Paper-based digital microfluidic biochips (P-DMFBs) have recently emerged as a promising low-cost and fast-responsive platform for biochemical assays. In P-DMFBs, electrodes and control lines are printed on a piece of photograph paper using an inkjet printer and carbon nanotubes (CNTs) conductive ink. Compared with traditional digital microfluidic biochips (DMFBs), P-DMFBs enjoy significant advantages, such as faster in-place fabrication with printer and ink, lower costs, and better disposability. Since electrodes and CNT control lines are printed on the same side of this paper, a critical design challenge for P-DMFB is to prevent control interference between moving droplets and the voltages on CNT control lines. Control interference may result in unexpected droplet movements and thus incorrect assay outputs. To address this design challenge, a control-fluidic codesign methodology is proposed in this paper, along with two demonstrative design flows integrating both fluidic design and control design, i.e., the droplet-oriented codesign flow and the electrode-oriented codesign flow. The droplet-oriented flow is suitable for designing biochips with sparse electrodes and relatively larger number of droplets, whereas the electrode-oriented flow is suitable for biochips with dense electrodes and smaller number of droplets. The computational simulation results of real-life bioassays demonstrate the effectiveness of the proposed codesign flows.

Flow-based microfluidic biochips are one of the most promising platforms used in biochemical and pharmaceutical laboratories due to their high efficiency and low costs. Inside such a chip, fluids of nanoliter volumes are transported between devices for various operations, such as mixing and detection. The transportation channels and corresponding operation devices are controlled by microvalves driven by external pressure sources. Since assigning an independent pressure source to every microvalve would be impractical due to high costs and limited system dimensions, states of microvalves are switched by a control logic using time multiplexing. Existing control-logic designs, however, still switch only a single control channel per operation, leading to a low efficiency. In this article, we present the first automatic synthesis approach for a control logic that is able to switch multiple control channels simultaneously. Moreover, we propose the first fault-aware design in control logic by introducing backup control paths to maintain the correct function even when manufacturing defects occur. The construction of control logic is achieved by a highly efficient framework based on particle swarm optimization, Boolean logic simplification, grid routing, together with mixing multiplexing. The simulation results demonstrate that the proposed multichannel switching mechanism leads to fewer valve-switching times and lower total logic cost, while realizing fault tolerance for all control channels.

Continuous flow-based biochips are one of the promising platforms used in biochemical and pharmaceutical laboratories due to their efficiency and low costs. Inside such a chip, fluid volumes of nanoliter size are transported between devices for various operations, such as mixing and detection. The transportation channels and corresponding operation devices are controlled by microvalves driven by external pressure sources. Since assigning an independent pressure source to every microvalve would be impractical due to high costs and limited system dimensions, states of microvalves are switched using a control logic by time multiplexing. Existing control logic designs, however, still switch only a single control channel per operation – leading to a low efficiency. In this paper, we propose the first automatic synthesis approach for a control logic that is able to switch multiple control channels simultaneously to reduce the overall switching time of valve states. In addition, we propose the first fault-aware design in control logic to introduce redundant control paths to maintain the correct function even when manufacturing defects occur. Compared with the existing direct connection method, the proposed multi-channel switching mechanism can reduce the switching time of valve states by up to 64%. In addition, all control paths for fault tolerance have been realized.

Flow-based microfluidic biochips are attracting increasing attention with successful applications in biochemical experiments, point-of-care diagnosis, etc. Existing works in design automation consider the flow-layer design and control-layer design separately, lacking a global optimization and hence resulting in degraded routability and reliability. This paper presents a novel integrated physical co-design methodology, which seamlessly integrates the flow-layer and control-layer design stages. In the flow-layer design stage, a sequence-pair-based placement method is presented, which allows for an iterative placement refinement based on routing feedbacks. In the control-layer design stage, the minimum cost flow formulation is adopted to further improve the routability. Besides that, effective placement adjustment strategies are proposed to iteratively enhance the solution quality of the overall control-layer design. Experimental results show that compared with the existing work, the proposed design flow obtains an average reduction of 40.44% in flow-channel crossings, 31.95% in total chip area, and 22.02% in total flow-channel length. Moreover, all the valves are successfully routed in the control-layer design stage.

Continuous-flow microfluidics rapidly evolved in the last decades as a solution to automate laboratory procedures in molecular biology and biochemistry. Therefore, the physical design of the corresponding chips, i.e., the placement and routing of the involved components and channels, received significant attention. Recently, several physical design solutions for this task have been presented. However, they often rely on general heuristics which traverse the search space in a rather arbitrary fashion and, additionally, consider placement and routing independently from each other. Consequently, the obtained results are often far from being optimal. In this work, a methodology is proposed which aims for determining close-to-optimal physical designs for continuous-flow microfluidic biochips. To this end, we consider all - or, at least, as much as possible - of the valid solutions. As this obviously yields a significant complexity, solving engines are utilized to efficiently traverse the search space and pruning schemes are proposed to reduce the search space without discarding too many promising solutions. Evaluations show that the proposed methodology is capable of determining optimal results for small experiments to be realized. For larger experiments, close-to-optimal results can efficiently be derived. Moreover, compared to the current state-of-the-art, improvements of up to 1-2 orders of magnitude can be observed.

Flow-based microfluidic biochips have progressed significantly in the past decade. Thanks to innovations in multilayer soft lithography (MSL) fabrication technology, the integration of thousands of microvalves along with large-scale networks of microchannels on a chip has been enabled. This progress has even been compared to the evolution of VLSI circuits following Moore's Law. In flow-based microfluidic biochips, microvalves are critical components to control the fluidic transportation for complex operations. To activate the open/close states of a microvalve, off-chip control pins are required. Due to the tremendous increase of the number of microvalves, a software-programmable microfluidic platform has been proposed to reduce the number of off-chip control pins, which integrates a microfluidic multiplexer on a separate control layer to control the array of microvalves. The multiplexer needs to be switched when the states of microvalves are changed between every two adjacent time slots. High switching frequency will make the multiplexer vulnerable and decrease the chip's reliability. We observe that different switching orders of microvalves lead to different switching frequencies of a multiplexer. Based on this observation, this paper proposes the first Hamming-distance-based switching order optimization method for microvalves to enhance the reliability of the multiplexer. Experimental results show that our method can significantly reduce the switching frequency of multiplexer, and the solution is very close to the theoretical optimal lower bound.

Flow-based microfluidic biochips are attracting increasing attention with successful applications in lab-on-a-chip experiments and point-of-care diagnosis. Physical design for flow-based biochips determines the number of flow-channel intersections, and thus affects the number of microvalves. As reducing microvalves will significantly improve the overall design quality and reliability, physical design is of great importance. Typically, physical design consists of two major stages, i.e., component placement and routing. Existing works follow the step-by-step scheme, which perform placement and routing separately. The lack of interactions between the two design stages results in degraded design with large number of unfavorable channel intersections and microvalves. This paper presents a novel placement and routing method based on the sequence-pair representation, which seamlessly integrates placement and routing stages and allows iterative placement adjustment upon routing feedbacks. Experimental results show that compared with the existing work, the proposed method obtains average 54.10% improvement in flow-channel crossings, 42.15% improvement in total chip area, and 23.43% improvement in total channel length.

Paper-based digital microfluidic biochips (P-DMFBs) have recently emerged as a promising low-cost and fast-responsive platform for biochemical assays. In P-DMFBs, electrodes and control lines are printed on a piece of photo paper using inkjet printer and conductive ink of carbon nanotubes (CNTs). Compared with traditional digital microfluidic biochips (DMFBs), P-DMFBs enjoy notable advantages, such as faster in-place fabrication with printer and ink, lower costs, better disposability, etc. Because electrodes and CNT control lines are printed on the same side of a paper, a new design challenge for P-DMFB is to prevent the interference between moving droplets and the voltages on CNT control lines. These interactions may result in unexpected droplet movements and thus incorrect assay outputs. To address the new challenges in automated design of P-DMFBs, this paper proposes the first control-fluidic codesign flow, which simultaneously adjusts the control line routing and fluidic droplet scheduling to achieve an optimized solution. As the control line routing may not be able to address all the interferences between moving droplets and the voltages on control lines, droplet rescheduling is performed to effectively deal with the remaining interferences in the routing solution. Computational simulation results on real-life bioassays show that the proposed codesign method successfully eliminates all the interferences, while a state-of-the-art maze routing method cannot solve any of the benchmarks without conflicts.

Digital microfluidic biochips (DMFBs) are gaining increasing attention with promising applications for automating and miniaturizing laboratory procedures in biochemistry. In DMFBs, cross-contamination of droplets with different biomolecules is a major issue, which causes significant errors in bioassays. Washing operations are introduced to clean the cross-contamination spots. However, existing works have oversimplified assumptions on the washing behavior, which either assume infinite washing capacity, or ignore the routing conflicts between functional and washing droplets. This paper proposes the first integrated functional and washing droplet routing flow, which considers practical issues including the finite washing capacity constraint, and the routing conflicts between functional and washing droplets. Washing droplets of different sizes are also proposed to wash the congested cross-contamination spots. Effectiveness of the proposed method is validated by real-life biochemical applications.

The chip-level design problem is critical in pin-constrained electrowetting-on-dielectric (EWOD) biochips, which not only affects the number of control pins and PCB routing layers from the manufacturing cost point of view, but also determines the functional reliability induced by excessive applied voltage. Existing works either greedily minimize the number of control pins with degraded routability, or disregard the differences in driving voltages on the electrodes, where the trapped charge due to excessive applied voltage causes significant reliability issue. This paper presents the first SVM-based classifier for electrode addressing in chip-level design stage, which simultaneously optimizes the number of control pins, routability, as well as reliability. Experimental results on both real-life chips and synthesized benchmarks show that, compared with the state-of-the-art method, the SVM-based electrode addressing method obtains significant improvements in both routability and reliability.

In digital microfluidic biochips, cross-contamination of different biomolecule droplets is a major issue. Washing operations are introduced to clean the cross-contamination sites. Existing works have oversimplified assumptions on the washing behavior, which either assume unrealistic infinite washing capacity, or ignore the execution time constraint and/or the routing conflicts between functional and washing droplets. This paper presents the first practical droplet routing flow, which considers realistic issues including the finite washing capacity constraint, and the routing conflicts between washing and functional droplets. Effectiveness of the presented method are validated by real-life biochemical applications.