Digital microfluidic biochips (DMFBs) are being increasingly used for DNA sequencing, point-of-care clinical diagnostics, and immunoassays. DMFBs based on a micro-electrode-dot-array (MEDA) architecture have recently been proposed, and fundamental droplet manipulations, e.g., droplet mixing and splitting, have also been experimentally demonstrated on MEDA biochips. There can be thousands of microelectrodes on a single MEDA biochip, and the fine-grained control of nanoliter volumes of biochemical samples and reagents is also enabled by this technology. MEDA biochips offer the benefits of real-time sensitivity, lower cost, easy system integration with CMOS modules, and full automation. This review paper first describes recent design tools for high-level synthesis and optimization of map bioassay protocols on a MEDA biochip. It then presents recent advances in scheduling of fluidic operations, placement of fluidic modules, droplet-size-aware routing, adaptive error recovery, sample preparation, and various testing techniques. With the help of these tools, biochip users can concentrate on the development of nanoscale bioassays, leaving details of chip optimization and implementation to software tools.

Micro-Electrode-Dot-Array Digital Microfluidic Biochips: Technology, Design Automation, and Test Techniques

A digital microfluidic biochip (DMB) is an attractive platform for automating laboratory procedures in microbiology. To overcome the problem of cross-contamination due to fouling of the electrode surface in traditional DMBs, a contactless liquid-handling biochip technology, referred to as acoustofluidics, has recently been proposed. A major challenge in operating this platform is the need for a control signal of frequency 24 MHz and voltage range $\pm 10/\pm 20$ V to activate the IDT units in the biochip. In this paper, we present a hardware design that can efficiently activate/de-activated each IDT, and can fully automate an bio-protocol. We also present a fault-tolerant synthesis technique that allows us to automatically map biomolecular protocols to acoustofluidic biochips. We develop and experimentally validate a velocity model, and use it to guide co-optimization for operation scheduling, module placement, and droplet routing in the presence of IDT faults. Simulation results demonstrate the effectiveness of the proposed synthesis method. Our results are expected to open new research directions on design automation of digital acoustofluidic biochips.

Hardware Design and Fault-Tolerant Synthesis for Digital Acoustofluidic Biochips

A digital microfluidic biochip is an attractive platform for revolutionizing immunoassays, clinical diagnostics, drug discovery, DNA sequencing, and other laboratory procedures in biochemistry. A recent generation of biochips uses a microelectrode-dot-array (MEDA) architecture, which provides finer controllability of droplets and seamlessly integrates microelectronics and microfluidics using CMOS technology. In order to simplify the wiring problem for MEDA biochips, all microelectrodes and their control registers are daisy-chained together. Therefore, chain diagnosis and fault tolerance are critical for MEDA biochips. We propose the first daisy-chain design that can perform self-diagnosis and repair the detected faults. In our design, every microelectrode cell is fully controlled, and faults in the daisy chain can be detected and repaired in a timely manner. Moreover, the proposed design can be used in both online and off-line modes. Experimental results demonstrate the effectiveness of the proposed daisy-chain design.

Built-In Self-Diagnosis and Fault-Tolerant Daisy-Chain Design in MEDA Biochips*

The design process for digital microfluidic biochips (DMFBs) is becoming more complex due to the growing need for essential bio-protocols. A number of significant fluid- and chip-level synthesis tools have been offered previously for designing an efficient system. Several important cost drivers like bioassay schedule length, total pin count, congestion-free wiring, total wire length, and total layer count together measure the efficiency of the DMFBs. Besides, existing design gaps among the sub-tasks of the fluid and chip level make the design process expensive delaying the time-to-market and increasing the overall cost. In this context, removal of design cycles among the sub-tasks is a prior need to obtain a low-cost and efficient platform. Hence, this paper aims to propose a fluid-chip co-design methodology in dealing with the consideration of the fluid-chip cost drivers, while reducing the design cycles in between. A simulation study considering a number of benchmarks has been presented to observe the performance.

A New Fluid-Chip Co-Design for Digital Microfluidic Biochips Considering Cost Drivers and Design Convergence

Recent advancement of microelectrode-dot-array (MEDA)-based architecture for digital microfluidic biochips has enabled a major enhancement in microfluidic operations for traditional lab-on-chip devices. One critical issue for MEDA-based biochips is the transportation of droplets. MEDA allows dynamic routing for droplets of different size. In this article, we propose a high-performance droplet routing technique for MEDA-based digital microfluidic biochips. First, we propose the basic concept of droplet movement strategy in MEDA-based design together with a definition of strictly shielded zones within the layout in MEDA architecture. Next, we propose transportation schemes of droplets for MEDA architecture under different blockage or crossover conditions and estimate route distances for each net in offline. Finally, a priority-based routing strategy combining various transportation schemes stated earlier has been proposed. Concurrent movement of each droplet is scheduled in a time-multiplexed manner. This poses critical challenges for parallel routing of individual droplets with optimal sharing of cells formulating a routing problem with higher complexity. The final compaction solution satisfies the timing constraint and improves fault tolerance. Simulations are carried out on standard benchmark circuits, namely, Benchmark suite I and Benchmark suite III. Experimental results show satisfactory improvements and prove a high degree of robustness for our proposed algorithm.

A High-performance Homogeneous Droplet Routing Technique for MEDA-based Biochips

Digital microfluidic biochips (DMFBs) are an emerging technology that are replacing traditional laboratory procedures. With the integrated functions which are necessary for biochemical experiments, DMFBs are able to achieve automatic experiments. Recently, DMFBs based on a new architecture called micro-electrode-dot-array (MEDA) have been demonstrated. Compared with conventional DMFBs which sensors are specifically located, each microelectrode is integrated with a sensor on MEDA-based biochips. Benefiting from the advantage of MEDA-based biochips, real-time reaction-outcome detection is attainable. However, to the best of our knowledge, synthesis algorithms proposed in the literature for MEDA-based biochips do not fully utilize the real-time detection since completion-time uncertainties have not yet been considered. During the execution of a biochemical experiment, operations may finish earlier or delay due to variability and randomness in biochemical reactions. Such uncertainties also have effects when allocating modules for each fluidic operation and placing them on a biochip since a biochip with a fixed size area restricts the number and the size of these modules. Thus, in this paper, we proposed the first operation-variation-aware placement algorithm that fully utilizes the real-time detection since completion-time uncertainties have been considered. Simulation results demonstrate that with the proposed approach, it leads to reduced time-to-result and minimizes the chip size while not exceeding completion time compared to the benchmarks.

Wen-Chun Chung

Papers

Module Placement under Completion-Time Uncertainty in Micro-Electrode-Dot-Array Digital Microfluidic Biochips