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京都大学 / 新制・論文博士 / 博士(医学) / 乙第13481号 / 論医博第2256号 / 新制||医||1059(附属図書館) / (主査)教授 平井 豊博, 教授 岩田 想, 教授 秋山 芳展 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

INTRODUCTION: Pubertal growth is an important time during development for bone accrual and attainment of peak bone mass. Suboptimal bone gain has been observed in females with reproductive abnormalities such as primary and secondary amenorrhea and these conditions are very prevalent in female athletes. Amenorrhea is associated with decreased estradiol levels. Previous research has shown that in prepubertal animals a low estrogen environment significantly decreased mechanical strength, but there was no significant loss in bone area and actually an increase in moment of inertia. The decrease in mechanical properties may be related to the microstructure of the bone. Two types of bone are involved in growth-- woven bone, which is added for structural support in the short term, and lamellar bone , which is highly organized and has a greater contribution to overall strength. We will test the hypotheses that suppressed estradiol will result in bones with no change in cortical area and decreased strength properties but will have a larger composition of non lamellar bone as opposed to lamellar bone. PURPOSE: The goal of this study was to determine the relative amounts of woven and lamellar tissue in a bone and the relationship with the bone's mechanical strength in two models of low estrogen-- pre- and post-pubertal onset. METHODS: Fifty-Five female Sprague-Dawley rats were randomly assigned into four groups: a control group (n=14) and three experimental groups injected with gonadotropin releasing-hormone antagonist (GnRH-a)-- the Dose 1 group was injected with 1.25 mg/kg/dose daily (n=14), the Dose 2 was injected with 2.5 mg/kg/dose daily (n=14), and the Dose 3 group was injected with 5.0 mg/kg/dose, 5 days per week (n=13). All groups were sacrificed at Day 49. Additionally, twenty-nine Sprague Dawley rats were randomly assigned into three groups. The baseline day 65 group (BL 65) was sacrificed on day 65 (n=9). There was an aged match control group that was sacrificed on day 90 (n=12). Finally, there was an AMEN experiment group injected with 2.5 mg/kg/dose daily that was sacrificed on day 90 (n=9). All experimental groups for both protocols received injections of gonadotropin releasing hormone antagonists (GnRH-a) (Zentaris GmbH) intraperitoneally. Left femora were mechanically tested under 3-point bending. The right femora were dehydrated, embedded in polymethylmethacrylate, cut and ground to 100 µm thickness. Bones were analyzed under polarized light using Stereo Investigator Software (MBF Bioscience, VT). The proportion of the cortex with primary lamellar vs. non-lamellar/other primary tissue type was measured and expressed as percent of the total cortical bone area. Outcome measures included lamellar endocortical area, lamellar periosteal area, cortical area, endocortical area, % lamellar area and % non-lamellar area. RESULTS: There was a significant decrease (p<.05) in the distribution of lamellar versus non-lamellar cortical tissue type in the experimental group in the model of delayed puberty. Additionally, the pre-pubertal bones had a lower percentage of lamellar periosteal and endocortical area. The post-pubertal group showed no significant differences between the control and experimental group in any of the outcome measures. CONCLUSION: There were significant differences in relative bone distribution throughout the femoral cortex. Relative decreases in lamellar tissue distribution, especially on the periosteal surface, will result in decreased mechanical strength due to increased percentage of woven bone in pre-pubertal models. / Kinesiology / Accompanied by one .pdf file: Lamellar/Woven Database.

γ-TiAl based alloys have attracted considerable research interest in the past few decades and have gained niche high temperature applications in aero-engines and automobiles. As high temperature structural materials, these alloys require stable microstructures. This thesis aims at addressing knowledge gaps in the understanding of microstructural stability in two technologically important γ-TiAl based alloys in different microstructures, viz. fully lamellar (FL) and duplex. Creep and exposure tests were complemented with a variety of microstructural characterization tools (SEM, EBSD, TEM, XRD). Density functional theory based calculations were also performed to further the understanding of stability of phases. In the first part of the thesis, microstructural stability of a FL microstructure was studied under creep and high temperature exposure conditions. An aim of these studies was to probe the effect of stress orientation with respect to lamellar plates on microstructural changes during primary creep. It was observed that retention of excess α2 resulted in an unstable microstructure and so under stress and temperature, excess α2 was lost. However, depending on stress orientation, the sequence of precipitates formed was different. In particular, for certain stress orientations, the formation of the non-equilibrium C14 phase was observed. The stress dependence of microstructural evolution was found to be stem from internal stresses due to lattice misfit and elastic moduli mismatch between α2 and γ. In the second part of this thesis, microstructural stability of a duplex alloy was probed, with an emphasis on understanding mechanisms that lead to tertiary creep. The as-extruded microstructure consisted of bands of equiaxed grains and lamellar grains. During creep, loss of lamellar grains was observed and this was attended by kinking of laths and formation of dynamically recrystallized equiaxed grains. Significant dislocation activity was seen in both lamellar and equiaxed grains at all stages of creep. Initially, dislocation activity leads to strengthening and primary creep behavior, but at later stages, it triggers dynamic recrystallization. Dynamic recrystallization was found to be the rate controlling creep mechanism. Accelerating creep behavior was due to strain localization during the constant load tensile test resulting from microstructural instabilities such as kinking.

Orientador: José Luiz Laus / Banca: Auero Evangelista Santana / Banca: Thiago Luiz de Salles Gomes / Resumo: Avaliaram-se descritivamente, à clínica, à histopatologia e à imunoistoquímica (ki 67- marcador de proliferação celular) os resultados, da cicatrização da córnea, após ceratoplastias lamelares com membrana de celulose microfibrilar em coelhos. Para tal, utilizaram-se 30 coelhos , distribuídos em 5 grupos de 6 animais, avaliados por até 60 dias de pós operatório. A avaliação clínica revelou manifestações moderadas de edema, blefaroespasmos, fotofobia desde o segundo dia, evoluindo para formas discretas ou ausentes a partir do sétimo dia, onde observou-se clinicamente o reparo do defeito da córnea. A histopatologia revelou uma fina camada de células escamosas, recobrindo totalmente a área lesada, aos sete dias, e com leve infiltrado de células polimorfonucleares. Observou-se a presença de vasos no epitélio a partir do 15º dia , com regressão aos 48º dias .A imunoistoquímica mostrou aumento de células em proliferação aos 15 dias no epitélio (p= 0,049) e aos trinta dias no estroma (p= 0,042). Frente aos resultados obtidos, há como admitir que mesmo com o defeito corneal concluído, aos sete dias, o sistema de defesa celular ainda se manteve ativo, pois a proliferação celular no epitélio se mostrou mais intensa aos 15 dias de observação ,conforme demonstrado imunoistoquimicamente. Onde nesse período ocorreu remodelamento e adesão epitelial da córnea, características satisfatórias em ceratoplastia lamelar em coelhos . / Abstract: Were evaluated the clinic, the histopathology and immunohistochemistry (ki 67 - marker of cell proliferation), the results of the membrane of cellulose in lamellar keratoplasty in rabbits. To this end, 30 rabbits were used, divided into 5 groups of 6 animals, assessed by up to 60 days of post-operative. The assessment showed clinical manifestations of moderate swelling, blefarospasmos, photophobia since the second day, evolving into discrete forms or absent from the seventh day, where there was clinically repair the defect of the cornea. The histopathology revealed a thin layer of squamous cells, completely covering the injured area, the seven days, and with mild infiltration of polymorphonuclear cells. There was the presence of vessels in the epithelium from the 15 th day, with regression of days to 48. Immunohistochemistry showed increased cell proliferation in the 15 days in the epithelium (p = 0049) and the thirty days in the stroma (p = 0042) . Facing the results achieved, as there admit that even with the beginning of healing, and with the defect of the cornea closed to seven days, the system of defence cell remained active, as in the epithelial cell proliferation was more intense at 15 days, as shown imunoistochemistry. Where in that period showed epithelial remodeling and membership, characteristics satisfactory in lamellar keratoplasty in rabbits. / Mestre

O objetivo desta pesquisa foi desenvolver e aperfeiçoar uma formulação com fase gel lamelar contendo óleo de Calendula officinalis e avaliar seu potencial na atividade cicatrizante de úlceras em ratos. A formulação estudada possui valor de EHL 6,0, constituída por óleo de calêndula e sistema tensoativo formado por derivados etoxilados dos alcoóis cetílico e estearílico (Ceteth 2/Steareth 20). Primeiramente, determinou-se a região do diagrama ternário de fases em que se encontravam as emulsões com fase gel lamelares (EFGL), macroscopicamente estáveis. Em seguida foi avaliada a estabilidade do sistema e parâmetros que poderiam influenciar na formação das estruturas anisotrópicas. Avaliou-se o comportamento das emulsões utilizando o teste de perda de massa por evaporação. Na avaliação in vitro, foram realizados testes de citotoxidade do óleo de calêndula frente às células de fibroblastos da linhagem L929 através do ensaio de apoptose e necrose. O teste in vivo foi realizado através do Índice de Cicatrização de Úlceras (ICU) no modelo em dorso de ratos (úlcera excisional contrátil) a fim de avaliar o potencial cicatrizante da emulsão proposta comparando com o sham (grupo controle). As úlceras foram avaliadas mediante análise de imagem nos tempos de 0, 2, 7, 14 e 21 dias após o procedimento cirúrgico. A EFGL demonstrou maior estabilidade frente aos testes de estabilidade preliminar e acelerada em relação as demais formulações. Além disso, esta formulação demonstrou menor área de histerese (tixotropia), portanto menor grau de espalhabilidade e com maior tempo de contato com a úlcera. Durante a evaporação das emulsões houve manutenção das estruturas anisotrópicas O óleo bruto da Calendula officinalis não apresentou interferência na via da apoptose e necrose na concentração de até 1000 ?g/mL em fibroblastos L929. A formulação proposta promoveu melhor cicatrização no modelo de úlcera cutânea (ICU) na região dorsal de ratos, supondo- se modular a fase inflamatória do processo de cicatrização, pois o maior recrutamento de células inflamatórias bem como a colagênese, diminuída no grupo EFGL, foram fatores essenciais que permitiram a total reepitelização das úlceras cutâneas. Portanto, pode-se concluir que a metodologia utilizada nesta pesquisa foi útil para a obtenção de emulsões com fase gel lamelar, sendo que a formação dessa estrutura é importante para a estabilidade do sistema, podendo ser utilizada como uma formulação viável e eficaz no processo cicatricial de feridas. / The aim of this research was to improve a lamellar gel phase emulsion containing Calendula officinalis oil and to investigate its potential as a modern wound dressing. First, we determined the region of the ternary phase diagram in which the emulsions were stable and we also evaluated the intrinsic stability of the system and the action of some parameters which may influence the formation of lamellar gel phase. In addition, we analyzed the samples\' behavior during the evaporation process. Moreover, an in vitro cytotoxicity assay of the calendula oil was performed in order to evaluate apoptosis and necrosis in fibroblast cell line L929. Then, an in vivo test was carried out by the wound healing rate (WHR), using a specific model of ulcer in rats (excisional contractile ulcer), in order to assess potential healing of the proposed emulsion (LGP) by comparing with the sham group. The ulcers were evaluated by image analysis at 0, 2, 7, 14 and 21 days after surgery. The emulsion 6 \'showed greater stability in the preliminary and accelerated stability tests in relation to the previous studied formulation. Moreover, this formulation presented more compatible characteristics, because it showed smaller hysteresis area of ? (thixotropy), therefore a lower degree of spreadability and, accordingly, the formulation may increase contact span with ulcer, which is a desirable characteristic. During evaporation of the emulsions, the anisotropic structures were maintained, but their type varied depending on the decreased amount of water in the system. The crude oil of Calendula officinalis showed no interference with the pathway of apoptosis and necrosis in the concentration of 1000 mg / mL in L929 fibroblasts. The proposed model has promoted better wound healing rate in the ulcers in the dorsal region of rats. It seemed to modulate the inflammatory phase of the healing process, because of the increased recruitment of inflammatory cells as well as collagenesis, once LGP emulsion decreased in the group, were factors essential that allowed total reepithelialization of skin ulcers in rats treated with LGP emulsion. In conclusion, this study produced an enhanced and useful LGP which can be used as a new approach to stimulate the healing process and treat wounds efficiently.

Compostos lamelares do tipo da hidrotalcita ou hidróxidos duplos lamelares (HDL), são materiais que possuem notáveis propriedades estruturais, químicas, eletrônicas, iônicas, ópticas e magnéticas. Em função dessas propriedades, os HDL apresentam uma diversidade de aplicações tais como adsorventes e catalisadores. Este trabalho tem por objetivo utilizar polímeros e macromoléculas na preparação e caracterização de HDL, visando melhorar as propriedades texturais dos HDL de MgAl-CO3 preparados em meio contendo polímeros orgânicos ou a intercalação direta de dendrímeros tipo PAMAM de gerações -0,5 e +0,5 em HDL do sistema Zn/Al. Os HDL de MgAl-CO3 foram preparados pela adaptação do método de coprecipitação a pH decrescente, com a presença de polímeros solubilizados no meio, como molde. Os materiais foram caracterizados por difração de Raios X, análise termogravimétrica, espectroscopia no infravermelho e medidas de área superficial por BET. Baseando-se nos resultados obtidos, pode-se concluir que propriedades texturais dos HDL preparados são modificadas, quando na presença de alguns polímeros. Na maioria dos casos, os valores calculados de área superficial específica foram mais elevados, em comparação com aquele obtido para o HDL preparado em meio reacional sem polímero. Isto pode ser explicado pela diminuição do tamanho de partículas e aumento no diâmetro médio de poros dos materiais preparados, provocada pela presença de polímeros no meio reacional. Os HDL intercalados com dendrímeros PAMAM G-0,5 e PAMAM G+0,5 foram preparados por duas rotas diferentes: coprecipitação a pH constante e troca iônica em fase dupla. Os materiais obtidos foram caracterizados por meio de difração de Raios X, análise de termogravimétrica associada à espectrometria de massas e espectroscopia no infravermelho. Utilizando os dois procedimentos de preparação, a intercalação de PAMAM G-0,5 deu origem a HDL com os mesmos espaçamentos basais, concordando com a intercalação dos ânions do dendrímero em um arranjo perpendicular à lamela do HDL, enquanto que para a intercalação do PAMAM G+0,5, espaçamentos basais muito menores do que o tamanho da molécula foram obtidos. A diferença entre a distância interlamelar observada e a esperada pode ser explicada por um arranjo peculiar das moléculas desse dendrímero em uma forma elipsoidal, devido às interações intramoleculares. Espectros no infravermelho confirmam a presença dos dendrímeros nos materiais Zn2Al-PAMAM G-0,5 e Zn2Al-PAMAM G+0,5. Finalmente, a presença destes dendrímeros foi confirmada por análise térmica associada com espectrometria de massas. Os estudos de Raios X com variação de temperatura in situ e as análises termogravimétricas revelaram que o material obtido pela intercalação do PAMAM G+0,5 é termicamente menos estável do que aquele intercalado com PAMAM G-0,5, concordando com a diferença de estabilidade entre os dendrímeros livres. / Hydrotalcite-like lamellar compounds or layered double hydroxides (LDH) are materials that present notable structural, chemical, electronic, ionic, optical and magnetic properties. Depending on these properties, the LDH present a great variety of applications such as adsorbents and catalysts. The aim of this work is to prepare and to characterize MgAl-CO3-LDH prepared in aqueous media containing organic polymer to improve textural properties, and to prepare HDL by intercalation of dendrimer (PAMAM) of generations -0.5 and +0.5 in ZnAl-HDL. MgAl-CO3-HDL samples were prepared by an adaptation of the coprecipitation method at decreasing pH, with the presence of polymers in the aqueous media as template. The materials were characterized by powder X-ray diffraction, termogravimetric analysis, infrared spectroscopy and BET isotherms. Based on the obtained results, it can be concluded that the textural properties of the prepared LDH were modified. The calculated values of specific surface area were higher in most of the cases compared with those obtained by the LDH prepared without polymer due to a decrease of the particle size and an increase in the average pore diameter of the prepared materials due to the presence of polymers. HDL with intercalated (PAMAM) dendrimers G-0.5 and G+0.5 were prepared by two different methods: coprecipitation at constant pH, and ionic exchange in double phase. The obtained materials were characterized by powder X-ray diffraction, thermal gravimetric analysis associated with mass spectrometry, and infrared spectroscopy. X-ray powder diffraction patterns exhibit the characteristic profiles of the lamellar materials with basal spacing depending on the nature of the dendrimer. For both preparation methods, the intercalation of PAMAM G-0.5 gives rise to LDH with basal spacing in agreement with the dendrimer molecules perpendicular to the layer of the host structure, while for PAMAM G+0.5 a basal spacing smaller than the molecule size was obtained. The difference between the obtained and the expected value is explained by an accommodation of the dendrimer molecule in an ellipsoidal shape, due to the intra-molecular interactions. Infrared spectra confirm the presence of dendrimers in the Zn2Al-PAMAM G-0.5 and Zn2Al-PAMAM G+0.5 materials. Finally, thermal analyses associated with mass spectrometry confirm the presence of these dendrimers. Powder X-ray diffraction with in situ temperature variation reveals that the material obtained by the PAMAM G+0.5 intercalation is thermally less stable than that prepared by PAMAM G-0.5 intercalation, in agreement with the difference in the thermal stability of the free dendrimers.

L’évolution des structures poreuses du graphite et de la vermiculite expansés a été étudiée insitu sous pression uniaxiale. Les propriétés d'un matériau résultant des propriétés intrinsèques à lamatrice et de celles dues à la porosité, les études faites dans ce travail ont porté sur deux échellesdifférentes. Les évolutions structurales de la structure cristalline du graphite et de la vermiculite ontd'abord été étudiées à haute pression en cellule à enclumes de diamant. Cette partie du travail a permisd'établir les équations d'état de la vermiculite et de contribuer, de manière significative, à lacaractérisation de la phase haute pression du graphite: une nouvelle phase, le Carbone Z, a étéproposée après l’analyse des données de la spectroscopie Raman couplée aux simulations. Desdéveloppements techniques ont été particulièrement réalisés pour permettre d’étudier in situl'évolution de la porosité sous pression par diffusion aux petits angles sous pression. L’application dumodèle fractale à l’analyse des données a permis de suivre l’évolution de la dimension fractale et de lasurface spécifique apparente. Les échantillons étudiés sont des formes comprimées de graphite et devermiculite expansés dans lesquelles les plans basaux des cristallites ont une orientation préférentielle.Sous pression uniaxiale, la structure poreuse du graphite expansé comprimé évolue à travers uneffondrement irréversible des pores ou un cisaillement de la matrice suivant l'orientation de la pressionappliquée par rapport à l'orientation préférentielle des plans basaux des cristallites. Des expériencescomplémentaires de mesures électriques et de mesures de la porosité par intrusion de mercure ontpermis de confirmer ces modèles proposés. Dans la vermiculite expansée comprimée, les fissuresapparaissent, de manière générale, sous l’effet de la pression uniaxiale. / The porous structure of expanded graphite and expanded vermiculite has been studied insitu under uniaxial stress. The properties of a porous material being related to the matrix and to theporosity, the in situ evolution under of the crystalline structure (of the matrix) under high pressurehave been first investigated using diamond anvil cell. The equation of state of expanded vermiculitehas been established. This first part of this work allowed giving a particular insight to the study of theunsolved high pressure phase of graphite. Combining Raman scattering data and calculations, a newstructure, called Z-Carbon, has been proposed. Thanks to the specific technical developments of thiswork, the porosities of expanded graphite and expanded vermiculite based systems have been studiedin situ under uniaxial stress. The used of fractal model in data analysis allowed following the evolutionof the fractal dimension and of the apparent specific surface The studied samples were made ofcompressed forms of expanded graphite and expanded vermiculite in which the basal plane of thecrystallites have a preferential orientation. The uniaxial stress was taken perpendicular and parallel tothis preferential direction. The porous structure of the expanded graphite sample was found to undergoan irreversible collapse of the pores or a cracks and creation and propagation. Additional electrical andporosity measurements supported the proposed models. In the expanded vermiculite based systems,the crack apparition was observed under uniaxial stress.

Le travail de cette thèse vise le développement de systèmes intelligents d'inhibiteurs de corrosion à base d'un composé lamellaire de type orthophosphate de zirconium α-ZrP. Le principe repose sur le fait que le α-ZrP joue le rôle de microréservoir de sorte à stocker des entités d’inhibiteurs de la corrosion métallique. Les espèces inhibitrices à base de cations Ca2+, Mg2+ et Zn2+ ont pu être incorporées avec succès au sein des espaces interfeuillets de α-ZrP via des réactions d’échanges cationiques avec les protons labiles H+. De même, des entités de l’anion heptanoate ont pu être insérées via l’intercalation préalable du biopolymère cationique chitosane. Par ailleurs, l’intercalation des entités organiques telles que le 2-aminobenzimidazole et la dodécylamine a pu être achevée par des réactions acido-basiques avec les protons H+. Les caractérisations des matériaux avant et après fonctionnalisation par différentes techniques analytiques ont montré que l’ensemble de ces modifications a donné lieu au développement de matériaux hybrides inorgano-inorganiques ou organo-inorganiques. L’évaluation de leurs performances inhibitrices de la corrosion a été accomplie en utilisant des techniques électrochimiques stationnaires et dynamiques. Elles ont révélé que ces pigments, une fois utilisés soit à l’état libre dans le milieu corrosif soit dispersés dans des peintures, améliorent les performances d'inhibition de la corrosion du zinc et de l'acier doux par rapport aux composés commerciaux en relargant les entités intercalées et retenant les entités corrosives. Ceci permet d’assurer la longévité de l’action inhibitrice de la corrosion des substrats métalliques en milieu aqueux / This thesis generally aims at the development of corrosion inhibitors based on a lamellar compound, namely zirconium orthophosphate (α-ZrP). The principle consists in that α-ZrP acts as micro-tanks in such a way to store species of several compounds known for their metallic corrosion inhibition properties. On the other hand, inhibitive species based on Ca2+, Mg2+, and Zn2+ were be able to be successfully incorporated within α-ZrP interlayer spaces via cationic exchange with labile H+ protons. Similarly, entities of the heptanoate anion were inserted via the prior intercalation of the cationic biopolymer chitosan. Nevertheless, the intercalation of organic species such as 2-aminobenzimidazole, dodecylamine was accomplished via acid-basic reaction between –NH2 groups and H+ protons. The characterizations of the materials before and after functionalization by different analytical techniques denote that all these modifications give rise to inorgano-inorganic or organo-inorganic hybrid materials. The evaluation of their performances, in term of metallic corrosion inhibition, was performed by using stationary or dynamic electrochemical techniques. It has been shown that the use of these pigments in corrosive medium, either alone or dispersed in paints, improves corrosion inhibition of zinc and mild steel thanks to the progressive release of intercalated species compensated by the retention of corrosive entities better than those induced by commercial products. This in final allows lengthening the inhibition action of metallic substrates against aqueous corrosion