Error-Tolerant Biochemical Sample Preparation with Microfluidic Lab-on-Chip Microfluidic biochips have gained prominence due to their versatile applications to bio- chemistry and health-care domains such as point-of-care clinical diagnosis of tropical and cardiovascular diseases, cancer, diabetes, toxicity analysis, and for the mitigation of the global HIV crisis, among others. Microfluidic Lab-on-Chips (LoCs) offer a convenient platform for emulating various fluidic operations in an automated fashion. However, be- cause of the inherent uncertainty of fluidic operations, the outcome of biochemical experi- ments performed on-chip can be erroneous even if the chip is tested a priori and deemed to be defect-free. Error-Tolerant Biochemical Sample Preparation with Microfluidic Lab- on-Chip focuses on the issues encountered in reliable sample preparation with digital microfluidic biochips (DMFBs), particularly in an error-prone environment. It presents state-of-the-art error management techniques and underlying algorithmic challenges along with their comparative discussions. • Describes a comprehensive framework for designing a robust and error-tolerant bio- medical system which will help in migrating from cumbersome medical laboratory tasks to small-sized LoC-based systems • Presents a comparative study on current error-tolerant strategies for robust sample preparation using DMFBs and reports on efficient algorithms for error-tolerant sam- ple dilution using these devices • Illustrates how algorithmic engineering, cyber-physical tools, and software techniques are helpful in implementing fault-tolerance • Covers the challenges associated with design automation for biochemical sample preparation • Teaches how to implement biochemical protocols using software-controlled micro- fluidic biochips Interdisciplinary in its coverage, this reference is written for practitioners and researchers in biochemical, biomedical, electrical, computer, and mechanical engineering, especially those involved in LoC or bio-MEMS design. 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Dedication Toourparents,teachers,andstudents Tay&lF orra ncis Tay&lFo rra nGcriosu p http://taylorandfrancis.com Contents Foreword...................................................................................................................xi Acknowledgments...................................................................................................xiii Biographies..............................................................................................................xv SECTION I Introduction and Background Chapter1 Introduction.....................................................................................3 1.1 BasicsofMicrofluidicLab-on-Chips.....................................4 1.1.1 DigitalMicrofluidicLab-on-chips.............................5 1.1.2 Biochips based on Micro-Electrode Dot-Array (MEDA)architecture.................................................6 1.2 Basicsofsamplepreparationandvolumetricsplit-errors......9 1.3 Scopeofthebook.................................................................12 1.4 Organizationofthebook......................................................13 Chapter2 Background....................................................................................15 2.1 Preliminaries.........................................................................15 2.1.1 Mixingmodels.........................................................15 2.1.2 ConcentrationandDilutionfactors..........................16 2.1.3 AutomateddilutionofaSampleFluid.....................16 2.1.3.1 Linearandserialdilution.........................17 2.1.3.2 Exponentialandinterpolateddilution.....18 2.2 Prior-workonsamplepreparation........................................18 2.3 Effectofvolumetricsplit-errorsontargetconcentration......21 2.4 Error-correctionduringmulti-targetsamplepreparation......22 2.5 Conclusion............................................................................23 SECTION II Literature Review Chapter3 ErrorRecoveryMethodsforBiochips...........................................27 3.1 Designobjectivesforerror-recovery....................................27 3.2 ErrorRecoverywithregularDMFBs....................................29 3.2.1 Integratedcontrol-pathdesignanderrorrecovery...29 vii viii Contents 3.2.2 Synthesis of Protocols on DMFBs with opera- tionalvariability.......................................................30 3.2.3 Errorrecoveryincyber-physicalDMFBs................31 3.2.4 Dictionary-basedReal-timeErrorRecovery............32 3.2.5 Dynamicerrorrecoveryduringsamplepreparation33 3.2.6 Redundancy-basederrorrecoveryinDMFBs..........34 3.3 Error-recoverywithMEDABiochips...................................35 3.3.1 DropletSize-AwareandError-CorrectingSam- plePreparation.........................................................35 3.3.2 AdaptiveErrorRecoveryinMEDAbiochips..........37 3.3.3 Roll-ForwardErrorRecoveryinMEDABiochips..38 3.4 Conclusion............................................................................42 SECTION III Design Automation Methods Chapter4 Error-CorrectingSamplePreparationwithCyber-physical DMFBs ........................................................................................45 4.1 Automatedsamplepreparation.............................................46 4.1.1 RelatedPriorWork..................................................46 4.1.2 Roll-forwardSchemeforErrorRecovery................46 4.2 Motivationandproblemformulation....................................48 4.2.1 Errormodeling:effectoferrorsontarget-CFs........49 4.2.2 Impact of multiple errors on target-CF: error collapsing.................................................................51 4.2.3 criticalandnon-criticalerrors..................................52 4.2.4 Cancellationofconcentrationerroratthetarget......56 4.2.5 ProblemFormulation...............................................58 4.3 Error-correctingdilutionalgorithm......................................59 4.3.1 Reactionpath:criticaloperation..............................59 4.3.2 Roll-forwarderrorrecovery.....................................60 4.4 DesigninganLoCforimplementingECSP.........................64 4.4.1 Descriptionofthelayout..........................................64 4.4.2 Simulationoferror-correctingdilution....................64 4.5 ExperimentalResults............................................................65 4.6 Conclusions...........................................................................70 Chapter5 EffectofVolumetricSplit-ErrorsonTarget-Concentration..........73 5.1 Error-recoveryapproaches:priorart.....................................73 5.2 Cyber-physicaltechniqueforerror-recovery........................74 5.2.1 Compilationforerror-recovery................................74 5.2.2 Workingprincipleofcyber-physical-basedDMFBs75 5.3 Effectofsplit-errorsontarget-CFs.......................................77 5.3.1 Singlevolumetricsplit-error....................................77 Contents ix 5.3.2 Multiplevolumetricsplit-errors...............................78 5.4 Worst-caseerrorintarget-CF...............................................80 5.5 MaximumCF-error:Ajustification......................................84 5.6 Conclusion............................................................................89 Chapter6 Error-ObliviousSamplePreparationwithDMFBs.......................91 6.1 SamplepreparationusingDMFBs........................................92 6.1.1 Samplepreparation..................................................93 6.1.2 ErrorsinDMFB.......................................................93 6.1.2.1 Dispensingerror......................................93 6.1.2.2 Volumetricspliterror...............................93 6.1.2.3 Critical/non-criticalsetoferrors.............94 6.1.3 SummaryofPriorArt..............................................95 6.2 EOSP:MainIdea..................................................................96 6.2.1 Error-vector(E).......................................................97 6.3 Effectoferrors......................................................................99 6.3.1 CriticalandNon-criticalsetoferrors....................100 6.3.2 EffectofMultipleErrorsontarget-CFs.................101 6.4 Baselineapproachtoerror-obliviousness...........................103 6.5 Resultingmethodology.......................................................105 6.6 Experimentalresults...........................................................112 6.7 Conclusions.........................................................................118 Chapter7 Robust Multi-Target Sample Preparation On-Demand with DMFBs........................................................................................121 7.1 Motivation...........................................................................123 7.2 Basicsofsamplepreparation..............................................124 7.3 Literaturereview.................................................................125 7.4 On-demandmulti-targetdilution-problem(MTD).............126 7.4.1 Problemdefinition..................................................128 7.4.2 Mainresults............................................................129 7.5 Rapidproductionoftarget-CFson-the-fly..........................130 7.5.1 IntegerLinearProgramming(ILP)formulation....131 7.5.2 Approximationscheme..........................................132 7.6 Generatingpartialsetofconcentrationfactors...................136 7.7 Reductionofon-chipreservoirs..........................................138 7.8 Streamingofdifferentsourceconcentrations.....................139 7.9 Experimentalresults...........................................................141 7.9.1 PerformanceevaluationofILPandtheapproxi- mationscheme.......................................................141 7.9.2 PerformanceevaluationofBCSscheme................142 7.9.3 PerformanceevaluationofMTSE..........................142 7.9.4 Performance of the integrated dilution scheme withMTSE.............................................................142