A. James Clark School of Engineering
Permanent URI for this communityhttp://hdl.handle.net/1903/1654
The collections in this community comprise faculty research works, as well as graduate theses and dissertations.
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Item ENGINEERING TARGETED LIGHT ACTIVATABLE NANOPLATFORMS TO MANAGE RECURRENT CANCERS(2024) Pang, Sumiao; Huang, Huang Chiao HH; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cancer recurrence poses a significant challenge in various malignancies that adverselyaffect long-term survival and quality of life. Glioblastoma (GBM) and ovarian cancer exhibit particularly high recurrence rates. For GBM, tumor recurrence is nearly universal (90%) within 10 months post initial treatment due to its invasive characteristics, limited delivery of therapeutic agents, and persistent drug resistance, resulting in a 5-year survival rate of <10%. While standard chemotherapy and surgery can temporarily alleviate symptoms for both diseases, there has been no significant improvement in long-term disease management or survival extension over several decades. Therefore, it is critical to develop targeted therapies that integrates well with current standards of care strategies. Photomedicine is a promising treatment modality, and the two main phototherapies are photodynamic therapy (PDT) which involves photosensitizer administration followed by light activation resulting in non-thermal chemical damage and photothermal therapy (PTT) which involves exogenous or endogenous sensitizing agents followed by light activation resulting in thermal damage. Clinical applications of both modalities have shown its feasibility and safety; however, they face challenges due to (i) limited cancer selectivity, (ii) heterogenous treatment response, and (iii) low monotherapy treatment efficacy. Leveraging strategic therapeutic targets to advance the current sensitizing agents for targeted delivery is a potential solution to overcome these limitations. The overall objective of this dissertation is to advance and evaluate targeted light-activatable nanoplatforms for phototherapy delivery with considerations for the current clinical workflow of GBM and advanced ovarian cancer. This is achieved through the following goals, (1) engineering a novel Fn14 receptor-directed gold nanorods (DART-GNRs) to assess selectivity and PTT efficacy for GBM, and (2) evaluate safety and long-term efficacy of targeted light-activatable multi-agent nanoplatform (tLAMP) to deliver targeted PDT for peritoneal carcinomatosis. First, this work establishes a reproducible synthesis protocol for DART-GNRs, characterizes its photothermal properties, and demonstrate high selectivity towards the Fn14 receptor of cancer cells. Second half of this dissertation established and investigated a two-fiber tissue optical property (TOP) monitoring method for liquid phantoms and for peritoneal carcinomatosis mouse model to enable safer light dosimetry during PDT, established an irinotecan active loading method to reproducibly synthesize tLAMP, and determined tLAMP tumor nodule penetration depth for enhanced targeted PDT combination therapy with adjuvant chemotherapy to enhance long-term survival for ovarian cancer.Item PREPARATION OF A NANOSUSPENSION OF THE PHOTOSENSITIZER VERTEPORFIN FOR PHOTODYNAMIC AND LIGHT-INDEPENDENT THERAPY IN GLIOBLASTOMA(2024) Quinlan, John Andrew; Huang, Huang-Chiao; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Photodynamic therapy (PDT) using verteporfin (VP) has treated ocular disease for over 20 years, but recent interest in VP’s light-independent properties has reignited interest in the drug, particularly in glioblastoma (GBM) (NCT04590664). Separate efforts to apply PDT to GBM using 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) have also garnered attention (NCT03048240), but, unfortunately, clinical trials using 5-ALA-induced PpIX-PDT have yet to yield a survival benefit. Previous studies have shown VP to be a superior PDT agent than 5-ALA-induced PpIX. Our lab has shown that 690 nm light activates VP up to 2 cm into the brain, while 635 nm light only activates PpIX at depths <1 cm into the brain. Additionally, VP is a more effective photosensitizer than PpIX because it has a higher singlet oxygen yield and is active in the vasculature as well as target tumor cells. However, the hydrophobicity of VP limits effective delivery of the drug to the brain for treatment of GBM.In this context, this thesis aims to re-evaluate the delivery method for VP. VP traditionally requires lipids for delivery as Visudyne. Recent shortages of Visudyne and potential drawbacks of liposomal carriers motivated our development of a carrier-free nanosuspension of VP, termed NanoVP. Previous work has shown that cellular uptake of VP is greater when delivered as NanoVP rather than liposomal VP, resulting in improved cell killing after light activation. This thesis builds on this previous work by (1) evaluating synthesis and storage parameters for NanoVP, (2) determining the pharmacokinetics, biodistribution, and brain bioavailability of NanoVP, and (3) evaluating the potential efficacy of NanoVP as a PDT and a chemotherapy agent, and by supporting development of a zebrafish model of the blood-brain barrier (BBB) for mechanistic studies of improved drug delivery to the brain.Item DEVELOPMENT OF GLYCOSAMINOGLYCAN MIMICKING NANOGEL TECHNOLOGIES FOR CONTROLLED RELEASE OF THERAPEUTICS TO TREAT RETINAL DISEASES IN DIFFERENT AGE GROUPS(2024) Kim, Sangyoon; Lowe, Tao L.; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Retinal diseases, such as diabetic retinopathy, glaucoma, macular degeneration, and retinoblastoma, affect around 13 million people worldwide, with projections indicating a rise to 20 million by 2030. These conditions lead to irreversible vision loss and significant impairment in both adults and children, with an annual economic burden of $139 billion in the United States alone. Aging significantly increases the risk of certain retinal conditions, and with improvements in healthcare leading to increased life expectancy, these conditions are becoming more prevalent due to the natural aging process and associated physiological changes in the eye. Current treatments are either destructive or have low efficacy and are not optimized for the younger population. While therapeutics including small molecular drugs, proteins and antibodies show promise in treating these diseases by reducing inflammation and neuronal apoptosis, their effectiveness is hindered by short half-lives and inability to cross the blood-retinal barrier (BRB). Nanoparticles offer a potential solution by improving drug delivery across biological barriers, yet no nanoparticles have been developed to effectively transport intact proteins or small molecules across the BRB to the retina without toxicity, slow clearance and stability. Therefore, there is an unmet need to evaluate the physical and physiological property changes of the eye along development and develop nanoparticle systems that can control and sustain the release of therapeutics across the blood retinal barrier (BRB) to treat the retinal diseases. In this project, the thickness, rheological property, permeability and morphological property changes of ocular barriers including sclera, cornea and vitreous humor in the developing eye from preterm to adult were evaluated using porcine ex vivo model. Two glycosaminoglycan mimicking nanogel systems, poly(NIPAAm-co-DEXcaprolactoneHEMA) nanogels with and without positive or negative charges and β-cyclodextrin based poly(β-amino ester) (CD-p-AE) nanogels were developed for sustained release of intact proteins including insulin and anti-TNFα, and small hydrophobic drugs, respectively across the ex vivo porcine sclera and in vitro BRB models: human fetal retinal pigment epithelial (hfRPE), adult retinal pigment epithelial (ARPE-19) and human cerebral microvascular endothelial (hCMEC/D3) cell monolayers. Completion of this project will have a significant impact on developing novel personalized nanotherapeutics to treat retinal diseases in different age groups.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 PERFORMANCE ENHANCEMENTS OF MICRO CORIOLIS VIBRATORY GYROSCOPES THROUGH LINEARIZED TRANSDUCTION AND TUNING MECHANISMS(2023) Knight, Ryan; DeVoe, Don L; Mechanical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)A quadruple mass Microelectromechanical System (MEMS) Coriolis vibratory gyroscope has been re-engineered with the singular focus of minimizing nonlinear transduction mechanisms, thereby allowing for angle random walk (ARW) noise reduction when operating at amplitudes higher than 2 μm. The redesign involved six primary steps: (i) the creation of an aspect-ratio independent deep reactive ion etch with minimal notching on 100 μm thick silicon-on-insulator device layer, (ii) the creation of micro-torr vacuum packaging capability, enabling operation at the thermoelastic dissipation limit of silicon, (iii) the redesign of Coriolis mass folded flexures and shuttle springs, (iv) the linearization of the antiphase coupler spring rate while maintaining parasitic modal separation, (v) the substitution of parallel plate transducers with linear combs, and (vi) the implementation of dedicated force-balanced electrostatic frequency tuners. Cross-axis stiffness is also reduced through folded-flexure moment balancing to further reduce ARW. By balancing positive and negative Duffing frequency contributions, net fractional frequency nonlinearity was reduced to -20 ppm. The gyroscope presented in this research has achieved, a first reported of its kind, an ARW of 0.0005 °/√hr, with an uncompensated bias instability of 0.08 °/hr. These advancements hold promise for enhancing navigation and North-finding applications. In tandem with gyroscope performance enhancements, vacuum packaging of ceramic chip carrier physics packages has achieved pressure levels below 1 micro-torr, a first in the field and remains state-of-the-art. Besides high-performance MEMS inertial sensors, ultrahigh vacuum packaging proves beneficial for chip scale atomic clocks, which require micro-torr vacuum levels to maintain fractional frequencies less than 10^-12. Finally, an approach to tuning the quality factor mismatch between degenerate modes in as-fabricated gyroscopes has demonstrated a reduction in gyroscope bias instability. This tuning can be achieved by incorporating lead zirconate titanate into regions where the trade-off between mechanical Q, tuning Q, and bias instability reduction is balanced. Both modeling and empirical frequency data justify this approach, suggesting, for typical MEMS foundry Q mismatch of 7%, a 70× reduction in bias instability.Item Functionalized Nanoparticles for the Controlled Modulation of Cellular Behavior(2023) Pendragon, Katherine Evelyn; Fisher, John; Delehanty, James; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The ability to control cellular behavior at the single-cell level is of great importance for gaining a nuanced understanding of cellular machinery. This dissertation focuses on the development of novel hard nanoparticle (NP) bioconjugate materials, specifically gold nanoparticles (AuNPs) and quantum dots (QDs), for the controlled modulation of cellular behavior. These hard NPs offer advantages such as small size on the order of 1 – 100 nm, high stability, unique optical properties, and the ability to load cargo on a large surface area to volume ratio, making them ideal tools for understanding and controlling cell behavior. In Aim 1, we demonstrate the use of AuNPs to manipulate cellular biological functions, specifically the modulation of membrane potential. We present the conception of anisotropic-shaped AuNPs, known as gold nanoflowers (AuNFs), which exhibit broad absorption extending into the near-infrared region of the spectrum. We demonstrate the effectiveness of utilizing the plasmonic properties AuNFs for inducing plasma membrane depolarization in rat adrenal medulla pheochromocytoma (PC-12) neuron-like cells. Importantly, this is achieved with temporal control and without negatively impacting cellular viability. Aim 2 explores the use of QDs as an optical, trackable scaffold for the multivalent display of growth factors, specifically erythropoietin (EPO), for the enhanced induction of protein expression of aquaporin-4 (AQPN-4) within human astrocytes. This results in enhanced cellular water transport within human astrocytes, a critical function in the brain's glymphatic system. We show that EPO-QD-induced augmented AQPN-4 expression does not negatively impact astrocyte viability and augments the rate of water efflux from astrocytes by approximately two-fold compared to cells treated with monomeric EPO, demonstrating the potential of EPO-NP conjugates as research tools and prospective therapeutics for modulating glymphatic system function. Overall, the body of work presented in this dissertation develops new NP tools, namely solid anisotropic AuNFs and growth factor-delivering QDs, for the understanding and control of cell function. These new functional nanomaterials pave the way for the continued development of novel NP-based tools for the precise modulation of cellular physiology.Item MONOLAYER MOLYBDENUM DISULFIDE IN SEMICONDUCTOR ELECTRONICS(2023) Mazzoni, Alexander; Daniels, Kevin M; Electrical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Two-dimensional (2D) semiconductors are a new class of materials being researched due to their unique electrical, optical, and mechanical properties compared to their bulk counterparts. Here I investigate the use of the 2D semiconductor molybdenum disulfide (MoS2) as the active channel material in various electronic devices and circuits. Motivation is provided for 2D materials in general and monolayer MoS2 in particular, followed by an overview of the material properties of MoS2 and a relevant literature review. Back-gated field-effect transistors (FETs) were fabricated and characterized to investigate the impact of growth conditions on material properties, and to study the performance of different contact metals. A top-gated fabrication process was developed to make RF transistors and simple amplifier circuits on rigid and flexible substrates. Finally, device operating characteristics were modeled using simple transistor current-voltage equations, and Monte Carlo electron transport simulations were performed to demonstrate the importance of device operating temperature and intervalley separation in the conduction band.Item LEVERAGING SELF-ASSEMBLY AND BIOPHYSICAL DESIGN TO BUILD NEXT-GENERATION IMMUNOTHERAPIES(2022) Froimchuk, Yevgeniy; Jewell, Christopher M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The immune system has evolved mechanisms to respond not only to specific molecular signals, but also to biophysical cues. Interestingly, research at the interface of biomaterials and immunology has also revealed that the biophysical properties and form of vaccines and immunotherapies impact immunological outcomes. For example, the intermolecular distance between antigen molecules on the surface of nanoparticles can impact formation of T cell receptor clusters that are critical during T cell activation. Despite the importance of biophysical cues in tuning the immune response, the connections between these parameters and immunological outcomes are poorly understood in the context of immunotherapy. Immunotherapies harness an individual’s immune system to battle diseases such as autoimmunity. During autoimmune disease, the immune system malfunctions and mistakenly attacks self-tissue. Immunotherapies can help tailor and guide more effective responses in these settings, as evidenced by recent advances with monoclonal antibodies and adoptive cell therapies. However, despite the transformative gains of immunotherapies for patients, many therapies are not curative, work only for a small subset of patients, and lack specificity in distinguishing between healthy and diseased cells, which can cause severe side effects. To overcome these challenges, experimental strategies are attempting to co-deliver self-antigens and modulatory cues to reprogram dysfunctional responses against self-antigens without hindering normal immune function. These strategies have shown exciting potential in pre-clinical models of autoimmune disease but are unproven in clinical research. Understanding how biophysical features are linked to immunological mechanisms in these settings would add a critical dimension to designing translatable, antigen-specific immunotherapies. Self-assembling materials are a class of biomaterials that spontaneously assemble in aqueous solution. Self-assembling modalities are useful technologies to study the links between biophysical parameters and immune outcomes because they offer precise control and uniformity of the biophysical properties of assembled moieties. Our lab leveraged the benefits of self-assembly to pioneer development of “carrier-free” immunotherapies composed entirely of immune signals. The therapies are composed of self-antigens modified with cationic amino acid residues and anionic, nucleic acid based modulatory cues. These signals are self-assembled into nanostructured complexes via electrostatic interactions. The research in this dissertation utilizes this platform as a tool to understand how tuning the biophysical properties of self-antigens impacts molecular interactions during self-assembly and in turn, how changes in biophysical features are linked to immunological outcomes. Surface plasmon resonance studies revealed that the binding affinity between signals can be tuned by altering overall cationic charge and charge density of self-antigen, and by anchoring the self-antigen with arginine or lysine residues. For example, the binding affinity between signals can be increased by increasing the total cationic charge on the self-antigen, and by anchoring the self-antigen with arginine residues rather than lysine residues. Computational modeling approaches generated insights into how molecular interactions between signals, such as hydrogen bonding, salt-bridges, and hydrophobic interactions, change with different design parameters. In vitro assays revealed that a lower binding affinity between self-assembled signals was associated with greater reduction of inflammatory gene expression in dendritic cells and more differentiation of self-reactive T cells towards regulatory phenotypes that are protective during autoimmunity. Taken all together, these insights help intuit how to use biophysical design to improve modularity of the self-assembly platform to incorporate a range of antigens for distinct disease targets. This granular understanding of nanomaterial-immune interactions contributes to more rational immunotherapy design.Item ENGINEERING LIGHT-ACTIVATABLE NANOCOMPLEX TO OVERCOME MULTIDRUG RESISTANCE AND IMPROVE DRUG DELIVERY(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.Item Data-driven design of MXene aerogels with programmable mechanical performance via active learning and collaborative robots(2022) Shrestha, Snehi; Chen, Po-Yen; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)There is a solid demand for developing intelligent pressure sensing materials for the next generation of soft machines and robots. The piezoresistive pressure sensor requires a high sensitivity within a specific pressure range and possesses superior mechanical stability. Ti3C2Tx MXene-based aerogels with high electrical conductivities have been demonstrated as promising piezoresistive materials for the fabrication of intelligent pressure sensors for diverse sensing applications, from ultra-low stress vibration detection to irregular object grasping. MXene aerogels' piezoresistive behaviors can easily be tuned by changing the fabrication recipes that affect micro/nanostructures. Although many techniques have been reported for fabricating MXene aerogels for specific detection limits, the influence of the interplaying factors and their effect on the aerogels' structures and mechanical properties are not clearly understood. To achieve the custom design for pressure sensors for any given sensing windows and mechanical requirements, understanding the complex correlations between fabrication recipes, aerogel microstructures, and mechanical properties becomes necessary. Since traditional trial-and-error approaches require the production and manual processing of a large amount of data and, therefore, are highly time-consuming. Also, it is impossible to use a trial-and-error-based approach to study multi-dimensional design space as the one needed to construct an enormous amount of MXene-based aerogel sensors. Machine learning is a powerful and versatile tool that uses data-driven computation to uncover underlying trends and complex correlations. Machine learning requires a data-rich system to study the correlations and make accurate analyses and predictions. As the quality and size of the data obtained from the literature remain narrow and biased, it becomes essential to design high-throughput experiments to supply high-quality data to develop prediction models via machine learning. In this presentation, we adopt a hybrid strategy using wet-lab experiments, a machine learning framework, and collaborative robot assistance to build up a prediction model and uncover the underlying design principles to understand the mechanical properties of MXene-based aerogel sensors. Three functional materials (i.e., Ti3C2Tx MXene nanosheets, cellulose nanofibers, and gelatin), and one crosslinker (i.e., glutaraldehyde), are used for the fabrication of piezoresistive aerogels. First, a support-vector machine classifier is trained with 264 different compositions to confirm a feasible fabrication regime. Second, 160 piezoresistive aerogels with various recipes and morphologies are fabricated through active learning loops. Third, through data analyses, data-driven design principles for piezoresistive aerogels were uncovered and validated via in situ microscopic studies. Through this study, we make a crucial discovery about the roles of mass loading and cellulose nanofiber concentration on the mechanical properties of the resulting aerogels. Finally, we demonstrate how the implementation of collaborative robots can accelerate the prediction model construction.