第1-4章-微流控芯片

第1-4章微流控芯片,目录,发展背景制备技术流体控制典型实例商品简介,目录,发展背景制备技术流体控制典型实例商品简介,Doyouknow?,Biochip生物芯片Lab-on-a-Chip芯片实验室LabchipMicrofluidicChip微流控芯片MicroTotalAnalysisSystem(MicroTAS,TAS)微全分析系统,Researchintominiaturizationisprimarilydrivenbytheneedtoreducecostsbyreducingtheconsumptionofexpensivereagentsandbyincreasingthroughputandautomation.Forexample,mostareawareoftheincreasingcostofhealthcare,driveninpartbythecostofimplementingthelatestdiagnosticassays.Theseassays,whichareusuallyperformedinmicrotiterplatesthatconsumehundredsofmicrolitersofreagents,wouldbenefitfromtheuseofmicrofabricatedarraysofnanolitervolumevials.Byreducingreagentconsumptionbyafactorof103104,thesedevicescouldprovidedramaticsavingsfortherepetitiveassaysoftenperformedindiagnosticlaboratories.,Whyminiaturization？,Anal.Chem.2000,72,330A-335A,Inthesamewaythatintegratedcircuitsallowedfortheminiaturizationofcomputersfromthesizeofaroomtothesizeofanotebook,miniaturizationhasthepotentialtoshrinkaroomfullofinstrumentsintoacompactlab-on-a-chip.,Anal.Chem.2000,72,330A-335A,尺寸效应（cm100m）尺寸1/100分子扩散时间1/10,000(1h0.36s)体积1/1,000,000试剂用量1t1g,mlnl传热速度1500oC/s由此将带来：方法上的变革理论上的突破还有巨大的经济和社会效益,微流控分析芯片,微流控分析芯片目的是通过化学分析设备的微型化与集成化，最大限度地把分析实验室的功能转移到便携的芯片中。微流控分析芯片通过微机电加工技术把整个实验室的功能，包括采样、稀释、加试剂、反应、分离、检测等集成在几平方厘米的微流控芯片上，且可多次使用，因而极大地减少了样品和分析试剂的用量，降低了分析的成本，加快了分析的速度，具有广泛的适用性。,TheEarlyDays:1975-1989,ThefirstanalyticalminiaturizeddeviceAgaschromatographicairanalyzerfabricatedonasiliconwaferTerry,S.C.Ph.D.Thesis,Stanford,Stanford,CA,1975Terry,StephenC.;etal.IEEETransactionsonElectronDevices,1979,ED-26(12),1880Aminiaturegasanal.systembasedontheprinciplesofgaschromatog.ThemajorcomponentsarefabricatedinSiusingphotolithog.andchem.etchingtechniques,whichallowssizeredns.ofnearly3ordersofmagnitudecomparedtoconventionallaboratoryinstruments.consistsofasampleinjectionvalve,a1.5-m-longcapillarycolumn.Athermalconductivitydetectorfabricatedonaseparatesiliconwafer.sepns.ofgaseoushydrocarbonmixts.areperformedin10s.,发展历史,PhotographofagaschromatographintegratedonaplanarsiliconwaferfabricatedbyTerryandco-workersatStanfordUniversity.,However,theresponseofthescientificcommunitytothisfirstsiliconchipdevicewasvirtuallynone,presumablybecauseofthelackoftechnologicalexperience(oftheseparationscientists)todealwiththiskindofdevice.theresearchworkrelatedtominiaturizationonsiliconfocusedonthefabricationofcomponentssuchasmicropumps,microvalves,andchemicalsensors.,TheRenaissance:1990-1993,thereemergenceofsilicon-basedanalyzersDesignofanopen-tubularcolumnliquidchromatographusingsiliconchiptechnologyManz,A.;etal.SensorsandActuators,B:Chemical(1990),B1(1-6),249Anovelconceptofhighpressureliquidchromatog.asiliconchipwithanopen-tubularcolumnandaconductometricdetector.A55mmchipcontaininganopen-tubularcolumnof6m2m15cmwasfabricated,whichhastheor.separationefficienciesof8000and25,000platesin1and5min,resp.Thetotalcolumnvolumeis1.5nLandthedetectioncellvolume1.2pL.,MicrographofLiquidChromatographchipmanufacturedbyManzandco-workersatHitachiLtd.,TheconceptofminiaturizedtotalchemicalanalysissystemorTASwasproposedbyManzetal.themainreasonforminiaturizationwasthereforetoenhancetheanalyticalperformanceofthedeviceratherthantoreduceitssize.itwasalsorecognizedthatasmallsizepresentedtheadvantageofasmallerconsumptionofcarrier,reagent,andmobilephase.,GrowingtoCriticalMass:1994-1997,In1994,thenumberofpublishedpapersrelatedtoTASincreasedabruptlysincemoreresearchgroupsjoinedtheeffortstodevelopthearea.MicrofabricationDesignSeparationsBiochemicalReactorsDetection,分类与特点,分类：材料：硅、玻璃、石英、聚合物、复合材料功能：分离、采样与前处理、检测、化学合成等特点：高效、低耗、集成、一致性好、昂贵,目录,发展背景制备技术流体控制典型实例商品简介,微结构的形成1经典的光刻技术,Photolithographproceduresformakingglasstemplate.(a)Spinecoatingofphotoresist,(b)coveredwithphotomask,(c)exposure,(d)developing,(e)etching,and(f)removalofphotoresist.,适合硅、玻璃、石英等材料，与传统的半导体工业的方法一致。分为湿法和干法两种，干法的分辨率较湿法高，相应的制造成本也高。,Analyst,2004,129,305308,制备技术之,微结构的形成2模版浇注法（模塑法）,Processoverviewformassmanufacturingofplasticmicrofluidicsystems,适合聚合物材料。大批量生产时成本低。,Anal.Chem.,2002,74,78A-86A,微结构的形成3模版热压法,Schematicrepresentationofthefabricationmethodinvolvinghotembossingofthermoplasticpolymerpelletsandthermalbonding.,适合热塑性聚合物。,AppliedPhysicsLetters,2002,80,3614-3616,微结构的形成4激光刻蚀法,用激光直接在聚合物或玻璃上加热形成微结构.,Anal.Chem.,1997,69,2035-2042,Microfilter,SensorsandActuatorsB672000203208,芯片的封装1热键合,对玻璃和石英材质刻蚀的微结构一般使用热键合方法，将加工好的基片和相同材质的盖片洗净烘干对齐紧贴后平放在高温炉中，在基片和盖片上下方各放一块抛光过的石墨板，在上面的石墨板上再压一块重0.5kg的不锈钢块，在高温炉中加热键合。玻璃芯片键合时，高温炉升温速度为10oC/分，在620oC时保温3.5小时，再以10oC/分的速率降温。石英芯片键合温度高达1000oC以上。此方法对操作技术要求较高。,现代科学仪器，2001，4，8-12,制备技术之,芯片的封装2阳极键合,在玻璃、石英与硅片的封接中已广泛采用阳极键合的方法。即在键合过程中，施加电场，使键合温度低于软化点温度。在500-760伏电场下，升温到500oC时，可使两块玻璃片键合。在两块玻璃板尚未键合时，板间空气间隙承担了大部分电压降，玻璃板可视为平行板电容器，板间吸引力与电场强度的平方成正比，因此，键合从两块玻璃中那些最接近的点开始，下板中可移动的正电荷（主要是Na+）与上板中的负电荷中和，生成一层氧化物（正是这层过渡层，使两块玻璃板封接），该点完成键合后，周围的空气间隙相应变薄，电场力增大，从而键合扩散开来，直至整块密合。,现代科学仪器，2001，4，8-12,芯片的封装3室温键合,Anal.Chem.2004,76,5597-5602,芯片的封装4贴合将聚合物薄片直接覆盖在玻璃或石英板上。5压合,Schematicillustrationofsealingandconnectionmethod.Thetopandbottomplatesarepressedbyascrewandholders.,Anal.Chem.2002,74,1724-1728,目录,发展背景制备技术流体控制典型实例商品简介,遵循低雷诺数流动的规律。除了组分间的扩散，两层或者多层流体可以相邻流动而不互相混合，使得样品的混合变得困难。,Anal.Chem.2002,74,45-51,液体流动的特点,液体流动的特点,由于比表面积增大，表面张力、摩擦力的影响非常显著。,微通道中的液液界面与通道壁平行，因为表面张力和摩擦力大于重力。,Anal.Sci.2001,17,89-93,液体流动的特点,液体的物理性质发生变化，如表观粘度变大,纯水通过微通道的时间：理论值2.3ms实验值10ms,Anal.Chem.2002,74,6170-6176,MicrofabricationInsideCapillariesUsingMultiphaseLaminarFlowPatterning,Science1999,285,83,液体流动的特点,MicrochipFlowCytometryUsingElectrokineticFocusing,Anal.Chem.1999,71,4173,液体流动的特点,APicoliter-VolumeMixerforMicrofluidicAnalyticalSystems,Anal.Chem.2001,73,1942-1947,液体的混合,UltrasonicMixinginMicrofluidicChannelsUsingIntegratedTransducers,Anal.Chem.,2004;76;3694-3698,液体的混合,外加压力驱动,Anal.Chem.2000,72,1711-1714,重力驱动,Anal.Chem.2005,77,1330-1337,离心力驱动,CentrifugalMicrofluidicsPlatform,Anal.Chem.2002,74,5569-5575,毛细作用驱动,Microfilterdevicedesignanddetail:(a)topviewofgenericdevicedesignwithnarrowandexpandedchannels,(b)filterdetailareashowingfilterporesandexpandedchannellayout,(c)microfiltercrosssection.,LabChip,2005,5,922-929,单向阀,Cylinderdiametersareapproximately100and25m.,Anal.Chem.2002,74,4913-4918,目录,发展背景制备技术流体控制典型实例商品简介,Schematicillustrationofexperimentalsetupandionpairextractionmodel,Anal.Chem.2001,73,1382-1386,离子检测,determinationofCo(II)as2-nitroso-1-naphtholchelatesbysolventextractionandthermallensmicroscopy,LabChip2001,1,72-75,SchematicdiagramsofCEprocedureswithpinchedinjection(toppanels),floatinginjection(middle),and(C)simplestinjectionmode(bottom).,Anal.Chem.,2001.73,2656-2662,电泳分离,Generalideaofpolymermembraneformationunderorganic/aqueoustwo-phaseflowinanX-shapedmicrochannel,Anal.Chem.2003,75,350-354,固定化酶反应,Substratepermeationandsubsequentenzymereactionexperiment,Anal.Chem.2003,75,350-354,Schematicillustrationsofmicrochip-basedimmunosorbentassay.,Anal.Chem.2001,73,1213-1218,免疫检测,Glassmicrochipforimmunosorbentassay:,DesignofaCompactDisk-likeMicrofluidicPlatformforEnzyme-LinkedImmunosorbentAssay,Schematicsof(a)aCD-ELISAdesignwith24setsofassays,(b)asingleassay,(1,waste;2,detection;3,firstantibody;4,6,8,10,washing;5,blockingprotein;7,antigen/sample;9,secondantibody;and11,substrate),and(c)photoofasingleassay.,Anal.Chem.,2004,76(7),1832-1837,免疫检测,(a)Schematicoffive-stepflowsequencingCD(1,waste;2,detection;7,antigen/sample;8,9,washing;10,secondantibody;and11,substrate)and(b)aCNC-machinedCD.,NatureBiotechnology，2008，26，1373-1378,免疫检测,Anal.Chem.2004,76,1824-1831,核酸分析,Self-Contained,FullyIntegratedBiochipforSamplePreparation,PolymeraseChainReactionAmplification,andDNAMicroarrayDetection,MicrofabricatedDeviceforDNAandRNAAmplificationbyContinuous-FlowPolymeraseChainReactionandReverseTranscription-PolymeraseChainReactionwithCycleNumberSelection,Anal.Chem.2003,75,288-295,PCR反应,DevelopmentofaMicrochip-BasedBioassaySystemUsingCulturedCells,Conceptofthemicrochip-basedbioassaysystem,Anal.Chem.,2005.77(7),2125-2131,细胞培养和操作,(A)Illustrationand(B)photoshowingthearrangementofPeltierelements.(C)Photoofthetemperaturecontroldevice,(A)Illustrationand(B)photographofthebioassaymicrochip.(C)Anenlargedillustrationofthemicrochamberforcellculture,Completesystemforthemicrochip-basedbioassay,(A)Photoofthetemperaturecontroldevicewiththemicrochip.(B)Thermographofthemicrochipsurface,Micrographsof(A)mouseperitonealmacrophagesand(B,C)J774.1cellsinthemicrochip.Thedamsuccessfullykeptcellsinthemicrochamber.,MicrographsofJ774.1cellsculturedinthemicrochipfor2days(A)undercontinuousmediumflowconditionsand(B)staticconditions.Thecellsstainedinblueweredead.,Chemicalprocessescarriedoutinthemicrochipforbioassayofmacrophage-stimulatingagent,CalibrationcurvesofNOdissolvedinthemedium(A)determinedonthebulkscaleand(B)inamicrochip.,TypicalresultsofNOreleasedfromJ774.1cells.,目录,发展背景制备技术流体控制典型实例商品简介,微流控芯片主要应用相关商业化产品,微流控芯片供应链情况,Caliper-LabChipSystems,LabChipGX,LabChipXT,LabChipEZReader,LabChipXT分馏系统进行快速，自动化分离核酸,LabChipGXII是一个蛋白质样品的精确的分析完整的解决方案，是一种蛋白质研究用户的理想工具。利用微流体技术，无需处理SDS-PAGE凝胶。,LabChipEZReader是一个突破性的台式仪器，有利于激酶检测和其他酶的筛选和分析。以微流控分离为基础。,GEHealthcare-BiacoreSystems,Serialflowcellsystems,Independentflowcellsy