Microfluidics is a vibrant and expanding field that has the potential for solving many analytical challenges. Microfluidics shows promise to provide rapid, inexpensive, efficient, and portable diagnostic solutions that can be used in resource-limited settings. Microfluidic devices have gained immense interest as diagnostic tools for various diseases through biomarker analysis. My dissertation work focuses on developing electrokinetically operated integrated microfluidic devices for the analysis of biomarkers indicative of preterm birth risk. Preterm birth (PTB), a birth prior to 37 weeks of gestation, is the most common complication of pregnancy and the leading cause of neonatal deaths and newborn illnesses. In this dissertation, I have designed, fabricated and developed several microfluidic devices that integrate various sample preparation processes like immunoaffinity extraction, preconcentration, fluorescent labeling, and electrophoretic separation of biomarkers indicative of PTB risk. I developed microchip electrophoresis devices for separation of selected PTB biomarkers. I further optimized multiple reversed-phase porous polymer monoliths UV-polymerized in microfluidic device channels for selective retention and elution of fluorescent dyes and PTB biomarkers to facilitate on-chip labeling. Successful on-chip fluorescent labeling of multiple PTB biomarkers was reported using these microfluidic devices. These devices were further developed using a pH-mediated approach for solid-phase extraction, resulting in a ~50 fold enrichment of a PTB biomarker. Additionally, this approach was integrated with microchip electrophoresis to develop a combined enrichment and separation device that yielded 15-fold preconcentration for a PTB peptide. I also developed an immunoaffinity extraction device for analyzing PTB biomarkers directly from a human serum matrix. A glycidyl methacrylate monolith was characterized within microfluidic channels for immobilization of antibodies to PTB biomarkers. Antibody immobilization and captured analyte elution protocols were optimized for these monoliths, and two PTB biomarker proteins were successfully extracted using these devices. This approach was also integrated with microchip electrophoresis for combined extraction and separation of two PTB biomarkers in spiked human serum in <30 min. In the future, these optimized microfluidic components can be integrated into a single platform for automated immunoaffinity extraction, preconcentration, fluorescent labeling, and separation of PTB biomarkers. This integrated microfluidic platform could significantly improve human health by providing early diagnosis of PTBs.

On assiste aujourd’hui au développement massif des technologies nomades. L’utilisation de boîtiers compacts est ainsi en plein croissance, non seulement à cause des téléphones portables et tablettes, mais aussi à cause de l’introduction massive de l’électronique dans les appareils portables de la vie quotidienne. La microélectronique embarquée dans ces appareils représente le principal outil d’information et de communication des personnes avec le monde extérieur. Le rythme de développement de ces technologies dans les dernières années est tel que les possibilités d’utilisation des appareils portables d’aujourd’hui étaient de la science-fiction il y a seulement 10 ans.Les fonctionnalités qui verront le jour dans les années à venir ne peuvent donc pas toutes être encore imaginées. Ces fonctionnalités vont toutefois très certainement impliquer une augmentation des performances de calcul des dispositifs, et par conséquent de la chaleur qu’ils dissipent.Aujourd’hui, on envisage des puces complexes comprenant plusieurs niveaux logiques et basées sur technologies hétérogènes. On demande également que ces technologies soient intégrées dans les appareils utilisés dans la vie quotidienne, qu’ils soient connectés entre eux et qu’ils réagissent de façon intelligente. Les stratégies de dissipation de la chaleur doivent donc être en adéquation avec la réduction des dimensions des dispositifs de la microélectronique.L’objectif de la thèse présentée dans ce manuscrit est ainsi d’étudier les stratégies de dissipation thermique des boîtiers compacts avec l’aide de répartiteurs de chaleur intégrés. Ce travail porte sur la caractérisation des performances et contraintes des répartiteurs thermiques avec matériaux carbonés. Les répartiteurs sont capables de dissiper sur sa surface la chaleur produite dans un point chaud.Afin d’étudier le phénomène de la dissipation avec un répartiteur, on a mis en place une méthodologie qui prend en compte le caractère multiniveau de la dissipation thermique. L’objectif est de pouvoir se concentrer sur l’interaction entre le répartiteur thermique et chacun des éléments de l’ensemble. On a réutilisé deux véhicules de test et on a désigné un véhicule de test spécifique pour l’étude de la thermique des puces imageurs.Les travaux sont basés sur deux axes : Les études d’intégration et les études thermiques. Les études d’intégration prennent en compte les contraintes dérivées de l’implémentation des couches répartiteurs dans des boitiers compactes. On se concentre d’abord sur les procès d’implémentation des couches répartiteurs au sein de l’ensemble dans un procès industriel. Ensuite on étudie les effets thermomécaniques et les effets sur l’intégrité des signaux à haute fréquence.Les études thermiques caractérisent le gain en performances dérivé de cette intégration. On analyse ces phénomènes thermiques avec des mesures et des simulations. Premièrement au niveau silicium et répartiteur, deuxièmement au niveau boitier et finalement on se concentre sur les effets dans une puce et boitier imageur.A la lumière des résultats on peut dire que les matériaux carbonés se présentent comme l’alternative plus intéressante pour l’implémentation à grande échelle de répartiteurs dans des boitiers compacts. Cette implémentation sera poussée par la recherche des prestations dans des boitiers de plus en plus complexes et hétérogènes, ou l’empreinte du répartiteur doit être minimale. La combination des couches de carbone a tous les niveaux du boitier, avec des TIMs des épaisseurs réduites sera la tendance dans les années à venir pour ce type de dispositifs.Cette thèse s’inscrit dans le cadre d’une collaboration tripartie entre le CEA-LETI de Grenoble, le laboratoire G2Elab de l’INP Grenoble et STMicroelectronics à Crolles. / We witness today an explosion of nomadic technologies. Portable devices have become the main tool that people use to connect with the rest of the world. The microelectronics embedded in these devices is the technology that drives this process. The pace of development of these technologies is such that the versatility of portable devices today were science fiction only 10 years ago.The functionalities that will be integrated in the coming years cannot be imagined yet. These features will imply an increase of the computing demands, and consequently, of the heat dissipated inside them. The trend leads to complex stacks with heterogeneous modules of heat dissipating layers.These technologies will be integrated in everyday life. Internet of Things, as we call it, will demand an increasing amount of independent low footprint devices that will be connected. Heat dissipation strategies must therefore be compatible with increasingly smaller dimensions. Compact packages demand is growing rapidly, not only because of telephones and tablets, but also because of the massive introduction of electronics into in everyday life devices.The objective of the thesis is to study the integration of heat-spreaders in compact packages to enhance its thermal performance. This work goes deeply in the characterization of the thermal performance of carbon-base heat spreaders. Heat-spreaders are able to extract the heat produced in hot spots and transport it along its surface.In order to study the heat spreading phenomenon, a methodology that takes into account the multi-level nature of heat dissipation has been implemented. The objective is to be able to focus on the interaction between the heat-spreader and each one of the elements of the package stack. Two test vehicles have been re-used from previous works. A specific test vehicle was also design in order to emulate the thermal behavior of imaging sensors.The thesis is based on two main axes: Integration studies and thermal studies. The integration studies take into account the constraints derived from the implementation of heat spreaders in compact packages. Firstly, we focus on the implementation processes within an industrial process. Latelly, we study the thermomechanical effects of heat spreaders and the impact on the integrity of high frequency signals.Thermal studies are aimed to characterize the performance gain derived from this heat spreader integration. The thermal phenomena are analyzed with measurements and simulations. First at silicon and interface level, then at package level, finally we focus on the effects in image sensor die and package.In the light of the results it can be said that carbon based materials are the most interesting alternative for large-scale implementation of heat spreaders in compact packages. This implementation will be driven by the research of new functionalities and performances in compact packages. The heat spreader will have to perform while maintaining a minimal footprint. The combination of carbon layers at all package levels, along with reduced thermal interface thickness will be the trend in the coming years for this type of device.This thesis is part of a tripartite collaboration between the CEA-LETI of Grenoble, the G2Elab laboratory of the INP Grenoble and STMicroelectronics in Crolles.

<p>The thesis focuses on the development of new homogeneous gels for the separation of drug enantiomers, peptides, DNA and virus by electrophoresis and electrochromatography in capillaries and microchips. This type of separation media offers high resolution and small zone broadening. Compared to particulate beds the resolution in this type of separation media is high because the eddy diffusion is zero and the resistance to mass transfer is small, since the diffusional distance between two polymer chains in the gel is considerably shorter than that between two beads in a packed bed.</p><p>The gels have been characterized in terms of plate heights, plate numbers, resolution, etc. Gels of agarose, polyvinyl alcohol, albumin and polyacrylamide have been employed for electrochromatography or electrophoresis. <i>N,N’</i>-methylene-bisacrylamide, the most widely used crosslinker in polyacrylamide gels, was exchanged for allyl-β-cyclodextrin to get a multi-purpose gel, <i>i.e.,</i> a separation medium the separation properties of which is determined not only by the polyacrylamide chains, but also by β-cyclodextrin with its complexation power.</p><p>A cost-effective, hybrid microdevice has been designed for fast electrophoretic and electrochromatographic analyses as well as for microchromatography. It consists of a fused silica capillary mounted on a supporting plate which integrates most of the compartments necessary for automation and sensitive detection at short UV wavelengths.</p>

The thesis focuses on the development of new homogeneous gels for the separation of drug enantiomers, peptides, DNA and virus by electrophoresis and electrochromatography in capillaries and microchips. This type of separation media offers high resolution and small zone broadening. Compared to particulate beds the resolution in this type of separation media is high because the eddy diffusion is zero and the resistance to mass transfer is small, since the diffusional distance between two polymer chains in the gel is considerably shorter than that between two beads in a packed bed. The gels have been characterized in terms of plate heights, plate numbers, resolution, etc. Gels of agarose, polyvinyl alcohol, albumin and polyacrylamide have been employed for electrochromatography or electrophoresis. N,N’-methylene-bisacrylamide, the most widely used crosslinker in polyacrylamide gels, was exchanged for allyl-β-cyclodextrin to get a multi-purpose gel, i.e., a separation medium the separation properties of which is determined not only by the polyacrylamide chains, but also by β-cyclodextrin with its complexation power. A cost-effective, hybrid microdevice has been designed for fast electrophoretic and electrochromatographic analyses as well as for microchromatography. It consists of a fused silica capillary mounted on a supporting plate which integrates most of the compartments necessary for automation and sensitive detection at short UV wavelengths.

Bacteria are the oldest, structurally simplest, and most abundant forms of life on earth. Its detection has always been a serious question since the emerging of modern science and technology. There has been a phenomenal growth in the field of real-time bacteria detection in recent years with emerging applications in a wide range of disciplines, including medical analysis, food, environment and many more. Two important analytical functions involved in bacteria detection are cell lysis and polymerase chain reaction (PCR). Cell lysis is required to break cells open to release DNA for use in PCR. PCR is required to reproduce millions of copies of the target genes to reach detection limit from a low DNA concentration. Conventionally, cell lysis and PCR are performed separately using specialized equipments. Those bulky machines consume much more than needed chemical reagents and are very time consuming. An efficient, cost-effective and portable solution involving Nanotechnology and Lab-on-a-Chip (LOC) technology was proposed. The idea was to utilize the excellent antibacterial property of surface-functionalized nanoparticles to perform cell lysis and then to perform PCR on the same LOC system without having to remove them from the solution for rapid detection of bacteria. Nanoparticles possess outstanding properties that are not seen in their bulk form due to their extremely small size. They were introduced to provide two novel methods for LOC cell lysis to overcome problems of current LOC cell lysis methods such as low efficiency, high cost and complicated fabrication process. The first method involved using poly(quaternary ammonium) functionalized gold and titanium dioxide nanoparticles which were demonstrated to be able to lyse E. coli completely in 10 minutes. The idea originated from the excellent antibacterial property of quaternary ammonium salts that people have been using for a long time. The second method involved using titanium dioxide nanoparticles and a miniaturized UV LED array. Titanium dioxide bears photocatalytic effect which generates highly reactive radicals to compromise cell membranes upon absorbing UV light in an aqueous environment. A considerable reduction of live E. coli was observed in 60 minutes. The thesis then evaluates the effect of nanoparticles on PCR to understand the roles nanoparticles play in PCR. It was found that gold and titanium dioxide nanoparticles induce PCR inhibition. How size of gold nanoparticles affected PCR was studied as well. Effective methods were discovered to suppress PCR inhibition caused by gold and titanium dioxide nanoparticles. The pioneering work paves a way for the integration of nanoparticle cell lysis and LOC PCR for rapid detection of bacteria. In the end, an integrated system involving nanoparticle cell lysis and microchip PCR was demonstrated. The prototyped system consisted of a physical microchip for both cell lysis and PCR, a temperature control system and necessary interface connections between the physical device and the temperature control system. The research explored solutions to improve PCR specificity in a microchip environment with gold nanoparticles in PCR. The system was capable of providing the same performance while reducing PCR cycling time by up to 50%. It was inexpensive and easy to be constructed without any complicated clean room fabrication processes. It can find enormous applications in water, food, environment and many more.

We study the chaotic phase synchronization (CPS) between the external periodically driving signals and the nonlinear dynamic systems. The periodical signal was applied to drive the Chua circuit system with two-scroll attractor and the four-scroll attractor circuit system. The phase synchronization between the outputs of these two circuit systems and the driving signals were investigated. Besides, the chaotic phase synchronization of the periodically pump-modulated microchip Nd:YVO4 laser and the microchip Nd:YVO4 laser with optical feedback were also examined in this study. Phase synchronization (PS) transition of these periodically driven nonlinear dynamic systems exhibited via the stroboscopic technique and recurrence probability. The recurrence probability and correlation probability of recurrence were utilized to estimate the degree of PS. In this thesis, the degree of PS was studied by taking into account the amplitude and frequency of the external driving signal. The experimental compatible numerical simulations also reflected the fact that the Arnold tongues are experimentally and numerically exhibited in the periodically driven nonlinear dynamic systems.

Determination of bio-material by using enzyme, fluorophore or metal-nanoparticles as markers is very important. Generally, gold-nanoparticles have been used frequently as marker for increasing the sensitivity in bio-chemical assay. In this research, gold-nanoparticles were used as marker for immunoassay, DNA sequence assay, and protein analysis. However, the size of gold-nanoparticles affects directly the results of electrochemical detection. For improving the sensitivity of electrochemical method, enlargement of gold-nanoparticles was used in this study. By electroless deposition, Au will be deposited on the surface of gold-nanoparticles. The electrochemical response will thus be increased substantially. In immunoassay and DNA sequence assay, traditional 96-wells microtiter plate was used for immobilizing antibody or oligonucleotide, and the gold-nanoparticles were marked subsequently base on the immunoreaction or protein reaction of streptavidin and biotin. After gold-nanoparticles were enlarged, they were dissolved and transferred to an electrochemical cell for square wave stripping voltammetry¡]SWSV¡^analysis. Under optimal experimental condition, dynamic range of 1 ~ 500 pg/mL and 0.52 ~ 1300 aM were found respectively for RIgG and Target DNA analysis, and a good linear relationship¡]R2 = 0.9975 and 0.9982¡^. The relative standard deviation¡]R.S.D.¡^ of blank were 2.8 % and 2.4 %¡]n = 11¡^for immunoassay and DNA assay, respectively. And the variance was 2.4 %¡]n = 9¡^and 2.4 %¡]n = 12¡^for immunoassay and DNA assay, respectively. The detection limit¡]based on S/N = 3¡^of RIgG and DNA were 0.25 pg/mL and 0.52 aM, respectively. They are very competitive compared with similar results reported in the literature. Additional, a gold nanoelectrode ensemble¡]GNEE¡^coupled microchip system was developed for bio-electrochemical analysis. Due to the difference in mobility of urea and urease were mixed and allowed the enzymatic reaction to proceed in microchannel. The enzymatic product NH4+ was determined by the coupled GNEE at the outlet of the channel. Another experiment of streptavidin conjugated gold-nanoparticles¡]streptavidin-Au¡^, reductant and gold-ion¡]Au3+¡^solution was be applied here, too. The product, NH4+ or Au3+ was passed through downstream of microchannel and detected by GNEE of electrochemical system. Satisfactory linear relationship¡]R2 = 0.9778 and 0.9657¡^were found from 0.1 mM to 50 mM for NH4+ and urea in the range of 0.02 mM to 5.0 mM, respectively. The other satisfactory linear relationship¡]R2 = 0.9842 and 0.9507¡^ were found between 3.75 mg/mL and 3.75 g/mL for Au3+ and streptavidin-Au in the range of 0.2 ng/mL to 100 ng/mL, respectively. Variances of 2.5 %¡]n = 6¡^was found for analysis of with the microchip system.

Mechanical assembly of systems and structures on the micro-scale can be inefficient as pthesiss of sub-millimeter dimensions are difficult to manipulate. Cutting edge manufacturing methods implement self-assembly as an approach to ordering micro and nano-sized parts into a desired arrangement. This thesis studies a technique utilizing surface tension as a method of actuating microparts on a liquid-liquid interface via lateral capillary interactions. Preliminary experimentation is conducted to investigate the feasibility of developing a new method for self-alignment of microparts by observing the influence of interfacial geometry on the movement of silicon tiles along a hexadecane-water interface. Different surface geometries are created by implementing vertical rods of different wetting properties that alter the curvature of the interface. Results demonstrate that the microparts attain an equilibrium separation distance from the vertical rods. It is indicated that this equilibrium distance is determined by the dimensions of the micropart and the curvature of the interface. With further investigation, these results may be used to cultivate a method for self-alignment of microparts into rings of a desired radius.

The purpose of this reasearch was to develop a respiratory monitoring system using a reflective object sensor based belt to measure the thoracic expansion of a neonatal for future application at the medical center of the Universidad Evangelica Boliviana (UEB). This medical center, being founded by the UEB University, is dedicated to help and serve the poor and currently has no respiratory monitoring system. The methodology used was first to build and test the respiratory sensor belt and test the relationship between the blet expansion and the voltage generated. The, to incorporate the respiratory sensor belt in a system that would allow individual testing as well as group testing in a wireless network. The system was simulated using an expandable plastic container that was expanded and extracted periodically, registering the results in a MATLAB software. The system gave successful results and generated the frequency results of each cycle, average frequency and deviation frequency. The system demonstrated to be reliable and to have repeatable results.

In this Thesis, we have developed a microtechnology-based method for culturing and visualizing high numbers of individual cells and cell-cell interactions over extended periods of time. The foundation of the device is a silicon-glass multiwell microplate (also referred as microchip) directly compatible with fluorescence microscopy. The initial microchip design involved thousands of square wells of sizes up to 80 µm, for screening large numbers of cell-cell interactions at the single cell level. Biocompatibility and confinement tests proved the feasibility of the idea, and further investigation showed the conservation of immune cellular processes within the wells. Although the system is very reliable for screening, limitations related to synchronization of the interaction events, and the inability to maintain conjugations for long time periods, led to the development of a novel ultrasonic manipulation multiwell microdevice. The main components of the ultrasonic device is a 100-well silicon-glass microchip and an ultrasonic transducer. The transducer is used for ultrasonic actuation on the chip with a frequency causing half-wave resonances in each of the wells (2.0-2.5 MHz for wells with sizes 300-350 µm). Therefore, cells in suspension are directed by acoustic radiation forces towards a pressure node formed in the center of each well. This method allows simultaneous aggregation of cells in all wells and sustains cells confined within a small area for long time periods (even up to several days). The biological target of investigation in this Thesis is the natural killer (NK) cells and their functional properties. NK cells belong to the lymphatic group and they are important factors for host defense and immune regulation. They are characterized by the ability to interact with virus infected cells and cancer cells upon contact, and under suitable conditions they can induce target cell death. We have utilized the ultrasonic microdevice to induce NK-target cell interactions at the single cell level. Our results confirm a heterogeneity within IL-2 activated NK cell populations, with some cells being inactive, while others are capable to kill quickly and in a consecutive manner. Furthermore, we have integrated the ultrasonic microdevice in a temperature regulation system that allows to actuate with high-voltage ultrasound, but still sustain the cell physiological temperature. Using this system we have been able to induce formation of up to 100 solid tumors (HepG2 cells) in parallel without using surface modification or hydrogels. Finally, we used the tumors as targets for investigating NK cells ability to infiltrate and kill solid tumors.  To summarize, a method is presented for investigating individual NK cell behavior against target cells and solid tumors. Although we have utilized our technique to investigate NK cells, there is no limitation of the target of investigation. In the future, the device could be used for any type of cells where interactions at the single cell level can reveal critical information, but also to form solid tumors of primary cancer cells for toxicology studies. / <p>QC 20150113</p>