Theses and Dissertations
This collection includes both ASU Theses and Dissertations, submitted by graduate students, and the Barrett, Honors College theses submitted by undergraduate students.
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- All Subjects: Biomedical Engineering
Description
Oxygen delivery is crucial for the development of healthy, functional tissue. Low tissue oxygenation, or hypoxia, is a characteristic that is common in many tumors. Hypoxia contributes to tumor malignancy and can reduce the success of chemotherapy and radiation treatment. There is a current need to noninvasively measure tumor oxygenation or pO2 in patients to determine a personalized treatment method. This project focuses on creating and characterizing nanoemulsions using a pO2 reporter molecule hexamethyldisiloxane (HMDSO) and its longer chain variants as well as assessing their cytotoxicity. We also explored creating multi-modal (MRI/Fluorescence) nanoemulsions.
ContributorsGrucky, Marian Louise (Author) / Kodibagkar, Vikram (Thesis director) / Rege, Kaushal (Committee member) / Stabenfeldt, Sarah (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2013-05
Description
Allogeneic islet transplantation has the potential to reverse Type 1 Diabetes in patients. However, limitations such as chronic immunosuppression, islet donor numbers, and islet survival post-transplantation prevent the widespread application of allogeneic islet transplantation as the treatment of choice. Macroencapsulation devices have been widely used in allogeneic islet transplantation due to their capability to shield transplanted cells from the immune system as well as provide a supportive environment for cell viability, but macroencapsulation devices face oxygen transport challenges as their geometry increases from preclinical to clinical scales. The goal of this work is to generate complex 3D hydrogel macroencapsulation devices with sufficient oxygen transport to support encapsulated cell survival and generate these devices in a way that is accessible in the clinic as well as scaled manufacturing. A 3D-printed injection mold has been developed to generate hydrogel-based cell encapsulation devices with spiral geometries. The spiral geometry of the macroencapsulation device facilitates greater oxygen transport throughout the whole device resulting in improved islet function in vivo in a syngeneic rat model. A computational model of the oxygen concentration within macroencapsulation devices, validated by in vitro analysis, predicts that cells and islets maintain a greater viability and function in the spiral macroencapsulation device. To further validate the computational model, pO2 Reporter Composite Hydrogels (PORCH) are engineered to enable spatiotemporal measurement of oxygen tension within macroencapsulation devices using the Proton Imaging of Siloxanes to map Tissue Oxygenation Levels (PISTOL) magnetic resonance imaging approach. Overall, a macroencapsulation device geometry designed via computational modeling of device oxygen gradients and validated with magnetic resonance (MR) oximetry imaging enhances islet function and survival for islet transplantation.
ContributorsEmerson, Amy (Author) / Weaver, Jessica (Thesis advisor) / Kodibagkar, Vikram (Committee member) / Sadleir, Rosalind (Committee member) / Stabenfeldt, Sarah (Committee member) / Wang, Kuei-Chun (Committee member) / Arizona State University (Publisher)
Created2023
Description
Cellular metabolism is an essential process required for tissue formation, energy production and systemic homeostasis and becomes dysregulated in many disease states. In the context of human cerebral cortex development, there’s a limited understanding of how metabolic pathways, such as glycolysis, impacts proliferation and differentiation of cortical cells. The technical challenges of studying primary in vivo cortical tissue at a cellular and molecular level led to the development of human pluripotent stem cell (PSC) derived cortical organoids. Cortical organoids are a highly tractable model system that can be used for high-throughput investigation of early stages of development and corresponding glycolytic programs. Through transplantation of cortical organoids into the developing mouse cortex, human cortical cells can also be studied in an in vivo environment that more closely resembles endogenous development where the impact of metabolism in typical developmental programs and disease states can be studied. While current data is preliminary, initial observations suggest that cortical populations increase glucose uptake over time and regulation of glucose uptake rates occur in cell type-specific manner. Additionally, mouse transplantation data suggests that glycolytic activity is downregulated post-transplantation, suggesting that the in vitro environment contributes metabolic state. The more dynamic range of metabolic states in vivo may impact the rate of differentiation and maturation in cellular populations in the transplant model. I hypothesize that the more endogenous-like regulation of glycolysis may impact the proliferative window and expansion of key progenitor cell types in the human brain, particularly the intermediate progenitor cells.
ContributorsMorales, Alexandria (Author) / Andrews, Madeline (Thesis advisor) / Newbern, Jason (Committee member) / Stabenfeldt, Sarah (Committee member) / Arizona State University (Publisher)
Created2023
Description
APOE encodes for a lipid transport protein and has three allelic variants-APOE ε2, ε3 and ε4 each of which differentially modulate the risk for Alzheimer’s disease (AD). The presence of the ε4 allele of APOE greatly increases AD risk compared to the presence of the more prevalent and risk neutral ε3 allele. An imbalance in the generation and clearance of amyloid beta (Aβ) peptides has been hypothesized to play a key role in driving the disease. APOE4 impacts several AD-relevant cellular processes. However, it is unclear whether these effects represent a gain of toxic function or a loss of function, specifically as it relates to modulating amyloid beta (Aβ) levels. Here, a set of APOE knockout (KO) and APOE4 isogenic human induced pluripotent stem cells (hiPSCs) were generated from a parental APOE3 hiPSC line with a highly penetrant familial AD (fAD) mutation to investigate this with respect to Aβ secretion in neural cultures and Aβ uptake in monocultures of microglia-like cells (iMGLs). Conversion of APOE3 to E4 as well as functionally knocking APOE out from the APOE3 parental line, result in elevated Aβ levels in neural cultures, likely through multiple mechanisms including the altered processing of the precursor protein to Aβ called amyloid precursor protein (APP). In pure neuronal cultures, a shift in the processing of APP was observed with the Aβ-generating amyloidogenic pathway being favored in both APOE3 as well as APOE4 neurons compared to APOE KO neurons, with APOE4 neurons exhibiting a greater shift. In iMGLs derived from the isogenic hiPSC lines, expression of APOE, regardless of the isoform, lowered the uptake of Aβ. Overall, APOE4 modulates Aβ levels through distinct loss of protective and gain of function effects. Dissecting these effects would contribute towards a better understanding of the design of potential APOE-targeted therapeutics in the future.
ContributorsRajaram Srinivasan, Gayathri (Author) / Brafman, David (Thesis advisor) / Plaisier, Christopher (Committee member) / Newbern, Jason (Committee member) / Stabenfeldt, Sarah (Committee member) / Wang, Xiao (Committee member) / Arizona State University (Publisher)
Created2024
Description
Machine learning (ML) has played an important role in several modern technological innovations and has become an important tool for researchers in various fields of interest. Besides engineering, ML techniques have started to spread across various departments of study, like health-care, medicine, diagnostics, social science, finance, economics etc. These techniques require data to train the algorithms and model a complex system and make predictions based on that model. Due to development of sophisticated sensors it has become easier to collect large volumes of data which is used to make necessary hypotheses using ML. The promising results obtained using ML have opened up new opportunities of research across various departments and this dissertation is a manifestation of it. Here, some unique studies have been presented, from which valuable inference have been drawn for a real-world complex system. Each study has its own unique sets of motivation and relevance to the real world. An ensemble of signal processing (SP) and ML techniques have been explored in each study. This dissertation provides the detailed systematic approach and discusses the results achieved in each study. Valuable inferences drawn from each study play a vital role in areas of science and technology, and it is worth further investigation. This dissertation also provides a set of useful SP and ML tools for researchers in various fields of interest.
ContributorsDutta, Arindam (Author) / Bliss, Daniel W (Thesis advisor) / Berisha, Visar (Committee member) / Richmond, Christ (Committee member) / Corman, Steven (Committee member) / Arizona State University (Publisher)
Created2018
Description
Achieving effective drug concentrations within the central nervous system (CNS) remains one of the greatest challenges for the treatment of brain tumors. The presence of the blood-brain barrier and blood-spinal cord barrier severely restricts the blood-to-CNS entry of nearly all systemically administered therapeutics, often leading to the development of peripheral toxicities before a treatment benefit is observed. To circumvent systemic barriers, intrathecal (IT) injection of therapeutics directly into the cerebrospinal fluid (CSF) surrounding the brain and spinal cord has been used as an alternative administration route; however, its widespread translation to the clinic has been hindered by poor drug pharmacokinetics (PK), including rapid clearance, inadequate distribution, as well as toxicity. One strategy to overcome the limitations of free drug PK and improve drug efficacy is to encapsulate drug within nanoparticles (NP), which solubilize hydrophobic molecules for sustained release in physiological environments. In this thesis, we will develop NP delivery strategies for brain tumor therapy in two model systems: glioblastoma (GBM), the most common and deadly malignant primary brain tumor, and medulloblastoma, the most common pediatric brain tumor. In the first research chapter, we developed 120 nm poly(lactic acid-co-glycolic acid) NPs encapsulating the chemotherapy, camptothecin, for intravenous delivery to GBM. NP encapsulation of camptothecin was shown to reduce the drug’s toxicity and enable effective delivery to orthotopic GBM. To build off the success of intravenous NP, the second research chapter explored the utility of 100 nm PEGylated NPs for use with IT administration. Using in vivo imaging and ex vivo tissue slices, we found the NPs were rapidly transported by the convective forces of the CSF along the entire neuraxis and were retained for over 3 weeks. Based on their wide spread delivery and prolonged circulation, we examine the ability of the NPs to localize with tumor lesions in a leptomeningeal metastasis (LM) model of medulloblastoma. NPs administered to LM bearing mice were shown to penetrate into LM mets seeded within the meninges around the brain. These data show the potential to translate our success with intravenous NPs for GBM to improve IT chemotherapy delivery to LM.
ContributorsHouseholder, Kyle Thomas (Author) / Sirianni, Rachael W. (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Vernon, Brent (Committee member) / Caplan, Michael (Committee member) / Wechsler-Reya, Robert (Committee member) / Arizona State University (Publisher)
Created2018
Description
Calcium imaging is a well-established, non-invasive or minimally technique designed to study the electrical signaling neurons. Calcium regulates the release of gliotransmitters in astrocytes. Analyzing astrocytic calcium transients can provide significant insights into mechanisms such as neuroplasticity and neural signal modulation.
In the past decade, numerous methods have been developed to analyze in-vivo calcium imaging data that involves complex techniques such as overlapping signals segregation and motion artifact correction. The hypothesis used to detect calcium signal is the spatiotemporal sparsity of calcium signal, and these methods are unable to identify the passive cells that are not actively firing during the time frame in the video. Statistics regarding the percentage of cells in each frame of view can be critical for the analysis of calcium imaging data for human induced pluripotent stem cells derived neurons and astrocytes.
The objective of this research is to develop a simple and efficient semi-automated pipeline for analysis of in-vitro calcium imaging data. The region of interest (ROI) based image segmentation is used to extract the data regarding intensity fluctuation caused by calcium concentration changes in each cell. It is achieved by using two approaches: basic image segmentation approach and a machine learning approach. The intensity data is evaluated using a custom-made MATLAB that generates statistical information and graphical representation of the number of spiking cells in each field of view, the number of spikes per cell and spike height.
In the past decade, numerous methods have been developed to analyze in-vivo calcium imaging data that involves complex techniques such as overlapping signals segregation and motion artifact correction. The hypothesis used to detect calcium signal is the spatiotemporal sparsity of calcium signal, and these methods are unable to identify the passive cells that are not actively firing during the time frame in the video. Statistics regarding the percentage of cells in each frame of view can be critical for the analysis of calcium imaging data for human induced pluripotent stem cells derived neurons and astrocytes.
The objective of this research is to develop a simple and efficient semi-automated pipeline for analysis of in-vitro calcium imaging data. The region of interest (ROI) based image segmentation is used to extract the data regarding intensity fluctuation caused by calcium concentration changes in each cell. It is achieved by using two approaches: basic image segmentation approach and a machine learning approach. The intensity data is evaluated using a custom-made MATLAB that generates statistical information and graphical representation of the number of spiking cells in each field of view, the number of spikes per cell and spike height.
ContributorsBhandarkar, Siddhi Umesh (Author) / Brafman, David (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Tian, Xiaojun (Committee member) / Arizona State University (Publisher)
Created2019
Description
Several debilitating neurological disorders, such as Alzheimer's disease, stroke, and spinal cord injury, are characterized by the damage or loss of neuronal cell types in the central nervous system (CNS). Human neural progenitor cells (hNPCs) derived from human pluripotent stem cells (hPSCs) can proliferate extensively and differentiate into the various neuronal subtypes and supporting cells that comprise the CNS. As such, hNPCs have tremendous potential for disease modeling, drug screening, and regenerative medicine applications. However, the use hNPCs for the study and treatment of neurological diseases requires the development of defined, robust, and scalable methods for their expansion and neuronal differentiation. To that end a rational design process was used to develop a vitronectin-derived peptide (VDP)-based substrate to support the growth and neuronal differentiation of hNPCs in conventional two-dimensional (2-D) culture and large-scale microcarrier (MC)-based suspension culture. Compared to hNPCs cultured on ECMP-based substrates, hNPCs grown on VDP-coated surfaces displayed similar morphologies, growth rates, and high expression levels of hNPC multipotency markers. Furthermore, VDP surfaces supported the directed differentiation of hNPCs to neurons at similar levels to cells differentiated on ECMP substrates. Here it has been demonstrated that VDP is a robust growth and differentiation matrix, as demonstrated by its ability to support the expansions and neuronal differentiation of hNPCs derived from three hESC (H9, HUES9, and HSF4) and one hiPSC (RiPSC) cell lines. Finally, it has been shown that VDP allows for the expansion or neuronal differentiation of hNPCs to quantities (>1010) necessary for drug screening or regenerative medicine purposes. In the future, the use of VDP as a defined culture substrate will significantly advance the clinical application of hNPCs and their derivatives as it will enable the large-scale expansion and neuronal differentiation of hNPCs in quantities necessary for disease modeling, drug screening, and regenerative medicine applications.
ContributorsVarun, Divya (Author) / Brafman, David (Thesis advisor) / Nikkhah, Mehdi (Committee member) / Stabenfeldt, Sarah (Committee member) / Arizona State University (Publisher)
Created2016
Description
Relapse after tumor dormancy is one of the leading causes of cancer recurrence that ultimately leads to patient mortality. Upon relapse, cancer manifests as metastases that are linked to almost 90% cancer related deaths. Capture of the dormant and relapsed tumor phenotypes in high-throughput will allow for rapid targeted drug discovery, development and validation. Ablation of dormant cancer will not only completely remove the cancer disease, but also will prevent any future recurrence. A novel hydrogel, Amikagel, was developed by crosslinking of aminoglycoside amikacin with a polyethylene glycol crosslinker. Aminoglycosides contain abundant amount of easily conjugable groups such as amino and hydroxyl moieties that were crosslinked to generate the hydrogel. Cancer cells formed 3D spheroidal structures that underwent near complete dormancy on Amikagel high-throughput drug discovery platform. Due to their dormant status, conventional anticancer drugs such as mitoxantrone and docetaxel that target the actively dividing tumor phenotype were found to be ineffective. Hypothesis driven rational drug discovery approaches were used to identify novel pathways that could sensitize dormant cancer cells to death. Strategies were used to further accelerate the dormant cancer cell death to save time required for the therapeutic outcome.
Amikagel’s properties were chemo-mechanically tunable and directly impacted the outcome of tumor dormancy or relapse. Exposure of dormant spheroids to weakly stiff and adhesive formulation of Amikagel resulted in significant relapse, mimicking the response to changes in extracellular matrix around dormant tumors. Relapsed cells showed significant differences in their metastatic potential compared to the cells that remained dormant after the induction of relapse. Further, the dissertation discusses the use of Amikagels as novel pDNA binding resins in microbead and monolithic formats for potential use in chromatographic purifications. High abundance of amino groups allowed their utilization as novel anion-exchange pDNA binding resins. This dissertation discusses Amikagel formulations for pDNA binding, metastatic cancer cell separation and novel drug discovery against tumor dormancy and relapse.
Amikagel’s properties were chemo-mechanically tunable and directly impacted the outcome of tumor dormancy or relapse. Exposure of dormant spheroids to weakly stiff and adhesive formulation of Amikagel resulted in significant relapse, mimicking the response to changes in extracellular matrix around dormant tumors. Relapsed cells showed significant differences in their metastatic potential compared to the cells that remained dormant after the induction of relapse. Further, the dissertation discusses the use of Amikagels as novel pDNA binding resins in microbead and monolithic formats for potential use in chromatographic purifications. High abundance of amino groups allowed their utilization as novel anion-exchange pDNA binding resins. This dissertation discusses Amikagel formulations for pDNA binding, metastatic cancer cell separation and novel drug discovery against tumor dormancy and relapse.
ContributorsGrandhi, Taraka Sai Pavan (Author) / Rege, Kaushal (Thesis advisor) / Meldrum, Deirdre R (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Caplan, Michael (Committee member) / Tian, Yanqing (Committee member) / Arizona State University (Publisher)
Created2016
Description
Through decades of clinical progress, cochlear implants have brought the world of speech and language to thousands of profoundly deaf patients. However, the technology has many possible areas for improvement, including providing information of non-linguistic cues, also called indexical properties of speech. The field of sensory substitution, providing information relating one sense to another, offers a potential avenue to further assist those with cochlear implants, in addition to the promise they hold for those without existing aids. A user study with a vibrotactile device is evaluated to exhibit the effectiveness of this approach in an auditory gender discrimination task. Additionally, preliminary computational work is included that demonstrates advantages and limitations encountered when expanding the complexity of future implementations.
ContributorsButts, Austin McRae (Author) / Helms Tillery, Stephen (Thesis advisor) / Berisha, Visar (Committee member) / Buneo, Christopher (Committee member) / McDaniel, Troy (Committee member) / Arizona State University (Publisher)
Created2015