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ATOMPROBETOMOGRAPHYAHIGHTHROUGHPUTSCREENINGTOOLFORATOMICSCALECHEMISTRYKRISHNARAJANDEPARTMENTOFMATERIALSSCIENCETEL5152942670EMAILKRAJANIASTATEEDUDIFFRACTIONTOAVARIETYOFSCANNINGPROBEMETHODSAFUNDAMENTALCHALLENGEINALLTHESEMETHODS,ISTHATHIGHTHROUGHPUTDOESNOTNECESSARILYTRANSLATETOHIGHRESOLUTIONFROMOFAMICROSTRUCTURAL,CRYSTALSTRUCTUREORELECTRONICSTRUCTUREPERSPECTIVESEEFIG2DESPITETHEVASTAMOUNTOFWORKINTHEFIELDOFCOMBINATORIALMATERIALSSCIENCEANDCHEMISTRY,CHARACTERIZINGINFORMATIONWITHHIGHRESOLUTIONWHILEACQUIRINGDATAVERYFASTISSTILLACHALLENGEFIG1THESPECIMEN1ISINSERTEDINTOACRYOGENICALLYCOOLED,UHVANALYSISCHAMBERTHEANALYSISCHAMBERISCRYOGENICALLYCOOLEDTOFREEZEOUTATOMICMOTIONITISATULTRAHIGHVACUUMUHVTOALLOWINDIVIDUALATOMSTOBEIDENTIFIEDWITHOUTINTERFERENCEFROMTHEENVIRONMENTAPOSITIVEVOLTAGEISAPPLIEDTOTHESPECIMENVIAAVOLTAGE/LASERPULSETHEPOSITIVEVOLTAGEATTRACTSELECTRONSANDRESULTSINTHECREATIONOFPOSITIVEIONSTHESEIONSAREREPELLEDFROMTHESPECIMENANDPULLEDTOWARDAPOSITIONSENSITIVEDETECTORTHELOCATIONOFTHEATOMINTHESPECIMENISDETERMINEDFROMTHEIONSHITPOSITIONONTHEDETECTOR2THISCONFIGURATIONMAGNIFIESTHESPECIMENBYAMILLIONTIMESANDINDUECOURSE,ATOMSFROMTHESURFACEIONIZE,EXPOSINGANOTHERLAYEROFATOMSUNDERTHEMTHISPROCESSOFFIELDIONIZATIONCONTINUESUNTILTHESPECIMENHASBEENFULLYANALYZED,ANDPROVIDESA3DIMAGEOFTHEENTIRESPECIMENCOURTESYDSEIDMANINTHISPAPER,WEWANTTODISCUSSACHARACTERIZATIONAPPROACHTHATPROVIDESANEWANDEXCITINGAPPROACHTOHIGHTHROUGHPUTSCREENINGOFATOMICSCALECHEMISTRYATOMPROBETOMOGRAPHYTHETERMHIGHTHROUGHPUTSCREENINGCOMESINTOPLAYHEREINTHECONTEXTTHATITREFERSTOTHENATUREANDSPEEDOFDETECTINGMASSIVEAMOUNTSDATAFROMINDIVIDUALATOMS/MOLECULARFRAGMENTSATYPICALANALYSISWITHATHREEDIMENSIONALATOMPROBEDATACANCONTAINUPTOHALFABILLIONATOMSIFNOTHIGHERANDTHEDATAACQUISITIONRATECANBEEASILY100MILLIONATOMSADAYALSOASISDISCUSSEDBELOW,THATAPTCANBEINTEGRATEDWELLINTOTHESTUDYOFTWODIMENSIONALCHEMICALLIBRARYARRAYS11AKEYCHALLENGEFORATOMPROBETOMOGRAPHYISTOFABRICATEASAMPLEINTOANEEDLESHAPEWITHTIPRADIUSOF50NMFORTHESTUDYOFORGANICMATERIALS,PROBABLYTHEMOSTEFFICIENTWAYISTOCOATASHARPPREFABRICATEDNEEDLE12AMICROTIPARRAYISANORDEREDCOLLECTIONOFTALL100MICRONSIPOSTSFORMEDONASICOUPONWITHSTANDARDMICROELECTROMECHANICALSYSTEMSMEMSTECHNIQUESTHEARRAYENABLESTHEATOMPROBETOFIELDEVAPORATEATOMSEXCLUSIVELYFROMASINGLENEEDLESHAPEDSPECIMENLOCATEDAMONGAFIELDOFSIMILARNEEDLESHAPEDSPECIMENSTHESEMICROTIPARRAYSENABLETHERAPIDPREPARATIONOFALARGENUMBEROFNEARLYIDENTICALATOMPROBESAMPLESBYPROVIDINGACONSISTENTPLATFORMFORMOUNTINGTHESAMPLESECTIONONCEITISEXTRACTEDFROMTHEMATERIALOFINTERESTTHISPROVIDESAUSEFULWAYOFDEVELOPINGCOMBINATORIALARRAYSOFATOMPROBESPECIMENINTHEFOLLOWINGDISCUSSION,WEREVIEWTHELIMITEDAMOUNTOFWORKINTHEOPENLITERATURETHATADDRESSESTHEAPPLICATIONOFATOMPROBETOMOGRAPHYTOTHESTUDYOFORGANIC/BIOLOGICALMATERIALS,ESPECIALLYFROMTHEPERSPECTIVEOFHIGHTHROUGHPUTANALYSISTHISISFOLLOWEDBYASUMMARYOFTHEDATAANALYSISANDSPECIMENPREPARATIONCHALLENGESASSOCIATEDWITHBIOLOGICALSYSTEMSFORTHISKINDOFSTUDYATOMPROBETOMOGRAPHYASHIGHTHROUGHPUTSCREENINGTOOLNORMALLYATOMPROBETOMOGRAPHYISNOTCONSIDEREDASASCREENINGTOOLFORCOMBINATORIALLIBRARIESHOWEVER,WHENONECONSIDERSTHEPROCESSOFHIGHTHROUGHPUTSCREENINGOFCOMBINATORIALLIBRARIES,ONECRITICALISSUETHATISOFTENOVERLOOKED,ESPECIALLYINTERMSOFCHEMICAL/STRUCTURALCHARACTERIZATIONOFLIBRARIES,ISTHETRADEOFFBETWEENSPEEDANDSPATIALRESOLUTION/SENSITIVITYOFTHEANALYSISTHISPROBLEMBECOMESEVENMOREACUTEASTHESPATIALDENSITYOFTHEARRAYSDECREASESWITHTHECAPACITYOFUSINGNANOSCALELITHOGRAPHYTECHNIQUESASSHOWNINFIG3,ONECANPRODUCEAVERYHIGHDENSITYOF“NANOARRAYS”INSTEADOFTHEUSUALMICROARRAYSEACHTIPWITH50NMRADIUSCANSERVEEITHERASASUBSTRATEFORGENERATINGGRADIENTTHINFILMSTRUCTURESWITHEACHNEEDLEASSOCIATEDWITHASPECIFICCHEMISTRYORTHISARRAYCANBEEXTRACTED,USINGFOCUSEDIONBEAMTECHNIQUESFROMABULKMATERIALWITHKNOWNCHEMICALAND/ORMICROSTRUCTURALGRADIENTSNORMALLYIN2DIMENSIONALCOMBINATORIALLIBRARIES,ASCANNINGPROBETECHNIQUESOFTENPROVIDESTHEKEYMEANSOFSCREENINGTHELIBRARYWITHTHEATOMPROBE,WEHAVEANINASENSEA“REVERSE”GEOMETRYWHERETHESPECIMENTOBESCREENEDNEEDSTOBEINTHEFORMOFATIPANDWENEEDAWAYTOCHARACTERIZEATTHETIPOFEACHSPECIMENWITHEXTREMELYHIGHRESOLUTIONANDSENSITIVITYASSHOWINFIG2,ATOMPROBETOMOGRAPHYPROVIDESUSTHEHIGHESTLEVELOFBOTHSPATIALRESOLUTIONANDCHEMICALSENSITIVITYOFANYTECHNIQUETOANALYSESMATERIALSCHEMISTRYHENCELIBRARYGEOMETRIESTHATLENDTHEMSELVESWELLTOTHEUSEOFATOMPROBETOMOGRAPHYASAHIGHTHROUGHPUTSCREENINGTOOLFORCOMBINATORIALARRAYSINCLUDEFIG2ACOMPARATIVECHARTSHOWINGTHEVALUEOFATOMPROBETOACHIEVEBOTHCHEMICALRESOLUTIONANDCHEMICALSENSITIVITYRELATIVETOOTHERHIGHTHROUGHPUTATOMICSCALECHEMICALCHARACTERIZATIONTECHNIQUESFIG3ASILICONMICROTIPARRAYOFATOMPROBETIPSFORUSEASAPLATFORMFORDEPOSITINGCOMBINATORIALARRAYSOFFILMOVERLAYSONTHINTIPS12THINFILMGRADIENTSACROSSNANOARRAYSSUBSTRATETIPSDEVELOPINGDIFFUSIONBASEDPHASELIBRARIESONEACHTIPTOADDATHIRDDIMENSIONTOOURABILITYTOCREATECOMPOUNDLIBRARIESINTHISCASE,WEUSETHEATOMPROBETOALSOINTERROGATECHEMISTRIESINTHEVERTICALDIRECTIONALONGTHEAXISOFEACHSPECIMENTIPANEXAMPLEOFTHISISSHOWNINFIG4BELOWFORTHEDETECTIONOFCOMPOUNDPHASELIBRARIESBASEDONINTERDIFFUSIONBETWEENTHINFILMOVERL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LETOABILLIONATOMSWEHAVESHOWNHOWTODIRECTLYANDQUANTITATIVELYTRACKTEMPORALCHANGESINCHEMICALCLUSTERINGASSOCIATEDWITHNUCLEATIONANDGROWTHOFNANOSCALEPRECIPITATESINMULTICOMPONENTALLOYSTHEOUTPUTOFTHESTUDYWASTHEDEVELOPMENTOFDENSITYCORRELATIONFUNCTIONSTHATMAPHOWDIFFERENTELEMENTSINTHEALLOYCLUSTERINTHREEFIG7MASSSPECTRUMFROMGLYCINEONSINGLEWALLEDCARBONNANOTUBES17ASCITEDINREF13FIG8ATOMMAPSOBTAINEDFROM3DAPANALYSISOFAWSPECIMENUSINGLASERPULSEENERGIESOFA04MJ,B2MJINTOASPOTAPPROXIMATELY100MMINDIAMETERNOTETHATWHEREASATLOWLASERPOWER,ATHE110ATOMICPLANESARECLEARLYVISIBLE,THESEBECOMEFARLESSDISTINCTATHIGHLASERPOWERS18DIMENSIONSLEADINGTOTHEFORMATIONOFNANOSCALEPRECIPITATESCONCLUSIONSPROGNOSISFORTHEFUTUREAPTHASEXTRAORDINARYPROMISEASAHIGHTHROUGHPUTSCREENINGTOOLSATTHENANOSCALEINCOMBINATORIALCHEMISTRYTHEATOMPROBECANPROVIDEBIOLOGISTSWITHAPOWERFULNEWTECHNIQUEFORSTRUCTURALANDCHEMICALCHARACTERIZATIONTOAIDINUNDERSTANDINGMOLECULARANDCELLULARSCALEMECHANISMSINBIOLOGICALSYSTEMSTHEFUNDAMENTALSTUMBLINGBLOCKINUSINGAPTFORBIOLOGICALSTUDIESISTHEDIFFICULTYINPREPARINGSAMPLESFORAPTSTUDIESUNDERCRYOGENICENVIRONMENTS,ANDTRANSFERRINGTHOSESPECIMENSINSITUTOTHEAPTJUSTASTHEREARECRYOFIXATIONMETHODSDEVELOPEDFORTEM,WENEEDTOADAPTTHOSETECHNIQUESFORTHEUNIQUECHALLENGESOFAPTATPRESENTNOGENERALCRYOFIXATIONMETHODHASBEENDEVELOPEDTHATALLOWSFORTHECRYOFIXATIONOFAPTSPECIMENSINTHENEEDLELIKEGEOMETRYTHATISREQUIREDFORAPTANALYSISIFTHESETECHNICALCHALLENGESAREOVERCOME,THEADVANCESIN3DSINGLEMOLECULEIMAGINGOFFEREDBYAPTWILLENABLENEWAPPROACHESTOHELPLINKCHEMICALBONDINGTOMOLECULARSTRUCTUREINBIOLOGICALSYSTEMSTHATWILLIMPACTFUNDAMENTALBIOLOGICALRESEARCHRANGINGFROMSTRUCTURALBIOLOGYTOADDRESSINGPROBLEMSINAVARIETYOFDISEASESSUCHASCANCERANDHIVTHECOMBINEDATOMICSCALECHEMICALANDSTRUCTURALRESOLUTIONINTEGRATEDWITHTHEABILITYTOIMAGEIN3DOPENSNEWDOORSINBIOLOGICALCHARACTERIZATIONTHATXRAYDIFFRACTIONANDTEMCANNOTPROVIDEFORINSTANCE,BYTHECRYOGENICPREPARATIONOFAPTSPECIMENS,THECONFORMATIONOFAPROTEINMOLECULEINICEMIGHTBE,INPRINCIPLE,DETERMINEDFROMVERYSMALLVOLUMESZEPTOLITERSOFMOLECULESINSOLUTIONTHISCOULDOBVIATETHENEEDFORCRYSTALLIZATIONANDMIGHTENABLECONFORMATIONDETERMINATIONFORMEMBRANEPROTEINSITWOULDOPENUPTHEPROSPECTOFANALYZINGPROTEINSINTHEIRNATURALENVIRONMENTWITHORWITHOUTSMALLMOLECULEDRUGSATTACHEDWECANUSETHEAPTTODETERMINEPROTEINDNAANDPROTEINPROTEININTERACTIONS,ANDHOWTHESEBIOMOLECULESSPECIFICALLYRECOGNIZEEACHOTHERFURTHER,WEEXPECTTHATTHEATOMPROBEWILLENABLEUSTOELUCIDATEFUNDAMENTALBIOCHEMICALPROCESSESSUCHASPROTEINFOLDING,MEMBRANESTRUCTURE,PROTEINDRUGANDANTIBODYANTIGENINTERACTIONSACKNOWLEDGEMENTSSUPPORTFROMTHISWORKCOMESFROMONRMURIAWARDNN000140611176ANDTHENATIONALSCIENCEFOUNDATIONAWARDSPHYCDI0941576,CMMIARI09389018ANDCCFAF0917202REFERENCES1MILLER,MKKENIK,EAATOMPROBETOMOGRAPHYATECHNIQUEFORNANOSCALECHARACTERIZATIONMICROSCMICROANAL,2004,10,3363412HONO,KATOMPROBEMICROANALYSISANDNANOSCALEMICROSTRUCTURESINMETALLICMATERIALSACTAMATERIALIA,1999,47,312731453KELLY,TFLARSON,DJTHOMPSON,KOLSON,JDALVIS,RLBUNTON,JHGORMAN,BPATOMPROBETOMOGRAPHYOFELECTRONICMATERIALSANNUREVMATERRES,2

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