Theses and Dissertations from UMD
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New submissions to the thesis/dissertation collections are added automatically as they are received from the Graduate School. Currently, the Graduate School deposits all theses and dissertations from a given semester after the official graduation date. This means that there may be up to a 4 month delay in the appearance of a give thesis/dissertation in DRUM
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Item INGESTIBLE BIOIMPEDANCE SENSING DEVICE FOR GASTROINTESTINAL TRACT MONITORING(2024) Holt, Brian Michael; Ghodssi, Reza; Electrical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Gastrointestinal (GI) diseases, such as inflammatory bowel disease (IBD), result in dilated adherens and tight junctions, altering mucosal tissue permeability. Few monitoring techniques have been developed for in situ monitoring of local mucosal barrier integrity, and none are capable of non-invasive measurement beyond the esophagus. In this work, this technology gap is addressed through the development of a noise-resilient, flexible bioimpedance sensor integrated ingestible device containing electronics for low-power, four-wire impedance measurement and Bluetooth-enabled wireless communication. Through electrochemical deposition of a conductive polymeric film, the sensor charge transfer capacity is increased 51.4-fold, enabling low-noise characterization of excised intestinal tissues with integrated potentiostat circuitry for the first time. A rodent animal trial is performed, demonstrating successful differentiation of healthy and permeable mice colonic tissues using the developed device. In accordance with established mucosal barrier evaluation methodologies, mucosal impedance was reduced between 20.3 ± 9.0% and 53.6 ± 10.7% of its baseline value in response to incrementally induced tight junction dilation. Ultimately, this work addresses the fundamental challenges of electrical resistance techniques hindering localized, non-invasive IBD diagnostics. Through the development of a simple and reliable bioimpedance sensing module, the device marks significant progress towards explicit quantification of “leaky gut” patterns in the GI tract.Item Sutureless Anastomosis: Electroadhering a Hydrogel Sleeve Over Cut Pieces of Tubular Tissue(2024) Grasso, Samantha Marie; Raghavan, Srinivasa R; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Recently, our lab demonstrated that cationic gels could be adhered to animal tissues by applying an electric field (10 V DC, for ~ 20 s). This phenomenon, termed electroadhesion (EA), could potentially be used to repair injured tissues without sutures. An extreme injury is when a tube in the body (e.g., a blood vessel or an intestine) is cut into two segments. The surgical process of joining the segments is termed anastomosis, and thus far has only been done clinically with sutures. Here, we explore the use of EA for performing sutureless anastomoses in vitro with bovine aorta and chicken intestine. For this purpose, we make a strong and stretchable cationic gel in the form of a sleeve (i.e., a hollow tube). By using a custom plastic mold, we control both the sleeve diameter and wall thickness. A sleeve with a diameter matching that of the tubular tissue is slipped over the cut segments of the tube, followed by application of the DC electric field. Thereby, the sleeve becomes strongly adhered by EA to the underlying tube. Water or blood is then flowed through the repaired tube, and we record the burst pressure Pburst of the tube. We find that Pburst is > 80 mm Hg and close to the Pburst of an intact (uncut) tube. In comparison to the sleeve, a long strip of the gel attached around the cut tubular pieces allows a much lower Pburst. Thus, our study shows that gel-sleeves adhered by EA could enable anastomoses to be performed in the clinic without the need for sutures.Item SAMPLE-TO-ANSWER POINT-OF-CARE VIRUS DIAGNOSTIC SYSTEM USING THERMALLY RESPONSIVE ALKANE PARTITIONS(2024) Boegner, David John; White, Ian M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Many viral infections can be accurately diagnosed using today’s most sophisticated detection systems. Unfortunately, many of these detection systems fail to benefit society as a whole, but rather favor select areas of the world that are able to install and maintain the infrastructure such diagnostics require. Thus, in an effort to eliminate the barrier of access to diagnosis and treatment in low-and-middle-income areas, portable point-of-care devices are fabricated such that rapid results can be obtained without the need for bulky lab equipment or skilled technicians. An ideal point-of-care diagnostic device can easily collect an untampered sample and limits a patient’s encounter with a clinician to a single visit for both the diagnosis and the treatment. Many so-called point-of-care diagnostics for blood-borne viruses first require blood sample preparation (e.g. centrifugation) prior to testing in the device. Other point-of-care devices sacrifice diagnostic accuracy in favor of speed and portability. Both cases demonstrate our inability to properly distribute the benefits of sophisticated diagnostics worldwide.I present a solution in the form of an affordable handheld diagnostic device with the sensitivity and specificity of benchtop lab equipment and built-in automatic sample preparation. Automatic sample preparation will be achieved using thermally responsive alkane partitions, which are solid at ambient temperatures and liquid at moderately elevated temperatures. When liquid, the alkane partitions allow passage of magnetically activated microbeads coated with material that captures viruses. Despite magnetic beads with virus particles passing through, the alkane partition continues to prevent unwanted sample components (e.g. blood cells, DNases, etc.) from interfering with the virus-detecting mechanism on the other side. To address the lack of sensitivity in many point-of-care diagnostics, the virus-detecting mechanism will feature isothermal amplification which enables detection of attomolar concentrations of virus within 30 minutes without expensive thermo-cycling equipment that standard detection systems require. The novel technology described here is demonstrated in a platform which detects SARS-CoV-2 from blood, a capability currently unachievable in point-of-care settings.Item Synthetic Mucus Hydrogels for Antimicrobial Peptide Delivery and Treatment of Bacterial Infections(2024) Yang, Sydney; Duncan, Gregg A; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Antibiotic resistant infections have the propensity to form biofilms that contribute to chronic infections and result in hyper-inflammatory response in tissues. Recent studies pose antimicrobial peptides (AMPs) as alternatives to antibiotics and to modulate inflammatory response. However, AMPs have a short half-life due to rapid clearance and degradation reducing AMP bioavailability and efficacy. In the human body, AMPs interact and may associate with mucins which result in the sequestering of AMPs within mucus. Previously, we have developed a synthetic mucus (SM) hydrogel inspired by the innate properties of mucins. The objective of this work was to evaluate the SM hydrogel as a tool for local antimicrobial peptide delivery of LL37 to enhance the treatment for infection and inflammation. To study this, we (1) assessed the release of LL37 and antimicrobial activity of LL37 loaded SM (LL37-SM) hydrogels on Pseudomonas aeruginosa, (2) evaluated the antibiofilm activity of LL37-SM hydrogel treatment on Pseudomonas aeruginosa biofilms, and (3) determined the impact of LL37-SM hydrogel treatment on RAW 264.7 macrophage activation and phagocytic activity. The association of LL37 to SM hydrogels enabled the sustained release of LL37 over 8 hours and retained antimicrobial activity. Treatment with LL37-SM hydrogels for 24 hours disrupted biofilm growth and resulted in a mixed inflammatory response in macrophages. Our results highlight the antimicrobial, antibiofilm, and potentially inflammatory modulating capabilities of SM hydrogels which can further inform the use of mucins in bioactive biomaterials for biomedical applications.Item Investigation and development of induced pluripotent stem cell derived extracellular vesicle-based therapeutics(2024) Levy, Daniel H; Jay, Steven; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Due to their complex, multicomponent nature, extracellular vesicle (EV)-based therapeutics have arisen as an intriguing option for treatment of complex diseases that require the simultaneous modulation of distinct pathways. Due to their inherent regenerative properties, mesenchymal stem cell (MSC)-derived EVs have been the most heavily investigated and utilized in clinical trials for diseases including acute respiratory distress syndrome, wound healing and many more. While pre-clinical studies have demonstrated promise for such EV-based therapeutics, source cell limitations act as a hurdle to the widespread clinical translation of MSC EV therapies. MSCs and other cells reported to produce therapeutic EVs (cardiac progenitor cells, neural stem cells, etc.) have limited expansion capabilities ex vivo before cellular senescence, therefore limiting the amount of therapeutic EVs that can be produced by a single cell line. Due to these limited expansion capabilities, alternative, self-renewing therapeutic EV source cells are needed. One such source cell is induced pluripotent stem cells (iPSCs), which possess self-renewing capabilities. However, the baseline bioactivity of iPSC EVs have yet to be rigorously evaluated; in our work, we report for the first time that iPSC EVs possess robust anti-inflammatory properties in addition to confirming previous reports of their ability to promote vascularization in a murine diabetic wound healing model. Building off these baseline results, we sought to augment iPSC EV potency by utilizing genetic approaches to load of bioactive RNAs including microRNA (miRNA) and long non-coding RNA (lncRNA) into iPSC EVs. In our miRNA loading studies, we effectively demonstrate that the natural biogenesis pathways of miRNA can be probed to facilitate export of bioactive miRNAs to secreted EVs, thereby enhancing their anti-inflammatory bioactivity. Lastly, we utilize a genetic engineering approach to enhance active sorting of lncRNAs into secreted EVs and test their therapeutic potential in a murine colitis model. The work described in this dissertation provides a foundation towards the clinical translation of iPSC EV-based therapeutics by benchmarking them against more established therapeutic EV sources (iPSC-derived MSC EVs) and developing strategies to enhance their bioactivity via RNA cargo loading.Item TLR9 Activation as Immunotherapy in a Murine Model of Metastatic Lymphangioleiomyomatosis(2024) Amosu, Oluwamayowa; Maisel, Katharina; Cell Biology & Molecular Genetics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Pulmonary Lymphangioleiomyomatosis (LAM) is a slow progressing, metastasizing neoplasm primarily affecting women of reproductive age, marked by abnormal growth of smooth muscle-like cells leading to cystic lung destruction. Rapamycin, the only approved treatment for LAM, slows disease progression but ~40% of patients have partial or no response to treatment. There is an urgent need for new treatments. Research shows that LAM has hallmarks of cancer, like expression of immune checkpoint receptors, and is responsive to immune checkpoint inhibition in mouse models. This suggests that other anti-cancer strategies could be effective in treating LAM. In this thesis, we investigated toll like receptor (TLR) activation using intranasal administration of CpG, a TLR9 agonist, as LAM immunotherapy. We used a mouse model of metastatic LAM to determine survival after biweekly intranasal CpG therapy (10µg/ 5µg) with and without systemic α-PD-1, rapamycin, or α-CD317 therapy. We used ELISA to measure the cytokine profile and flow cytometry to quantify cell populations and characterize differences in the immune response between CpG-treated and untreated LAM lungs. We found that CpG treatment enhanced median survival from 32 to 60 days in murine LAM. Survival benefit of CpG treatment was inversely dose-dependent and more effective during early stages of disease. CpG-treatment was synergistic with both α-PD-1 checkpoint inhibition and rapamycin, with survival increasing from 60 days (CpG) to 71 days (CpG + α-PD-1) and 100 days (CpG + Rapamycin). Histological analysis showed that CpG treatment decreased the LAM nodule burden but inevitably caused tissue inflammation. Efficacy of CpG treatment in LAM is facilitated in part by plasmacytoid dendritic cells through decreased regulatory T cell numbers, priming of Th17 cells, and increased secretion of inflammatory and cytotoxic cytokines by CD8 T cells. Our findings suggest that adjuvant immunotherapy, like CpG, may offer new treatment strategies for LAM that are compatible with the current standard of care, rapamycin.Item SPECTROSCOPY-BASED METHODS FOR BIOLOGICAL APPLICATIONS(2024) Zhou, Xuewen; Scarcelli, Giuliano; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Spectroscopy plays a crucial role in biological measurements by offering functional insights across various biological scales, from cellular to organ levels. It has become an important complement to imaging technologies. The thesis focuses on enhancing spectroscopy-based methods, addressing both technical advancements and application-oriented improvements. The first part of the research presents the development of standardized test methods for multispectral photoacoustic imaging (MPAI), a phantom-based test method specific for evaluating MPAI performance in breast cancer detection. This test method contributes to standardizing the evaluation of multispectral photoacoustic imaging across different research and clinical settings with better reliability and reproducibility. The next segment of the thesis introduces an innovative 2D-dispersion spectrometer, utilizing an etalon and grating setup. This instrument significantly improves the sensitivity in detecting Whispering Gallery Mode (WGM) microlasers by providing spectral resolution less than 0.3 pm. The enhanced sensitivity allows for the measurement of hyperfine refractive index and absorption changes in liquid environments, which expands the application limit of microlasers as biosensors. In the final part, the thesis extends the application of the 2D-dispersion spectrometer to detect Brillouin and low-frequency Raman signals. For the best of our knowledge, this is the first setup demonstrating simultaneous Brillouin and low-frequency Raman measurement, which can provide mechanical and chemical information of a sample such as the viscoelasticity and intermolecular dynamic.Item ENHANCING BIOPRINTING STRATEGIES TOWARDS THE DEVELOPMENT OF BIOMIMETIC OSTEOCHONDRAL TISSUE ENGINEERING SCAFFOLDS(2023) Choe, Robert; Fisher, John P; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Osteoarthritis is a highly prevalent rheumatic musculoskeletal disorder that affects approximately 900,000 Americans annually and is characterized by the progressive breakdown of the articular cartilage and remodeling of the subchondral bone in the synovial joint. During early-stage osteoarthritis, the articular cartilage begins to degrade, the synovial joint space narrows, and the subchondral bone undergoes rapid bone turnover, leading to insufficient bone mineralization and compromised matrix integrity. While decades of research have revealed that an intricate balance between the bone and cartilage layers influences biochemical and biomechanical changes experienced within the osteochondral unit, most osteochondral tissue engineering scaffolds have not achieved clinical viability. Tissue engineering (TE) strategies, such as 3D bioprinting (3DP), offer a new avenue to help develop novel osteochondral tissue engineering scaffolds to regenerate healthy and diseased osteochondral joints. In this project, our immediate goal is to expand the repertoire of osteochondral bioprinting strategies toward developing a biomimetic, 3D-printed osteochondral scaffold that can be implanted into acute focal cartilage defects during early-stage OA. We will explore the designs and fabrication strategies of various 3D-printed biomimetic osteochondral interface scaffolds with enhanced mechanics guided by computational simulations. Additionally, we will examine the potential of utilizing osteoblast- and osteoclast-lineage cell co-cultures to improve regenerative outcomes at the bone scaffold layer of osteochondral tissue engineering scaffolds. The long-term goal of this work is to aid in developing a biomimetic 3D printed osteochondral scaffold that has enhanced load-bearing properties and elevated regeneration potential to recreate the unique osteochondral architecture at each distinct tissue layer.Item DIRECT LASER WRITE PROCESSES FOR SPIDER INSPIRED MICROHYDRAULICS AND MULTI-SCALE LIQUID METAL DEVICES(2023) Smith, Gabriel Lewis; Bergbreiter, Sarah; Sochol, Ryan; Mechanical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Direct Laser Write (DLW) through two-photon polymerization (2PP) empowers us to delveinto the realm of genuine three-dimensional design complexity for microsystems, enabling features smaller than a single micrometer. This dissertation develops two novel fabrication processes that leverage DLW for functional fluidic microsystems. In the first process, we are inspired by arachnids that use internal hemolymph pressure to actuate extension in one or more of their leg joints. The inherent large foot displacement-to-body length ratio that arachnids can achieve through hydraulics relative to muscle-based actuators is both energy and volumetrically efficient. Until recent advances in nano/microscale 3-D printing with 2PP, the physical realization of synthetic complex ‘soft’ joints would have been impossible to replicate and fill with a hydraulic fluid into a sealed sub-millimeter system. This dissertation demonstrates the smallest scale 3D-printed hydraulic actuator 4.9 × 10^−4 mm^3 by more than an order of magnitude. The use of stiff 2PP polymers with micron-scale dimensions enable compliant membranes similar to exoskeletons seen in nature without the requirement for low-modulus materials. The bio-inspired system is designed to mimic similar hydraulic pressure-activated mechanisms in arachnid joints utilized for large displacement motions relative to body length. Using variations on this actuator design, we demonstrate the ability to transmit forces with relatively large magnitudes (milliNewtons) in 3D space, as well as the ability to direct motion that is useful towards microrobotics and medical applications. Microscale hydraulic actuation provides a promising approach to the transmission of large forces and 3D motions at small scales, previously unattainable in wafer-level 2D microelecromechanical systems (MEMS). The second fabrication process focuses on incorporating functionality through the use of liquid metals in 3D DLW structures. Room temperature eutectic Gallium Indium (eGaIn)- based liquid metal devices with stretchable, conductive, and reconfigurable behavior show great promise across many areas of technology, including robotics, communications, and medicine. Microfluidics provide one means of creating eGaIn devices and circuits, but these devices are typically limited to larger feature sizes. Developments in 3D printing via DLW have enabled sub-100 µm complex microfluidic devices, though interfacing microfluidic devices manufactured with DLW to larger millimeter-scale systems is difficult. The reduced channel diameter creates challenges for removing resist from the channels, filling microchannels with eGaIn, and electrically integrating them to larger channels or other circuitry. These challenges have prevented microscale liquid metal devices from being used more widely. In this dissertation, we demonstrate a facile, low-cost multiscale process for printing DLW microchannels and devices onto centimeter-scale custom fluidic channel substrates fabricated via stereolithography (SLA). This work demonstrates a robust interface between the two independently printed materials and greatly simplifies the filling of eGaIn microfluidic channels down to 50 µm in diameter, with the potential to achieve even smaller feature sizes of liquid metals. This work also demonstrates eGaIn coils with resistance of 43-770 mΩ and inductance of 2-4 nH. As a result, this process empowers us to manufacture interfaces that are not only low-temperature but also conductive and flexible. These interfaces find their application in connecting with sensors, actuators, and integrated circuits, thereby opening new avenues in the field of 3D electronics. Furthermore, our approach extends the lower limits of size-dependent properties for passive electronic components like resistors, capacitors, and inductors crafted from liquid metal, expanding the frontiers of possibilities in miniature electronic design.Item Methods and Tools for Real-Time Neural Image Processing(2023) Xie, Jing; Bhattacharyya, Shuvra; Chen, Rong; Electrical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)As a rapidly developing form of bioengineering technology, neuromodulationsystems involve extracting information from signals that are acquired from the brain and utilizing the information to stimulate brain activity. Neuromodulation has the potential to treat a wide range of neurological diseases and psychiatric conditions, as well as the potential to improve cognitive function. Neuromodulation integrates neural decoding and stimulation. As one of the twocore parts of neuromodulation systems, neural decoding subsystems interpret signals acquired through neuroimaging devices. Neuroimaging is a field of neuroscience that uses imaging techniques to study the structure and function of the brain and other central nervous system functions. Extracting information from neuroimaging signals, as is required in neural decoding, involves key challenges due to requirements of real-time, energy-efficient, and accurate processing and for large-scale, high resolution image data that are characteristic of neuromodulation systems. To address these challenges, we develop new methods and tools for design andimplementation of efficient neural image processing systems. Our contributions are organized along three complementary directions. First, we develop a prototype system for real-time neuron detection and activity extraction called the Neuron Detection and Signal Extraction Platform (NDSEP). This highly configurable system processes neural images from video streams in real-time or off-line, and applies techniques of dataflow modeling to enable extensibility and experimentation with a wide variety of image processing algorithms. Second,we develop a parameter optimization framework to tune the performance of neural image processing systems. This framework, referred to as the NEural DEcoding COnfiguration (NEDECO) package, automatically optimizes arbitrary collections of parameters in neural image processing systems under customizable constraints. The framework allows system designers to explore alternative neural image processing trade-offs involving execution time and accuracy. NEDECO is also optimized for efficient operation on multicore platforms, which allows for faster execution of the parameter optimization process. Third, we develop a neural network inference engine targeted to mobile devices.The framework can be applied to neural network implementation in many application areas, including neural image processing. The inference engine, called ShaderNN, is the first neural network inference engine that exploits both graphics-centric abstractions (fragment shaders) and compute-centric abstractions (compute shaders). The integration of fragment shaders and compute shaders makes improved use of the parallel computing advantages of GPUs on mobile devices. ShaderNN has favorable performance especially in parametrically small models.