No description available.

京都大学 / 新制・課程博士 / 博士(生命科学) / 甲第24052号 / 生博第478号 / 新制||生||63(附属図書館) / 京都大学大学院生命科学研究科高次生命科学専攻 / (主査)教授 朝長 啓造, 教授 野田 岳志, 教授 今吉 格 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

SammanfattningInledningIPS e.max® Press är en polykromatisk litiumdisilikat-förstärkt glaskeram utformad för termisk press- ning. Den produceras i olika grader av opacitet, translucens, färg och färgmättnad. En polykromatisk skiktad variant, IPS e.max® Press Multi, har tillkommit med en gradvis skiftning av opacitet, trans- lucens, färg och färgmättnad.SyfteSyftet med studien är att jämföra hållfastheten mellan polykromatiska skiktade normkronor fram- ställda av multipuckar och normkronor framställda av de konventionella monokromatiska presspuck- arna.Material och metodTill studien framställdes totalt 30 stycken standardiserade normkronor indelade i tre grupper, tio stycken IPS e.max® Press LT A2, tio stycken IPS e.max® Press Multi A2 och tio IPS e.max® Press Multi Bl2. Det framställdes 30 stycken stansar i ett ljushärdande 3D-material.Normkronorna termocyklades varpå de cementerades på de printade stansarna, följt av cyklisk me- kanisk förbelastning innan de belastades till brott i en universaltestmaskin. Värdena vid brott regi- strerades i Newton (N). Analysen av brotthållfastheten gjordes med one-way ANOVA, Tukey’s test. Konfidensintervallet sattes till 95% och signifikansnivån sattes på α= 0,05.ResultatDet kunde påvisas en statistisk signifikant skillnad i brotthållfasthet mellan samtliga tre grupper. Det lägsta medelvärdet påvisade grupp Multi A (IPS e.max® Press Multi A2) med 866 N följt av grupp Multi B (IPS e.max® Press Multi Bl2) med 987 N. Det högsta medelvärdet påvisade grupp Mono C (IPS e.max® Press LT A2) med 1108 N.SlutsatsInom ramen för studiens begränsningar kan följande slutsatser dras:• Den monokromatiska litiumdisilikat-förstärkta glaskeramen IPS e.max® Press LT A2 är ur hållfasthetssynpunkt starkare än de polykromatiska glaskeramerna IPS e.max® Press Multi A2 och Bl2.• Hypotesen bekräftas, men ytterligare studier behövs inom ämnet för att säkerställa resultaten. / AbstractIntroductionIPS e.max® Press is a polychromatic, lithium disilicate glass-ceramic designed for thermal pressing. It is produced in various degrees of opacity, translucency, color and saturation. A polychromatic layered variant, the IPS e.max® Press Multi, has been developed to show gradual shifts of opacity, translucency, color and saturation similar to those of natural teeth.PurposeThe purpose of present study is to compare the strength of polychromatic, layered, standardized norm crowns made of multi ingots and standardized norm crowns made of the conventional monochromatic ingots.Material and methodFor the study, 30 specimens of standardized norm crowns were generated and divided into three spci- men groups: ten IPS e.max® Press LT A2, ten IPS e.max® Press Multi A2 and ten IPS e.max® Press Multi BL2. 30 dies were produced in a light-curing 3D material.The crowns were thermocycled, whereupon they were cemented on the printed dies, followed by cyclic mechanical pre-load before load to fracture in a universal testing machine. The values at fracture were recorded in Newtons (N). Analysis of the fracture strength was performed using one- way ANOVA, Tukey’s test. The confidence interval was 95% and the significance level was α= 0.05.ResultsA statistically significant difference in breaking strength was detected between all three groups. The group with the lowest average result was A Multi (IPS e.max® Press Multi A2), with 866 N, followed by group Multi B (IPS e.max® Press Multi BL2) with 987 N. The highest average was detected in group Mono C (IPS e.max® Press LT A2) with 1108 N.ConclusionWithin the scope of present study, the following conclusions can be drawn:• The monochromatic, lithium disilicate glass-ceramic IPS e.max® Press LT A2 has a higher fracture strength than the polychromatic glass-ceramics IPS e.max® Press Multi A2 and BL2.• The hypothesis is confirmed, but further studies on the subject are necessary to secure sufficient results.

Although great progress has been made, cancer still remains one of the most prevalent maladies plaguing mankind. New treatment methodologies using nanoparticles have come to the forefront by allowing for enhanced delivery of therapeutics to the tumor site. The design of the nanoparticle should allow for long circulation times, tumor-specific targeting and efficient release at the site of action. This requires that both the external shell and internal core of the nanoparticle be carefully selected to meet the maximal criteria of each of these steps. Poly(sialic acid) (PSA), a naturally occurring polysaccharide, meets all of the benchmarks of an effective exterior coating yet remains relatively unexplored in the field of drug delivery. Due to stealth properties, natural tumor targeting ability, and inherent pH-responsive elements, PSA has frequently been viewed as a “next-generation” surface coating. Just as important, the internal composition of the carrier should aid in effective drug loading but also rapid release. The selection of the core containing groups as well as therapeutic should be maximized in order to customize the carrier to drug. Here, we have developed PSA micelles composed of various internal groups selected to maximize drug loading and facilitate release. Loading of the chemotherapeutic doxorubicin was optimized through variations in non-covalent bonding forces between drug and carrier. Furthermore, PSA micelles composed of internal pH-responsive groups of varying hydrophobicity were also developed to tailor micelle swelling points at conditions analogous towards those found upon cellular uptake. Both of these were effective delivery platforms towards MCF-7 human breast adenocarcinoma cells. / Bioengineering

Properties of plasticized thermoplastic com and pulse starches and their blends with poly (lactic acid) (PLA) were studied. Water and glycerol acted as plasticizer components for a ratio of starch/glycerol/water (wt/wt) fixed at 50/36/14 based on previous studies. PLA was used in blends to improve the properties of thermoplastic starch (TPS). Maleic anhydride (MA) was used as a coupling agent to increase the miscibility of PLA and TPS phases. Cloisite 30B, a type of organoclay, was added into the material system to improve the properties of blends. In order to enhance the hydrophobicity, alkyl ketene dimmer (AKD), used as a sizing agent, were introduced to material system. Both internal and surface sizing methods were applied. Measurements of rheological and mechanical properties were performed on a Rosand capillary rheometer and Instron tensile testing machine. The thermal and morphological properties of blends were characterized using differential scanning calorimetry and scanning electron microscopy. The contact angles were measured using a goniometer equipped with a video camera and a computer with drop shape analysis software for calculating the contact angles. The use of maleic anhydride as a coupling agent significantly improved the tensile strength and modulus of blends and the blend morphologies were more homogeneous. Improvements in tensile strength and modulus were achieved as Cloisite 30B nanoclay was used as a filler in TPS/PLAgMA blends. Some hydrophobicity was obtained for blends with Cloisite 30B. Blends ofTPS/PLAgMA/clay showed shear-thinning behaviors at 150°C . . / Thesis / Master of Applied Science (MASc)

Polymeric biomaterials have created significant advances in the field of biomedical engineering, however, very few polymeric drug delivery devices have achieved clinical and commercial success. Thus, the motivation for this thesis was to encourage long-term success of materials through expanding the fundamental understanding of polymer properties. Poly(ethylene glycol) was specifically chosen for study as its polyether backbone provides it with many unique properties that are still not fully understood, and are not seen with other similar polymers. PEG has been shown to exhibit amphiphilic character, due to its high conformational freedom, and the ability to hydrogen-bond 2-3 water molecules for each ethylene oxide subunit, creating a very structured water shell and large hydrodynamic radius. Together, the properties formed the hypothesis for the possibility for PEG to control drug release and its environment, expanding its potential in biomedical applications. This hypothesis was investigated with PEG in three states – free PEG, conjugated and blended. Free PEG was determined to inhibit melanoma cell viability by activating apoptosis via PEG effects on the osmolality of the cell medium (Chapter 3). Novel silicone hydrogels incorporating methacrylated PEG as the sole hydrophilic component showed advantageous properties for biomedical applications across a range of formulations (such as low contact angle and protein deposition), as well as altering the release of highly hydrophilic antibiotics from the materials, presumably via PEG-drug hydrogen bonding (Chapter 4). Novel siloxane-PEG blended materials were shown to have the ability to influence drug release of hydrophilic, hydrophobic and drug salts through the structure of PEG (Chapter 5). Overall, the work within this thesis expanded understanding of the abilities and limitations of PEG based on its distinct structure, and expanded the potential for PEG in biomedical applications to more than being used as simply a hydrophilic additive. / Thesis / Doctor of Philosophy (PhD) / Polymeric biomaterials have created significant advances in the field of biomedical engineering, however, very few polymeric drug delivery devices have achieved clinical and commercial success. Thus, the motivation for this thesis was to encourage long-term success of materials through expanding the fundamental understanding of polymer properties. Poly(ethylene glycol) was specifically chosen for study due to its unique exhibition of amphiphilic character and the ability to hydrogen-bond multiple water molecules, that together suggest the possibility for PEG to control drug release and its environment. Through strategic experimental designs, greater understanding of the abilities and limitations of PEG was established and shown to be the result of the distinct structure of PEG. Specifically, two novel drug delivery systems were developed with demonstrated understanding of the structure-function relationship between polymers and drugs, and the activity of PEG as a melanoma cell viability inhibitor was discovered and found correlated to the PEG structure. Overall the work within this thesis expanded the potential for PEG in biomedical applications to more than being used as simply a hydrophilic additive.

An efficient delivery system and patient compliance are two of the most important factors for any drug delivery system design to be successful. The current standard, particularly to the ocular anterior segment, are topical applications including eye drops. However, due to ocular physical barriers including blinking, the varying tear film layers, and the structure of the corneal epithelium, less that 5% of drug reach the target tissue from a single eye drop dose. While most treatment regiments combat this with increased frequency of dosage and higher than needed concentrations, the need for a more efficient and controlled system has been recognized to reduce the risk of possible side effects. Contact lenses (CL) have been a widely discussed potential drug delivery device given their accepted use in the population, their ability to hold drug, as well as their placement on the ocular surface. The current work focuses on testing a novel delivery system using CLs with the incorporation of drug specific oligonucleotide chains known as aptamers on the surface of the lenses. This application of contact lenses is aimed at capitalizing on the strong affinity of aptamers to hold drug on the surface of the lenses until they are applied to the eyes. The aptamers were covalently attached to the surface via the activation of the hydroxyl groups on pHEMA as a model lens material using 1’1-carbonyldiimidazone CDI chemistry and subsequent reaction with the amine group on the 5' end of the aptamer. The presence of aptamers was confirmed using 6-carbofluorescein (6-FAM) fluorescence detection and x-ray photoelectron spectroscopy (XPS). The release of kanamycin B in comparison to regular pHEMA gels using a soaking uptake method was assessed. In this work, aptamers were confirmed through fluorescence to have been successfully reacted onto the surface, however XPS was not able to confirm a consistent reading. This may have been due to low initial amounts of aptamer or uneven distributions along the surface. The efficiency of the aptamer reaction was not tested and would need to be further investigated. The contact angle had a significant change with increased hydrophilicity at 60.7 ± 1.55° compared to 66.6 ± 0.67°, however physically it should not affect wettability. The lower aptamer amounts resulted in no significant difference during drug release. Kanamycin B was detected using liquid chromatography mass spectroscopy (LCMS) with a reverse phase method using a C18 column however quite a few errors in the methodology led to the conclusion that this method of drug release requires further investigation. It is recommended an aptamer-surface reaction efficiency be determined with the use of a much larger starting aptamer amount, as well as a follow up drug release. / Thesis / Master of Applied Science (MASc)

A series of mixed matrix membranes based on zeolites incorporated into fluorinated polyimides were fabricated and characterized in this study. The first system consisted of a polyimide (6FDA-6FpDA-DABA) with carboxylic acid groups incorporated into its backbone and amine-functionalized zeolite particles (ZSM-2). FTIR indicated that these functional groups interacted with each other through hydrogen bonding. Both SEM and TEM images revealed good contact between the polyimide and the zeolite. Permeability studies showed a drop in He permeability suggesting there were no voids between the two components. While simple gases such as O2 and N2 followed effective permeabilities predicted by mixing theories, polar gases such as CO₂ did not. The second system fabricated used the same polyimide with amine-functionalized zeolite L. This zeolite differs from ZSM-2 in that zeolite L's pores are not clogged with an organic template, and it possesses 1-D pores as opposed to ZSM-2's 3-D pore structure. XPS and zeta potential experiments were performed to verify the presence of amine groups on the zeolite surfaces. FTIR data showed that after a heat treatment, amide linkages were created between the amine group on the zeolite and the carboxylic acid group of the polyimide. SEM images showed a good distribution of zeolite L throughout the polymer matrix, and no indication of voids between the two components. Permeability experiments were performed to determine if the addition of zeolite L to the polyimide improved its separation performance. The permeability was unchanged between the pure polyimide membrane and the mixed matrix membrane, suggesting there were no voids present within the matrix. Permeability results of larger gases followed a Maxwell Model. A third system was prepared using a poly(imide siloxane) (6FDA-6FpDA-PDMS) and untreated zeolite L. The primary focus of this investigation was to determine if the addition of the flexible segment would promote direct contact with the zeolite surface and remove the need to amine-functionalize the zeolite. Poly(imide siloxane)s were synthesized at 0, 22, and 41 wt % PDMS as verified using 1H-NMR. FTIR was employed to qualitatively verify the successful imidization of the polymers. SAXS patterns and TEM images did not reveal distinct phases indicative of phase separation, however, AFM images did show the presence of phase separation of the surfaces of the poly(imide siloxane)s. Permeability results showed a decrease in selectivity and an increase in permeability as the wt % of PDMS was increased. Permeabilities and selectivities dropped as the zeolite loading was increased from 0 to 20 wt %. Upon increasing the zeolite loading from 20 to 30 wt %, increases in permeability were observed, but both the permeability and selectivity were still below that of the pure polymer. The final system studied employed the 41 wt % PDMS poly(imide siloxane) as the polymer matrix and either closed-ended or open-ended carbon nanotubes as the filler. SEM images showed regions of agglomeration for both types of nanotubes. Helium permeability dropped in both types MMMs, but more so in closed-ended carbon nanotubes MMM. Nitrogen permeability was unchanged for the closed-ended carbon nanotubes MMM, and dropped slightly in the open-ended carbon-nanotube MMM. / Ph. D.

Amphiphilic tri- and penta-block copolymers containing a polyurethane central block with pendant carboxylic acid groups flanked by hydroxyl functional polyether tails were synthesized. Our intention was to investigate the activities of these copolymers as dispersants for magnetite nanoparticles in biological media. A benzyl alkoxide initiator was utilized to prepare poly(ethylene oxide) (BzO-PEO-OH), poly(propylene oxide) (BzO-PPO-OH) and poly(ethylene oxide-b-propylene oxide) (poly(BzO-EO-b-PO-OH)) oligomeric tail blocks with varying lengths of PEO and PPO. The oligomers had a hydroxyl group at the terminal chain end and a benzyl-protected hydroxyl group at the initiated end. The polyether oligomers were incorporated into a block copolymer with a short polyurethane segment having approximately three carboxylic acid groups per chain. The block co-polyurethane was then hydrogenated to remove the benzyl group and yield primary hydroxyl functionality at the chain ends. End group analysis by 1H NMR showed the targeted ratio of PEO to PPO demonstrating control over block copolymer composition. Number average molecular weights determined by both 1H NMR and GPC were in agreement and close to targeted values demonstrating control over molecular weight. Titrations of the pentablock copolymers showed that the targeted value of approximately three carboxylic acid groups per chain was achieved. Heterobifunctional poly(ethylene oxide) (PEO) and poly(ethylene oxide-b-propylene oxide) (PEO-b-PPO) copolymers were synthesized utilizing heterobifunctional initiators to yield polymers having a hydroxyl group at one chain end and additional moieties at the other chain end. For PEO homopolymers, these moieties include maleimide, vinylsilane, and carboxylic acid functional groups. Heterobifunctional PEO oligomers with a maliemide end group were synthesized utilizing a double metal cyanide coordination catalyst to avoid side reactions that occur with a basic catalyst. PEO oligomers with vinylsilane end groups were synthesized via alkoxide-initiated living ring-opening polymerization, and this produced polymers with narrow molecular weight distributions. Heterobifunctional PEO-b-PPO block copolymers were synthesized in two steps where the double metal cyanide catalyst was used to polymerize propylene oxide (PO) initiated by 3-hydroxypropyltrivinylsilane. The PPO was then utilized as a macroinitiator to polymerize ethylene oxide (EO) with base catalysis. Heterobifunctional PEO and PEO-b-PPO block copolymers possessing carboxylic acid functional groups on one end were synthesized by reacting the vinyl groups with mercaptoacetic acid via an ene-thiol addition. / Ph. D.

High temperature, solvent resistant materials which also display good mechanical properties are desired for use as aerospace structural adhesives and polymer matrix/carbon fiber composites. High molecular weight amorphous poly(arylene ether sulfone) thermoplastic materials display many of these desirable characteristics but are deficient in solvent resistance. Previous attempts to prepare poly(arylene ether) based thermosets to improve solvent resistance have been largely unsuccessful due to processiblity issues from the low curing temperature and high glass transition temperature of the thermoset precursor. Incorporation of a high temperature curable (* 350°C) endgroup such as 3-phenylethynylphenol in the synthesis of controlled molecular weight poly(arylene ether sulfone) oligomers has allowed for a large processing window prior to the exothermic cure that forms the desired networks. Control of oligomer molecular weight and backbone structure has allowed for further control of the processing, thermal transitions and adhesive properties of the thermosets. A systematic series of phenylethynyl terminated oligomers derived from either bisphenol A, or wholly aromatic hydroquinone or biphenol has been synthesized and characterized to determine the influence of backbone structure, molecular weight, and endgroup structure on thermoset properties. The features most affected by backbone structure included thermal stability (weight loss behavior) as well as transition temperatures (Tg, Tm), and processing characteristics. Increasing molecular weight of the oligomer produced a decrease in the glass transition temperature of the network and an increase in the adhesive properties of the thermoset. Comparison of the curing behavior of the 3-phenylethynylphenol endcapped materials with other related phenylethynyl terminated compounds led to the synthesis and systematic investigation of the curing behavior of phenylethynyl endcappers in which the electronic environment in relation to the reactive ethynyl carbons was systematically varied. Electron withdrawing groups, eg. sulfone, ketone, imide on the aryl ring para to the acetylene bond enhanced the rate of cure and also appear to improve the lap shear adhesion to suface treated titanium adherands. Discussion of the background, synthesis and characterization are described in this dissertation. / Ph. D.