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ItemThe Biomechanical Role of Hyaluronan in Cell Migration(Georgia Institute of Technology, 2022-05-06) Cohen, ShlomiCell adhesion and migration are essential to fundamental processes throughout the lifespan of multicellular organisms, including in embryonic development, tissue maintenance, and disease. Over the past several decades, researchers have established a deep molecular understanding of the mechanisms governing the attachment of cells to the extracellular matrix (ECM) through assemblies of adhesion proteins at the cell-ECM interface. However, sizable sugars and glycoproteins residing at the very same cell-ECM interface may also play an important yet unrecognized mechanical role in the regulation of cell adhesion and migration. Hyaluronan (HA), a giant sugar synthesized on the cell membrane by the HA synthase family is often confined at the cell-ECM interface as part of the membrane-bound HA-rich glycocalyx or embedded into macromolecular structures in the ECM. We hypothesized that confined HA at the cell-ECM interface is compressed, and the consequent repulsion may counteract adhesive forces to decrease the effective cell adhesion strength, and thereby modulate cell migration speed. We explored the potential biomechanical role of HA in vitro, ex vivo and in vivo, by manipulating cells to change the levels of interfacial HA and by quantifying the resulting cell morphology, adhesion, and migration responses. We then compared our results with polymer physics-based theoretical predictions and integrated them into experiment-driven models that predicted the repulsion force by compressed HA at the interface as well as HA-induced membrane configurations at the dorsal and ventral sides of the cell. Taken together, our results suggest another layer of regulation by HA exists in the molecular mechanisms governing cell adhesion and migration and they emphasize the hidden mechanical role sugars may play in other biological processes.
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ItemSPATIOTEMPORAL IMPACT OF PHAGE EXPOSURE ON BIOFILM SYSTEMS(Georgia Institute of Technology, 2021-12-14) Selvakumar, HemaaWhen single-celled prokaryotic organisms, one of the simplest forms of life, develop the ability to exhibit complex emergent properties such as social cooperation, resource capture, and enhanced survivability, the individual limitations of existence can be overcome which would otherwise be unlikely. Emergent properties of biofilms such as matrix production, quorum sensing, and coordinated lifecycle offers structural and functional advantages which makes them highly successful at evading destruction by antimicrobials and immune defenses. With few, if any, novel antibiotics in the clinical pipeline, there is a resurgence of interest in alternatives such as phage therapy, the practice of bacterial viruses known as bacteriophages that infect and lyse bacteria to treat infections. In this thesis, we explore the understudied impact of phage titer on biofilm dynamics and outcomes. We determined that the biofilm developmental stage at the time of phage addition modulates its response. These responses vary as a function of the phage dose and can be broadly organized into four distinct classes. In each of these classes, we observe that high phage doses restrain the biofilm from transitioning into the next stage of their developmental cycle. A paradoxical aspect of this result is that mature biofilms exposed to high phage titers are enhanced by phage treatment. Despite this apparently unwanted outcome, the inhibition of biofilm dispersion in phage-treated samples could potentially minimize the further spread of infections to other locations. These results comprehensively demonstrate predictable biofilm outcomes versus phage dosage and biofilm age, and will provide guidance in advancing phage-based personalized medicine when generalized treatments fail. Collectively, this dissertation derives insights on the advantages and limitations of phages to inhibit, control, and eliminate biofilms.
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ItemHYALURONAN POLYMER BRUSH STRUCTURE, TOPOGRAPHICAL CONTROL, AND ITS RESPONSE TO THE ENVIRONMENT: CHARACTERIZING A NOVEL ULTRA-THICK BIOMATERIAL(Georgia Institute of Technology, 2021-04-29) Faubel, JessicaPolymer brushes are dense assemblies of end-grafted polymers which have a wide range of applications in lubrication, colloidal stabilization, surface functionalization, and fundamental polymer physics. This thesis focuses on developing and leveraging a new class of polymer brush generated by the enzyme, hyaluronan synthase. The hyaluronan brushes are tunable and can reach heights of up to ~22 µm – 2 orders of magnitude thicker than most brushes and more than one order of magnitude thicker than any previously reported brush. These ultra-thick brushes enable unprecedented characterization through direct visualization with confocal microscopy, as well as manipulation for future applications. In this thesis, I first establish control over brush synthesis, the ability to stop and start the brush growth, and demonstrate the inherent regenerative capability of the brushes. Then, building on those results, my focus is to elucidate and manipulate the internal brush structure and response to stimuli by exploiting the rapid characterization capabilities of confocal microscopy. Techniques to fluorescently label the brush were developed to acquire high-resolution concentration profiles of the hyaluronan brush versus brush height. The profiles are consistently convex and decay in an exponential-like fashion consistent with theoretical predictions for polydisperse brushes. When coupled with experimentally acquired molecular weight distribution, these profiles can be used to directly test theoretical polymer physics, especially in the domain of polyelectrolytes where theory is still being established. Next, spatial manipulation of the local brush grafting density was developed to enable precision patterning and sculpting of the topography of the thick brush. Careful studies revealed that the mechanism behind the grafting density alteration arises from the indirect laser deactivation of the HA synthase enzymes via the generation of reactive oxygen species from light-substrate interactions, specifically the bacterial membrane fragments containing the HA synthase. The patterning is most efficient at shorter wavelengths (405nm), but also can be achieved using wavelengths in the visible spectrum. The same technique can also be used to make binary-brush landscapes consisting of brush-rich and brush-free regions. The stimulus-responsiveness of the brush was explored as both an exercise in polymer physics, as well as for future materials applications. In response to varying salt concentration (NaNO3), the hyaluronan brushes reversibly traverse through the osmotic and salted brush regimes, while irreversibly collapsing in the presence of 90% ethanol, a poor solvent. Groundwork for future studies of the time-dependent nature of the stimulus response and of the dynamics of flow over the brushes has been established. These studies will be integral for potential applications such as anti-microbial implant coatings, where understanding the stimulus response time and flow-dependent decay of the brush will be key. The knowledge and tools gained in this work will aid in a spectrum of rich research arenas ranging from polymer physics to cell biophysics to materials science.