Theses and Dissertations

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    Discovery and Development Strategies of Combination Nanomedicines for Childhood Blood Cancers
    (Georgia Institute of Technology, 2023-04-17) Kelvin, James Michael ; Dreaden, Erik C. ; DeRyckere, Deborah ; Kemp, Melissa L. ; Du, Yuhong ; Xia, Younan ; Biomedical Engineering (Joint GT/Emory Department)
    Blood cancers are the most frequently diagnosed and the second deadliest of malignancies in children. Despite advances in multiagent chemotherapy that have contributed to improved survival rates, nearly half of patients who survive will suffer from treatment associated long-term toxicities, and a considerable number of patients eventually relapse with poor survival prognoses thereafter. Thus, there is an urgent and unmet clinical need to develop novel therapies that improve treatment outcomes for pediatric patients with leukemia. This Dissertation describes the discovery and development of combination nanomedicines to address this need. We integrate three distinct treatment strategies to maximize the therapeutic potential of novel drug combinations: (i) use tyrosine kinase inhibition to exploit ectopic molecular vulnerabilities; (ii) identify synergistic drug ratios that amplify tumor cell killing; and (iii) formulate therapeutic combinations in liposomal nanocarriers for intracellular delivery of constitutively synergistic drug ratios. Governing our approach is the hypothesis that the conditional delivery of synergistic drug ratios identified in vitro will result in reduced disease burden and prolonged survival in mouse models of leukemia when compared to additive or antagonistic nanoformulations. Our efforts to discover and develop synergistic nanomedicines are mirrored between studies of pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). We begin by describing results from a novel, combinatorial high-throughput drug screen in which we identified ratio-dependent synergy between a dual MERTK/FLT3 inhibitor, MRX-2843, and cytotoxic chemotherapy (vincristine) in T-cell ALL (T-ALL) or BCL-2 inhibition (venetoclax) in AML. We then used computational models to select optimal pairwise drug combinations that exhibited robust inhibition of cell expansion and conserved ratiometric synergy in T-ALL and AML lineages. We characterized pairwise drug synergy by building predictive classifiers of drug responses between MRX-2843 and venetoclax in AML cell lines, and used RNA sequencing to explore functional ontologies that undergird the mechanism of drug synergy between MRX-2843 and vincristine in T-ALL. Next, we developed a clinical-scale manufacturing method that (co-)encapsulated defined drug ratios in liposomal nanoparticles. Nanoformulations delivered intracellular drug ratios at defined stoichiometries and demonstrated synergistic activity in primary patient samples—consistent with high-throughput screens—such that nanoparticles magnified dose-dependent synergy relative to matched free drug ratios. Finally, we directly compared synergistic, additive, and antagonistic nanomedicines in a mouse model of early thymic precursor ALL (ETP-ALL). We found that increasing the dose of MRX-2843 sensitized ETP-ALL cells to vincristine chemotherapy in vivo, and that synergistic and additive nanoformulations reduced disease burden and extended survival relative to liposomal controls. Counter to the hypothesis, the additive nanoformulation most effectively controlled disease and extended survival, a finding that contextualizes the prioritization of ratiometric synergy and therapeutic efficacy in nanomedicine design. In sum, we present a systematic approach to combination drug discovery and development for novel nanomedicines in pediatric leukemias. Our findings underscore the clinical relevance of MRX-2843 in combination with venetoclax in pediatric AML and support the translation of co-formulated MRX-2843 and vincristine nanomedicines for the treatment of pediatric patients with T-ALL. Our generalizable approach may be applied to different drug combinations that treat hematologic neoplasms or other cancers.
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    Development of Additively Manufactured Molybdenum and Improvement via Lanthanum Oxide Addition
    (Georgia Institute of Technology, 2023-08-30) Hutchinson, Andrew ; Stebner, Aaron ; Kurfess, Thomas ; Neu, Richard ; Curran, David ; Mechanical Engineering
    Additive manufacturing (AM) technologies have provided an avenue for processing traditionally difficult to manufacture metals. Manufacturability of one such material, molybdenum, has remained on the forefront of challenges hindering its widespread application. In fact, the current manufacturing methods employed by Framatome to create sintering boats for fissionable fuel out of a molybdenum-lanthanum oxide alloy often result in residual stress buildup, defects, and subsequent part failure. Thus, the use of AM methods could provide a promising path to remediate the expensive operations and tooling needed to manufacture molybdenum parts. To date, work done on the additive manufacturing of molybdenum has focused on small scale parts with processes such as powder bed fusion. Novel investigation of both pure molybdenum and molybdenum alloyed with nanoparticle lanthanum oxide manufactured by a directed energy deposition – laser beam – powder blown (DED-LB-PB) AM process is presented in this work. Importantly, the discovery of process parameter sets corresponding to high densities of molybdenum is accomplished via response surface methodology experimental design. Maximum densities achieved are 96.99% and 99.87% in the pure molybdenum and alloyed molybdenum systems, respectively, thus demonstrating the capability of the DEDLB-PB method for manufacturing commercial parts with future work. Furthermore, microstructural characterization of the AM specimens produced has demonstrated the effectiveness of the nanoparticle lanthanum oxide addition to reduce grain size, reducing millimeter-tall grains to hundreds of microns. Accordingly, grain boundary cracking is reduced significantly, allowing for the creation of larger mechanical samples. The compression testing of these alloyed samples yielded an average strength of 217 MPa, further indicating the possibility of commercial part manufacturability. Chemical analysis data alluded to the loss of lanthana during the DED-LB-PB process. Dimensional stability and accuracy of parts made with the AM method showed relationships to varied parameters of laser power, scan speed, and mass flow, as well as to the addition of lanthana.
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    Methodologies for Modeling and Optimization of 2.5-D and 3-D Integration Architectures for Compute-In-Memory Applications
    (Georgia Institute of Technology, 2023-08-28) Kaul, Ankit ; Bakir, Muhannad S. ; Raychowdhury, Arijit ; Naeemi, Azad ; Datta, Suman ; Smet, Vanessa ; Dhavaleswarapu, Hemanth ; Electrical and Computer Engineering
    The objective of this research is to investigate power delivery network (PDN) and thermal management constraints in emerging 3-D heterogeneous integration (HI) architectures for compute-in-memory (CIM) applications. First, design trade-offs in the PDN of bridge-chip based 2.5-D heterogeneous platforms are investigated. It is demonstrated that including a PDN in the bridge-chip can provide significant reduction in DC-IR drop, Ldi/dt noise, and high-frequency ripple compared to the baseline. Second, a comprehensive design-space exploration of PDN design for 3-D-HI CIM hardware is presented. A methodology is proposed to evaluate and quantify trade-offs between power delivery design parameters and CIM performance metrics. Subsequently, a device-integration methodology is proposed to quantify the thermal-driven impact of integration architectures on resistive random-access memory (RRAM) reliability for CIM applications. Two 3-D-HI accelerator designs are benchmarked against monolithic 2-D and balanced integration design parameters are reported. Finally, a back-end-of-line (BEOL)-embedded chiplet integration architecture (polylithic 3-D) is proposed. Polylithic 3-D integration represents a densely integrated system divided into multiple device tiers where custom chiplets can be embedded into the back end of a primary tier with extremely efficient signaling and large bandwidth density. Design optimization strategies for PDN and thermal management in polylithic 3-D integration are presented and benchmarked against conventional 3-D integration. The potential impact of this research and potential future directions are summarized.
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    Rhythm Recreation Study To Inform Intelligent Pedagogy Systems
    (Georgia Institute of Technology, 2023-08-28) Alben, Noel ; Condit-Schultz, Nat ; Freeman, Jason ; Brown, Thackery ; Music
    Web-based intelligent pedagogy systems have great potential to provide interactive music lessons to those unable to access conventional, face-to-face music instruction from human experts. A key component of any effective pedagogy system is the expert domain knowledge used to generate, present, and evaluate the teachable content that makes up the ''syllabus'' of the system (Brusilovskiy, 1994). In this work, we investigate the application of computational musicology algorithms to devise the ''syllabus'' of intelligent rhythm pedagogy software. Many computational metrics that quantify and characterize rhythmic patterns have been proposed (Toussaint). We employ Cao et al.'s (2012) family theory of rhythms as a metric of rhythmic similarity and an entropy-based coded-element metric of rhythmic complexity (Thul, 2008). Both metrics have been shown to correlate with human judgments of rhythmic similarity and complexity. A rhythmic syllabus that uses these metrics to determine the order in which rhythmic patterns are learned will be easier for musicians to progress through. We test this hypothesis in a rhythm reproduction study hosted on a custom-designed web-based experimental interface. Our experiment consists of six individual blocks: In each block, a participant listens to five unique rhythmic patterns, which they must then reproduce by clapping into their computer's microphone. Each rhythmic pattern is two measures long on an eighth-note grid, presented at 105 BPM, and looped four times. The order and content of rhythmic patterns within each block are determined using our chosen complexity and similarity metrics. A participant completes a block when they reproduce all the rhythmic patterns of the block within the performance constraints defined by automatic performance assessment built into the experimental interface. Each of our six blocks represents key interactions: the order of the stimuli determined by our prescribed metrics, melodic information added to the rhythmic stimuli, and the presence of a visual representation of the rhythmic pattern. We also have control blocks where the patterns of each block are selected randomly without any theoretically informed metrics. Dependent variables to measure the effectiveness of the syllabus are the number of trials taken to reproduce a given rhythmic stimuli accurately. Participant reproductions are stored to afford future analyses, and the designed interface helps efficiently automate the data collection, making it more accessible for future rhythm reproduction studies. We conducted the rhythm recreation study with 28 participants across the United States, who accessed the experiment through a web-based portal. The data gathered from our experiment implies that computational music theory algorithms can contribute to creating syllabi that align with human perception. However, these results deviate from my initial predictions. Furthermore, It appears that while incorporating visual stimuli aided in learning rhythmic patterns, the introduction of pitched onsets negatively affected reproduction performance.
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    Device-level thermal management and reliability of gallium nitride and aluminum gallium nitride high electron mobility transistors
    (Georgia Institute of Technology, 2023-08-24) Hines, Nicholas J. ; Graham, Samuel ; Kumar, Satish ; Smet, Vanessa ; Choi, Sukwon ; Klein, Brianna A. ; Mechanical Engineering
    The fields of power and radio frequency (RF) electronics have experienced tremendous growth over recent years as gallium nitride (GaN) device technology is maturing. GaN high electron mobility transistors (HEMTs) are particularly well-suited for high-power and high- frequency applications due to their excellent sheet charge density and channel mobility, and the large bandgap energy of GaN. However, GaN HEMTs suffer from acute self-heating that limits their performance in high-power and high-frequency applications. The most recent advancements in GaN HEMT device-level thermal management consist of integrating high-thermal conductivity CVD diamond substrates to GaN HEMT device layers (GaN-on-diamond technology). While the thermal merits for CVD diamond substrate integration are clear, the structural integrity and reliability of GaN-on-diamond HEMTs requires further investigation. To study the structural impact that CVD diamond integration has on GaN HEMTs, GaN-on-diamond materials fabricated by various techniques have been examined via optical stress metrology techniques. Ultra-wide bandgap (UWBG) aluminum gallium nitride (AlGaN) HEMTs have the potential to exceed the performance limitations of GaN HEMTs for the next generation of power and RF electronic device technologies. The acute self-heating challenges for high-power GaN HEMTs are exacerbated for AlGaN HEMTs because the thermal conductivity of AlGaN is an order of magnitude lower than that of GaN. The low thermal conductivity of AlGaN increases the device thermal resistance of AlGaN HEMTs and changes the transient thermal dynamics of AlGaN HEMTs under pulsed-mode operation. Therefore, AlGaN HEMT devices require novel device- level thermal management solutions to realize their theoretical performance potential. To address the thermal management challenges, novel device-level thermal management approaches have been identified via thermal finite element analysis (FEA) and in situ junction temperature experiments.