Fault Modeling and Defect Analysis on Digital Microfluidics Based Biochips

An emerging technology Digital Microfluidics Biochips, an integrating concept of electronics and biology is anticipated to play an important role in the area of medical diagnostics, drug discovery, DNA sequencing, toxicity supervising and other bio-chemical applications. This bio-microelectromechanical system is supposed to have defects if it fails to accomplish the specified assignment dedicated to it. This paper focuses on different possible cases responsible for the misbehavior of the bio-MEMS

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

A Review on Key Issues and Challenges in Devices Level MEMS Testing

The present review provides information relevant to issues and challenges in MEMS testing techniques that are implemented to analyze the microelectromechanical systems (MEMS) behavior for specific application and operating conditions. MEMS devices are more complex and extremely diverse due to the immersion of multidomains. Their failure modes are distinctive under different circumstances. Therefore, testing of these systems at device level as well as at mass production level, that is, parallel testing, is becoming very challenging as compared to the IC test, because MEMS respond to electrical, physical, chemical, and optical stimuli. Currently, test systems developed for MEMS devices have to be customized due to their nondeterministic behavior and complexity. The accurate measurement of test systems for MEMS is difficult to quantify in the production phase. The complexity of the device to be tested required maturity in the test technique which increases the cost of test development; this practice is directly imposed on the device cost. This factor causes a delay in time-to-market

A Review on Key Issues and Challenges in Devices Level MEMS Testing

The present review provides information relevant to issues and challenges in MEMS testing techniques that are implemented to analyze the microelectromechanical systems (MEMS) behavior for specific application and operating conditions. MEMS devices are more complex and extremely diverse due to the immersion of multidomains. Their failure modes are distinctive under different circumstances. Therefore, testing of these systems at device level as well as at mass production level, that is, parallel testing, is becoming very challenging as compared to the IC test, because MEMS respond to electrical, physical, chemical, and optical stimuli. Currently, test systems developed for MEMS devices have to be customized due to their nondeterministic behavior and complexity. The accurate measurement of test systems for MEMS is difficult to quantify in the production phase. The complexity of the device to be tested required maturity in the test technique which increases the cost of test development; this practice is directly imposed on the device cost. This factor causes a delay in time-to-market

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

Electrical Coupling Between Micropatterned Cardiomyocytes and Stem Cells

To understand how stem cells functionally couple with native cardiomyocytes is crucial for cell-based therapies to restore the loss of cardiomyocytes that occurs during heart infarction and other cardiac diseases. Due to the complexity of the in vivo environment, our knowledge of cell coupling is heavily dependent on cell-culture models. However, conventional in vitro studies involve undefined cell shapes and random length of cell-cell contacts in addition to the presence of multiple homotypic and heterotypic contacts between interacting cells. Thus, it has not been feasible to study electrical coupling corresponding to isolated specific types of cell contact modes. To address this issue, we used microfabrication techniques to develop different geometrically-defined stem cell-cardiomyocyte contact assays to comparatively and quantitatively study functional stem cell-cardiomyocyte electrical coupling. Through geometric confinements, we will construct a matrix of identical microwells, and each was constructed as a specific microenvironment. Using laser-guided cell micropatterning technique, individual stem cells or cardiomyocytes can be deposited into the microwells to form certain contact mode. In this research, we firstly constructed an in-vivo like cardiac muscle fiber microenvironment, and the electrical conductivity of stem cells was investigated by inserting stem cells as cellular bridges. Then, the electrical coupling between cardiomyocytes and stem cells was studied at single-cell level by constructing contact-promotive/-preventive microenvironments