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Theses and Dissertations

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Browsing Theses and Dissertations by Author "James, Susan P., advisor"

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    Development of bioinspired hyaluronan enhanced synthetic polymers for medical applications
    (Colorado State University. Libraries, 2023) Gangwish, Justin Phillip, author; James, Susan P., advisor; Bailey, Travis S., advisor; Dasi, Lakshmi Prasad, committee member; Popat, Ketul, committee member; Monnet, Eric, committee member
    The first transcatheter aortic valve replacement (TAVR) was performed in 2002, and over the past two decades has become as prevalent as surgical aortic valve replacements in America. TAVR's have significant potential to provide relief for patients with aortic valve disease, but due to their high cost remain accessible primarily in wealthy nations. Furthermore, TAVR's have limited lifespans and are radiotransparent so they can only be evaluated for function through echocardiography. Thus, an expensive medical implant with limited durability is only replaced after it has begun to fail and cause the patient further stress on their heart. To address these issues this dissertation reviews the research performed in generating a novel heart valve leaflet material that is radiopaque, made primarily out of linear low-density polyethylene (LLDPE), and incorporates the biological polymer hyaluronan (HA). These leaflets could significantly reduce the cost of TAVR's potentially allowing for global adoption of the technology. They are radiopaque and easily imaged using x-ray fluoroscopy allowing changes in leaflet shape or movement to be identified prior to when the echocardiography would have shown a deleterious effect to function. They incorporate HA which is found in the interior lumen of blood vessels and has been shown to decrease calcification and thrombosis, both of which have caused polymeric leaflets to fail in previous research. Finally, they can be easily shaped and reinforced allowing for a potentially far greater device lifespan. The leaflets are made by melt pressing in radiopaque powders of either tungsten or bismuth trioxide into sheets of LLDPE followed by treatment with HA to form an interpenetrating polymer network. The material properties of the leaflets were evaluated for their tensile mechanical properties, their hydrophilicity, their radio transparency (or lack thereof), and their hemodynamics. The biocompatibility of the leaflets was evaluated through a cytotoxicity assay, whole blood clotting on the surface of the material, and the ability for platelets to adhere and activate on the material surface. The results demonstrate the material has significant potential to function as a heart valve leaflet in a TAVR. Beyond evaluating this novel material, the process by which HA is incorporated into LLDPE was examined and optimized for commercial scale up. First, the need for solvent distillation and nitrogen blankets during treatment were determined to be unnecessary to produce an HA IPN with LLDPE. Then the rate at which the LLDPE is drawn from the HA solution as well as the vacuum pressure and temperature during this process was found to affect the amount of active HA at the surface of the material. Finally initial evidence was found that shows that HA IPN does not form through the bulk of the material, but rather in the first few microns of the LLDPE. Unrelated to TAVR's a study was performed to enhance the non-woven polypropylene used in surgical masks and N-95 masks against COVID-19 using HA and polyethylene glycol (PEG). HA was used to form a microcomposite on the surface of the non-woven polypropylene while PEG was grafted to the surface with oxygen plasma. The resulting materials were evaluated for their tensile mechanical properties, breathability, chemical composition, hydrophilicity, cytotoxicity, and ability to adsorb COVID-19 spike protein. The results indicate the material has notable potential to make masks more effective at preventing the transfer of COVID-19, however further studies using live SARS-CoV-2 virus beyond the capabilities of this laboratory are necessary before that potential can be fully confirmed.
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    Failure analysis and durability enhancement of polymeric heart valve leaflets
    (Colorado State University. Libraries, 2024) Khair, Nipa, author; James, Susan P., advisor; Bailey, Travis S., advisor; Li, Vivian, committee member; McGilvray, Kirk, committee member
    Rheumatic and calcified aortic heart valve disease is prevalent globally among all aged people, and the number is rapidly increasing. Clinically accepted, minimally invasive xenograft-based transcatheter aortic heart valve replacement (TAVR) shows limited durability (<10 years). Hyaluronic acid (HA) enhanced polyethylene polymeric TAVR shows excellent in vitro and in vivo anti-calcific, anti-thrombotic, and hydrodynamic performance, making it a suitable candidate for heart valve leaflets. The main problem, however, is during durability testing, cyclic impact loading causes premature failure in a consistent fashion related to TAVR assembly. This dissertation investigates leaflet premature failure mechanisms and provides two plausible solutions to upgrade heart valve durability without sacrificing performance. With regard to the failure mechanism, representative areas of retrieved failed leaflets are examined under electron microscopy and small angle x-ray scattering. The investigation finds abrasive wear, wear polishing, fine scratching, and imprints of the metal stent of the leaflet surface, indicating surface wearing from soft plastic rubbing against hard metal. A strong permanganate oxidizer etches away low-energy amorphous domain to unveil stable spherulitic structures of approximately 3 µm, bridging and tie molecular domains of pristine LLDPE. The oxidizer partially etches away polymeric buildups of failed leaflets only to reveal thinned-out and fractured spherulites beneath them, identifying the buildups as stress precursors. SAXS study reports local lamellar disruption further confirming the SEM results. Most. Notably, this is the first study that, to our knowledge, to directly image stable craze cross-tie microstructure that formed due to chain disentanglement from high amplitude cyclic stress. The SEM images validate previous theoretical and computational molecular dynamics models of cross-tie structure architecture. Therefore, leaflet premature failures are the compound effect of cyclic fatigue-initiated crazing and surface wear. Heart valve leaflet durability can be upgraded by controlling crazing and surface wearing. Both the crazing and surface wearing can be controlled by crosslinking of randomly folded amorphous chains. Because they are direct impacts of chain disentanglement under high amplitude cyclic stress. Crosslinked covalent bonds of polymer limit chain movements. LLDPE thin sheets are crosslinked at 50, 70, 100, and 150 kGy doses using 200 KeV (low energy) and 4 MeV (low energy) electron beams at room temperature in the air. Their effects are characterized by measuring gel content percentage, tensile testing, Differential Scanning Calorimetry (DSC), nanoindentation, and nano scratch test. Crosslinked LLDPE heart valve leaflet tested in in vitro flow loop and wear tester to determine valve performance and durability, respectively. Low energy electron beam (LEEB) forms 28% xylene insoluble gel whereas high energy electron beam (HEEB) forms 58 % gel at 100 kGy doses. LEEB does not affect mechanical properties, but HEEB significantly increases stiffness and yield strength. A slight reduction of melting temperature is found for LLDPE crosslinked by both of the energy sources. Nanomechanical tests show crosslinking improves hardness and coefficient of friction, an indication of improving surface wear resistance, which can explain durability improvement. Heart valve durability can also be improved by strengthening the leaflet with fiber reinforcement. A thin plastic sheet is assembled into a cylindrical form by welding two ends, which never fails. The weld at the commissure post is found to be mechanically stronger than the rest of the leaflet, which protected this region. Braided fibers are embedded on the leaflet regions of the commissure post perpendicular to the valve circumference, mimicking the weld but at a much higher strength. Leaflet durability skyrockets from a few million ISO 5840-2005 cycles to 73 million. The entire cardiac cycle of the heart valve with embedded fibers of varying angles, lengths, and numbers is simulated in Finite Element Analysis (FEA) to study their effects on leaflet maximum principal stress and leaflet opening dynamics. Horizontal fibers wrap the leaflet 360° to relax the leaflet completely during peak diastolic. However, the leaflet has a higher coaptation gap and delayed opening. The heart valve with embedded horizontal fibers is physically manufactured and tested in an in vitro flow loop and wear tester, which showed improved durability, but compromised hemodynamics. Finally, strategically crosslinked leaflet was simulated in FEA where leaflet regions of the commissure post and stent line are assigned with stiff crosslinked LLDPE material property, but the rest of the cusps undergo maximum bending are assigned with uncrosslinked LLDPE material property. Results show that strategically crosslinked leaflets open more easily than fully crosslinked leaflets. The final chapter discusses 3D shaped LLDPE leaflet bio enhancement process. Leaflets are 3D shaped in a vacuum thermoformer followed by the HA enhancement. Whole blood clotting resistance, platelet adhesion, activation, and cytotoxicity studies are conducted to determine at 10-4 µmol/mm2 ranged HA population density is required to achieve the best biocompatibility. Generally, water contact angle, Toluidine Blue O (TBO) elution assays, ATR-FTIR are used to determine overall HA presence on the leaflet. This study reports TBO staining and elution is the most effective and accurate measurement tool for determining HA population density. Fiber-reinforced LLDPE, and crosslinked LLDPE are HA-treated, and TBO staining predicts heavily populated HA surface density.
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    Hydroxyapatite structures created by additive manufacturing with extruded photopolymer
    (Colorado State University. Libraries, 2019) López Ambrosio, Katherine Vanesa, author; James, Susan P., advisor; Ma, Kaka, committee member; Prawel, David A., committee member
    Bone tissue has the ability to regenerate and heal itself after fracture trauma. However, this ability can be affected by different risk factors that are related to the patient and the nature of the fracture. Some of the factors are age, gender, diet, health, and habits. Critical-sized defects are particularly difficult, if not impossible, to heal correctly. Particularly in large defects, bone regeneration ability is impeded, disrupting normal healing processes, resulting in defective healing, integration, and non-union. To prevent and treat defective healing or non-union, surgical intervention is needed. Surgeons implant various forms of devices between the ends of the broken bone, usually with external fixation. Implants function by guiding and enabling new bone ingrowth while giving support to the healing tissue. Some of the most common implants are autografts, allografts, and metallic endoprostheses. Unfortunately, these common techniques have drawbacks such as the risk of infection and relatively poor biological or mechanical compatibility with host tissue, in addition to the limited source of donor tissue and high cost, often resulting from secondary surgical interventions. Critical defects are particularly problematic. Hence, there is a necessity for bone implant substitutes that diminish the risk of infection and incompatibility while also providing similar mechanical properties to real bone tissue. Hydroxyapatite (HAp) is a ceramic with a chemical composition similar to bone tissue that has shown biocompatibility and osteoconductive properties with host bone tissue, but it is difficult to manufacture into complex structures with mechanical properties comparable to bone tissue. Therefore, significant efforts are directed to produce materials and methods that could produce HAp synthetic implants to treat bone defects. This research aimed to create and characterize a hydroxyapatite photo-polymeric resin suitable for 3D printing, which could produce dense HAp ceramic parts in complex shapes without requiring support material. We created a HAp-based photopolymer slurry that achieved 41 vol% HAp loading in homogenous slurries. The HAp slurries presented a strong shear thinning behavior and dispersion stability over 20 days under dark storage conditions. The resultant rheological behavior of HAp slurries enabled 3D printing of HAp green bodies in complex shapes using a combination of viscous extrusion and layer-wise photo-curing processes. Complex structures with concave and convex forms and scaffolds with interconnected pores ranging from 130 µm to 600 µm pore sizes and 10% to 40% porosity were successfully built with high resolution and no support material. Moreover, HAp/PEGDMA green bodies presented complete layer cohesion. After 3D printing, sintering was used to densify HAp structures and eliminate the polymer matrix. The resultant HAp structures maintained their complex details, had a relative density of ~78% compared to fully dense HAp and a dimensional shrinkage of ~15% compared to its green body. Sintered HAp structures were found to be non-cytotoxic for ADSCs cells. Flexural properties of HAp green and sintered structures were also determined. It was found that green bodies had a flexural strength of ~30.42MPa comparable to trabecular bone. To summarize, a photopolymerizable resin with 41 vol% of HAp was created to produce ~78% dense HAp complex structures. This was achieved by using additive manufacturing that combined viscous extrusion and layer-wise photo-curing and a sintering process. HAp/PEGDMA showed flexural strength comparable to the trabecular bone, and HAp sintered structures demonstrated non-cytotoxic behavior.