Fischell Department of Bioengineering Theses and Dissertations

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    Acquired Platelet And Neutrophil Dysfunction Due To High Mechanical Shear Stress
    (2022) Arias, Katherin; Wu, Zhongjun; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Heart failure (HF) is a public health burden. In the next ten years, 8 million Americans are expected to have HF. A subset of these patients will develop advanced HF. They are refractory to medical therapies and have limited treatment options, including heart transplantation or a left ventricular assist device (LVAD). Heart transplants for all advanced HF patients are impractical due to the scarcity of donors. LVAD therapy is the sole viable option for advanced HF patients as a bridge to transplant, a temporary treatment while the heart recovers, and a long-term destination therapy. Over the last two decades, significant progress in LVADs have been made through various iterations. Advances in LVADs have been due to redesign focused on lowering adverse events. However, bleeding and infections are still the most prevalent adverse complications. LVADs and other mechanical circulatory support devices induce damage to blood cells and plasma components due to the high mechanical shear stress (HMSS) generated. Therefore, there must be a link between LVAD-induced cellular damage and the adverse events experienced in LVAD patients. This dissertation aimed to investigate the relationship between cellular blood damage and LVAD-associated complications and qualify the extent of cellular damage/defects and functional alterations.The overall objective of this dissertation was to investigate the acquired cellular defects of platelets and neutrophils in blood after shear stress exposure. This objective was accomplished through in-vivo, in-vitro, and in-silico studies. The in-vivo studies examined the shear stress-induced injury of platelets in LVAD recipients and linked the adverse bleeding events (Chapter 3). The in-vitro studies explored the shear stress-induced injury of leukocytes (Chapter 4). The extent of the structural damage and functional alterations related to shear stress level and the exposure time was quantified (Chapter 5 and Chapter 6). Finally, the in-silico studies developed a simulation of leukocyte function with experimental data that was used to predict the extent of the shear stress-induced leukocyte function change (Chapter 6). The damaging effects of the high shear stress produced by mechanical circulatory support devices such as LVADs were conveyed through an integrated biological and engineering approach.
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    Assessment of Mechanical Cues to Enhance the Clinical Translation of Extracellular Vesicles
    (2022) Kronstadt, Stephanie Marie; Jay, Steven M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Mesenchymal stem cells (MSCs) are a common source for cell-based therapies due to their innate regenerative properties. However, these cells often die shortly after injection and, if they do survive, run the risk of forming tumors. Cell-secreted nanoparticles known as extracellular vesicles (EVs) have been identified as having therapeutic effects similar to those of their parental cells without the safety risks. Specifically, MSC EVs have emerged as a promising therapeutic modality in a multitude of applications, including autoimmune and cardiovascular diseases, cancer, and wound healing. Despite this promise, low levels of naturally occurring EV cargo may necessitate repeated doses to achieve clinical benefit, countering the advantages of EVs over MSCs. The current techniques to combat low EV potency (e.g., loading external molecules or using chemicals) are not agreeable to large-scale manufacturing techniques and would substantially increase the regulatory burden associated with EV translation. Fortunately, mechanical cues within the microenvironment have potential to overcome these translational barriers as they can alter EV therapeutic effects but are also cost-effective and can be precisely manipulated in a reproducible manner. The goal of this project is to understand how these cues impact MSC EV secretion and physiological effects. We showed that flow-derived shear stress applied to MSCs seeded within a 3D-printed scaffold (i.e., the bioreactor) can significantly upregulate EV production (EVs/cell) while maintaining the in vitro pro-angiogenic effects of MSC EVs. Interestingly, we demonstrated that MSC EVs generated using the bioreactor system significantly improved wound healing in a diabetic mouse model, with increased CD31+ staining in wound bed tissue compared to animals treated with flask cell culture-generated MSC EVs. Furthermore, for the first time, we showed that mechanical confinement of MSCs within micropillars could augment MSC EV production and bioactivity. Lastly, we demonstrated that soft substrates composed of various polydimethylsiloxane (PDMS) formulations could increase MSC EV production and activity as well. Through the work performed here, we have laid the groundwork to elucidate the relationship between cell mechanobiology and EV activity that will ultimately enable an adaptable and scalable EV therapeutic platform.
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    (2022) Liang, Barry; Huang, Huang-Chiao; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Chemotherapy remains the main strategy for combating cancer, despite significant advances in alternative treatment modalities. It has been estimated that up to 90% of cancer-related deaths are caused by chemotherapy failure due to cancer multidrug resistance (MDR). MDR is a cellular phenomenon where cells are able to evade drug-induced cell death by developing resistance to multiple structurally and mechanistically distinct therapeutic compounds. Insufficient drug delivery, activation of compensatory survival pathways, and enhanced drug efflux by ATP-binding cassette (ABC) drug transporters are the primary challenges underlying MDR. As a result, an ideal cancer treatment strategy should involve selective delivery, retention, and activation of multiple therapeutic agents at the diseased site.Photodynamic therapy (PDT) is a photochemistry-based treatment modality that has shown promise in overcoming cancer drug resistance due to its unparalleled spatiotemporal control over treatment induction using light. The overall objective of this dissertation is to combine engineering strategies and PDT to overcome the existing challenges of MDR. The findings from this dissertation reveal PDT photochemically inactivates ABC drug transporters via functional (i.e., ATPase activity) inhibition and protein structural damage in a dose dependent manner. Our data suggest conjugation of a photosensitizer to conformation-sensitive antibody enables selective photosensitizer delivery to drug-resistant cancer cells and fluorescence visualization of functionally active ABC drug transporters. Our findings further show that targeted nanotechnology can improve photosensitizer delivery and allow for multidrug packaging for PDT-based combination treatment. Lastly, we leverage a dual fluorescence-guided approach to monitor the biodistribution of a targeted nanoformulation and customize intraoperative PDT dosimetry in vivo. Together, these findings from this dissertation advance the current understanding on using a light-activatable strategy to combat cancer drug resistance in three major ways: 1) elucidating the mechanism underlying photochemical inactivation of ABC drug transporters, 2) providing novel engineering strategies to improve multidrug delivery to cancer cells, and 3) demonstrating fluorescence-guided drug delivery and PDT light dosimetry.
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    Quantitative Motion Analysis of the Upper Limb: Establishment of Normative Kinematic Datasets and Systematic Comparison of Motion Analysis Systems
    (2022) Wang, Sophie Linyi; Kontson, Kimberly L; White, Ian; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Upper limb prosthetic devices with advanced capabilities are currently in development. With these advancements brings to light the importance of objectively and quantitatively measuring effectiveness and benefit of these devices. Recently, the application of motion capture (i.e., digital tracking of upper body movements in space) to performance-based outcome measures has gained traction as a possible tool for human movement assessment that could facilitate optimal device selection, track rehabilitative progress, and inform device regulation and review. While motion capture shows promise, the clinical, regulatory, and industry communities would benefit from access to large clinical and normative datasets from different motion capture systems and a better understanding of advantages and limitations of different motion capture approaches. The first objective of this dissertation is to establish kinematic datasets of normative and upper-limb prosthesis user motion. The normative kinematic distributions of many performance-based outcome measures are not established, and it is difficult to determine departures from normative patterns without relevant clinical expertise. In Specific Aim 1, normative and clinically relevant datasets were created using a gold standard motion capture system to record participants performing standardized tasks from outcome measures. Without kinematic data, it is also difficult to identify informative kinematic features and tasks that exhibit characteristic differences from normative motion. The second objective is to identify salient kinematic characteristics associated with departures from normative motion. In Specific Aim 2, an unsupervised K-means machine learning algorithm was applied to the previously collected data to determine motions and tasks that distinguish between normative and prosthesis user movement. The third objective is to compare three commonly used motion capture systems that vary in motion tracking mechanisms. The most informative tasks and kinematic characteristics previously identified will be used to evaluate the detection of these differences for several motion capture systems with varying tracking methods in Specific Aim 3.
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    (2022) Handler, Chenchen; Scarcelli, Giuliano; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Neurulation is a process that serves as the precursor to the spinal cord in vertebrates. Neural tube closure (NTC), part of primary neurulation, involves the extensive coordination of cellular, molecular, and mechanical events to transform the flat neural epithelium to a luminated epithelial tube. Neural tube defects (NTD) are the result of mechanical failures that arise during neurulation. Recent research has focused on understanding the molecular mechanisms underlying neurulation but has difficulty correlating them to physical mechanisms. To better understand how physical mechanisms are integrated and responsible for neurulation, several techniques have been applied to study NTC in a range of in vitro environments. However, many of these techniques have been limited due requiring the specimen to be fixed and/ or being invasive and requiring physical contact with the specimen to extract the modulus. As such, there is limited resolution and only the superficial layer of the sample is measured making assessing 2D/3D tissue mechanics inside a growing organism is highly challenging. In this dissertation, we aim to quantify the mechanical state of the neural tube without disruption to development. To do this, we adapted Brillouin microscopy, a non-invasive, label- and contact-free imaging technique, to allows us to probe thelongitudinal modulus of the neural plate at every step of NTC with cellular resolution. This quantification is performed as the embryo develops in real time using time-lapse Brillouin and an improved ex-ovo culture method. We observed an increase in the Brillouin modulus of the neural plate as the embryo develops from Hamburger-Hamilton stage (HH)-6 to HH-12. This increase in modulus is consistent with previous data from other vertebrates such as Xenopus and Mouse embryos and demonstrates the process of neurulation is driven by mechanical forces. Time-lapse Brillouin imaging depicted stiffening and thickening of the neural plate during NTC, suggesting these are coordinated events for NTC. Here, we show that tissue stiffness plays an integral role in NTC and directly quantifying tissue mechanics during neurulation should allow us to better determine the biomechanical nature of NTD.