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Proceedings ArticleDOI

A cross-referencing-based droplet manipulation method for high-throughput and pin-constrained digital microfluidic arrays

16 Apr 2007-pp 552-557
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

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Citations
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Proceedings ArticleDOI
08 Jun 2008
TL;DR: A broadcast-addressing-based design technique for pin-constrained multi-functional biochips that provides high throughput for bioassays and it reduces the number of control pins by identifying and connecting control pins with "compatible" actuation sequences.
Abstract: Recent advances in digital microfluidics have enabled lab-on-a-chip devices for DNA sequencing, immunoassays, clinical chemistry, and protein crystallization. Basic operations such as droplet dispensing, mixing, dilution, localized heating, and incubation can be carried out using a two-dimensional array of electrodes and nanoliter volumes of liquid. The number of independent input pins used to control the electrodes in such microfluidic "biochips" is an important cost-driver, especially for disposable PCB devices that are being developed for clinical and point-of-care diagnostics. However, most prior work on biochip design-automation has assumed independent control of the electrodes using a large number of input pins. Another limitation of prior work is that the mapping of control pins to electrodes is only applicable for a specific bioassay. We present a broadcast-addressing-based design technique for pin-constrained multi-functional biochips. The proposed method provides high throughput for bioassays and it reduces the number of control pins by identifying and connecting control pins with "compatible" actuation sequences. The proposed method is evaluated using a multifunctional chip designed to execute a set of multiplexed bioassays, the polymerase chain reaction, and a protein dilution assay.

137 citations

Patent
15 Feb 2008
TL;DR: In this article, a method, circuit and apparatus for detecting capacitance on a droplet actuator, inter alia, for determining the presence, partial presence or absence of an active droplet at an electrode on the actuator is presented.
Abstract: A method, circuit and apparatus for detecting capacitance on a droplet actuator, inter alia, for determining the presence, partial presence or absence of a droplet at an electrode on a droplet actuator by: (a) providing a droplet actuator comprising: (i) a substrate comprising electrodes arranged on the substrate for conducting droplet operations on a surface of the substrate; (ii) a capacitance detection circuit for detecting capacitance at the droplet operations surface at one or more of the electrodes; (b) detecting capacitance at the droplet operations surface at one or more of the electrodes; and (c) determining from the capacitance the presence, partial presence or absence of a droplet at the droplet operations surface at the electrode.

117 citations

Patent
11 Feb 2008
TL;DR: In this article, a method of providing a droplet in contact with a magnetically responsive bead and having a reduced quantity of a substance was proposed, where the beads are magnetically immobilized at a location which is at a distance from a target droplet splitting zone.
Abstract: A method of providing a droplet in contact with a magnetically responsive bead and having a reduced quantity of a substance. The method generally includes the steps of (a) providing a droplet actuator (200) comprising: (i) a substrate (210) comprising electrodes (214) arranged for conducting droplet operations on a surface; (ii) a starting droplet (218/222) comprising: (1) one or more magnetically responsive beads (220); (2) a starting quantity of the substance; and (3) a starting volume; (b) magnetically immobilizing the one or more magnetically responsive beads at a location which is at a distance from a target droplet splitting zone, (224); (c) conducting one or more droplet operations comprising droplet dividing operations selected to divide the combined droplet to yield a set of droplets comprising: (i) a droplet (218) comprising substantially all of the one or more magnetically responsive beads and having a decreased quantity of the substance relative to the starting concentration; and (ii) a droplet (222) substantially lacking the magnetically responsive beads.

102 citations

Patent
17 Dec 2010
TL;DR: In this article, a droplet actuator device and assay methods for multiplexed newborn testing for metabolic disorders are described, among other things, droplet-based enzymatic assays and immunoassays.
Abstract: The invention is directed to droplet actuator devices and assay methods for multiplexed newborn testing for metabolic disorders. The methods include, among other things, droplet-based enzymatic assays and immunoassays for testing for metabolic disorders. The invention includes methods and devices for conducting multiple assays for different metabolic disorders on a single droplet actuator, as well as multiple assays for the same metabolic disorder using samples from different subjects and/or multiple samples from the same subject on a single droplet actuator. In various embodiments, the invention includes methods for conducting enzymatic activity assays and/or immunoassays in a single fresh blood and/or plasma samples and dried blood and/or plasma samples.

89 citations

Patent
21 Sep 2011
TL;DR: A microfluidic device having a substrate with an electrically conductive element made using a conductive ink layer underlying a hydrophobic layer was described in this paper. But the authors did not specify the type of substrate.
Abstract: A microfluidic device having a substrate with an electrically conductive element made using a conductive ink layer underlying a hydrophobic layer.

89 citations

References
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Book
01 Jan 1979
TL;DR: The second edition of a quarterly column as discussed by the authors provides a continuing update to the list of problems (NP-complete and harder) presented by M. R. Garey and myself in our book "Computers and Intractability: A Guide to the Theory of NP-Completeness,” W. H. Freeman & Co., San Francisco, 1979.
Abstract: This is the second edition of a quarterly column the purpose of which is to provide a continuing update to the list of problems (NP-complete and harder) presented by M. R. Garey and myself in our book ‘‘Computers and Intractability: A Guide to the Theory of NP-Completeness,’’ W. H. Freeman & Co., San Francisco, 1979 (hereinafter referred to as ‘‘[G&J]’’; previous columns will be referred to by their dates). A background equivalent to that provided by [G&J] is assumed. Readers having results they would like mentioned (NP-hardness, PSPACE-hardness, polynomial-time-solvability, etc.), or open problems they would like publicized, should send them to David S. Johnson, Room 2C355, Bell Laboratories, Murray Hill, NJ 07974, including details, or at least sketches, of any new proofs (full papers are preferred). In the case of unpublished results, please state explicitly that you would like the results mentioned in the column. Comments and corrections are also welcome. For more details on the nature of the column and the form of desired submissions, see the December 1981 issue of this journal.

40,020 citations

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


"A cross-referencing-based droplet m..." refers background in this paper

  • ..., any two nodes in this subgraph are connected by an edge [24]....

    [...]

  • ...The problem of finding the minimum number of groups can be directly mapped to the clique partitioning problem from graph theory [24]....

    [...]

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


"A cross-referencing-based droplet m..." refers background or methods in this paper

  • ...In [7], the multiplex bioassays were mapped to a digital microfluidic platform containing a 15×15 array, as shown in Fig....

    [...]

  • ...As more bioassays are concurrently executed on digital microfluidic platforms [7,8], system complexity and the number of electrodes is expected to...

    [...]

  • ...Demonstrated applications of digital microfluidics include the on-chip detection of explosives such as commercial-grade 2,4,6-trinitrotoluene (TNT) and pure 2,4-dinitrotoluene [6], automated on-chip measurement of airborne particulate matter [15, 16], and colorimetric assays [7]....

    [...]

  • ...In another method proposed in [7], the number of control pins for a fabricated electrowetting-based biochip is minimized by using a multi-phase bus for the fluidic pathways....

    [...]

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


"A cross-referencing-based droplet m..." 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]....

    [...]