membranes, which lead to a homeostatic imbalance and cell death. Because IRE is a membrane-based effect, it does not rely on thermal effects to generate cellular injury, which allows it to be administered to tumors that are adjacent to critical tissue structures such as major nerves and vasculature.
Though IRE opened the door to treating otherwise inoperable tumors, procedures are technically challenging and require specialized anesthesia protocols. High-frequency irreversible electroporation (H-FIRE) was introduced by our group roughly a decade ago to simplify the procedure through the use of an alternate pulsing strategy. These higher frequency pulses offer several advantages such as limiting muscle contractions and reducing the risk of cardiac interference, both of which were concerns with IRE. However, H-FIRE ablations have been limited in size, and there is limited knowledge regarding the optimal pulsing strategy needed in order to maximize the ratio of therapeutic benefits to undesirable side effects like muscle stimulation and Joule heating. In this dissertation, we sought to understand how different pulse parameters affect these outcomes. Using a combination of computational, benchtop, and in vivo experiments, we comprehensively characterized the behavior of user-tunable pulse parameters and identified optimal methods for constructing H-FIRE protocols. We then translated our findings in a proof-of-principle study to demonstrate the ability of newly introduced waveform designs to increase ablation size with H-FIRE. Overall, this dissertation improves our understanding of how H-FIRE waveform selection affects clinical outcomes, introduces a new strategy for maximizing therapeutic outcomes with minimal side effects, and provides a framework for selecting parameters for specific applications.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/114233 |
| Date | 30 March 2023 |
| Creators | Aycock, Kenneth N. |
| Contributors | Department of Biomedical Engineering and Mechanics, Davalos, Rafael V., McKillop, Iain H., Tuohy, Joanne, Robertson, John L., Verbridge, Scott, Arena, Christopher Brian |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf, application/x-zip-compressed |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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