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Browsing OU - Theses by Author "Acar, Handan"
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Item Open Access Activation of Interferon Through Glycated Chitosan Administration(2024-08-01) Unkel, Malayna; Chen, Wei; Acar, Handan; Tang, QinggongN-dihydrogalactochitosan (GC) is a novel immunoadjuvant with unique physiochemical properties that poses significant improvements upon its parent molecule, chitosan. Its potent immune stimulation properties make it promising in the world of vaccinations, with already proven reduction of morbidity in COVID studies. The key to generating immunity against intracellular pathogens is to generate a type I/II interferon (IFN) response. GC stimulates the desired IFN responses while other currently used adjuvants such as MF-59 often fail to do so. For comparison purposes, the immune response specific to GC stimulation needs to be understood. It has been previously demonstrated that application of GC in combination with photothermal therapy reduces mortality in cancer treatment studies. Furthermore, intranasal application of GC in combination with recombinant viral proteins has reduced COVID-19 mortality in mice. The fundamental question remains: Is GC acting as a physical barrier, or is GC stimulating a local type I IFN response which in turn activates antiviral pathways in the respiratory epithelium? Building on previously found GC immune activations, now presented are the results of gene activation and interferon activation in in vivo studies over time. This provides insight into the specific mechanisms by which GC succeeds at inducing anti-tumor and anti-viral immunological responses.Item Open Access Automated Algorithm for Optical Coherence Tomography (OCT) Images of 3D Spheroids(2020-12-18) Valerio, Trisha; Tang, Qinggong; Acar, Handan; Yuan, HanThe application of three-dimensional (3D) tumor spheroids has been expanding due to their ability to closely mimic several features of solid tumors such as their cellular heterogeneity/organization and growth kinetics. Optical Coherence Tomography (OCT) system has been utilized to characterize 3D morphological and physiological information of multicellular tumor spheroids. In order to characterize and analyze the results of 3D OCT spheroid datasets, there is a need to develop an automated algorithm with high accuracy that can calculate the volume of a tumor spheroid and its necrotic tissues. The developed automated algorithm can automatically detect the margin of the 3D tumor spheroids and its necrotic region. The measurements from the automated program were then compared with the manual method to assess the accuracy of the developed algorithm through calculations of the Dice coefficient, and the results show a Dice number of 0.9449 and 0.9145 for spheroid and necrotic volume algorithms, respectively. Additionally, curve fitting was performed to further study the growth kinetics of the spheroid and its necrotic tissues, and measures such as root-mean-square error (RMSE) and corrected Akaike information criterion (AICc) were taken for this assessment. According to the RMSE measure, Boltzmann was the best-fitted model for the overall spheroid volume growth. The logistic model, on the other hand, was best fitted in modeling the growth of necrotic core according to both RMSE and AICc values. Quantification of the spheroid volume (and its necrotic core) is significant as morphological features are often related to tumor activities, and determination of the best model is also vital in predicting the behavior of the spheroids. Overall, the algorithm used for this study allows for more efficient, in both time and accuracy, studies such as evaluating the growth medium’s effect on tumor spheroids, growth characterization of varying cell lines, as well as the efficacy of a certain drug.Item Open Access An Investigation of Tricuspid Valve Leaflet Decellularization and Effects on Leaflet Biomechanics and Collagen Architecture(2022-05-13) Vopat, Catherine; Lee, Chung-Hao; Acar, Handan; Breen, SarahThe Tricuspid Heart Valve is composed of three leaflets: the anterior leaflet, posterior leaflet, and septal leaflet. The function of this valve is to open during diastole to allow blood to flow from the atrium to the ventricle, then close during systole to prevent backwards flow of blood, called regurgitation. Valve regurgitation can decrease the effectiveness of the heartbeat and can lead to death over time. Two common heart valve replacements are mechanical heart valves and xenografts. These options have both shown clinical success, however no replacement currently meets the criteria for hemocompatibility, immunological tolerance, and the potential to grow and remodel itself. The decellularized tissue-engineered heart valve (TEHV) may be the key to achieving all of these goals. Decellularization has the potential to remove any immunogenic markers from the tissue while maintaining the complex microstructure that is vital for proper cell differentiation and remodeling. In this study, an H&E staining procedure was optimized for further use in the lab. Nine decellularization procedures with different exposure times to detergent and enzyme solutions were compared to find the optimal procedure. We found that 24-hour exposure to detergent and 12-hour exposure to enzymes was the optimal decellularization procedure for all three leaflets. This optimized decellularization procedure was then used in a biaxial mechanical and collagen microstructural analysis study to determine if the biaxial mechanical characteristics and collagen fiber architecture change as a result of the decellularization treatment. After statistical analysis of several parameters, we found that there were no statistically significant changes from the pre-treatment values to the post-treatment values due to decellularization reagent exposure. These results provide strong evidence that the chosen decellularization procedure is effective at decellularizing the tissue while maintaining the microstructure architecture and mechanical properties of the native leaflet.Item Open Access Investigations of the Tricuspid Heart Valve Function: An Integrated Computational-Experimental Approach(2019-05-10) Laurence, Devin; Lee, Chung-Hao; Siddique, Zahed; Chang, Kuang-Hua; Acar, Handan; Baumwart, RyanThe objective of this research is to employ both in silico modeling and in vitro experimental characterization methods to enhance the understanding of the biomechanical function of the tricuspid heart valve. A finite element (FE)-based computational model of the tricuspid valve (TV) is first developed. Specifically, the geometry used in this computational model is based on parametric representations of the TV leaflets from porcine and ovine hearts and a parametric representation of the chordae tendineae. A nonlinear, isotropic constitutive model is used to describe of the mechanical behaviors of the TV leaflets, while the TV chordae tendineae are modeled as a nonlinear, elastic solid. The developed FE model of the TV apparatus is then used to simulate various pathological states including: (i) pulmonary hypertension, (ii) TV annulus dilation, (iii) papillary muscle displacement associated with right ventricular enlargement, (iv) flattening of the TV annulus, and (v) the rupture of the TV chordae tendineae. Numerical results from this study, as compared to available clinical observations, suggest that the TV annulus dilation and papillary muscle displacement resulting from right ventricular enlargement are key contributors to TV regurgitation. On the other hand, pulmonary hypertension resulted in the largest increase in TV leaflet stress (+65%) indicating pulmonary hypertension may be a key contributor to the adverse remodeling of the leaflet and myocardium tissues. In addition, the simulations of the chordae rupture scenarios reveal that those chordae tendineae attached to the TV anterior and septal leaflets may be more important to preventing TV leaflet prolapse. Extensive biaxial mechanical testing of the TV leaflets is conducted to expand on the limited number of mechanical characterizations of the TV leaflets. These experimental efforts include: (i) a quantification of the TV leaflets’ biaxial mechanical responses, (ii) an investigation of the loading-rate and temperature effects on the TV leaflet tissue mechanics, (iii) an examination of the influence of species and aging on the TV leaflet’s mechanical properties, (iv) an evaluation of the spatial variations of the TV leaflet’s tissue mechanics, and (v) a determination of the contribution of the glycosaminoglycans (GAGs) to the TV leaflet’s mechanical responses. These in vitro experimental results suggest that (i) the TV leaflets are more extensible than the mitral valve leaflets, (ii) the TV leaflets’ responses depend slightly on the loading rate and temperature, (iii) the mechanical responses of the TV leaflets become stiffer with aging (+3.5%-6.1%), (iv) the TV leaflets exhibit spatial variance in the mechanical properties, and (v) the removal of the GAGs leads to an increased extensibility of the TV leaflets (+4.7%-7.6%). Finally, a constitutive modeling framework, based on the hyperelasticity theory, is formulated to describe the mechanical behaviors of the heart valve leaflets from the acquired biaxial mechanical data. Through the differential evolution optimization, model parameters of two strain energy density functions commonly adopted in the soft tissue biomechanics society are estimated by fitting to the representative biaxial mechanical testing data. Results from this numerical study suggest that a refined strain energy density function may be warranted, as part of the future extensions, to fully capture the complex mechanical responses of the heart valve leaflet, especially under combined tensile and compressive loading.Item Restricted Quantification of nanoparticle interactions with the Nanoparticle Clearance System(2020-05-08) Quine, Skyler; Wilhelm, Stefan; Acar, Handan; Moore, MarcThe goal of nanomedicine is to target therapeutic and diagnostic agents to target tissues. However, there are multiple physiological barriers which prevent nanoparticles from reaching the desired destination in the body. Progress has been made in rationally designing nanoparticles to evade physiological barriers and optimize biodistribution, but many still fail to demonstrate significant efficacy to attain clinical approval and use. Contributing to this problem is a lack of quantitative reporting and analysis of nanoparticle interactions with nanoparticle-clearing physiological compartments, which we call the Nanoparticle Clearance System (NCS). In this master’s thesis, we quantify nanoparticle-NCS interactions through a literature review, a quantitative literature survey, preparation of liposomal nanoparticle formulations, and a planned experiment for future research. We identify certain promising techniques to evade the NCS such as the saturation strategy, and conclude that thorough quantitative reporting for novel nanoparticle formulations and the combination of nanomedicine with other fields of knowledge will lead to advances in the efficacy and safety of nanotherapeutics.