Irreversible electroporation (IRE) is a non-thermal ablation technique that allows for eradication of unresectable tumors in a minimally invasive procedure. While IRE will preferentially kill larger cells over smaller ones, it does not discriminate between cells with larger and small nuclei. Given that one of the hallmarks of cancer cell morphology is larger, more abundant nuclei, our team set out to explore the possibility of preferentially targeting this physical and geometrical characteristic. / Master of Science

Since its conception in 2005, irreversible electroporation (IRE), a non-thermal tumor ablation modality, was investigated for safety and efficacy in clinical applications concerning different organs. IRE utilizes high voltage (~3kV), short duration (~100us) pulses to create transient nanoscale defects in the plasma membrane to cause cell death due to irreversible defects, osmotic imbalances and ATP loss. More recently, high-frequency irreversible electroporation (H-FIRE), which employs narrow bipolar pulses (~0.5-10us) delivered in bursts (on time ~100us), was invented to provide benefits such as the mitigation of intense muscle contractions associated with IRE-based treatments. Furthermore, H-FIRE exhibits the potential to improve lesion predictability in homogeneous and heterogeneous tissue masses. Therapeutic IRE and H-FIRE utilize source and sink electrodes inserted into or around the tumor to deliver the treatment. Prediction of the ablation size, for a set of parameters, can be achieved by the use of pre-treatment planning algorithms that calculate the induced electric field distribution in the target tissue. An electric field above a certain threshold induces cell death and parameters are tuned to ensure complete tumor coverage while sparing the nearby healthy tissue. IRE studies have shown that the underlying field is influenced by the increase in tissue conductivity due to enhanced membrane permeability, and treatment outcome can be improved when this nonlinearity is accounted for in numerical models. Since IRE pulses far exceed the time constant of the cell (~1us), the tissue response can be treated as essentially DC a static approximation can be used to predict the field distribution. Alternately, as H-FIRE pulses are on the order of the time constant of the membrane, the tissue response can no longer be treated as DC. The complexity of the H-FIRE-induced field distribution is further enhanced due to the dispersion and non-linearity in biological tissue impedance during treatment. In this dissertation, we have studied the electromagnetic fields induced in tissue during H-FIRE using several experimental and modeling techniques. In addition, we have characterized the nonlinearity and dispersion in tissue impedance during H-FIRE treatments and proposed simpler methods to predict the field distribution to enable easier translation to the clinic. / Ph. D. / Development within urbanized regions increase impervious surfaces, which further cause significant storm events in watersheds. The increased impervious surfaces result in hotter stormwater particularly during hot summers, which has diverse effects on aquatic health of downstream receiving streams. The main objective of the current study is to evaluate the thermal impact of urbanization on aquatic health habitats in Stroubles Creek Watershed, Blacksburg, Virginia. To aim this goal and achieve the thermal evaluation of the highly urbanized Stroubles Creek Watershed, a U.S. Environmental Protection Agency’s Storm Water Management Model (SWMM) and a Minnesota Urban Heat Export Tool (MINUHET) models from scratch of the Stroubles Creek watershed, using Town of Blacksburg and Virginia Tech Physical Facility information were developed. This necessitated combining information from a wide variety of sources, including geologic maps, geodatabases, hydraulic models, computer-aided design (CAD) files, and scanned as-built information. In addition to the models, a hybrid model was developed that combines SWMM and MINHET outputs. The temperatures and heat loads at the downstream of the watershed were predicted using SWMM, MINUHET, and Hybrid models for two summer periods of 2016 and 2015, and the predicted temperature were compared to the criteria for survival of aquatic health such as trout. Furthermore, a number of thermal mitigation strategies such as bioretentions systems, concrete pavements (which has lighter color compared to asphalt pavements), and increased vegetation canopies were simulated within the MINUHET and SWMM models configurations to reduce simulated temperatures and heat loads at the watershed scale. The simulated temperatures and heat loads represented that concrete pavements results in better performance of thermal mitigation within watersheds than bioretention systems, and increased vegetation canopies.

Brain tumors are among the most devastating types of solid tumors to treat. Standard of care for glioblastoma (GBMs), the most aggressive form of primary brain tumors, has failed to improve the current survival rates in the past decades. Despite many other solid tumors, recent advances in cancer immunotherapies have also shown disappointing outcomes in GBMs. The heterogenous nature of GBMs, the immunosuppressive tumor microenvironment and the restrictive role of blood brain barrier (BBB) are some of the main challenges faced for treating GBMs. Electroporation-based treatments have demonstrated promising results, treating preclinical models of GBMs. It has been shown that low and high frequency irreversible electroporation treatments shift the immunosuppressive tumor microenvironment and reversibly open large areas of blood brain barrier (BBB). In this dissertation, in vitro cell culture models are utilized to study electroporation-based treatments for achieving a more optimized treatment for glioblastoma. We are proposing to utilize the immunomodulatory effects of electroporation treatments to improve the outcomes of immunotherapies in the brain. / Doctor of Philosophy / Despite the current advancements in treating solid tumors, brain tumors remain among the most difficult cancers to treat. The special structure of the brain as an organ as well as tumor complexity can lead to treatment failure. It is also known that infiltration of the immune cells within the tumor mass is limited due to the tumor's immunosuppressive nature. Hence, the use of newly advancing immunotherapy techniques is limited in the brain. Local treatments have become one of the most promising tools against brain tumors. Such treatments include methods that use excessive heating of the tissue to kill the tumors. Relying on heat for tissue destruction could damage the critical structures near the tumor and will reduce the favorable immune response after the treatment. A new treatment modality known as electroporation has been introduced for non-thermal treatment of brain tumors. Due to its non-thermal nature, electroporation treatments will allow for sparing of critical structures and can lead to a more robust immune response comparing to thermal treatment modalities. In this dissertation, we utilize electroporation-based treatments to try to overcome some of the challenges associated with treating brain tumors such as tumor heterogeneity and immune suppression.