Zipeng Li

High-level synthesis for micro-electrode-dot-array digital microfluidic biochips

A digital microfluidic biochip (DMFB) is an attractive technology platform for automating laboratory procedures in biochemistry. However, todays DMFBs suffer from several limitations: (i) constraints on droplet size and the inability to vary droplet volume in a fine-grained manner; (ii) the lack of integrated sensors for real-time detection; (iii) the need for special fabrication processes and reliability/yield concerns. To overcome the above problems, DMFBs based on a micro-electrode-dot-array (MEDA) architecture have recently been demonstrated. However, due to the inherent differences between todays DMFBs and MEDA, existing synthesis solutions cannot be utilized for MEDA-based biochips. We present the first biochip synthesis approach that can be used for MEDA. The proposed synthesis method targets operation scheduling, module placement, routing of droplets of various sizes, and diagonal movement of droplets in a two-dimensional array. Simulation results using benchmarks and experimental results using a fabricated MEDA biochip demonstrate the effectiveness of the proposed co-optimization technique.

Experimental demonstration of error recovery in an integrated cyberphysical digital-microfluidic platform

Digital (droplet-based) microfluidics enables the integration of fluid-handling operations and reaction-outcome detection. Despite these benefits, defects and erroneous fluidic operations continue to be major barriers to the adoption and deployment of these devices. We describe the first practical and fully integrated cyberphysical error-recovery system that can be implemented in real time on a field-programmable gate array (FPGA). The hardware-assisted solution is based on an error dictionary containing the error-recovery plans for various anticipated errors. The dictionary is computed and stored in FPGA memory before the start of the biochemical experiment. Errors in droplet operations on the digital microfluidic platform are detected using capacitive sensors, the test outcome is interpreted by control hardware, and corresponding error-recovery plans are triggered in real-time. Experimental results are reported for a fabricated silicon device, and links to videos are provided for the first-ever experimental demonstration of real-time error recovery in cyberphysical digital-microfluidic biochips using a hardware-implemented dictionary.

Advances in Design Automation Techniques for Digital-Microfluidic Biochips

Due to their emergence as an efficient platform for pointof-care clinical diagnostics, digital-microfluidic biochips (DMFBs) have received considerable attention in recent years. They combine electronics with biology, and they integrate various bioassay operations, such as sample preparation, analysis, separation, and detection. In this chapter, we first present an overview of digital-microfluidic biochips. We next describe emerging computer-aided design (CAD) tools for the automated synthesis and optimization of biochips from bioassay protocols. The chapter includes solutions for fluidic-operation scheduling, module placement, droplet routing, and pin-constrained chip design. We also show how recent advances in the integration of sensors into a DMFB can be exploited to provide cyberphysical system adaptation based on feedback-driven control.

Optimization of 3D Digital Microfluidic Biochips for the Multiplexed Polymerase Chain Reaction

A digital microfluidic biochip (DMFB) is an attractive technology platform for revolutionizing immunoassays, clinical diagnostics, drug discovery, DNA sequencing, and other laboratory procedures in biochemistry. In most of these applications, real-time polymerase chain reaction (PCR) is an indispensable step for amplifying specific DNA segments. To reduce the reaction time to meet the requirement of “real-time” applications, multiplexed PCR is widely utilized. In recent years, three-dimensional (3D) DMFBs that integrate photodetectors (i.e., cyberphysical DMFBs) have been developed, which offer the benefits of smaller size, higher sensitivity, and faster result generations. However, current DMFB design methods target optimization in only two dimensions, thus ignoring the 3D two-layer structure of a DMFB. Furthermore, these techniques ignore practical constraints related to the interference between on-chip device pairs, the performance-critical PCR thermal loop, and the physical size of devices. Moreover, some practical issues in real scenarios are not stressed (e.g., the avoidance of the cross-contamination for multiplexed PCR). In this article, we describe an optimization solution for a 3D DMFB and present a three-stage algorithm to realize a compact 3D PCR chip layout, which includes: (i) PCR thermal-loop optimization, (ii) 3D global placement based on Strong-Push-Weak-Pull (SPWP) model, and (iii) constraint-aware legalization. To avoid cross-contamination between different DNA samples, we also propose a Minimum-Cost-Maximum-Flow-based (MCMF-based) method for reservoir assignment. Simulation results for four laboratory protocols demonstrate that the proposed approach is effective for the design and optimization of a 3D chip for multiplexed real-time PCR.

Exact routing for micro-electrode-dot-array digital microfluidic biochips

Digital microfluidics is an emerging technology that provide fluidic-handling capabilities on a chip. One of the most important issues to be considered when conducting experiments on the corresponding biochips is the routing of droplets. A recent variant of biochips uses a micro-electrode-dot-array (MEDA) which yields a finer controllability of the droplets. Although this new technology allows for more advanced routing possibilities, it also poses new challenges to corresponding CAD methods. In contrast to conventional microfluidic biochips, droplets on MEDA biochips may move diagonally on the grid and are not bound to have the same shape during the entire experiment. In this work, we present an exact routing method that copes with these challenges while, at the same time, guarantees to find the minimal solution with respect to completion time. For the first time, this allows for evaluating the benefits of MEDA biochips compared to their conventional counterparts as well as a quality assessment of previously proposed routing methods in this domain.

Droplet Size-Aware High-Level Synthesis for Micro-Electrode-Dot-Array Digital Microfluidic Biochips

A digital microfluidic biochip (DMFB) is an attractive technology platform for automating laboratory procedures in biochemistry. In recent years, DMFBs based on a microelectrode-dot-array (MEDA) architecture have been demonstrated. However, due to the inherent differences between todays DMFBs and MEDA, existing synthesis solutions for biochemistry mapping cannot be utilized for MEDA biochips. We present the first synthesis approach that can be used for MEDA biochips. We first present a general analytical model for droplet velocity and validate it experimentally using a fabricated MEDA biochip. We then present the proposed synthesis method targeting reservoir placement, operation scheduling, module placement, routing of droplets of various sizes, and diagonal movement of droplets in a two-dimensional array. Simulation results using benchmarks and experimental results using a fabricated MEDA biochip demonstrate the effectiveness of the proposed synthesis technique.

Reliability-Driven Pipelined Scan-Like Testing of Digital Microfluidic Biochips

A digital micro fluidic biochip (DMFB) is an attractive platform for immunoassays, point-of-care clinical diagnostics, DNA sequencing, and other laboratory procedures in biochemistry. Effective testing methods are required to ensure robust DMFB operation and high confidence in the outcome of biochemical experiments. Prior work on DMFB testing does not address the problem of designing the test to minimize reliability degradation during test application. It also ignores physical constraints arising from fluidic behavior and the physics of electro wetting-on-dielectric. We develop a practical and realistic testing method by first systematically analyzing the influence of actuation voltage and actuation frequency on the distribution of the electric field, and its resulting effect on dielectric degradation. Next, we use this analysis to choose appropriate parameter settings for testing, and proposes a new pipelined scan-like testing method. Both static and dynamic fluidic constraints are considered in the new testing method, and a diagnosis technique is presented to easily locate defects. Finally, simulation results are presented to demonstrate the effectiveness of the proposed testing approach in minimizing test-completion time.

Error recovery in a micro-electrode-dot-array digital microfluidic biochip?

A digital microfluidic biochip (DMFB) is an attractive technology platform for automating laboratory procedures in biochemistry. However, todays DMFBs suffer from several limitations: (i) constraints on droplet size and the inability to vary droplet volume in a fine-grained manner; (ii) the lack of integrated sensors for real-time detection; (iii) the need for special fabrication processes and the associated reliability/yield concerns. To overcome the above problems, DMFBs based on a micro-electrode-dot-array (MEDA) architecture have been proposed recently, and droplet manipulation on these devices has been experimentally demonstrated. Errors are likely to occur due to defects, chip degradation, and the lack of precision inherent in biochemical experiments. Therefore, an efficient error-recovery strategy is essential to ensure the correctness of assays executed on MEDA biochips. By exploiting MEDA-specific advances in droplet sensing, we present a novel error-recovery technique to dynamically reconfigure the biochip using real-time data provided by on-chip sensors. Local recovery strategies based on probabilistic-timed-automata are presented for various types of errors. A control flow is also proposed to connect local recovery procedures with global error recovery for the complete bioassay. Laboratory experiments using a fabricated MEDA chip are used to characterize the outcomes of key droplet operations. The PRISM model checker and three analytical chemistry benchmarks are used for an extensive set of simulations. Our results highlight the effectiveness of the proposed error-recovery strategy.

Efficient and Adaptive Error Recovery in a Micro-Electrode-Dot-Array Digital Microfluidic Biochip

A digital microfluidic biochip (DMFB) is an attractive technology platform for automating laboratory procedures in biochemistry. In recent years, DMFBs based on a micro-electrode-dot-array (MEDA) architecture have been proposed. MEDA biochips can provide advantages of better capability of droplet manipulation and real-time sensing ability. However, errors are likely to occur due to defects, chip degradation, and the lack of precision inherent in biochemical experiments. Therefore, an efficient error-recovery strategy is essential to ensure the correctness of assays executed on MEDA biochips. By exploiting MEDA-specific advances in droplet sensing, we present a novel error-recovery technique to dynamically reconfigure the biochip using real-time data provided by on-chip sensors. Local recovery strategies based on probabilistic-timed-automata are presented for various types of errors. An online synthesis technique and a control flow are also proposed to connect local-recovery procedures with global error recovery for the complete bioassay. Moreover, an integer linear programming-based method is also proposed to select the optimal local-recovery time for each operation. Laboratory experiments using a fabricated MEDA chip are used to characterize the outcomes of key droplet operations. The PRISM model checker and three benchmarks are used for an extensive set of simulations. Our results highlight the effectiveness of the proposed error-recovery strategy.

Built-in self-test for micro-electrode-dot-array digital microfluidic biochips

A digital microfluidic biochip (DMFB) is an attractive platform for immunoassays, point-of-care clinical diagnostics, DNA sequencing, and other laboratory procedures in biochemistry. However, todays DMFBs suffer from several limitations, including (i) the lack of integrated sensors for real-time detection, (ii) constraints on droplet size and the inability to vary droplet volume in a fine-grained manner, and (iii) the need for special fabrication processes and the associated reliability/yield concerns. To overcome the above limitations, DMFBs based on a micro-electrode-dot-array (MEDA) architecture have been proposed recently. Droplet manipulation on MEDA biochips has also been experimentally demonstrated. In order to ensure robust fluidic operations and high confidence in the outcome of biochemical experiments, MEDA biochips must be adequately tested before they can be used for bioassay execution. We present an efficient built-in self-test (BIST) architecture for MEDA biochips. The proposed BIST architecture can effectively detect defects in a MEDA biochip, and faulty microcells can be identified. Simulation results based on HSPICE and experiments using fabricated MEDA biochips highlight the effectiveness of the proposed BIST architecture.