Indiana University-Purdue University Indianapolis (IUPUI) / The thesis includes two application studies of computational fluid dynamics. The first is new and efficient drug delivery to the posterior part of the eye, a growing health necessity worldwide. Current treatment of eye diseases, such as age-related macular degeneration (AMD), relies on repeated intravitreal injections of drug-containing solutions. Such a drug delivery has significant cant drawbacks, including short drug life, vital medical service, and high medical costs. In this study, we explore a new approach of controlled drug delivery by introducing unique porous implants. Computational modeling contains physiological and anatomical traits. We simulate the IgG1 Fab drug delivery to the posterior eye to evaluate the effectiveness of the porous implants to control the drug delivery. The computational model was validated by established computation results from independent studies and experimental data. Overall, the results indicate that therapeutic drug levels in the posterior eye are sustained for eight weeks, similar to those performed with intravitreal injection of the same drug. We evaluate the effects of the porous implant on the time evaluation of the drug concentrations in the sclera, choroid, and retina layers of the eye. Subsequent simulations were carried out with varying porosity values of a porous episcleral implant. Our computational results reveal that the time evolution of drug concentration is distinctively correlated to drug source location and pore size. The response of this porous implant for controlled drug delivery applications was examined. A correlation between porosity and fluid properties for the porous implants was revealed in this study. The second application lays in the computational modeling of the oscillating

Objectives: Our goal was to explore the association between vision with cognitive change scores and incident depression. Methods: A 3-year prospective cohort study was performed. Incident depression was defined using a cut-off score of 10 on the Center for Epidemiologic Studies Depression scale. Cognitive change was examined by calculating the difference between baseline and follow-up cognitive tests scores. Multivariable Poisson and linear regression were used. Results: Cataract was associated with incident depression (relative risk=1.20, 95% confidence interval 1.05, 1.37). Visual impairment was associated with the 3-year change in Rey Auditory Verbal Learning Test (RAVLT) (β=-0.18, 95% CI= -0.28, -0.07), RAVLT-Delayed (β=-0.13, 95% CI= -0.25, -0.02), and Animal Naming Test (β=-0.95, 95% CI= -1.44, -0.45) scores. Glaucoma was associated with 3-year Mental Alternation Test change scores (β=-0.40, 95% CI -0.77, -0.04). Conclusions: Cataract was associated with increased depression risk. VI and glaucoma are associated with 3-year changes in cognitive test scores.

Final publication is available at http://www.sciencedirect.com/science/article/pii/S0002939414000488 / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19586号 / 医博第4093号 / 新制||医||1014(附属図書館) / 32622 / 京都大学大学院医学研究科医学専攻 / (主査)教授 大森 孝一, 教授 宮本 享, 教授 横出 正之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20975号 / 医博第4321号 / 新制||医||1026(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川上 浩司, 教授 鈴木 茂彦, 教授 開 祐司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20994号 / 医博第4340号 / 新制||医||1027(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 鈴木 茂彦, 教授 伊佐 正, 教授 大森 孝一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Gaining knowledge about methods of memory enhancement is important because it allows us to develop effective strategies and interventions to increase memory performance, optimize cognitive function, and potentially alleviate memory-related challenges such as age-related cognitive decline or memory disorders. This thesis aims to examine the influence of age on self-reported mental imagery (MI) experiences and investigate the potential effects of age and MI on memory training performance using the Method of Loci (MoL). The thesis utilizes data collected from a mobile application from a previous research project conducted at Umeå University. The main findings of this thesis indicate that older adults spent more time on encoding and retrieval tasks, suggesting a decline in cognitive processing speed. However, there was no significant decline in MI ability with age, challenging previous research and suggesting that MI ability may remain relatively stable throughout the lifespan. The findings also suggest that there was no significant correlation between higher MI ability and performance in MoL training. Participants rating themselves as having weaker MI were often achieving high levels in the MoL-training, indicating the potential utilization of alternative cognitive strategies than MI. Spending more time on encoding and retrieval tasks was associated with better performance in MoL training. The findings suggest that age-related declines in processing speed may not necessarily hinder individuals' ability to utilize MoL effectively. However, the findings challenge the idea that MI is such a decisive factor in MoL training and raise questions about which other mechanisms work together for a successful result.

Despite being the most prevalent presentation of Age-Related Macular Degeneration (AMD), dry AMD (dAMD) lacks a therapeutic treatment. Retinal pigment epithelium (RPE) dysfunction preceding the onset of dAMD has inspired interest in regenerative medicine approaches seeking to replenish the RPE and preserve visual acuity. Cell delivery to the subretinal space however has been met with challenges surrounding ease of access and invasive surgical implantation. Two-dimensional scaffolds have made use of natural and polymeric materials to act as carriers for RPE cells and various progenitor lines. These substrates mitigate issues surrounding the handling of delicate cell sheets harvested for transplant. As well, they are often successful in preserving RPE phenotype, supporting growth, and can be fine tuned to possess morphologies comparable to native extracellular matrix (ECM). Despite aiming to act as replacement Bruch’s membrane on which RPE resides, two-dimensional substrates are often notably bulky and require traumatic surgery for implantation. As a result, the use of injectable methods of cell delivery has gained appeal. Bolus injections, despite improved methods of administration, are correlated with issues of inadequate cell localization. In response, three-dimensional hydrogel carriers for retinal applications aim to encapsulate cells, allowing for better cell distribution as these materials spread throughout the subretinal space. Increased viscosity of hydrogels as compared to saline injections, is hypothesized to improve cell loss and reduce aggregation. Of particular interest are in situ gelling systems, which undergo physical changes upon injection. Gelation upon delivery works to further assist in maintaining the cells within their target site. Purity and reproducibility concerns associated with the use of natural materials in the development of hydrogel cell carriers, have inspired the use of synthetic thermoresponsive poly-N-isopropylacrylamide (pNIPAAm). pNIPAAm undergoes a liquid to gel transition at a lower critical solution temperature (LCST) of 32°C. Copolymerization with various hydrophobic and hydrophilic groups can be used to adjust gel properties such as increasing or decreasing LCST, allowing for degradation, and improving water retention. In the work described herein, two NIPAAm-based thermoresponsive hydrogels intended for use as subretinal cell carriers are proposed. / Thesis / Master of Applied Science (MASc)

This thesis discusses pyridinium bisretinoid compounds (PBRs), which were prepared for two purposes: 1) to use them as standards for detection of novel fluorophores in human RPE cells, which may be involved in age-related macular degeneration (AMD), and 2) to use them in the development of a targeted and triggered drug delivery system for cancer therapy. We prepared a selection of PBRs using a one-pot biomimetic method; synthesis, mechanisms for formation, and characterization of these compounds is described. We also explored the photoreactivity of three novel PBR compounds and found that these PBRs form oxidation products under blue-light irradiation. The photoinduced cytotoxity of A2P and A2EE was examined in HL-60 cells. Results from this work suggest that the PBRs presented have the potential to be involved in AMD and to be developed into a targeted and triggered drug delivery system for cancer therapy.

Several studies have assessed the effects of intermittent hypoxia-normoxia training (IHNT), intermittent hypoxia-hyperoxia training (IHHT), and obstructive sleep apnea (OSA) on aging and age-related diseases in humans; however, the results remain contradictory. Therefore, this review aims to systematically summarize the available studies on the effects of IHNT, IHHT, and OSA on aging and age-related diseases. Relevant studies were searched from PubMed, Google Scholar, Cochrane Library databases, and through manual searching from reference lists of eligible studies. A total of 38 eligible studies were included in this systematic review. IHHT and IHNT provide positive effects on several age-related parameters including quality of life, cognitive and physical functions, plasma level of glucose and cholesterol/LDL, systolic blood pressure, red blood cells, and inflammation. Moreover, moderate intermittent hypoxia induces telomerase reverse transcriptase (TERT) activity and telomere stabilization, delays induction of senescence-associated markers expression and senescence-associated b-galactosidase, upregulates pluripotent marker (Oct4), activates a metabolic shift, and raises resistance to pro-apoptotic stimuli. On the contrary, intermittent hypoxia in OSA causes hypertension, metabolic syndrome, vascular function impairment, quality of life and cognitive scores reduction, advanced brain aging, increase in insulin resistance, plasma hydrogen peroxide, GSH, IL-6, hsCRP, leptin, and leukocyte telomere shortening. Thus, it can be speculated that the main factor that determines the direction of the intermittent hypoxia action is the intensity and duration of exposure. There is no direct study to prove that IHNT/IHHT actually increases life expectancy in humans. Therefore, further study is needed to investigate the actual effect of IHNT/IHHT on aging in humans.