10. an introduction to nanomedicine-2 - extendsim · chapter 10 an introduction to nanomedicine ......

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Chapter10

AnIntroductiontoNanomedicine

Amber Bhargava, Janet Cheung, Mary Eshaghian-Wilner, Wan Lee, Mike Schlesinger, Abhishek Uppal1

Abstract:Inthispaperwepresentthestatusofresearchinnanomedicineforthetreatmentofcancer as well as other biological diseases. We analyze the development of nanomedicineresearch based on – but not limited to – recent studies in the detection of diseased cells(includingcancerouscells),drugdelivery,andnanorobotics. Thesameapproachmayalsobeadopted inother respects, suchas the targetingand removalof plaqueand/or cholesterol inarteriesaswellasrepairingdamagedcells.Manyoftheseapproachestonanomedicinecanbesimulated through the use of computer models. We will discuss one such model from theUniversity of Southern California. Outstanding issues relating to the preliminary stage ofnanomedical research will be covered as well, along with various approaches for cancertreatment using nanotechnology. Current challenges associated with these treatmentapproaches,aswellaspossiblesolutionsforthesechallenges,willbediscussed. Weconcludewithadiscussionofbiocompatibility,nanoscalepower,andthecurrentstateofresearchinthefield.

1. Introduction

Nanotechnologypromisesahostofinnovativesolutionsinmedicinethroughprecise,targetedoperationsonthecellularlevel.Formorethanadecade,researchershavebeensearchingforwaystorealizethesesolutionsandovercomethedifficultiesencounteredwhenattemptingtousenanotechnologyforthetreatmentofvariousailments.Recently,researchershavebeguntolookintonanorobotics,arelativelynewsubsetofnanotechnologythatinvolvesthecontrolofmultifunctionalnanosystems.Nanorobotscouldintegratethediagnosisandtreatmentofcancerintoacohesive,potentiallynon-invasiveunit.Althoughthefieldofnanoroboticsremainslargelytheoretical,anumberofadvanceshavebeenmadeinthepastfewyearsthatleadustobelievethatamultifunctionalmedicinalnanorobotcouldbepossible.Inordertoachievethisgoal,weneedtoknowwhathasalreadybeenachievedandwhatstillremainstobedone.

Nanotechnologyasawholeisarelativelyrecentdevelopmentinscientificresearch.FirstdefinedbyNorioTaniguchifromtheTokyoScienceUniversityin1974,nanotechnology“mainlyconsistsoftheprocessofseparation,consolidation,anddeformationofmaterialsbyoneatomormolecule[1].”Priortotheyear2000,nanotechnologyfocusedonpassivenanostructures;now,activenanostructuresandsystemssuchastargeteddrugsandnanorobotsarebeingstudied.Today,awidelyaccepteddefinitionfornanotechnologyis“engineeringoffunctionalsystemsatthemolecularscale,”accordingtothe

1 Authors are listed alphabetically by last name, as opposed to by order of contribution

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CenterforResponsibleNanotechnology(CRN)[2].Themolecularscaleornanoscalereferstotechnologysmallerthan100nanometers.

Nanomedicineisasub-disciplineofnanotechnologyfirstdefinedinlate1999andearly2000.RobertA.Freitasfirstcomprehensivelyaddressedthetopicinhisbook,Nanomedicine,whichaddressesthetechnicalissuesinvolvedinthemedicalapplicationsofmolecularnanotechnologyandmedicalnanodevices.Currently,thereisnointernationallyagreedupondefinitionfornanomedicine.Forthepurposesofthispaper,weapplytheaccepteddefinitionofnanotechnologytomedicine.Wedefinenanomedicineastheuseofnanoscaledevicesormaterialsfordiagnosingandcuringdiseasesbyactivelyinteractingatthemolecularlevelwithinacellularsystem.Thisdefinitionisfairlybroad,sowefurtherrestrictourselvesbyincludingonlythosemedicineswhoseactiveingredientswerespecificallyengineeredwiththeintentoffunctioningonthenanoscale.Thisrequirementrejectsmedicationssuchaschapstickorsunscreen,whichwerenotdesignedwithafocusonthenanoscale.Webelievethisdefinitionadheresmostcloselytotheoriginalintentoftheterm.Nanomedicineisabroadfieldthatencompassesmultipletopicsfromdetection,drugdelivery,andnanodevicestonanoimagingandclinicalissues,allofwhichwewilladdressindetail.

Nanomedicineisexcitingbecausemanyofitsfindings–thoughoftenbasedonpreliminaryoreventheoreticalexperimentation–promiseresultsthatareimpossibleatthemacroscale.Forexample,manydevicesandmaterialsbeingstudiedexperimentallymaybeusedtodetectfaultycellsviaantibodyconjugation.Carbonnanotubes,forinstance,arecapableofdetectingparticularDNAmutationsequencesthatcouldgiverisetocancer.Anotherviableapplicationofnanoparticlesinmedicineismolecularimaging.Specificbiomoleculescanbetaggedandquantitativelyanalyzedviananoparticlesthatglowunderinfraredlight.Bothoftheseapproacheshaveexcitingandnovelapplicationsinmedicine,buttheyonlyscratchthesurfaceofhownanotechnologycanpotentiallyinfluencethefutureofmedicine.Inordertoimaginethetruescope,wemustlookatactivenanostructures,ornanorobotics.

Nanoroboticsisamultidisciplinaryfieldthatrequiresknowledgeofphysics,chemistry,biology,computerscience,andelectricalengineering.Nanorobotsmustpossessthecapabilityofactuation,control,communication,andinterfacingbetweentheorganic,inorganicandbioticrealms[3].Therearemanydirectionsfromwhichtoapproachtheproblemofcreatingaviablenanorobot.SomeresearchersfocusesonbionanoroboticsystemsmadeofbiologicalcomponentssuchasproteinsandDNA,whileothersfocusoninorganicmaterialslikeCMOSandcarbonnanotubesatthecellularlevel.Stillotherschoosetofocusonhybridnanosystems,combiningtheorganicandinorganicdomainstogetherinordertothebestofbothdomainsintoonenanorobot.

Thispaperwilladdressthetypesofdiseasesinvestigatedandthenanotechnologyinvolvedinmedicaltreatment.Next,itwilldiscussthecurrentdetectionandtreatmentmethodsusedbyresearchers.Thepaperwillthenconcludewithcurrentnanotechnologyusedincancertreatment,issueswithbiocompatibility,andcurrentresearch.Specificexamplesofcomputermodelingwillbediscussedindepth.

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2. NanomedicalTechnology

Inthissectionwewilldiscussnanotechnologyasitappliestomedicine,includingdifferenttypesofnanorobotsandsomeofthechallengesinherenttobuildingrobotsonthenanoscale.

Nanoroboticsisanemergingtechnologicalfieldthatcomprisesthedevelopmentofrobotswhosecomponentsareatorclosetothenanometerscale[4].Nanorobotsdesignedtooperateinsidethehumanbodyshouldbelessthan800µmindiameterinordertotraversethebloodstream[5].Sofar,nocomplexnanorobothasbeenfabricated-currentmedicalrobotsareconstrainedtothemillimeterlevel.Thus,inorganicnanorobotconstructionatthenanoscaleisonlyatheoreticalmodel.Inthissectionwepresentashortoverviewofmedicalnanotechnology,includingnanorobots,nanoparticles,andcarbonnanotubes(CNTs)asnanodevicesrelatedtomedicine.Wealsotakealookatmicroscaledevicesthatrepresentthecurrentstate-of-the-artinmedicalimplantableandnon-invasivetechnology.

Figure2.1:Sizeofnanorobotsrelativetoredbloodcells

Treatmentsbasedonnanorobotsareexpectedtohavetwomajoradvantagesovertraditionalapproaches:concentrationandprecision.Theseadvantagesenabletherapiestobecomemoreefficientandcausefewersideeffectsbecauseoftheirabilitytoconcentratedrugsonasingletissueareaorcell.Nanorobotscanalsoworktogetherinresponsetoenvironmentalstimuliandpre-programmedfunctionalityintheircontrolunit.

Therearetwomainapproachestodevelopinganassemblednanorobotsystem:organicandinorganic.Organicnanorobotsarebasedonadenosinetriphosphate(ATP)andDNAmolecularassemblyandfunction.Anothersubsetoforganicnanorobotsisnanorobotsbasedonbacteria,whichhavebeenproposedexperimentallyfordrugdelivery.Inorganicnanorobotsareessentiallynano-electromechanicalsystems(NEMS).Astechnologyhasdeveloped,someapproacheshavebeguntocombinebothorganicandinorganicelements,creatingamoreadvancedrobotsystemknownasahybridnanosystem.Althoughsomenanorobotshavealreadybeentested,themajorityofthecurrentresearchisstillinatheoreticalsimulationstage.Mostofthesubpartsofnanorobotsarebeingstudiedasindividualentities,or‘modular-wise,’ratherthanasentiresystems,sincetheelementsofnanoroboticsarestillprimarilyintheresearchphase.

Webelievethatinorganicnanorobotsarebestsuitedascandidatesfornanomedicine,andsowewillconcentrateoursurveyoninorganicnanorobots.Thereareseveraldifferencesbetweeninorganicandorganicnanorobots,whichdeterminehowthesetwosubsetswillapproachthemanyproblemsinherent

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tomedicalnanorobots.Forexample,inorganicnanorobotscouldlocatetheexactpositionofacellusingtheintensifiedmagneticpropertyfromtheforceofattractioninsidethehumanbody.Inotherwords,theycanisolateatargetcellfromanormalcellandatthesametimeallowfortargeteddrugdeliveryviaananorobotatthatdestination.AnorganicnanorobotmaybeabletoperformthesametaskusingDNAbiomarkers.However,theinherentprogrammabilityofinorganicnanorobotsbasedonCMOStechnologyandtheabilitytoleveragetheexistingcontrolstructuresofmacro-sizedrobotsmakesinorganicnanorobotsthemostlikelytosucceedinperformingthecomplex,precisetasksrequiredofmedicalnanorobots.

Still,therearemanychallengestobuildingamulti-functionalinorganicnanorobot.Inordertocreatearobotinthenanoscale,wemusttakeintoaccountsensing,actuation,control,datatransmission,power,andinterfacingacrossspatialscalesaswellasbetweentheorganic/inorganicandbiotic/abioticrealms[6].

Althoughinorganicrobotsdonotexistinthenanoscaletoday,wecanlookatmicroscaleandlargermedicalrobotsthatcanbeusedastestcasesforextendingfunctionalityintothenanoscale.Additionally,researchonsurgicallyimplanteddevicescanprovideinformationonhownanorobotsmaybeabletosolvetheproblemsofbiocompatibility,energytransfer,anddatatransfer.

Onesuchareaisdiagnosticmedicineinthedigestivetract.Medicaldevicecompanieshaveusedcapsuleendoscopesforviewinganddiagnosingdiseases.Thesedevicesareconsideredmicrorobots–onthescaleofaone-centimeterdiameterbytwocentimeterslength–andhaveonboardcamerasandLEDs,andcansendvideowirelesslyoutofthebody[7].However,theyarestilllimitedinscopeastheypassthroughthebodywithoutself-propulsion,drawnsolelythroughperistalticpressure,andthereforecannotcompletetaskssuchastrulytargetedmedicationorathoroughsearchforcancerousregions.Therearegroupssearchingforwaystoovercomethesechallenges,however,bydevelopingmotors[7],controllingseveralmicrorobotsinasystem[8],andlookingatthepotentialformicrorobotsthatcoulddispensemedicineintothestomachformonthsatatime[9].

Althoughmicroscaleandnanoscalerobotsfaceverydifferentproblemsintermsofmotionandenergysupply[10],microscalemedicaldevicesareimportanttotheemergingfieldofnanoroboticsbothasatechnologicalprecursorandasatestinggroundforthehumansideofmedicalnanorobotics.Microrobotsopenthediscussionofthelegalissuesofdatasecurityandhowthemedicalanddevice-makingcommunitywilldealwithimplantabledevicesthatareconstantlystreamingimportantpersonaldata.

Today,nanoroboticsisrapidlybecomingareality.PennStatepublishedanarticleinFebruary2014showingnanomotorsindividuallycontrolledinsidelivingcells[11].Thisisanimportantstep,asitaddressesbothcontrolmethodsandbiocompatibility.However,therearestillmanystepstobetakenbeforenanorobotsareviableinsidethehumanbody.

Currentnanorobotcomponents,controlmethods,anddevelopingmanufacturingmethodsprovideplatformsandpossibilitiesforbuildingmultifunctionalnanorobotsthatmaybeabletoswimthrough

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vessels,detectanddestroycancercells,orsendpicturesbacktoitscontrollingdevicewithaccuracy,controllability,andprecision.Aspreviouslystated,wewishtodevelopnanorobotsinordertoperformprecisedrugdelivery.

3. Detection

Inthelastsectionwelookedatnanotechnologyasitappliestomedicine,differenttypesofnanorobots,andwhywechosetofocusthischapteroninorganicnanorobots.Inthefollowingsection,wewilldiscussanumberofdifferentnanostructureswecanusetodetectthepresenceofcancerorotherdiseasesinthebody.

Nanomedicinecanassistinthetreatmentofawiderangeofdiseases.Ourresearchfocusesonthosethatcanbetreatedbynanorobotsinthebloodstream,includingdiabetes,cardiovasculardisease,neurodegenerativedisease,andcancer,amongothers.Whileamajorpartofnanomedicalresearchisstillinitsinfantstages,significantresearchandexperimentshavebeenperformedontheseandotherdiseases.Whileallofthesediseasesareathreattopublichealthandcouldpotentiallybetreatedorcuredbynanomedicine,ourresearchfocusesspecificallyoncancer.

Cancerisagroupofdiseasescharacterizedbyuncontrolledcellgrowth.Thebodydoesnotregulatecancercellsasitdoeshealthycells,therebyallowingthemtoreplicateatarapidratewithoutbeingkilledoffastheynormallywould.Cancercellsreplicatesouncontrollablyduetodamageddeoxyribonucleicacid(DNA),whichpreventsthecell’snaturaldeathandcauseschangesinmaterial(physical,electrical,orchemical)propertieswithinthecell.

Earlydetectionandpreventionarethebestcuresforanydisease,includingcancer.Currently,earlydetectionisaccomplishedbyidentifyingbiomarkers,anindicatorofabiologicalstateofdisease.BiomarkerscanbeDNA,RNA,oraproteinanditsfragments.Inthefuture,evenearlierdetectionmaybepossiblethankstoubiquitouscomputingandconstantmonitoringofat-riskpatients.Today’sdetectiontools,however,functioninresponsetochangesinmaterialproperties,suchasthosecausedbythedamagedDNAincancercells.Detectiontoolsunderdiscussioninthispaperarenanowires,carbonnanotubes,nanoscalecantilevers,variousnanoparticles(goldandmagnetic,amongothers),quantumdots,andnanorobots.Inthissection,detectiontoolsforbiomarkersarediscussed.

3.1 Nanowires

Nanowiresinherentlyhaveexcellentselectivityandspecificityproperties.Forexample,nanowirescanbelaiddownacrossamicrofluidicchannel,notunlikeafilteroraspider’sweb.Ascellsorparticlesflowthroughit,nanowirescansenseandpickuptumorcells.Nanowirescanbecoatedwithaprobesuchasanantibodyoroligonucleotide–ashortstretchofDNAthatcanbeusedtorecognizespecificDNA/RNAsequences–thatbindstoatargetproteinontheenemycell.Proteinsthatbindtotheantibodywillchangethenanowire’selectricalconductance,whichcanbemeasuredbyadetector[12].

3.2 CarbonNanotubes

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CarbonnanotubesarealsobeingusedasDNAbiosensors.TheyscandownDNAandlookforsinglepolymorphicnucleotidesthatcanleadtoapossibledetectionofanindividualwhomaydevelopdiseasesinthefuture.Thisapplicationusesself-assembledcarbonnanotubesandsearchesforcovalentlybondedDNAoligonucleotides.WhenhybridizationbetweentheprobeandthetargetDNAsequenceoccurs,thevoltammetricpeakpicksupthechange[13].DNAbiosensorsbeingdevelopedforfutureusearemoreefficientandmoreselectivethancurrentdetectionmethods.

3.3 NanoscaleCantilevers

Anotherpotentialtoolisthenanoscalecantilever.Similarinstructuretorowsofdivingboards,thesecantileversareconstructedusingsemiconductorlithographictechniques[14]andcoatedwithantibodiesthatspecificallytargetmoleculesproducedbycancercells.Thesetargetmoleculesbindtotheantibodiesonthecantilever,causingachangeinitsphysicalproperties.Forquantitativeanalysis,researcherscanstudythebindinginrealtime.ThesecantileversareexceptionallysensitiveandcandetectsinglemoleculesofDNAorprotein,henceprovidingprecisedetectionmethodsforcancerrelatedmolecules.Figure3.1belowshowshownanoscalecantileversdetectproteinsproducedbycancercells.

Figure3.1:Detectionofcancercellsbynanoscalecantilevers

3.4 GoldNanoparticles

Goldnanoparticles(GNPs)havebeenemergingaspowerfulimaginglabelsandcontrastagents–henceeffectivedetectives.GNPsreadilygetconjugatedtoantibodiesandotherproteinsduetotheaffinityofthefunctionalgroup(-SH)fortheirgoldsurface.Theyareespeciallyeffectivewhentargetingcancercells[15].GNPsareusedforphotothermaltherapy,wheretunableopticalpropertiescausethemtoconvertlaserlightintoheatanddestroycancercells[16,17].InadditiontosphericalGNPs,goldnanoshellsandgoldnanorodshavebeenappliedtobiomarkerdetection[18-20].Theycanabsorbandemitlightatnearinfraredregion,providingdeeptissuepenetration.

3.5 MagneticNanoparticlesandMagneto-ElectricNanoparticles

Magneticnanoparticleshavebeenwidelyusedasanimagingtool.Sincetransverserelaxationtimedecreasesduetoaggregationofmagneticnanoparticleswhentargetmoleculesarepresent,theconcentrationofcancerbiomarkerscanbemeasured.Thisallowsforinvivo,localmonitoringforcancerbiomarkersandpossiblecontinuousmonitoring.Magneto-electricnanoparticleshavealsoproventobeapromisingnewtechnology.Inonespecificstudy,researchershavebeenabletoisolatea

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cancerouscellbasedondifferencesintheelectricpropertiesofitsmembrane[21].Thismethodofdetectionhasbeenproveneffectiveasappliedtoovariancancercells,butmaypotentiallybeappliedtoothertypesofcanceraswell.Moreonthistopiccanbefoundinchapter11ofthisbook.

3.6 QuantumDots

Quantumdotscanbelinkedtoantibodiesandcombinedtocreatearraysthatarecapableofdetectingmultiplesubstancessimultaneously.TheycanbeusedtomeasurelevelsofcancermarkerssuchasbreastcancermarkerHer-2,actin,microfibrilproteins,andnuclearantigens[14].Quantumdotsarerobustandverystablelightemitters.Thephotochemicalstabilityandtheabilitytotunebroadwavelengthsmakequantumdotsextremelyusefulforbiolabelling[22].

3.7 TheMedicalNanorobot

Theultimatetoolofnanomedicineisthemedicalnanorobot–arobotthesizeofabacteriumcomposedofmultiplemechanicalparts[23].Althoughstillahypotheticalconcept,themedicalnanorobotisapromisingtoolforthefutureofthefieldofmedicine–afutureinwhichartificiallyintelligentnanorobotscanbefabricatedtorepairtissues,cleanbloodvesselsandairways,andtransformphysiologicalcapabilities.Amorein-depthdiscussionofthetechnologybehindnanorobotscanbefoundinthepreviousnanomedicaltechnologysectionofthischapter,aswellaschapter2ofthisbook.Thenextsectionwilldealwithactuallytreatingthediseasecellsoncetheyaredetected.

4. Treatment

Intheprevioussection,weidentifiedsixmethodsofcancerdetection.Inthefollowingsectionwediscusstheproblemswithcurrentcancertreatments,aswellasmethodsthatcanbeusedtotreatdiseaseatthecellularlevelwithinthebody.

Moderncancertreatmentisanythingbutideal.Conventionaltreatmentssuchaschemotherapy,radiation,surgery,andimmunotherapydestroymalignanttissue,butalsodamagebenigntissue.Thesemethodsarefoundtobeusefulinremission,butdependontheconcentrationanddeliveryofthedrug.Highlytoxicdrugconcentrationsthatdestroythetumorcellscanpotentiallykillthepatient.Thus,theaggressivenessofchemotherapytreatmentisusuallydeterminedbythedosagethatthepatientcanwithstand,ratherthanthedosageneededtoeliminateallcancerouscells.

Amoreefficientapproachtocancertreatmentwouldbethedestructionofcancercellswithlittletonosideeffectsonhealthycells.Withthecurrenttrendofrapiddevelopmentsinnanomedicine,itseemsthatthistechnologycanbeusedfordetection,analysis,anddestructionofcancercellsmoreeffectivelyandwithmoreprecisionthanispossiblewithcurrenttreatments.

Asstated,thekeyproblemsofconventionaltechnologyarethemethodofdrugdeliveryandtheconcentrationofthedrugcocktailrequiredtodestroythecancerouscells–problemsthatcanbeeasilyovercomebynanotechnology,astheparticlesizehasaneffectonserumlifetimeandpatternofdeposition.Thisallowsdrugsonthenanoscaletobeusedinlowerconcentrations,whichresultsinan

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earlieroutsetofaction.Nanotechnologyalsoallowsdrugstobedirectedtotheexactlocationwherecancerouscellshavebeenobserved,thuskillingmalignanttissuewhileleavinghealthytissuerelativelyunaffected.Therehavebeenseveralstudiesdoneintotheindividualtreatmentofcancercells.Thissectionwillexploresomeofthesetreatmentsinmoredetail.

4.1 NanoparticleHeatingMethod

Thenanoparticleheatingmethodforcancertherapyhasgreatpotentialfortreatingselectivecancertissue.Theconceptisveryefficient.Inthismethod,thenanoparticlesconjugatedwithantibodiesareinjectedintothehumanbodyandareallowedtopositionthemselvesaroundthecancertissue.Theseparticlesarethenheatedbyanexternalnon-invasiveheatingsource,destroyingthetargetedcancertissuesviathermalnecrosis[24].CapacitivelycoupledRFfieldsources[25]andNear-InfraredLightsources(NIR)[26]aretwooftheheatingsourcesthatcouldbeusedtoheatupthesenanoparticles.Amajoradvantageofthistechniqueisitslackofdependenceontraditionaldrugs.Asinvadingbacteriabecomelessandlesssensitivetoantibioticsandotherdrugs,anewsolutionmaysoonberequiredtotreatthesebacterialinfections.Nanoparticleheatingmaywellbeonesolution.Twotreatmentsthatemploythenanoparticleheatingmethodbywayofinfraredandlaserlightarediscussedbelow.

4.1.1 GoldNanoparticles

Asdiscussedinsection3.1.4,oneofthemostresearchednanomedicicalapplicationsisgoldnanoparticles(GNPs).Thesenanoparticlesbindtocertainproteinsthatonlycancercellsproduce.Goldnanoparticlescanalsobeseenas“thedrugsthatdeliverthemselves”fortheirspecialheatingability,which,whenexposedtolaserlight,killscellswithwhichthenanoparticleinteracts.Thedownsideofthismethodisthatunlessproperlycoated,theimmunesystemwouldattacksuchparticlesbecausethebodywouldtreatthemasunwantedforeignagents.Seesection5.1onbiocompatibilityformoreinformationonimmunereactionsandimmunosuppression.

4.1.2 MetalNanoshells

Anothernovelapproachusesmetalnanoshells.Theseshellshavetheabilitytocaptureandabsorblight,andarecoatedwithabioactivesubstancethatbindsthemtocancercells[27-29].Near-infraredlightisusedtoheatuptheseshells,leadingtothedestructionofthecancercellswithminimaldamagetoadjacenthealthycells.Theadvantagesofhighsensitivity,specificity,andcost-effectivenesshavemademetallicnanoshellsaparticularlyattractivechoiceformodern-daycancertreatment.AlamandMassoudhavedevelopedanaccurateanalyticalclosed-formmodelforthefrequencyresonanceandscatteringcharacteristicsofasinglenanoshell[16].

4.2 SupermagneticBeads

Apartfromgoldnanoparticlesandmetalnanoshells,anothermethodthatemphasizesthedestructionoftargetedcancercellsusesmono-sizedsupermagneticbeads.Thebeadsaremacroporousparticleshavingnarrowporesthatcontainmagneticmaterials(Fe203andFe3O4)distributedthroughouttheirentirevolume.Instudies,twodifferenttypesofbeadshavingdifferentmagneticmasssusceptibility

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anddifferentdiameterswereused:DynabeadsPanMouseIgG(diameter4.5±.2um,magneticsusceptibility(16±3)x10-5m3/kg)andDynabeadsProteinG(diameter2.8±.2um,magneticmasssusceptibility(10±2.5)x10-5m3/kg).Thesemagnetizablebeadsaggregateunderinstantaneouspulsedmagneticforcesandpenetrateforcefullytoeffectivelydestroythecancerouscells[21].

4.3 MagneticManipulation

Magneticmanipulationisanotherviablemethodtoefficientlydelivermedication.Recently,scientistshavesuccessfullyusedadirectcurrentmagneticfieldtomanipulatethemembranesofmagneto-electricparticles.Theythenusedthisabilitytoloadthesamemagneto-electricparticleswithpaclitaxel,acommoncancerdrug,anddeliverittoamixofhealthyandcancerouscellsin-vitro.Thedrugs,whenreleasedbytheparticles,passedthroughthemembranesofthecancercellsandkilledonlythetargetedcells.Thehealthycellswereleftalive[30].Inthesamestudyaspreviouslymentionedinsection3.5ofthischapter,magneto-electricnanoparticleswereusedtomanipulatethemagneticfieldofthemembraneofthetumorcelltoallowlargequantitiesofmedicationtopassthroughintothecell.Thediseasedcellwaskilledwithnoharmatalltosurroundinghealthycells[21],ascanbeseeninmoredetailinthefollowingchapter.Theseresultsshowearlypromiseinspecifictargetingofcancercellswithinthehumanbody,andcertainlydeservefurtherresearch.

4.4 E-cadherin

NanorobotscanalsobeusedtoanalyzelevelsofE-cadherininthebodyandtargetcancercellsbasedonthevaryingE-cadherinlevelsfromonecelltothenext[31,32].E-cadherinisacalcium-regulatedadhesionexpressedinmostnormalepithelialtissues.E-cadherinisassociatedwithglandformation,stratification,andepithelialpolarization.PerturbationorselectivelossofthisE-cadherinfunctionresultsinthelossofintercellularadhesion,withpossibleconsequentcellulartransformationandtumorgeneration.Theefficientuseofnanorobotsbypropercontrolmethodologiesisoneofthemethodsunderstudyforthetreatmentofcancercells,asitisquitecapableofdifferentiatingnormalcellsfrommalignantcellsbycheckingsurfaceantigens.Thisinturngreatlyreducestheprobabilityofdestroyingnormalcells.

4.5 TreatmentsforOtherDiseases

Whilethispaperdoesfocusprimarilyoncancertreatment,therearealsomanyothernanoscaletechniquesfortreatingdiseasesotherthancancer.Thefollowingsubsectionswilldescribethreeofthembriefly.

4.5.1 Transfection

Asopposedtothemethodsofdrugdeliverydiscussedthroughouttherestofthissection,transfectionisamethodofgenedelivery.Transfectioncanbeaccomplishedbybothchemicalandnon-chemicalprocesses.Chemical-basedtransfectioncanbedividedintoseveralcategories,includingcyclodextrin,polymers,liposomes,andnanoparticles.Therearevariousnon-chemicalprocessesaswell,includingelectroporation,sonoporation,andimpalefection.Impalefectionisdifferentfromtheseothernon-

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chemicalmethodsinthatDNAisintroducedintothecellthroughtheuseofnanomaterials.Inthisprocess,nanowiresandsimilarnanoparticlesareusedastransportsystems.VerticalarraysofnanowiresarepreparedbyphotolithographyandplasmaenhancedchemicalvapordepositionbeforetheyarecoatedinDNAcontainingthesequencemeantfordelivery.Targetcellsareculturedonthesenanowirearrays,whichproceedtoimpalethetargetcellsastheysettleonthesurfaceofthenanowires.ThismethodisabletodeliverDNAdirectlytothecellcytoplasmofthenucleusofthecell,whichthenbeginstoactinaccordancewiththenewlyintroducedsequenceofDNA.Appropriately,theterm“transfection”isacombinationofboth‘impalement’and‘infection[33-36].’

4.5.2 TissueEngineering

Nanomedicaltechnologyisbeinginvestigatedasapossiblemethodtofurtherthefieldoftissueengineering.Nanotechnologycouldpotentiallybeusedtohelprepairdamagedtissuethroughtheuseofsuitablenanomaterial-basedscaffoldsandgrowthfactors.Ifsuccessful,tissueengineeringmaybeabletoreplaceconventionaltreatmentssuchasorgantransplantsandartificialimplants.Nanoparticlessuchasgraphene,CNTs,molybdenumdisulfide,andtungstendisulfidearebeinginvestigatedaspotentialreinforcingagentstomakestrong,biodegradablepolymericnanocompositesforbonetissueengineeringapplications.Asaresultoftheadditionofthesenanoparticlesintothepolymermatrixatlowconcentrationsofabout0.2%byweight,thecompressiveandflexuralmechanicalpropertiesofpolymericnanocompositesaresignificantlyincreased.Thesenanocompositescouldpotentiallybeusedtofurthernanonephrology(definedasnanomedicineofthekidney),createstrong,lightweightcompositeboneimplants,orevenweldarteriesduringsurgery[37,38].

4.5.3 Monitoring

Medicalmonitoringisthepracticeofobservingapatienttoeithermakesuretheyremainhealthyorgatheringdatatoassistindiagnosisortreatment.Traditionally,thishasbeendoneprimarilyincontrolledenvironmentswhereadoctoracphysicallyobservethepatient.Usingcurrenttechnology,however,doctorscanobservepatientsfromanywherebywayofasmallchipeitherimplantedunderthepatent’sskin,swallowedinpillform,orintroducedtothebodybyothermeans.Thisisamajorimprovementoverin-personmonitoring,duetothefactthatitenablesconstantmonitoring.Constantmonitoringofthepatientallowsdoctorstogathermoredatafromthepatient,allwhilethepatientgoesabouttheirnormaldailyroutine.Bothofthesebenefitscanresultinfaster,moreaccuratediagnosisandtreatmentofdisease.Unfortunately,duetotherelativelylargesizeofthesemodernimplantsascomparedtoobjectsonthenanoscale,theycanonlybeimplementedinlimitedlocationsthroughoutthebody.Thisrestrictstheiraccesstocertaindatathatcanonlybeobtainedinlocationsinwhichtheycannotbeutilized.Nanomedicaltechnologyhasthepotentialtoovercomethisobstaclebyproducingnanoscaleimplantsthatcanbeutilizedvirtuallyanywherewithinthebody.Usingtheconceptofananoscalelab-on-chipimplant,scientistscanpotentiallygatherdatafromtestsrangingfromcontinuousevaluationofbloodsugarlevelsandneuroimagingtopredictingbothhypoandhyperglycemicstatesaswellasseizures.InVivoBioMEMSbasedbiosensorsandserotoninbiosensorsmayalsobeusedinpreventinganearlydetectionofmentalhealthdisorders,suchasdepression[39,40].

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Thissectiondiscussedjustsomeofthemultitudeoftreatmentoptionscurrentlyunderinvestigation.Inthenextsection,wewillexplorechallengesintroducedwhenintroducinganyoftheseforeignagentsintothehumanbody–atopicknownasbiocompatibility.

5. Biocompatibility

Inpastsections,wehavecoveredmethodstodetectandcurecanceronthenanoscale.Achievingatreatment,however,ismoredifficultthanthat.Thenanorobotsneedtobeabletosurvivewithinthebodyforlongenoughtoarriveatthecancerouscellsanddelivertheirmedication.Inthefollowingsectionwediscussthechallengespresentedbythisrequirement,commonlyknownasbiocompatibility.

Biocompatibility,or“theabilityofamaterialtoperformwithanappropriatehostresponseinaspecificsituation,”[41]isanimportantfactorinthedevelopmentofnanomedicalrobots.Anynanorobotdesignedtoenterthehumanbodymustbebiocompatibleinordertofunctioncorrectly,oritsintroductionwilltriggerunwantedimmuneresponsesinthebody.Biocompatibilityhastraditionallybeenanimportantconsiderationinprostheticsandorgantransplants,asarejectedtransplantcanhaveseriouscomplications.Biocompatibilityinnanomedicine,however,inpartduetoitslargesurfaceareatovolumeratio,introduceschallengesuniquetoitsscale[42].Thissectionwilladdressbothpossibleeffectsofnanorobotsonthebodyandfactorsthatdeterminebiocompatibilityonthenanoscale.

5.1 Immunostimulation

Ifmedicalnanorobotsarenotappropriatelybiocompatible,thereisariskofanumberofcomplicationswithinthehost.Thetwoverybroadcategoriesofimmuneresponsestonanoparticlesareimmunostimulationandimmunosuppression.Ifthenanorobotstriggeranimmuneresponsewithinthehost,thereactioncanbeconsideredoneofimmunostimulation[43].Itisimportanttonoteherethatbiocompatibilityrequiresanimmunereactionappropriatetothedesiredfunction,notsimplyanon-reaction.Immunostimulationisnotnecessarilyanegativereaction;itcan,infact,bethedesiredeffect.Forexample,nanoparticlescanbeinjectedintothebloodstreamtoaidtheimmunesysteminfightingoffadisease[42,43].Infact,thismethodhasbeenusedsincetheadventofvaccineswithnon-nanoscalematerialsknownasimmunologicadjuvants[44,45].Immunostimulationcan,however,beharmfultobothhostandnanorobots.Immunostimulationproducessideeffectsincludinghypersensitivitytoallergens,inflammation,fever,andotherflu-likesymptoms[43].Itcanalsoaggravateotherconditions,suchasautoimmunity.Immunostimulationalsoresultsintheincreasedproductionofmacrophages,whichcanattackanddestroynanorobotsbeforetheyareabletoaccomplishtheirtaskwithinthebody.

5.2 Immunosuppression

Introducingnanoparticlesintothebodydoesnotalwayscauseimmunostimulation–itcanalsotriggerimmunosuppression.Asitsnamesuggests,immunosuppressionistheoppositeofimmunostimulation:itisdefinedas“suppressionofthebody'simmunesystemanditsabilitytofightinfectionsandotherdiseases[46].”Immunosuppressionisvitaltosuccessfulorgantransplantsandskingrafts,aswellas

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autoimmunitytreatments.Immunosuppressioncanmakeiteasierfordrug-deliverynanorobotstoaccomplishtheirjobsinthebody,butalsohasthepotentialtoharmorevenkillthehost[43].Immunosuppressionleavesthebodyopentoattack,andisthesymptomofdiseaseslikeHIVandAIDSthateventuallyleadstodeath.Whennanorobotsareusedasdrugdeliverydevices,asisthefocusofthispaper,theywilllikelybemosteffectiveiftheyareseenasnativeentitieswithnoimmunostimulationorimmunosuppression[44].Thisisthegoalofnanoscalebiocompatibility.

5.3 FactorsofNanobiocompatibility

Intheprevioussubsections,wediscussedtwomajoreffectsthattheintroductionofforeignnanorobotscanhaveontheimmunesystem–theimmunostimulationandimmunosuppressionreactions.Inthissubsection,wepresentmanyofthefactorsthatcaninfluencethesereactions.Biocompatibilityonthenanoscalepresentschallengesnotfacedintraditionalprostheticsortransplants.Onthenanoscale,biocompatibilityisdeterminedbyanumberoffactors:size,amount,density,location,duration,geometricsurfaceplanes,andmaterial,amongothers[34-36].Materialmaybethelargestfactorindeterminingbiocompatibility.Somematerials,suchasmetaltracesincertaincarbonnanotubes[42],areknowntocauseundesiredimmunereactions,whileothers,suchasdiamond[47,48]andpossiblygraphene[43],havebeenshowntohaveminimalbiocompatibilityissuesinanimals.Sizeisakeyfactoraswell–evenifamaterialisconsideredbiocompatibleonalargerscale,nanoparticlesofthesamematerialcanpotentiallyprovetobecarcinogenic[48].Also,thesmallertheparticle,thelongertheytendtosurviveinthebloodstream.AccordingtoBastúsetal,thisisanobservable,universaltrend[44].Surfaceorientationplaysalargeroleindeterminingbiocompatibilityaswell,aseachgeometricplanepresentsadifferentphysicalstructuretothesurroundingenvironment.Immuneresponsesdifferbetweenplanes,causingbiocompatibilitytovaryevenwithinnanoparticlesofthesamematerial[47].Biocompatibilityalsodiffersbasedonlocation.Forexample,nanorobotswillencounterverydifferentbiologicalconditionsifinjecteddirectlyintothebloodstream,asopposedtobeingingestedorallyorinhaled.Eachsetofconditionswillaffectthenanorobotdifferently,sothesamenanorobotmaybebiocompatibleinthebloodstream,butnotinthestomach.Durationisalsoamajor–ifoftenoverlooked–factorinbiocompatibility.Nanorobotsmusthaveapre-plannedwaytoleavethebodyoncetheyaccomplishtheirtask.Theymaybeexcretednormally,mimicpathogenssoastoberemovedbytheimmunesystem,ormakeuseofotherexittechniques[43].Ifthereisnoexitstrategynanorobotscanbuildupinvitalinternalorgans,suchastheliverorspleen,causingsideeffectsincludingliverfailureandcancer[42-44].

Nanomedicinedoeshavethepotentialtorevolutionizethewaymedicineispracticedaroundtheworld,butitisclearthatbiocompatibilityonthenanoscaleisoneofmanymajorchallengesthatmustbeovercomebeforenanomedicinecanbesafelyimplementedonalargescale.

6. Power

Intheprevioussection,wediscussedbiocompatibilityandthedifficultiespresentedbythisconcept.Butevenifananorobotcandetectcancer,treatcancer,andbefullybiocompatible,itstillneedsawaytopoweritself.Inthissection,wewilldiscussrecentprogressinwirelesspowerandhowthisideacanbe

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directlyappliedtonanomedicine.

Unlessthenanorobotsofthefuturearedesignedtobetotallypassive–relyingonlyonoutsidesourcesforallmovementandactions–theywillneedasourceofpower.Poweringananorobotwithwiresasitcirculatesthroughthehumanbloodstreamisobviouslyimpractical,andnanoscalebatterieswouldlikelyholdonlyaverylimitedchargeanddonotcurrentlyexistinformsusefulinnanomedicicalapplications.Ignoringexternalwiresandinternalbatteriesleavesuswithaverylikelysolutiontonanorobotpower:wirelessinductivepower.

Whenpoweringadevicelikeananorobotremotely,afour-partsystemconsistingofatransmitter,rectifier,bandgapreferencecircuit,andmatchingnetworkisrequired.ThetransmittertransmitsACpower,whichisconvertedtoDCpowerbytherectifier.ThebandgapreferencecircuitandaregulatoruseanalogcircuitrytechniquestotransformthisDCvoltageintoastable,non-temperaturedependentvoltagesourceusablebythedevice.Thenetworkmustbeimpedancematchedfortheparticularoperatingtominimizepowerloss,therebyprovidingmorepowertothechip[41].Therearemanyknowndesignsforwirelessinductivepowersystemsthatcouldpotentiallybeadaptedforimplantabledevices,someofwhichhavebeenshowntooperatewithupto72%powerefficiency[42].TheCaltechNanofabricationlabdevelopedonesuchdevice,a1.4mmby1.4mmglucosemonitoringimplantthatispoweredbyanexternalRFsignalat900Mhzanduses5μWofpower[43].

Figure6.1:Basicblockdiagramofafour-partwirelesspowersystem

Inductivepowerisnotperfect.Thecoilsmustbebothmatchedperfectlyandinperfectalignmentwitheachothertorealizemaximumrange,whichisstillnormallyonlyamatterofcentimeters.ResearchersatMIT,however,havedevelopedasolutiontotheseproblemsknownashighlyresonantwirelesspowertransfer.Usingthistechnology,theydevelopedasystemtoefficientlytransmit60wattsovertwometers[44].Thistechnologycouldbehugelybeneficialinlonger-termimplants,suchascochlearimplantsorpacemakers,whicharecurrentlybatterypoweredandrequireinvasivesurgerytoreplacethebatterywhenitbeginstofail.Highlyresonantwirelesspowercouldalsobeusedtomoreeasilypowernanomedicaldevices.Assumingashortlifespanfornanorobotsinthebody,thepatientmaybeabletostayeasilywithinrangeofahospitaltransmitterimplantedintheirbedorwallfortheentireprocedure–potentiallyeliminatingthecomplicationsintroducedbytherangeandalignmentrequirementsofmoretraditionalinductivepower.

Otherrecentexamplesofstudiesusingwirelesspowerincludethedesignofatelemetrysystembased

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onwirelesspowertransmissionforphysiologicalparametermonitoring[41]andamethodoftrackingoptimalefficiencyofmagneticresonancewirelesspowertransfersystemforbiomedicalcapsuleendoscopy[42].Intheformer,animplantedtelemetrysystemforexperimentalanimalscanbeusedtocontinuouslymonitorphysiologicalparameters.Thissystemissignificantnotonlyinthestudyoforganismsbutalsointheevaluationofdrugefficacy,artificialorgans,andauxiliarydevices.Thesystemiscomposedofaminiatureelectroniccapsule,awirelesspowertransmissionmodule,adata-recordingdevice,andaprocessingmodule.Anelectrocardiograph,atemperaturesensor,andapressuresensorareintegratedintheminiatureelectroniccapsule,inwhichthesignalsaretransmittedinvitrobywirelesscommunicationafterfiltering,amplification,andA/Dsampling.Toovercomethepowershortageofbatteries,awirelesspowertransmissionmodulebasedonelectromagneticinductionwasdesigned.Inthelatter,researcherswerelookingforasolutiontotheproblemoflimitedbatterycapacityincommercializedcapsuleendoscopy.TheirpaperpresentsatheoryfortrackingtheoptimalefficiencyofanMR-WPT(ResonantWirelessPowerTransfer)system,alongwithitsexperimentalverification.Asystemwitha9-mm-diameterreceiverisimplemented,whichissmallenoughtofitinthecurrentcapsuleendoscope.

Thecurrentadvancesinwirelesspowertechnologyareessentialforthefuturedevelopmentofnanomedicalrobots.However,powerisonlyonepieceofthepuzzle.Untilwecanassembleacompletenanorobotfortestingpurposes,wemustrelyonothermethodstodeterminehowdifferentdesignsinteractwiththehumanbody.Inthefollowingsection,wewilldiscussonesuchmethod:computermodeling.

7. ComputerModeling

Inprevioussections,wehavediscussedmanyofthebasicrequirementsforcancer-treatingnanorobots.Inthefollowingsection,wewalkthroughoneattempttomodelallofthesesystemstogetherwithinthehumanbodythroughtheuseofcomputers.

Inordertocreateviablenanorobotsformedicalpurposes,allofthesesystemsmustcometogetherinoneunit.Becausewearenotyetabletophysicallyproducerobotsontherequiredscale,wecanusecomputermodelingtoattempttodeterminehowspecificcombinationsofalloftheabovesystemswillfunctiononceintroducedintothebody.Inonerecentexampleofcomputermodelingfornanomedicine,aresearchteamattheUniversityofSouthernCaliforniahasdevelopedasystemthatmodelsnanoscaledrugdeliverythroughthebloodstream.Ithastheabilitytorepresentbothactiveandpassivetargetingnanorobots.Itsimulatestheflowofnanorobotsthroughthebloodstreamuntiltheydetectcancercells,atwhichpointtheymaneuvertothetumorandbegintheprocessofdrugdelivery.Thismodelaccountsforvariouspossibledrugdeliveryfailures,suchasearlyrelease,delayedrelease,non-release,powerfailure,andimmunostimulation.Uponfailure,therepresentationofthenanorobotexitsthemodel.Eachfaileddeliverycanbeviewedinabargraphbytypeoffailure.Whenananorobotsuccessfullyattachestoacancercell,therepresentativenanorobotinthemodelincurslatency,whichaccountsforattachingtothecancercellandtheactualactofdrugdeployment.Thenumberofsuccessfuldeliveriesascomparedtothenumberoffaileddeliveriescanbeseeninanotherbargraph.

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Figure7.1showsanexampleoftheincludedPositionTrackingScatterPlot,whichdisplaysthelocationofeachnanoparticleornanorobotcurrentlyinthebody.Thefigureshowsthisplotimmediatelybeforenanorobotsarefirstintroducedtothebody.

Themodelalsotakesintoaccountdrugtoxicityandbiocompatibilityissues,topicsdiscussedinthebiocompatibilitysectionofthischapter.Thesetopicscanbeimpracticaltotestforinthelab,duetothedifficultyofintroducingdifferentplanesofdifferentmaterialstoarealistichumanimmunesystemwithoutendangeringanyoneintheprocess.Whilemodeloutputsarenotasdefinitiveaslabresults,computermodelscancheaplysimulatetheintroductionofdifferentmaterialsintothehumanbloodstreamtowithinanacceptabledegreeofaccuracy.Inthisspecificmodelthebodyhasanassumedtoxicitycapacity,whichisthedensityoftoxinsitcancontainandstillbehealthy.Eachdrughasitsowntoxicitylevel,whichcanbethoughtofasgenerallyanti-proportionaltoitsbiocompatibility.Thenanorobotsreleasetheirtoxinsintothebloodstreameverytimetheyfaildrugdeliveryinspecificways.Thisgraduallyincreasesthecurrentconcentrationoftoxinsinthebodybasedontheamountreleased,thetimebetweensubsequentreleases,thedistancebetweensubsequentreleases,andthetoxicityvalueassignedtothemedicineinquestion.Oncethetoxicitylevelistoogreat,thesimulationendsinfailure.

Figure7.1:PositionTrackingScatterPlotbeforeintroductionofnanorobots

ThismodelwascreatedinExtendSim9,aprogramdesignedspecificallyforcreatingdynamicsystemmodels.ThesoftwarewasrununderaneducationalgrantprovidedbyImagineThat!,thecreatorsofExtendSim.Figure7.2showsaflowchartofthemodeldesignwithinExtendSim9.

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Figure7.2:FlowchartofmodelasseenwithinExtendSim9

Datafromthismodelcanpointscientiststowardmaterialsandmolecularplanesthatareviablecandidatesforsuccessfulintroductiontothehumanbody,whichcanthenbetestedinthelab.Thismodelcanalsopredictboththeoverallamountanddensityofaspecificmedicationcanbesafelyreleasedintothebloodstreambeforetheconcentrationduetonanorobotfailuresishighenoughtobedangeroustothepatient.

Thismodelhasbeenpurposelydesignedtogrowwiththeincreaseofknowledgewithinthestillrelativelynewfieldofnanomedicine.Asmoreresearchisdoneandnewresultsbecomeavailable,thisdatacanbeaddedtothemodel.Thiswillfurtherrefinetheresults,makingthismodel–intheory–incrediblyaccurateovertime.Aswelearnmoreaboutnanomedicine,Datafromthismodelcanpointscientiststowardmaterialsandmolecularplanesthatareviablecandidatesforsuccessfulintroductiontothehumanbody,whichcanthenbetestedinthelab.Theinformationcollectedcanalsohelpscientistsdevelopappropriatedosagesfortreatmentordesignmoreefficientnanorobotswithahigherdeliverysuccessrate.

8. ResearchInstitutions

Inprevioussections,wehaveexploredsomeofthespecificsofnanomedicalresearchforcancer.Inthefollowingsection,wewilldiscusstheorganizations,centers,universities,andscientistsactuallydoingtheresearchasofthefallof2014.

Fundingfornanomedicalresearchhasbeengrowingsteadily.Researchinstitutionsarereceivingfundingtostudynanomedicineandnanotechnologyaroundtheworld.TheNationalInstituteofHealth(NIH)hasformedanationalnetworkofnanomedicinecentersintheUnitedStates.ThisnetworkiscomprisedofeightNanomedicineDevelopmentCenters.Thesecenters,orNDCs,werecreatedtobothadvancethefieldofnanomedicinethroughresearchand“begintrainingthenextgenerationofstudentsin[the]emergingfield[ofnanomedicine][55].”

TheNIHfocusestheireffortsonunderstandingtheinnerworkingsofcellsonthenanoscaleandusing

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thatknowledgeto“developnewtechnologiesthatcouldbeappliedtotreatingdiseases,and/orleveragethenewknowledgetofocusworkdirectlyontranslationalstudiestotreatadiseaseorrepairdamagedtissue[56].”Theprogramrunsfortenyears,from2005to2015.TheNIHcountsNewYorkUniversity,theUniversityofCaliforniaSanFrancisco,andtheUniversityofCaliforniaBerkeleyamongitseightNDClocations.Asof2014,currentresearchatNewYorkUniversityincludes“developingculturesystemstoimproveadoptiveimmunotherapy[57],”throughgrowingculturesofmemoryTcellsinculturesbeforeinjectingthemintothebodytostimulateimmuneresponsetospecificpathogens.Meanwhile,theNanomedicineCenterforNucleoproteinMachinesatGeorgiaTechisresearchingproteincreationandDNAmodificationwiththehopesofusingthatknowledgetoeithermoreeffectivelytreatorevencuresicklecelldisease[58],andtheUniversityofCalifornia,SanFranciscoistryingtocreateentirelynewnanotechnologicalsystemstodiagnoseandtreatdiseaseslikecancer[59].

InEurope,theEuropeanCommissioncreatedtheEuropeanTechnologyPlatformonNanomedicine(ETPN)in2005withthegoalsoffocusingresearchandraisingmoneyforfunding.Theirthreepriorityfocusareasarenanotechnology-baseddiagnosticsincludingimaging,targeteddrugdeliveryandrelease,andregenerativemedicine[60].Current(2014)researchundertheETPNincludesNANOCI,orNanotechnologyBasedCochlearImplants,whoareworkingonjustthat–creatingcochlearimplantsthatconnectdirectlytoauditorynervefibers,solvingmultipleproblemswithcurrentassistiveaudiotechnologyatonce[61,62].Anothergroup,NANOFOL,isworkingtodesignnanorobotstocureinflammatorydiseasessuchasrheumatoidarthritis[61,63].

BoththeNIHandtheETPN,alongwithotherinstitutionsworldwide,haveseenthepotentialfornanomedicinetoforeverchangethelandscapeofmodernmedicine.Onlywithcontinuedfundingandresearch,however,willwedevelopthetechnologytorealizetheincrediblepotentialofnanomedicine.

9. Conclusion

Althoughnanomedicinehasthetheoreticalpotentialtorepairorgans,restorelostspinalfunction,andevenreversetheagingprocess,forthispaperwehavefocusedspecificallyontheroleofnanorobots,nanoparticles,carbonnanotubes,andothernanoscaledevicesinthetreatmentofdisease.Thoughmanyoftheabovescenariosarecurrentlyonlyhypothetical,modernnanomedicalresearchprovidesasolidfoundationforfutureadvancesinnanoscalehealthcaretechnology.

10. Acknowledgements

WewouldliketothankSamitsubhroBanerji,YixinCai,SauravChowdhury,BiyiFang,WanlingJiang,KrishnaSureshReddyPadala,PadminiPrakash,IshanPurohit,KarthikRajamane,YeshaShah,YilinXu,andSantoshYerrapragadafortheircontributionstothispaper.

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