Glioblastoma Multiforme (GBM) is a highly aggressive and prevalent brain tumor with an average 5-year survival rate of approximately 6.9%. Its complex pathophysiology, characterized by the capacity to invade surrounding tissues beyond the visible tumor margin, intratumor heterogeneity, hypoxic core, and the presence of the blood-brain barrier (BBB) that restricts the penetration of large therapeutic agents, all pose formidable challenges for effective therapeutic intervention. The standard of care for GBM has thus far exhibited limited success, and patients often face a poor prognosis. Electroporation-based therapies, such as irreversible electroporation (IRE), have emerged as promising alternatives to conventional treatments. By utilizing high amplitude pulsed electric fields, IRE is able to permeabilize cells, disrupt the BBB, and induce non thermal ablation of soft tissues. However, IRE is oftentimes accompanied by undesirable secondary effects such as muscle contractions, complex anesthetic protocols, and susceptibility to electrical heterogeneities, which have impeded its clinical translation. To address these limitations, high-frequency IRE (H-FIRE) was developed. H-FIRE employs short bursts of bipolar pulses, similar in duration to the cell charging time constant, enabling the desired tissue ablation while minimizing nerve excitation and muscle contractions. Additionally, H-FIRE reduces susceptibility to electrical heterogeneities, allowing for more predictable treatment volumes, thus enhancing the feasibility of clinical translation. This dissertation investigates H-FIRE for targeting malignant gliomas while looking into improved efficacy when administering the therapy in conjunction with other treatment forms and technologies. Specifically, the presented work focuses on several key areas: (1) determining the effect of pulsing protocol and geometric configuration selection on the biological outcomes from electroporation; (2) using a tumor bearing rodent glioma model to evaluate the effects of H-FIRE as a standalone therapy and as a combinatorial therapy with liposomal doxorubicin; (3) investigating the effects of waveform shape on biological outcomes; (4) utilizing real-time Fourier Analysis SpecTroscopy (FAST) to accurately model rises in temperature during treatment; and (5) modifying real-time FAST methods to determine treatment endpoints for safe and effective ablation volumes. / Doctor of Philosophy / Glioblastoma Multiforme (GBM) is one of the deadliest tumors, with an overall five-year survival rate of approximately 6.9%. Unfortunately, it also holds the position of being the most prevalent malignant brain tumor, constituting nearly 50.1% of all primary malignant brain tumor diagnoses. Despite its widespread occurrence, there has been limited success in improving survival rates. The tumor's infiltrative nature and its location behind the blood-brain barrier (BBB), which often screens out large drug molecules like chemotherapeutics, contribute significantly to these unfavorable treatment outcomes. This dissertation explores the potential of high-frequency irreversible electroporation (H-FIRE) as a solution to these challenges. H-FIRE employs bursts of pulsed electric fields to induce nanoscale defects in the cell membrane. The response to these defects may involve temporary pores that facilitate the uptake of therapeutic molecules into the cell, or larger and longer lasting pores that disrupt cell homeostasis, ultimately leading to cell death. Furthermore, this pulsed field therapy has shown success in enabling molecules to bypass the BBB. Thus, this dissertation aims to elucidate the various biophysical phenomena associated with H-FIRE, shedding light on how to manipulate treatment protocols to maximize BBB disruption and enhance therapy when used in conjunction with combinatorial agents.
Additionally, this work aims to further develop technologies to provide real-time feedback, ensuring the safe and effective delivery of the treatment. Through these efforts, this dissertation aspires to offer valuable insights into optimizing H-FIRE for the treatment of malignant gliomas and advancing the understanding of combinatorial therapies in this specific context.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/117270 |
| Date | 21 December 2023 |
| Creators | Campelo, Sabrina Nicole |
| Contributors | Department of Biomedical Engineering and Mechanics, Davalos, Rafael V., Arena, Christopher Brian, Debinski, Waldemar, Rossmeisl, John H., Verbridge, Scott |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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