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

152 Pages·2019·6.61 MB·English

by  Zipeng Li

Zipeng Li · Krishnendu Chakrabarty 
Tsung-Yi Ho · Chen-Yi Lee
Micro-Electrode-
Dot-Array Digital
Microfl uidic
Biochips
Design Automation, Optimization, and
Test Techniques
Micro-Electrode-Dot-Array Digital Microfluidic
Biochips
Zipeng Li • Krishnendu Chakrabarty
Tsung-Yi Ho • Chen-Yi Lee
Micro-Electrode-Dot-Array
Digital Microfluidic Biochips
Design Automation, Optimization, and Test
Techniques
123
ZipengLi KrishnenduChakrabarty
Intel(UnitedStates) DepartmentofECE
SantaClara,CA,USA DukeUniversity
Durham,NC,USA
Tsung-YiHo
NationalTsingHuaUniversity Chen-YiLee
Hsinchu,Taiwan NationalChiaoTungUniversity
Hsinchu,Taiwan
ISBN978-3-030-02963-0 ISBN978-3-030-02964-7 (eBook)
https://doi.org/10.1007/978-3-030-02964-7
LibraryofCongressControlNumber:2018962868
©SpringerNatureSwitzerlandAG2019
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Tomybelovedwife,
MengjieWei.
—ZipengLi
Preface
Digital microfluidic biochips (DMFBs) are revolutionizing many biochemical
analysis procedures, e.g., high-throughput DNA sequencing and point-of-care
clinical diagnosis. However, today’s DMFBs suffer from several limitations: (1)
constraintsondropletsizeandtheinabilitytovarydropletvolumeinafine-grained
manner; (2) the lack of integrated sensors for real-time detection; (3) the need for
specialfabricationprocessesandtheassociatedreliability/yieldconcerns.
Toovercometheabovelimitations,DMFBsbasedonamicro-electrode-dot-array
(MEDA) architecture have recently been proposed. Unlike conventional digital
microfluidics, where electrodes of equal size are arranged in a regular pattern,
the MEDA architecture is based on the concept of a sea-of-micro-electrodes, i.e.,
thousands of microelectrodes can be integrated on a MEDA biochip. The MEDA
architecture allows microelectrodes to be dynamically grouped to form a micro-
componentthatcanperformdifferentmicrofluidicoperationsonthechip.
DesignautomationtoolscanreducethedifficultyofMEDAbiochipdesignand
help to ensure that the manufactured MEDA biochips are versatile and reliable.
However, the increase in integration level introduces new challenges in the design
optimization and testing of MEDA biochips, which impede their further adoption
anddeployment.Thisbookisfocusedonenhancingtheautomateddesignanduseof
MEDAbiochipsandondevelopingasetofsolutionstofacilitatethefullexploitation
of design complexities that are possible with current MEDA platform. In order to
fully exploit MEDA-specific advantages (e.g., real-time droplet sensing), four key
research challenges are addressed in this book; these include high-level synthesis,
errorrecovery,samplepreparationoptimization,andtesting.
The book first presents a droplet-size-aware synthesis approach that can con-
figure the target bioassay on a MEDA biochip. The proposed synthesis method
targetsreservoirplacement,operationscheduling,moduleplacement,androutingof
dropletsofvarioussizes.Thebookalsopresentsananalyticalmodelforestimating
droplet velocity, and the model was experimentally validated using fabricated
MEDA chips. In order to effectively exploit the advantages offered by MEDA,
MEDA-specificfluidicoperations,suchasdropletdiagonalmovementanddroplet
shapemorphing,havebeenconsideredintheproposedsynthesisapproach.
vii
viii Preface
Next,thisbookpresentsanefficienterror-recoverystrategytoensurethecorrect-
nessofassaysexecutedonMEDAbiochips.ByexploitingMEDA-specificadvances
in droplet sensing, the book presents the first probabilistic timed automata (PTA)-
basederror-recoverytechniquetodynamicallyreconfiguretheMEDAbiochipusing
real-time data provided by on-chip sensors. The book also presents an on-line
synthesis technique and a control flow to connect local recovery procedures with
globalerrorrecoveryforthecompletebioassay.
ApotentiallyimportantapplicationofMEDAbiochipsliesinsamplepreparation
via a series of dilution steps. Sample preparation in digital microfluidics refers
to the generation of droplets with target concentrations for on-chip biochemical
applications. The book presents the first droplet size-aware and error-correcting
samplepreparationmethodforMEDAbiochips.Incontrasttopreviousmethods,the
proposedapproachconsidersdropletsizesandincorporatesvariousmixingmodels
in sample preparation. Moreover, the proposed approach utilizes MEDA-enabled
microfluidicoperationsandfullyexploitsthefeatureofreal-timedropletsensingon
MEDAbiochipsforerrorcorrection.Theproposedmethodcansignificantlyreduce
thenumberofdilutionsteps,hencethetimeneededforsamplepreparation.
In order to ensure high confidence in the outcome of biochemical experiments,
MEDA biochips must be adequately tested before they can be used for bioassay
execution. Thebookpresentsefficientstructuralandfunctionaltesttechniques for
MEDA biochips. The proposed structural test techniques can effectively detect
defects and identify faulty microcells, and the proposed functional test techniques
addressfundamentalfluidicoperationsonMEDAbiochips.
Insummary,thebooktacklesimportantproblemsrelatedtokeystagesofMEDA
chipdesignandusage.Theresultsemergingfromthisdissertationprovidethefirst
set of comprehensive design automation and test solutions for MEDA biochips.
These methods are expected to not only shorten the product development cycle
but also accelerate the adoption and further development of MEDA biochips by
facilitatingthefullexploitationofdesigncomplexitiesthatarepossiblewithcurrent
fabricationtechniques.Itisanticipatedthatchipdesignersandchipuserswillalso
benefitfromthesemethods.
SantaClara,CA,USA ZipengLi
Durham,NC,USA KrishnenduChakrabarty
HsinchuCity,Taiwan Tsung-YiHo
HsinchuCity,Taiwan Chen-YiLee
Acknowledgments
TheauthorsacknowledgeProfessorMiroslavPajicfromDukeUniversity,Durham,
NC,USA,forvaluablediscussionsandcollaboration.Theauthorsalsoacknowledge
Dr. Kelven Yi-Tse Lai and Po-Hsien Yu from National Chiao Tung University,
Hsinchu,Taiwan,forconstructivesuggestions.
Zipeng Li and Krishnendu Chakrabarty acknowledge the financial support
receivedfromtheUSNationalScienceFoundation.
Tsung-YiHoandChen-YiLeeacknowledgethefinancialsupportreceivedfrom
theTaiwanMinistryofScienceandTechnology.
ix
Contents
1 Introduction .................................................................. 1
1.1 ChapterOverview....................................................... 1
1.2 OverviewofDigitalMicrofluidics ..................................... 2
1.2.1 PrincipleofEWODandFluidicOperations................... 3
1.2.2 ApplicationsofDigitalMicrofluidics.......................... 6
1.3 BackgroundofMEDABiochips ....................................... 9
1.3.1 MEDAArchitecture ............................................ 10
1.3.2 MajorFunctionsforEachMicroelectrodeCell ............... 10
1.3.3 NovelCharacteristicsforMEDA .............................. 13
1.4 DesignAutomationandTestTechniquesforMEDABiochips....... 14
1.4.1 CADFlowandTestTechniques ............................... 15
1.4.2 MotivationforMEDA-SpecificResearch ..................... 16
1.5 OutlineoftheBook..................................................... 17
References..................................................................... 17
2 DropletSize-AwareHigh-LevelSynthesis................................. 21
2.1 ChapterOverview....................................................... 21
2.2 MotivationandProblemFormulation.................................. 22
2.2.1 MotivationofHigh-LevelSynthesisforMEDA .............. 22
2.2.2 ProblemFormulation........................................... 24
2.3 DropletVelocityModel................................................. 25
2.3.1 ModelConstruction............................................. 25
2.3.2 ModelValidation................................................ 28
2.4 UnifiedHigh-LevelSynthesis.......................................... 29
2.4.1 ReservoirPlacement............................................ 30
2.4.2 DynamicPriorityAssignment.................................. 32
2.4.3 ModulePlacement.............................................. 33
2.4.4 DropletRouting................................................. 35
2.4.5 OperationScheduling........................................... 41
xi
xii Contents
2.5 SimulationandExperimentalResults.................................. 43
2.5.1 SimulationResults.............................................. 43
2.5.2 ExperimentalResults........................................... 46
2.6 Conclusion .............................................................. 50
References..................................................................... 50
3 EfficientandAdaptiveErrorRecovery.................................... 53
3.1 ChapterOverview....................................................... 53
3.2 PriorWorksandMotivation............................................ 54
3.3 ErrorRecoveryforLocalErrors........................................ 55
3.3.1 TargetErrorsinMEDA......................................... 55
3.3.2 OutcomeClassificationofFluidicOperations................. 56
3.3.3 ExperimentallyCharacterizedOutcomeProbability.......... 58
3.3.4 LocalRecoveryApproaches ................................... 60
3.4 Time-LimitSelectionforLocalRecovery............................. 65
3.4.1 ILPFormulation ................................................ 65
3.4.2 RandomizedRounding ......................................... 68
3.5 ErrorRecoveryfortheCompleteBioassay............................ 68
3.5.1 ControlFlow.................................................... 69
3.5.2 On-LineSynthesis.............................................. 70
3.6 ExperimentalResults ................................................... 73
3.6.1 ResultsforLocalFaults ........................................ 73
3.6.2 ResultsforBioassays........................................... 75
3.6.3 ResultsforTLLRSelection.................................... 77
3.7 Conclusion .............................................................. 79
References..................................................................... 79
4 FaultModeling,StructuralTesting,andFunctionalTesting............ 83
4.1 ChapterOverview....................................................... 83
4.2 DefectsandFaultModeling............................................ 84
4.3 PriorWorks.............................................................. 86
4.4 StructuralTestforMEDABiochips.................................... 86
4.4.1 OverviewofTestMethod ...................................... 87
4.4.2 Scan-ChainTestStrategy....................................... 88
4.4.3 MCTestStrategy ............................................... 89
4.5 FunctionalTestforMEDABiochips................................... 94
4.5.1 DispensingTest................................................. 95
4.5.2 RoutingTest..................................................... 97
4.5.3 MixingandSplittingTest ...................................... 98
4.6 ExperimentalResults ................................................... 103
4.6.1 ResultsforStructuralTest...................................... 103
4.6.2 ResultsforFunctionalTest..................................... 107
4.7 Conclusion .............................................................. 110
References..................................................................... 110