第1-4章微流控芯片目錄開展背景制備技術流體控制典型實例商品簡介目錄開展背景制備技術流體控制典型實例商品簡介Doyouknow?Biochip 生物芯片Lab-on-a-Chip 芯片實驗室 LabchipMicrofluidicChip 微流控芯片MicroTotalAnalysisSystem (MicroTAS,

TAS) 微全分析系統Researchintominiaturizationisprimarilydrivenbytheneedtoreducecostsbyreducingtheconsumptionofexpensivereagentsandbyincreasingthroughputandautomation. Forexample,mostareawareoftheincreasingcostofhealthcare,driveninpartbythecostofimplementingthelatestdiagnosticassays.Theseassays,whichareusuallyperformedinmicrotiterplatesthatconsumehundredsofmicrolitersofreagents,wouldbenefitfromtheuseofmicrofabricatedarraysofnanolitervolumevials. Byreducingreagentconsumptionbyafactorof103–104,thesedevicescouldprovidedramaticsavingsfortherepetitiveassaysoftenperformedindiagnosticlaboratories.Whyminiaturization？Anal.Chem.2000,72,330A-335A Inthesamewaythatintegratedcircuitsallowedfortheminiaturizationofcomputersfromthesizeofaroomtothesizeofanotebook,miniaturizationhasthepotentialtoshrinkaroomfullofinstrumentsintoacompactlab-on-a-chip.Anal.Chem.2000,72,330A-335A尺寸效應〔cm→100m〕尺寸 1/100分子擴散時間 1/10,000(1h→0.36s)體積 1/1,000,000 試劑用量 1t→1g,ml→nl傳熱速度 1500oC/s由此將帶來：方法上的變革理論上的突破還有巨大的經濟和社會效益微流控分析芯片微流控分析芯片目的是通過化學分析設備的微型化與集成化，最大限度地把分析實驗室的功能轉移到便攜的芯片中。微流控分析芯片通過微機電加工技術把整個實驗室的功能，包括采樣、稀釋、加試劑、反響、別離、檢測等集成在幾平方厘米的微流控芯片上，且可屢次使用，因而極大地減少了樣品和分析試劑的用量，降低了分析的本錢，加快了分析的速度，具有廣泛的適用性。TheEarlyDays:1975-1989ThefirstanalyticalminiaturizeddeviceAgaschromatographicairanalyzerfabricatedonasiliconwaferTerry,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.areperformedin<10s.發展歷史PhotographofagaschromatographintegratedonaplanarsiliconwaferfabricatedbyTerryandco-workersatStanfordUniversity.However,theresponseofthescientificcommunitytothisfirstsiliconchipdevicewasvirtuallynone,presumablybecauseofthelackoftechnologicalexperience(oftheseparationscientists)todealwiththiskindofdevice.theresearchworkrelatedtominiaturizationonsiliconfocusedonthefabricationofcomponentssuchasmicropumps,microvalves,andchemicalsensors.TheRenaissance:1990-1993thereemergenceofsilicon-basedanalyzersDesignofanopen-tubularcolumnliquidchromatographusingsiliconchiptechnologyManz,A.;etal.SensorsandActuators,B:Chemical(1990),B1(1-6),249Anovelconceptofhighpressureliquidchromatog.asiliconchipwithanopen-tubularcolumnandaconductometricdetector.A5×5mmchipcontaininganopen-tubularcolumnof6

m×2

m×15cmwasfabricated,whichhastheor.separationefficienciesof8000and25,000platesin1and5min,resp.Thetotalcolumnvolumeis1.5nLandthedetectioncellvolume1.2pL.MicrographofLiquidChromatographchipmanufacturedbyManzandco-workersatHitachiLtd.Theconceptof"miniaturizedtotalchemicalanalysissystem"or

TASwasproposedbyManzetal.themainreasonforminiaturizationwasthereforetoenhancetheanalyticalperformanceofthedeviceratherthantoreduceitssize.itwasalsorecognizedthatasmallsizepresentedtheadvantageofasmallerconsumptionofcarrier,reagent,andmobilephase.GrowingtoCriticalMass:1994-1997In1994,thenumberofpublishedpapersrelatedto

TASincreasedabruptlysincemoreresearchgroupsjoinedtheeffortstodevelopthearea.MicrofabricationDesignSeparationsBiochemicalReactorsDetection分類與特點分類：材料：硅、玻璃、石英、聚合物、復合材料功能：別離、采樣與前處理、檢測、化學合成等特點：高效、低耗、集成、一致性好、昂貴目錄開展背景制備技術流體控制典型實例商品簡介微結構的形成

1．經典的光刻技術Photolithographproceduresformakingglasstemplate.(a)Spinecoatingofphotoresist,

(b)coveredwithphotomask,

(c)exposure,(d)developing,(e)etching,and(f)removalofphotoresist.適合硅、玻璃、石英等材料，與傳統的半導體工業的方法一致。分為濕法和干法兩種，干法的分辨率較濕法高，相應的制造本錢也高。Analyst,2004,129,305–308制備技術之微結構的形成

2．模版澆注法

〔模塑法〕Processoverviewformassmanufacturingofplasticmicrofluidicsystems適合聚合物材料。大批量生產時本錢低。Anal.Chem.,2002,74,78A-86A微結構的形成

3．模版熱壓法Schematicrepresentationofthefabricationmethodinvolvinghotembossingofthermoplasticpolymerpelletsandthermalbonding.適合熱塑性聚合物。AppliedPhysicsLetters,2002,80,3614-3616微結構的形成

4．激光刻蝕法 用激光直接在聚合物或玻璃上加熱形成微結構.Anal.Chem.,1997,69,2035-2042MicrofilterSensorsandActuatorsB672000203–208芯片的封裝

1．熱鍵合 對玻璃和石英材質刻蝕的微結構一般使用熱鍵合方法，將加工好的基片和相同材質的蓋片洗凈烘干對齊緊貼后平放在高溫爐中，在基片和蓋片上下方各放一塊拋光過的石墨板，在上面的石墨板上再壓一塊重0.5kg的不銹鋼塊，在高溫爐中加熱鍵合。玻璃芯片鍵合時，高溫爐升溫速度為10oC/分，在620oC時保溫3.5小時，再以10oC/分的速率降溫。石英芯片鍵合溫度高達1000oC以上。此方法對操作技術要求較高。現代科學儀器，2001，4，8-12制備技術之芯片的封裝

2．陽極鍵合在玻璃、石英與硅片的封接中已廣泛采用陽極鍵合的方法。即在鍵合過程中，施加電場，使鍵合溫度低于軟化點溫度。在500-760伏電場下，升溫到500oC時，可使兩塊玻璃片鍵合。在兩塊玻璃板尚未鍵合時，板間空氣間隙承擔了大局部電壓降，玻璃板可視為平行板電容器，板間吸引力與電場強度的平方成正比，因此，鍵合從兩塊玻璃中那些最接近的點開始，下板中可移動的正電荷〔主要是Na+〕與上板中的負電荷中和，生成一層氧化物〔正是這層過渡層，使兩塊玻璃板封接〕，該點完成鍵合后，周圍的空氣間隙相應變薄，電場力增大，從而鍵合擴散開來，直至整塊密合。現代科學儀器，2001，4，8-12芯片的封裝

3．室溫鍵合Anal.Chem.2004,76,5597-5602芯片的封裝

4．貼合

將聚合物薄片直接覆

蓋在玻璃或石英板上。

5．壓合Schematicillustrationofsealingandconnectionmethod.Thetopandbottomplatesarepressedbyascrewandholders.Anal.Chem.2002,74,1724-1728目錄開展背景制備技術流體控制典型實例商品簡介遵循低雷諾數流動的規律。除了組分間的擴散，兩層或者多層流體可以相鄰流動而不互相混合，使得樣品的混合變得困難。Anal.Chem.2002,74,45-51液體流動的特點液體流動的特點由于比外表積增大，外表張力、摩擦力的影響非常顯著。微通道中的液液界面與通道壁平行，因為外表張力和摩擦力大于重力。Anal.Sci.2001,17,89-93液體流動的特點液體的物理性質發生變化，如表觀粘度變大純水通過微通道的時間：理論值 2.3ms實驗值 10msAnal.Chem.2002,74,6170-6176

MicrofabricationInside

CapillariesUsingMultiphase

LaminarFlowPatterningScience1999,285,83液體流動的特點MicrochipFlowCytometryUsingElectrokineticFocusingAnal.Chem.1999,71,4173液體流動的特點APicoliter-VolumeMixerforMicrofluidicAnalyticalSystemsAnal.Chem.

2001,73,1942-1947液體的混合UltrasonicMixinginMicrofluidicChannelsUsingIntegratedTransducersAnal.Chem.,2004;76;3694-3698液體的混合外加壓力驅動Anal.Chem.2000,72,1711-1714重力驅動Anal.Chem.2005,77,1330-1337離心力驅動CentrifugalMicrofluidicsPlatformAnal.Chem.2002,74,5569-5575毛細作用驅動Microfilterdevicedesignanddetail:(a)topviewofgenericdevicedesignwithnarrowandexpandedchannels,(b)filterdetailareashowingfilterporesandexpandedchannellayout,(c)microfiltercrosssection.LabChip,2005,5,922-929單向閥Cylinderdiametersareapproximately100and25

m.Anal.Chem.2002,74,4913-4918目錄開展背景制備技術流體控制典型實例商品簡介SchematicillustrationofexperimentalsetupandionpairextractionmodelAnal.Chem.

2001,73,1382-1386離子檢測determinationofCo(II)as2-nitroso-1-naphtholchelatesbysolventextractionandthermallensmicroscopy

LabChip

2001,1,72-75SchematicdiagramsofCEprocedureswithpinchedinjection(toppanels),floatinginjection(middle),and(C)simplestinjectionmode(bottom).Anal.Chem.,2001.73,2656-2662電泳別離Generalideaofpolymermembraneformationunderorganic/aqueoustwo-phaseflowinanX-shapedmicrochannel

Anal.Chem.2003,75,350-354固定化酶反響SubstratepermeationandsubsequentenzymereactionexperimentAnal.Chem.2003,75,350-354Schematicillustrationsofmicrochip-basedimmunosorbentassay.Anal.Chem.2001,73,1213-1218免疫檢測Glassmicrochipforimmunosorbentassay:

DesignofaCompactDisk-likeMicrofluidicPlatformforEnzyme-LinkedImmunosorbentAssaySchematicsof(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免疫檢測 (a)Schematicoffive-stepflowsequencingCD(1,waste;2,detection;7,antigen/sample;8,9,washing;10,secondantibody;and11,substrate)and(b)aCNC-machinedCD.NatureBiotechnology，2023，26，1373-1378免疫檢測Anal.Chem.2004,76,1824-1831核酸分析Self-Contained,FullyIntegratedBiochipforSamplePreparation,PolymeraseChainReactionAmplification,andDNAMicroarrayDetectionMicrofabricatedDeviceforDNAandRNAAmplificationbyContinuous-FlowPolymeraseChainReactionandReverseTranscription-PolymeraseChainReactionwithCycleNumberSelectionAnal.Chem.2003,75,288-295PCR反響DevelopmentofaMicrochip

-BasedBioassaySystemUsingCulturedCellsConceptofthemicrochip-basedbioassaysystemAnal.Chem.,2005.77(7),2125-2131細胞培養和操作(A)Illustrationand(B)photoshowingthearrangementofPeltierelements.(C)Photoofthetemperaturecontroldevice(A)Illustrationand(B)photographofthebioassaymicrochip.(C)AnenlargedillustrationofthemicrochamberforcellcultureCompletesystemforthemicrochip-basedbioassay(A)Photoofthetemperaturecontroldevicewiththemicrochip.(B)ThermographofthemicrochipsurfaceMicrographsof(A)mouseperitonealmacrophagesand(B,C)J774.1cellsinthemicrochip.Thedamsuccessfullykeptcellsinthemicrochamber.MicrographsofJ774.1cellsculturedinthemicrochipfor2days(A)undercontinuousmediumflowconditionsand(B)staticconditions.Thecellsstainedinblueweredead.Chemicalprocessescarriedoutinthemicrochipforbioassayofmacrophage-stimulatingagentCalibrationcurvesofNOdissolvedinthemedium(A)determinedonthebulkscaleand(B)inamicrochip.TypicalresultsofNOreleasedfromJ774.1cells.目錄開展背景制備技術流體控制典型實例商品簡介COMPANYPRODUCTSCaliperLabChip?Systems(LabChip?3000/LabChip?EZReader/LabChip?EZReaderII/LabChip?90/LabChip?GX/LabChip?GXII/LabChip?DS/LabChip?XT/LabChip?Xte)Agilent2100Bioanalyzer/5100AutomatedLab-on-a-Chip/HPLC-ChipGEHealthcareBiacore? Systems(Biacore?4000/Biacore?T200/Biacore?X100/Biacore?C/Biacore?3000/Biacore?Q/EarlierSystemsFluidigmBioMark?HDSystem/EP1?System/AccessArray?SystemCepheidGenexpertRaindanceRDT1000CellectriconDynaflow?Systems(Dynaflow?HT/Dynaflow?ProII/Dynaflow?TC)微流控芯片主要應用相關商業化產品微流控芯片供給鏈情況Caliper-LabChip?Systems

LabChipGX

LabChipXTLabChipEZReader

LabChipXT分餾系統進行快速，自動化別離核酸LabChipGXII是一個蛋白質樣品的精確的分析完整的解決方案，是一種蛋白質研究用戶的理想工具。利用微流體技術，無需處理SDS凝膠。LabChipEZReader是一個突破性的臺式儀器，有利于激酶檢測和其他酶的篩選和分析。以微流控別離為根底。GEHealthcare-Biacore? SystemsSerialflowcellsystemsIndependent

flowcellsystems