The author presents the successful development of an on-chip, monolithic, integrated rubidium vapor-cell. These vapor-cells integrate ridge waveguide techniques with hollow-core waveguiding technology known as Anti-Resonant Reflecting Optical Waveguides (ARROWs). These devices are manufactured on-site in BYU's Integrated Microelectronic Laboratory (IML) using common silicon wafer microfabrication techniques. The ARROW platform fabrication is outlined, but the bulk of the dissertation focuses on novel packaging techniques that allow for the successful introduction and sealing of rubidium vapor into these micro-sized vapor-cells. The unique geometries and materials utilized in the ARROW platform render common vapor-cell sealing techniques unusable. The development of three generations of successful vapor-cells is chronicled. The sealing techniques represented in these three generations of vapor-cells include high-temperature epoxy seals, cold-weld copper crimping, variable pressure vacuum capabilities, indium solder seals, and electroplated passivation coatings. The performance of these seals are quantified using accelerated lifetime tests combined with optical spectroscopy. Finally, the successful probing of the rubidium absorption spectrum, electromagnetically induced transparency, and slow light on the ARROW-based vapor-cell platform is reported.

No description available.

In both, cell secretome analysis and bacteria evolution, controlled handling of particles with a few to sub-micrometers in size and media exchange are inevitable in order to investigate body fluid’s proteins or change the surrounding culture conditions for pivoted evolution. Typically, nanofiltration and ultra-centrifugation are employed which can lead to cell damage, need large sample volumes and have a high sample loss. Using contactless and label-free acoustic cell manipulation, disadvantages of other magnetic, dielectric or hydrodynamic methods can be avoided. Here, a novel design using acoustic forces for small particle trapping and media exchange is thoroughly numerically investigated including first- and second-order acoustic effects. The device comprises parallel aligned medium and air channels separated by a thin wall. Particle trapping occurs at this thin wall. The medium channel dimensions (height and width) and thin wall thickness are optimized with respect to trapping forces. Thinnest walls are preferable and an aspect ratio of 0.8. First preliminary experimental variation with polystyrene particles showed good agreement with the simulations. Thereby the particle trapping efficiency is evaluated under quiescent flow conditions. For particle trapping, a device with a channel height of 290μm and an aspect ratio of 0.7 is superior which supports the numerical results. Finally, medium exchange of E. coli bacteria is demonstrated with best results for a device with a channel height of 450μm and an aspect ratio of 0.8 showing that 13.4% of the initial bacteria were released after medium exchange which can be used for further processing.

<p>Microdroplets have large and varied areas of application ranging from document printing to complex lab-on-chip devices. Lab-on-chip systems often require precise volume control as well as high throughput operations. Microdroplets fulfill these requirements and have become a staple in these devices. The work presented in this thesis involves the design and characterization of two individual devices capable of droplet generation utilizing flow focusing and electrogeneration methods.</p> <p>The first design involved the generation of gel microdroplets utilizing the flow focusing technique. This device proved to be robust and reliable producing large volumes of uniformly mixed droplets. Long term operation of this device was analyzed and determined to be a feasible route for the manufacture of large quantities of droplets. The device was operated for over 30 hours creating gel droplets ranging from 40-200 μm in diameter with acceptable polydispersities for use in drug release studies.</p> <p>The second device involved the design and characterization of a system for the electrogeneration of microdroplets. This novel device involved the injection of droplets via high voltage and high frequency signals into a cross-flow of oil. The droplet generation was characterized and different droplet generation modes were observed. With the careful selection of parameters ideal conditions were obtained to generate monodisperse droplets of sizes ranging from under 5 to over 100 μm in a highly repeatable manner.</p> <p>To conclude, two separate microfluidic droplet generation devices operating in distinct modes were designed and analyzed. These devices are robust, reliable, and flexible with some applications being tested.</p> / Master of Applied Science (MASc)

Lab-on-a-chip (LOC) technology has blossomed into a major new technology fundamentally influencing the sciences of life and nature. From a systemic point of view however, microfluidics is still in its infancy. Here, we present the concept of a microfluidic central processing unit (CPU) which shows remarkable similarities to early electronic Von Neumann microprocessors. It combines both control and execution units and, moreover, the complete power supply on a single chip and introduces the decision-making ability regarding chemical information into fluidic integrated circuits (ICs). As a consequence of this system concept, the ICs process chemical information completely in a self-controlled manner and energetically self-sustaining. The ICs are fabricated by layer-by-layer deposition of several overlapping layers based on different intrinsically active polymers. As examples we present two microchips carrying out long-term monitoring of critical parameters by around-the-clock sampling. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Integration and miniaturisation in electronics has undoubtedly revolutionised the modern world. In biotechnology, emerging lab-on-a-chip (LOC) methodologies promise all-integrated laboratory processes, to perform complete biochemical or medical synthesis and analysis encapsulated on small microchips. The integration of electrical, optical and physical sensors, and control devices, with fluid handling, is creating a new class of functional chip-based systems. Scaled down onto a chip, reagent and sample consumption is reduced, point-of-care or in-the-field usage is enabled through portability, costs are reduced, automation increases the ease of use, and favourable scaling laws can be exploited, such as improved fluid control. The capacity to manipulate single cells on-chip has applications across the life sciences, in biotechnology, pharmacology, medical diagnostics and drug discovery. This thesis explores multiple applications of optical manipulation within microfluidic chips. Used in combination with microfluidic systems, optics adds powerful functionalities to emerging LOC technologies. These include particle management such as immobilising, sorting, concentrating, and transportation of cell-sized objects, along with sensing, spectroscopic interrogation, and cell treatment. The work in this thesis brings several key applications of optical techniques for manipulating and porating cell-sized microscopic particles to within microfluidic chips. The fields of optical trapping, optical tweezers and optical sorting are reviewed in the context of lab-on-a-chip application, and the physics of the laminar fluid flow exhibited at this size scale is detailed. Microfluidic chip fabrication methods are presented, including a robust method for the introduction of optical fibres for laser beam delivery, which is demonstrated in a dual-beam optical trap chip and in optical chromatography using photonic crystal fibre. The use of a total internal reflection microscope objective lens is utilised in a novel demonstration of propelling particles within fluid flow. The size and refractive index dependency is modelled and experimentally characterised, before presenting continuous passive optical sorting of microparticles based on these intrinsic optical properties, in a microfluidic chip. Finally, a microfluidic system is utilised in the delivery of mammalian cells to a focused femtosecond laser beam for continuous, high throughput photoporation. The optical injection efficiency of inserting a fluorescent dye is determined and the cell viability is evaluated. This could form the basis for ultra-high throughput, efficient transfection of cells, with the advantages of single cell treatment and unrivalled viability using this optical technique.

The rapid development of optofluidics, the combination of microfluidics and integrated optics, since its formal conception in the early 2000's has aided in the advance of single-molecule analysis. The optofluidic platform discussed in this dissertation is called the liquid core anti-resonant reflecting optical waveguide (LC-ARROW). This platform uses ARROW waveguides to orthogonally intersect a liquid core waveguide with solid core rib waveguides for the excitation of specifically labeled molecules and collection of fluorescence signal. Since conception, the LC-ARROW platform has demonstrated its effectiveness as a lab-on-a-chip fluorescence biosensor. However, until the addition of optical multiplexing excitation waveguides, the platform lacked a critical functionality for use in rapid disease diagnostics, namely the ability to simultaneously detect different types of molecules and particles. In disease diagnostics, the ability to multiplex, detect and identify multiple biomarkers simultaneously is paramount for a sensor to be used as a rapid diagnostic system. This work brings optofluidic multiplexing to the sensor through the implementation of three specific designs: (1) the Y-splitter was the first multi-spot excitation design implemented on the platform, although it did not have the ability to multiplex it served as a critical stepping stone and showed that multi-spot excitation could improve the signal-to-noise ratio of the platform by ~50,000 times; (2) a multimode interference (MMI) waveguide which took the multi-spot idea and then demonstrated spectral multiplexing capable of correctly identifying multiple diverse biomarkers simultaneously; and, (3) a Triple-Core design which incorporates excitation and collection along multiple liquid cores, enabling spatial multiplexing which increases the number of individual molecules to be identified concurrently with the MMI waveguide excitation. In addition to describing the development of optical multiplexing, this dissertation includes an investigation of another LC-ARROW based design that enables 2D bioparticle trapping, the Anti-Brownian Electrokinetic (ABEL) trap. This design demonstrates two-dimensional compensation of a particle's Brownian motion in solution. The capability to maintain a molecule suspended in solution over time enables the ability to gain a deeper understanding of cellular function and therapies based on molecular functions.

The field of micro total analysis systems (μTAS) aims at developments toward miniaturized and fully integrated lab-on-a-chip systems for applications, such as drug screening, drug delivery, cellular assays, protein analysis, genomic analysis and handheld point-of-care diagnostics. Such systems offer to dramatically reduce liquid sample and reagent quantities, increase sensitivity as well as speed of analysis and facilitate portable systems via the integration of components such as pumps, valves, mixers, separation units, reactors and detectors. Precise microfluidic control for such systems has long been considered one of the most difficult technical barriers due to integration of on-chip fluidic handling components and complicated off-chip liquid control as well as fluidic interconnections. Actuation principles and materials with the advantages of low cost, easy fabrication, easy integration, high reliability, and compact size are required to promote the development of such systems. Within this thesis, liquid displacement in microfluidic applications, by means of expandable microspheres, is presented as an innovative approach addressing some of the previously mentioned issues. Furthermore, these expandable microspheres are embedded into a PDMS matrix, which composes a novel thermally responsive silicone elastomer composite actuator for liquid handling. Due to the merits of PDMS and expandable microspheres, the composite actuator's main characteristic to expand irreversibly upon generated heat makes it possible to locally alter its surface topography. The composite actuator concept, along with a novel adhesive PDMS bonding technique, is used to design and fabricate liquid handling components such as pumps and valves, which operate at work-ranges from nanoliters to microliters. The integration of several such microfluidic components promotes the development of disposable lab-on-a-chip platforms for precise sample volume control addressing, e.g. active dosing, transportation, merging and mixing of nanoliter liquid volumes. Moreover, microfluidic pumps based on the composite actuator have been incorporated with sharp and hollow microneedles to realize a microneedle-based transdermal patch which exhibits on-board liquid storage and active dispensing functionality. Such a system represents a first step toward painless, minimally invasive and transdermal administration of macromolecular drugs such as insulin or vaccines. The presented on-chip liquid handling concept does not require external actuators for pumping and valving, uses low-cost materials and wafer-level processes only, is highly integrable and potentially enables controlled and cost-effective transdermal microfluidic applications, as well as large-scale integrated fluidic networks for point-of care diagnostics, disposable biochips or lab-on-a-chip applications. This thesis discusses several design concepts for a large variety of microfluidic components, which are promoted by the use of the novel composite actuator. Results on the successful fabrication and evaluation of prototype devices are reported herein along with comprehensive process parameters on a novel full-wafer adhesive bonding technique for the fabrication of PDMS based microfluidic devices. / QC 20100817

With the completion of the human genome sequencing project, attention is currently shifting toward understanding how genetic variation, such as single nucleotide polymorphism (SNP), leads to disease. To identify, understand, and control biological mechanisms of living organisms, the enormous amounts of accumulated sequence information must be coupled to faster, cheaper, and more powerful technologies for DNA, RNA, and protein analysis. One approach is the miniaturization of analytical methods through the application of microfluidics, which involves the manipulation of fluids in micrometer-sized channels. Advances in microfluidic chip technology are expected to play a major role in the development of cost-effective and rapid DNA analysis methods. This thesis presents microfluidic approaches for different DNA genotyping assays. The overall goal is to combine the potential of the microfluidic lab-on-a-chip concept with biochemistry to develop and improve current methods for SNP genotyping. Three genotyping assays using miniaturized microfluidic approaches are addressed. The first two assays are based on primer extension by DNA polymerase. A microfluidic device consisting of a flow-through filter chamber for handling beads with nanoliter liquid volumes was used in these studies. The first assay involved an allelespecific extension strategy. The microfluidic approach took advantage of the different reaction kinetics of matched and mismatched configurations at the 3’-ends of a primer/template complex. The second assay consisted of adapting pyrosequencing technology, a bioluminometric DNA sequencing assay based on sequencing-bysynthesis, to a microfluidic flow-through platform. Base-by-base sequencing was performed in a microfluidic device to obtain accurate SNP scoring data on nanoliter volumes. This thesis also presents the applications of monolayer of beads immobilized by microcontact printing for chip-based DNA analysis. Single-base incorporation could be detected with pyrosequencing chemistry on these monolayers. The third assay developed is based on a hybridization technology termed Dynamic Allele-Specific Hybridization (DASH). In this approach, monolayered beads containing DNA duplexes were randomly immobilized on the surface of a microheater chip. DNA melting-curve analysis was performed by dynamically heating the chip while simultaneously monitoring the DNA denaturation profile to determine the genotype. Multiplexing based on single-bead analysis was achieved at heating rates more than 20 times faster than conventional DASH provides. / QC 20101008

Within the realm of biosensing, DNA analysis has become an indispensable research tool in medicine, enabling the investigation of relationships among genes, proteins, and drugs. Conventional DNA microarray technology uses multiple lasers and complex optics, resulting in expensive and bulky systems which are not suitable for point-of-care medical diagnostics. The immobilization of DNA probes across the microarray substrate also results in substantial spatial variation. To mitigate the above shortcomings, this thesis presents a set of techniques developed for the CMOS image sensor for point-of-care spectrally-multiplexed fluorescent DNA sensing and other fluorescence biosensing applications. First, a CMOS tunable-wavelength multi-color photogate (CPG) sensor is presented. The CPG exploits the absorption property of a polysilicon gate to form an optical filter, thus the sensor does not require an external color filter. A prototype has been fabricated in a standard 0.35μm digital CMOS technology and demonstrates intensity measurements of blue (450nm), green (520nm), and red (620nm) illumination. Second, a wide dynamic range CMOS multi-color image sensor is presented. An analysis is performed for the wide dynamic-range, asynchronous self-reset with residue readout architecture where photon shot noise is taken into consideration. A prototype was fabricated in a standard 0.35μm CMOS process and is validated in color light sensing. The readout circuit achieves a measured dynamic range of 82dB with a peak SNR of 46.2dB. Third, a low-power CMOS image sensor VLSI architecture for use with comparator based ADCs is presented. By eliminating the in-pixel source follower, power consumption is reduced, compared to the conventional active pixel sensor. A 64×64 prototype with a 10μm pixel pitch has been fabricated in a 0.35μm standard CMOS technology and validated experimentally. Fourth, a spectrally-multiplexed fluorescence contact imaging microsystem for DNA analysis is presented. The microsystem has been quantitatively modeled and validated in the detection of marker gene sequences for spinal muscular atropy disease and the E. coli bacteria. Spectral multiplexing enables the two DNA targets to be simultaneously detected with a measured detection limit of 240nM and 210nM of target concentration at a sample volume of 10μL for the green and red transduction channels, respectively.