Error-Tolerant Biochemical Sample Preparation with Microfluidic Lab-on-Chip

223 Pages·2022·17.211 MB·English

by  Sudip Poddar, Bhargab B. Bhattacharya

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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Error-Tolerant
Biochemical Sample
Preparation with
Microfluidic Lab-on-Chip
Sudip Poddar and Bhargab B. Bhattacharya
First edition published 2023
by CRC Press
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ISBN: 978-1-032-11380-7 (hbk)
ISBN: 978-1-032-11385-2 (pbk)
ISBN: 978-1-003-21965-1 (ebk)
DOI: 10.1201/9781003219651
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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