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 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 Processing and structural characterization toward all-cellulose nanocomposites(2021) Henderson, Doug A; Briber, Robert M; Material Science and Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cellulose is the most abundant biopolymer on the planet and is used in a variety of industry sectors including paper, coatings, medicine, and food. A deep understanding of cellulose is important for its development as an alternative polymer to those based on petroleum. This work focuses on two cellulose systems. The first of these, cellulose nanofibers, are the basic structural elements of naturally-occurring cellulosic materials; they exhibit excellent mechanical characteristics due to high crystallinity and a dense network of hydrogen bonding. These fibers can be separated from bulk cellulose via a TEMPO oxidation reaction followed by mechanical homogenization into a suspension in water. In this work, the production of these fibers is investigated by monitoring the change in structure of cellulose as a function of TEMPO reaction time and mechanical homogenization using small angle neutron scattering, atomic force microscopy, and optical microscopy. The second cellulose system is a molecular solution of cellulose formed using a binary solvent mixture consisting of ionic liquid and an aprotic solvent. Cellulose is difficult dissolve due to a dense hydrogen bonding network, and ionic liquids have been shown to be an effective alternative to more hazardous and energy-intensive dissolution methods for cellulose currently used in industry. The phase behavior of these solutions has been investigated using small angle neutron scattering as a function of temperature. The process of regenerating cellulose from these solutions is also investigated, as dense gels of cellulose and ionic liquid were produced with a unique multiscale ordered structure. The ultimate goal of this work is to combine cellulose nanofibers and molecular cellulose solutions in order to create all-cellulose nanocomposite films. These films are characterized using tensile testing, atomic force microscopy, and water uptake measurements in order to understand the interaction between cellulose nanofibers and molecular cellulose solutions, water resistance and tunability of mechanical properties.Item Development of Nanoparticle-Based Intracellular Dual Sensing and Actuation Modalities(2017) Field, Lauren D.; White, Ian M; Medintz, Igor L; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The integration of therapeutics with diagnostic agents, or theranostics, is vital for the development of novel and effective disease treatments. To effectively design new and efficient theranostic materials, a thorough understanding of the carrier ensemble, the interactions within the construct components, and the surrounding environment is required. This dissertation focuses on the development of new strategies to produce an effective ‘toolbox’ of nanoscale theranostics, namely through the use of a central NP scaffold and the visualization technique of Förster Resonance Energy Transfer (FRET). The NP scaffold used throughout this work, the semiconductor quantum dot (QD), is ideal for visualizing sensing modalities due to their high quantum yield (QY), tunable, narrow and symmetric emission profiles with broad, far-UV excitation, and resistance to photobleaching - making them optimal FRET donors. We first examined the intracellular assembly of QDs to proteins by injecting 545 nm emitting QDs, coated with various capping ligands, into cells transfected to express mCherry at two distinct intracellular locations: the cytosol and the plasma membrane. We found that the small, zwitterionic capping ligand CL4 and the cytosolically located mCherry protein assembled into the most efficient FRET complexes. We used this knowledge to design and implement a novel intracellular actuation modality for drug delivery that used a 520 nm emitting QD with the carrier maltose binding protein appended to the surface and carrying drug or dye conjugated to a maltose analog, -cyclodextrin in the binding pocket. Rather than relying on intracellular environmental changes or external stimuli to actuate release, the addition of the innocuous sugar maltose to the medium induced cargo actuation and could be visualized via FRET. Finally, the same methods were implemented to develop a novel pH sensor to report on the extracellular changes that occur in tumor development where the physiological pH is lowered dramatically. Using a 464 nm QD scaffold conjugated to pH-responsive FITC, we successfully monitored changes in extracellular pH and accurately determined unknown pH values. With the work in this thesis, we believe we have contributed greatly to the advancement and development NPs for the design and implementation of sensing and actuation complexes.Item Bio-templated Substrates for Biosensor Applications(2013) Fu, Angela Li-Hui; Kofinas, Peter; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Nanopatterning of materials is of particular interest for applications in biosensors, microfluidics, and drug delivery devices. In biosensor applications there is a need for rapid, low cost, and durable system for detection. This dissertation aims to investigate methods to pattern nanostructured surfaces using virus particles as templates. The virus species used in these experiments is a cysteine modified tobacco mosaic virus. The first project utilized the lamellar microphase separation of a block copolymer to pattern the virus particles. Although microphase separation of the poly(styrene-b-2-vinylpyridine) (PS-P2VP) into lamellae was confirmed, specificity of the viruses to the gold doped block of the polymer could not be achieved. Single virus particles lay across multiple lamellae and aggregated in side-to-side and head-to-tail arrangements. The second project studied the effect of a surfactant on virus assembly onto a gold chip. The experiments included placing a gold chip in virus solutions with varying triton concentrations (0-0.15%), then plating the virus particles with a metal. Results showed that as the triton concentration in the virus solution increases, the virus density on the surface decreases. The gold coated virus particles were applied to Surface Enhanced Raman Spectroscopy (SERS) detection in the final project. SERS is of interest for biosensor applications due to its rapid detection, low cost, portability, and label-free characteristics. In recent years, it has shown signal enhancement using gold, silver, and copper nanoparticles in solutions and on roughened surfaces. The gold plated virus surfaces were tested as SERS substrates using R6G dye as the analyte. An enhancement factor (EF) of 10^4 was seen in these samples versus the non-SERS substrate. This corresponded to the sample with 0.05% triton in the virus solution which showed the most intersection points between the virus particles and the most uniform coverage of the viruses on the surface. This value is lower than that of previous studies; however, future work may be performed to optimize conditions to achieve the highest signal possible.Item Scanning Tunneling Microscopy at milliKelvin Temperatures: Design and Construction(2010) Gubrud, Mark Avrum; Anderson, James R; Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)This dissertation reports on work toward the realization of a state-of-the-art scanning tunneling microscopy and spectroscopy facility operating at milliKelvin temperatures in a dilution refrigerator. Difficulties that have been experienced in prior efforts in this area are identified. Relevant issues in heat transport and in the thermalization and electrical filtering of wiring are examined, and results are applied to the design of the system. The design, installation and characterization of the pumps, plumbing and mechanical vibration isolation, and the design and installation of wiring and fabrication and characterization of electrical filters are described.Item "Smart" Fluids: Self-Assembled Systems with Viscosity Tunable by Light(2008-03-19) Ketner, Aimee Marie; Raghavan, Srinivasa R; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)A "smart" fluid is one that undergoes a change in some macroscopic property in response to an external stimulus, such as light or magnetic fields. One class of "smart" fluids is photorheological (PR) fluids, which exhibit changes in their rheological or flow properties (such as viscosity) upon irradiation with light at a given wavelength. These PR fluids may be useful in a variety of applications, such as in sensors and microfluidic devices. Currently, the need to synthesize complex photosensitive molecules hampers the widespread use of these fluids. In this dissertation, we are working toward simple classes of PR fluids that require no special synthesis and can thereby be easily replicated in any laboratory from inexpensive chemicals. In the first part of this study, we report a new aqueous PR fluid that exhibits a 10,000-fold reduction in viscosity upon UV irradiation. The fluid consists of the cationic surfactant, cetyl trimethylammonium bromide (CTAB), and the photoresponsive organic derivative, trans-ortho-methoxycinnamic acid (OMCA). Aqueous mixtures of CTAB and OMCA self-assemble into long, chainlike structures called "wormlike micelles", and the solution thereby has a very high viscosity. Upon irradiation by UV light (< 400 nm), OMCA undergoes a photoisomerization from its trans to its cis form, which alters the molecular packing at the micellar interface. The result is to transform the long wormlike micelles into much shorter entities and, in turn, the solution viscosity decreases by more than 4 orders of magnitude. We use small-angle neutron scattering (SANS) to confirm the dramatic reduction in micellar length. Our studies also show how one can tune the magnitude of viscosity reduction in these PR fluids based on the composition of the mixture as well as the duration of the irradiation. In the second part of this study, we turn our attention to non-aqueous solvents and demonstrate how to make PR fluids in such solvents. The PR effect in these fluids relies on transformations of "reverse" micellar structures formed by a common lipid (lecithin) in conjunction with a stilbene-based photoresponsive additive, 4-hydroxy-4'-nitrostilbene (HNS). Certain mixtures of lecithin/HNS/water in cyclohexane undergo an increase in viscosity (photogelling) upon irradiation with UV light. Interestingly, other compositions of the same mixtures undergo a decrease (photothinning) in viscosity upon irradiation. Both PR fluids described above provide a one-way (high to low, or low to high) viscosity switch. In the third and final part of this study, we report an aqueous system that provides a true, reversible PR fluid, where the viscosity can be switched from high to low and back using different wavelengths of light. These fluids are based on mixtures of a 22 carbon-tailed cationic surfactant with an azobenzene-based photosensitive molecule, 4-azobenzene carboxylic acid (ACA). The conceptual basis for these fluids is similar to that in our first study, and moreover, these molecules are also inexpensive and available from commercial sources. This opens the door to future investigations on PR fluids from both academic and industrial laboratories and should eventually lead to new applications for this interesting class of responsive materials.Item COMPOSITE QUANTUM WELL: CO-EXISTENCE OF ELECTRONS AND HOLES(2005-04-28) Mampazhy, Arun Sankar; Yang, Chia-Hung; Electrical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)A field effect transistor is fabricated using a composite quantum well structure consisting of adjacent semiconductor quantum wells, GaSb and InAs, sandwiched by AlSb and GaSb barriers. It is found that with a proper gate bias the concentration of the hole and the electron carriers in this device can be controlled. Properties of this device can be utilized in realizing lateral resonant interband tunneling diodes, single electrons transistors and other interesting quantum devices.Item On the Typical and Average Contributions to the Persistent Current in Mesoscopic Rings(2004-07-27) Jariwala, E. Manher Q.; Webb, Richard A; Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Low-temperature measurements of the magnetic response of one or more electrically-isolated, micron-sized metallic rings yield an unexpected yet unequivocal result: the presence of equilibrium persistent currents, with nanoampere-sized amplitudes and either h/e- or h/2e-periodicity in the applied magnetic flux. This effect follows from the extended phase coherence of the conduction electrons in this disordered mesoscopic system. As with transport phenomena, this thermodynamic effect demonstrates sample-specific as well as ensemble-averaging qualities common to mesoscopic physics. With few exceptions, however, there is strong disagreement between the different theoretical calculations and the few successful experiments to date. For this thesis work, we have designed and executed a unique and unprecedented new experiment: the measurement of the sign, amplitude, and temperature dependences of both the typical and average current contributions to the h/e- and h/2e-periodic magnetic response of the same sample of thirty mesoscopic Au rings. Of particular interest here is the innovative design of our custom SQUID-based detector as well as the unusually long phase coherence of electrons in our lithographically-patterned Au sample. Remarkably, both the typical and average contributions are diamagnetic in sign near zero field, over multiple cooldowns, and comparable in magnitude per ring to the Thouless scale Ec of energy level correlations. Taken in conjunction with earlier experiments, the new data strongly challenge conventional theories of the persistent current.