SensorsandActuatorsB269(2018)468–478
ContentslistsavailableatScienceDirect
Sensors
and
Actuators
B:
Chemical
j ourn a l h o m e pa g e :w w w . e l s e v i e r . c o m / l o c a t e / s n b
Standardized
and
modular
microfluidic
platform
for
fast
Lab
on
Chip
system
development
S.
Dekker
a,
W.
Buesink
b,
M.
Blom
b,
M.
Alessio
c,d,
N.
Verplanck
c,d,
M.
Hihoud
e,
C.
Dehan
e,
W.
César
f,
A.
Le
Nel
f,
A.
van
den
Berg
a,
M.
Odijk
a,∗aBIOSLabonChipGroup,MESA+instituteforNanotechnology,UniversityofTwente,7500AE,Enschede,Netherlands bMicronitMicrotechnologiesB.V.,Colloseum15,7521PV,Enschede,Netherlands
cUniv.GrenobleAlpes,F-38000Grenoble,France dCEA,LETI,MINATECCampus,F-38054Grenoble,France
eEVEON,345rueLavoisier,38330Montbonnot-Saint-Martin,France fFluigent,1mailduProfesseurMathé,94800Villejuif,France
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received17October2017
Receivedinrevisedform27March2018 Accepted2April2018
Availableonline22April2018 Keywords: Microfluidicstandardization Platform Modular Commercialization Microfluidicdesign Characterization
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SincetheLabonaChipconceptwasintroducedinthe1990s,alotofscientificadvancementshave occurred.However,largescalecommercialrealizationofmicrofluidictechnologyisbeingpreventedby thelackofstandardization.ThereseemstobeagapbetweenLabonaChipsystemsdevelopedinthelab andthosethataremanufacturableonalargescaleinafab.Inthispaper,weproposeamodularplatform whichmakesuseofstandardizedparts.Usingthisplatform,afunctional-basedmethodofdesigning microfluidicsystemsisenvisioned.Toobtainacertainmicrofluidicfunction,abottom-updesignismade. Thisresultsinmicrofluidicbuildingblocksthatperformamicrofluidicfunction.Thismicrofluidicbuilding blockisthenstoredinalibrary,readyforreuseinthefuture.Keycharacteristicsareshownforseveralbasic microfluidicbuildingblocks,developedaccordingtoafootprintandinterconnectstandardbyvarious playersinthemicrofluidicworld.Suchalibraryofreusableandinteroperablemicrofluidicbuilding blocksisimportanttofillthegapbetweenlabandfab,asitreducesthetime-to-marketbylowering prototypetimecycles.ThewidesupportofkeyEuropeanplayersactiveinmicrofluidics,whichisshown byanISOworkshopagreement(IWA23:2016),makesthisapproachmorelikelytosucceedcompared toearlierattemptsinmodularmicrofluidics.
©2018ElsevierB.V.Allrightsreserved.
1. Introduction
The concept of Lab ona Chip (LOC) and micro total analy-sis(TAS)systemswasintroducedin 1990by Manzet al.,one ofthe pioneersin thefield [1]. Seventeen yearslater, the field hasalreadyshowedmajoradvancementbydemonstratingmany promisingconceptsforthevariouscomponentssuchassample prep,separationanddetectionthatarecombinedintoaTAS.Yet in2006Whitesidesarguedthatthefieldhadnotyetfullyreachedits potential,discussingthetypicalstrugglesfacedbynew technolo-giesincludingtheeaseofusefornon-experts,andthetransferof technologyfromacademytoindustry[2].Today,microfluidic tech-nologystillhasnotfullybecomemainstreamtechnology.Itappears
∗ Correspondingauthor.
E-mailaddress:m.odijk@utwente.nl(M.Odijk).
thattherearestillmanyhurdlestoovercomewhenmigratingan ideafromacademicsintoaproductreadyforthemarket[3].
Tobridgethegapbetweenacademicresearcheffortsandthe utilizationofmicrofluidictechnologiestoaddressrealworld prob-lems,standardizationisessential[4].Often,monolithic,bywhich Imeanout ofonepart,LabonChipsaredeveloped,integrating severalfunctionsontoasingledevice.Thisapproachoftenleads totherepeateddevelopmentofalreadyexistingconcepts, result-ing inlong development times.The need forhigh investments makesitexclusivelyeconomicforlargevolumes.Instead,a modu-larapproachcouldsignificantlyspeedupdevelopmentandprevent thewasteofdevelopmentresourcesbynot“reinventingthewheel”. Lessdevelopmenteffortisneededinmodularsystemsas standard-izedpartsofthesystemcanbereused.Theelectronicsindustry canbetakenasa goodexample ofwhere suchstandardization workswell.Inthatindustry,standardsexistforalmosteveryaspect frompackagedimensions,tostandardclassesforprintedcircuit boardmanufacturing,tosolderjoints.Thedevelopmentof stan-https://doi.org/10.1016/j.snb.2018.04.005
S.Dekkeretal./SensorsandActuatorsB269(2018)468–478 469 dardsmovedtheelectronicsindustryfromtheearly“spiderweb
assembly”inthe1950stothecomplexsystem-on-a-chip technol-ogyoftoday.
Toshowthatstandardizationdoesn’texists,atleastuptothe levelofinteroperability,inthestateoftheartmodular microflu-idics,alistismadeinTable1.Severalpapersandindustrialefforts toproducemodularmicrofluidicsystemsareshown.Itcanbeseen thatalthoughthesystemsaremodular,theyaredefinitelynot stan-dardizedandtherebypreventinginteroperabilitybetweenvarious modularsystems.Thetableshowselementsneededtoobtaina functionalsystem,frominterconnectstofunctionalblocks.Inour approachstandardizedfootprintsandstandardizedinterconnect gridsareused,weseeafuturewithinteroperablemodularblocksto buildmicrofluidicsystems.Lookingtowardsthefutureandbigger productionvolumes,severalexamplesareincludedwhere modu-larityisusedduringthedesignphase;linkingfunctionstogether, butstillproducingamonolithicdevice.
Oneoftheearliestmodularconceptswasdevelopedby Lam-merinket al.,introducingtheconcept ofa MixedCircuit Board (MCB)[5].Theboardconsistedofaprintedcircuitboardanda poly-carbonatesubstrate,respectivelyresponsiblefortheelectricaland fluidicinterconnectsbetweenactuatorandsensormodules.Others focusedmoreontheinterconnectitselfGonzalezetal.[6]described aself-aligningreversibleinterconnect.Greyetal.[7]useda differ-entapproachusingplasticpressfitcouplerstoconnecttubingto asiliconsystem.Asystemsimilartothemixedcircuitboard,but usinganodicbondinginsteadofadhesives,tomountthefunctional partsontheinterconnectpartswasdevelopedbySchabmulleretal. [8]
Initialeffortstoproduceamodularmicrofluidicsystemoften usedsiliconorglass,wellknownfromMEMStechnology.However, adisadvantageofthesematerialsisthattheyareonlyeconomically feasibleiflargenumbersareproduced.Forthefunctionalmodules thisisnotaproblem,asthesecanbemanufacturedinhighnumbers. However,theinterconnect solutionis oftenapplication-specific andthustendstobeproducedinlowernumbers.
Wegoetal.[9]lookedatprinted circuitboardtechnologyto fabricateintegratedmicrosystems.Printedcircuitboard technol-ogyhasless accuratedimensionaltolerancesthen conventional fabricationmethodsusedinthemicrofluidicfield.Howeveritis cheaper,especiallywhenproducinglownumbervolumes.Bythe introductionofpolymerlayersinthestack,theywereableto per-formmicrofluidicfunctions.
Othermaterialswerealsoinvestigatedforuseinmodular sys-tems.Microfluidicassemblyblocks,(MABs)madefromPDMSwere introducedbyRheeetal.[10].Theyaremountedsidebysideand sealedbyanadhesive.
Lego©wasaninspirationforVittayarukskuletal.[15]who pro-ducedafullyreversiblemicrofluidicsystembasedonPDMSLego blocks.TheelasticityofPDMSwasusedtoprovideasealbetween theblocks.Anotherplug-and-playsystemwasdevelopedbyYuen [12].Stereolithography3Dprintingwasusedtofabricatetheblocks forthissystem,whichwereinterconnectedusingmini-Luer con-nections.Miserendino[23] showedasystemusedaclampingto seal,withpatternablesiliconemicrogasketsbetweenthebaseplate andfunctionalblocks.
Strohmeier et al. [11] used a differentapproach when they definedafunctionalunitcell.Withthesefunctionalunitcellsthey designedcentrifugalmicrofluidicsdevices.Usingmodularityinthe designphasewhilestillproducingamonolithicdevice.Milletetal. [17]achievedsomethingsimilar,butthenforPDMSdevices.On thepouringmoldtheyaddedAcrylonitrilebutadienestyrene(ABS) stringsbetweenthevariouscomponentstocreateintegrated tub-inginthecasting.
Themicrofluidicindustryitselfhasalsolookedforsolutionsto interconnectmicrofluidicsystems.Oneexampleofsuchasolution
istheMATASplatform[20,24].ThisplatformisbasedonPCB tech-nologywiththeadditionofanextralayerforthefluidics.Blocks implementingmicrofluidicfunctionsareplacedinsidemilled cav-itiesin thePCBand areconnectedtothefluidiclayerbyusing O-rings. The blocks are fixed in place by solder. Another plat-formwasdevelopedbyEpigem[21]thatissimilartotheMATAS platform,butinsteadofPCBtechnologyitisfullybasedon thermo-plastics.Labsmithoptedforaslightlydifferentsysteminwhichthe modulesaremountedonaboardandforinterconnectionstubing isused.
Fromtheaboveitisclearalargevarietyofmodularplatforms exists,bothintermsofthelevelofintegrationinasingle mod-uleandtheplacewherethemodularityisimplemented.Hereby, makingreuseofthemodulesofseveralplatformsdifficult.
Inthefuture weforesee modularityinboth;physicalblocks intheendproductandalreadyduringthedesignprocess.Atone endofthespectrumistheunitcelloperationapproachduringthe designphaseusedbyStrohmeieretal.[11]andtheplug-and-play systemsofYuenetal.[12–14]attheother.However,itwouldbe beneficialiftheseapproachescouldbeusedinconjunctionwith each other;forexampleiftheauxiliary componentsofthe sys-temarein aplug-and-play fashionwhilethemain chipcanbe designedusingfunctionalunits.Inthispaperwefocusonthe plug-and-play systemfor auxiliary components.To reachthis, some degreeofstandardizationisneeded.Unfortunately,developmentof thesemodularplatformsuntilnowisdonemostlyindependently bysmallgroupsofinterestedparties.Themodularplatform pro-posedin thispaper stronglyarguesforstandardization.A large multinationalconsortiumisbackingandco-developingthis stan-dard[25].Thefocusliesontheabilitytointerconnectpartsfrom varioussupplierstogether.Withthiswehopetoattaina flourish-ingecosysteminwhichmicrofluidicpartsproducedusingvarious techniques (polymer, glass,and silicon) are both available and interconnectable.Tohelptheenduser,alibraryofstandardized partsandfunctionalityisalsodeveloped,supportedbysoftware managingthecompletepipelinefromdesigntotheproductionofa microfluidicsystem[26].Ifwedrawanotheranalogyfromthe elec-tronicsindustry,thislibrarycouldberegardedasthecatalogofbig componentsupplierssuchasNewarkandFarnell.Using schemat-icsandroutingsoftware,thesecomponentstogetheraredesigned tofunctionascomplexelectronicsdevices.
Following our approach, we make use of a combination of microfluidic building blocks (MFBB) and fluidic circuit boards (FCBs).Inthisapproach,theMFBBcontainsthefluidic function-ality and the FCB connectsallthe buildingblock togetherin a microfluidicsystem.BoththeMFBBsandFCBsaredesignedand fab-ricatedbyindustrialandacademicpartnersaccordingtoguidelines, documentedinaISOworkshopagreement[27–29].This standard-izedapproachmakesitpossibletoreusemodulesandhavethem interoperablebetweenseveralpartners. Moreover,it allowsfor atop-downdesignapproachsavingvaluabledevelopmenttime. Havingindustrialpartnersinsidetheprojectgivestheprospectof havingcommercialofthe-shelf-partsavailableinthefuture.
2. Standardizationanddesignconcepts
2.1. Definespecificationfromrequirements
Whendesigningamicrofluidicsystemitis,ofcourse,important toknowwhattherequirementsfortheindividualsystemare. Mov-ingforward,decisionsaremadewithregardtothespecifications ofthemicrofluidicsystem.Fromthispoint,astartismadewith thephysicalrealizationofthesystem.Inthemicrofluidicworld,a bottomupapproachisoftenusedwherethefabricationtechnology playsalargeroleinthedesignconsiderations.Animportant
advan-470 S. Dekker et al. / Sensors and Actuators B 269 (2018) 468–478 Table1
overviewofmodularityinmicrofluidics.
Inventor(s) Typeoffluidicpart Mainmaterial Totalsystem Typicalapplicationfield ModularinPhysical part/design
Reversible
Academics
Lammerinketal.[5] Functionalblocks connectedbyabaseboard.
Si/Glass Yes Chemistry Modularityinphysicalsense No,modulesare
permanentlyfixedtothe baseboard
Gonzalezetal.[6] Interconnectsforassembly ofamodularsystem
Si/Glass No,onlyfocusedon interconnect
Broadapplication Modularityinphysicalsense Yes,SiliconeO-ringare usedsotheconnectionis reversible.
Grayetal.[7] Interconnectsforassembly ofamodular
system
SI/Glassdevice PlasticCoupler
No,onlyfocusedonworld tochipinterconnects
Broadapplication Modularityinphysicalsense Yes,butanewcoupler mightberequired Schabmulleretal.[8] Functionalblocks
connectedbyabaseboard.
Si/Glass Yes Chemistry Modularityinphysicalsense No,modulesareanodically
bondedtothebaseplate. Wego[9] Functionalblocksmadein
PCBtechnology
CopperplatedFR-4 No,afewcomponentare showninPCBtechnology
Broadapplication Modularityinphysicalsense Yes,tubingisusedfor interconnection. Rhee[10] Functionalblockconnected
directlytoeachother
PDMS Yes Biological,PCRandcellculturing Modularityinphysicalsense No,Adhesiveisusedto interconnecttheblocks Strohmeieretal.[11] Unitoperationsconnected
togetherinamonolithic centrifugaldevice
Mainlypolymer Yes Broadapplication Modularityindesign No,amonolithicdeviceis fabricated
Yuen[12–14] Systembuildentirelyout ofblocks
Polymerwith3dprintingas structuringmethod
Yes Simplesystems Modularityinphysicalsense Yes,aminiLuerormagnet isusedtoconnectthe blocks.
Vittayarukskuletal.[15] Systembuildentirelyout ofblocks
PDMS Yes Simplesystems Modularityinphysicalsense Yes,compressionofPDMS
isusedtomakeafluidic seal.
Shaikhetal.[16] Interconnectsaremadeon abaseplatecontaining multiplefunctionalities.
PDMS Silicon
Yes Biochemicalanalysis Modularityindesign Noteasy,asthePDMSis bondedtotheSilicon. Milletetal.[17] Functionalunitsare
connectedby3dtubes
PDMS Yes Biochemicalanalysis Modularityindesign No,amonolithicPDMS
deviceiscasted. Bhargavaetal.[18] Systembuildentirelyout
ofblocks
Polymerwith3dprintingas structuringmethod
Yes Dropletbasedapplications Modularityinphysicalsense Yes,anelasticreversible sealisused
Loskilletal.[19] Differentorganchambers, interconnectablewith connectors
PDMS Yes Organ-on-a-chip Modularityinphysicalsense Yes,connectionsmade
withtheconnectorblocks arereversible
Industry
Lionix[20] Functionalblocksare mountedinaPCB/base board
FR-4 Si/Glass
Yes Chemistry Modularityinphysicalsense Yes,modulesare
mechanicallyfixedby solderingandsealingis donewithO-rings. Epigem[21] Functionalblocks
connectedbyabaseboard
Polymerbased Yes Broadapplication Modularityinphysicalsense Yes,modulesare mechanicallyhelddown.A PTFEferruleprovidesthe seal
Labsmith[22] Functionalblocksmounted onabaseboard,connected bytubing
Several Yes Broadapplication Modularityinphysicalsense Yes,Tubingconnectorsare reversible
S.Dekkeretal./SensorsandActuatorsB269(2018)468–478 471
Fig.1.Standardizeddimensions:a.MFBBoutlinedimensions,b.Gridstartingposition,c.Gridpitchandd.Portannotationandpreferred(bold)portpositions.,e.cross sectionoffiguredinatypicalusagescenario,wheretheMFBBisclampedtotheFCBandthesealbetweenthemisfacilitatedbyanO-ring.
tageofusingamodularplatformisthatthefunctionaldesignand physicaldesigncanbedecoupled.Again,usingtheanalogywiththe electronicsindustry,thiswouldtranslatetothefunctionaldesign describedbyaschematic,whilethephysicaldesignisthelayout ofall thetransistorsinside anintegratedcircuit. Accordingly, a topdowndesignschemecanbeusedforthedevelopmentofthe microfluidicsystem.
2.2. Functionalvs.physicaldesign
Thisdecouplingofthefunctionaldesign andphysical design makesit possibletowork withstandardized functional blocks, whichonlyneedtobedesignedandcreatedonce.These standard-izedfunctionalblocksgiveamicrofluidicdesignertheopportunity tofocusmerelyonthefunctionofamicrofluidicsystem.Forthis systemofstandardizedmicrofluidicblocks,mostofthecommon functionsshouldbeavailabletothedesignerinastandardform. Thedesignershouldalsohavetheopportunitytodesignnewblocks thathaveaspecificfunctionality,butwhichstillconformstothe standard.AdesignercanbeassistedbymakinguseofaCAD sys-tem.Alibrarycontainingthefunctionalbuildingblockshelpsthe designertoquicklycreateanewmicrofluidicsystemandprevents thereinventionofthewheeloftenseeninmicrofluidics.
2.3. Flexibility
Theflexibilityinthissystemisthefreedomtochoosehowto interconnectthebuildingblockstogether.Thisflexibilityfindsits implementationintheFCB.Thismeansthateachsystemhasits owncustomimplementationofaFCB.Nevertheless,theinterface betweentheFCBandtheMFBBremainsstandardized.Thisprovides practicaladvantagessuchasthesecondsourcingofpartsfrom var-ioussuppliersandtheabilitytointerchangebuildingblocksthat haveslightlyvaryingfunctionality.Mostoftheinterfacing hard-wareissituatedintheFCB,sotheinterfacingcanbemadetofitthe requirementsthatarespecifictoaparticularapplication.
3. Standardizationinphysicaldimensions
TomakethisbuildingblockandFCBcombinationwork, inter-operabilitybetweenthevariouscomponentsisneeded.Therefore,
thereisaneedtostandardizetheoutsidedimensions.Thismakes itpossibletouseastandardizedsystemtoconnectthebuilding blockstotheFCB.Toaligntheports,a standardgridisusedas showninFig.1.Inletandoutletsareplacedonthisgrid. Further-more,thestandarddictatesthatthesealingbetweentheFCBand MFBBisrealizedintheFCB,whichsealstotheflatbottomofthe MFBB.Howthissealisrealizedisuptothemanufacturerofthe FCB,providingapossibilityforindustrialpartnerstodistinguish themselves.AnexamplewithO-ringsisshowninFig.1E.
Withinthestandardframework,thereareseveraloptions(see [28]forfulllist)fortheoutsidedimensionsoftheMFBB:forsmaller chips15×15mmoramultipleof15mmsuchas15×30mm.For largerchips,thestandardincludesouterdimensionsof75×25mm, 75×50mmand84×54mm.Theselargesizesaresimilartothe alreadycommonformatssuchasthemicroscopyslide,orthecredit cardinthemicrofluidicworld.
Thepitch,ascanbeseeninFig.1,isalsochosentobecompatible withalreadycurrentlyusedformats(e.g.microtiterplate)inthe microfluidicworld,whilestilltryingtoobtainasmallpitchsothat highinterconnectapplicationsarepossible.
Besidesfluidicinterconnects,amicrofluidicsystemsometimes needsaninterconnectwhichisdifferentthanafluidicone. Electri-calandopticalinterconnectsaretypicalexamples.Intheelectronic field,therearealreadyplentyofstandardsandproductsavailable asitisamuchmorematuremarket.Theguidelinesalso recom-mendusingthesestandardproductsforexampleconnectorsand springloadedprobes,buttogrouptheinterconnectsinaspecific areaontheMFBB.
4. Methods
Theaboveparagraphsdescribeanewwayofdesigning microflu-idicsandthecorrespondingnecessarystandardization,whichthe MFManufacturingconsortium[25]isattemptingtorealize.Inthis paper,thefocusisonvariouspartsneededtodesignaccordingto thisnewmethod,withafocusonthetypicalauxiliarypartsused inamicrofluidicsystem:inletreservoir,pump,flowandpressure measurementandinterfacing.Ourapproachwillalsotostaytrue totheLabonaChipconcept,ratherthantheChipinaLabwhich iscurrentlyoftenseen.Tobeabletodesignwiththisfunctionality drivenapproachasmallpartofalibraryofbasicbuildingblocksis
472 S.Dekkeretal./SensorsandActuatorsB269(2018)468–478 proposedinTable2.ForsixoftheMFBBs,amoredetailed
descrip-tion,includingfabricationdetailsanddevicecharacterizationtests, aregiveninthefollowingparagraphs.
4.1. DifferentialpressuresensorMFBB
The pressure sensor building block (as shown in Table 2A) is a package to connect to a Honeywell differential pressure (24PCAFA6D).Thispackagemakesitpossibletofitthissensortoa FCBusingastandardizedinterface.Togetherwithahydraulic resis-torintheFCB(e.g.asimplechannel),thisbuildingblockcanalso serveasaflowsensorbymeasuringadifferentialpressuredrop acrossthischannel.
ThematerialofchoiceforthesebuildingblocksisaCOC(Topas grade6013, Axxicon,The Netherlands).Thismaterial is chosen becauseofitschemicalresistancetoawiderangeofchemicalsand theopportunitytoscaleupproductionapplyingmethodssuchas hotembossingorevenroll-to-rollhot embossing.Thisprovides theabilitytosuitapplicationsthatwillbesubjecttohighchemical constraintsandhigherproductionvolumesinthefuture,whilefor quickprototypingmicro-millingwasused.Tobondthefourlayers together,solventassistedthermalbondingwasused[30].APCB wasmountedontopoftheMFBBtoprovideelectrical interconnec-tiontotheMFBBusingaflatflexcable.
4.2. ClampingMFBB
ToconnectthebuildingblocksfortheFCB,severalclamping connectorsaredeveloped.TheseclampsarescrewedontotheFCB tofixtheMFBBand ensureport alignmentand compressionof theO-ringstoachieveaneffectiveseal.ClampsA(Table2E)and B(Table2F)areusediffluidicconnectionsaremadebetweenFCB andMFBB.ClampC(Table2G)isusedifadirectfluidicconnection totheMFBBorFCBviatubingisrequired.Allclampsarefabricated bydirectmilling.ThetubingusedincombinationwithclampCis connectedusingferrulestoformatightfittotheMFBBorFCB. 4.3. ValveMFBB
CEA-LETIdevelopedapneumaticvalve(seeTable2B), consist-ingofanassemblyofCOClayers,includinganEPDMdiaphragm [31].Thisvalveispneumaticallyactuated.Thedesignisadaptedto theend-userapplication(flowrate,deadvolumes,anddiaphragm material). Depending on the design, the flowrate can reach 50mL/min,andthepneumaticpressuretoclosethevalveis engi-neeredtobebetween100kPaand500kPa.Thefootprint(layout, I/Oposition)isidenticalforallthevalves.
4.4. PumpMFBB
ThepumpMFBBisbasedonthepreviouslypatented[32] oscil-latingrotarypistonpumpprinciple(seeTable2D).Thispumpis manufacturedusingthermoplasticinjectionmoldingusing poly-mersandelastomersthatcanbeadaptedtotheapplication. 4.5. ReservoirMFBB
ThereservoirMFBB(seeTable2C)isfabricatedbymillingablock ofPMMAasatopholderfor1.5mLHPLCsamplevials.Thistopblock alsocontainsholesforthreeneedles;twooftheseneedlespuncture theseptumofthevialtobeabletoapplypressureinsidethevial andcollecttheresultingflowofliquid.Thethirdholeisusedfora bluntneedlethatfitsontotubingandconnectstheexternal pres-surepumptotheMFBB.Alayercontainingmicrofluidicchannelsis
Fig.2. FCBwithintegratedvalves.
solvent-bondedtothistopblocktoroutethefluidsorgasesfrom theseneedlestothedesiredpositions,asdefinedbythestandard. 4.6. ReactionchamberMFBB
Thereactionchamberisacustom30×15MFBB(seeTable2H). Thevolumeofthechamber,thefiltersandtheembeddedreagents (powders,beads...)areadaptedtotheapplication.Somedesigns integratepneumatic valves(seeTable2B).In theexample,two 20m stainless steelfilters are embeddedin thechamber and 50mbeadsarepackedbetweenthetwofilters.TheMFBBis com-posedoftwoCOClayers(orthreedependingonthedesigns).
5. Fluidiccircuitboard
TheFCBisalwaysacustompartthatfitsaspecificapplication andinterconnectsthebuildingblocksinaspecificway.Three differ-enttypesofFCBarediscussedwithdifferentlevelsofcomplexity. 5.1. Simplepolymer-basedFCB
ThisFCBwasdevelopedtotestthepressuresensorMFBB,to evaluatehowitfunctionsasaflowsensor.ThisFCBisfabricated inasimilarwaytotheMFBBandconsistsoftwolayersofZeonor 1020Rwhichcontainsaremilledcavitiesandchannels.An assem-bledversionofthisFCBisshowninFig.3.Thechannelsmilledinto thefirstlayerareclosedoffbythesecondlayerbymeansofsolvent bonding.Thecavitiesmilledinthetopsideofthesecondlayerare opentoacceptthebuildingblocksandtoensureaccurate align-mentbetweenthechannelsintheFCBandthoseinthebuilding block.TheinterconnectbetweentheFCBandthebuildingblockis formedbystandardVitonO-rings.TherearecavitiesintheFCBto holdtheO-ringsinplace.
5.2. Complexpolymer-basedFCB
ThisFCB shown inFig. 2incorporates integrated membrane valvesforcustomizedflowcontroltotheMFBBs.Thesemembrane valvescanbepneumaticallyactuatedtodirectflowbothfromand toMFBBsattachedtotheFCB.Thisallows,forinstance,the direct-ingoffluidstoamixerchamberandholdtheseliquidsinsidethe chamberduringthemixingprocessbeforedirectingthefluids fur-ther.ThisFCBisfabricatedinasimilarfashiontothatdescribedfor thesimpleFCBalsousingmillingandthermalcompressionsolvent bonding.WhatmakesthisFCBcomplexisthatitconsistofsix lay-ersincludingamembranelayer.Eachlayerconsistsof1.5mmclear
S. Dekker et al. / Sensors and Actuators B 269 (2018) 468–478 473 Table2
Overviewofbuildingblockswiththeircharacteristics
Buildingblockwithphoto Description Mostrelevantcharacteristics
A.Differentialpressuresensor Abuildingblocktomeasurepressure.Duetothe differentialnatureofthemeasurement,aflow
measurementisalsopossible,bymeasuringpressuredrop overalengthofchannel
Flowcharacterization(R2=0.98928),Errorbarsindicatethe hysteresisoverthe1repetitionofthereferencepattern.
B.Pneumaticvalve15×15mm Avalvebuildingblocktoconditionallyrouteliquidsina microfluidicsystem.Controlledbypneumaticactuation.
PressureneededtocloseMFBBvalve.Lineforvisualguidance.
C.1.5mLFluidreservoir A1.5mLfluidreservoirwhichcanbeusedtoactivelypush liquidtroughamicrofluidicsystembyapplyingaregulated pressureabovetheliquid.
InternalVolumeof1.5mL
D.Highvolumepump Apumpcapableofobtaininghighflowratesevenwhena largebackpressureexists.
Pumpingperformanceatconstantactuation,withrespectto changingbackpressure.
474 S. Dekker et al. / Sensors and Actuators B 269 (2018) 468–478 Table2(Continued)
Buildingblockwithphoto Description Mostrelevantcharacteristics
E.15×15mmclampMFBB AclamptomountaMFBBwith15×15mmouter dimensionstothefluidiccircuitboard.Alsocompresses theO-ringbetweentheFCBandtheMFBBtofacilitate sealing.
ThisclampissuitedtomountdevicesshowninTable2A–C toafluidiccircuitboard.
Toplineforincreasingpressure,bottomlinefordecreasing pressure.Lineforvisualguidance.
F.15×30mmclampMFBB AclamptomountaMFBBwith15×30mmouter dimensionstothefluidiccircuitboard.Alsocompresses theO-ringbetweentheFCBandtheMFBBtofacilitate sealing.
Thisclampissuitedtomountthedeviceshownin
Table2H.
Similarcharacteristicsto15×15mmclamp
G.Fluidicseal30×15mm clampMFBB
Abuildingblockusedtoconnect10individualtubestoa FCBatonce.Elastomericferulesareusedtosimultaneously facilitatesealingbetweentheFCBandthetubes.
Similarcharacteristicsto15×15mmclamp
H.Customreactionchamber 30×15mmMFBB
S.Dekkeretal./SensorsandActuatorsB269(2018)468–478 475 polystyreneplatesandaSEBS(styreneethylenebutyleneethylene)
membranelayer.ThisSEBSmembranewaspreciselycutbyaCO2 laser.
5.3. Glass-basedFCB
Insomecases,polymerscannotbeusedduetotheirmaterial properties.Foroneofthesecases,aglassFCBisdeveloped.This FCBconsistsoftwoborosilicateglasslayers.Bothglasslayershave wetetchedchannelsusingtwo depthsof75 and200m.After bondingofthesetwolayers,thefinalchannelswillbe approxi-mately150mand400mindiameter.Thetoplayerhaspowder blastedthrough-holesfortopdownaccess,whereasinasecond designincludedinthesamebatch,anotherFCBallowsfordirect capillarygluinginsidethedeepchannelsfromtheside.Onthetop surfaceoftheFCB,platinumelectrodesaresputteredtoathickness of125nm,usingatantalumseedlayerof15nmtoimprove adhe-sion.Theseplatinumelectrodesareusedtocreatearoutingforthe electricalactuationoftheMFBBvalvesusedincombinationwith thisFCBdesign.TheconnectionbetweentheseMFBBsandtheFCB aremadeusingwirebonds.ThisFCBtherebydemonstratesboth fluidicandelectricalfunctionalitybyprovidinginterconnectsfor bothdomains.
6. Testmethods
6.1. Differentialpressuresensor
Thepressuresensorbuildingblocksarecharacterizedbothas apressuresensorandasaflowsensor.Forboththepressureand flowcharacterization,aknownpressureorflowisappliedtothe systembyapressuredrivenpump(FluigentMFCS-4C,France).A flowsensor(FluigenttypeL,France)wasusedinacontrolloopto obtainareliableflowrate.Whileapplyingvariousflowratestothe system,theoutputsignalofthebuildingblockisrecordedwitha custom-madeLabview2014applicationandMyDAQdata acqui-sitionsystem(National Instruments,TheNetherlands).Boththe pressureand flow areappliedina staircasepattern whichwas cycledfourtimes.Thepressure/flowofeachstepinthestaircase patterniskeptconstantataplateauvaluefor30s.Fig.3showsthe completetestsystem,whichisbasedonthesimplepolymerFCB, andincludestheflowsensorMFBB.Itconsistsoffourstandardized buildingblocksconnectedserially,startingwithaninletblock, fol-lowedbythedifferentialpressuresensor,ablockingplatetoallow forfutureextensions,andanoutletblock.
6.2. ValvesintegratedinthecomplexpolymerPCB
Thevalvesintegratedinthecomplexpolymer-basedFCBare testedusingapressurepump(FluigentMFCS-EZ)fittedwithan in-lineflowsensor(FluigenttypeL).Thepressuretothevalvecontrol channelisvariedfrom0tomax.200kPa,whiletheresultingflow isrecorded.Thisisrepeatedforthreedifferentpressures(40,60, 80kPa)appliedtothereservoirholdingtheliquidflowingthrough thevalve.
6.3. ValveMFBB
AvalveMFBBischaracterizedusingacustomFluigenttest plat-formincludingatwo-channelpressure regulatorandanin-line flowsensor(FluigenttypeXL).Thesystemisrunthrougha ded-icatedLabVIEW(NationalInstrument)interfaceusingtheFluigent SDKthatprovidesafullyautomatedoperationanddataanalysis. Thepressureneededtoactuatethevalveisvariedfrom0to100kPa in5kPa steps.For eachstep,theflow rateis recordedduringa periodof1s(10pointsevery100ms)afterwaitingfor3stoensure
thesystemisinasteadystatecondition.Thisoperationisrepeated forthreefluidinletpressures(25kPa,50kPaand100kPa).
6.4. PumpMFBB
The pump MFBB is characterized using a measurement of thedisplacementvolumeinvariousbackpressureconditions.The backpressurepressureiscontrolledusingaclosedcontainer,the pumpisactuatedataspeedof30rpmforagivennumberofcycles. Theobtainedfluidvolumeallowsthemeasurementofthepump displacement.Thetestisrepeatedforseveraldownstream pres-sures.Theobtaineddisplacementwithabackpressureof0kPais normalizedto100%.Theefficiencyofthepumpiscalculatedbased ontheabilitytosustainthisdisplacementathigherbackpressures.
6.5. ClampingMFBB
ThesamesystemasthatshowninFig.3isusedforleaktesting. TheclampingMFBBwasattachedtotheFCBusingfourboltsfor eachMFBB.AVitonO-ring,placedinarecessintheFCB,provides thesealbetweentheMFBBsandtheFCB.Onlyaninletblockwas used,whiletheotherportsontheFCBwerecappedbyablocking plate.Totestforleaks,thesystemwasfilledwithDIwaterbefore positioningthefinalblockingplate.Thepressureattheinletwas appliedbyapressure-drivenpump(FluigentMFCS-4C,France)ina rangefrom0kPato600kPa.Aflowsensor(FluigenttypeL,France) wasplacedinlinetocheckiftheflowremainedatzero.Thepressure wasappliedinastaircasepatternbothupwardsanddownwards. Thesystemwasallowedtocometoequilibriumbeforetakinga flowmeasurement.
7. Resultsanddiscussion
7.1. Characterization
7.1.1. DifferentialpressuresensorMFBB
Repackagingthiscommercialpressuresensor,tocomplytothe new standard, does not negatively impact its excellent perfor-mance.Thepressureresponsestillbehaveshighlylinear.Withthe MFBBconnectedtothesystemshowninFig.3,itsperformance asaflowsensorwasalsoevaluated.ThefigureinTable2Ashows thesensoroutputvoltageforvaryingflowrates.Theoutputofthe flowsensorisverylinear(R2=0.98928).However,asmall devia-tionfromperfectlinearbehaviorcanbeobserved.Thisisprobably causedbythefactthatthereferenceflowsensor(FluigenttypeL) wasoperatingatlowflowrates,outsideofitsoptimumoperating range.Thissuspicionisconfirmedbycheckingthemeasuredflow bytheMFBBasafunctionoftheappliedpressurebythepump,we againseeahighlylineartrend.
7.1.2. HighvolumepumpMFBB
TheMFBBpumpisabletodisplace300Lpercycle,achieving flowratesupto90mL/min.Anotherkeyfeatureisitsself-priming, valveless, blockingnature:makingthepumpsuitedtoparticle loadedliquids.Moreimportantly,nofluidflowthroughthepump ispossiblewhenthepumpisnotdriven.Thisisanadvantagewhen eitherhighorlowpressuremustbemaintainedattheportsofthe pumpbeforeorafterpumpingphases.ThefigureinTable2Dshows asustaineddisplacementforvariousbackpressures.Thediaphragm pumpisnotabletosustainaconstantdisplacementforthevarious backpressures.Moreover,thepumpMFBBisalsoreversibleasit behavesinexactlythesamewaywhentheactuationdirectionis reversed;theinletbecomingtheoutletandviceversa.
476 S.Dekkeretal./SensorsandActuatorsB269(2018)468–478
Fig.3. CompletesystemtomeasureflowinfluidiccircuitboardwithmountedMFBBs.
Fig.4. Closingpressureofanintegratedvalve.Lineforvisualguidance.
7.1.3. ValveMFBB
ThefigureinTable2BshowstheclosurebehavioroftheMFBB valve.Theresultsshowsthatbyapplyingsufficientpressuretothe controlline,thevalvecanbeclosedforallthreeinputpressures. Whenpressureshigherthanthefluidpressureareappliedtothe controlline,theflowisreduced.
7.1.4. IntegratedFCBvalvefromthecomplexFCBdesign
Fig.4showstheclosurebehavioroftheintegratedvalvesinthe complexFCBdesign.In Fig.4,three linesarevisibleforvarious pressures(Ps)appliedtothereservoirholdingtheliquidflowing throughthevalve.Asexpected,thevalvesareabletocloseandstop theflowifsufficientpressureisappliedtothecontrolchannels.A controlpressureequaltothepressureappliedtotheliquidreservoir resultsinclosureofthevalve.
7.1.5. ClampingMFBB
ThefigureinTable2EshowstheO-ringsealsbetweentheFCB andMFBBuptoapressureofatleast600kPa.Whenthepressureis increasedfrom0to100kPathereisaslightpositiveflow,whereas forthedecreasingstepstheoppositeeffectisseen.Thiscanbe explainedbytheairthatwastrappedinthesystembeing com-pressedandrelaxing,allowingliquidtoflowintothesystemand outagain.
7.1.6. Designconsiderations
The current stateof standardization is compatible with fre-quently used fabrication technologies, including less accurate technologieslikedirectmilling.Thisresultsinrelativelylarge build-ingblocksformicrofluidicsystems,withlongchannelstoconnect theseblocks.Trade-offs betweenforexample dead-volumeand pressure dropover thechannelsneed tobemade. Thevarious 90◦ corners,thefluid encounters,traveling fromtheFCB tothe MFBBandbackcanhaveunintendedbehaviorlikebubbletrapping, addingdeadvolumeormixing.Thesedrawbacksofamodular plat-formarenotnecessarilyaproblem,byintegratingsensitiveparts intheMFBBandhavingrobustinputandoutputsontheMFBB.
8. Conclusions
Inthispaper,wehaveproposedamodularplatformthatuses standardmicrofluidicbuildingblocks.Togetherwitharapid man-ufacturing processes, this demonstrates a unique platform for quickandstraightforwardresearchanddevelopment.Thisis espe-cially important to reduce the existing gap for applicationsto bridgethelab-to-fabgap,byreducingthetime-to-market.Thisis mainlyachievedbyseparatingthefunctionalandphysicaldesign byusingatop-downdesign approach.We havedeveloped sev-eralbuildingblockswithbasicfunctionalityincludingreservoirs, valves,flowandpressuresensors,andahighvolumepump. Dur-ingdevelopment materialswerechosen tobe compatible with quickprototypingfabrication,butalsoscalabletoother manufac-turingtechniquestoachievehighervolumes.Weshowhowthese buildingblockscanbecombinedbyusingaFCB.Theuseof stan-dards,inboththeMFBBandinterconnects,allowsstraightforward andrapiddevelopmentofearlyprototypes.Moreover,it demon-stratesthecombineduseofavarietyoffabricationtechnologies inseveralmaterialssuchasglass,polymersandsilicon.The com-bineduseoftheseisdifficulttoachieveinatraditionalmonolithic lab-on-chipdevice.Inthefuture,wewilldevelopmorebuilding blockstoextendourlibrary.Thislibrarywillbemadeavailable in2017throughtheMicrofluidicsManufacturingwebsite[25]and on-linethroughamarketplace[26]toenablebroadadoptionbythe microfluidicscommunity.ThewidesupportofkeyEuropean play-ersthatareactiveinbothmanufacturing,designandequipmentfor microfluidicsiswhatwillmakethedifferencecomparedtoearlier attemptsatmodularmicrofluidicsdesign.
Acknowledgementsandcontributions
HennevanHeeren(EnablingMNT)isgratefullyacknowledged forhisinputonstandardizationinthispaper.HansdeBoerandJan vanNieuwkasteeleareacknowledgedfortechnicalsupport.
S.Dekkeretal./SensorsandActuatorsB269(2018)468–478 477 ThisworkwassupportedbyENIACJointUndertaking (JU),a
public-privatepartnershipfocusingonnanoelectronicsthatbrings together ENIAC Member/Associated States, the European Com-mission,andAENEAS(anassociationrepresentingEuropeanR&D actorsinthisfield).
ThevalveMFBBisdevelopedbyCEA,boththecomplexpolymer andglassFCB,andtheclampsaredevelopedbyMicronit.Eveon developedthehighvolumepumpMFBB,whilethepressure/flow sensor,liquidreservoir,andsimpleFCBisdevelopedbythe Uni-versityofTwente.
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Biographies
S.DekkerStefanDekkerisaPhDstudentattheUniversityofTwente.Heobtained hismasterinElectricalEngineeringattheUniversityofTwente(2014).Currently, heisworkingonstandardizationinthefieldofmicrofluidics.
W.BuesinkWilfredBuesinkisHeadofProductDesignatMicronit Microtechnolo-giesBV,leadingthedesignteamandcoordinatingthemicrofluidicsbusinessunit. HereceivedaMSc.inmechanicalengineeringfromtheUniversityofTwentein2007, focusingoninterfacingformicrofluidics.
M.BlomMarkoBlom(M),PhDisCTOatMicronit.Priortothisheworkedasa researchscientistforPolymerLaboratoriesaftercompletinghisPhDentitled “On-chipseparationandsensingsystemsforhydrodynamicchromatography”in2002. DuringhisPhDandsubsequentworkMarkohasfocusedonenablingandapplying microfabricationandmicrofluidicstechniquesforsolvingchallengesinthe lab-on-a-chipandBioMEMSfields.
M.AlessioM.AlessiograduatedfromJ.FourierUniversityofGrenobleinthephysical measurementsdepartment(IUT1)andobtainedaprofessionallicense(Optronic)in 2006.Since2009heisworkingasmanufacturingandpackagingtechnicianat CEA-Letiinthemicro-technologiesforbiologyandhealthcaredivisiontodesignand producemicrofluidiccomponentsandpackagesiliconmicrosystems.
N.VerplanckNicolasVerplanckobtained hisMScinInstrumentationat Poly-tech’Lille,anengineerschoolfromtheUniversityofLille(France)in2004inparallel withhisMScinMicrotechnologyandhisPhDattheIEMN/UniversityofLille(France) in2007.Hisworkwasfocusedonelectrowettingonsuperhydrophobicsurfaces formassspectrometry.Followingthis,hejoinedVariopticinLyon(France)asa projectleaderanddeveloped,fromtheprototypetotheindustrialization,aliquid lensforopticalimagestabilization.From2011–2013,heheldacustomerproject managementpositionatSMCPneumaticswhereheworkedwithworldleading medicalcompaniestoprovideassembledfluidiccomponents.Sincesummer2013, heisworkingasresearchengineerandprojectmanageratCEA-LETIinthe micro-technologiesforbiologyandhealthcaredivisiontomanage(i)thedevelopmentand theproductionofmicrofluidiccomponents(lab-on-a-chipsandpoint-of-care)and (ii)thestandardizationinmicrofluidics(MFManufacturingproject,AFNORB35A, ISOTC48/WG3).
M.HihoudMajidHIHOUDisMechanicalEngineeratEVEONspecializedinactuation andmechatronics.Afterworkinginvariousfieldslikeaeronautics,spaceanddefense industries,hejoinedEVEONwherehecontributestomedicaldevicesdesignand tests.
C.DehanChristopheDehanisBusinessDevelopperandIPManageratEVEON.He graduatedfromParisTechArtsetMetiers(1987)andobtainedhisMasterofScience inMaterialsatVPI&SUUSA(1989).Hehassincepursuedcustomerandoutcome focusedmultidisciplinaryinnovationinseveralindustriesacrosspositionsfromR&D DirectortoProductManagement.AsR&DDirectorwhenhejoinedEveon,hewas theco-inventorofcoretechnologiesformedicalmicropumpsandautomatedmixing andreconstitutionssystems.
W.CésarWilliamCésarisanR&DprojectmanageratFluigent,workingonvarious projectonflowcontrolsystemsformicrofluidics.HerecievedaPh.D.in
engineer-478 S.Dekkeretal./SensorsandActuatorsB269(2018)468–478 ingworkingonmicro-chromatographsandnumericalmodelsforindoorairquality
monitoring.
A.LeNelDr.AnneLeNel,previouslyCSOofFluigent,hasbeenactiveformorethan12 yearsinthedevelopmentandmanufacturingofspecificinstrumentsandcustomized productsdedicatedtodifferentapplicationsinmicrofluidic.DrLeNelledteamsthat developmicrofluidicinstrumentsandplatformsforR&Dandoemmarkets.Shehas ledprojectsacrossflowcontrolfromproofofconceptthroughproductintroduction andsupport.Shewasinchargeofthedevelopmentandreleaseofthenewproduct rangesofthecompanyfrom2012to2015(>15products,hardware&software). Beforethat,shewasinchargeofthedevelopmentofsamplepreparation instru-mentsforabigFrenchactorinthedefensesectorintegratingpreconcentration, lysisandpurificationstepsinvolvingmolecularbiology,electronics,microfluidics, andmechanics.SheisnowresponsiblegloballyofindustrialprojectsandtheOEM business.
A.vandenBergAlbertvandenBergreceivedMScinappliedphysicsin1983,andhis PhDin1988bothattheUniversityofTwente,theNetherlands.From1988–1993he
workedinNeuchatel,Switzerland,attheCSEMandtheUniversity(IMT)on minia-turizedchemicalsensors.From1993until1999hewasresearchdirectorMicroTotal AnalysisSystems(TAS)atMESA,UniversityofTwente.In1998hewasappointed aspart-timeprofessor“BiochemicalAnalysisSystems”,andlaterin2000asfull pro-fessoronMiniaturizedSystemsfor(Bio)ChemicalAnalysisinthefacultyofElectrical Engineering.
M.OdijkMathieuOdijkisanassociateprofessorattheUniversityofTwente,leading theresearchthemeonmicro-andnanodevicesforChemicalAnalysis.Hereceived aPh.D.inelectricalengineeringfromtheUniversityofTwentein2011, develop-ingelectrochemicallab-on-chipstostudydrugmetabolismreactions.Hiscurrent researchfocussesonthedesigningnovelnano-andmicrofabricatedtoolstotackle challenginganalyticalmeasurementproblems,unsolvablebytraditionalmethods duetotheirslowspeed,lackofsensitivity,orpoorspatialresolution.
