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Theses and Dissertations

Permanent URI for this collectionhttps://hdl.handle.net/10217/197901

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Browsing Theses and Dissertations by Author "Bailey, Travis S., committee member"

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    Tuning interfacial biomolecule interactions with massively parallel nanopore arrays
    (Colorado State University. Libraries, 2021) Wang, Dafu, author; Kipper, Matt J., advisor; Snow, Chris D., advisor; Bailey, Travis S., committee member; Stasevich, Tim J., committee member
    This project studied interfacial interactions of macromolecules with nanoporous materials, with an ultimate goal of exploiting these interactions in functional biomaterials. We quantified interaction forces and energies for guest molecules threaded into the pores of protein crystals via nano-mechanical atomic force microscopy (AFM) pulling experiments. We demonstrated that both double-stranded DNA and poly(ethylene glycol) are rapidly absorbed within porous protein crystals, where they presumably bind to the inner "wall" surfaces of the protein crystal nanopores. These "guest" molecules can be retrieved from the "host" crystal by chemically modified AFM tips, enabling precise measurements of the adhesion forces and interaction energies. Based on these experiments, machine learning approaches were developed to classify hundreds of thousands of individual force-distance curves obtained in the AFM experiments. Furthermore, we showed that the interactions between protein crystal "hosts" and "guest" macromolecules can be used to modulate cell behavior, by presenting cell adhesion ligands tethered to different lengths of macromolecules that thereby modulate the maximum traction force cells can apply before rupturing bonds tethering the adhesion ligand to the porous protein crystal interior. This method affords the opportunity to create biomaterials that store an internal reservoir of cell-specific signals that can be presented to independently modulate the behavior of different cell populations in a single material. In the first chapter, some recent advancements, and methodologies of measuring interfacial biomolecule interactions are reviewed and compared. The reviewed technics include atomic force microscopy, fluorescence recovery after photobleaching, the total internal reflection fluorescence, confocal microscopy, and optical tweezers. Furthermore, this chapter interduces the application of machine learning to assist the interfacial biomolecule interaction studies, especially the AFM measurements. This chapter further prospects of the future of interfacial biomolecule interactions studies. In the second chapter, the methodologies of probing and observing the surface of highly porous Camphylobacter Jejuni formed protein crystals (CJ protein crystals) by high-resolution AFM are introduced. Throughout this chapter, the morphologies of CJ protein crystals are comprehensively investigated by AFM and have been discussed in this chapter. In the third chapter, for the first time, the interactions of DNA with porous protein crystals are quantitatively measured by high-resolution AFM and chemical force microscopy. The surface structure of protein crystals with unusually large pores was observed in liquid via high-resolution AFM. Force-distance (F-D) curves were also obtained using AFM tips modified to present or capture DNA. The interactions of DNA molecules with protein crystals to be quantitatively studied while revealing the morphology of the protein crystal surface in detail, in buffer, reveals how a new protein-based biomaterial can be used to bind DNA guest molecules. In the fourth chapter, strategies of machine learning are introduced which pioneered the use of machine learning to classify and cluster the interaction patterns between DNA and protein crystals, enabling us to process thousands of F-D curves collected by AFM. Finally, in the fifth chapter, we quantitatively measure and take advantage of the interaction between poly(ethylene glycol) (PEG)-arginine-glycine-aspartic acid (RGD) complex and nanoporous protein crystals to understand how non-covalent surface presentation of peptide adhesion ligands can influence cell behavior. Through AFM, F-D curves of interactions between PEG-RGD and host protein crystals were obtained for the first time. Furthermore, a strategy is developed that enables us to design surfaces that non-covalently present multiple different ligands to cells with tunable adhesive strength for each ligand, and with an internal reservoir to replenish the precisely defined crystalline surface.
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    Zwitterionic polymeric nanoparticles for drug delivery
    (Colorado State University. Libraries, 2024) Lee, Jeonghun, author; Herrera-Alonso, Margarita, advisor; Bailey, Travis S., committee member; Popat, Ketul C., committee member; Peebles, Christie, committee member
    Bottlebrush block copolymers, characterized by their densely grafted side chains stemming from a highly persistent backbone, offer unique advantages for drug delivery, including enhanced micellar stability, reduced critical micelle concentration, and controlled surface topography, setting them apart from traditional linear polymers. This dissertation focuses on zwitterionic bottlebrush block copolymers (ZBCPs) composed of poly(D, L-lactide) (PLA) and poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) side chains, synthesized via a combination of ring-opening and controlled radical polymerization using a grafting-from approach. ZBCPs were self-assembled into uniform spherical micelles and nanoparticles through direct dissolution and rapid mixing methods, and these self-assembled nanostructures were systematically evaluated. Compared to non-ionic PEG micelles (standard), zwitterionic bottlebrush micelles (ZBM) demonstrated superior stability under high salt conditions, elevated temperatures cycles, and in the presence of fetal bovine serum, whereas kinetically assembled nanoparticles (ZBNP) exhibited greater drug loading capacity. Both ZBM and ZBNP also showed excellent hemocompatibility, with ZBM displaying exceptional redispersibility in the absence of cryoprotectants. In parallel, this dissertation investigates boronic acid-functionalized zwitterionic polymers for drug delivery. A linear ABC-type amphiphilic copolymer containing poly(3-aminophenylboronic acid) as the central block was synthesized and compared to its non-functional counterpart. The boronic acid-containing nanoparticles exhibited pH- and oxidation-responsive behavior, enabling controlled drug release. Expanding this concept to a bottlebrush architecture, boronic acid-functionalized bottlebrush triblock copolymers were developed to further enhance nanoparticle performance. The inclusion of a boronic acid interlayer in the bottlebrushes significantly improved redispersibility of drug-loaded nanoparticles while maintaining high drug loading capacity, superior stability, and excellent hemocompatibility. This dissertation provides fundamental insights into solution-based self-assembled nanostructures derived from ZBCPs and boronic acid-functionalized polymers, establishing them as promising advanced drug delivery platforms. These systems offer tunable release kinetics, robust colloidal stability in harsh biological environments, excellent hemocompatibility, and superior redispersibility, thereby enhancing their translational potential in the field of nanomedicine.