京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第20297号 / 人健博第45号 / 新制||人健||4(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 坪山 直生, 教授 山田 重人, 教授 妻木 範行 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

L’ostéoporose est une maladie du squelette caractérisée par une dégradation de la qualité osseuse conduisant à une majoration du risque fracturaire. Le seul examen permettant actuellement de prédire ce risque est l’ostéodensitométrie à double rayonnement X (DXA) par la mesure de la densité minérale osseuse (DMO). Cependant, la DMO seule ne rend compte que de 40 à 70% de la variation de la résistance mécanique osseuse. Les 3 buts ce travail étaient : 1/ d’évaluer les rôles respectifs de la microarchitecture corticale et trabéculaire dans le comportement mécanique vertébral, 2/ d’évaluer le rôle propre de l’hétérogénéité de la microarchitecture trabéculaire et 3/ de décrire le comportement mécanique vertébral post-fracturaire et d’en identifier les déterminants. Nous montrons que la mesure de l’épaisseur de la corticale antérieure et de son rayon de courbure ainsi que la détermination de la variation régionale de la microarchitecture trabéculaire améliorent significativement la prédiction du risque fracturaire. Il existe une variation marquée du comportement mécanique vertébral après une fracture de grade 1 de Genant. La microarchitecture osseuse, et non la masse osseuse, explique les propriétés mécaniques vertébrales plastiques et élastiques post-fracturaires. / Osteoporosis is characterized by altered bone quality and compromised bone strength leading to increased fracture risk. Measurement of areal bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA) is the most widely used index of bone strength. However, BMD alone can only account for 40 to 70% of the variation of bone strength. This study aimed to determine: 1/ the respective role of cortical and trabecular microarchitecture to vertebral mechanical behavior, 2/ the role of trabecular microarchitecture heterogeneity and 3/ the mechanical behavior of a vertebra after simulated mild fracture and its determinants. Our data imply that measurements of cortical thickness and curvature as well as determination of trabecular microarchitecture heterogeneity enhance prediction of vertebral fragility. We found marked variation in the post-fracture load-bearing capacity following simulated mild vertebral fractures. Bone microarchitecture, but not bone mass, was associated with post-fracture mechanical behavior of vertebrae.

L'ostéoporose est une maladie du squelette caractérisée par une dégradation de la qualité osseuse conduisant à une majoration du risque fracturaire. Le seul examen permettant actuellement de prédire ce risque est l'ostéodensitométrie à double rayonnement X (DXA) par la mesure de la densité minérale osseuse (DMO). Cependant, la DMO seule ne rend compte que de 40 à 70% de la variation de la résistance mécanique osseuse. Les 3 buts ce travail étaient : 1/ d'évaluer les rôles respectifs de la microarchitecture corticale et trabéculaire dans le comportement mécanique vertébral, 2/ d'évaluer le rôle propre de l'hétérogénéité de la microarchitecture trabéculaire et 3/ de décrire le comportement mécanique vertébral post-fracturaire et d'en identifier les déterminants. Nous montrons que la mesure de l'épaisseur de la corticale antérieure et de son rayon de courbure ainsi que la détermination de la variation régionale de la microarchitecture trabéculaire améliorent significativement la prédiction du risque fracturaire. Il existe une variation marquée du comportement mécanique vertébral après une fracture de grade 1 de Genant. La microarchitecture osseuse, et non la masse osseuse, explique les propriétés mécaniques vertébrales plastiques et élastiques post-fracturaires.

Magma-crust interaction in magma reservoirs and conduits is a crucial process during magma evolution and ascent. This interaction is recorded by crustal xenoliths that frequently show partial melting, inflation and disintegration textures. Frothy xenoliths are widespread in volcanic deposits from all types of geological settings and indicate crustal gas liberation. To unravel the observed phenomena of frothy xenolith formation we experimentally simulated the behaviour of crustal lithologies in volcanic conduits. We subjected various sedimentary lithologies to elevated temperature (maximum 916 °C) and pressure (maximum 160 MPa) in closed-system autoclaves. Experimental conditions were held constant between 24h and 5 days. Controlled decompression to atmospheric pressure then simulated xenolith ascent. Pressure release was a function of temperature decline in our setup. Temperature lapse rate proceeded exponentially; the mean rate during the first 30 minutes was 17.8 ˚C/min and the mean decompression rate during the same interval was 3.0 MPa/min, eventually reaching room temperature after approximately 5.5 hours of slow cooling. The experimental products have been analysed for internal textures by synchrotron X-ray μ-CT at a resolution of 3.4 – 9 microns/pixel. This method permits visualisation and quantification of vesicle volumes, -networks and-connectivity in 3D without destroying the sample. Experimental products closely reproduced textures of natural frothy xenoliths in 3D and define anevolutionary sequence from partial melting to gas exsolution and bubble nucleation that eventually leads to the development of three-dimensional bubble networks. Experimental P-T-t conditions and especially rock lithology proved decisive for degassing behaviour and ensuing bubble nucleation during decompression. Progressive bubble nucleation leads to subsequent bubble coalescence to form interconnected bubble networks. This, in turn, enables efficient gas liberation and release. Our results attest to significant potential of even very common crustal rock types to release volatiles and develop interconnected bubble networks upon heating and decompression in magmatic systems. Crustal volatile input from xenoliths affects magma rheology and may drive magmas to sudden explosive eruptions. Our experiments offer insight into the mechanism of how such crustal volatile liberation is accomplished.

Cochlear implants are electronic devices intended for restoring hearing to the profoundly deaf. Unfortunately the degree of restored hearing varies greatly between subjects. To investigate some of the mechanisms that determine this variability, mathematical models of the auditory system are used. The level of detail that these models incorporate varies greatly. The present study describes the development of a method to create high detail, subject specific cochlea models. μ-CT scans and photomicrographs were used to obtain the morphology and histology of a specific guinea pig cochlea. A 3D model was constructed from this data and the finite element method was used to determine the potential distribution inside the cochlea. The potential distribution was calculated for different stimulus protocols applied to different modelled electrodes. A neuron model was then used to obtain neural excitation profiles. The modelled excitation profiles were compared to data from literature and it was found that this model is valid and can be used as a tool in electric hearing research. The model output was also compared to brainstem response data from the specific subject to assess the degree to which this model can predict brain stem data from a specific subject. Possible improvements to the model were also discussed. / Dissertation (MEng)--University of Pretoria, 2009. / Electrical, Electronic and Computer Engineering / unrestricted

In this thesis, micro computed tomography (μ−CT) scans of a bio-glass scaffold produced by the robocasting technique was used to create finite element method (FEM) models with the purpose of determining its mechanical strength. Prior to this, a Matlab script was used to create several simplified geometries of the scaffold in an effort to determine the importance of scaffold design parameters (such as the fiber compenetration between two adjacent printing planes) on the strength of the scaffold. Furthermore, to assess the influence of micro-structural defects such as voids and micro-cracks that are intrinsic to the robocasting manufacturing process, the total number of voids and their respective volume was calculated using the μ-CT scan imagery and fitted to a statistical distribution. The distribution of voids was then used to create several scaffold models in Matlab with either spherical or ellipsoidal voids present. In the final two models, one scaled-down and one scaled-up FEM based on μ-CT scans were investigated.To model the crack initiation, propagation and final failure, the phase-field method was used. The method was implemented by the use of a publicly available Fortran user subroutine and was edited to account for asymmetric tension/compression energy degradation. The resulting strength of the produced models have been presented as non-dimensional values. The finite element analysis (FEA) of the Matlab produced scaffolds showed that the fiber shifting between two adjacent layers, porosity, and voids of ellipsoidal shape that were perpendicular to the loading direction had the highest effect on the strength of the scaffold. The resulting normalized strength values obtained from the μ-CT models was partially validated through a comparison with the literature available.The different failure modes and overall architectural arrangement of cracks also showed promising results. / I den här uppsatsen så användes mikrotomografi (μ-CT) skanning av en bio-glas stödstruktur tillverkad av robocasting tekniken för att skapa finita element modeller med syftet att bestämma dess mekaniska styrka. Innan detta så användes ett Matlab-skript för att skapa flera förenklade geometrier av stödstrukturen i ett försök att fastställa betydelsen av viktiga designparametrar (som t.ex fiberpenetrering mellan två intilliggande plan) på stödstrukturens styrka. Vidare, för att bedöma påverkan av mikrostrukturella defekter som tomrum och mikrosprickor som är naturligt förekommande i robocasting-tillverkningsprocessen så uppmättes det totala antal hålrum och deras respektive volym med hjälp av μ-CT-skannade bilder. Denna data blev anpassad till en statistisk fördelning. Fördelningen av tomrum och mikcrosprickor användes sedan för att skapa flera modeller av stödstrukturerna i Matlab med antingen sfäriska eller ellipsoida hålrum närvarande. I de sista två modellerna undersöktes en en nedskalad och en uppskalad finita elementmodell baserad på μ-CT-skanning.För att modellera sprickinitiering, sprickpropagering och slutligen brott användes fasfältsmetoden. Fasfältsmetoden implementerades med hjälp av en för allmänheten tillgänglig Fortran användarrutin som redigerades för att ta hänsyn till en asymmetrisk energidegradering i drag-och tryck. Den resulterande styrkan hos alla modeller har presenterats som icke-dimensionella värden. Finita elementanalysen av Matlab modellerna visade att fiberskiftningen mellan två intilliggande plan, porositet och hålrum med ellipsoid form som var vinkelräta mot belastningsriktningen hade störst effekt på stödstrukturens styrka. De resulterande normaliserade styrkevärdena erhållna från μ-CTmodeller validerades delvis genom en jämförelse med tillgänglig litteratur. Dom olika felmoderna och övergripande strukturella fördelningen av sprickor visade också lovande resultat.

Les agents d’imagerie aux rayons X sont essentiels en combinaison avec la tomodensitométrie pour améliorer le contraste de manière à permettre la visualisation complète des vaisseaux sanguins et de fournir l'information structurelle et fonctionnelle de lésions permettant la détection d'une tumeur. Ces outils fondamentaux permettent également de faire la distinction entre les cellules et les agents pathogènes sains. Les agents de contraste aux rayons X commercialisés sont limités dans leur succès dans le cas du Fenestra® VC par le temps court de circulation dans le sang et celui qui est lié à l'élimination rénale rapide du corps comme dans le cas du Xenetix® (Iobitriol). Nous avons développé des agents de contraste à base d’α-tocophérol (vitamine E), de Cholécalciférol (vitamine D3), d'huile de ricin, de Capmul® MCMC8 et d’acide oléique qui sont tous dénués de toxicité, qui contiennent de l’iode sous forme de nano-émulsion et qui sont destinés à l’imagerie préclinique en μ-CT. Ces nano-émulsions formulées ont été préparées par la technique d’émulsification spontanée de basse énergie avec une légère modification pour chaque composé iodé. Ces formulations ont montré de nouvelles caractéristiques spécifiques les rendant prometteuses dans des expérimentations in vivo avec une augmentation du rapport de la toxicité et de celui des interventions thérapeutiques visées. Nous avons étudié l'effet de la taille et de la composition chimique des systèmes nanoparticulaires sur leur biodistribution, leur pharmacocinétique et leur toxicité. Ces études ont permis de mettre en évidence l’importance de la constitution chimique des agents iodés utilisés avec par exemple la vectorisation du foie dans le cas de la vitamine E et une accumulation passive dans la rate pour les formulations à base d'huile de ricin, faisant la preuve-de-concept de l'effet EPR. D'autre part, des formulations identiques ayant deux tailles de gouttelettes différentes et contenant du cholécalciférol indiquent qu’il n’y a pas de réels impacts sur la pharmacocinétique et la biodistribution mais présentaient une augmentation importante de la toxicité. Une autre étude a consisté a étudié l’effet des charges de surface des systèmes nanoparticulaires sur leur biodistribution, c’est pourquoi la nano-émulsion a été sélectionnée pour réaliser cette étude en présence d’un polymère amphiphile tel que le poly (anhydride-alt-1-octadecene maléique) (PMAO). Les résultats in vitro et les évaluations in vivo étaient tout à fait cohérents sachant que les systèmes nanoparticulaires neutres présentent moins de toxicité comparée à celles qui sont chargés négativement qui ont été capturés de manière plus importante dans les cellules causant un stress cellulaire et delà affectent la toxicité. Selon les résultats, elles présentent des biodistributions et des pharmacocinétiques différentes. Dans ce contexte, pour la première fois, nous avons pu fonctionnaliser les nanogouttes des nanoémulsions en fixant des ligands par des liaisons covalentes. Nous avons conçu des nanogouttes enrobées avec un enrobage de silice terminé par des groupements aminés et ainsi réalisé la formation de liaisons amides avec le greffage d’un colorant modèle (colorant bleu coumarine). La quantification des groupements aminés a été réalisée à l'aide de techniques spectroscopiques et microscopiques ainsi que la détermination de l'efficacité du greffage déterminé à 41%. [...] Un de nos objectifs réalisés était de concevoir des systèmes nanoparticulaires polymères multifonctionnels qui peuvent encapsuler des principes actifs hydrophobes modèles et des agents de contraste pour l’imagerie à rayons X, de sorte à construire des dispositifs théranostiques. Pour conclure, de nouveaux agents de contraste et des systèmes de délivrance ont été synthétisés ayant des caractéristiques physico-chimiques exceptionnelles et acceptables pour être utilisées in vivo avec une grande efficacité et une faible toxicité. / X-ray imaging agents are essential in combination with X-ray computed tomography to improve contrast enhancement aiming at providing complete visualization of blood vessels and giving structural and functional information on lesions allowing the detection of a tumor. As well as it is fundamental tool to discriminate between healthy cells and pathogens. We successfully limit the problems presented in commercial Xray contrast agents like poor contrasting in Fenestra® VC associated with short blood circulation time and to avoid rapid renal elimination from the body as found in Xenetix (Iobitriol). We developed nontoxic and blood pool iodine-containing nano-emulsion contrast agents serving in preclinical X-ray μ-CT imaging such as, α- Tocopherol (vitamin E), Cholecalciferol (vitamin D3), Castor oil, Capmul MCMC8 oil and oleic acid. Those formulated nanoemulsions were prepared by low energy spontaneous emulsification technic with slight modification for each platform. They showed new specific features rendering them promising agents in in vivo experiments as improving the balance between the efficacy and the toxicity of targeted therapeutic interventions. We investigate the effect of size and the chemical composition of the nanoparticles on their biodistribution, pharmacokinetics and toxicity. They demonstrated that the chemical structures of the droplet’s cores have significant role in targeting for example vitamin E was mainly accumulated in liver and castor oil formulation was passively accumulated in spleen explaining the proof-of-concept of EPR effect. On the other hand, two different platform sizes of Cholecalciferol molecule revealing that no real impact on the pharmacokinetics and biodistribution but presented remarkable effect on the toxicity. Of particular interest is studying the effect of the surface charge of nanoparticles on their biodistribution, this is why oleic acid nano-emulsion was selected to proceed this study by presence of amphiphilepolymer poly(maleic anhydride-alt-1-octadecene) (PMAO). The in vitro results and in vivo evaluations were completely coherent approving that the neutral charged NPs are less toxic compared to the negatively charged ones that were highly uptaked in the cells causing stress to the cells and thereby affecting the toxicity. As a result they are different in biodistribution and pharmacokinetics. In this context, for the first time, we were able to functionalize the nano-emulsion droplets with ligand molecules by covalent bonds. Likewise we designed nano-droplets and coated by silica shell ended by amino groups and then followed by formation of amide bonds with grafting to dye ligand model (coumarin blue dye). The quantification of amino groups was performed by using spectroscopic and microscopic techniques, with a grafting efficiency as high as 41%. This process improves the targeting properties of such chemotherapeutic agents to the location of interest following active targeting mechanism (ligand receptorstrategy). One of our achieved objectives was to engineer multifunctional polymer-based NPs encapsulating hydrophobic drug model as DDs and iron oxide NPs as a theranostic model. To conclude, novel contrast agents and delivering systems were synthesized with outstanding physicochemical characteristics and suitable for in vivo medium with high efficacy and low toxicity.

The origin of silicic magma in basalt-dominated oceanic settings is fundamental to our understanding of magmatic processes and formation of the earliest continental crust. Particularly significant is magma-crust interaction that can modify the composition of magma and the dynamics of volcanism. This thesis investigates silicic magma genesis on different scales in two ocean island settings. First, volcanic products from a series of voluminous Neogene silicic centres in northeast Iceland are investigated using rock and mineral geochemistry, U-Pb geochronology, and oxygen isotope analysis. Second, interfacial processes of magma-crust interaction are investigated using geochemistry and 3D X-ray computed microtomography on crustal xenoliths from the 2011-12 El Hierro eruption, Canary Islands. The results from northeast Iceland constrain a rapid outburst of silicic magmatism driven by a flare of the Iceland plume and/or by formation of a new rift zone, causing large volume injection of basaltic magma into hydrated basaltic crust. This promoted crustal recycling by partial melting of the hydrothermally altered Icelandic crust, thereby producing mixed-origin silicic melt pockets that reflect the heterogeneous nature of the crustal protolith with respect to oxygen isotopes. In particular, a previously unrecognised high-δ18O end-member on Iceland was documented, which implies potentially complex multi-component assimilation histories for magmas ascending through the Icelandic crust. Common geochemical traits between Icelandic and Hadean zircon populations strengthen the concept of Iceland as an analogue for early Earth, implying that crustal recycling in emergent rifts was pivotal in generating Earth’s earliest continental silicic crust. Crustal xenoliths from the El Hierro 2011-2012 eruption underline the role of partial melting and assimilation of pre-island sedimentary layers in the early shield-building phase of ocean islands. This phenomenon may contribute to the formation of evolved magmas, and importantly, the release of volatiles from the xenoliths may be sufficient to increase the volatile load of the magma and temporarily alter the character and intensity of an eruption. This thesis sheds new light on the generation of silicic magma in basalt-dominated oceanic settings and emphasises the relevance of magma-crust interaction for magma evolution, silicic crust formation, and eruption style from early Earth to present.