Yes / Despite the rising interest in pharmaceutical cocrystals in the past decade, there is a lack of research in the solid processing of cocrystals downstream to crystallization. Mechanical stress induced by unit operations such as milling could affect the integrity of the material. The purpose of this study is to investigate the effect of milling on pharmaceutical cocrystal and compare the performance of ball mill and jet mill, using caffeine-glutaric acid (1:1) cocrystal as the model compound. Our results show that ball milling induced polymorphic transformation from the stable Form II to the metastable Form I; whereas Form II remained intact after jet milling. Jet milling was found to be effective in reducing particle size but ball milling was unable to reduce the particle beyond certain limit even with increasing milling intensity. Heating effect during ball milling was proposed as a possible explanation for the difference in the performance of the two types of mill. The local increase in temperature beyond the polymorphic transformation temperature may lead to the conversion from stable to metastable form. At longer ball milling duration, the local temperature could exceed the melting point of Form I, leading to surface melting and subsequent recrystallization of Form I from the melt and agglomeration of the crystals. The findings in this study have broader implications on the selection of mill and interpretation of milling results for not only pharmaceutical cocrystals but pharmaceutical compounds in general.

An analytic treatment of stresses and temperatures generated during grinding is presented from an elasticity approach. A two-dimensional heat conduction model employs an energy partition scheme in the grinding zone to produce realistic temperature profiles. By using the basic equations of thermoelasticity, the temperature profiles yield thermal stresses. An extension of the Hertzian contact theory yields mechanical stresses, which are then superimposed on the thermal stresses. Approximate plasticity corrections are used to approximate the deformation as the grinding wheel passes over the workpiece. Subsurface results are qualitatively consistent with those found experimentally. However, they still do not agree with near-surface experimental results. Possible explanations and areas of further research are discussed. / Master of Science

Etudier le séchage est un moyen original de caractériser les propriétés de fluides complexes. Cette technique permet de concentrer continûment des fluides : d'un état dilué à un état sec. A l'échelle microfluidique, la manipulation, les observations et les processus qui entrent en jeu sont simplifiés. Ce travail de thèse s'attache à décrire le séchage de ces fluides et plus particulièrement le cas de dispersions colloïdales. Ces travaux présentent deux méthodes pour étudier l'extraction du solvant d'un fluide à l'échelle microfluidique : la micropervaporation et la goutte confinée. Ces techniques ont notamment permis de réaliser des estimations précises de coefficients de diffusion collective sur toute la gamme de concentrations pour un mélange eau/glycérol et pour une dispersion colloïdale de nanoparticules de silice chargées. Par ailleurs, le séchage induit des contraintes mécaniques conséquentes. Ces contraintes peuvent générer des déformations importantes, des phénomènes de délamination ou de fracturation du matériau solidifié. Une méthode originale de mesure in situ de contraintes a été mise en place pendant ces travaux. Les mesures réalisées avec une dispersion colloïdale modèle permettent de mettre en évidence expérimentalement l'apparition de contraintes mécaniques au moment de la transition sol/gel de la dispersion. L'augmentation de la contrainte est ensuite associée au séchage d'un gel poroélastique. / Drying complex fluids is an original technique to study their properties. Solvent extraction enables the continuous concentration of fluids from a dilute to a solid state. The use of the microfluidic scale allows one to limit side effects and simplify experiments, observations and modeling. This project mainly describes the drying of colloidal dispersions in two confined geometries: microfluidic channels and confined droplets between two plates. With these two techniques, we estimate collective diffusion for a water/glycerol mixture and a model dispersion of charged silica nanoparticles over the whole concentration range. Moreover, the drying of complex fluids often induces mechanical stresses which are the root for deformation, delamination phenomena and cracks. We developed an original technique to measure these stresses in situ. For a model colloidal dispersion, we evidenced experimentally that these forces arise from a liquid to solid state transition. The increase of these stresses is then associated with the drying of a poroelastic gel.

Le cartilage est un tissu clé des articulations synoviales. Suite à un problème mécanique, traumatique ou inflammatoire, le cartilage est dégradé entrainant des douleurs articulaires et une perte de mobilité. Le cartilage étant un tissu non innervé et non vascularisé, son auto-réparation est très faible. De plus en plus de techniques sont développées pour la réparation des défauts cartilagineux mais aucune n’a encore permis d’obtenir un nouveau cartilage pleinement fonctionnel. En particulier, l’ingénierie tissulaire (IT) est une technique très prometteuse qui consiste à obtenir un greffon de cartilage dont les propriétés mécaniques et structurales soient satisfaisantes une fois implantée dans l’articulation. L’IT est basée sur l’association de cellules, d’un biomatériau et de facteurs de croissance. Le but de cette thèse est d’étudier l’effet de l’âge du donneur des cellules sur la synthèse du greffon par l’IT in vitro et sur la qualité du cartilage obtenu lors de l’implantation dans un modèle de rat NUDE. Puis dans une dernière partie, l’impact de l’environnement chimique et mécanique est étudié sur la qualité du greffon. Nos études montrent ainsi que l’âge du donneur aussi bien dans un contexte in vitro ou in vivo impacte la qualité du greffon et la réparation une fois implanté dans l’animal. En effet, les greffons issus des donneurs âgés ont des propriétés mécaniques légèrement plus élevées et une synthèse des protéines de la matrice extracellulaire (MEC) du cartilage significativement plus élevée que les greffons issus de donneurs jeunes. De plus, la réponse inflammatoire des greffons implantés dans un défaut cartilagineux chez le rat NUDE est plus faible pour les donneurs âgés. Enfin, nous montrons que le microenvironnement mécanique (compression ou pression hydrostatique) et chimique (liquide synovial (LS) ou TGF-β pur) joue un rôle important sur la réponse cellulaire. Par ailleurs, en fonction de l’âge, l’association de ces différents facteurs donnent des résultats différents. Par exemple, pour une sollicitation de type compression, c’est le LS qui est à favoriser pour obtenir les greffons de meilleure qualité dans le cas des donneurs âgés. Au contraire, pour la même sollicitation de type compression, c’est la présence de TGF-β1 qui conduit au greffon de meilleure qualité pour les donneurs jeunes. Ces études mettent en évidence l’importance de l’âge du donneur et montrent de plus qu’un protocole IT patient spécifique est la meilleure solution. / Cartilage is an important tissue of synovial joints. Following a mechanical problem, traumatic or inflammatory, the cartilage is degraded causing joint pain and loss of mobility. Because cartilage is a non-innervated and non-vascularized tissue, its self-repair is very weak. More and more techniques are being developed for the cartilage but none has resulted in a new fully functional cartilage. In particular, tissue engineering (TE) is a very promising technique that consists in obtaining a cartilage graft whose mechanical and structural properties are satisfactory once implanted in the joint. TE is based on the association of cells, biomaterial and growth factors. The aim of this thesis is to study the effect of cell donor’s age on graft synthesis by TE in vitro and on the quality of the cartilage obtained during implantation in a NUDE rat model. Then in a last part, the impact of the chemical and mechanical environment is studied on the quality of the graft. Our studies show that the age of the donor both in vitro and in vivo has an impact on graft quality and repair once implanted in the animal. In fact, grafts from older donors have slightly higher mechanical properties and significantly higher synthesis of extracellular matrix proteins (ECM) than grafts from younger donors. In addition, the inflammatory response of grafts implanted in a cartilage defect in the NUDE rat is lower for older donors. Finally, we show that the mechanical microenvironment (compression or hydrostatic pressure) and chemical microenvironment (synovial fluid (SF) or TGF-β) play an important role in the cellular response. Moreover, depending on age, the combination of these different factors gives different results. For example, for a compression solicitation, it is the SF that is to be favored to obtain better quality grafts in the case of elderly donors. On the contrary, for the same compression stress, it is the presence of TGF-β1 that leads to the best quality graft for young donors. These studies highlight the importance of donor age and further show that a specific patient protocol of TE is the best solution.

As células endoteliais são capazes de converter o estímulo mecânico em sinais intracelulares e produzir fatores vasoativos como o óxido nítrico (oNO). Evidências recentes sugerem que as beta-arrestinas desempenham um papel importante não somente na dessensibilização e internalização de receptores acoplados à proteína G (GPCR) como também na mecanotransdução. Nós testamos a hipótese de que células endoteliais submetidas ao shear stress (SS) produzem oNO por meio da ativação da via de sinalização dependente de beta-arrestina. Para tal, células endoteliais de veia safena (hSVEC) foram transfectadas com siRNA contra as isoformas 1 e 2 da beta-arrestina e, posteriormente, submetidas ao SS (15 dinas/cm2) durante 10 min. Nós encontramos que as SVEC silenciadas para a beta-arrestina 1/2 (70%) exibiram uma menor produção de nitrito no meio de cultura em resposta ao SS (166±17 vs. 326±44% comparado com hSVEC transfectadas com siRNA controle). Além disso, o silenciamento da beta-arrestina 1 e 2 preveniu os níveis de fosforilação da Akt no resíduo de serina 473 e a fosforilação da eNOS no resíduo de serina 1177, enquanto que a fosforilação da ERK 1/2 manteve-se inalterada. Curiosamente, análises de imunoprecipitação mostraram que a beta-arrestina interage com caveolina-1, um mecanossensor do shear stress, mas não é influenciado pelo SS. Além disso, na situação estática, a beta-arrestina encontra-se em uma localização perinuclear e, após o SS, adquiriu um padrão mais difuso no citosol. Coletivamente, esses dados sugerem que a beta-arrestina e a sinalização downstream Akt/ eNOS são necessárias para a produção de oNO induzido por shear stress em células endoteliais vasculares humana / Endothelial cells are capable of converting mechanical stimuli into intracellular signals generating vasoactive factors such as nitric oxide (oNO). Recent evidence suggests that beta-arrestins play a role not only on G protein-coupled receptors (GPCR) desensibilization but also in mechanotransduction. We tested the hypothesis that beta-arrestin and its downstream signaling influence laminar shear stress (SS)-induced oNO production by endothelial cells. Towards this end, human saphenous vein endothelial cells (hSVEC) transfected with siRNA against beta-arrestins isoforms 1 and 2 were subjected to SS (15 dynes/cm2, 10 minutes). We found that the SS-induced production of nitrite in the cell culture medium from down-expressed beta-arrestin 1/ 2 (70%) SVEC decreased (166±17 vs. 326±44% compared to wild-type hSVEC; P < 0.001). The beta-arrestin 1 and 2 down-regulation in SVEC also inhibited the phosphorylation levels of Akt at the serine residue 473 and the phosphorylation levels of eNOS at the serine residue 1177, whereas ERK phosphorylation remained unchanged. Interestingly, immunoprecipitation analysis showed that beta-arrestin interacts with caveolin-1, a shear stress mechanosensor, which is not influenced by SS despite the fact that the static perinuclear localization of beta-arrestins changed to the cytosol upon SS. Collective these data suggest that beta-arrestin and Akt/eNOS downstream signaling are required for shear stress-induced nitric oxide production in human vascular endothelial cells

La manipulation de parois de domaine magnétique – qui séparent des régions d’aimantation uniforme dans les matériaux – est associée à des enjeux à la fois fondamentaux et technologiques. De nombreux travaux portent sur l’utilisation de champs magnétiques et de courants électriques pour leur déplacement. Cependant, des préoccupations particulières – notamment la dissipation d’énergie - motivent la recherche d’alternatives. Parmi les solutions potentielles, le couplage magnétoélectrique par l’intermédiaire de contraintes mécaniques dans des hétérostructures magnétoélastique/piézoélectrique paraît prometteur. Dans cette thèse, il est montré que l’association d’un champ magnétique de biais et de contraintes mécaniques uniformes peut engendrer le déplacement unidirectionnel d’une paroi de domaine transverse dans des nanostructures à anisotropie uniaxiale. Les considérations statiques et dynamiques de ce phénomène sont étudiées par le biais de procédures numériques ad hoc simulant le couplage mécanique entre substrat de PMN-PT de coupe 011 générant des contraintes, et nanostructures multicouches magnétoélastiques TbCo2/FeCo. Le design du profil de section des nanostructures permet de moduler la réponse du système, par exemple pour contrôler la position de parois confinées. La dynamique du système se distingue des régimes habituels de par la forme de la paroi de domaine. L’atteinte de régimes permanents dans des nanorubans montre que des vitesses comparables aux autres techniques sont obtenues, pour une dissipation d’énergie beaucoup plus faible. Des travaux expérimentaux ont permis de mettre au point un process de fabrication sur PMN-PT et d’explorer l’effet magnétoélectrique / The manipulation of magnetic domain walls – that separate regions of uniform magnetization – is associated with both fundamental and technological research interests. A large part of the literature on domain wall motion deals with the use of magnetic fields and electric currents. However, several concerns – most notably energy dissipation – motivates the search for alternatives. Among potential candidates, the mechanical stress-mediated magnetoelectric coupling in magnetoelastic/piezoelectric heterostructures seems promising. In this thesis, it is shown that the combination of a bias magnetic field and uniform mechanical stress can induce unidirectional domain wall motion in nanostructures with uniaxial anisotropy. Static and dynamic aspects of this phenomenon are studied by means of ad hoc numerical procedures simulating the mechanical coupling of 011-cut PMN-PT generating the stress, and TbCo2/FeCo multilayers magnetoelastic nanostructures. The design of the cross section profile in nanostructures allows to tailor the response of the system, enabling for instance the control of domain wall position in confined geometries. The associated dynamics stands apart from known regimes because of the shape of the domain wall. The existence of steady-state regimes in nanostripes of constant width shows that velocities comparable to those of other techniques can be obtained, for a fraction of the energy required. Experimental investigations resulted in the development of a successful fabrication process on PMN-PT and the exploration of the magnetoelectric effect

Metal-oxide-semiconductor field-effect transistors (MOSFETs) are major devices inintegrated circuit, extensively used in various electronic products. In order to improve the electrical characteristics, scaling channel width and length, using high-£e gate dielectric insulator, and strained silicon may be utilized to increase the driving current and circuit speed. Nevertheless, the scaling of the channel width and length must overcome the limitation of the photolithographytechnology and cost. Once the method is employed, the MOSFETs will face a serious short-channel effect and gate leakage current. In the aspect of high-£e gate dielectric insulator, there still have problems, containing the trap states, phonon scattering, dipole-induced threshold voltage variation, needed to be solved. This dissertation focuses on the properties of MOSFETs experienced an external-mechanical strain, where the channel will be strained. Hence, the mobility, driving current, and circuit speed will increase. Our research can be divided into three topics: fabricating process-induced strained Si, external mechanical stress-induced strained Si, and the properties of strained Si MOSFETs at different temperatures. Except the electrical measurement, we also used the ISE-TCAD to simulate the electrical characteristic of MOSFETs under stress. Firstly, we apply the stress on n-MOSFETs by utilizing the nitride-capping layer. Once the lattice is strained, the mobility will increase, hence resulting in the operating speed. Secondly, the electrical characteristics under external stress is explored by introduced the external mechanical stress along the channel length of nMOSFETs. In addition to the fabricating process-induced strain, the fabricating process condition will also influence the device characteristics. As a result, we propose a new strain technology for our following research. Thirdly, the device performance of strained Si under different temperatures is investigated. Finally, we discuss the gate leakage current in strained Si depending on the ultra-thin gate oxide layer.

No description available.

As células endoteliais são capazes de converter o estímulo mecânico em sinais intracelulares e produzir fatores vasoativos como o óxido nítrico (oNO). Evidências recentes sugerem que as beta-arrestinas desempenham um papel importante não somente na dessensibilização e internalização de receptores acoplados à proteína G (GPCR) como também na mecanotransdução. Nós testamos a hipótese de que células endoteliais submetidas ao shear stress (SS) produzem oNO por meio da ativação da via de sinalização dependente de beta-arrestina. Para tal, células endoteliais de veia safena (hSVEC) foram transfectadas com siRNA contra as isoformas 1 e 2 da beta-arrestina e, posteriormente, submetidas ao SS (15 dinas/cm2) durante 10 min. Nós encontramos que as SVEC silenciadas para a beta-arrestina 1/2 (70%) exibiram uma menor produção de nitrito no meio de cultura em resposta ao SS (166±17 vs. 326±44% comparado com hSVEC transfectadas com siRNA controle). Além disso, o silenciamento da beta-arrestina 1 e 2 preveniu os níveis de fosforilação da Akt no resíduo de serina 473 e a fosforilação da eNOS no resíduo de serina 1177, enquanto que a fosforilação da ERK 1/2 manteve-se inalterada. Curiosamente, análises de imunoprecipitação mostraram que a beta-arrestina interage com caveolina-1, um mecanossensor do shear stress, mas não é influenciado pelo SS. Além disso, na situação estática, a beta-arrestina encontra-se em uma localização perinuclear e, após o SS, adquiriu um padrão mais difuso no citosol. Coletivamente, esses dados sugerem que a beta-arrestina e a sinalização downstream Akt/ eNOS são necessárias para a produção de oNO induzido por shear stress em células endoteliais vasculares humana / Endothelial cells are capable of converting mechanical stimuli into intracellular signals generating vasoactive factors such as nitric oxide (oNO). Recent evidence suggests that beta-arrestins play a role not only on G protein-coupled receptors (GPCR) desensibilization but also in mechanotransduction. We tested the hypothesis that beta-arrestin and its downstream signaling influence laminar shear stress (SS)-induced oNO production by endothelial cells. Towards this end, human saphenous vein endothelial cells (hSVEC) transfected with siRNA against beta-arrestins isoforms 1 and 2 were subjected to SS (15 dynes/cm2, 10 minutes). We found that the SS-induced production of nitrite in the cell culture medium from down-expressed beta-arrestin 1/ 2 (70%) SVEC decreased (166±17 vs. 326±44% compared to wild-type hSVEC; P < 0.001). The beta-arrestin 1 and 2 down-regulation in SVEC also inhibited the phosphorylation levels of Akt at the serine residue 473 and the phosphorylation levels of eNOS at the serine residue 1177, whereas ERK phosphorylation remained unchanged. Interestingly, immunoprecipitation analysis showed that beta-arrestin interacts with caveolin-1, a shear stress mechanosensor, which is not influenced by SS despite the fact that the static perinuclear localization of beta-arrestins changed to the cytosol upon SS. Collective these data suggest that beta-arrestin and Akt/eNOS downstream signaling are required for shear stress-induced nitric oxide production in human vascular endothelial cells

Les muscles infraépineux et petit rond sont cruciaux sur le plan fonctionnel et sont altérés dans le cadre des pathologies de la coiffe des rotateurs. La proportion de tissu graisseux dans l’infraépineux est actuellement un critère pronostic du résultat fonctionnel des réparations des lésions tendineuses de la coiffe des rotateurs. Les buts de ce travail sont de caractériser ces muscles sur le plan anatomique, de proposer une meilleure exploration de leur morphologie par IRM, d’utiliser l’analyse de texture informatique pour objectiver leur composition et enfin, d’utiliser l’élastographie ultrasonore pour analyser leur comportement viscoélastique en contrainte. L’infraépineux et le petit rond sont respectivement de conformation tripennée et parallèle. Les critères d’acquisition IRM de routine peuvent être aisément optimisés pour analyser plus précisément les muscles rotateurs externes. L’analyse de texture semble prometteuse pour évaluer la proportion de tissu graisseux dans le muscle squelettique. L’élastographie ultrasonore permet d’appréhender le degré d’anisotropie musculaire, et donc l’état d’organisation du muscle infraépineux. / Infraspinatus and teres minor muscles are crucial functionally and are regularly impaired in the context of of the rotator cuff pathology. The proportion of fatty tissue in the infraspinatus is currently a strong prognosis criterion of functional outcomes of rotator cuff tendon repair. The goals of this work are to characterize these muscles anatomically, to provide a better exploration of their morphology by MRI, to use computer texture analysis to objectify their composition and finally to use the ultrasound elastography for analysing their viscoelastic behaviour under stress. Infraspinatus and teres minor muscles have a tripennate and parallel organization, respectively. Routine MRI acquisition criteria can be easily optimized to analyse more precisely the external rotator muscles. Texture analysis seems promising to assess the proportion of fatty tissue in the skeletal muscle. The ultrasound elastography allows us to estimate the degree of muscle anisotropy, and therefore the state of organization of the infraspinatus muscle.