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Bioanalysis Series Editor: Tuan Vo-Dinh Manabu Tokeshi Editor Applications of Microfl uidic Systems in Biology and Medicine Bioanalysis Advanced Materials, Methods, and Devices Volume 7 Series editor Tuan Vo-Dinh Fitzpatrick Institute for Photonics Duke University Durham, NC, USA Moreinformationaboutthisseriesathttp://www.springer.com/series/8091 Manabu Tokeshi Editor fl Applications of Micro uidic Systems in Biology and Medicine Editor ManabuTokeshi DivisionofAppliedChemistry,Faculty ofEngineering HokkaidoUniversity Sapporo,Japan ISSN2364-1118 ISSN2364-1126 (electronic) Bioanalysis ISBN978-981-13-6228-6 ISBN978-981-13-6229-3 (eBook) https://doi.org/10.1007/978-981-13-6229-3 LibraryofCongressControlNumber:2019935498 ©SpringerNatureSingaporePteLtd.2019 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartofthe materialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation, broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinformation storageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodology nowknownorhereafterdeveloped. Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthispublication doesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevant protectivelawsandregulationsandthereforefreeforgeneraluse. The publisher, the authors, and the editorsare safeto assume that the adviceand informationin this bookarebelievedtobetrueandaccurateatthedateofpublication.Neitherthepublishernortheauthorsor theeditorsgiveawarranty,expressorimplied,withrespecttothematerialcontainedhereinorforany errorsoromissionsthatmayhavebeenmade.Thepublisherremainsneutralwithregardtojurisdictional claimsinpublishedmapsandinstitutionalaffiliations. ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSingaporePteLtd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Preface About 30 years have passed since the concept of μTAS was proposed by Andreas Manzin1990.Inthemid-1990s,asthehumangenomeprojectwasbeingpromoted, manyresearcherswereworkingonthedevelopmentofmicrofluidic“electrophoresis” devices. From around 2000, development of devices integrating chemical analysis, bioassay, etc. has increased. Then, this research field called μTAS, lab-on-a-chip, microfluidicdevice,etc.hasgreatlyexpandedanddeveloped.Currently,μTASfield continuestoexpand;newconceptssuchasdigitalmicrofluidics,nanofluidics,μPAD (microfluidic paper-based analytical device), and organ-on-a-chip which were origi- nallyunexpectedhavebeenproposed;andnotonlytoanalyticalchemistrybutalsoto variousfieldssuchasmedicaldiagnosisandbiologicalapplicationshasbeingcarried out.Especially,medicalandbiologicalapplicationsaredevelopingrapidly,andthere arestrikingthings.However,thepublishedscientificpapersontheseapplicationsare enormous,anditishardforexpertsinthisfieldtoreadallofthem. This book focuses on state-of-the-art microfluidic research in medical and bio- logicalapplications.Thetop-levelresearchersinthisresearchfieldexplaincarefully andclearlywhatcanbedonebyusingmicrofluidicdevices.Beginnersinthefield— undergraduates, engineers, biologists, medical researchers—will easily learn to understandmicrofluidic-basedmedicalandbiologicalapplications.Becauseawide rangeoftopicsaresummarizedhere,italsohelpsexpertstolearnmoreaboutfields outsidetheirownspecialties.Thebookcoversmanyinterestingsubjects,including protein separation, protein crystallization, cell separation, single-cell analysis, cell diagnosis, point-of-caretesting, immunoassay, and regenerative medicine. Readers will be convinced that microfluidic devices have great potential for medical and biologicalapplications. IwouldliketothankShinichiKoizumiandAsamiKomadaatSpringerfortheir help in pulling the book together. The publication of this book would have been impossiblewithouttheirhelp.Finally,Iwouldliketoexpressmysincerethanksto theauthorsforallofthetimeandeffortstheyspentwritingtheirchapters. Sapporo,Japan ManabuTokeshi August2018 v Contents 1 AcoustofluidicBloodComponentSamplePreparation andProcessinginMedicalApplications. . . . . . . . . . . . . . . . . . . . . 1 MariaAntfolkandThomasLaurell 2 MicrofluidicTechnologiesandPlatforms forProteinCrystallography. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 MasatoshiMaekiandManabuTokeshi 3 ApplicationofSERS-BasedMicrofluidics forInVitroDiagnostics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 JinhyeokJeon,NamhyunChoi,Joung-IlMoon,HaoChen, andJaebumChoo 4 MiniaturizedElectrochemicalSensorstoFacilitateLiquid BiopsyforDetectionofCirculatingTumorMarkers. . . . . . . . . . . . 71 Yi-GeZhou,LeylaKermansha,LibingZhang, andRezaM.Mohamadi 5 SpiralInertialMicrofluidicsforCellSeparation andBiomedicalApplications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 NingLiu,ChayakornPetchakup,HuiMinTay,KingHoHoldenLi, andHanWeiHou 6 WormsonaChip. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Han-ShengChuang,Wen-HuiWang,andChang-ShiChen 7 MicrofluidicDevicesforGameteProcessingandAnalysis, FertilizationandEmbryoCultureandCharacterization. . . . . . . . . 197 SéverineLeGac,VerenaNordhoff,andBastienVenzac 8 MicrofluidicOrgans-on-ChipstoReconstituteCellular Microenvironments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 Yu-sukeTorisawa vii viii Contents 9 InVitroTissueConstructionforOrgan-on-a-Chip Applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 YuyaMorimoto,NobuhitoMori,andShojiTakeuchi 10 NanobiodevicesforCancerDiagnostics andStemCellTherapeutics. . .. . . . . .. . . . . . .. . . . . . .. . . . . .. . 275 DaisukeOnoshima,HiroshiYukawa,andYoshinobuBaba 11 NanoporeDeviceforSingle-MoleculeSensingMethod andItsApplication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 MasateruTaniguchiandTakahitoOhshiro 12 PaperMicrofluidicsforPOCTesting inLow-ResourceSettings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 ElainFu 13 Paper-BasedMicrofluidicsforPoint-of-Care MedicalDiagnostics. . . .. . . . . .. . . . . .. . . . . . .. . . . . .. . . . . .. . 353 KentaroYamadaandDanielCitterio Chapter 1 fl Acousto uidic Blood Component Sample Preparation and Processing in Medical Applications MariaAntfolkandThomasLaurell Abstract Recent developments of bulk acoustofluidic technology (BAW – bulk acoustic wave) in biomedical applications is described in this chapter. The basic principles for setting up an acoustic standing wave in a microchannel in 1 or 2 dimensions in the transversal direction to flow is outlined. BAW acoustofluidics is a preferred solution as compared to SAW based acoustofluidics due to the relatively higher acoustic energies that can be accomplished in BAW systems. This in turn lends BAW technology to perform cell manipulation based handling in a sufficiently high flow through format that can fulfill many biomedical and bioanalytical applications. Several unit operations for BAW based cell handling havetodayreachedalevelofmaturitywherethesearebeingintegralcomponentsin cytometry and cell processing instrumentation. Most of these applications are still realizedatananalyticallevelandhavenotyetreachedprocessscaleortherapeutic scalethroughput.However,intensedevelopmentsareinprogresstoalsoreachinto thisdomainoflargerscaleprocessingsincetheperformanceandlabelfreeoperation offeredfromBAW systems wouldsignificantlyimpact currentbioprocess industry and clinical practice. The importance of having full control of the buffer systems used is discussed since poorly matched buffers/fluids, with respect to the acoustic properties(acousticimpedance),maysignificantlyimpacttheprocessingoutcomeas aconsequenceofacousticallydrivenfluidrelocation.Also,thechallengeofmanip- ulatingsmallerbioparticles,e.g.bacteria,isdiscussedandstrategiestotacklethefact that the inherent acoustic streaming in acoustic standing wave based microfluidics maybecounteractingthedesiredalignmentofcell/particlesdefinedbytheacoustic standingwave.Afocusisputonapplicationsinbloodcomponentprocessing,where unitoperationssuchascellseparation(WBC,RBC,WBCsubpopulations,CTCand platelets), buffer exchange and concentrating cell samples have become important modalities in cell based microfluidics. The current state of diagnostic BAW appli- cations such as blood plasma separation, circulating tumor cell (CTC) isolation, rapid hematocrit determination and bacteria enrichment/purification in sepsis are discussed. M.Antfolk·T.Laurell(*) DepartmentofBiomedicalEngineering,LundUniversity,Lund,Sweden e-mail:[email protected] ©SpringerNatureSingaporePteLtd.2019 1 M.Tokeshi(ed.),ApplicationsofMicrofluidicSystemsinBiologyandMedicine, Bioanalysis7,https://doi.org/10.1007/978-981-13-6229-3_1 2 M.AntfolkandT.Laurell Keywords Acoustofluidics·Acoustophoresis·Cellseparationplasmapheresis· CTC·Sepsis·Hematocrit 1.1 Introduction Acoustofluidics uses ultrasound to separate and handle cells either in continuous flow, using bulk acoustic waves (BAW) [1–3] or standing surface acoustic waves (SSAW) [4], or in a batch mode using acoustic trapping. The methods rely to a majority on the formation of standing acoustic waves to handle and process cells basedontheirsize,density,and/orcompressibility. Acoustophoresis is most often operated in a label-free mode which is advanta- geous when isolating cells that are not susceptible to surface marker based separa- tions,buthasalsobeencombinedwithaffinitybeadstotargetspecificcelltypes.Ina continuous flow mode, devices depending on BAW can be operated at relatively highflowratescomparedtoothermicrofluidicmethods,andwhereSSAWdevices have not shown the same throughput. Devices based on SSAW, however, are fabricatedinsoftermaterialssuchasPDMS,whileBAWdevicesgenerallyrelyon morerigidmaterialssuchassiliconorglassinordertoefficientlysupportastanding wave formation defined solely by the geometry of the microfluidic compartment. BAW systems are commonly operated by exciting the entire chip structure at an oscillation frequency that coincides with a fundamental resonance mode of a microfluidic compartment. By designing the resonance cavity as a microchannel, particles orcellscanbefocusedinwell-definedandreproduciblepositions/stream- lines[5].InaSAWdevicethemicrochannelisplacedbetweenapairofIDTsona piezoelectricsubstrate.Whenactuating thesubstratetheSAWspropagateinoppo- sitedirectionsonthesubstratesurfaceandleakintotheliquidofthemicrochannel. Theinterferencebetweenthetwopropagatingfieldscausespressurefluctuationsin the liquid resulting in the formation of acoustic pressure nodes and antinodes [6]. Both types of acoustophoresis offer opportunities for a number of different unitoperationssuchascellseparation,sampleconcentration,alignment andbuffer exchange(Fig.1.1). 1.1.1 Acoustofluidics When a particle is suspended in an ultrasound standing wave field, the particle is subjectedtobothaprimaryandsecondaryradiationforce,aswellasaStokes’drag force induced by the acoustic streaming. The primary acoustic radiation force originatesfromscatteringofthestandingwaveonaparticleandaffectstheparticles position within the microchannel. The secondary acoustic radiation force is due to interactionsofthescatteredwavesfromtwoparticlesandaffectstheparticle-particle

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