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)

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24494号 / 医博第4936号 / 新制||医||1063(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 村川 泰裕, 教授 小杉 眞司, 教授 松田 文彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24877号 / 医博第5011号 / 新制||医||1068(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 森田 智視, 教授 長船 健二 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23813号 / 医博第4859号 / 新制||医||1059(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 中本 裕士, 教授 花川 隆, 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

No / PURPOSE. Previous studies suggest that optimal reading speed is unaffected by cataract, yet is significantly reduced in age-related macular degeneration (ARMD ). This raises the question of whether a reading speed test could be developed to assess potential vision after cataract surgery. METHODS. Nineteen subjects with cataract, 15 with ARMD, and 13 control subjects with normal, healthy eyes read Bailey-Lovie word charts aloud, and subsequently, critical print size and optimal reading speed were calculated. Measurements were also taken with the charts in reversed-contrast polarity and after pupillary dilation. RESULTS. Although the subjects with cataract had reduced word acuity and increased critical print size, optimal reading speed was similar to that of the control group at a mean of approximately 100 wpm. Optimal reading speed in the subjects with ARMD was substantially worse (mean of 39 wpm). Reversing the contrast polarity of the charts slightly increased the word acuity and optimal reading speed of the subjects with cataract. CONCLUSIONS. The results suggest that optimal reading speed would be useful as a potential-vision test. The proposed test would use text size of at least 1.32 degrees (1.2 log minimum angle of resolution [logMAR]), and pupil dilation would be unnecessary. A reading test with black letters on a white background would be adequate, because charts with reversed-contrast polarity made minimal difference in reading speed.