Droplet Routing in the Synthesis of Digital Microfluidic Biochips
06 Mar 2006-Vol. 1, pp 323-328
TL;DR: This work develops the first systematic droplet routing method that can be integrated with biochip synthesis, which minimizes the number of cells used fordroplet routing, while satisfying constraints imposed by throughput considerations and fluidic properties.
Abstract: Recent advances in microfluidics are expected to lead to sensor systems for high-throughput biochemical analysis. CAD tools are needed to handle increased design complexity for such systems. Analogous to classical VLSI synthesis, a top-down design automation approach can shorten the design cycle and reduce human effort. We focus here on the droplet routing problem, which is a key issue in biochip physical design automation. We develop the first systematic droplet routing method that can be integrated with biochip synthesis. The proposed approach minimizes the number of cells used for droplet routing, while satisfying constraints imposed by throughput considerations and fluidic properties. A real-life biochemical application is used to evaluate the proposed method.
Citations
More filters
TL;DR: The most recent advances in the DMF platforms are discussed, and the feasibility of developing multifunctional packages for performing complete sets of processes of biochemical assays, particularly for point-of-care applications is evaluated.
Abstract: Following the development of microfluidic systems, there has been a high tendency towards developing lab-on-a-chip devices for biochemical applications. A great deal of effort has been devoted to improve and advance these devices with the goal of performing complete sets of biochemical assays on the device and possibly developing portable platforms for point of care applications. Among the different microfluidic systems used for such a purpose, digital microfluidics (DMF) shows high flexibility and capability of performing multiplex and parallel biochemical operations, and hence, has been considered as a suitable candidate for lab-on-a-chip applications. In this review, we discuss the most recent advances in the DMF platforms, and evaluate the feasibility of developing multifunctional packages for performing complete sets of processes of biochemical assays, particularly for point-of-care applications. The progress in the development of DMF systems is reviewed from eight different aspects, including device fabrication, basic fluidic operations, automation, manipulation of biological samples, advanced operations, detection, biological applications, and finally, packaging and portability of the DMF devices. Success in developing the lab-on-a-chip DMF devices will be concluded based on the advances achieved in each of these aspects.
337 citations
TL;DR: This work proposes a system design methodology that attempts to apply classical high-level synthesis techniques to the design of digital microfluidic biochips and develops an optimal scheduling strategy based on integer linear programming and two heuristic techniques that scale well for large problem instances.
Abstract: Microfluidic biochips offer a promising platform for massively parallel DNA analysis, automated drug discovery, and real-time biomolecular recognition. Current techniques for full-custom design of droplet-based “digital” biochips do not scale well for concurrent assays and for next-generation system-on-chip (SOC) designs that are expected to include microfluidic components. We propose a system design methodology that attempts to apply classical high-level synthesis techniques to the design of digital microfluidic biochips. We focus here on the problem of scheduling bioassay functions under resource constraints. We first develop an optimal scheduling strategy based on integer linear programming. However, because the scheduling problem is NP-complete, we also develop two heuristic techniques that scale well for large problem instances. A clinical diagnostic procedure, namely multiplexed in-vitro diagnostics on human physiological fluids, is first used to illustrate and evaluate the proposed method. Next, the synthesis approach is applied to a protein assay, which serves as a more complex bioassay application. The proposed synthesis approach is expected to reduce human effort and design cycle time, and it will facilitate the integration of microfluidic components with microelectronic components in next-generation SOCs.
172 citations
TL;DR: A high-performance droplet router for a digital microfluidic biochip (DMFB) design that achieves over 35 x and 20 x better routability with comparable timing and fault tolerance than the popular prioritized A* search and the state-of-the-art network-flow-based algorithm, respectively.
Abstract: In this paper, we propose a high-performance droplet router for a digital microfluidic biochip (DMFB) design. Due to recent advancements in the biomicro electromechanical system and its various applications to clinical, environmental, and military operations, the design complexity and the scale of a DMFB are expected to explode in the near future, thus requiring strong support from CAD as in conventional VLSI design. Among the multiple design stages of a DMFB, droplet routing, which schedules the movement of each droplet in a time-multiplexed manner, is one of the most critical design challenges due to high complexity as well as large impacts on performance. Our algorithm first routes a droplet with higher by passibility which is less likely to block the movement of the others. When multiple droplets form a deadlock, our algorithm resolves it by backing off some droplets for concession. The final compaction step further enhances timing as well as fault tolerance by tuning each droplet movement greedily. The experimental results on hard benchmarks show that our algorithm achieves over 35 x and 20 x better routability with comparable timing and fault tolerance than the popular prioritized A* search and the state-of-the-art network-flow-based algorithm, respectively.
141 citations
Cites background from "Droplet Routing in the Synthesis of..."
...Although multiple technologies to control droplets, such as chemical [13], [14] or thermal [15] methods, have been proposed, electrical methods such as dielectrophoresis (DEP) [16] and electrowetting-on-dielectric (EWOD) [8], [17] have received more attention due to their high accuracy....
[...]
...The first generation of biochips is based on a continuousflow system where liquid flows through microfabricated channels continuously using electrokinetic-based microactuators....
[...]
TL;DR: A dilution/mixing algorithm is presented that significantly reduces the production of waste droplets and also the total number of input droplets compared to earlier methods and always yields nonnegative savings in the number of waste Droplets.
Abstract: The recent emergence of lab-on-a-chip (LoC) technology has led to a paradigm shift in many healthcare-related application areas, e.g., point-of-care clinical diagnostics, high-throughput sequencing, and proteomics. A promising category of LoCs is digital microfluidic (DMF)-based biochips, in which nanoliter-volume fluid droplets are manipulated on a 2-D electrode array. A key challenge in designing such chips and mapping lab-bench protocols to a LoC is to carry out the dilution process of biochemical samples efficiently. As an optimization and automation technique, we present a dilution/mixing algorithm that significantly reduces the production of waste droplets. This algorithm takes O(n) time to compute at most n sequential mix/split operations required to achieve any given target concentration with an error in concentration factor less than [1/(2n)]. To implement the algorithm, we design an architectural layout of a DMF-based LoC consisting of two O(n)-size rotary mixers and O(n) storage electrodes. Simulation results show that the proposed technique always yields nonnegative savings in the number of waste droplets and also in the total number of input droplets compared to earlier methods.
127 citations
Cites background from "Droplet Routing in the Synthesis of..."
...Descriptions of a DMF biochip and the four fundamental fluidic operations (dispensing, transporting, mixing, and splitting) have been elaborated elsewhere [1], [40], [41]....
[...]
22 Oct 2006
TL;DR: A partitioning algorithm based on the concept of "droplet trace", which is extracted from the scheduling and droplet routing results produced by a synthesis tool, is proposed and an efficient pin assignment method, referred to as the "Connect-5 algorithm", is combined with the array partitioning technique based on droplet traces.
Abstract: Microfluidics-based biochips combine electronics with biology to open new application areas such as point-of-care medical diagnostics, on-chip DNA analysis, and automated drug discovery. Bioassays are mapped to microfluidic arrays using synthesis tools, and they are executed through the manipulation of sample and reagent droplets by electrical means. Most prior work on CAD for biochips has assumed independent control of electrodes using a large number of (electrical) input pins. Such solutions are not feasible for low-cost disposable biochips that are envisaged for many field applications. A more promising design strategy is to divide the microfluidic array into smaller partitions and use a small number of electrodes to control the electrodes in each partition. We propose a partitioning algorithm based on the concept of "droplet trace", which is extracted from the scheduling and droplet routing results produced by a synthesis tool. An efficient pin assignment method, referred to as the "Connect-5 algorithm", is combined with the array partitioning technique based on droplet traces. The array partitioning and pin assignment methods are evaluated using a set of multiplexed bioassays.
127 citations
Cites background from "Droplet Routing in the Synthesis of..."
...The time spans for all the partitions can be easily calculated from the operation schedule, module placement and droplet routing results [19]; the overlaps can then be readily determined....
[...]
...The guard rings are a consequence of the fluidic constraint described in [19]....
[...]
References
More filters
TL;DR: It was found that the system of phenol and 4-amino phenazone is well suited to the determination of glucose and the development of phosphatase is described.
Abstract: the oxygen acceptors originally used were 0 tolidine, benzidine and o-dianisidine. It has since been established that these three substances are carcinogens and many alternative oxygen acceptors have been suggested. Any dye showing oxidation-reduction properties or any dye formed by oxidation, such as those used in colour photography, are potentially useful but it is obviously advantageous to use reagents which have high stability. For manual work on blood a two-solution technique is desirable, one solution being used to precipitate the protein and the other to develop the colour. The development of such a method will now be described. In the determination of phosphatase, use is made of the fact that phenol in the presence of an oxidising reagent gives a purple colour with 4-amino phenazone. The possibility that the H.Oz released in the reaction of glucose oxidase with glucose could act as the oxidising agent was investigated and it was found that the system of phenol and 4-amino phenazone is well suited to the determination of glucose. By suitable adjustment of conditions the colour develops completely in 10 minutes, being stable thereafter for at least 30 minutes. Using a single-solution phosphotungstic acid precipitant containing phenol to precipitate blood protein the only other solution required is one containing glucose oxidase, peroxidase and 4-amino phenazone. These solutions contain azide as preservative; azide has no effect on the rate of colour development. In the micro and macro automated methods, the two solutions required are a diluent containing 4-amino phenazone and a colour reagent containing glucose oxidase, peroxidase and phenol.
4,548 citations
"Droplet Routing in the Synthesis of..." refers methods in this paper
...The assay protocol, based on Trinder’s reaction [18], can be modeled by a sequencing graph, as shown in Figure 5....
[...]
TL;DR: This work presents an alternative paradigm--a fully integrated and reconfigurable droplet-based "digital" microfluidic lab-on-a-chip for clinical diagnostics on human physiological fluids, and demonstrates reliable and repeatable high-speed transport of microdroplets.
Abstract: Clinical diagnostics is one of the most promising applications for microfluidic lab-on-a-chip systems, especially in a point-of-care setting. Conventional microfluidic devices are usually based on continuous-flow in microchannels, and offer little flexibility in terms of reconfigurability and scalability. Handling of real physiological samples has also been a major challenge in these devices. We present an alternative paradigm—a fully integrated and reconfigurable droplet-based “digital” microfluidic lab-on-a-chip for clinical diagnostics on human physiological fluids. The microdroplets, which act as solution-phase reaction chambers, are manipulated using the electrowetting effect. Reliable and repeatable high-speed transport of microdroplets of human whole blood, serum, plasma, urine, saliva, sweat and tear, is demonstrated to establish the basic compatibility of these physiological fluids with the electrowetting platform. We further performed a colorimetric enzymatic glucose assay on serum, plasma, urine, and saliva, to show the feasibility of performing bioassays on real samples in our system. The concentrations obtained compare well with those obtained using a reference method, except for urine, where there is a significant difference due to interference by uric acid. A lab-on-a-chip architecture, integrating previously developed digital microfluidic components, is proposed for integrated and automated analysis of multiple analytes on a monolithic device. The lab-on-a-chip integrates sample injection, on-chip reservoirs, droplet formation structures, fluidic pathways, mixing areas and optical detection sites, on the same substrate. The pipelined operation of two glucose assays is shown on a prototype digital microfluidic lab-on-chip, as a proof-of-concept.
1,124 citations
"Droplet Routing in the Synthesis of..." refers background or methods in this paper
...To allow droplet mixing simultaneously during their transport, which is preferable for efficient assay operations [2], we need to model such fluidic routes using 3pin nets, instead of two individual 2-pin nets....
[...]
...These sensor systems rely on miniaturized devices that can manipulate fluids at nanoliter and microliter scales; such devices are referred to interchangeably in the literature as microfluidic biochips, lab-on-a-chip, and bioMEMS [1, 2]....
[...]
...By varying the electrical potential along a linear array of electrodes, droplets can be moved along this line of electrodes due to the principle of electrowetting [2, 3]....
[...]
...Following the analogy of digital electronics, this technology is referred to as digital microfluidics [2]....
[...]
Book•
31 Jan 1993
TL;DR: This book is a core reference for graduate students and CAD professionals and presents a balance of theory and practice in a intuitive manner.
Abstract: From the Publisher:
This work covers all aspects of physical design. The book is a core reference for graduate students and CAD professionals. For students, concept and algorithms are presented in an intuitive manner. For CAD professionals, the material presents a balance of theory and practice. An extensive bibliography is provided which is useful for finding advanced material on a topic. At the end of each chapter, exercises are provided, which range in complexity from simple to research level.
927 citations
"Droplet Routing in the Synthesis of..." refers background in this paper
...Due to the analogy between digital microfluidics and digital electronics, many classical VLSI routing techniques can be leveraged for the droplet routing problem [7, 8, 9]....
[...]
15 Feb 1995
TL;DR: PathFinder as mentioned in this paper uses an iterative algorithm that converges to a solution in which all signals are routed while achieving close to the optimal performance allowed by the placement, which is achieved by forcing signals to negotiate for a resource and thereby determine which signal needs the resource most.
Abstract: Routing FPGAs is a challenging problem because of the relative scarcity of routing resources, both wires and connection points. This can lead either to slow implementations caused by long wiring paths that avoid congestion or a failure to route all signals. This paper presents PathFinder, a router that balances the goals of performance and routability. PathFinder uses an iterative algorithm that converges to a solution in which all signals are routed while achieving close to the optimal performance allowed by the placement. Routability is achieved by forcing signals to negotiate for a resource and thereby determine which signal needs the resource most. Delay is minimized by allowing the more critical signals a greater say in this negotiation. Because PathFinder requires only a directed graph to describe the architecture of routing resources, it adapts readily to a wide variety of FPGA architectures such as Triptych, Xilinx 3000 and mesh-connected arrays of FPGAs. The results of routing ISCAS benchmarks on the Triptych FPGA architecture show an average increase of only 4.5% in critical path delay over the optimum delay for a placement. Routes of ISCAS benchmarks on the Xilinx 3000 architecture show a greater completion rate than commercial tools, as well as 11% faster implementations.
706 citations
TL;DR: This paper studies the effects of varying droplet aspect ratios on linear-array droplet mixers, and proposes mixing strategies applicable for both high and low aspect ratio systems, and presents a split-and-merge mixer that takes advantage of the ability to perform droplet splitting at these ratios.
Abstract: The mixing of analytes and reagents for a biological or chemical lab-on-a-chip is an important, yet difficult, microfluidic operation. As volumes approach the sub-nanoliter regime, the mixing of liquids is hindered by laminar flow conditions. An electrowetting-based linear-array droplet mixer has previously been reported. However, fixed geometric parameters and the presence of flow reversibility have prevented even faster droplet mixing times. In this paper, we study the effects of varying droplet aspect ratios (height ∶ diameter) on linear-array droplet mixers, and propose mixing strategies applicable for both high and low aspect ratio systems. An optimal aspect ratio for four electrode linear-array mixing was found to be 0.4, with a mixing time of 4.6 seconds. Mixing times were further reduced at this ratio to less than three seconds using a two-dimensional array mixer, which eliminates the effects of flow reversibility. For lower aspect ratio (≤0.2) systems, we present a split-and-merge mixer that takes advantage of the ability to perform droplet splitting at these ratios, resulting in a mixing time of less than two seconds.
491 citations
"Droplet Routing in the Synthesis of..." refers background in this paper
...example, it has been reported that mixing in a 2×4-array mixer takes about 10 seconds, whereas it takes only 10 ms for a droplet to move across one cell during its route (with 100Hz clock frequency) [17]....
[...]