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Proceedings ArticleDOI

Automated design of pin-constrained digital microfluidic arrays for lab-on-a-chip applications*

24 Jul 2006-pp 925-930
TL;DR: A design automation method for pin-constrained LoCs that manipulate nanoliter volumes of discrete droplets on a microfluidic array by assigning a small number of independent control pins to a large number of electrodes in the LoC, thereby reducing design complexity and product cost.
Abstract: Microfluidics-based biochips, also referred to as lab-on-a-chip (LoC), are devices that integrate fluid-handling functions such as sample preparation, analysis, separation, and detection. This emerging technology combines electronics with biology to open new application areas such as point-of-care diagnosis, on-chip DNA analysis, and automated drug discovery. We propose a design automation method for pin-constrained LoCs that manipulate nanoliter volumes of discrete droplets on a microfluidic array. In contrast to the direct-addressing scheme that has been studied thus far in the literature, we assign a small number of independent control pins to a large number of electrodes in the LoC, thereby reducing design complexity and product cost. We apply the proposed method to a microfluidic array for a set of multiplexed bioassays.

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Citations
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Proceedings ArticleDOI
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 or methods from "Automated design of pin-constrained..."

  • ...However, the design method presented in [17] suffers from several drawbacks....

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  • ...More recently, a promising design method based on array partitioning has been proposed for pin-constrained biochips [17]....

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  • ...However, both array partitioning and the assignment of control pins to electrodes in [17] are done in an ad-hoc manner....

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  • ...Recent experimental studies have shown that five independent pins are adequate to route a droplet to any place on the chip for single droplet manipulation [17]....

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  • ...The above partitioning solution was proposed recently in [17]....

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Proceedings ArticleDOI
04 Jun 2007
TL;DR: The proposed approach allows architectural-level design choices and droplet-routing-aware physical design decisions to be made simultaneously and uses a large-scale protein assay as a case study to evaluate the proposed synthesis method.
Abstract: Microfluidic biochips are revolutionizing many areas of biochemistry and biomedical sciences Several synthesis tools have recently been proposed for the automated design of biochips from the specifications of laboratory protocols However, only a few of these tools address the problem of droplet routing in microfluidic arrays These methods typically rely on post-synthesis droplet routing to implement biochemical protocols Such an approach is not only time-consuming, but it also imposes an undue burden on the chip user Moreover, post-synthesis droplet routing does not guarantee that feasible droplet pathways can be found for area-constrained biochip layouts; non-routable fabricated biochips must be discarded We present a droplet-routing-aware automated synthesis tool for microfluidic biochips Droplet routability, defined as the ease with which droplet pathways can be determined, is estimated and integrated in the synthesis flow The proposed approach allows architectural-level design choices and droplet-routing-aware physical design decisions to be made simultaneously We use a large-scale protein assay as a case study to evaluate the proposed synthesis method

121 citations


Cites background or methods from "Automated design of pin-constrained..."

  • ...These design automation methods address operation scheduling and module placement for digital microfluidics [11, 12, 13, 14, 15, 16], as well the design and optimization of routing channels in continuous-flow microfluidics [17]....

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  • ...Recent years have seen growing interest in the automated design and synthesis of microfluidic biochips [11,12,13,14,15,16,17]....

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Proceedings ArticleDOI
16 Apr 2007
TL;DR: A droplet manipulation method based on a "cross-referencing" addressing method that uses "row" and "columns" to access electrodes that allows simultaneous movement of a large number of droplets on a microfluidic array is proposed.
Abstract: Digital microfluidic biochips are revolutionizing high-throughput DNA sequencing, immunoassays, and clinical diagnostics. As high-throughput bioassays are mapped to digital microfluidic platforms, the need for design automation techniques for pin-constrained biochips is being increasingly felt. However, most prior work on biochips CAD has assumed independent control of the underlying electrodes using a large number of (electrical) input pins. The authors propose a droplet manipulation method based on a "cross-referencing" addressing method that uses "row" and "columns" to access electrodes. By mapping the droplet movement problem to the clique partitioning problem from graph theory, the proposed method allows simultaneous movement of a large number of droplets on a microfluidic array. This in turn facilitates high-throughput applications on a pin-constrained biochip. The authors use random synthetic benchmarks and a set of multiplexed bioassays to evaluate the proposed method

86 citations


Cites background or methods from "Automated design of pin-constrained..."

  • ...The method presented in [9] uses array partitioning and careful pin assignment to reduce the number of control pins....

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  • ...Pin-constrained design of digital microfluidic biochips was recently proposed in [9]....

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Journal ArticleDOI
TL;DR: Based on the pin-constrained chip design, an efficient shuttle-passenger-like droplet manipulation method and test procedure is presented to achieve high-throughput and defect-tolerant well loading.
Abstract: Protein crystallization is a commonly used technique for protein analysis and subsequent drug design. It predicts the 3-D arrangement of the constituent amino acids, which in turn indicates the specific biological function of a protein. Protein crystallization experiments are typically carried out in well-plates in the laboratory. As a result, these experiments are slow, expensive, and error-prone due to the need for repeated human intervention. Recently, droplet-based ?digital? microfluidics have been used for executing protein assays on a chip. Protein samples in the form of nanoliter-volume droplets are manipulated using the principle of electrowetting-on-dielectric. We present the design of a multi-well-plate microfluidic biochip for protein crystallization; this biochip can transfer protein samples, prepare candidate solutions, and carry out crystallization automatically. To reduce the manufacturing cost of such devices, we present an efficient algorithm to generate a pin-assignment plan for the proposed design. The resulting biochip enables control of a large number of on-chip electrodes using only a small number of pins. Based on the pin-constrained chip design, we present an efficient shuttle-passenger-like droplet manipulation method and test procedure to achieve high-throughput and defect-tolerant well loading.

71 citations


Cites background from "Automated design of pin-constrained..."

  • ...Recent experimental studies have shown that five independent pins are adequate to route a droplet to any place on the chip for 1x volume manipulation [ 29 ]....

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Patent
16 Oct 2008
TL;DR: In this article, a method of defining partitions for pin layouts in a droplet actuator for a specific assay, including: defining droplet traces for the assay; and defining a guard ring along the traces.
Abstract: A droplet actuator with arrays of electrodes electrically coupled to a number of controllable voltage sources that is less than the number of electrodes. A method of defining partitions for pin layouts in a droplet actuator for a specific assay, the method including: defining droplet traces for the assay; and defining a guard ring along the traces. Other methods, systems, droplet actuators, and algorithms are also provided.

70 citations

References
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Journal ArticleDOI
TL;DR: In this article, a microactuator for rapid manipulation of discrete microdroplets is presented, which is accomplished by direct electrical control of the surface tension through two sets of opposing planar electrodes fabricated on glass.
Abstract: A microactuator for rapid manipulation of discrete microdroplets is presented. Microactuation is accomplished by direct electrical control of the surface tension through two sets of opposing planar electrodes fabricated on glass. A prototype device consisting of a linear array of seven electrodes at 1.5 mm pitch was fabricated and tested. Droplets (0.7–1.0 μl) of 100 mM KCl solution were successfully transferred between adjacent electrodes at voltages of 40–80 V. Repeatable transport of droplets at electrode switching rates of up to 20 Hz and average velocities of 30 mm/s have been demonstrated. This speed represents a nearly 100-fold increase over previously demonstrated electrical methods for the transport of droplets on solid surfaces.

1,471 citations


"Automated design of pin-constrained..." refers background in this paper

  • ...Droplet-based systems also offer reconfigurability and a scalable system architecture based on a two-dimensional array [6,7]....

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Book
30 Dec 1998
TL;DR: In this article, the authors present a model for drawing graphs and digraphs based on the topology of low dimensions Higher-Order Surfaces and a model of a graph.
Abstract: INTRODUCTION TO GRAPH MODELS Graphs and Digraphs Common Families of Graphs Graph Modeling Applications Walks and Distance Paths, Cycles, and Trees Vertex and Edge Attributes: More Applications STRUCTURE AND REPRESENTATION Graph Isomorphism Revised! Automorphisms and Symmetry Moved and revised! Subgraphs Some Graph Operations Tests for Non-Isomorphism Matrix Representation More Graph Operations TREES Reorganized and revised! Characterizations and Properties of Trees Rooted Trees, Ordered Trees, and Binary Trees Binary-Tree Traversals Binary-Search Trees Huffman Trees and Optimal Prefix Codes Priority Trees Counting Labeled Trees: Prufer Encoding Counting Binary Trees: Catalan Recursion SPANNING TREES Reorganized and revised! Tree-Growing Depth-First and Breadth-First Search Minimum Spanning Trees and Shortest Paths Applications of Depth-First Search Cycles, Edge Cuts, and Spanning Trees Graphs and Vector Spaces Matroids and the Greedy Algorithm CONNECTIVITY Revised! Vertex- and Edge-Connectivity Constructing Reliable Networks Max-Min Duality and Menger's Theorems Block Decompositions OPTIMAL GRAPH TRAVERSALS Eulerian Trails and Tours DeBruijn Sequences and Postman Problems Hamiltonian Paths and Cycles Gray Codes and Traveling Salesman Problems PLANARITY AND KURATOWSKI'S THEOREM Reorganized and revised! Planar Drawings and Some Basic Surfaces Subdivision and Homeomorphism Extending Planar Drawings Kuratowski's Theorem Algebraic Tests for Planarity Planarity Algorithm Crossing Numbers and Thickness DRAWING GRAPHS AND MAPS Reorganized and revised! The Topology of Low Dimensions Higher-Order Surfaces Mathematical Model for Drawing Graphs Regular Maps on a Sphere Imbeddings on Higher-Order Surfaces Geometric Drawings of Graphs New! GRAPH COLORINGS Vertex-Colorings Map-Colorings Edge-Colorings Factorization New! MEASUREMENT AND MAPPINGS New Chapter! Distance in Graphs New! Domination in Graphs New! Bandwidth New! Intersection Graphs New! Linear Graph Mappings Moved and revised! Modeling Network Emulation Moved and revised! ANALYTIC GRAPH THEORY New Chapter! Ramsey Graph Theory New! Extremal Graph Theory New! Random Graphs New! SPECIAL DIGRAPH MODELS Reorganized and revised! Directed Paths and Mutual Reachability Digraphs as Models for Relations Tournaments Project Scheduling and Critical Paths Finding the Strong Components of a Digraph NETWORK FLOWS AND APPLICATIONS Flows and Cuts in Networks Solving the Maximum-Flow Problem Flows and Connectivity Matchings, Transversals, and Vertex Covers GRAPHICAL ENUMERATION Reorganized and revised! Automorphisms of Simple Graphs Graph Colorings and Symmetry Burnside's Lemma Cycle-Index Polynomial of a Permutation Group More Counting, Including Simple Graphs Polya-Burnside Enumeration ALGEBRAIC SPECIFICATION OF GRAPHS Cyclic Voltages Cayley Graphs and Regular Voltages Permutation Voltages Symmetric Graphs and Parallel Architectures Interconnection-Network Performance NON-PLANAR LAYOUTS Reorganized and revised! Representing Imbeddings by Rotations Genus Distribution of a Graph Voltage-Graph Specification of Graph Layouts Non KVL Imbedded Voltage Graphs Heawood Map-Coloring Problem APPENDIX Logic Fundamentals Relations and Functions Some Basic Combinatorics Algebraic Structures Algorithmic Complexity Supplementary Reading BIBLIOGRAPHY General Reading References SOLUTIONS AND HINTS New! INDEXES Index of Applications Index of Algorithms Index of Notations General Index

1,407 citations


"Automated design of pin-constrained..." refers background in this paper

  • ...Given a two-dimensional microfluidic chip, the problem of determining the minimum number of independent control pins, k, necessary to have full control of a single droplet can be reduced to the well-known graph-coloring problem [18]....

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Journal ArticleDOI
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


"Automated design of pin-constrained..." refers background or methods in this paper

  • ...To show how the proposed virtual partitioning method can be used for pin-constrained microfluidic biochips, we apply it to a multiplexed biochemical assay consisting of a glucose assay and a lactate assay based on colorimetric enzymatic reactions, which have been demonstrated recently [3]....

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  • ...A problem related to pin-constrained design of digital microfluidic biochips has been analyzed in [3]....

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  • ..., point-of-care diagnosis, on-chip DNA analysis, and drug screening [2,3]....

    [...]

  • ...Microfluidic biochips, or lab-on-achip, are devices that integrate various fluid-handling functions, such as sample preparation, analysis, separation, and detection [1,2,3]....

    [...]

Journal ArticleDOI
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


"Automated design of pin-constrained..." refers background in this paper

  • ...For example, mixing can be performed by routing two droplets to the same location and then turning them about some pivot points [14]....

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Journal ArticleDOI
25 Jun 2003
TL;DR: Developments that have emerged from the increasing interaction between the MEMS and microfluidics worlds, including how to integrate electrical or electrochemical function into chips for purposes as diverse as heating, temperature sensing, electrochemical detection, and pumping are explored.
Abstract: The use of planar fluidic devices for performing small-volume chemistry was first proposed by analytical chemists, who coined the term "miniaturized total chemical analysis systems" (/spl mu/TAS) for this concept. More recently, the /spl mu/TAS field has begun to encompass other areas of chemistry and biology. To reflect this expanded scope, the broader terms "microfluidics" and "lab-on-a-chip" are now often used in addition to /spl mu/TAS. Most microfluidics researchers rely on micromachining technologies at least to some extent to produce microflow systems based on interconnected micrometer-dimensioned channels. As members of the microelectromechanical systems (MEMS) community know, however, one can do more with these techniques. It is possible to impart higher levels of functionality by making features in different materials and at different levels within a microfluidic device. Increasingly, researchers have considered how to integrate electrical or electrochemical function into chips for purposes as diverse as heating, temperature sensing, electrochemical detection, and pumping. MEMS processes applied to new materials have also resulted in new approaches for fabrication of microchannels. This review paper explores these and other developments that have emerged from the increasing interaction between the MEMS and microfluidics worlds.

491 citations


"Automated design of pin-constrained..." refers background in this paper

  • ...Currently, most commercially-available microfluidic devices rely on continuous-flow in etched microchannels [1,4,5]....

    [...]

  • ...Microfluidic biochips, or lab-on-achip, are devices that integrate various fluid-handling functions, such as sample preparation, analysis, separation, and detection [1,2,3]....

    [...]