A housekeeping prognostic health management framework for microfluidic systems

Micro-Electro-Mechanical Systems (MEMS) and Microfluidics are becoming popular solutions for sensing, diagnostics and control applications. Reliability and validation of function is of increasing importance in the majority of these applications. On-line testing strategies for these devices have the potential to provide real-time condition monitoring information. It is shown that this information can be used to diagnose and prognose the health of the device. This information can also be used to provide an early failure warning system by predicting the remaining useful life. Diagnostic and prognostic outcomes can also be leveraged to improve the reliability, dependability and availability of these devices. This work has delivered a methodology for a “lightweight” prognostics solution for a microfluidic device based on real-time diagnostics. An oscillation based test methodology is used to extract diagnostic information that is processed using a Linear Discriminant Analysis based classifier. This enables the identification of current health based on pre-defined health levels. As the deteriorating device is periodically classified, the rate at which the device degrades is used to predict the devices remaining useful life

Test analysis & fault simulation of microfluidic systems

This work presents a design, simulation and test methodology for microfluidic systems, with particular focus on simulation for test. A Microfluidic Fault Simulator (MFS) has been created based around COMSOL which allows a fault-free system model to undergo fault injection and provide test measurements. A post MFS test analysis procedure is also described.A range of fault-free system simulations have been cross-validated to experimental work to gauge the accuracy of the fundamental simulation approach prior to further investigation and development of the simulation and test procedure.A generic mechanism, termed a fault block, has been developed to provide fault injection and a method of describing a low abstraction behavioural fault model within the system. This technique has allowed the creation of a fault library containing a range of different microfluidic fault conditions. Each of the fault models has been cross-validated to experimental conditions or published results to determine their accuracy.Two test methods, namely, impedance spectroscopy and Levich electro-chemical sensors have been investigated as general methods of microfluidic test, each of which has been shown to be sensitive to a multitude of fault. Each method has successfully been implemented within the simulation environment and each cross-validated by first-hand experimentation or published work.A test analysis procedure based around the Neyman-Pearson criterion has been developed to allow a probabilistic metric for each test applied for a given fault condition, providing a quantitive assessment of each test. These metrics are used to analyse the sensitivity of each test method, useful when determining which tests to employ in the final system. Furthermore, these probabilistic metrics may be combined to provide a fault coverage metric for the complete system.The complete MFS method has been applied to two system cases studies; a hydrodynamic “Y” channel and a flow cytometry system for prognosing head and neck cancer.Decision trees are trained based on the test measurement data and fault conditions as a means of classifying the systems fault condition state. The classification rules created by the decision trees may be displayed graphically or as a set of rules which can be loaded into test instrumentation. During the course of this research a high voltage power supply instrument has been developed to aid electro-osmotic experimentation and an impedance spectrometer to provide embedded test

Molecular Microfluidic Bioanalysis: Recent Progress in Preconcentration, Separation, and Detection

This chapter reviews the state-of-art of microfluidic devices for molecular bioanalysis with a focus on the key functionalities that have to be successfully integrated, such as preconcentration, separation, signal amplification, and detection. The first part focuses on both passive and electrophoretic separation/sorting methods, whereas the second part is devoted to miniaturized biosensors that are integrated in the last stage of the fluidic device

Transport Properties of Nanometer-sized Assemblies through Nanofluidic Channels with Single Entity Electrical Detection

Recently, there have been reports on biological and solid-state nanopores that identify single biopolymers or their constituent monomers by analyzing changes in ionic current blockades when they block the flux of buffer ions while travelling through the nanopores. Nevertheless, there have been several limitations in their application, especially as DNA detectors; Poor confinement of the DNA strand within the nanopore (~0.1 % of a 10 kilobase (kb) DNA), poor signal sensitivity and random motion experienced by the DNA in solution that results in a large amount of noise in the signal. These have led to the development of nanochannel-based devices, which can directly address the aforementioned challenges. Nanochannels have widths comparable to nanopores but with longer lengths. As molecules travel through nanochannels, they undergo confinement, hydrophobic and van der Waals interactions with the walls of the channel generating some interesting physics, such as the elongation of DNA molecules. The small scale analyses offer high throughput with interesting attributes not accessible at the micro-scale. Presently, an expanding research area involves the integration of nanochannels with nanogap electrodes to provide new transduction modalities for single molecules traveling through nanochannels. In these detectors, the electrical behavior (field effect, impedance, capacitance, resistance, conductance, etc.) of biomolecules are observed. These have become powerful tools for bio-sensing, single molecule manipulation and design of high throughput systems, for example as systems for DNA sequencing. This work focuses on developing a novel technique for the fabrication of mixed-scale systems (nm to mm) in quartz used for the molecular-scale sensing of single-molecules (DNAs, RNAs, peptides and proteins). These systems consist of both microchannels and nanochannels (10-100 nm). Results on the fabrication of such systems will be reported. I will also discuss our ultimate goal; to develop a platform for the rapid and efficient sequencing of biopolymers by measuring flight-times of monomer units clipped from a single polymer digested with an enzyme. The flight times will be transduced using a non-labeling electrical approach via conductivity in a detection volume defined by nano-scale electrodes (5-10 nm). Theoretical computations performed to describe the variation of the Signal-to-Noise with the nano-electrode area and nano-gap size have provided promising results

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

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

Smart chemical sensing microsystem : towards a nose-on-a-chip

The electronic nose is a rudimentary replica of the human olfactory system. However there has been considerable commercial interest in the use of electronic nose systems in application areas such as environmental, medical, security and food industry. In many ways the existing electronic nose systems are considerable inferior when compared to their biological counterparts, lacking in terms of discrimination capability, processing time and environmental adaptation. Here, the aim is to extract biological principles from the mammalian olfactory systems to create a new architecture in order to aid the implementation of a nose-on-a-chip system. The primary feature identified in this study was the nasal chromatography phenomena which may provide significant improvement by producing discriminatory spatio-temporal signals for electronic nose systems. In this project, two different but complimentary groups of systems have been designed and fabricated to investigate the feasibility of generating spatio-temporal signals. The first group of systems include the fast-nose (channel 10 cm x 500 μm2), proto-nose I (channel 1.2 m x 500 μm2) and II (channel 2.4 m x 500 μm2) systems that were build using discrete components. The fast-nose system was used to characterise the discrete sensors prior to use. The proto-nose systems, in many ways, resembles gas chromatography systems. Each proto-nose system consists of two microchannels (with and without coating) and 40 polymer-composite sensors of 10 different materials placed along it. The second group of systems include the hybrid-nose and the aVLSI-nose microsensor arrays assembled with microchannel packages of various lengths (5 cm, 32 cm, 7lcm, 240 cm) to form nose-on-a-chip systems. The hybrid-nose sensor array consists of 80 microsensors built on a 10 mm x 10 mm silicon substrate while the aVLSI-nose sensor array consists of 70 microsensors built on a 10 mm x 5 mm silicon substrate using standard CMOS process with smart integrated circuitries. The microchannel packages were fabricated using the Perfactory microstereolithography system. The most advanced microchannel package contains a 2.4 m x 500 J.lm2 microchannel with an external size of only 36 mm x 27 mm x 7 mm. The nose-on-a-chip system achieved miniaturisation and eliminates the need for any external processing circuitries while achieving the same capability of producing spatio-temporal signals. Using a custom-designed vapour test station and data acquisition electronics, these systems were evaluated with simple analytes and complex odours. The experimental results were in-line with the simulation results. On the coated proto-nose II system, a 25 s temporal delay was observed on the toluene vapour pulse compared to ethanol vapour pulse; this is significant compared to the uncoated system where no delay difference was obtained. Further testing with 8 analyte mixtures substantiated that spatio-temporal signals can be extracted from both the coated proto-nose and nose-on-a-chip (hybrid-nose sensor array with 2.4 m long microchannel) systems. This clearly demonstrates that these systems were capable of imitating certain characteristics of the biological olfactory system. Using only the temporal data, classification was performed with principal components analysis. The results reinforced that these additional temporal signals were useful to improve discrimination analysis which is not possible with any existing sensor-based electronic nose system. In addition, fast responding polymer-composite sensors were achieved exhibiting response times of less than 100 ms. Other biological characteristics relating to stereolfaction (two nostrils sniffing at different rates), sniffing rate (flow velocity) and duration (pulse width) were also investigated. The results converge with the biological observations that stereolfaction and sniffing at higher rate and duration improve discrimination. Last but not least, the characterisation of the smart circuitries on the aVLSI-nose show that it is possible to achieve better performance through the use of smart processing circuitries incorporating a novel DC-offset cancellation technique to amplify small sensor response with large baseline voltage. The results and theories presented in this study should provide useful contribution for designing a higher-performance electronic nose incorporating biological principles

Development of a PDMS Based Micro Total Analysis System for Rapid Biomolecule Detection

The emerging field of micro total analysis system powered by microfluidics is expected to revolutionize miniaturization and automation for point-of-care-testing systems which require quick, efficient and reproducible results. In the present study, a PDMS based micro total analysis system has been developed for rapid, multi-purpose, impedance based detection of biomolecules. The major components of the micro total analysis system include a micropump, micromixer, magnetic separator and interdigitated electrodes for impedance detection. Three designs of pneumatically actuated PDMS based micropumps were fabricated and tested. Based on the performance test results, one of the micropumps was selected for integration. The experimental results of the micropump performance were confirmed by a 2D COMSOL simulation combined with an equivalent circuit analysis of the micropump. Three designs of pneumatically actuated PDMS based active micromixers were fabricated and tested. The micromixer testing involved determination of mixing efficiency based on the streptavidin-biotin conjugation reaction between biotin comjugated fluorescent microbeads and streptavidin conjugated paramagnetic microbeads, followed by fluorescence measurements. Based on the performance test results, one of the micromixers was selected for integration. The selected micropump and micromixer were integrated into a single microfluidic system. The testing of the magnetic separation scheme involved comparison of three permanent magnets and three electromagnets of different sizes and magnetic strengths, for capturing magnetic microbeads at various flow rates. Based on the test results, one of the permanent magnets was selected. The interdigitated electrodes were fabricated on a glass substrate with gold as the electrode material. The selected micropumps, micromixer and interdigitated electrodes were integrated to achieve a fully integrated microfluidic system. The fully integrated microfluidic system was first applied towards biotin conjugated fluorescent microbeads detection based on streptavidin-biotin conjugation reaction which is followed by impedance spectrum measurements. The lower detection limit for biotin conjugated fluorescent microbeads was experimentally determined to be 1.9 x 106 microbeads. The fully integrated microfluidic system was then applied towards immuno microbead based insulin detection. The lower detection limit for insulin was determined to be 10-5M. The total detection time was 20 min. An equivalent circuit analysis was performed to explain the impedance spectrum results

Platforms and Protocols for the Multidimensional Microchip Electrophoretic Analysis of Complex Proteomes

The need for rapid, portable and high-throughput systems in proteomics is now prevalent because of demands for generating new protein-based disease biomarkers. However, 2-D protein profile patterns are lending themselves as potential diagnostic tools for biomarker discovery. It is difficult to identify protein biomarkers which are low abundant in the presence of highly abundant proteins, especially in complex biological samples like serum. Protein profiles from 2-D separation of the protein content of cells or body fluids, which are unique to certain physiological or pathological states, are currently available on internet databases. In this work, we demonstrate the ability to separate a complex biological sample using low cost, disposable, polymer-based microchips suitable for a multidimensional techniques that employed sodium dodecyl sulfate micro-capillary gel electrophoresis (SDS µ-CGE) in the 1st dimension and micellar electrokinetic capillary chromatography (MEKC) or microemulsion electrokinetic capillary chromatography (MEEKC) in the 2nd dimension. The peak capacity generated by this microchip technique was about 3-fold greater compared to conventional 2-D separation methods and the complete separation time was 60X faster. To minimize electroosmotic flow effects, we dynamically coated the channels with methylhydroxyethyl cellulose. Proteins were detected by laser-induced fluorescence following their labeling with dyes. To mitigate challenges posed by labeling the proteins, we investigated the use of a label-free technique that relied upon conductivity measurements. Preliminary data are presented on the fabrication of on-chip electrodes using a conductive SU-8 polymer via lithography