With the electronic equipments becoming more and more complicated, the requirements for the power management are more and more strict. Efficient performance, high functionality, small profile, fast transient and low cost are the most wanted features for modern power management ICs, especially for mobile power. In order to reduce profile, the number of external components should be as small as possible, which means that compensator, ramp compensation, current sensor, driver and even power devices should be all implemented on a single chip, i.e. monolithic integration. Comparing with discrete switching DC-DC converter, monolithic integration brings a number of benefits and new design challenges. Besides monolithic integration, high switching frequency is another trend for power management ICs due to its higher bandwidth and the ability to further reduce external passive component size. Comparing with low frequency counterparts, high frequency switching converter design is more difficult in terms of the stability modeling, high switching loss and difficult current sensing etc. The objective of this dissertation is to study the design issues for monolithic integration of high frequency switching DC-DC converter. For this purpose, a high frequency, wide input range monolithic buck converter ASIC with fast transient response is designed based on advanced trench BCD technology. Stability is the fundamental requirement in designing switching converter ASIC. Achieving this requires an accurate loop gain design, especially for monolithically integrated high frequency switching converter since compensator is fixed on silicon and loop delay is comparable with switching cycle. Since DC-DC switching converters are time-varying system, traditional small signal analysis in SPICE cannot be directly used to simulate the loop gain of this kind of system. A periodic small signal analysis based method is proposed to analyze and simulate DC-DC switching converter inside a SPICE like simulator without the need for averaging. This general method is suitable for any switching regulators. The results are accurate comparing with average modeling and experiment results even at high frequency part. A general procedure to design loop gain is proposed. Several novel design concepts are proposed for monolithic integration of high frequency switching DC-DC converter; a novel control scheme-Cotangent Control (Ctg control) is proposed for fast transient response; In order to realize on-chip implementation of the compensator, especially for low frequency zero, active feedback compensator is developed and a general design procedure is proposed. Adaptive compensation concept is proposed to stabilize the whole system for a wide application range. Multi-stage driver and multi-section device concepts are investigated for high efficiency and low noise power stage design. And finally, a new noise insensitive lossless RC sensor is proposed for high speed current sensing. At the end of this dissertation, the test results of the fabricated chip are presented to verify the correctness of these design concepts. / Ph. D.

Paralleling operation of DC/DC converters is widely used in today's distributed power systems. To ensure balanced output currents among paralleled power modules, current sharing control is usually necessary.Active current sharing controls with current feedback mechanism are widely used in today's power supplies. However, the dynamic performance of these current sharing control schemes are not yet clearly explored. In this work, the dynamic current sharing performance is evaluated for paralleling systems with the output impedance approach. As the representative of the terminal characteristic of a power converter, output impedance is a powerful tool to study the dynamic response under load transients. The dynamic current sharing analyses are then conducted for three different active current sharing control structures and a comprehensive comparison among them helps the designer to choose appropriate controls for different applications. On the other hand, high-frequency load transients are possible to happen for voltage regulators, which are the power supplies of microprocessors. In order to study the dynamic current sharing performance for a paralleling system when the perturbation frequency is higher than half of the switching frequency,the conventional output impedance concept needs to be extended. Due to the non-linear behavior of a switching modulator, the beat-frequency phenomenon could cause unexpected failure of a power supply when the perturbation frequency is close to the switching frequency. To address this issue, an unconventional multi-frequency model is proposed for high-frequency dynamic current sharing studies. With this model, the sideband components are possible to be included and the beat-frequency oscillations can be predicted. After that, the conventional impedance concept is expanded in the form of extended describing function, so that the terminal characteristics of paralleled converters are represented by a series of impedances. Besides the analyses, this work also proposed several solutions for the beat-frequency oscillation issue which are experimentally verified. In summary, both low-frequency and high-frequency dynamic current sharing performances are studied in this dissertation. The output impedance concept and its extension in the form of extended describing function are utilized as the tools for researches. With these powerful tools, more insights are obtained to help better design of a paralleling system. / Ph. D.

Irreversible electroporation (IRE) is an energy directed focal ablation technique. This procedure typically involves the placement of two or more electrodes into, or around, a region of interest within the tissue and administering a sequence of short, intense, pulsed electric fields (PEFs). The application of these PEFs results in an increase in the transmembrane potential of all cells within the electric field above a critical value, destabilizing the lipid bilayer of the cellular membrane and increasing the cell-tissue permeability. For years, many have used this phenomenon to assist the transport of macromolecules typically unable to penetrate the cell membrane with the intent of avoiding cell necrosis or irreversible electroporation. More recently, however, irreversible electroporation has proven to be a successful alternative for the treatment of cancer. Proper tuning of the pulse parameters has allowed for a targeted treatment of localized tumors, and has shown immense value in the treatment of surgically inoperable tumors located near major blood vessels and nerves. While it is critical to ensure sufficient treatment of the target tissue, it can be equally vital to the treatment and patients overall outcome that the pulsing conditions are set to moderate the associated thermal effects with the electroporation of biological tissue. The development of thermal mitigation strategies for IRE treatment is the focus of this dissertation. Herein, the underlying theory and thermal considerations of tissue electroporation in various scenarios are described. Additionally, new thermal mitigation approaches with the intention of maintaining tissue temperature below a thermally damaging threshold, while also preserving or improving IRE lesion volume are detailed. Further, numerical models were developed and ex vivo tissue experiments performed using a perfused organ model to examine three thermal mitigation strategies in their ability to moderate temperature. Tests conducted using thermally mitigating treatment delivery on live tissue confirm the capacity to deliver more energy to the tissue at a thermally acceptable temperature, and provide the potential for a replete IRE lesion. / Doctor of Philosophy / Irreversible electroporation (IRE) is a minimally invasive therapy utilized to treat a variety of cancers. This procedure involves the delivery energy in the form of pulsed electric fields (PEFs) through two or more needle electrodes. These PEFs destabilize the cell membrane, increase the cell-tissue permeability, and ultimately induce cell death for any given cell within the targeted treatment region. Over the years, this treatment modality has shown a great deal of promise in the treatment of unresectable tumors in which the tumor is positioned near or around sensitive regions making the surgical removal of the tumor impossible and thermal ablation techniques limited in their ability to treat without irrevocably damaging the underlying tissue architecture and other critical surrounding structures. Thus, it can be vital to the treatment and patients overall outcome that the IRE therapy is set to moderate any associated thermal effects with the electroporation of biological tissue. However, the design of an electric field that simultaneously maps the entire region of interest for a single treatment and avoids undesirable thermal effects can be challenging when treating larger or irregularly shaped volumes of tissue. Thus, in this dissertation, we demonstrate various treatment delivery methods/ enhancements to reduce temperature rise during IRE therapy. The underlying theory of tissue electroporation and associated thermal considerations are described to provide a foundation and general context. Additionally, novel approaches to tissue electroporation therapy with the intention of maintaining tissue temperature below a thermally damaging threshold throughout treatment are detailed.

Because of the increasing emphasis on environmental concerns, there has been a growing demand for lower fuel consumption in modern transportation applications. To reduce fuel comsumption, higher efficiency, higher power density power converters are desired. The new generation of wide bandgap (WBG) power semiconductor devices pushs the switching frequency and output power of the electric system in transportation to a higher level thanks to their higher blocking voltage, higher operating frequency, and smaller parasitic elements. With benefits such as size reudcetion, costs saving, and reliability improvement, integration technologies have been widely adopted in power electronic systems, especially with the emergence of WBG semiconductor devices. These improvements will futher translate into reduced fuel consumption, extended operating range, and increased passenger compartment. Transportation applications pose a challenging environment for converter integration. The fast switching speed and the high blocking voltage of WBG semiconductor devices also put forward higher requirements for converter integration. First, the power converters used in transportation applications are often powered from the batteries that support multiple loads. During load changes, crank, or jump-start, undesired transients exist, which requires the power converters to be capable of operating under a wide-input-voltage range. This requirement results in a very limited design region of acceptance, making the converter hard to handle uncertainties. However, the integration process might bring large uncertainties, such as material property changes. This phenomenon can degrade converter performance or even cause design failures. Besides, the power converters for transporation applications often work in harsh environment, such as high ambient temperature or low air density. The former can lead to overheated and the latter degrades insulation strength, both of which hinder high power density design. Moreover, with the advent of all kinds of portable devices, converters are required to deliver more power. The introduction of universal serial bus (USB) power delivery (PD) extends the delivered power. To meet the specification, the power converters should provide a wide-output-voltage range, which brings challenges to the converter design. Furthermore, the charger is usually fed by an ac voltage of more than 100 V, which is then stepped down to 5 V – 20 V. The high step-down ratio increases the converter loss. To address the wide-input-voltage and high-temperature challenges, a dual-output, PCB-embedded transformer based active-clamp Flyback (ACF) gate-drive power supply (GDPS) for automotive applications is proposed. It has been demonstrated that the PCB-embedding technique effectively improves converter power density. The final prototype achieves a power density of 53.2 W/in3, a peak efficiency of 89.7 %, a transformer input-output capacitance of 9.7 pF, an input-voltage range of 9.9 V – 28 V, and a maximum operating temperature at low-line (LL) voltage of 105 °C and 115 °C at high-line (HL) voltage. Yet the above unit failed to meet all of the design targets due to the material property degradation in transformer. This degradation is caused by the mechanical stress induced in the integration process. To investigate its impact on wide-input-voltage converter design, several PCB-embedded magnetic boards are fabricated with different core materials and stress levels. Based on the analysis, experimentally derived correction factors are proposed and applied to the models used in the multi-objective optimization (MDO) process. The improved design successfully achieves the targeted wide-input-votlage range. When aircrafts climb during flight, air density reduces and the breakdown voltage decreases correspondingly. The insulation design becomes a challenge for the gate driver for SiC-based airborne applications. To provide sufficient insulation strength and achieve high power density simultaneously, a Paschen curve based insulation co-ordination is proposed. Electric-field control methodology is applied to the layout design. By properly designing the field control plates, the peak electric field has been shifted from the air to fr4 material that features much higher dielectric strength. The proposed gate driver attains a small size of 128.7 mm × 61.2 mm × 23.8 mm. Partial discharging tests are conducted in an altitude chamber. The experimental result shows that the proposed gate driver provides sufficient insulation strength at 50, 000 ft. To tackle the wide-output-voltage range and high-step-down ratio challenges in the USB-C PD charger in airborne applications, a LLC converter with PCB-winding based transformer with built-in leakage inductance is presented. A flying-capacitor based voltage divider (FCVD) switching bridge is proposed to replace the conventional half-bridge or full-bridge switching bridge. The propsed FCVD shows a current reduction of over 50 % than the conventional half-bridge with the same circuit elements. The prototype achieves a high efficiency of 90.3 % to 93.2 % over 5 V to 20 V outputs, and a high power density of 73.2 W/ in³, which is almost two time larger than the state-of-the-art power density. Partial discharging tests are also conducted in an altitude chamber. A partial discharing inspection voltage of 800 V is found at 10, 000 ft, which is much higher than the requirement. / Doctor of Philosophy / Because of the increasing emphasis on environmental concerns, there has been a growing demand for lower fuel consumption in modern transportation applications. The new generation of wide bandgap (WBG) power semiconductor devices and various integration technologies enable electronic systems in transportation to achieve higher efficiency and higher power density. These improvement will futher translate into reduced fuel consumption, extended operating range, and increased passenger compartment. However, transportation applications put more requirements on power converter designs. This dissertation, therefore, focusing on addressing the integration challenges in high power density WBG-based circuits for transportation applications from the aspects of wide-input-voltage range, material properties degradation, harsh environment, and wide-output-voltage range together with high step-down ratio. To meet the wide-input-voltage and high temperature requirements in automotive applications, a dual-output, PCB-embedded transformer based active-clamp Flyback (ACF) dc-dc converter is proposed. The final prototype achieves a power density of 53.2 W/in3, a peak efficiency of 89.7 %, a transformer input-output capacitance of 9.7 pF, an input-voltage range of 9.7 V â€" 28 V, and a maximum operating temperature at low-line (LL) voltage of 105 °C and 115 °C at high-line (HL) voltage. Yet the above unit failed to meet all of the design targets due to the material property degration in PCB-embedded transformer. This degradation is caused by the mechanical stress during integration process. To investigate its impact on automotive converter, several PCB-embedded magnetic boards are fabricated with different core materials and stress levels. Based on the analysis, experimentally derived correction factors are proposed and applied to the models used in the multiobjective optimization process. The improved design successfully achieves the targeted wide-input-votlage range. When aircrafts climb during flight, air density reduces and thus insulation strength decreases correspondingly. Instead of using oversized altitude correction factors provided by IEC standards, a Paschen curve based insulation co-ordination is proposed. Electric-field control methodology is applied to the gate driver layout. The proposed gate driver attains a small size of 128.7 mm × 61.2 mm × 23.8 mm. Partial discharging test is conducted in an altitude chamber. The experimental result shows that the proposed gate driver provide sufficient insulation strength at 50, 000 ft. To tackle the wide-output-voltage range and high-step-down ratio challenges in the USB-C PD charger in airborne applications, a LLC converter with PCB-winding based transformer with built-in leakage inductance is presented. A flying-capacitor-based voltage divider (FCVD) switching bridge is proposed to replace the conventional half-bridge or full-bridge switching bridge. The propsed FCVD shows a current reduction of over 50 % than the conventional half-bridge with the same circuit design. The prototype achieves a high efficiency of 90.3 % to 93.2 % over 5 V to 20 V outputs, and a high power density of 73.2 W/ in3, which is more than two time larger than the state-of-the-art power density. Partial discharging tests are also conducted in an altitude chamber. A partial discharing inspection voltage (PDIV) of 800 V is found at 10, 000 ft, which is much higher than the requirement.

A high frequency impedance-based qualitative non-destructive evaluation (NDE) technique has been successfully applied for structural health monitoring at the Center for Intelligent Material Systems and Structures (CIMSS) [1-3]. This new technique uses piezoceramic (PZT) patches as actuator-sensors to provide a low-power driven constant voltage dynamic excitation, and to record the modulated current flow through the structure. Therefore, it relies on tracking the electrical point impedance to identify incipient level damage. The high frequency excitation provided by the PZT, ensures the detection of minor changes in the monitored structure. It also limits the sensing area to a region close to the PZT source, therefore only changes in the near field of the PZT are detected, enhancing the ability of this technique to localize incipient damage. The phenomena of the PZT's sensing region localization has been the driving motivation for this research. More fundamental analytical research should be performed before full application of this technique is possible. Thereby, a wave propagation continuum mechanics based approach has been applied to model the high frequency vibrations of one dimensional structures. Energy dissipation mechanisms, such as bolted connections and internal friction, are considered to have a major role in the attenuation of the PZT's induced wave, therefore these mechanisms has been extensively studied. To analyzed bolted connections, linear and nonlinear joint models have been used to describe the wave interaction with such nonconservative discontinuities. Also, with the use of an impedance based model, the electromechanical coupling of the PZT and the host structure is added into the formulation. The wave interaction and energy dissipated at the bolted discontinuity has been assessed with energy flux computations of the incident, transmitted, and reflected waves. The effect of loosening the bolted joint has been also analyzed by reducing the spring stiffness and increasing the damping in the dash pots for the linear joint model, and reducing the Coulomb stiffness and shearing force at the interface for the nonlinear case. A scheme based on the correspondence principle has been applied to calculate the specific damping capacity of a system, at any given frequency, as a quantification of the energy dissipated through the system. The material damping was added into the formulation assuming the modulus to have a complex representation, and therefore the corresponding loss factors were found with active measurement of the material properties of the specimen via a wave propagation method, that monitories the wave's speed at two locations. Once the bases of the analytical model have been set up and corroborated with experiments, a parametric study has been developed to account for the various factors that can affect the sensing range of the PZT’s induced wave, and therefore to have a “rule of thumb on how to go about” when bonding PZTs to structures to monitor them. Apart from the energy dissipation mechanisms, other parameters responsible for the reflection of the incoming wave, and its consequent attenuation, has also been reconstructed. With the extensive analysis of these parameters, an impedance damage metric, based on the undamaged and damaged impedance, has been developed for various factors that can be the source of incipient damage. An attenuation metric has also been introduced to identify the degree of transmission of the propagating wave at certain discontinuities. The analysis of the case scenarios reproduced in this parametric study will aid in the knowledge about the number of PZTs needed to be placed in the monitored structure, the most critical locations, and when a monitored member in a system need to be replaced. / Ph. D.

Advanced power semiconductor devices have consistently proven to be a major force in pushing the progressive development of power conversion technology. The emerging wide-band-gap (WBG) material based power semiconductor devices are considered as gaming changing devices which can exceed the limit of silicon (Si) and be used to pursue groundbreaking high-frequency, high-efficiency, and high-power-density power conversion. The switching performance of cascode GaN HEMT is studied at first. An accurate behavior-level simulation model is developed with comprehensive consideration of the impacts of parasitics. Then based on the simulation model, detailed loss breakdown and loss mechanism analysis are studied. The cascode GaN HEMT has high turn-on loss due to the reverse recovery charge and junction capacitor charge, and the common source inductance (CSI) of the package; while the turn-off loss is extremely small attributing to unique current source turn off mechanism of the cascode structure. With this unique feature, the critical conduction mode (CRM) soft switching technique is applied to reduce the dominant turn on loss and significantly increase converter efficiency. The switching frequency is successfully pushed to 5MHz while maintaining high efficiency and good thermal performance. Traditional packaging method is becoming a bottle neck to fully utilize the advantages of GaN HEMT. So an investigation of the package influence on the cascode GaN HEMT is also conducted. Several critical parasitic inductance are identified, which cause high turn on loss and high parasitic ringing that may lead to device failure. To solve the issue, the stack-die package is proposed to eliminate all critical parasitic inductance, and as a result, reducing turn on loss by half and avoiding potential failure mode of the cascode GaN device effectively. Utilizing soft switching and enhanced packaging, a GaN-based MHz totem-pole PFC rectifier is demonstrated with 99% peak efficiency and 700 W/in3 power density. The switching frequency of the PFC is more than ten times higher than the state-of-the-art industry product while it achieves best possible efficiency and power density. Integrated power module and integrated PCB winding coupled inductor are all studied and applied in this PFC. Furthermore, the technology of soft switching totem-pole PFC is extended to a bidirectional rectifier/inverter design. By using SiC MOSFETs, both operating voltage and power are dramatically increased so that it is successfully applied into a bidirectional on-board charger (OBC) which achieves significantly improved efficiency and power density comparing to the best of industrial practice. In addition, a novel 2-stage system architecture and control strategy are proposed and demonstrated in the OBC system. As a continued extension, the critical mode based soft switching rectifier/inverter technology is applied to three-phase AC/DC converter. The inherent drawback of critical mode due to variable frequency operation is overcome by the proposed new modulation method with the idea of frequency synchronization. It is the first time that a critical mode based modulation is demonstrated in the most conventional three phase H-bridge AC/DC converter, and with 99% plus efficiency at above 300 kHz switching frequency. / Ph. D. / Power electronics and power conversion are enabling technologies for almost any applications that are powered by electricity. It is very widely used in consumer electronics, household and industrial appliances, automobiles, utilities, infrastructures, and etc. It is essential but at the same time people want it to be invisible. Therefore the development of power electronics is consistently moving toward high efficiency (less and less energy waste), high density (small volume and less weight), high reliability, and low cost. Thanks to the development of silicon (Si) based semiconductor technology, especially silicon based power semiconductor devices, a great amount of achievements had been made in last three decades. However such high speed progress probably cannot be maintained for any longer since Si-based power devices are approaching their glass ceiling (theoretical limit) of what can be ultimately achieved. That is why people are looking for power devices made with material different than Si but with greater potential. Gallium Nitride (GaN) and Silicon Carbide (SiC) based power devices are chosen due to its great potential. It is believed to outperform Si-based devices by 2-3 orders which means power converters made with GaN and/or SiC can be even more efficient, smaller and lighter, more reliable, and of course with less cost. The most important approach to achieve such objective is high switching frequency. In order to turn the vision into reality, there are a lot of technology barriers in front of us, which in summary are how to understand the device and how to use the device into real applications with efficient high frequency operation. Therefore the major achievement of this work is comprehensive evaluation of GaN devices, and then demonstration of GaN and SiC in several AC/DC power converters for different applications. In the evaluation of GaN devices, an accurate simulation model was built and verified. Then based on the assistance of the model, switching loss mechanism is elaborated. The major conclusion is GaN has large turn on loss and very small turn off loss so that soft switching, which at least achieves zero-voltage-switching (ZVS) turn on, is important for GaN. Packaging related issues are addressed as well including analysis of package impacts on device performance and a new proposal of advanced package. It is very proud to claim that the proposal now are widely used by GaN device manufacturers into their real commercial products. After the know-how of how to use GaN was built, the potential of GaN was demonstrated in several different applications. The focus of this dissertation is on its application in AC/DC rectifier/inverter. Critical mode based totem-pole rectifier/inverter were built for 1 kW server power, 6.6 kW on board charger, and 25 kW solar inverter. A series of challenges were identified and the corresponding solutions were proposed. Today, the proposed design is becoming a benchmark and many of the industrial people are adopting our technology and applying it into real high performance products.

Meteors enter earth's atmosphere with a great amount of kinetic energy. As a result of this atmospheric contact, many meteors will be burned up before they can make it to earth's surface, but not before they cause atmospheric disturbances. The SuperDARN HF radar is designed to measure the ionosphere, typically to create hemisphere wide maps of ionospheric plasma convection, but meteor events are attributed to noise experienced in its data. This thesis first brings together plasma physics understanding with currently available research to clarify the physical behaviors that must be considered to evaluate radar data. The implications of this towards SuperDARN findings is examined in two parts. First, how a meteor's atmospheric interaction is recorded by the SuperDARN HF radar is evaluated. To do this, the physical interaction the meteor has with the atmosphere is examined from the sub-atomic to atmospheric scale. Previous research that used other radars to find these interactions is analyzed to create an understanding of a possible SuperDARN HF radar outcome and provide a new comparison of radars. This understanding is compared against meteor event and location based SuperDARN data to select an optimal event. The second part of the SuperDARN analysis reviews meteor event options based on the time and location of a meteor event meeting defined parameters. Common SuperDARN analysis tools are applied. The data saved by SuperDARN is examined for unique results. Finally, the practicality and meaning of results is considered. / Master of Science / SuperDARN radars emits radio waves that reflect within earth's ionosphere to study how it changes. The ionosphere is a part of earth's upper atmosphere; many of the atoms there are hydrogen and helium. Lower in earth's atmosphere, the sun's energy is just felt as heat that gets dissipated at night or when clouds move in front of the sun. In the thin upper atmosphere, this energy does not transfer as easily, so the atoms ionize to store energy as charge. This can occur lower down in earth's atmosphere, such as when a hypersonic traveling meteor impacts the air with a lot of energy. This ionized trail of atoms behind a meteor is called a meteor trail. Just as the ionosphere can reflect some radio waves, meteor trails can reflect radio waves. It was questionable how well these reflections could be found in SuperDARN data since that radar looks over a large area and meteor trails are comparatively small. This research seeks to answer that. Current research on meteor trails and analysis with radar was analyzed along with a review of the underlying physics concepts involved. Once this background is established, actual SuperDARN radar data is analyzed for a time and place that gives the best chance of seeing some change as a result of a meteor trail.

Glioblastoma (GBM) is the most common adult malignant glioma (MG) variant, and the median survival of persons with GBM is about 2 years, even with aggressive treatments. Dogs and humans are the only species in which brain tumors commonly develop spontaneously, with an estimated post-mortem frequency of primary brain tumors approximating 2% in both species. Gliomas represent about 35% of all canine primary brain tumors, with high-grade oligodendroglioma and astrocytoma phenotypes accounting for about 70% of all canine gliomas. Canine gliomas are also treated using surgical, radiotherapeutic, and chemotherapeutic regimens similar to those used in humans. The efficacy of these therapies in dogs with MG is also poor, with median survival times ranging from 3-8 months, which closely mirrors the dismal prognosis associated with human GBM. Thus, treatment of MG represents a current and critically unmet need in both human and veterinary medicine. In this work, we investigate minimally invasive methods to access the brain for the purposes of ultimately improving the diagnosis and treatment of malignant brain tumors. Chapter 1 reviews the current clinical challenges associated with the treatment of GBM, highlights the value of using the spontaneous canine glioma model in translational brain tumor studies, and introduces High-Frequency Irreversible Electroporation (H-FIRE) and Convection Enhanced Delivery (CED), which are two novel treatment platforms for GBM being developed in our lab. In Chapter 2, we demonstrate that definitive diagnosis of brain tumors, a critical first step in patient management, can be safely and accurately performed in dogs with naturally occurring brain tumors using a stereotactic brain biopsy procedure. Chapter 3 evaluates the in vivo safety and biocompatibility of fiberoptic microneedle devices, a major technical component of our convection-enhanced thermotherapy catheter system (CETCS), chronically implanted in the rodent brain. The CETCS is a novel technology being developed and used in our laboratory to improve the delivery of drugs to brain tumors using CED. This study provides regulatory data fundamental to the commercialization of the CETCS device for brain tumor treatment by illustrating that the device did not cause clinically significant neurological complications and resulted in mild pathologic changes in brain tissue, similar to other types of devices designed and approved for use in the brain. In Chapters 4 and 5 we explore possible bystander effects of H-FIRE on glutamate metabolism in the brain. H-FIRE has been shown to be able to both ablate brain tumors as well as disrupt the blood-brain barrier (BBB). As these therapeutic effects of H-FIRE are dependent on applying electrical fields to the tissue that either reversibly permeabilize the cell membrane, allowing treated cells to survive, or permanently disrupt the structure of the cell membrane, causing cell death, we hypothesized that altering the membrane permeability with HFIRE would increase the extracellular glutamate concentrations and contribute to excitotoxic brain tissue damage. Chapters 4 used in vitro brain cell culture systems and in vivo experiments in normal and glioma-bearing rat brains to determine if glutamate release in the brain occurs as a bystander effect following H-FIRE treatment, identify concentrations of glutamate necessary to induce death of cells or BBB disruption, and characterize glutamatergic gene expression in response to H-FIRE treatment. Chapter 5 describes the use of magnetic resonance spectroscopic and spatial transcriptomic methods to further quantify the in vivo effects of H-FIRE treatment on glutamate release and metabolism in dogs with spontaneous brain tumors. The in vitro results indicated that the magnitude of glutamate release following H-FIRE is insufficient to induce cytotoxicity in normal or neoplastic brain cell lines, and also did not increase the permeability of the BBB. In our in vivo model systems, we documented significant, transient post-H-FIRE increases in glutamate to concentrations previously associated with excitotoxicty, with upregulation of the expression of genes involved with ionotropic and metabotropic glutamatergic receptor signaling. A contemporaneous upregulation of genes associated with glutamate uptake and recycling were also noted, indicating an adaptive, protective response to the glutamate release. Our work summarily demonstrates that the diagnosis and potential treatment of malignant brain tumors can be achieved through the use of minimally invasive techniques that provide local access to brain tissue. While complications will always be possible anytime the brain is manipulated surgically, and further investigations are required to characterize the spectrum and mechanisms of adverse events that can occur following CETCS CED and H-FIRE treatment, our results support the continued development of these novel therapeutic platforms for the treatment of GBM. / Doctor of Philosophy / Glioblastoma (GBM) is the most common adult malignant glioma (MG) variant, and the median survival of persons with GBM is about 2 years, even with aggressive treatments. Dogs and humans are the only species in which brain tumors commonly develop spontaneously, with an estimated post-mortem frequency of primary brain tumors approximating 2% in both species. Gliomas represent about 35% of all canine primary brain tumors, with high-grade oligodendroglioma and astrocytoma phenotypes accounting for about 70% of all canine gliomas. Canine gliomas are also treated using surgical, radiotherapeutic, and chemotherapeutic regimens similar to those used in humans. The efficacy of these therapies in dogs with MG is also poor, with median survival times ranging from 3-8 months, which closely mirrors the dismal prognosis associated with human GBM. Thus, treatment of MG represents a current and critically unmet need in both human and veterinary medicine. In this work, we investigate minimally invasive methods to access the brain for the purposes of ultimately improving the diagnosis and treatment of malignant brain tumors. Chapter 1 reviews the current clinical challenges associated with the treatment of GBM, highlights the value of using the spontaneous canine glioma model in translational brain tumor studies, and introduces High-Frequency Irreversible Electroporation (H-FIRE) and Convection Enhanced Delivery (CED), which are two novel treatment platforms for GBM being developed in our lab. In Chapter 2, we demonstrate that definitive diagnosis of brain tumors, a critical first step in patient management, can be safely and accurately performed in dogs with naturally occurring brain tumors using a stereotactic brain biopsy procedure. Chapter 3 evaluates the in vivo safety and biocompatibility of fiberoptic microneedle devices, a major technical component of our convection-enhanced thermotherapy catheter system (CETCS), chronically implanted in the rodent brain. The CETCS is a novel technology being developed and used in our laboratory to improve the delivery of drugs to brain tumors using CED. This study provides regulatory data fundamental to the commercialization of the CETCS device for brain tumor treatment by illustrating that the device did not cause clinically significant neurological complications and resulted in mild pathologic changes in brain tissue, similar to other types of devices designed and approved for use in the brain. In Chapters 4 and 5 we explore possible bystander effects of H-FIRE on glutamate metabolism in the brain. H-FIRE has been shown to be able to both ablate brain tumors as well as disrupt the blood-brain barrier (BBB). As these therapeutic effects of H-FIRE are dependent on applying electrical fields to the tissue that either reversibly permeabilize the cell membrane, allowing treated cells to survive, or permanently disrupt the structure of the cell membrane, causing cell death, we hypothesized that altering the membrane permeability with HFIRE would increase the extracellular glutamate concentrations and contribute to excitotoxic brain tissue damage. Chapters 4 used in vitro brain cell culture systems and in vivo experiments in normal and glioma-bearing rat brains to determine if glutamate release in the brain occurs as a bystander effect following H-FIRE treatment, identify concentrations of glutamate necessary to induce death of cells or BBB disruption, and characterize glutamatergic gene expression in response to H-FIRE treatment. Chapter 5 describes the use of magnetic resonance spectroscopic and spatial transcriptomic methods to further quantify the in vivo effects of H-FIRE treatment on glutamate release and metabolism in dogs with spontaneous brain tumors. The in vitro results indicated that the magnitude of glutamate release following H-FIRE is insufficient to induce cytotoxicity in normal or neoplastic brain cell lines, and also did not increase the permeability of the BBB. In our in vivo model systems, we documented significant, transient post-H-FIRE increases in glutamate to concentrations previously associated with excitotoxicty, with upregulation of the expression of genes involved with ionotropic and metabotropic glutamatergic receptor signaling. A contemporaneous upregulation of genes associated with glutamate uptake and recycling were also noted, indicating an adaptive, protective response to the glutamate release. Our work summarily demonstrates that the diagnosis and potential treatment of malignant brain tumors can be achieved through the use of minimally invasive techniques that provide local access to brain tissue. While complications will always be possible anytime the brain is manipulated surgically, and further investigations are required to characterize the spectrum and mechanisms of adverse events that can occur following CETCS CED and H-FIRE treatment, our results support the continued development of these novel therapeutic platforms for the treatment of GBM.

High-frequency irreversible electroporation (H-FIRE) is a non-thermal ablation technique that uses intense, short, bipolar electrical pulses to induce cell death in cancerous tissues. It's being studied for treating hepatocellular carcinoma (HCC) in dogs. Previous in vitro research suggests H-FIRE may impact the release of extracellular vesicles (EVs). This study aims to explore how H-FIRE affects peripheral extracellular vesicle (EV) dynamics, potentially providing insights into its broader systemic effects and implications for biomarker development in canine liver cancer treatment. Dogs diagnosed with HCC were enrolled in a clinical trial. H-FIRE was applied to tumors, followed by surgical resection at three different time points. Peripheral blood samples were collected before and immediately after H-FIRE treatment. Plasma was isolated, aliquoted, and stored at -20°C. EVs were enriched from plasma via filtration and ultracentrifugation. Nanoparticle Tracking Analysis (NTA) quantified EV concentration and size distribution. Ten patients provided pre- and post-treatment plasma samples. The median EV concentration in peripheral blood increased from 2.56 x 10^11 particles/ml pre-treatment to 2.68 x 10^11 particles/ml post-treatment (p = 0.0048). The mean EV size decreased from 99.32 nm pre-treatment to 87.82 nm post-treatment (p = 0.007). The mode of EV size decreased from 83 nm pre-treatment to 70.5 nm post-treatment (p = 0.0076). The results of this study raise intriguing questions on the significance of changes in extracellular vesicle size and concentration post-treatment, as well as the potential clinical implications of these changes. / Master of Science / High-frequency irreversible electroporation (H-FIRE) is a new method to destroy cancer cells without using heat. It's being tested for treating liver cancer in dogs. Previous lab studies suggest H-FIRE might affect the release of small structures known as extracellular vesicles (EVs). This study aims to see how H-FIRE affects EVs in the blood of dogs with liver cancer. Understanding these changes could help develop new ways to diagnose and treat the disease in dogs and humans. Dogs with liver cancer were part of a study. They received H-FIRE treatment followed by surgery, and blood samples were taken before and right after treatment. The plasma was separated and stored. EVs were collected from plasma using special methods, including Nanoparticle Tracking Analysis (NTA) to help measure the number and size of EVs.

Switch mode power supplies are widely used in different applications. High efficiency and high power density are two driving forces for power supply systems. However, high dv/dt and di/dt in switch mode power supplies will cause severe EMI noise issue. In a typical front-end converter, the EMI filter usually occupies 1/3 to 1/4 volume of total converter. Hence, reducing the EMI noise of power converter can help reduce the volume of EMI filter and improving the total power density of the converter. The EMI noise can be separated as differential mode (DM) noise and common mode (CM) noise. For off-line switch mode power supplies, DM noise is dominated by PFC converter. CM noise is a more complicated issue. It is contributed by both PFC converter and DC/DC converter. The DM noise is contributed by input current ripple. Therefore, one method to reduce DM noise is interleaving. There are three methods to reduce CM noise: symmetry, balance and shielding. The idea of symmetry concept is generating another dv/dt source to cancel the original dv/dt source. However, this method is very difficult to achieve and usually has more loss. The balance technique forms a Wheatstone bridge circuit to minimize the CM noise. However, the balance technique cannot achieve very good attenuation at high frequency due to parasitics. Shielding technique is very popular in isolated DC-DC converters to reduce CM noise. However, the previous shielding method requires precise control of parasitic capacitance and dv/dt. It is very difficult to achieve good CM noise attenuation in mass production. In this dissertation, a novel one-layer shielding method for PCB winding transformer is provided. This shielding technique can block CM noise from primary side and also cancel the CM noise from secondary side. In addition, shielding does not increase the loss of converter too much. Furthermore, this shielding technique can be applied to matrix transformer structure. For matrix transformer LLC converter, the inter-winding capacitor is very large and will cause severe CM noise problem. By adding shielding layer, CM noise has been greatly reduced. Although flyback and LLC resonant converter are used as examples to demonstrate the concept, the novel shielding technique can also be applied to other topologies that have similar transformer structure. With Wide-band-gap power devices, the switching frequency of power converter can be pushed 10 times higher than traditional Si based converters. This provides an opportunity to use PCB winding magnetics. In order to reduce the switching loss, critical conduction mode is used in PFC converter. Because of high AC current in the inductor winding, litz wire was used to build the inductor. However, with coupled inductor concept and the proposed winding structure, CRM inductor is integrate into PCB winding for the first time. Furthermore, balance technique is applied to reduce CM noise for PFC converter. With PCB winding, the balance technique has better high frequency performance. The PCB winding inductor can achieve high power density, high efficiency and automated manufacture. Traditionally, two-stage EMI filter was utilized to achieve required EMI noise attenuation. With the developed high frequency, low EMI noise converter, single-stage EMI filter can be applied. However, there are self-parasitic and mutual parasitic components to impact the filter performance on high frequency. The near-field measurement is utilized to visualize the magnetic flux near those filter components. Thus, a better filter design and layout can be achieved to have better high frequency performance. / Ph. D. / Switch mode power supplies are widely used in different applications. High efficiency and high power density are two driving forces for power supply systems. In a world full of electronic devices, it is very important that these devices can work properly in a complicated electromagnetic environment. Thus, electromagnetic compatibility (EMC) is a significant characteristic of electronic devices. However, high dv/dt and di/dt in switch mode power supplies will cause severe EMI noise issue. In a typical front-end converter, the EMI filter usually occupies 1/3 to 1/4 volume of total converter. Hence, reducing the EMI noise of power converter can help reduce the volume of EMI filter and improving the total power density of the converter. In this dissertation, several methods to reduce EMI noise are proposed and analyzed. First, the shielding method for PCB winding transformer is proposed. It can effectively reduce EMI noise at wide frequency range. Second, balance technique is applied to reduce EMI noise of PFC converter. Traditionally, two-stage EMI filter was utilized to achieve required EMI noise attenuation. With the developed high frequency, low EMI noise converter, single-stage EMI filter can be applied. However, there are self-parasitic and mutual parasitic components to impact the filter performance on high frequency. The near-field measurement is utilized to visualize the magnetic flux near those filter components. Thus, a better filter design and layout can be achieved to have better high frequency performance.