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

Design and Optimization Methods for Pin-Limited and Cyberphysical Digital Microfluidic Biochips

<p>Microfluidic biochips have now come of age, with applications to biomolecular recognition for high-throughput DNA sequencing, immunoassays, and point-of-care clinical diagnostics. In particular, digital microfluidic biochips, which use electrowetting-on-dielectric to manipulate discrete droplets (or "packets of biochemical payload") of picoliter volumes under clock control, are especially promising. The potential applications of biochips include real-time analysis for biochemical reagents, clinical diagnostics, flash chemistry, and on-chip DNA sequencing. The ease of reconfigurability and software-based control in digital microfluidics has motivated research on various aspects of automated chip design and optimization.</p><p>This thesis research is focused on facilitating advances in on-chip bioassays, enhancing the automated use of digital microfluidic biochips, and developing an "intelligent" microfluidic system that has the capability of making on-line re-synthesis while a bioassay is being executed. This thesis includes the concept of a "cyberphysical microfluidic biochip" based on the digital microfluidics hardware platform and on-chip sensing technique. In such a biochip, the control software, on-chip sensing, and the microfluidic operations are tightly coupled. The status of the droplets is dynamically monitored by on-chip sensors. If an error is detected, the control software performs dynamic re-synthesis procedure and error recovery.</p><p>In order to minimize the size and cost of the system, a hardware-assisted error-recovery method, which relies on an error dictionary for rapid error recovery, is also presented. The error-recovery procedure is controlled by a finite-state-machine implemented on a field-programmable gate array (FPGA) instead of a software running on a separate computer. Each state of the FSM represents a possible error that may occur on the biochip; for each of these errors, the corresponding sequence of error-recovery signals is stored inside the memory of the FPGA before the bioassay is conducted. When an error occurs, the FSM transitions from one state to another, and the corresponding control signals are updated. Therefore, by using inexpensive FPGA, a portable cyberphysical system can be implemented.</p><p>In addition to errors in fluid-handling operations, bioassay outcomes can also be erroneous due the uncertainty in the completion time for fluidic operations. Due to the inherent randomness of biochemical reactions, the time required to complete each step of the bioassay is a random variable. To address this issue, a new "operation-interdependence-aware" synthesis algorithm is proposed in this thesis. The start and stop time of each operation are dynamically determined based on feedback from the on-chip sensors. Unlike previous synthesis algorithms that execute bioassays based on pre-determined start and end times of each operation, the proposed method facilitates "self-adaptive" bioassays on cyberphysical microfluidic biochips.</p><p>Another design problem addressed in this thesis is the development of a layout-design algorithm that can minimize the interference between devices on a biochip. A probabilistic model for the polymerase chain reaction (PCR) has been developed; based on the model, the control software can make on-line decisions regarding the number of thermal cycles that must be performed during PCR. Therefore, PCR can be controlled more precisely using cyberphysical integration.</p><p>To reduce the fabrication cost of biochips, yet maintain application flexibility, the concept of a "general-purpose pin-limited biochip" is proposed. Using a graph model for pin-assignment, we develop the theoretical basis and a heuristic algorithm to generate optimized pin-assignment configurations. The associated scheduling algorithm for on-chip biochemistry synthesis has also been developed. Based on the theoretical framework, a complete design flow for pin-limited cyberphysical microfluidic biochips is presented.</p><p>In summary, this thesis research has led to an algorithmic infrastructure and optimization tools for cyberphysical system design and technology demonstrations. The results of this thesis research are expected to enable the hardware/software co-design of a new class of digital microfluidic biochips with tight coupling between microfluidics, sensors, and control software.</p>Dissertatio

Evolvable Smartphone-Based Point-of-Care Systems For In-Vitro Diagnostics

Recent developments in the life-science -omics disciplines, together with advances in micro and nanoscale technologies offer unprecedented opportunities to tackle some of the major healthcare challenges of our time. Lab-on-Chip technologies coupled with smart-devices in particular, constitute key enablers for the decentralization of many in-vitro medical diagnostics applications to the point-of-care, supporting the advent of a preventive and personalized medicine. Although the technical feasibility and the potential of Lab-on-Chip/smart-device systems is repeatedly demonstrated, direct-to-consumer applications remain scarce. This thesis addresses this limitation. System evolvability is a key enabler to the adoption and long-lasting success of next generation point-of-care systems by favoring the integration of new technologies, streamlining the reengineering efforts for system upgrades and limiting the risk of premature system obsolescence. Among possible implementation strategies, platform-based design stands as a particularly suitable entry point. One necessary condition, is for change-absorbing and change-enabling mechanisms to be incorporated in the platform architecture at initial design-time. Important considerations arise as to where in Lab-on-Chip/smart-device platforms can these mechanisms be integrated, and how to implement them. Our investigation revolves around the silicon-nanowire biological field effect transistor, a promising biosensing technology for the detection of biological analytes at ultra low concentrations. We discuss extensively the sensitivity and instrumentation requirements set by the technology before we present the design and implementation of an evolvable smartphone-based platform capable of interfacing lab-on-chips embedding such sensors. We elaborate on the implementation of various architectural patterns throughout the platform and present how these facilitated the evolution of the system towards one accommodating for electrochemical sensing. Model-based development was undertaken throughout the engineering process. A formal SysML system model fed our evolvability assessment process. We introduce, in particular, a model-based methodology enabling the evaluation of modular scalability: the ability of a system to scale the current value of one of its specification by successively reengineering targeted system modules. The research work presented in this thesis provides a roadmap for the development of evolvable point-of-care systems, including those targeting direct-to-consumer applications. It extends from the early identification of anticipated change, to the assessment of the ability of a system to accommodate for these changes. Our research should thus interest industrials eager not only to disrupt, but also to last in a shifting socio-technical paradigm

Modern Applications in Optics and Photonics: From Sensing and Analytics to Communication

Optics and photonics are among the key technologies of the 21st century, and offer potential for novel applications in areas such as sensing and spectroscopy, analytics, monitoring, biomedical imaging/diagnostics, and optical communication technology. The high degree of control over light fields, together with the capabilities of modern processing and integration technology, enables new optical measurement systems with enhanced functionality and sensitivity. They are attractive for a range of applications that were previously inaccessible. This Special Issue aims to provide an overview of some of the most advanced application areas in optics and photonics and indicate the broad potential for the future

Factories of the Future

Engineering; Industrial engineering; Production engineerin