Development of Microwave/Droplet-Microfluidics Integrated Heating and Sensing Platforms for Biomedical and Pharmaceutical Lab-on-a-Chip Applications

Interest in Lab-on-a-chip and droplet-based microfluidics has grown recently because of their promise to facilitate a broad range of scientific research and biological/chemical processes such as cell analysis, DNA hybridization, drug screening and diagnostics. Major advantages of droplet-based microfluidics versus traditional bioassays include its capability to provide highly monodispersed, well-isolated environment for reactions with magnitude higher throughput (i.e. kHz) than traditional high throughput systems, as well as its low reagent consumption and elimination of cross contamination. Major functions required for deploying droplet microfluidics include droplet generation, merging, sorting, splitting, trapping, sensing, heating and storing, among which sensing and heating of individual droplets remain great challenges and demand for new technology. This thesis focuses on developing novel microwave technology that can be integrated with droplet-based microfluidic platforms to address these challenges. This thesis is structured to consider both fundamentals and applications of microwave sensing and heating of individual droplets very broadly. It starts with developing a label-free, sensitive, inexpensive and portable microwave system that can be integrated with microfluidic platforms for detection and content sensing of individual droplets for high-throughput applications. This is, indeed, important since most droplet-based microfluidic studies rely on optical imaging, which usually requires expensive and bulky systems, the use of fluorescent dyes and exhaustive post-imaging analysis. Although electrical detection systems can be made inexpensive, label-free and portable, most of them usually work at low frequencies, which limits their applications to fast moving droplets. The developed microwave circuitry is inexpensive due to the use of off-the-shelf components, and is compact and capable of detecting droplet presence at kHz rates and droplet content sensing of biological materials such as penicillin antibiotic, fetal bovine serum solutions and variations in a drug compound concentration (e.g., for Alzheimer’s Disease). Subsequently, a numerical model is developed based on which parametrical analysis is performed in order to understand better the sensing and heating performance of the integrated platform. Specifically, the microwave resonator structure, which operates at GHz frequency affecting sensing performance significantly, and the dielectric properties of the microfluidic chip components that highly influence the internal electromagnetic field and energy dissipation, are studied systematically for their effects on sensing and heating efficiency. The results provide important findings and understanding on the integrated device operation and optimization strategies. Next, driven by the need for on-demand, rapid mixing inside droplets in many applications such as biochemical assays and material synthesis, a microwave-based microfluidic mixer is developed. Rapid mixing in droplets can be achieved within each half of the droplet, but not the entire droplet. Cross-center mixing is still dominated by diffusion. In this project, the microwave mixer, which works essentially as a resonator, accumulates an intensive, nonuniform electromagnetic field into a spiral capacitive gap (around 200 μm) over which a microchannel is aligned. As droplets pass by the gap region, they receive spatially non-uniform energy and thus have non-uniform temperature distribution, which induces non-uniform Marangoni stresses on the interface and thus three-dimensional (3D) chaotic motion inside the droplet. The 3D chaotic motion inside the droplet enables fast mixing within the entire droplet. The mixing efficiency is evaluated by varying the applied power, droplet length and fluid viscosity. In spite of various existing thermometry methods for microfluidic applications, it remains challenging to measure the temperature of individual fast moving droplets because they do not allow sufficient exposure time demanded by both fluorescence based techniques and resistance temperature detectors. A microwave thermometry method is thus developed here, which relies on correlating fluid temperature with the resonance frequency and the reflection coefficient of the microwave sensor, based on the fact that liquid permittivity is a function of temperature. It is demonstrated that the sensor can detect the temperature of individual droplets with ±1.2 °C accuracy. At the final part of the thesis, I extend my platform technology further to applications such as disease diagnosis and drug delivery. First, I develop a microfluidic chip for controlled synthesis of poly (acrylamide-co-sodium acrylate) copolymer hydrogel microparticles whose structure varies with temperature, chemical composition and pH values. This project investigates the effects of monomer compositions and cross-linker concentrations on the swelling ratio. The results are validated through the Fourier transform infrared spectra (FTIR), SEM and swelling test. Second, a preliminary study on DNA hybridization detection through microwave sensors for disease diagnosis is conducted. Gold sensors and biological protocols of DNA hybridization event are explored. The event of DNA hybridization with the immobilized thiol-modified ss-DNA oligos and complimentary DNA (c-DNA) are monitored. The results are promising, and suggests that microwave integrated Lab-on-a-chip platforms can perform disease diagnosis studies

Embedded Energy Landscapes In Soft Matter For Micro-Robotics And Reconfigurable Structures

The ability to manipulate microscale objects with precision to form complex structures is central to the field of micro-robotics and to the realization of reconfigurable systems. Understanding and exploiting the forces that dominate at the microscale in complex environments pose major challenges and open untapped opportunities. This is particularly the case for micro-particles in soft milieu like fluid interfaces or nematic liquid crystalline fluids, which deform or reorganize around dispersed colloids or near bounding surfaces. These energetically costly deformations can be designed as embedded energy landscapes, a form of physical intelligence, to dictate emergent colloidal interactions. The fluid nature of these soft milieu allows colloids to move to minimize the free energy and externally forced robotic structures to re-write the embedded energy landscapes in the domain. Such physically intelligent systems are of great interest at the intersection of materials science and micro-robotics. Micro-particles on fluid interfaces deform the interface shape, migrate, and assemble to minimize the capillary energy. In the first part of my thesis, I design and fabricate a magnetic micro-robot as a mobile curvature source to interact with passive colloids on the water/oil interface. An analytical expression that includes both capillary and hydrodynamic interactions is derived and captures the main feature of experimental observations. I further demonstrate multiple micro-robotic tasks including directed assembly, cargo carrying, desired release and cargo delivery on the interface. Micro-particles in confined nematic liquid crystals (NLCs) distort the nematic director field, generating interactions. These interactions depend strongly on the colloids shape and surface chemistry, geometric frustration of director field and behavior of dynamic topological defects. To probe far-from-equilibrium dynamics, I fabricate a magnetic disk with hybrid anchoring. Upon controlled rotation, the disk’s companion defect undergoes periodic rearrangement, executing a complex swim stroke that propels disk translation. I study this new swimming modality in both high and low Ericksen number regimes. At high rotation rates, the defect elongates significantly adjacent to the disk, generating broken symmetries that allow steering of the disk. This ability is exploited in path planning. Thereafter, I design a four-armed micro-robot as a mobile distortion source to promote passive colloids assembly at particular sites via emergent interactions in NLCs whose strengths are characterized and found to be several orders of magnitude larger than thermal energies. While the strength of theses interactions allows colloidal cargo to be carried with the micro-robot during translation, it poses challenges for cargo release. We find that rotation of this micro-robot generates a complex dynamic defect-sharing event with colloidal cargo that spurs cargo release. Thereafter, I demonstrate the ability to exploit NLC elastodynamics to construct reconfigurable colloidal structures in a micro-robotics platform. At the colloidal scale, rotation dynamics are easier to generate, and this motivated me to exploit the topological swimming modality of the micro-robot. Using programmable rotating fields to direct the micro-robot’s motion, I achieve fully autonomous cargo manipulations including approach, assembly, transport and release. The ability to dynamically manipulate micro-particles and their structures in soft matter systems with embedded energy landscapes, as demonstrated in this thesis, creates new possibilities for micro-robotics and reconfigurable systems

Electric and Magnetic Manipulation of Liquid Metals

Over the past decade, gallium-based liquid metals have attracted enormous attention, emerging as a new cutting-edge multi-functional material for reconfigurable electronics, soft robotics, microfluidics, and biomedical applications, based on utilizing the intrinsic advantages of liquid metal. These unique advantages that combine high electrical conductivity, thermal conductivity, biocompatibility, low mechanical compliance, and viscosity all-in-one make the liquid metal applicable for a tremendous number of applications. Moreover, the self-passivating oxide skin of the liquid metal in an ambient environment forms a unique core (oxide skin)-shell (liquid metal) structure and provides a new strategy for two-dimensional thin films with a thickness of a few nanometers. The reports on the liquid metal can be mainly divided into three categories: 1) liquid-metal-based composite structures; 2) the core-shell strategy for thin films; and 3) electrochemical manipulation of the liquid metal in electrolyte. The liquid metal (LM) composites represent material systems in which LM alloys are either suspended as small droplets within a soft polymer matrix or mixed with metallic nanoparticles to form a biphasic composition, through which the electrical, dielectric, and thermal properties of composites can be controlled, thus enabling their applications in soft-matter sensing, actuation, and energy harvesting. Moreover, the fluidity and conductivity of the liquid metal make it suitable to be directly patterned (i.e., liquid metal ink) on various soft substrates (e.g., polydimethylsiloxane (PDMS) for ultra-stretchable electronics. Compared to the traditional electronics, which are typically composed of intrinsically rigid materials that have limited deformability, the liquid metal based soft electronics are highly flexible, stretchable, and conformable. Most importantly, they are capable of electrical self-healing, enabling their electrical functionality, even under severe damage. These properties and applications of liquid metal composites show great potential for practical usage

NASA's Microgravity Research Program

This fiscal year (FY) 1997 annual report describes key elements of the NASA Microgravity Research Program (MRP) as conducted by the Microgravity Research Division (MRD) within NASA's Office of Life and Microgravity, Sciences and Applications. The program's goals, approach taken to achieve those goals, and program resources are summarized. All snapshots of the program's status at the end of FY 1997 and a review of highlights and progress in grounds and flights based research are provided. Also described are major space missions that flew during FY 1997, plans for utilization of the research potential of the International Space Station, the Advanced Technology Development (ATD) Program, and various educational/outreach activities. The MRP supports investigators from academia, industry, and government research communities needing a space environment to study phenomena directly or indirectly affected by gravity

Droplet-based Microfluidic Chip Design for High Throughput Screening Applications

Droplet-based microfluidics has been considered as a prospective tool for high throughput screening analysis, which is highly demanded in a wide range of areas including but not limited to life science research, drug discovery, material synthesis and environmental monitoring. Low sample consumption, reduced reaction time, high throughput manipulation, fast mixing, and prevention of cross contamination at channel walls are just some of the benefits of droplet-based microfluidics. Although extensive research efforts have been reported in the study of droplet-based microfluidics over the past decades, it has yet to be widely commercialized. One of the challenges that limit droplet microfluidic chips from being commercialized is the difficulty in integrating multiple functions robustly without increasing the device footprint. Major functionalities of interest include generating droplets with controlled volume and frequency, and precisely controlling and manipulating each individual droplet such as sorting, detecting, merging, splitting, pairing, mixing, trapping, releasing, long term and short term storing, etc. Since many of these functionalities rely on the accuracy of droplet generation which is the first step, it is crucial to investigate the droplet formation process and understand how to design microfluidic structures to manipulate each individual droplet effectively. To this end, this thesis started with a fundamental study of droplet generation in a flow focusing geometry based on extensive experimental data, from which a physical model was developed to describe droplet formation processes, then move on to study droplet generation in a geometry with two junctions in series, with the goal of improving single encapsulation (one particle per droplet) efficiency. Later, droplet merging towards whole genome amplification and drug screening applications was investigated, and finally a microfluidic chip integrated with multiple functionalities was developed, and its robustness was validated. The first project studied the fundamental principles of liquid-liquid droplet generation in a flow focusing device. This work presents a 3D physical model with less fitting parameters than existing ones. The model describes droplet formation process in flow focusing devices operating in the squeezing regime, where droplet size is usually larger than the channel width, and was developed based on a systematic and extensive experimental study. In particular, it incorporates an accurate geometric description of the 3D droplet shape during the formation process, an estimation of the time period for the formation cycle based on the conservation of mass, and a semi-analytical model predicting the pressure drop over the 3D corner gutter between the droplet curvature and channel walls, which allows droplet size, spacing and formation frequency to be determined accurately. The model takes into account change in channel geometry (height to width ratio), viscosity contrast, flow rate ratio and capillary number with a wide variety. In the second project, liquid-liquid droplet generation in a flow focusing device with two junctions in series was investigated using experimental approach. Extra emphasis was placed on the device’s ability to encapsulate single cell and particle. . This study employs glycerol solutions with different concentrations as the dispersed phase, which tends to form stratified flow at the first junction due to viscosity contrast. The stratified flow proceeds to form droplets in oil stream at the second junction. To obtain a comprehensive understanding of the droplet formation dynamics involving stratified flow, five different scenarios were considered. These include a single stream of 10%glycerol aqueous solution, a single stream of 80%glycerol aqueous solution, as well as the simultaneous flow of multiple streams of the above mentioned solution. Droplet size and formation period for these cases were compared and analyzed considering the same geometric and flow conditions. It is found that stratified flow structure strongly influences droplet formation dynamics such as droplet size and formation frequency and the scenario with 80%glyc surrounded by 10%glyc in the first junction generates the largest droplet size. Each structure finds its own applications. For the purpose of single encapsulation, the scenario with 80%glyc surrounded by 10%glyc in the first junction is most suitable because the high viscosity of 80%glyc allows particles to be focused into a thin stream and spaced out before entering droplets. On the other hand, the scenario with two fluids side by side in the first junction generates droplets with high monodispersity for a larger range of flow ratios, which is useful for high throughput reactions involving different reagents. After understanding the fundamentals of the droplet generation process, several designs for practical use were proposed to generate or manipulate droplets. These designs include: i) a flow focusing device that improve droplet size uniformity through changing junction angle; ii) a system for droplet generation on demand, which is essential to controlling droplets of specific reagents; iii) a geometry for generating droplet pairs with uniform droplet sizes and controlled droplet spacing , and to study the interaction between two nearby droplets; iv) a simple droplet merging chamber for controlled reagent volume; and v) a droplet trapping and releasing on demand system for drug screening. The final part of this thesis presents a complex microfluidic system that integrates multiple functionalities, including droplet generation, pairing, trapping, merging, mixing, and releasing. The criterion of this design was analyzed and verified by experiments. This design does not require any synchronization of droplet frequency, spacing or velocity, which makes the microfluidic chip work robustly, and is controlled entirely by liquid flow eliminating the needs for electrodes, magnets or any other moving parts. This design can be applied to many chemical or biological reactions, such as drug screening, chemical synthesis, and cell culture, etc

Droplet Production and Transport in Microfluidic Networks with Pressure Driven Flow Control

Droplet based microfluidics is a developing technology with great potential towards improving large scale combinatorial studies that require high throughput and accurate metering of reagents. Each droplet can be thought of as a miniature microreactor where complex reactions can be performed on the micro-scale by mixing, splitting and combining droplets. This thesis investigates the operation and control of droplet microfluidic devices operating using constant pressure sources to pump fluids where feedback from the droplets influences the overall performance of the device. For this purpose, a model system consisting of a single T-junction droplet generator and a single network node is used to understand how pressure source control effects droplet generation and transport through microfluidic networks. The first part of this thesis focuses on the generation of Newtonian liquid-liquid droplets from a microfluidic T-junction operating within the squeezing-to-transition regime with stable flow rates. An experimental study was performed to characterize the effects of geometry (height/width ratio, channel width ratio) and flow parameters (Capillary number, flow rate ratio, viscosity ratio) on the droplet size, spacing and rate of production. Three stages of droplet formation were identified (lag, filling and necking), including the newly defined lag stage that appears at the beginning of the formation cycle once the interface pulls back after a droplet detaches. Based on the experimental observations, a model was developed to describe the formation process which incorporates a detailed geometric description of the drop shape with a force balance in the filling stage and a control volume analysis of the necking stage. The model matches well with the experimental results as data falls within 10% of the predicted values. Subsequently, the effect of surfactants on the formation process was investigated. Surfactant transport occurs on a timescale comparable to the production rate of droplets resulting in dynamic interfacial tension effects. This causes strong coupling between the mass transport of surfactants and the drop production process. Using the previously defined force balance, the apparent interfacial tension at the end of the filling stage was measured. The results show that there is a significant deviation from the equilibrium interfacial tension at normal operating conditions for the T-junction generators due to the rapid expansion of the interface. A model was developed to calculate the dynamic interfacial tension for pre and post micellar solutions, which was then incorporated into the overall model for droplet formation in T-junction generators. Next, the behaviour of microfluidic droplet generators operating under pressure source control was investigated. Coupling between the changing interface and hydrodynamic resistance of the droplets and the flow rate of the two phases creates fluctuations in the output of the droplet generator. Oscillations were found to occur over the short term (one droplet formation cycle) and long term (many formation cycles). Two metrics were developed to quantify these oscillations. Short term oscillations were quantified by tracking droplet speed in the output channel and long term oscillation were quantified by measuring changes in droplet spacing. Analysis of experimental and numerical data shows that long term oscillations have a periodicity that matches the residence time of droplets in the system. A simple model is developed to determine the influence of Laplace pressure, droplet resistance, T-junction generator design and network architecture on the magnitude of these oscillations. From the model a set of design rules are developed to improve the overall operation of T-junction generators using pressure driven flow. The final part of this thesis studies the transport of droplets through a single microchannel junction under various geometric and flow conditions applied to the two outlet channels. Droplets alter the hydrodynamic resistance of the channel they travel within which creates a feedback effect where the decision of preceding droplets influences the trajectory of subsequent droplets. Multifaceted behaviour occurs where sometimes the trajectory of droplets follows a repeatable pattern and other times it is chaotic. As part of this work, a discrete analytical model was developed that predicts droplet transport through the junction including transitions between filtering and sorting, bifurcation in the patterns, composition of the patterns, and an estimation of when patterns will disintegrate into chaos. The model was validated by comparing it to compact numerical simulations and microfluidic experiments with good agreement.The complex behaviour of a simple junction emphasizes the challenge that remains for more highly integrated droplet microfluidic networks operating with pressure driven flow

Artificial Brownian motors: Controlling transport on the nanoscale

In systems possessing spatial or dynamical symmetry breaking, Brownian motion combined with symmetric external input signals, deterministic or random, alike, can assist directed motion of particles at the submicron scales. In such cases, one speaks of "Brownian motors". In this review the constructive role of Brownian motion is exemplified for various one-dimensional setups, mostly inspired by the cell molecular machinery: working principles and characteristics of stylized devices are discussed to show how fluctuations, either thermal or extrinsic, can be used to control diffusive particle transport. Recent experimental demonstrations of this concept are reviewed with particular attention to transport in artificial nanopores and optical traps, where single particle currents have been first measured. Much emphasis is given to two- and three-dimensional devices containing many interacting particles of one or more species; for this class of artificial motors, noise rectification results also from the interplay of particle Brownian motion and geometric constraints. Recently, selective control and optimization of the transport of interacting colloidal particles and magnetic vortices have been successfully achieved, thus leading to the new generation of microfluidic and superconducting devices presented hereby. Another area with promising potential for realization of artificial Brownian motors are microfluidic or granular set-ups.....Comment: 57 pages, 39 figures; submitted to Reviews Modern Physics, revised versio

Microfluidics for Biosensing

There are 12 papers published with 8 research articles, 3 review articles and 1 perspective. The topics cover: Biomedical microfluidics Lab-on-a-chip Miniaturized systems for chemistry and life science (MicroTAS) Biosensor development and characteristics Imaging and other detection technologies Imaging and signal processing Point-of-care testing microdevices Food and water quality testing and control We hope this collection could promote the development of microfluidics and point-of-care testing (POCT) devices for biosensing

Culinary fluid mechanics and other currents in food science

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BioMEMS

As technological advancements widen the scope of applications for biomicroelectromechanical systems (BioMEMS or biomicrosystems), the field continues to have an impact on many aspects of life science operations and functionalities. Because BioMEMS research and development require the input of experts who use different technical languages and come from varying disciplines and backgrounds, scientists and students can avoid potential difficulties in communication and understanding only if they possess a skill set and understanding that enables them to work at the interface of engineering and biosciences. Keeping this duality in mind throughout, BioMEMS: Science and Engineering Perspectives supports and expedites the multidisciplinary learning involved in the development of biomicrosystems. Divided into nine chapters, it starts with a balanced introduction of biological, engineering, application, and commercialization aspects of the field. With a focus on molecules of biological interest, the book explores the building blocks of cells and viruses, as well as molecules that form the self-assembled monolayers (SAMs), linkers, and hydrogels used for making different surfaces biocompatible through functionalization. The book also discusses: Different materials and platforms used to develop biomicrosystems Various biological entities and pathogens (in ascending order of complexity) The multidisciplinary aspects of engineering bioactive surfaces Engineering perspectives, including methods of manufacturing bioactive surfaces and devices Microfluidics modeling and experimentation Device level implementation of BioMEMS concepts for different applications. Because BioMEMS is an application-driven field, the book also highlights the concepts of lab-on-a-chip (LOC) and micro total analysis system (μTAS), along with their pertinence to the emerging point-of-care (POC) and point-of-need (PON) applications