Mixing of fluids at the microscale poses a variety of challenges, many of which arise from the fact that molecular diffusion is the dominant transport mechanism in the laminar flow regime. The unfavorable combination of low Reynolds numbers and high Péclet numbers implies that cumbersomely long microchannels are required to achieve efficient levels of micromixing. Although considerable progress has been made toward overcoming these limitations (e.g., exploiting chaotic effects), many techniques employ intricate 3-D flow networks whose complexity can make them difficult to build and operate. In this research, we show that enhanced micromixing can be achieved using topologically simple and easily fabricated planar 2-D microchannels by simply introducing curvature and changes in width in a prescribed manner. This is accomplished by harnessing a synergistic combination of (i) Dean vortices that arise in the vertical plane of curved channels as a consequence of an interplay between inertial, centrifugal, and viscous effects, and (ii) expansion vortices that arise in the horizontal plane due to an abrupt increase in a conduit’s cross-sectional area. We characterize these effects using top-view imaging of aqueous streams labeled with tracer dyes and confocal microscopy of aqueous fluorescent dye streams, and by observing binding interactions between an intercalating dye and double-stranded DNA. These mixing approaches are versatile, scalable, and can be straightforwardly integrated as generic components in a variety of lab-on-a-chip systems.

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Doctor of Philosophy / Department of Chemistry / Christopher T. Culbertson / Analytical separations form the bulk of experiments in both research and industry. The choice of separation technique is governed by the characteristics of the analyte and purpose of separation. Miniaturization of chromatographic techniques enables the separation and purification of small volume samples that are often in limited supply. Capillary electrophoresis and immunoaffinity chromatography are examples of techniques that can be easily miniaturized with minimum loss in separation efficiency. These techniques were used in the experiments presented in this dissertation. Chapter 1 discusses the underlying principles of capillary electrophoresis and immunoaffinity chromatography. In the second chapter, the results from immunoaffinity chromatography experiments that utilized antibody-coated magnetic beads to purify serine proteases and serine protease inhibitors (serpins) from A. gambiae hemolymph are presented and discussed. Serine proteases and serpins play a key role in the insect innate immunity system. Serpins regulate the activity of serine proteases by forming irreversible complexes with the proteases. To identify the proteases that couple to these serpins, protein A magnetic beads were coated with SRPN2 antibody and then incubated with A. gambiae hemolymph. The antibody isolated both the free SRPN2 and the SRPN2-protease complex. The purified proteases were identified by ESI-MS from as few as 25 insects. In Chapter 3, an integrated glass/PDMS hybrid microfluidic device was utilized for the transportation and lysis of cells at a high throughput. Jurkat cells were labeled with 6-CFDA (an internal standard) and DAF-FM (a NO specific fluorophore). Laser-induced fluorescence (LIF) detection was utilized to detect nitric oxide (NO) from single Jurkat cells. The resulting electropherograms were used to study the variation in NO production following stimulation with lipopolysaccharide (LPS). 3 h LPS-stimulation resulted in a two fold increase in NO production in both bulk and single cell analysis. A comparison of bulk and single cell NO measurements were performed and the average NO production in single cells compared well to the increase measured at the bulk cell level. Chapter 4 discusses the preliminary experiments with a T-shaped microfluidic device that exploit the property of poly(dimethylsiloxane) (PDMS) as an electroactive polymer (EAP), to enhance fluid mixing. EAPs deform when placed in an electric field. A thin layer of PDMS was sandwiched between chrome electrodes, positioned on the horizontal arms of the T design, and the electrolyte-filled fluidic channel. A potential difference across the PDMS layer caused it to shrink and stretch, thereby increasing the channel volume. The electrodes were actuated at 180[degrees] out of phase and this caused the fluid stream in the vertical channel to fold and stretch resulting in enhanced contact surface area and shorter diffusion distances of the fluid, thereby improving mixing efficiency. All the experiments presented in this dissertation demonstrate the application of miniaturized chromatographic techniques for the efficient analysis of small volume biological samples.

The focus of this thesis is the study of turbulent solid-liquid stirred suspensions, which are involved in many common unit operations in the chemical, pharmaceutical and food industries. The studies of two-phase flows present a big challenge to researchers due to the complexity of experiments; hence there is a lack of quantitative solid and liquid hydrodynamic measurements. Therefore, an investigation of turbulence modulation by dispersed particles on the surrounding fluid in stirred vessels has been carried out, via two-phase fluorescent Particle Image Velocimetry (FPIV) and micromixing experiments. The main property of interest has been the local dissipation rate, as well as root-mean-square (rms) velocities and turbulent kinetic energy (TKE) of the fluid. Initially a single-phase PIV study was conducted to investigate the flow field generated by a sawtooth (EkatoMizer) impeller. The purpose of this study was to gain insight into various PIV techniques before moving on to more complex two-phase flows. Subsequently stereo-, highspeed and angle-resolved measurements were obtained. The EkatoMizer formed a good case study as information regarding its hydrodynamics is not readily available in literature, hence knowledge has been extended in this area. An analysis of the mean flow field elucidated the general structure of fluid drawn into the impeller region axially and discharged radially; the latter characterised the impeller stream. The radial rms velocity was considered to represent best the system turbulence, even though the tangential rms velocity was greater close to the blade; however the radial component was more prevalent in the discharge stream. Due to differences in rms velocities, TKE estimates obtained from two and three velocity components deviated, being greater in the latter case. Integral (1-D and 2-D) length scales were overestimated by the quantity W / 2 in the impeller region. Ratios of longitudinal-to-lateral length scales also indicated flow anisotropy (as they deviated from 2:1). The anisotropy tensor showed that the flow was anisotropic close to the blade, and returned to isotropy further away from the impeller. Instantaneous vector plots revealed vortices in the discharge stream, but these were not associated with flow periodicity. Alternatively, the vortex structures were interpreted as low frequency phenomena between 0-200 Hz; macro-instabilities were found to have a high probability of occurrence in the discharge stream. Dissipation is the turbulent property of most interest as it directly influences micromixing processes, and its calculation is also the most difficult to achieve. Its direct determination from definition requires highly resolved data. Alternative methods have been proposed in the literature, namely dimensional analysis, large eddy simulation (LES) analogy and deduction from the TKE balance. All methods were employed using 2-D and 3-D approximations from stereo-PIV data. The LES analogy was deemed to provide the best estimate, since it accounts for three-dimensionality of the flow and models turbulence at the smallest scales using a subgrid scale model. (Continues...).

Scaling down operations and functions into the fascinating micro world not only improve performance, lower costs, and enable easier integration, but also opens the door to new functionalities. This truly multidisciplinary thesis presents novel solutions to current and relevant challenges in the areas of 1) on-chip liquid manipulation which has applications in micro total analysis systems, medical diagnostics, and drug discovery and 2) pressure sensing which has an established market in the automotive and industrial processes industry. Especially in the area of liquid manipulation, the aim was to take advantage of forces and properties dominating on the micro scale whenever possible, rather than compensating for these effects, and to create solutions with universal appeal and application areas. In the area of liquid manipulation, this thesis discusses a novel method of passively synchronizing liquid movement on-chip based on liquid surface tension and device geometry. This technique has potential applications in timing independent processes, liquid-liquid interactions, and digitizing liquid movement. A fast and passive discrete sample micromixer is also presented based on the same principles. A unique way of direct access, bubble tolerant sample interfacing with flow-through microfluidics using a closed-open-closed channel is also introduced. This method can be used to regulate flow on-chip without the need for any moving parts or electrical contact. Moreover, work is presented on two types of out-of-plane electrospray ionization mass spectrometry (ESI-MS) emitter tips which mimic ideal mass spectrometry tips. Fabrication of these tips is uncomplicated and results in robust structures with good performance. In the field of pressure sensing, this thesis investigates a form based resonating principle. The Q factor of the sensor is improved by low pressure encapsulation and structure design. A novel technique for excitation and detection of resonant microsensors using 'burst' technology is also demonstrated. This method involves temporally separating excitation and detection, thereby eliminating crosstalk and the need for electrical feedthroughs. It also allows high voltages to be used with sensitive circuitry and a single electrode to be used for both excitation and detection.

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Competitive-Consecutive and Competitive-Parallel reactions are both mixing sensitive reactions; the yield of desired product from these reactions depends on how fast the reactants are brought together. Recent experimental results have suggested that the mixing effect may depend strongly on the stoichiometry of the reactions. To investigate this, a 1-D, non-dimensional, reaction-diffusion model at the micro-mixing scale has been developed. Assuming constant mass concentration and diffusivities, systems of PDEs have been derived on a mass fraction basis for both types of reactions. A single general Damkhler number and specific dimensionless reaction rate ratios were derived for both reaction schemes. The resulting dimensionless equations were simulated to investigate the effects of mixing, reaction rate ratio and stoichiometry of the reactions. It was found that decreasing the striation thickness and the dimensionless rate ratio maximizes yield for both types of reactions and that the stoichiometry has a considerable effect on yield. All three variables were found to interact strongly. Phase plots showing the interactions between the three variables were developed.

Micro particle image velocimetry (microPIV) is a non-intrusive tool for visualizing flow in micron-scale conduits. Using this investigative instrument, two experimental studies were performed to understand flow behaviors in microfluidic channels - a sudden expansion step flow and laminar velocity profile variation in diffusion driven mixing. First, flow in a backward facing step feature (1:5 expansion ratio) in a microchannel was taken as the subject of microPIV flow visualization. The onset and development of a recirculation flow was studied as a function of flow rate. This flow pattern was further used to investigate two major parameters affecting microPIV measurements; the depth-of-focus and recording time-intervals between images in a microPIV image pair. The onset of recirculation was initiated at flow rates that correspond to Reynolds numbers, Re > 95, which is well beyond the typical working range of microfluidic devices (Re=0.01-10). The recirculation flow has a 3D structure due to the dimensions of the microchannel and the effect of no slip condition on the walls. Ensemble cross-correlation was found not to be sensitive to variations of depth-of-focus and the output flow fields were similar as long as the overall optical focus remained within the upper and lower bounds of the microchannel. However, variations of time intervals between images in a microPIV pair, resulted in quantitatively and qualitatively different flow patterns for a given constant flow rate and depth-of-focus. In the second experiment, the effect of the laminar velocity profile and its variation on mixing phenomena at the reduced scale is studied. It is shown that the diffusive mass flux between two miscible streams, flowing in a laminar regime in a microchannel, is enhanced if the velocity at their diffusion interface is increased. Based on this idea, an in-plane passive micromixing concept is proposed and implemented in a working device (sigma micromixer). This mixer shows considerable mixing performance by periodically varying the flow velocity profile, such that the maximum of the profile coincides with the transversely progressing diffusion fronts repeatedly throughout the mixing channel. microPIV has been used to visualize the behavior of laminar flow inside the micromixer device and to confirm the periodic variation of the velocity profile through the mixing channel.

Semi-batch crystallization experiments have been performedboth in a loop reactor and in stirred tank reactors.Hydrochloric acid was fed to a stirred solution of sodiumbenzoate, and benzoic acid immediately formed. Benzoic acid isformed in excess of the solubility making the solutionsupersaturated. The loop reactor is U-shaped. In one leg a propeller stirrerwas placed to circulate the solution and in the other a turbinestirrer was placed in front of the feed point to vary the localmixing intensity. The objective was to analyse the relativeimportance of different levels of mixing on the product sizedistribution. The importance of mixing as well as scaling-upeffects on the product size distribution were studied in threestirred tank reactors of volumes 2.5 L, 10 L, and 200 L. Thestirred tank reactors had different geometry and were equippedwith either a marine propeller or a pitched blade turbine. The weight mean size generally increases with increasingtotal feeding time and increasing mixing intensity. The weightmean size increases by locating an extra turbine impeller atthe feed point in the 10 L stirred tank reactor. The turbineimpeller provides the desired feed point mixing intensitywithout raising the mixing intensity of the whole tank. The weight mean size increases with decreasing feed pipediameter in the loop reactor and for low feed rates in the 10 Lstirred tank reactor. The weight mean size increasessignificantly by changing the feed pipe opening from circularto rectangular with a constant cross-sectional area at equalfeed rates. Backmixing is visually observed in the largest feedpipe diameter in the loop reactor, thus, reducing the weightmean size. However, backmixing is not considered to be adominant phenomenon in the present work. Mesomixing time constants have been calculated according tothe turbulent dispersion mechanism and the inertial-convectivemechanism. The time constants for mesomixing are generallylonger than the time constant for micromixing. Thus, the ratioof the mesomixing and the micromixing time constants shows aninfluence of mesomixing as is shown by the experimentalresults. The experimental results are best described by theinertial-convective disintegration mechanism showing that thefeed plume mixing increases with decreasing feed pipe diameterand increased feed point mixing. The weight mean size is not strongly affected by the reactorvolume. However, the mixing conditions in the reactors have astrong influence on the weight mean size. No suggestedscaling-up rule can satisfactorily predict the weight mean sizein the different volumes. No single physical parameter, such asthe local energy dissipation rate, the mean energy dissipationrate or the circulation time, can satisfactorily explain theexperimental results. A new dimensionless mixing parameter, TR,has been defined as the ratio of the total feeding time and themesomixing time constant. The mesomixing time constant isdefined as the shortest dimension of the feed pipe divided bythe resultant bulk velocity passing the feed pipe entrance. Theexperimental results from both the loop reactor and the stirredtank reactors of different volumes can be correlated with TR.The weight mean size increases with increasing TR. <b>Keywords</b>: reaction crystallization, precipitation,benzoic acid, macromixing, mesomixing, micromixing,semi-batch, loop reactor, backmixing, colour experiments,scaling-up. <b>Keywords</b>: reaction crystallization, precipitation,benzoic acid, macromixing, mesomixing, micromixing,semi-batch, loop reactor, backmixing, colour experiments,scaling-up.

<p>Semi-batch crystallization experiments have been performedboth in a loop reactor and in stirred tank reactors.Hydrochloric acid was fed to a stirred solution of sodiumbenzoate, and benzoic acid immediately formed. Benzoic acid isformed in excess of the solubility making the solutionsupersaturated.</p><p>The loop reactor is U-shaped. In one leg a propeller stirrerwas placed to circulate the solution and in the other a turbinestirrer was placed in front of the feed point to vary the localmixing intensity. The objective was to analyse the relativeimportance of different levels of mixing on the product sizedistribution. The importance of mixing as well as scaling-upeffects on the product size distribution were studied in threestirred tank reactors of volumes 2.5 L, 10 L, and 200 L. Thestirred tank reactors had different geometry and were equippedwith either a marine propeller or a pitched blade turbine.</p><p>The weight mean size generally increases with increasingtotal feeding time and increasing mixing intensity. The weightmean size increases by locating an extra turbine impeller atthe feed point in the 10 L stirred tank reactor. The turbineimpeller provides the desired feed point mixing intensitywithout raising the mixing intensity of the whole tank.</p><p>The weight mean size increases with decreasing feed pipediameter in the loop reactor and for low feed rates in the 10 Lstirred tank reactor. The weight mean size increasessignificantly by changing the feed pipe opening from circularto rectangular with a constant cross-sectional area at equalfeed rates. Backmixing is visually observed in the largest feedpipe diameter in the loop reactor, thus, reducing the weightmean size. However, backmixing is not considered to be adominant phenomenon in the present work.</p><p>Mesomixing time constants have been calculated according tothe turbulent dispersion mechanism and the inertial-convectivemechanism. The time constants for mesomixing are generallylonger than the time constant for micromixing. Thus, the ratioof the mesomixing and the micromixing time constants shows aninfluence of mesomixing as is shown by the experimentalresults. The experimental results are best described by theinertial-convective disintegration mechanism showing that thefeed plume mixing increases with decreasing feed pipe diameterand increased feed point mixing.</p><p>The weight mean size is not strongly affected by the reactorvolume. However, the mixing conditions in the reactors have astrong influence on the weight mean size. No suggestedscaling-up rule can satisfactorily predict the weight mean sizein the different volumes. No single physical parameter, such asthe local energy dissipation rate, the mean energy dissipationrate or the circulation time, can satisfactorily explain theexperimental results. A new dimensionless mixing parameter, TR,has been defined as the ratio of the total feeding time and themesomixing time constant. The mesomixing time constant isdefined as the shortest dimension of the feed pipe divided bythe resultant bulk velocity passing the feed pipe entrance. Theexperimental results from both the loop reactor and the stirredtank reactors of different volumes can be correlated with TR.The weight mean size increases with increasing TR.</p><p><b>Keywords</b>: reaction crystallization, precipitation,benzoic acid, macromixing, mesomixing, micromixing,semi-batch, loop reactor, backmixing, colour experiments,scaling-up.</p><p><b>Keywords</b>: reaction crystallization, precipitation,benzoic acid, macromixing, mesomixing, micromixing,semi-batch, loop reactor, backmixing, colour experiments,scaling-up.</p>