77 research outputs found

    Synthesis of biochemical applications on digital microfluidic biochips with operation variability

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    Abstract—Microfluidic-based biochips are replacing the con-ventional biochemical analyzers, and are able to integrate on-chip all the necessary functions for biochemical analysis using microfluidics. The digital microfluidic biochips are based on the manipulation of liquids not as a continuous flow, but as discrete droplets. Researchers have presented approaches for the synthesis of digital microfluidic biochips, which, starting from a biochemical application and a given biochip architecture, determine the allocation, resource binding, scheduling and place-ment of the operations in the application. Existing approaches consider that on-chip operations, such as splitting a droplet of liquid, are perfect. However, these operations have variability margins, which can impact the correctness of the biochemical application. We consider that a split operation, which goes beyond specified variability bounds, is faulty. The fault is detected using on-chip volume sensors. We have proposed an abstract model for a biochemical application, consisting of a sequencing graph, which can capture all the fault scenarios in the application. Starting from this model, we have proposed a synthesis approach that, for a given chip area and number of sensors, can derive a fault-tolerant implementation. Two fault-tolerant scheduling techniques have been proposed and compared. We show that, by taking into account fault-occurrence information, we can derive better quality implementations, which leads to shorter application completion times, even in the case of faults. The proposed synthesis approach under operation variability has been evaluated using several benchmarks. I

    Compilation and Synthesis for Fault-Tolerant Digital Microfluidic Biochips

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    Synthesis of Digital Microfluidic Biochips with Reconfigurable Operation Execution

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    A Framework for Automated Correctness Checking of Biochemical Protocol Realizations on Digital Microfluidic Biochips

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    Recent advances in digital microfluidic (DMF) technologies offer a promising platform for a wide variety of biochemical applications, such as DNA analysis, automated drug discovery, and toxicity monitoring. For on-chip implementation of complex bioassays, automated synthesis tools have been developed to meet the design challenges. Currently, the synthesis tools pass through a number of complex design steps to realize a given biochemical protocol on a target DMF architecture. Thus, design errors can arise during the synthesis steps. Before deploying a DMF biochip on a safety critical system, it is necessary to ensure that the desired biochemical protocol has been correctly implemented, i.e., the synthesized output (actuation sequences for the biochip) is free from any design or realization errors. We propose a symbolic constraint-based analysis framework for checking the correctness of a synthesized biochemical protocol with respect to the original design specification. The verification scheme based on this framework can detect several post-synthesis fluidic violations and realization errors in 2D-array based or pin-constrained biochips as well as in cyberphysical systems. It further generates diagnostic feedback for error localization. We present experimental results on the polymerase chain reaction (PCR) and in-vitro multiplexed bioassays to demonstrate the proposed verification approach

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

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    <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

    Microfluidic very large-scale integration for biochips: Technology, testing and fault-tolerant design

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    Microfluidic biochips are replacing the conventional biochemical analyzers by integrating all the necessary functions for biochemical analysis using microfluidics. Biochips are used in many application areas, such as, in vitro diagnostics, drug discovery, biotech and ecology. The focus of this paper is on continuous-flow biochips, where the basic building block is a microvalve. By combining these microvalves, more complex units such as mixers, switches, multiplexers can be built, hence the name of the technology, “microfluidic Very Large-Scale Integration” (mVLSI). A roadblock in the deployment of microfluidic biochips is their low reliability and lack of test techniques to screen defective devices before they are used for biochemical analysis. Defective chips lead to repetition of experiments, which is undesirable due to high reagent cost and limited availability of samples. This paper presents the state-of-the-art in the mVLSI platforms and emerging research challenges in the area of continuous-flow microfluidics, focusing on testing techniques and fault-tolerant design

    Digital Microfluidic (DMF) devices based on electrowetting on dielectric (EWOD) for biological applications

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    Microfluidic devices have been used in various applications including automated analysis systems, biological applications like DNA sequencing, antigen-antibody reactions, protein studies, chemical applications, single cell studies, etc. Microfluidic devices are primarily categorised into two types. First are continuous microfluidic devices. These devices consist of predefined microchannels, micro-valves, and syringe pumps. Fluid is continuously flowing in these channels. The second type is digital microfluidic platforms. In this type, MXN array of electrodes is patterned on non-conducting substrate. Fluid is discretized to form tiny droplets. These droplets are transported, mixed and split using external electric field. Digital microfluidic devices are configurable as there are no permanently etched channels. Also, they have high throughput. Multiple reactions can be performed on the same platform at the same time. The time taken to complete one reaction is less compared to the continuous devices. Thus they help in faster analysis. These devices are controlled by electrical field and thus unlike continuous devices, digital microfluidic devices are free from mechanically moving parts. Digital microfluidic devices may suffer from charge accumulation due to electrostatic forces. Also, voltage levels applied play an important role. The applied voltage has to be enough to move droplets but should not cause electrolysis of the liquid used. Also voltage switching time between electrodes and frequency applied are important. These parameters can change the mixing quality. In this work, 2D simulations of droplet manipulation due to voltage application, transport and mixing are carried out. Also digital microfluidic device is designed and fabricated to carry out biological mixing experiments
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