Capstone2011:MicrofluidicLab‐on‐a‐ChipforDeliveringTargetedAlphaTherapy

PresentedtotheMaterialsScienceandEngineeringDepartment,UniversityofMarylandby:

TriciaAlward,TunjiGodo,CoitHendley,IainKierzewski,MichaelMeadows,NinoskaMoratin,WilliamSchoenfelder,NicholasStrnad,RobertThompson

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TableofContents

Title1

TableofContents2

Abstract3

Motivation3

MaterialsScienceandEngineeringAspectsandReviewofPriorWork3

DesignGoals4

TechnicalApproach5

EthicsandEnvironmentalConcerns9

IntellectualMerit10

BroaderImpact11

SimulationResultsandDiscussion11

Conclusions30

AcknowledgementsandReferences31

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IAbstract:

Thegoalofthisprojectistodesignamicrofluidicdevicethatwilltreattumorcells.TargetedAlphaTherapy(TAT)isusedtodelivertheradiationsourceasindividualradioisotopestothedesiredtumorcellsinthebody.Thechelatingagent,DTPA,willbemixedwithamonoclonalantibody(mAb)inasolutionofwater.Actinium225,whichhasahalf‐lifeof10days,isthentransferredtothedeviceusingalpharecoil,resultinginimplantedBismuth213.BasicmodelingwasdoneforthedissolutionofthesucrosefilmthatcapturestheBismuth,andFluentwasusedtomodelthemixingbehaviorofthefluid.

IIMotivation:

OurmotivationforthisprojectistodesignamicrofluidicdevicethatwilladministerTargetedAlphaTherapy(TAT)quicklyandefficientlytoapatient.TATitselfiscurrentlyinclinicaltrialsforabroadrangeofcancers,butisextremelyexpensive,withthecostofonedoserangingfrom$10,000‐$40,000.AnotherimportantproblemwithTATistheneedtohaveageneratoron‐sitebecauseoftheshorthalflifeoftheradio‐isotope,Bismuth213(45min).Alab‐on‐a‐chipdevicewouldsignificantlyreducethecost(to$7.77pergenerator)andmakethetreatmentavailabletoamuchwiderrangeofhospitalsandasaresult,patients.

IIIMaterialsScienceEngineeringAspectsandImportantPriorWork:

Asmaterialsscienceandengineeringstudentsourmainobjectivewastodesignapracticalsystemwithanemphasisontheinterconnectionbetweenthestructuresofthematerialsweintendedtouse,thewaywewouldprocessthembasedonourdesign,thepropertiestheywouldhaveasaresultoftheprocessingandthewaythematerialsperformedbasedontheirproperties.

Ourdesignrequiredasucrosefilmthathadathicknessof1μmandbasedonour

discussionwithDr.PhaneufandwhatwelearnedfromkineticsENMA471,apolycrystallinefilmwithasmallcrystallitesizewouldbedesirablebecausethesepropertieswillaidthedissolutionrateofsucrosemicroprocessing.BasedonourskillsacquiredfromtakingENMA465,aclassonnanoscaleandmicroscaleprocessingofmaterialswithanemphasisonthinfilmprocessingforadvancedtechnologies,wenowspincoatedsucroseonasiliconwafertomakeafilmof1μmthicknessattheFabLaboncampus.

Materialscharacterization:Wenowhadtoverifyifthefabricationprocessyieldedthe

propertiesofthesucrosefilmwedesired,sobasedonwhatwelearnedfromENMA310,amaterialslaboratory,weusedx‐raydiffractiontodeterminethecrystalstructureand

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crystallitesizeofthesucrosefilm.Wehadalsolearnedaboutthetheoreticalprinciplesofx‐raydiffractionfromENMA460,solidstatephysics.

OurknowledgeofkineticsandourdiscussionwithDr.Phaneufenabledusto

understandthattheprecipitationandthenheterogeneousnucleationatthesurfaceofthefilmwouldbegovernedbykineticsandthermodynamics,ENMA461.Theteam’sknowledgeofsolidstatephysicsalsoenabledustounderstandthatphononsaregeneratedthroughcollisionsofBiatomsintosucrosefilmbysimulatingionimplantation.ThekineticMonteCarlosimulationofnucleardecayandtimestep,thediffusivityofBiintocollectionareaandthediffusionandconvectionofBismuthacrosschannelsareallmaterialsscienceandengineeringaspectsbasedonkinetics.

TargetedAlphaTherapyinvolvingtheuseofradioisotopeslikeAc225andBi213forbiomedicalapplicationsandparticularlycancerhasbeeninvestigatedextensivelybythescientificcommunity[20].Itiscurrentlyinclinicaltrialsandhasbeenproventowork.TheapplicationofBi213astheradionuclidetobedeliveredasthedosetothepatientanditsgenerationfromAc225isalsowelldocumentedinliterature[22].Thistherapytargetsthetumorcellwithinthebody.Theantibodiesareadministeredtothebodywhichtargetandbindtothetumorcellsandtheradioisotopedecaysandbecomesbenignafterreleasinganalphaparticlewhichkillspartsofthetumorcellperdose.Theseparationofthealpha‐emittingisotopeisdonethroughrecoil‐ionseparation.Asthedecayproceeds,Th229producesanalphaparticleandrecoilRa225ion.Thisoccursthroughconservationofmomentumandenergy.ThisenergyisenoughtodislodgetheRa225ionintoaneighboringsubstrate.ThenthedecaycontinuesonuntilbecomingstableatBi213,whichisbenigntothebody.[18]Thistreatmenthasarangeof70microns.TAThasbeentestedagainstmelanoma,leukemia,colorectal,breast,ovarian,prostate,andpancreaticcancers.ThereactionkineticsofBi213withthechelationagent,DPTAhasalsobeenwelldocumented[23].ThekineticsofadsorptionanddesorptionofBismuthfromaqueoussolutionswasalsostudied[25].Thekinetics,therateofdiffusionandtheroleoftheNernstlayerinunderstandingthedissolutionprocessofsucrosehasalsobeenofinteresttoresearchers[2].ThemathematicalcalculationoftheDiffusioncoefficientinliquidssuchaswaterhasalsobeendoneinthepast[24].Theroleofthecrystallitesizeintherateofsucrosedissolutionandunderstandingtheroleofthephasechangeandmicrostructureofthesucrosefilmwasalsofoundinliterature[26].Thedifferencebetweenthecurrenttechnologyandourprojectisthesizeandcontainmentofthedose.Usinglab‐on‐a‐chiptoadministerthistherapymakesitmorewidelyavailable,affordableandabletobemassproduced.

IVDesignGoals:

Ourgoalsforthisdeviceareprimarilylimitedbytime,becauseweonlyhave3halflives(2.25hours)tomakeanddelivertheradio‐labeledantibodysuccessfullytothepatient.However,westillhaveseveralsubstantialgoalsforthedeviceasawhole.Becauseitisamicrofluidicdevicewemustthereforebeabletofitseveralonastandardwafer,nomorethan3.5squarecentimetersforthedissolutionchamberandmixingchannels.Additionally,inorder

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tomaximizetheoveralldeviceefficiency,andgivenwehaveagoodamountofsizetoworkwith;wemake100%mixingourgoalwithinthedevice.Also,sinceweplanonusinganIVpump,thedevicemustbeabletohandleavolumeflowrateof5‐20mL/hr.Thesegoalsareallcomparablewithpreviousdevices[3,4,5,8,16].However,thegoalsforthenewestpartofourdesign,thesucrosedissolutionchamber,havebeensetbasedonourmodeling.WewantthesucroselayertodissolvequicklyenoughsothattheBismuthcaneasilydiffuseacrossthesystemandbemixedwithplentyoftimetoreactwiththechelate‐antibodyconjugate(lessthan2or3minutes).

VTechnicalApproach:

OakRidgeNationalLabsellsActinium225for$1,450permilliCurie,whichgreatlysimplifiestheprocessofpurificationbeforeinsertionintothedevice.Wewillonlyneedtodoonestepofrecoilseparation:fromtheactiniumthin‐filmgeneratortothesucrosecollectionlayer.Inordertoprovethatoursystemisfeasibleintermsofthismaterialcost,wedidasimulationtocalculatetheavailablequantityofBismuthfordosages.

ThefirststepinknowinghowmanyBismuthatomshavebeenimplantedintothesugaristoknowhowmanyatomshaverecoiledinaparticulartimeintervalwithaparticularstartingamountofAc.Thesimplesolutiontothisproblemistostartfromafilmof100%pureAcandprojectthequantitiesofeachrespectivedaughterastheycontinuedownthechain.TheresultingchartisaPoissondistribution,andsincetheAchasthesmallestdecayrate,thisdecaybecomesthelimitingfactor.

Thekineticsoftherecoilseparationprocessarenontrivialandresultinacertainlossbetweenthegeneratorandthesugar.Howeverthissimulationisconcernedonlywiththe'ceiling'ofavailableBiasdecidedbytheexponentialnucleardecay.Thusfarintheproject,thenumberscalculatedherearemostusefulforfeasibilityestimates,suchasthepotentialsizeofthesucrosefilmonthechip,ortheestimatedcostoftheAcperchip.

Sincetheisotopesareconstantlyinastateoffluxfromhighertolowerorderisotope(atleastuntilBi209),wecreatedabasicKineticMonteCarlosimulationtomodelindividualatoms.Thetimethatacertainatomexistsasanisotopebeforedecayingisdefinedusingthelogarithmofarandomnumberdividedbytheconstantdecayrate,λ.

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Bysimulating10millionatoms,wecanseethattheamountofBi213existinginthemixtureofelementsapproachesasteady‐stateatabout3ordersofmagnitudelessthanthequantityofActinium.ThisnumberallowsustocalculatethemaximumamountofBiinthesugarfilmasafunctionofthestartingamountofAcinthegenerator.

Generator‐CollectorInteractionTheprevioussectiondetailsthetheoreticalmaximumamountofactiveisotopethatis

availabletooursystem,whichwecanholdconstantduetothelimitsofthedecayrates.WhilewecanchangethestartingamountofAc225inourgenerator,theavailableBi213willalwaysbeafractionofthatquantity.

Inordertonowunderstandthelossofthealpha‐recoilmethod,wesimulatethe

interactionwiththeenergeticBi213ionsastheytravelthroughthethreeregimesoftherecoilsteponthechip:thegeneratorwhichholdstheAc225,theairthatseparatesthetwofilms,andthesucroselayerthatcollectstheions.Theenergyoftherecoilparticlesisaconstantduetothenatureofthealphadecay‐thedecayreleasesenergyfrom5.6to5.8MeV,andduetoconservationofmomentumtherecoilparticlemusthaveanenergyfrom101to105keV.

Figure1:Simulatedratioofisotopedensities,beginningwithaquantityof1unitofAc225.Thesteady

stateregimeoftheBi213isotopeisseenat2.5hours.

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UsingthepackageStoppingandRangeofIonsinMatter(SRIM),wecanfindthepenetrationdepthvalueofBiionsat100keVtravellingthrougheachofourthreeregimes.Wecanusethedepthvaluestocalculateanenergylossperdistancetravelled,dE/dx,orstoppingpower.InourPMMAgeneratorfilm,thestoppingpowerwasfoundtobe1380keV/µm;inair,1.3keV/µm,andinsucrose,1250keV/µm.

UsingMatlab,wesimulatedthedimensionsofthetwofilmsastheywouldbewhilethe

sucroselayerwas‘charging’onthegenerator,asseeninfigure2a.

Assumingthattheparticlesdecayinrandomdirections,weknowthatmorethanhalfof

theparticleswillfireinthewrongdirection.Eithertheparticlesgointhedirectionoppositetothecollectionplaneortheyareclosetotheedgeofthegeneratorandfireoutwards.Sincetheaspectratiooftheplaneareaversusthedistanceisverylarge,closeto200,wecanclassify

Figure2:(a):SchematicofCollector‐GeneratorArrangementshowingrecoilandthefacethatisdisplayedintheMonteCarloSimulation(b)MonteCarloSimulationshowingrelativedensitiesfortwo

distinctgeneratorthicknesses.Simulationwasbasedonstoppingpowersfoundinliterature.

(a)

(b)

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thesecasesassomewhattrivial.Thisimmediatelylowersourcollectionefficiencytoroughlyhalfoftheparticlesthatdecayonthegenerator.Furthermore,weknowthatacertainpercentofionswilldecaywithadirectionveryclosetoparalleltotheplates,andsomewillneverhaveenoughenergytotraversethedistancefromthebottomofthegeneratortothetop.Thesecasesalsoconstitutelosses.ThewaytominimizetheselosseswassimulatedbyreducingthefilmthicknessofthePMMAgenerator.Bychangingthisdepth,particleshaveamuchhigherprobabilityofleavingthefilm.Withathicknessof50nm,approximately20.3%oftheionsremainstuckinthegenerator.Witha10nmfilm,thisnumberisreducedto4%.SimilarlywecanreducethestoppingpowerdE/dxordensityofthegeneratorfilmtomaximizeourionfluxbetweenfilms.Therelativedensityofionsinthethreerangesaregiveninfigure2.

Forthe10nmgeneratorfilm,still41.4%oftheionslosetheirenergywhileinthespace

(air)betweenthefilms.Howeversincetheyarechargedparticlesandthesucrosefilmisbiasedto‐200V,wecanassumethatthemajorityoftheionswillmoveacrossthegapwiththeelectricfield.BehaviorofBiIsotopewithinChannelsAfterthesucrosefilmhasbeendissolved,thefluidbeginsdownthechannelpathinthesucrose.Thegoalofthechannelsistomixthebismuthwiththechelatedantibodyasthoroughlyaspossible.Originallywewantedconvectivemixing,butthisisimpossibleonthelengthandflowratescalesdesiredonsuchasmallchip.Theflowconditionsinsidethechannelareentirelylaminar,whereviscousforcesdominateoverinertial.Sincethefluidismovingslowly,wecannotassumeconvectivemixingofthebismuth.Instead,weusedtheHayduk‐LaudierelationtoapproximatethediffusivityoftheBismuthionswithinthewater.Withthiswecangetanapproximatemasstransfer.

Hayduk‐Laudieequation ThediffusivityallowsustosolveFick’s2ndlawandcreateaconcentrationcurveasafunctionoftimeanddistancefromthebottomofthechannel.Sincethesourceofbismuthisfinite,thesolutiontoFick’slawisagaussianfunctionandapproachesauniformconcentrationwithtime.Ourdiffusivitywashigh,soafteronlythreeminuteswecanassumeanearlyuniformgradient.Fick’sandGaussianEQs

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VIEthicsandEnvironmentalConcerns:

Thesocietalimpactrepresentedbysuccessfulimplementationofthissystemforcancertreatmentisobvious.Targetedalphatherapyhasbeenshowntobeeffectiveintreatingcancerbutbecauseoftheneedforaradioisotopesourceinhouseithasprovenveryexpensiveandthefacilitieswhichcanprovidesuchtreatmentaregreatlylimited.Oursystemwouldcentralizetheproductionofradioactivespeciesandthenecessarymaterialstoadministertargetedalphatherapyintoonecompactmicro‐fluidicsystem.Despitethesemajorsocietalbenefitsthefactthatoursystemisdisposablepresentsethicalconcernsintheformofwastegeneration.Materialsthatwereimplementedintothedesignwereevaluatedtoensurethattheyarenotharmfultotheenvironmentandwillnotcauseanylongtermdisposalissues.Polydimethylsiloxane(PDMS)isusedinthechanneldesign.PDMSdoesnotposeanyenvironmentalthreatswhendisposed.PDMShasshowntodegradetolowermolecularweightcompoundswhenincontactwithsoil.ItwilldegradetoMe2Si(OH)2afteronlyafewweeks[21].WeusedSiliconbasedwafersforthefabricationofthechip.Siliconisnotknowntocause

Figure3:SimulationofBismuthConcentrationGradientacrossthechannellengthbasedontheDiffusivityfromHaydukLaudieequationandassumptionoffinitesource.

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anyadverseeffectsontheenvironmentortothebodybecauseitisaninertmaterial.Waterandsucrosearenotharmful.SmallamountsorUVepoxycontainingurethaneacrylatewereusedinthedesignofthechip.Urethaneacrylateifreleasedintoanyaquaticenvironmentcancauselongtermeffectsinaquaticorganisms.TheMaterialsSafetyDataSheetforurethaneacrylatestatesthatitisimportanttoavoiddisposalintodrains,soilorsurfacewater.Disposalofthisagentissubjectofregulationsandrequireschemicaldisposalthatensuresregulatorycompliance.SECgelisagarbased,andsobiodegradesreadily.TheBi213isotopedegradesreadilytoanon‐radioactivespeciesBi209whichisnon‐toxic,nonbio‐accumulative,andistheleasttoxicofallheavymetals.Theconcentrationofitissosmallthatitwillnotposeanysignificantdangers.TheisotopegeneratorisprovidedbyOakridgeNationalLab(ORL)andisembeddedinPMMA.Appropriateprecautionsshouldbetakenwhenthegeneratorhastobedisposedofbecauseofremainingradioactivespeciesandtheirheavymetaldecayproductsthatcouldremainasremnantsinthegenerator.Thebiologicaleffectswereconsideredthoughtthedesignprojecttoensurethatallmaterialsthatweregoingtobeinjectedintothebodyarecompatible.Thisisveryimportantbecausepatientscouldhavesideeffectsorpossibledeathifthematerialswerenotdeemedcompatible.Overallthechipdesignandprocessprovesnottoinduceanymajorenvironmentaleffectsorsafetyproblems.

VIIIntellectualMerit:

Priortothiswork,theuseofalpharadiationforcancertreatmentshasbeenlimitedtoonlyahandfulofhospitalswhichcanproducetheseshortlivedsourceson‐site.Themainintellectualmeritofthisprojecthasbeentheconsiderationofmaterialsscience,nuclearphysics,andfluiddynamicstostreamlinetheprocessintoamicrofluidicsystem.

Therecoilseparationprocess,withwhichwedesignedourisotopeseparationgroup,hasverylittlepreviousresearch.Weinvestigatedthepossibilityofusingitonalab‐on‐chipanddecideditdefinitelyhasthepossibilityofcompetingwithresin‐orstrongacid‐basedsystems.Itstillhasmajordetractions:halfoftheionsrecoilawayfromthecollectorfilm,andthelackofconvectivefluidmovementinsidethechannelsmakesmixingverydifficult.Recoilseparationisanunresolvedtopic;mostlybecausethealphaemittersthatarerequiredtotestsuchasystemarerareandexpensive.OurtreatmentofthesubjectmakesastrongargumenttodelegateacertainamountofAc225tocancerresearchtoputoursystemtotrial.Sinceourcostanalysisputsdosagesontheorderof$10,thereisagreatmonetarybenefittoexploringourdesign.

Onebasicinsightthatwasgainedduringtheprocesswastheabilitytocoatathinfilmofsucroseonasiliconwafer.Fromwhatwesaw,spincoatingsucrosehadnotbeendonebefore.

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Whileitwasarelativelysimpleprocess,wefoundthatitwasquiteeasytomakethinanduniformcoatingsofsucrosedowntoonemicron.Thisabilitycanbeusedinrecoilseparationapplicationsandpossiblyotherapplicationswhereabiocompatiblesacrificiallayerisneeded.

Oursystembenefitsmedicineandsciencebecauseitexpandsthebaseofknowledgeforlab‐on‐chipdevicesingeneral.Wehavefurtheredtheunderstandingofhowmicrofluidicpropertiescanpermitthedeliveryofdrugs.Ourconceptallowsforscientistsanddoctorstorethinkthetypesoftreatmentsthatarepossible.Itreducestheneedtoworryabouttimesensitivityandprovidesaneffectivemodelforhowsuchtreatmentscanbemadeontheindustrialscale.

VIIIBroaderImpact:

Shouldthisdesignprovesuccessful,itwillhavesignificantbroaderimpact.Itgoeswithoutsayingthatagreatamountofresearchtowardscancertreatmentisrequired.Thepotentialforenormousreductionsincostandincreasesinavailabilitysuggestedbythisdesigncouldprovideanewstandardfordeliveryofcomplexmedicaltreatments,especiallyforcancertherapy.Currentlythemosteffectivecancertreatmentsareveryexpensive,andthosethatarehighlyeffectiveandlowriskevenmoreso.Thisdesigncouldheraldinanewtrendofmakingthosetopendtreatmentscheaperthroughminiaturization.

IXSimulationResultsandDiscussion:

Thesolidconsistsofasquarefilmofsurfaceofareax2andthicknessf,soS=x2

Ifthesolidmassiswrittenintermsofthedensity,ρ,thenm=ρx2f

Fromthis, ,andtheratecanbemodeledas

FromAntonel

ρ=1.4g‐cm‐3

Cs=0.67g‐cm‐3

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D=6.1x10‐6cm2‐s‐1

FromFluentSimulations,onecandeterminetheNernstLayerbasedonthemaximumvelocity.Itwasassumedthatvmax/10wouldprovidetheminimumvelocityrequiredfortransportlimitingkinetics.PriortotheNernstLayerduetothenoflowboundary

condition,thesurfacereactionisratelimitinganddissolutiontakestheformofanerrorfunction.Byestimatingthisasalinearconcentrationgradient,onecaneasilyobtainthedistanceofthisboundary.AftertheNernstLayer,theconcentrationofthesolidinthebulksolutionremainsconstantinawellstirredsolution.ThefollowingfiguredisplaysaschematicoftheNernstlayer.

Bycomparingone‐tenthofthemaxvelocity(fromvelocityprofilesobtainedwithFluentsimulations)withthediffusivityofsucroseinwater,onecanobtainacharacteristiclength,h,thatwehavedefinedastheNernstBoundaryLayerasdescribedabove.

Thisresultsinasucrosedissolutionrateof0.27µg‐s‐1assumingentiresurfacecoverageinawellstirredsolution.With14ngofsucrose(1cmx1cmx1µmfilm),thedissolutiontimeshouldtake52ms.

Crystallitesizealsohasaneffectondissolutionrate.UsingtheAvramiequation,onecansimulatetheeffectofgrainsizeonthedissolutiontime.Bydefiningdissolutionastheoppositemechanismofcrystallization,thefractionofsolidpresentataspecifictimeandtemperatureduringcrystallizationisgivenby:

Figure4:TheNernstDiffusionlayerexistsalongthechannelfromx=0tox=h.Bycomparingthediffusivitytothesimulatedvelocity

profiles,thecharacteristiclengthoftheboundarycanbeobtained.

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whereNisthenucleationrateandvisthecrystalgrowthrate.Thisequationwasderivedbasedontheassumptionthatnucleiarenucleatedthroughoutthetransformationataconstantrate,Nandareexpandingspheres,alsoataconstantrate,v.Atsmalltime,t,thisequationtendstoward0andatlargetime,fstendstoward1asexpected.Inordertomodeldissolutionwiththisequation,wemusttake1‐fs.Theequationcanbewrittenintheform

wherekis .Tosimplifythemodel,visassumedconstantduringanisothermal

transformation.Inthiscase,kisdirectlyproportionaltothenucleationrate,N,whichisinverselyproportionaltograinsize(moresitesfornucleationresultsinsmallerandmorenumerousgrains).ByplottingthedissolutionequationfromtheAvramiequationfordifferentvaluesofk,wecanmakeaqualitativecomparisonofhowgrainsizeeffectsdissolutiontime.Thefollowingplotshowscurvesforvaryingordersofmagnitudeofk.Itisapparentthataskincreases(Nincreases)thedissolutiontimedecreases.SinceNisincreasing,grainsizemustbe

Figure5:QualitativeresultsofthedissolutionmodelasafunctionofnucleationrateandgrowthrateappliedtoanAvramiequation.Increasingvaluesofksimulateincreasingnucleationrateforaconstantgrowthrate.Increasingnucleationrateleadstosmallergrainsize.Fromthefigureitisapparentthatasgrainsizedecreases,sodoesdissolutiontime.

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smaller.Therefore,smallergrainsizeswillresultinfasterdissolutiontimes.

FluidDynamicsSimulationsandCalculations

Thesimulationsteamhascontributedseveralessentialportionsoftheproject.Theseincludeunderstandingfluiddynamics,verifyingtheFluentandGambitsimulationsoftware,modelingtheradioactiveisotopedecay,modelingtheisotopeconcentrationprofileinthesucrosefilm,anddesigningandmodelingthefluidflowinthechip.Eachofthesecontributionswillbesummarized.

WehavedecidedtouseFluent©tomodelfluidflowandmixinginourmicrofluidicschip,andGambit©forgeometryandmeshgeneration.Thedecisiontousetheseparticularpiecesofsoftwarewasbasedentirelyonavailability.Wecontactedseveralexperts(seeprofessorsvisited),andthetakeawaypointswerethatCOMSOL©wouldbeoverallmoreuseful,andmoreflexible.COMSOL©MultiphysicsClasskitiscurrentlyavailableonthecomputersinthematerialsengineeringcomputerlab.However,aftercontactingtheCOMSOL©licensingdepartment,itwasdeterminedthatthelicensehadalreadyexpiredandthesoftwarewasbeingusedabusively.ThecostforastudenttoobtainasinglelicenseforCOMSOLMultiphysicsis$1,595.Additionally,theadd‐onfluiddynamicspackageis$1,595perlicense.Thepriceofthissoftwaregreatlyexceededourbudget,sowedecidedthatFluent©andGambit©wouldbeacceptablealternativesbecausetheyareavailable.

Thefirststepforthesimulationscommitteewastofamiliarizeourselveswiththegeneralprinciplesoffluiddynamics.Todothis,westudiedtheNavier‐Stokesequations,andderivedanexactsolutionfor2DPoiseuilleflow.2DPoiseuilleflowassumesthatwehavehardwallboundariesintheupanddownydirections,andinfinitelyspacedwallsinthezdirection.TheflowisinthepositivexdirectionbythecoordinatesysteminFigure11.ThesolutiontotheNavier–Stokesequationpresentedbelowalsoassumesano‐slipboundarycondition,whichmeansthatthereisano‐flowregiondirectlynexttothewallsofthechannel.Alsoassumedfortheanalyticsolutionisthatwehavecompletelylaminarflow.Duetothedimensionsofthechannel(1mmheightand1mlength)andtheaveragevelocityofthefluid,wecanbesurethatweareinthelaminarregime.Foranon‐circularduct,theReynoldsnumbercanbeapproximatedby(source“fluidflowresistance”blackboarddocument)Re=(ρ*v*D)/µwhereρisthedensityofthefluid,vistheaveragevelocity,DisthecharacteristicDiameter,andµisthefluidabsoluteviscosity.Forourduct,thecharacteristicdiametercanbeapproximatedbyD=2*h=2mm.Forwater,wehaveµ=.001003(kg*m^‐1*s^‐1),ρ998.2(kg*m^‐3)andsettheaveragevelocityto.001m/s.ThereforeweexpectaReynoldsnumberofapproximately2,whichputsuswellwithinthelaminarflowregime.

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Wehavedecidedtouse2dflowtomodelourchannelsduetotimeandcomputerpowerlimitations.BasedontheReynoldsnumber,weexpectthatdiffusionalmixingwillbethemajorcontributingfactortothemixingofourreagents,andwewillthereforeneedtohavelongchannelssothatourfluidswillbeincontactforalongtime.Longchannelsnecessitatelotsofnodes,anditiseasytoseehowa3dmeshwouldquicklystrainourcomputers.The2dmodelswillthereforeprovideuswithafundamentalunderstandingofthemixingandflowparameters,butspecificswillstillneedtobemeasuredandtestedinthelab.

Theflowbetweentheupperandlowerplatescanbemodeledbythefollowingapparatusinfigure11.Thechannelsareassumedtobehorizontalwiththeflowinthex‐directionandthewidthbetweenthechannelsinthechannelinthey‐direction.

Figure6:Poiseuilleflowgeometry

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Verification

Anexactsolutionfor2DPoiseulleflowwasobtainedfromtheNavier‐Stokes(NS)Equation.ThederivationfromtheNSsolutionassumedanoslipboundaryconditionwhichwaslikewisemodeledintheFluentsimulation.Thevelocityprofilesareplottedbothanalyticallyandnumerically.ForlowReynoldsnumbers,thereisstrongagreementbetweentheresults,however,astheReynoldsnumberincreases,slightdiscrepanciesoccurwhichisthoughttobecausedbyturbulenteffects.Anextensionofthisderivationtoa3DcasealongwithcorrespondingFluentsimulationswillbeusedtoverifythefinalchipgeometrywithappropriatechannelcrosssection.Thechannelparametersusedintheverificationincludeachannelwidthof0.001m,achannellengthof0.1m,fluidpropertiescorrespondingtowater(µ=0.001003kgm‐1s‐1andρ=998.2kgm‐3).Fromtheverification,the2Dmixingsimulationimplementingaswitchbackchannelgeometrycanbeconfidentlymodeledtomaintainawellmixedsolutionfor

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8‐10minutesforappropriatechelation.ThepressuredropacrossthechannelisexpectedtobelinearaccordingtoPoiseulle’sequationwhichiswhatresultedfromtheFluentsimulations.Figures12and13displaytheplottedanalyticalcalculationsandnumericalsimulations.

Figure7:Velocityprofilesfortheindicatedchannelforinletpressuredifferencesof8.016Pa,80.16Pa,and160.32Pa.

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Figure8:Pressureprofileacrossthelengthofthechannel.Thisprofileshowsthepressurechangeforthe8.016Painletpressuredifference.

UponhavingsimulatedandverifiedPoiseulleflowofasinglefluidinarectangularchannel,analyticallywithMatlabandnumericallywithFluent,itisnecessarytomodelthemixingoftwoseparatefluids.Multiphaseconsiderationswithinthefluids(suspensions/solutions)mayalsoberequiredforaccuratemodeling.

Undertheassumptionthatweareabletoachieveturbulentmixing,thechannelsmaybefabricatedonalargerscaleandadiffusionalmixingmodelwillnotbenecessary.Inthecasewhereturbulentmixingcannotbeachieved,channelscanbefabricatedsufficientlynarrow,andofsufficientlengthtoallowforoptimaldiffusionalmixing.Previousworkhasshownthatazig‐zagpatternedchannelcausesthegreatestdegreeofmixingmostefficiently[Jeon,W.2009].Figure14fromJeon[Jeon]showvariousgeometricalconfigurationsthatcausemixing.Alsoshownarecontourplotsdisplayingvolumefractionofphaseinfluid(goldnanoparticlesinthiscase).Fromthecontours,onecanquicklyobservethedegreeofmixingresultingfromthevariouschannelgeometries.Thiscanbefurtherdescribedquantitativelyforamoreconcretemixingcapabilityanalysis.

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Figure9:Mixingcontours(displayingvolumefractionofgoldnanoparticles)showingeffectsofdifferinggeometries(asshowninFigure10)atspecifiedtimeintervals.Byinspectionitisclearthatthezig‐zagtypegeometryismostefficient[Jeon].

Toestablishaquantitativemeanstodescribethedegreeofmixing,Fluentiscapableofproducingcontourplotsofvolumefractionandmolarconcentrationofcomponents,which,alongwithadiscretescale,canbeusedtomeasurethedegreeofmixingbasedonacertainchannelgeometry.Onceavaluecanbeassignedtothedegreeofmixing,thiscanbecomparedtothesizeofthechanneltodetermineamixingefficiency.Channelgeometrycanbealteredinordertooptimizemixingefficiency.Wedefinemixingefficiencyashavingahomogeneousconcentrationacrossthechannel,whichisdiscussedbelowinthesection“ChipDesign.”

FigurestofollowdisplaytheresultsfromtheFluentmixingsimulation.Velocityvectorandcontourplotsclearlyshowlaminarflowwiththeno‐slipboundarycondition.Thechannelwidthwasassumedtobeonemillimeterandthefluid,liquidwater.Onesampleofwaterwasdesignatedatinlet1andanothersampleofwaterwasintroducedatinlet2.Themassfractionofwatercorrespondstothefirstsample(i.e.100%water(inlet1)atinlet1correspondsto0%water(inlet2)atthisinlet.

ChipDesign

Theresultsfromtheisotopedecaysimulationsindicatethatwewillonlyhaveausabledoseinthechipforabout45minutesonceitisremovedfromtheactiniumsource.Theactiniumsourcemustbebroughttoeveryhospitalthatplansontreatingpatientsusingthechip,andthismeansthatthephysicalchipassemblymustbedoneinhospitaltoensurethatthedoseisdeliveredinatimelymanner.Theantibodiesandchelatingagentswillbemixedandreactedinaverysmallcontainer(ontheorderof1mLinvolume)offthechiptosavetime,and

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willbesubsequentlypumpedintothechipviaIVpumps.Themixedsolutionwillthendissolvethesucrosecontainingtheisotopes,andwillthenbemixedandreactedinswitchbackmixingchannels.Thedesignofthechannelswasinfluencedbythefactthataccordingtoasource(McDevittetal)thechelatingagentmustbeinawell‐mixedenvironmentwiththeisotopesfor8‐10minutestoachieve80%reactionefficiency.Also,theflowconstraintsofcertainIVpumpsweretakenintoconsideration;forexample,theAbbotLabsPlumXLDPumpIVInfusionhasaminimumvolumetricflowoutputof1ml/hour.Intotalweexpectthechiptobe3.5cmx3.5cm,withmostofthechipareacorrespondingtothemixingdomain,butwithonesquarecentimeterinthe“upperleft”correspondingtothesucrosefilmdissolutionchamber.Aschematicofanapproximateflowvelocityandmixingareshownbelowinfigures15,16and17.Thechannelwidthwasassumedtobeonemillimeterwide.Forflowratepurposes,thechannelsareassumedtobe1mm.Onesampleofwaterwasdesignatedatinlet1andanothersampleofwaterwasintroducedatinlet2.Bothoftheseareconnectedtogetherinthebeginningofthemixer.Themassfractionofwatercorrespondstothefirstsample(i.e.100%water(inlet1)atinlet1correspondsto0%water(inlet2)atthisinlet.Thisallowsforthemixingtobedisplayedasafunctionofmassfraction.

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Figure10:2Dsimulationofpurewaterthroughthemixingchamberatvolumetricflowrateof10ml/hour.Thisfigureshowstheexampleflowvelocityprofile.

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Figure11:2Dsimulationsofpurewaterthroughthemixingchamberatvolumetricflowrateof2ml/hour.Thisfigureshowstheblownupvelocityprofile.

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Figure12:2Dsimulationsofpurewaterthroughthemixingchamberatvolumetricflowrateof10ml/hour.ThisfigureshowstheExamplemixing

ThesimulationsshowninFigure15,16and17weredonewithpurewater,whichisnotthefluidwewillactuallyuse.Theactualfluidwillclosetotheviscosityofwaterbecausethereactantconcentrationsareontheorderofnanogramspermilliliter.Futuresimulationswillincludethesolutionwiththeappropriateviscosity.Forallofthesimulations,amassflowinletwasusedbecausethatisthecapabilityofFluent.Thevolumetricflowwasconvertedtothemassflowratebyusingthedensityofwater,whichis998.2071kg/m^3.

Fixingtheinletflowrateto10ml/houryieldsamaximumcenter‐linevelocityof5.25mm/s,andwithatravellengthof534.5mm,weexpectaminimumreactiontimeofabout2min.Thisfallsshortofthe8‐10minutesrequiredformixing.However,wehavedecreasedtheflowrateto2ml/hour(whichiswithinthecapabilityofstandardIVpumps).Figure16showsthat(usingafinermesh)thatthemaximumvelocitychangesto1.13mm/s,whichputstheminimumreactiontimenearidealtoat7.88min,andtheaveragedirectlyintheidealrange.MoreexpensiveIVpumpscangetfinerflowcontrol,andcouldbeimplementedtobetter“center”theflowvelocityintotheidealrange.

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Figure18shownbelowisaschematicofthesucrosedissolutionchamber.Thischamberwascreatedinordertogetsufficientsurfacecoverageanduptakeofsucroseandbismuth.Thelargeopenareainthemiddleisfortheinletholethatwillbepunchedintheglass.

Figure13:3Ddesignofthesucrosedissolutionchamber.Thesmallsquareinthemiddleisa2mmx2mm

Themain“square”ofthechamberis1cmx1cminarea,and1mminheight.Thechannelsareall.5mmx1mmincrosssection.Thechannelsweredesignedsothatonequarteroftheflowwouldbedirectedintoeachchannel.Duetotimeconstraints,wewerenotabletocomplete3Dfluentsimulationsforthisdesign.However,weassumedthattheflowwouldbeonequarterofthetotalflow(2ml/hour),andweranaMatlabsimulationassuminglaminarflowtodisplaythevelocitycross‐section.Figure19isthevelocitycontourofthissimulation.

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Figure14:Velocitycontourofthechannelsinthesucrosedissolutionchamber.TheNernstlayercorrespondstothewhiteborderaroundthecoloredcontours.

ThewhiteborderaroundthecoloredprofilerepresentstheNernstlayerwhichwillbediscussedinthenextsectiononsucrosedissolution.TheNernstlayerrepresentssectionofthevelocityprofilethatfallbelow10%ofthemaximumvelocity.TheMatlabcodewaswrittenbasedonanexercisebyMartinPederson(MartinPedersen,TechnicalUniversityofDenmark).Flowanalysisindicatesthatforthechannelregion,weexpectaReynoldsnumberofabout½.Thisputsuswellwithinthelaminarflowregime,whichisexactlywhatweseeinthesimulation.Itisabitdistortedfromatraditionallaminarprofilebecausethecross‐sectionisarectangle,notasquareorcircle.Thissimulationindicatesthatthemaximumvelocityisabout.4mm/secinthesechannels.AlthoughtheFluentsimulationsdidnotdirectlyrepresentmaterialsdesignaspects,theywereintegraltotheoveralldesignofthechip.Theflowprofilesallowedforyieldcalculations,andmixingestimationscouldbeusedtodeterminereactionefficiency.GambitservedbothasmeshgenerationsoftwareforFluent,andforCADapplicationsshowingtheschematicofthesucrosemixingchamber.

Facilities,Materials&Prototyping

Thedesignandfabricationofourtargetedalphatherapylab‐on‐chipdevicewillutilizenumeroussoftwareandlaboratoryresourcestoensuredesiredoperation.IndesigningourdevicethesimulationscommitteehasperformedworkusingtheANSYSsoftwarepackageFluent.Thegoalofthesesimulationshasbeentwofold,firsttoconfirmtheapplicabilityofthe

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softwareforourmicrofluidicdesignandsecondtomodeloursysteminsuchawayastoensurethatproperdesignparametersaremet.Theparametersofinterestincludeflowrate,mixingandgeneraldimensionalrequirements.Tooptimizetheseparametersfactorssuchassystemtopology,channeldiameterandlength,etcareconsideredinourcomputersimulations.Fromthesesimulationsthefinaldevicedesignwillbedeterminedandfabricationwillfollow.

Ourdevicewillbefabricatedusinglithographictechniquesanditthereforebecomesnecessarythatalithographicmaskbedesignedandprocuredsothatproductioncanbegin.WehavedesignedandsentoutthemasktoFineLinePrototypingforfabricationandarecurrentlyawaitingitsarrivalfordeviceproductiontobegin.EspeciallyimportantinthisearlyworkwillperfectingthepatterningofzigzaggedchannelsintotheSisubstrateasthemixingwhichoccursinourdevicewillrelyalmostentirelyonthesepatterns.Wemustbesurethatweareabletocreatethedesired1mmchannelsizeonSiandthattheywillbefreeofobstructionsforproperflow.OurmaskwasdesignedusingtheCorelDRAWX4softwarepackage.

Ourmicrofluidicsystemwillbefabricatedonasiliconchip.Therearefourmajorfabricationaspectswhichrequireconsideration:chipsurfacefeatures,thesugar/Bifilm,SizeExclusionChromatography(SEC)chamberandglasstop.AmaskofthefeaturesisshowninFigure20ThevarioussurfacefeaturesrequiredfortheproperfunctioningofthesystemwillbemoldedusingthepolymerPDMS.ThispolymerwillbepatternedbyusingaSiwaferwiththechipdesignetchedintothewafer’snativesilicondioxidelayer.ThisprocesswasexplainedtousbygraduatestudentMarianaMeyerandfromherguidancewehavelearnedthatallofthepatterningrequiredcanbeperformedrelativelysimply.Inordertocompletepatterningwefirstsurroundthepatternedwaferwithanaluminumfoil‘boat’andthenpourthePDMSoverthewafersurface.OncecuredthepatternedPDMScanbepeeledfromtheSimoldandinspectedforimperfections.Thisprocessrepresentsthelion’sshareoffabricationtimeandeffortduetoitsinherentlycomplicateddesignandneedforprecisionwhencomparedwiththeotherconstructionaspects.Thechip(s)usedforfabricationwillbesuppliedthroughtheFABLABwhichmaintainsalargestockofblankSiwafers.

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Figure15:Projectedmaskdesign.Contact(topleft)andchannels(right,bottom)

Thesecondmajorconsiderationliesinthesugar/Bifilmwhichwillcontaintheactivebismuthforalphatherapy.OncethedissolutionbehaviorofthisfilmisdetermineditshouldberelativelysimpletospincoatasugarfilmwhichcanbeimplantedwithBiatomsforintroductiontoourchip.Wehavedeterminedthatwecaneasilypatternsuchafilmwiththedesiredthickness(~1micronrange)byspincoating.Thusfarwehavecompletedtrialsusing33and50wt%sucroseinwatersolutionsandbothhaveviscositypropertieswhichhaveresultedinfilmsinthemicronrangeaccordingtomeasurementsmadeusingthen&kanalyzerdeviceintheFABLAB.Thesucrosefilmswerespincoatedat4000rpmfor40sec.,basedonaknownprocessforasimilarly‐viscous1812photoresist.Inthesetrialswewerealsoabletodeterminethatbyusingplasticbackedvacuumtapewecouldsimplycoverthepartsofthechipthatwedonotwishtohavesucroseon,spinonthefilmandremovethetape.UsingthistechniqueweareabletoquicklyandeasilymakeanysizedsucrosefilmontheSiwafer.YoucanseeafinishedsucrosefilminFigure21.

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Figure16:Sucrosefilmpatternedonpolishedsideofsiliconwafer.Squarearea(~1x1cm) tapedoffusingvacuumtape.

Wealsofoundthatafterafewdaysthefilmsbeganshowingregionsofcrystallitenucleation.ToconfirmordenythisobservationwecharacterizedthesucrosefilmswithXRD.Wetookmeasurementsoftheregionsofthefilmthatwerestillas‐spunandoftheregionsthatappearedtobecrystallizing.Theas‐spunregionshowednosignificantpeaks(excludingthelargepeaksfromtheSisubstrate),suggestingthattheas‐spunsucrosefilmisamorphous.ThecrystallizedregionsshowednoconclusiveresultsfromaregularXRD,sowetookawideranglerangescanofthatregioninapowderdiffractometer/XRD.Thediffractometerwouldbeabletodetectcrystallinepeaksforapoly‐crystallinesample,wherethenormalXRDwouldaverageoverallofthecrystallitesandshowinconclusiveresultsaswesaw.ThepowderdiffractometryresultsareshowninFigure22.ThecrystallizedregionhadmanypeaksincommonwiththesucrosereferenceintheXRDdatabanks,suggestingthatthecrystallizedregionwasinfactpoly‐crystalline.Thestrongpresenceofpeaksrelatedtothe(100)familyofsucrose,whichalignsat(400)withSi(002)suggeststhattheremaybesomeepitaxialeffectsonthenucleationfromtheSisubstrate.Furthertestingalongthisideawouldhavetobedonetoconclusivelyconcludeonewayoranother.

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Figure17:XRDResults.Thebottomscanistheas‐spunregion,andthetopscanisthecrystallizedregion.

TheSECchamberisanotherarearequiringmajorconsiderationinthefabricationofourdevice.FirstofallthedimensionsofthischambermustbedialedinsothatthedesiredseparationcanoccurbytheSECgelused.Thischamberwillbeplacedoffofthechipinordertoensurethattheproperdimensionscanbeachieved.Otherwiseitwouldbedifficultifnotimpossibletohavebothdimensionsandvolumefortheseparationcolumn.Secondlythepropergelmustbeselectedforbothexclusionsizeandcoarsenessagainforresolutionandalsoforflowratethroughthedevice.WehavechosentouseBio‐GelA‐0.5mSECgelfromBio‐Radwhichisaagarosebasedmaterialcommonlyusedfortheseparationofantibodiesandotherproteins.Fordesiredresolutionweneed5‐10:1length‐to‐diameterand4‐10:1bed‐to‐samplevolumeratiocolumn.Basedontheinformationfromoursimulationswehavedeterminedthatweneedacolumnwhichisapproximately5x1x1mmwhichiscorrectforbothnecessaryratios.

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Crystallitesizewasestimatedusingopticalmicroscopy.Figure23showstwopicturestakenwiththeopticalmicroscopeintheteachinglabintheFabLab.Thesmallestnucleatingcrystalliteswereneedle‐likestructuresapprox.5uminwidth.Largercrystallitestructureswereupto800um,withgroupsofradially‐orientedneedle‐likestructuresformingcirclesmultiplemillimetersindiameter.Thesmallestcrystallitesizeistheimportantsizewithrespecttodissolution,sinceitwouldbeonthatscalethatthesucrosewouldbedissolvingintothewatersolution.

Figure18:OpticalMicroscopepictures.5xmag(left)showssomenucleatingneedle‐likestructures.20xmag(right)showsfully‐grown,larger,moregrain‐likestructures.

ThefinalmajorconsiderationinfabricatingourdeviceisinfusingthetopPDMStothebottomSiwafer.Thisprocessshouldberelativelysimple,butitisnecessarytobeverycarefulandprecisetoensurethatthefinaldevicedoesnotleakinternallyorexternally.TobondthePDMSandglasswehavechosentouseaUVcuringepoxyUV30‐27seriesfromLoxeal.Thischoicewasmadefor3mainreasons:fastcuringtime(~5minorless),highbondstrength(20‐30N/mm^2)andmedicalusecertification(ISO10993).Speedisimportantbecauseoncethesucrosefilmisactivatedwithbismuththeclockbeginscountingdownuntiltherequireddosageofradiationisnolongerpresent.Highbondstrengthisofobviousimportanceasthedevicewillbesubjecttopressuresasfluidsflowthroughandmixwithinthesystem.Thisstrengthguaranteesthatthedevicewillneitherleaknor,evenworse,failtotally.Finallythemedicalusecertificationensuresthatwearenotintroducingpotentiallyharmfulcomponentstothesystembyoverlookingthecompositionofthesealantusedforthedevice.Theprototypemaybesealedwithpartially‐curedPDMSinsteadoftheepoxyforeaseandavailability(nothavingtopurchaseandwaitforspecialtyepoxy).

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FortestingwehavediscussedusingstreptavadinandbiotinasmodelantibodyandchelatewithDrPhaneuf.Thesespecificmoleculeswillbeusefulfortestingbecauseoftheirfluorescencepropertiesoncechelationhasoccurred.Asuccessfultrialwillresultinhighfluorescenceintheoutflowstreamfromourchipindicatingthatthebiotin/streptavadinchelationhasoccurred.

Totestthesucrosedissolutionrateagainstourmodels,wewouldhavetorunanexperimenttomeasurethemassdissolvedperunittime.Oneideawastoputthesucrosefilmincontactwithmixedwaterforafixedamountoftime.Aftereachtimeinterval,thefilmwouldbetakenout,dried,andmeasuredforthickness.Knowingthesurfacearea(1x1cmsquare)anddensity,wewouldplotdm(dt)andcomparewiththeresultsofthetheory.Oneproblemwiththismethodisintroducingwatertothefilminacontrolledmanner.Amicrofluidicchannelsystemwouldaccomplishthis,butrequiresextraworkaheadoftimecreatingone.Asecondproblemisquicklyandevenlydryingthefilmwithoutaffectingthefilmitself.Afterbeingsubmergedinwater,thefilmwillbepartiallyhydrated.Dryingthefilmfastenoughtoeffectivelyceasedissolutionwouldbedifficult,especiallysosincethefilmcannotbetakenpast90Cwithoutdegradingthesucrose.

Overthecourseofthesemestertheprototypegoalshavechangeddrastically.Atthemidtermpointwedecidedtofocusourenergiesonthemodelingandprototypingofthesucrosefilmwhileputtingtheproductionofanactualmicrofluidicchannelsystemasasecondaryobjective.Wemadesureateverystepofthewaythattheprototypingaspectofourprojectdidnotsacrificetimeormanpowerfromtheprimaryfocusofthecapstoneproject:thedesign.Theaspectsoftheprototypethatwefinallydecideduponwerethosethatwebelievedwouldhelpverifyandsupportthedesignportionsoftheproject.

XConclusions:

Ourdesignmetwithgreatsuccesswhenourresultsarecomparedwithourdesigngoals.Wemetthemall,andareabletoprovideadoseofradio‐isotopeatminimalcostandpotentially,wideavailability.Oursimulationsresultedinrapidmixing(100%mixingwithin2mmofchannellength),thesucrosedissolutionconfirmedarapiddissolutionrate,andtheBismuthdiffusionconfirmedasignificantspreadacrossthechannelgiventheassumptionsmadeforourmodel.

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XIAcknowledgementsandReferences:

Acknowledgements:Thankyouto:Dr.RaymondPhaneufDr.RobertBriberDr.ManfredWuttigDr.IchiroTakeuchiDr.KeithHeroldDr.DonDevoeDrSameerShahProfessorEmeritusGeorgeHelzProfessorAndreiVedernikovProfessorGareginPapoianJohnHummelJimO’ConnorTomLoughranJohnAbrahamsMarianaMeyerRichardSuchoskiReferences:[1]Allen,BarryJ.,ChandRaja,SyedRizvi,YongLi,WendyTsui,DavidZhang,EmmaSong,Chang

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