Le besoin croissant de réduction du volume, de la masse et de la consommation des dispositifs électroniques sans pertes deperformances concerne aussi les oscillateurs à quartz utilisés dans les applications métrologiques (bases de temps, capteurs),la téléphonie, la navigation... Dans le cadre de cette problématique, nous avons développé un ASIC (Application SpecificIntegrated Circuit) en technologie 0,35 μm SiGe BiCMOS (Austriamicrosystems®) fonctionnant sous 3,3 V (±10%) pourréaliser un oscillateur à quartz miniature opérationnel sur une gamme en fréquence allant de 10 MHz à 100 MHz. Ce circuitdont la surface ne dépasse pas les 4 mm2 est composé de diverses cellules RF, depuis le système d’entretien de type Colpitts,la mise en forme et jusqu’à l’adaptation du signal à sa charge d’utilisation (50 W ou HCMOS). Ces cellules sont toutespolarisées par une référence de tension interne de type bandgap CMOS. La consommation totale du circuit en charge resteinférieure à 100 mW pour un bruit blanc de phase visé de −150 dBc/Hz à 40 MHz. Pour minimiser la sensibilité thermiquedu résonateur et ainsi pouvoir s’orienter également vers des applications OCXO (Oven Controlled Crystal Oscillator),nous avons partiellement intégré une régulation de température dans notre ASIC. Cette régulation fortement dépendante del’architecture thermo-mécanique a été dimensionnée puis validée au travers de modélisations par analogie sous Spectre®.Notre électronique intégrée nécessite peu de composants externes et nous l’avons reportée par flip chip sur une interfacespécifique pour / The increasing demand for high-performance devices featuring compact, lighter-weight designs with low-power consumptionalso impacts quartz crystal oscillators used in metrological applications (time bases, sensors), telephony or navigation. Inthis context, we have developed an ASIC (Application Specific Integrated Circuit) in 0.35 μm SiGe BiCMOS technology(Austriamicrosystems®) supplied by 3.3 V (±10%) to realize a miniaturized quartz crystal oscillator operating in the 10 MHzto 100 MHz frequency range. The fabricated die hosts several RF cells in a 4 mm2 area, including a sustaining amplifier(Colpitts topology), a signal shaping circuit and an output buffer dedicated to a specific load (50 W or HCMOS). These cellsare biased by a fully integrated CMOS bandgap voltage reference. The die power consumption remains lower than 100 mWfor a targeted phase noise floor as low as −150 dBc/Hz at a 40 MHz carrier frequency. A thermal control loop has in additionbeen partially integrated to the ASIC, in order to reduce the quartz resonator thermal sensitivity as well as to extend thepotential application field of the developed die to oven applications (OCXO). The thermal control, that is strongly dependanton the mechanical design, has been designed and tested by using electrical analogy modeling on Spectre® simulator. Finallyour integrated circuit has been connected to a specific substrate using flip chip technology to realize a miniaturized quartzcrystal oscillator packaged on a TO-8 enclosure (Ø15.2 mm).

Depuis quelques décennies, la technologie de contrôle de la fréquence a été au coeur de l'électronique des tempsmodernes grâce à son vaste domaine d'applications dans les systèmes de communication, les ordinateurs, les systèmesde navigation ou de défense militaire. Les dispositifs temps-fréquence fournissent des stabilités de fréquence et despuretés spectrales élevées dans le domaine de la stabilité court-terme. L'amélioration de la performance de cesdispositifs reste un grand défi pour les chercheurs. La réduction du bruit afin d'augmenter cette stabilité court-terme etd'éviter les commutations non souhaitées entre les canaux est donc très souhaitable. Il est communément admis que lalimitation fondamentale à cette stabilité court-terme est due au bruit flicker de fréquence des résonateurs. Dans cemanuscrit, un premier chapitre rappelle quelques faits de base sur l’acoustique, la cristallographie et les définitions dudomaine temps-fréquence nécessaires à l’étude des résonateurs et oscillateurs ultra-stables. Le deuxième chapitre estconsacré à un résumé de la littérature sur le bruit de fréquence en 1/f. Ensuite, le troisième chapitre concerne nos étudessur le modèle quantique de bruit en 1/f du Pr. Handel, qui, bien que critiqué par beaucoup, est encore le seul qui fournitune estimation de l'amplitude de plancher de bruit en 1/f et qui n'est pas infirmé par les données expérimentales. Dans lequatrième chapitre, une autre approche, basée sur le théorème de fluctuation-dissipation, est utilisée afin de mettre descontraintes numériques sur un modèle de bruit en 1/f causé par une dissipation interne (ou de structure) proportionnelleà l'amplitude, et non à la vitesse. Le dernier chapitre est consacré aux résultats expérimentaux. Le design et lesparamètres du résonateur ultra-stable utilisé lors de cette étude sont décrits. Les mesures de bruit de phase sur plusieurslots de résonateurs sont données. Les mesures des paramètres de résonateur ont été effectuées à basse température afinde les corréler avec les résultats de bruit. Afin d'évaluer rapidement la qualité des différents résonateurs, une autreapproche dans le domaine temporel a été testée. Elle utilise des oscillations pseudo-périodiques transitoires mettant lesoscilloscopes numériques actuellement disponibles à leurs limites de capacité. Enfin, les conclusions et perspectivessont présentées. / Since a few decades, frequency control technology has been at the heart of modern day electronics due to its huge areaof applications in communication systems, computers, navigation systems or military defense. Frequency controldevices provide high frequency stabilities and spectral purities in the short term domain. However, improvement of theperformance of these devices, in terms of frequency stability, remains a big challenge for researchers. Reducing noise inorder to increase the short term stability and avoid unwanted switching between channels is thus very desirable. It iscommonly admitted that the fundamental limitation to this short-term stability is due to flicker frequency noise in theresonators. In this manuscript, a first chapter recalls some basic facts about acoustic, crystallography and definitions oftime and frequency domain needed to explore ultra-stable resonators and oscillators. The second chapter is devoted to asummary of the literature on flicker frequency noise. Then, the third chapter concerns our studies on Handel’s quantum1/f noise model, which although criticized by many, is still the only one that provides an estimation of the flooramplitude of 1/f noise that is not invalidated by experimental data. In the fourth chapter, another approach, based on thefluctuation-dissipation theorem, is used in order to put numerical constraints on a model of 1/f noise caused by aninternal (or structural) dissipation proportional to the amplitude and not to the speed. The last chapter is devoted toexperimental results. An ultra-stable resonator used during this study is described. Phase noise measurements on severalbatches of resonators are given. Measurements of resonator parameters have been done at low temperature in order tocorrelate them with noise results. Another approach with a procedure that use transient pseudo periodic oscillations andput to their limits the capacities of presently available digital oscilloscopes, is presented, in order to assess rapidly thequality of various resonators. Finally, conclusions and perspectives are given.

<p> </p><p>Control of protein immobilization at sensor surfaces is of great interest within various scientific fields, since it enables studies of specific biomolecular interactions. To achieve this, one must be able to immobilize proteins with retained native structure, while minimizing non-specific protein binding. The high affinity interaction between streptavidin (SA) and biotin is extensively used as a linker between a surface, where SA is immobilized, and the (biotinylated) molecule of interest. Self- assembled monolayers (SAMs) of poly- and oligo ethylene glycol (PEG and OEG) derivatives have been proven in literature to minimize non-specific protein binding, and biotin-exposing SAMs have been shown efficient for immobilization of SA.</p><p>The aim of this master's thesis project was to develop biotinylated gold surfaces for quartz crystal microbalance with dissipation monitoring (QCM-D) applications through the self-assembly of mixed monolayers of thiolated OEG (or PEG) derivatives with or without a terminal biotin head group. For this, different thiol compounds were to be compared and evaluated. For the systems under study, the required biotin density for maximum specific SA immobilization was to be established, while keeping the non-specific serum adsorption at a minimum. Model experiments with biotinylated proteins immobilized to the SA-functionalized surfaces were to be performed to evaluate the possibilities for commercialization.</p><p>A protocol for the preparation of a novel biotinylated surface was developed based on the immersion of gold substrates in an ethanolic incubation solution of dithiols with OEG chains (SS-OEG and SS-OEG-biotin, 99:1) and found to give reproducible results with respect to low non-specific protein binding and immobilization of a monolayer of SA. The modified surfaces allowed for subsequent immobilization of biotinylated bovine serum albumin (bBSA) and biotinylated plasminogen (bPLG). PLG was the subject of a challenging case study, using a combination of QCM-D and surface plasmon resonance (SPR), where the immobilized protein was subjected to low molecular weight ligands that were believed to induce conformational changes. The high control of the surface chemistry allowed for the interpretation of the increased dissipation shift upon ligand binding in terms of conformational changes.</p><p>An obstacle before commercialization of the described biotinylated surfaces is that they do not seem stable for storage > 7 days. The reasons for this have to be investigated further.</p>

Control of protein immobilization at sensor surfaces is of great interest within various scientific fields, since it enables studies of specific biomolecular interactions. To achieve this, one must be able to immobilize proteins with retained native structure, while minimizing non-specific protein binding. The high affinity interaction between streptavidin (SA) and biotin is extensively used as a linker between a surface, where SA is immobilized, and the (biotinylated) molecule of interest. Self- assembled monolayers (SAMs) of poly- and oligo ethylene glycol (PEG and OEG) derivatives have been proven in literature to minimize non-specific protein binding, and biotin-exposing SAMs have been shown efficient for immobilization of SA. The aim of this master's thesis project was to develop biotinylated gold surfaces for quartz crystal microbalance with dissipation monitoring (QCM-D) applications through the self-assembly of mixed monolayers of thiolated OEG (or PEG) derivatives with or without a terminal biotin head group. For this, different thiol compounds were to be compared and evaluated. For the systems under study, the required biotin density for maximum specific SA immobilization was to be established, while keeping the non-specific serum adsorption at a minimum. Model experiments with biotinylated proteins immobilized to the SA-functionalized surfaces were to be performed to evaluate the possibilities for commercialization. A protocol for the preparation of a novel biotinylated surface was developed based on the immersion of gold substrates in an ethanolic incubation solution of dithiols with OEG chains (SS-OEG and SS-OEG-biotin, 99:1) and found to give reproducible results with respect to low non-specific protein binding and immobilization of a monolayer of SA. The modified surfaces allowed for subsequent immobilization of biotinylated bovine serum albumin (bBSA) and biotinylated plasminogen (bPLG). PLG was the subject of a challenging case study, using a combination of QCM-D and surface plasmon resonance (SPR), where the immobilized protein was subjected to low molecular weight ligands that were believed to induce conformational changes. The high control of the surface chemistry allowed for the interpretation of the increased dissipation shift upon ligand binding in terms of conformational changes. An obstacle before commercialization of the described biotinylated surfaces is that they do not seem stable for storage &gt; 7 days. The reasons for this have to be investigated further.

Polymer/inorganic nanoparticle hybrid thin films, primarily composed of functional inorganic nanoparticles, are of great interest to researchers because of their interesting electronic, photonic, and optical properties. In the past two decades, layer-by-layer (LbL) assembly has become one of the most powerful techniques to fabricate such hybrid thin films. This method offers an easy, inexpensive, versatile, and robust fabrication technique for multilayer formation, with precisely controllable nanostructure and tunable properties. In this thesis, various ways to control the structure of hybrid thin films, primarily composed of polyelectrolytes and indium tin oxide (ITO), are the main topics of study. ITO is one of the most widely used conductive transparent oxides (TCOs) for applications such as flat panel displays, photovoltaic cells, and functional windows. In this work, polyethyleneimine (PEI) was used to stabilize the ITO suspensions and improve the film buildup rate during the LbL assembly of poly(sodium 4-styrenesulfonate) (PSS) and ITO. The growth rate was doubled due to the stronger interaction forces between the PSS and PEI-modified ITO layer. The assembly of hybrid films was often initiated by a polyelectrolyte precursor layer, and the characteristics of the precursor layer were found to significantly affect the assembly of the hybrid thin films. The LbL assembly of ITO nanoparticles was realized on several substrates, including cellulose fibers, write-on transparencies, silicon wafers, quartz crystals, and glasses. By coating the cellulose fibers with ITO nanoparticles, a new type of conductive paper was manufactured. By LbL assembly of ITO on write-on transparencies, transparent conductive thin films with conductivity of 10⁻⁴ S/cm and transparency of over 80 % in the visible range were also prepared. As a result of this work on the mechanisms and applications of LbL grown films, the understanding of the LbL assembly of polyelectrolytes and inorganic nanoparticles was significantly extended. In addition to working with ITO nanoparticles, this thesis also demonstrated the ability to grow bicomponent [PEI/SiO₂]n thin films. It was further demonstrated that under the right pH conditions, these films can be grown exponentially (e-LbL), resulting in much thicker films, consisting of mostly the inorganic nanoparticles, in much fewer assembly steps than traditional linearly grown films (l-LbL). These results open the door to new research opportunities for achieving structured nanoparticle thin films, whose functionality depends primarily on the properties of the nanoparticles.

The investigations are related to the influence of nonionic polyethoxylated surfactant on Tin- and Tin-Silver depositions. Cyclovoltammetry, electrochemical depositions in Hull cell, with quartz crystal microbalance, impedance spectroscopy, X-ray diffraction, REM and others were used as methods of characterization. / Die Untersuchungen befasssen sich mit dem Einfluss von nichtionischen polyethoxylierten Tenside auf die Zinn- und Zinn-Silber-Abscheidung, die durch Zyklovoltammetrie, Abscheidungen in der Hullzelle, mit der elektrochemischen Quarzmikrowaage, der Impedanzspektroskopie, Röntgendiffraktometrie, Rasterelektronenmikroskopie und Tensiometrie charakterisiert wurden.

This thesis mainly deals with the development of photochemical approaches to immobilize carbohydrates on surfaces for glycobiological studies. These approaches have been incorporated into a number of state-of-the-art nanobio-platforms, including carbohydrate microarrays, surface plasmon resonance (SPR), quartz crystal microbalance (QCM), atomic force microscopy (AFM), and glyconanomaterials. All the surfaces have displayed good binding capabilities and selectivities after functionalization with carbohydrates, and a range of important data have been obtained concerning surface characteristics and carbohydrate-protein interactions, based on the platforms established. Besides, a variety of non-carbohydrate and carbohydrate-based molecules have been synthesized, during which process the mutarotation of 1-glycosyl thiols and the stereocontrol in 1-S-glycosylation reactions have been thoroughly studied. / QC 20111004

Les nanoparticules de silice sont des plateformes idéales pour la conception d’outils de bioimagerie afin d’étudier les mécanismes de transfert de gènes par des lipoplexes. L’objectif de notre étude est le développement d’une modification chimique de surface permettant d’obtenir des colloïdes de silice chargés positivement susceptible de lier de l’ADN par des interactions électrostatiques. Deux stratégies pour la génération de groupements ammonium quaternaires sur des nanoparticules de silice sont présentées a) une silanisation directe par l’utilisation d’un agent de couplage silanique contenant un groupement ammonium quaternaire et b) un procédé en deux étapes mettant en jeu une modification de surface chimique par des aminosilanes primaires et secondaires suivie d’une alkylation des amines par l’iodomethane. Différentes méthodes physico-chimiques (essais de cosédimentation, des expériences de microbalance à cristal de quartz avec mesure de dissipation et d’imagerie MET et Cryo-MET) ont été utilisées pour mettre en évidence et caractériser les interactions entre les biomolécules et les surfaces quaternisées. Des études préliminaires ont montrées les capacités de marquage de lipoplexes par de telles nanoparticules. / Silica nanoparticles are ideal platforms for the conception of bioimaging tools serving for the elucidation of the mechanisms of gene transfection via lipoplex structures. The purpose of the present study is the development of a chemical surface modification for the generation of quaternary ammonium groups on silica nanoparticles permitting the obtainment of highly positively charged silica colloids which strongly attract DNA by electrostatic interactions. Two modification strategies to generate quaternary ammonium groups on silica are presented a) a direct silanization using quaternary ammonium groups containing silane derivatives and b) a modification of silica nanoparticles via a first modification with an amine group containing silane derivative and a subsequent quaternization of the amine groups via an alkylation with iodomethane. Different physicochemical methods were employed (cosedimentation assays, quartz crystal microbalance with dissipation monitoring measurements, TEM and Cryo-TEM imaging) to analyze interactions between quaternized surfaces, DNA and lipids. A preliminary study was carried out which shows the capacity of the synthesized nanoparticles to label DNA in lipoplexes.

Nous avons caractérisé différents cristaux piézoélectriques de Langatate La3Ga5.5Ta0.5O14 (LGT), de différentes couleurs afin d’évaluer l’influence des défauts sur la qualité de dispositifs du domaine Temps-Fréquence (résonateurs acoustiques).Nous avons étudié la composition de ces cristaux dont les variations autour de la composition stoechiométrique sont surtout dues à l’évaporation du Ga2O au cours de la croissance compensée par un excès de Ga2O3 dans le mélange initial. Pour déterminer cette composition, la technique ICP-AES, précédée par une mise en solution par fusion alcaline, est la plus fiable.La présence d’impuretés chimiques, telles que les éléments métalliques ou les terres rares, liée à la pureté des oxydes de base, au frittage de la charge dans un creuset alumine… est étudiée. Nous expliquons ainsi la nature des centres colorés qui évolue selon l’atmosphère de tirage ou lors d’un recuit particulier.C’est ainsi que nous avons déterminé certaines propriétés de LGT permettant l’obtention de dispositifs comme les résonateurs à ondes de volume dont le produit Q.f est supérieur à celui des résonateurs à quartz. Pour cela, nous montrons notamment qu’il est nécessaire que :- la composition du cristal soit la plus proche possible de la stoechiométrie,- la résistivité électrique soit la plus grande possible,- l’étude spectroscopique ne révèle aucune absorption dans le domaine du visible.Dans ces conditions, le facteur de qualité Q d’une résonance à 10 MHz peut être de 1.44 million au point d’inversion de la courbe fréquence-température (1.35 pour le quartz) mais qu’il diminue notablement pour atteindre 0.35 million si nous pratiquons un recuit sous air à 1000°C pendant 48 h. / We have characterized Langatate piezoelectric crystals La3Ga5.5Ta0.5O14 (LGT), differently colored in order to evaluate the defects influence on the quality of Bulk Acoustic Waves resonators for the Time and Frequency domain.We have analyzed the composition of crystals whose variations around stoichiometric composition are mainly due to the evaporation of the Ga2O during growth compensated by adding an excess of Ga2O3 in the initial mixture. Among different techniques, the ICP-AES spectrometry, preceded by a dissolution by alkaline fusion seems to be the most accurate technique to determine the composition.The inevitable presence of chemical impurities, such as metallic elements, rare earth… linked to the purities of the raw materials, to the sintering of the load in an alumina crucible… is also studied. We try to explain in particular the nature of the color centers that evolve according to the growth atmosphere or during a particular annealing.So, we conclude by a list of necessary properties to obtain BAW resonators exhibiting a Q.f product higher than quartz. For this, we establish that it is necessary that:- the crystal composition is as close as possible to the stoichiometric composition,- the electrical resistivity is the highest possible,- the spectroscopic study does not reveal any absorption band in the visible domain.In these conditions, we were able to highlight that the quality factor of a 10 MHz resonance is of 1.44 million at the inversion temperature of the frequency-temperature curve (1.35 for the quartz crystal in the same conditions), but that this one decreases significantly to reach 0.35 million if we perform an annealing under air at 1000 °C during 48 hours.

Protein (mis)folding into highly ordered, fibrillar structures, amyloid fibrils, is a hallmark of several, mainly neurodegenerative, disorders. The mechanism of this supra-molecular self-assembly reaction, as well as its relationship to protein folding are not well understood. In particular, the molecular origin of the metastability of the soluble state of proteins with respect to the aggregated states has not been clearly established. In this dissertation, it is demonstrated, that highly accurate kinetic experiments, using a novel biosensing method, can yield fundamental insight into the dynamics of proteins in the region of the free energy landscape corresponding to protein aggregation. First, a section on Method development describes the extension and elaboration of the previously established kinetic assay relying on quartz crystal microbalance measurements for the study of amyloid fibril elongation (Chapter 3). This methodology is then applied in order to study in great detail the origin of the various contributions to the free energy barriers separating the soluble state of a protein from its aggregated state. In particular, the relative importance of residual structure, hydrophobicity (Chapter 4) and electrostatic interactions (Chapter 5) for the total free energy of activation are discussed. In the last part of this thesis (Chapter 6), it is demonstrated that this biosensing method can also be used to study the binding of small molecules to amyloid fibrils, a very useful feature in the framework of the quest for potential inhibitors of amyloid formation. In addition, it is shown that Thioflavin T, to-date the most frequently employed fluorescent label molecule for bulk solution kinetic studies, can in the presence of potential amyloid inhibitor candidates be highly unreliable as a means to quantify the effect of the inhibitor on amyloid formation kinetics. In summary, the work in this thesis contributes to both the fundamental and the applied aspects of the field of protein aggregation.