Personalised medicine is widely considered to be the future of global healthcare, where diagnosis, treatment, and potentially even drug development, will become specific to, and optimised for, each individual patient. Traditional population based cell studies suppress the influence of outlier cells that are frequently those of most clinical relevance. Hence single-cell analysis is becoming increasingly important in understanding disease, aiding diagnosis and selecting tailored treatment; but remains the preserve of biomedical laboratories far from the patient. Current instruments depend upon cell-labelling to identify the cell type(s) of interest, which require that these be chosen a-priori and may not be those most clinically relevant. Furthermore, cell-labelling is fundamentally subjective, requiring highly-skilled operators to decide upon the validity of each and every test. Therefore, new test methods need to be developed to enable the widespread adoption of single-cell analysis. The passive electrical properties of biological cells are known to be indicative of the specific cell type, but no technology has demonstrated their comprehensive measurement within a mass-manufacturable device. This work aims to show that biologically meaningful information can be obtained in the form of identifiable “cell signatures” through broadband frequency measurements spanning 100 kHz to 100 MHz that exploit the properties of differential electric fields. This hypothesis is tested through the design, implementation and experimental testing of a dedicated microsystem that integrates two novel designs of electrical sensor within a standard, mass-manufacturable Complementary Metal-Oxide Semiconductor microelectronics technology. One sensor measures the absolute electrical environment above a single sense electrode. The other measures the difference in electrical environment between a pair of electrodes, with view to provide information regarding the suspended cell only, through rejecting the common signal due to its suspending medium. Both sensors are shown capable of detecting individual biological cells in physiological solution, and the differential sensor capable of identifying individually-fixed red blood cells, cervical cancer HeLa cells, and three diameters of homogeneous polystyrene micro-beads of comparable size, all while suspended in physiological saline. These results confirm the hypothesis that differential electric fields provide greater distinction of suspended cells from their environment than existing electrical methods. This finding shows that electrode polarisation arising from proximity to liquids, and particularly physiological media, can be overcome through fully-differential electrical cell sensing. However, misalignment between cells and sensor electrodes limits the sensitivity achieved with the microsystem. Methods to overcome such alignment issues should be investigated in future work, along with higher frequency measurements beyond those presented here.

Galvanotaxis is the movement of cells in an applied electric field. The first steps to design a chip for observations of galvanotaxic behavior of cells were done in this work. The chip is a miniaturised system of previous larger galvanotaxis systems and uses materials which are thought to be biocompatible. The system was constructed on microscope slides with a channel in PDMS with adjacent polymer electrodes. The polymer electrodes were made from poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate) (PEDOT:PSS), glycerol and Silquest A-187. The PEDOT:PSS electrodes were connected with either an evaporated metal electrode of titanium and gold or a gold net. Systems with PEDOT:PSS are neutralised when put in excessive amount of PBS (pH=7.4) for 24 hours. The final system had a channel with dimension length=14 mm, width=0.5 mm and height=0.25 mm. PEDOT:PSS worked as an electrode material and the achieved electric field through the channel was between 55 V/m and 160 V/m with an applied voltage of 1 V. The decrease of the electric field within the first hour was between 10 % and 30%.  Further development of this system could give an easy way to observe galvanotaxic behaviour of cells or an instrument that can distinguish between different cell types.

Ces dernières années, de nouvelles règlementations concernant la protection environnementale ont vu le jour, notamment avec la Directive Cadre sur l'Eau proposée en 2000. Celle-ci impose des normes de plus en plus contraignantes sur les rejets des systèmes d'assainissement dans les milieux récepteurs. Ces rejets sont d'autant plus conséquents que les évènements pluvieux sont plus intenses, causes du changement climatique, et que la population augmente comme le souligne le Plan National Santé Environnement (2009-2013). Le test de la Demande Biologique en Oxygène (DBO) est à ce jour le plus largement utilisé pour répondre à ces normes. Cependant, sa durée de réalisation ne permet pas aux gestionnaires de systèmes d'assainissement d'anticiper les pics de pollution, et de rétroagir sur le procédé d'assainissement avant déversement dans le milieu récepteur. De plus, ce test normalisé utilise un inoculum bactérien, issu de l'environnement, contenant différentes souches dont la diversité et la concentration est inconnue. Ceci ne permet pas, alors, d'avoir une bonne reproductibilité sur la mesure de la DBO. C'est donc dans ce contexte de protection environnementale que le projet BIOGUARD, issu d'une entente entre la recherche académique et les industriels du domaine, se positionne. Dans le cadre de ces travaux de thèse, nous avons développé des outils et méthodes permettant de réduire à la fois le volume d'échantillon utilisé pour la mesure par une approche d'intégration microsystème, et à la fois la durée de l'analyse par une optimisation du processus de biodégradation par les bactéries, et par une approche de modélisation mathématique. Deux types de capteurs optiques ont été utilisés, le premier permettant de mesurer l'oxygène dissous, et le second permettant de mesurer l'activité bactérienne. Ces deux capteurs ont été intégrés dans des dispositifs microfluidiques en technologie verre-PDMS, qui est une technologie tout à fait adapté à ce type de recherche du fait de sa biocompatibilité, de sa simplicité de mise en œuvre et de sa grande adaptabilité. L'une des innovations de ce projet est de proposer un biocapteur combinant les réponses de plusieurs souches bactériennes spécifiquement choisies afin d'augmenter la précision et la reproductibilité de la mesure. Lors de nos expériences, cependant, une seule souche bactérienne sera utilisée. Une étude des facteurs d'influence a été mené afin d'observer les changements du comportement bactérien. Avec les résultats expérimentaux obtenus, nous avons tenté d'expliquer ces changements par une approche mathématique, en utilisant des modèles théoriques de croissance bactérienne, dans le but de prédire la valeur de la DBO. Enfin, un prototype macro-fluidique, basé sur une seule souche bactérienne, réutilisable et automatique a également été développé dans le but de proposer une architecture fluidique simple que l'on pourrait alors dupliquer pour l'utilisation de la totalité des souches prévues dans le projet. / In recent years, new regulations concerning environmental protection have emerged, particularly with the Water Framework Directive proposed in 2000. It imposes standards more restrictive on discharges from wastewater systems in receiving environments. These discharges are even more consistent than the rainfall events are more intense, causes of climate change, and population increases as outlined in the Plan National Santé Environnement (2009-2013). The test of the Biological Oxygen Demand (BOD) is to date the most widely used to meet these standards. However, its achievement time does not allow managers sewerage systems to anticipate pollution peaks, and to retroact on the purification process prior to discharge into receiving environment. In addition, this standardized test uses a bacterial inoculum from the environment, containing different strains with the diversity and concentration is unknown. This does not, then, to have a good reproducibility of the measurement of the BOD. It is in this environmental protection context that the BIOGUARD project, result of an agreement between academic and industrial research in the field, is positioned. As part of these thesis works, we developed tools and methods to reduce both the volume of sample used for the measurement with a micro-integration approach, and both the duration of the analysis by an optimization of the biodegradation process by bacteria, and by mathematical modeling approach. Two types of optical sensors have been used, the first for measuring dissolved oxygen, and the second to measure the bacterial activity. Both sensors have been integrated into microfluidic devices in PDMS-glass technology, a technology perfectly suited to this type of research because of its biocompatibility, its simplicity of implementation and its great adaptability. One of the innovations of this project is to provide a biosensor combining responses to several bacterial strains specifically selected to increase the accuracy and reproducibility of the measurement. In our experiments, however, a single bacterial strain is used. A study of influencing factors was conducted to observe changes in bacterial behavior. With the experimental results, we have tried to explain these changes by a mathematical approach, using theoretical models of bacterial growth, in order to predict the value of BOD. Finally, a macro-fluidic prototype, based on a single bacterial strain, reusable and automatic was also developed to provide a simple fluidic architecture that could be duplicated for use with all strains included in the project.

The objective of the research in this dissertation is to develop microsystem based separation technologies for whole cell cancer analysis using human whole blood as the input sample. This research work is carried out with two different approaches; one based on a miniaturized cascade magnetophoresis system and a second based on dielectrophoresis. The miniaturized systems can be fabricated using MEMS technologies combined with plastic fabrication techniques. The design, fabrication, packaging, and characterization of several versions of the magnetophoresis and dielectrophoresis microsystems for whole cell cancer analysis in human whole blood sample are presented. The developed magnetophoresis systems have demonstrated improved throughput in the removal of RBC from a human whole blood sample and its application to the separation of tagged cancer cells based on their surface expression level of a specific protein. The dielectrophoresis microsystem has successfully shown the ability to steer a blood stream between two outlets and to separate WBCs or cancer cells from a human whole blood sample. The developed microsystem based separation technologies can be further applied to the development of integrated system for cancer detection and treatments.

Mobbning är ett kränkningsproblem som sprider sig över skolor i hela världen, inklusive Sverige. Lärarens roll är väldigt essentiellt vid granskning av mobbningen. Syftet med denna studie var att undersöka lärarens erfarenheter och upplevelser vid mobbningshantering i skolan, samt vilka utmaningar och förbättringsmöjligheter lärarna ser i denna hantering. Det genomfördes tio semistrukturerade intervjuer med legitimerade lärare från två olika län inom Sverige. Intervjuernaanalyserades utifrån en tematisk analysmetod som identifierade tre teman centrala för hur lärare hanterar mobbning: att få båda sidor av berättelsen, samarbete och delad lärande samt empati och lyhördhet som verktyg. Analysen identifierade även sex teman centrala för utmaningar och förbättringsmöjligheter som råder vid denna hantering: ett neutralt förhållningssätt, känslomässig belastning, att uppmärksamma och bryta tystnaden, balansera konfidientialitet och kommunikation, kompetensutveckling samt relationsfrämjande insatser. Resultatet visade att deltagarna använder sig av olika metoder och strategier vid hantering av mobbning, samt möter både utmaningar och förbättringsmöjligheter vid mobbningshantering.

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<p>This thesis addresses assembly issues encountered in optical and fluidic microsystem applications.</p><p>In optics, the first subject concerns the active alignment of components in optical fibersystems. A solution for reducing the cost of optical component assembly while retaining submicron accuracy is to integrate the alignment mechanism onto the optical substrate. A polymer V-shaped actuator is presented that can carry the weight of the large components - on a micromechanical scale - and that can generate movement with six degrees of freedom.</p><p>The second subject in optics is the CMOS-compatible fabrication of monocrystalline silicon micromirror arrays that are intended to serve as CMOS-controlled high-quality spatial light modulators in maskless microlithography systems. A wafer-level assembly method is presented that is based on adhesive wafer bonding whereby a monocrystalline layer is transferred onto a substrate wafer in a CMOS-compatible process without needing bond alignment.</p><p>In fluidics, a hybrid assembly method is introduced that combines two separately micromachined structures to create hotwire anemometers that protrude from a surface with minimum interference with the air flow. The assembled sensor enables one to make accurate time-resolved measurements of the wall shear stress, a quantity that has previously been hard to measure with high time resolution. Also in the field of hotwire anemometers, a method using a hotwire anemometer array is presented for measuring the mass flow, temperature and composition of a gas in a duct.</p><p>In biochemistry, a bio-analysis chip is presented. Single nucleotide polymorphism scoring is performed using dynamic allele-specific hybridization (DASH). Using monolayers of beads, multiplexing based on single-bead analysis is achieved at heating rates more than 20 times faster than conventional DASH provides.</p><p>Space and material e±ciency in packaging are the focus of the other two projects in fluidics. The first introduces an assembly based on layering conductive adhesives for the fabrication of miniature polymer electrolyte membrane fuel cells. The fuel cells made with this low-cost approach perform among the best of their type to date. The second project concerns a new cross-flow microvalve concept. Intended as a step towards the mass production of large-flow I/P converters, the silicon footprint area is minimized by an out-of-plane moving gate and in-plane, half-open pneumatic channels.</p>

Cette thèse a été effectuée dans un contexte industriel de forte concurrence en lien avec les capteurs miniatures en silicium, destinés au gigantesque marché dit "consumer", dont l'application phare est le "Smartphone", pour laquelle les fonctionnalités accrues engendrent un besoin en matière de multi-capteurs inertiels dits 10-axes (accéléromètre 3-axes, magnétomètre 3-axes, gyromètre 3-axes et capteur de pression). Tout comme les circuits intégrés, les contraintes de coût de tels capteurs se traduisent par une exigence en termes de densité d'intégration. La technologie M&NEMS (Micro- & Nano- Electro Mechanical Systems) a été développée pour répondre à cette attente. Elle repose sur l'intégration de jauges de contraintes de dimensions nanométriques (~250 nm) avec des structures électromécaniques micrométriques, ce qui prodigue une compacité hors-pair des capteurs, ouvrant la voie à la co-intégration de multi-capteurs sur la même puce de silicium. Toutefois, la nature différente des grandeurs physiques à mesurer impose des contraintes supplémentaires, parfois opposées, ce qui rend leur co-intégration difficile. Partant de ce constat, nous avons exploré et développé, des solutions devant permettre le fonctionnement sous une même pression environnante, d'accéléromètres et de gyromètres à force de Coriolis. Cette problématique de co-intégration, s'étend au-delà du couple accéléromètre-gyromètre. Des questions inhérentes au capteur de pression ainsi qu'aux 3 axes de mesure d'un accéléromètre, sont également traitées dans cette thèse / This thesis was carried out in an industrial context of strong competition in connection with miniature silicon sensors for the huge so-called “consumer” market, where the “Smartphone” is the killer application; its increasing functionality creates a need for the so-called ‘10-axis' inertial multi-sensors (3-axis accelerometer, 3-axis magnetometer, 3-axis gyro sensor and pressure). Similarly to integrated circuits, cost constraints on such sensors translate into a requirement in terms of integration density. The M & NEMS (Micro- & Nano- Electro-Mechanical-Systems) technology has been developed to meet this expectation. It is based on the integration of nanoscale (~ 250 nm) strain gauges together with micrometric electromechanical structures, which ensure unrivaled compactness, paving the way for the co-integration of multiple inertial sensors on the same silicon chip. However, the different nature of the physical quantities to be measured imposes additional constraints, sometimes conflicting, which leads to a difficult co-integration. Based on this observation, we have explored and developed solutions to allow operation under the same ambient pressure, of accelerometers together with Coriolis force based gyroscopes. This issue of co-integration extends beyond the accelerometer-gyroscope couple. Issues inherent to the pressure sensor and to the 3-axis accelerometer measurements, are also addressed in this thesis

Additive manufacturing (AM) is currently on the verge of redefining the way we produce and manufacture things. AM encompasses many technologies and subsets, which are all joint by a common denominator; they build three dimensional (3D) objects by adding materials layer-upon-layer. This family of methods can do so, whether the material is plastic, concrete, metallic or living cells which can function as organs. AM manufacturing at the micro scale introduces new capabilities for the AM family that has been proven difficult to achieve with established AM methods at the macro scale. Electrohydrodynamic jet (E-jet or EHD jet) printing is a micro AM technique which has the ability to print at high resolution and speed by exploiting physical phenomena to generate droplets using the means of an electric field. However, when printing metallic materials, this method requires nanoparticles for deposition. To obtain a stable structure the material needs to be sintered, after which the deposited material is left with a porous structure. In contrary, electrochemical methods using the well-known deposition mechanism of electroplating, can deposit dense and pure structures with the downside of slow deposition. In this thesis, a new method is proposed to micro additive manufacturing by merging an already existing technology EHD with simple electrochemistry. By doing so, we demonstrate that it is possible to print metallic structures at the micro- and nanoscale with high speeds, without the need for presynthesized nanoparticles. To achieve this, a printing setup was designed and built. Using a sacrificial wire and the solvent acetonitrile, metallic building blocks such as lines, pillars and other geometric features could be printed in copper, silver, and gold with a minimum feature size of 200 nm. A voltage dependence was found for porosity, where the densest pillars were printed at 135-150 V and the most porous at 260 V. The maximum experimental deposition speed measured up to 4.1 µm · s−1 at 220 V. Faraday’s law of electrolysis could be used to predict the experimental deposition speed at a potential of 190 V with vexp = 1.8 µm · s−1 and vtheory = 0.8 µm · s−1. The microstructure of the pillars could be improved through lowering the applied voltage. In addition, given that Faraday’s law of electrolysis could predict experimental depositions speeds well, it gives further proof to reduction being the mechanism of deposition.

Electromagnetic metamaterials have emerged as a powerful tool to tailor the electromagnetic material properties and control wave propagation using artificial sub-wavelength structures. During the past fifteen years, metamaterials have been intensively studied over the electromagnetic spectrum (from microwave to visible), giving rise to extraordinary phenomena including negative refractive index, invisibility cloaking, sub-diffraction-limit focusing, perfect absorption, and numerous novel electromagnetic devices and optical components. The terahertz regime, between 0.3 THz and 10 THz, is of particular interest due to its appealing applications in imaging, chemical and biological sensing and security screening. Metamaterials foster the development of terahertz sources and detectors and expand the potential applications of the terahertz technology through the realization of dynamic and tunable devices. The objective of this thesis is to present different mechanisms to implement active terahertz metamaterial devices by incorporating advanced microelectromechanical system technology. First, an optical mechanism is employed to create tunable metamaterials and perfect absorbers on flexible substrates. A semiconductor transfer technique is developed to transfer split ring resonators on GaAs patches to ultrathin polyimide substrate. Utilizing photo-excited free carriers in the semiconductor patches, a dynamic modulation of the metamaterial is demonstrated. Additionally, this thesis investigates how sufficiently large terahertz electric fields drive free carriers resulting in nonlinear metamaterial perfect absorbers. Second, a mechanically tunable metamaterial based on dual-layer broadside coupled split ring resonators is studied with the help of comb drive actuators. One of the layers is fixed while the other is laterally moved by an electrostatic voltage to control the interlayer coupling factors. As demonstrated, the amplitude and phase of the transmission response can be dynamically modulated. Third, a microcantilever array is used to create a reconfigurable metamaterial, which is fabricated using surface micromachining techniques. The separation distance between suspended beams and underlying capacitive pads can be altered with an electrostatic force, thereby tuning the transmission spectrum. The tuning mechanisms demonstrated in this thesis can be employed to construct devices to facilitate the development and commercialization of new compact and mechanically robust metamaterial-based terahertz technologies. / 2017-11-05T00:00:00Z