According to the World Health Organization, nearly 3.2 billion people are at risk of malaria. The most deadliest form of human malaria is caused by the pathogen Plasmodium falciparum, which has claimed over 400,000 lives worldwide in 20151. Even when optimally treated with drug and donor blood therapies, severe malaria has a high mortality rate. The parasites target a patient’s red blood cells and convert them into paramagnetic units before eventually rupturing the host cell, further spreading the infection. Combination drug therapies using quinine and artemisinin derivatives are common but are either expensive or have associated toxicities from mis-dosing. Moreover, antimalarial drugs are becoming increasingly ineffective against the growing number of drug-resistant malaria strains. Combination drug and blood exchange therapies are often implemented to flush out malaria-infected red blood cells (iRBC) but consume a great quantity of donor blood, carry a high risk of transmitting other blood-borne diseases, and have no agreed upon advantage or disadvantage among clinicians. Due to the relative disadvantages of other treatment methods, small scale high gradient magnetic separation (HGMS) devices, used in a variety of biological applications, may be another treatment option to consider. mPharesis (“magnetic apheresis”) is a proposed low-cost, disposable magnetic blood filtration device which continually removes iRBCs from a patient’s whole blood by capitalizing on the iRBC’s unique magnetic properties. The proposed treatment-scale system will provide emergency care with parameters similar to continuous hemofiltration systems in terms of blood flow rates (up to approximately 500 mL min-1), vascular access, and treatment times (up to about 3 hours). A novel medium-scale high gradient magnetic separation device is detailed here. The device consists of a disposable photo-etched embedded wire array and acrylic layered housing on an external permanent magnet set. The magnetic force and flow field design were computationally optimized. In-vitro feasibility experiments were conducted at several flow rates and physiological hematocrits (Hct) using a blood mixture composed of healthy RBCs and a non-pathogenic paramagnetic blood analog called methemoglobin RBCs (metRBCs). The device was able to selectively remove paramagnetic RBCs without excessive loss of healthy RBCs. Simplified experiments were performed with 30% Hct with 20% metRBCs. At steady state, the concentration of metRBCs was reduced by 27.0±2.2% in a single pass at a flow rate of 77 μL min-1 as compared to 1.6±0.7% in control experiments without a magnet present. The experimental paramagnetic RBC removal rate was over 380 times greater than similar published HGMS devices. These successful results were applied to a theoretical transport model. The model was designed to compare the parasite removal and Hct level changes between combination drug and exchange transfusion (ET) therapy versus treatment-scale mPharesis-drug therapy. When the mPharesis flow rate was set to typical continuous dialysis rates, treatment times and donor blood volumes were reduced for all 10 cases. Calculated treatment times were all less than 60% of the reported ET-drug treatments, with times ranging from 47 to 71 minutes. The mPharesis-drug treatment was calculated to need between 4% and 53% less donor blood than the reported ET-drug treatments. Between 775 and 1772 mL of packed donor RBCs (3 to 6 units of whole blood) were estimated for the mPharesis-drug treatments, versus the average 5 to 20 units used during ET2. Treatment reference charts were generated to provide time and donor blood volume estimates for a range of patient sizes and disease severities. Based on the maximum flow rate of 500 mL min-1, a treatment-scale mPharesis system was estimated to be the size of three stacked briefcases, which is a feasible size for deployment in a clinical setting. Finally, the design, fabrication, and microscopic visualization of a simple, benchtop-fabricated continuous HGMS device was detailed. This proof-of-concept microfluidic device was implemented to test the effect of hematocrit and flow rate on the separation of mixtures of metRBCs (heat-treated and un-heated) and transparent ghost RBCs. An automated image processing protocol provided feasible cell concentration profiles for each flow and rheological condition with a 6.5 to 9.7% lower sum than manual counting for three samples. For the no magnet conditions, the average near-magnet concentration of paramagnetic RBCs at the outlet (within 10% of 130 μm channel height adjacent to the wire array) was between 1.3 and 2.4 times greater than the average of the rest of the flow field (degree of separation, DOS). The most effective separation was found to occur at the lowest flow rate 0.4 μL min-1 and with the 0.5% Hct metRBC sample with DOS=26. The addition of 30% ghost RBCs reduced the efficiency for all flow rates, with DOS=7.4 for best flow rate of 0.4 μL min-1. Heat treatment did not significantly affect separation with DOS=7.3, likely due to the low impact of the relatively low concentration of metRBCs (0.5%). The mesoscale fabrication and design process, clearance model, cell counting algorithm, and HGMS fabrication protocol and microscopy study described in this thesis provides a useful framework for future HGMS optimization and the further development of a clinical treatment system for severe malaria patients with often limited treatment options.

<div> Underlying physics in bubble coalescence is critical for understanding bubble transportation. It is one of the major mechanisms of microfluidics. Understanding the mechanism has benefits in the design, development, and optimization of microfluidics for various applications. The underlying physics in bubble coalescence is investigated numerically using the free energy-based lattice Boltzmann method by massive parametrization and classification.</div><div><br></div><div> Firstly, comprehensive GPU (Graphics Processing Unit) parallelization, convergence check, and validation are carried out to ensure the computational efficiency and physical accuracy for the numerical simulations.</div><div><br></div><div> Then, the liquid-gas system is characterized by an Ohnesorge number (Oh). Two distinct coalescence phenomena with and without oscillation, are separated by a critical Oh (~0.477)number. For the oscillation cases(Oh<0.477), the mechanism of damped oscillation in microbubble coalescence is explored in terms of the competition between driving and resisting forces. Through an analogy to the conventional damped harmonic oscillator, the saddle-point trajectory over the entire oscillation can be well predicted analytically. Without oscillation in the range of 0.50r^-n </div><div><br></div><div> After that, the liquid-gas-solid interface is taken into consideration in the liquid-gas system. Six cases based on the experiment set-ups are simulated first for validation of the computational results. Based on these, a hypothesis is established about critical factors to determine if coalescence-induced microbubble detachment (CIMD) will occur. From the eighteen experimental and computational cases, we conclude that when the radius ratio is close to 1 and the father bubble is larger, then it will lead to CIMD.</div><div><br></div><div> Lastly, the effects of initial conditions on the coalescence of two equal-sized air microbubbles (R₀) in water are investigated. In both initial scenarios, the neck bridge evolution exhibits a half power-law scaling, r/R₀=A₀(t/t_i)^1/2 after development time. The development time is caused by the significant bias between the capillary forces contributed by the meniscus curvature and the neck bridge curvature. Meanwhile, the physical mechanism behind each behavior has been explored.</div>

Este trabalho apresenta o desenvolvimento de um sensor térmico de vazão integrado a um microcanal. Todo o ciclo de desenvolvimento é abordado: conceito, modelagem e simulação, fabricação e caracterização. O sensor é composto por um filamento de níquel fabricado sobre uma lâmina de vidro que é soldada a um bloco de polidimetilsiloxano (PDMS) contendo microcanais. A aferição da vazão no interior do microcanal é feita indiretamente através da medida da troca de calor entre o filamento e o fluido. As simulações por elementos finitos mostraram que o sensor apresenta três faixas de operação, sendo que em duas delas (fluxos menores do que 20 L/min ou maiores do que 130 L/min) a resposta elétrica do sensor varia linearmente com a vazão. Diversos sensores foram fabricados seguindo o processo de fabricação proposto e alguns dispositivos foram caracterizados eletricamente, tendo sido levantadas as curvas da tensão elétrica sobre o filamento em função da vazão no microcanal. Os resultados experimentais mostraram que os sensores fabricados são capazes de medir vazões da ordem de dezenas de microlitros por minuto na faixa de operação de menor sensibilidade. Métodos de fabricação alternativos foram propostos com o intuito de aumentar a sensibilidade do sensor, produzindo filamentos auto-sustentados no interior dos microcanais. Foi proposto um modelo para simulação comportamental dos sensores otimizados por elementos concentrados e os resultados preliminares tanto de simulação quanto de fabricação desses sensores foram apresentados. / This project presents the development of a thermal flow sensor integrated into a microchannel. The whole design cycle is discussed: concept, modeling and simulation, fabrication and characterization. The sensor consists of a nickel filament fabricated on a glass substrate which is bonded to a polydimethylsiloxane (PDMS) block containing the microchannels. The flow inside the microchannel is indirectly measured through the heat exchange between the filament and the fluid. Finite methods analysis revealed that the sensor has three operating ranges and in two of them (flows below 20 ìL/min or higher than 130 ìL/min) the electric response of the sensor varies linearly with respect to the flow. Several flow sensors were fabricated according to the fabrication method presented in this project and some of them were characterized electrically. The response of the voltage on the filament as a function of the flow inside the microchannel was obtained. The experimental results demonstrated that the flow sensors could measure flow rates as small as tens of microliters per minute even when working on the less sensitive operating range. Alternative fabrication methods were proposed in order to improve the sensor sensitivity, leaving the filaments self-sustained inside the microchannels. A lumped element model was introduced in order to simulate the behavior of the optimized flow sensors. Some preliminary results of these simulations and of the fabrication processes were presented.

Este trabalho apresenta o desenvolvimento de um sensor térmico de vazão integrado a um microcanal. Todo o ciclo de desenvolvimento é abordado: conceito, modelagem e simulação, fabricação e caracterização. O sensor é composto por um filamento de níquel fabricado sobre uma lâmina de vidro que é soldada a um bloco de polidimetilsiloxano (PDMS) contendo microcanais. A aferição da vazão no interior do microcanal é feita indiretamente através da medida da troca de calor entre o filamento e o fluido. As simulações por elementos finitos mostraram que o sensor apresenta três faixas de operação, sendo que em duas delas (fluxos menores do que 20 L/min ou maiores do que 130 L/min) a resposta elétrica do sensor varia linearmente com a vazão. Diversos sensores foram fabricados seguindo o processo de fabricação proposto e alguns dispositivos foram caracterizados eletricamente, tendo sido levantadas as curvas da tensão elétrica sobre o filamento em função da vazão no microcanal. Os resultados experimentais mostraram que os sensores fabricados são capazes de medir vazões da ordem de dezenas de microlitros por minuto na faixa de operação de menor sensibilidade. Métodos de fabricação alternativos foram propostos com o intuito de aumentar a sensibilidade do sensor, produzindo filamentos auto-sustentados no interior dos microcanais. Foi proposto um modelo para simulação comportamental dos sensores otimizados por elementos concentrados e os resultados preliminares tanto de simulação quanto de fabricação desses sensores foram apresentados. / This project presents the development of a thermal flow sensor integrated into a microchannel. The whole design cycle is discussed: concept, modeling and simulation, fabrication and characterization. The sensor consists of a nickel filament fabricated on a glass substrate which is bonded to a polydimethylsiloxane (PDMS) block containing the microchannels. The flow inside the microchannel is indirectly measured through the heat exchange between the filament and the fluid. Finite methods analysis revealed that the sensor has three operating ranges and in two of them (flows below 20 ìL/min or higher than 130 ìL/min) the electric response of the sensor varies linearly with respect to the flow. Several flow sensors were fabricated according to the fabrication method presented in this project and some of them were characterized electrically. The response of the voltage on the filament as a function of the flow inside the microchannel was obtained. The experimental results demonstrated that the flow sensors could measure flow rates as small as tens of microliters per minute even when working on the less sensitive operating range. Alternative fabrication methods were proposed in order to improve the sensor sensitivity, leaving the filaments self-sustained inside the microchannels. A lumped element model was introduced in order to simulate the behavior of the optimized flow sensors. Some preliminary results of these simulations and of the fabrication processes were presented.

No description available.

Les matériaux vitreux mous (émulsion concentrée, mousse, suspension concentrée...) présentent un comportement rhéologique entre solide et liquide. Aux petites contraintes le système reste élastique, mais au-dessus d’une contrainte seuil, le système s’écoule comme un liquide visqueux. Ce comportement se trouve dans de nombreux fluides industriels comme dans les cosmétiques, l’agro-alimentaire ou encore le béton. Une contrainte seuil n’apparait que au dessus d’une certaine fractions volumique. Au dessus de cette fraction les particules se bloquent entre elle, la relaxation n’est plus possible et l’écoulement devient fortement coopératif.Cette coopérativité influe sur la rhéologie à petite échelle, Quand le confinement devient de l’ordre de quelques particules, la viscosité ne dépend plus uniquement, comme habituellement, de la contrainte locale mais aussi de la contrainte au voisinage. C’est ce qu’on appelle rhéologie non-localeJ’ai étudié expérimentalement ce comportement en utilisant les outils de micro fluidiques. J’ai étudié une micro-émulsion concentrée s’écoulant dans un microcanal en observant directement l’écoulement des gouttes avec un microscope confocal. Les résultats sont comparés au model “Kinetic-Elasto-Plastic” de Bocquet et al. 2009 et à des simulations de dynamique moléculaire. / Soft glassy materials (concentrated emulsion, foams, concentrated suspension…) present rheological properties between solids and liquid. Under small stress they stay elastic but at stress higher than a yield stress they begin to flow as a liquid. Those fluids are used in cosmetics, food industry or building materials as concrete. The yield stress behavior only appears when the volume fraction is high enough, where the particles are blocked by their neighbors. So the systems cannot relax and the flow become highly cooperative.This cooperativity impacts the rheology at small scale. When the confinement is of the order of few particles, the viscosity does not only depend on the local stress as usually but also on the stress in the neighborhood. This is called non-local rheology.I studied experimentally this behavior by flowing concentrated emulsion in a microchannel and observing directly the flow of the droplet with a confocal microscopy. The results from these microfluidics experiments are compared to predictions of the Kinetic Elasto Plastic model of Bocquet et al. 2009 and molecular dynamic simulation of jammed soft particles.

Directed cancer cell migration induced by the environmental signals is a critical process in cancer metastasis. Cancer cells are exposed to complex chemical and mechanical signals stimulating directed migration in the tumor microenvironment, where the physical nature is highly complex. It is still barely understood how cells sense and process the complex environmental signals through the complex intercellular signaling networks to execute the cell responses. This study explores the migratory response of cancer cells under a single and combined signal. The driving hypothesis is that the cell innate capability constraints the signal stimulations physically in inducing directed cell migration. We assess the hypothesis by engineering the microenvironment in the microfluidic platform, exposing a single or combined signal environment. The combined signal environment is established by 1) two different chemoattractants (TGF-β1 and EGF) and 2) the convection-driven signal environment (TGF-β1 and interstitial flow). The results show that the performance of cancer cell directed migration is physically constrained when the environmental stimulation meets the cell’s innate physical limit. We illustrate the results in a physical and quantitative manner. This approach provides a novel insight to understand the cellular process and eventually enables to predict the cellular response under the complex environmental signals. <br>