3/7/2017 Carbonnanotubes:properties,synthesis,purification,andmedicalapplications

NanoscaleResLett.20149(1):393. PMCID:PMC4141964
Publishedonline2014Aug13.doi:10.1186/1556276X9393

Carbonnanotubes:properties,synthesis,purification,andmedical
applications
AliEatemadi, 1HadisDaraee, 1HamzehKarimkhanloo, 1MohammadKouhi, 4NosratollahZarghami, 1AbolfazlAkbarzadeh, 2,5
MozhganAbasi, 1YounesHanifehpour, 3andSangWooJoo 3
1
DepartmentofMedicalBiotechnology,FacultyofAdvancedMedicalSciences,TabrizUniversityofMedicalSciences,Tabriz5154853431,Iran
2
DepartmentofMedicalNanotechnology,FacultyofAdvancedMedicalSciences,TabrizUniversityofMedicalSciences,Tabriz5154853431,Iran
3
SchoolofMechanicalEngineering,YeungnamUniversity,Gyeongsan712749,SouthKorea
4
DepartmentofPhysics,CollegeofScience,TabrizBranch,IslamicAzadUniversity,Tabriz,Iran
5
DrugAppliedResearchCenter,TabrizUniversityofMedicalSciences,Tabriz,Iran
Correspondingauthor.
AliEatemadi:ali.eatemadi@yahoo.comHadisDaraee:Daraee@yahoo.comHamzehKarimkhanloo:karimkhanloo@yahoo.comMohammadKouhi:
kouhi@iaut.ac.irNosratollahZarghami:zarghami@tbzmed.ac.irAbolfazlAkbarzadeh:akbarzadehab@tbzmed.ac.irMozhganAbasi:
mozhgan.abasi@yahoo.comYounesHanifehpour:y_hanifehpour@yu.ac.krSangWooJoo:swjoo@yu.ac.kr

Received2014Apr29Accepted2014Jun27.

Copyright2014Eatemadietal.licenseeSpringer.

ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.org/licenses/by/4.0),
whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycredited.

ThisarticlehasbeencitedbyotherarticlesinPMC.

Abstract Goto:

Currentdiscoveriesofdifferentformsofcarbonnanostructureshavemotivatedresearchontheirapplicationsin
variousfields.Theyholdpromiseforapplicationsinmedicine,gene,anddrugdeliveryareas.Manydifferent
productionmethodsforcarbonnanotubes(CNTs)havebeenintroducedfunctionalization,filling,doping,and
chemicalmodificationhavebeenachieved,andcharacterization,separation,andmanipulationofindividualCNTs
arenowpossible.Parameterssuchasstructure,surfacearea,surfacecharge,sizedistribution,surfacechemistry,and
agglomerationstateaswellaspurityofthesampleshaveconsiderableimpactonthereactivityofcarbonnanotubes.
Otherwise,thestrengthandflexibilityofcarbonnanotubesmakethemofpotentialuseincontrollingother
nanoscalestructures,whichsuggeststheywillhaveasignificantroleinnanotechnologyengineering.

Keywords:Carbonnanostructures,Flexibility,Toxicity,Drugdelivery,Nanotubes

Review Goto:

Introduction
Carbonisthechemicalelementwithatomicnumber6andhassixelectronswhichoccupy1s2,2s2,and2p2
atomicorbital.Itcanhybridizeinsp,sp2,orsp3forms.Discoveriesofveryconstantnanometersizesp2carbon
bondedmaterialssuchasgraphene[1],fullerenes[2],andcarbonnanotubes[3]haveencouragedtomakeinquiries
inthisfield.Mostofthephysicalpropertiesofcarbonnanotubesderivefromgraphene.Ingraphene,carbonatoms
aredenselyorganizedinaregularsp2bondedatomicscalehoneycomb(hexagonal)pattern,andthispatternisa
basicstructureforothersp2carbonbondedmaterials(allotropes)suchasfullerenesandcarbonnanotubes.Carbon

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nanotubeistheoreticallydistinctasacylinderfabricatedofrolledupgraphemesheet.Itcandivideintoasinglewell
ormultiplewells.Nanotubeswithsinglewellaredescribedassinglewallcarbonnanotubes(SWCNTs)andwere
firstreportedin1993[4],whiletheoneswithmorethanonewellaremultiwallcarbonnanotubes(MWCNTs)and
werefirstdiscoveredin1991byIijima[5](Figure1).

Figure1
SchematicstructureandTEMimagesofSWCNTandMWCNT.(A)
SchematicstructureofSWCNTand(B)MWCNT.Thetransmission
electronmicroscope(TEM)imagesofa(C)SWCNTand(D)MWCNT[6
8].

Carbonnanotubes:structureandproperties
Carboncanbondindifferentwaystoconstructstructureswithcompletelydifferentproperties.Thesp2
hybridizationofcarbonbuildsalayeredconstructionwithweakoutofplanebondingofthevanderWaalsform
andstronginplanebounds.Afewtoafewtensofconcentriccylinderswiththeregularperiodicinterlayerspacing
locatearoundordinarycentralhollowandmadeMWCNTs.Therealspaceanalysisofmultiwallnanotubeimages
hasshownarangeofinterlayerspacing(0.34to0.39nm)[9].

Dependingonthenumberoflayers,theinnerdiameterofMWCNTsdivergesfrom0.4nmuptoafewnanometers
andouterdiametervariescharacteristicallyfrom2nmupto20to30nm.BothtipsofMWCNTusuallyhave
closedandtheendsarecappedbydomeshapedhalffullerenemolecules(pentagonaldefects),andaxialsizediffers
from1muptoafewcentimeter.Theroleofthehalffullerenemolecules(pentagonalringdefect)istohelpin
closingofthetubeatthetwoends.

Onotherhand,SWCNTdiametersdifferfrom0.4to2to3nm,andtheirlengthistypicallyofthemicrometer
range.SWCNTsusuallycancometogetherandformbundles(ropes).Inabundlestructure,SWCNTsare
hexagonallyorganizedtoformacrystallikeconstruction[3].

MWCNTandSWCNTstructure
Dependentonwrappingtoacylinderway,therearethreedifferentformsofSWCNTssuchasarmchair,chiral,and
zigzag(Figure2B).ASWCNT'sstructureischaracterizedbyapairofindices(n,m)thatdescribethechiralvector
anddirectlyhaveaneffectonelectricalpropertiesofnanotubes.Thenumberofunitvectorsinthehoneycomb
crystallatticeofgraphenealongtwodirectionsisdeterminedbytheintegersnandm.Asacommonopinion,when
m=0,thenanotubesarenamedzigzagnanotubeswhenn=m,thenanotubesarenamedarmchairnanotubes,and
otherstatearecalledchiral.

Figure2
DifferentformsofSWNTs.(A)ThechiralvectorCalsodeterminesthe
tubediameter.(B)ModelsofthreeatomicallyperfectSWCNTstructures
[10].

ThechiralvectorC=na1+ma2(a1anda2arethebasecellvectorsofgraphite)alsodeterminesthetubediameter
d[4,5],andthisvectorfindsoutthedirectionofrollingagraphenesheet(Figure2A).Therefore,thediameterofa
carbontubecanbecalculatedby

2 2
a m + mn + n
d =

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wherea = 1.42 3 correspondstothelatticeconstantinthegraphitesheet.

Whennmisamultipleof3,thenthenanotubeisdescribedasmetallicorhighlyconductingnanotubes,andif
not,thenthenanotubeisasemimetallicorsemiconductor.

Atalltimes,thearmchairformismetallic,whereasotherformscanmakethenanotubeasemiconductor.

Manyparametersandvectorscanhaveaneffectonnanotubestructuressuchasthefollowing[6]:

(1)Translationalvector=T=t1a1+t2a2(t1,t2)

(2)Chiralvector=Ch=na1+na2(n,m)

(3)Lengthofchiralvector=L=a(n2+m2+n*m),whereaisthelatticeconstant

(4)Chiralangle=cos=(2n+m)/(2*(n2+m2+n*m))

(5)Numberofhexagonsintheunitcell=N=(2*(n2+m2+n*m)/dR)

(6)Diameter=dt=L/

(7)Rotationangleofthesymmetryvector==2/N(inradians)

(8)Symmetryvector=R=pa1+qa2(p,q)

(9)Pitchofthesymmetryvector==((m*pn*q)*T)/N

Multiwalledcarbonnanotubescanbeformedintwostructuralmodels:RussianDollmodelandParchmentmodel.
Whenacarbonnanotubecontainsanothernanotubeinsideitandtheouternanotubehasagreaterdiameterthan
thinnernanotube,itiscalledtheRussianDollmodel.Onotherhand,whenasinglegraphenesheetiswrapped
arounditselfmanifoldtimes,thesameasarolledupscrollofpaper,itiscalledtheParchmentmodel.MWCNTs
andSWCNTshavesimilarproperties.BecauseofthemultilayernatureofMWCNTs,theouterwallscannotonly
shieldtheinnercarbonnanotubesfromchemicalinteractionswithoutsidesubstancesbutalsopresenthightensile
strengthproperties,whichdonotexistinSWCNTs(orexistpartially)[11](Table1).

Table1
ComparisonbetweenSWNTandMWNT[4]

Sincecarbonnanotubeshavethesp2bondsbetweentheindividualcarbonatoms,theyhaveahighertensile
strengththansteelandKevlar.Thisbondisevenstrongerthanthesp3bondfoundindiamond.Theoretically,
SWCNTsmayreallyhaveatensilestrengthhundredsoftimesstrongerthansteel.

Anotheramazingpropertyofcarbonnanotubesisalsoelasticity.Underhighforceandpresssittingandwhen
exposedtogreataxialcompressiveforces,itcanbend,twist,kink,andfinallybucklewithoutdamagingthe
nanotube,andthenanotubewillreturntoitsoriginalstructure,butanelasticityofnanotubesdoeshavealimit,and
underveryphysicallypowerfulforcespresses,itispossibletotemporarilydeformtoshapeofananotube.Someof
thedefectsinthestructureofthenanotubecanweakenananotube'sstrength,forexample,defectsinatomic
vacanciesorarearrangementofthecarbonbonds.

Elasticityinbothsingleandmultiwallednanotubesisdeterminedbyelasticmodulusormodulusofelasticity[7].
Theelasticitymodulusofmultiwallnanotubes(MWNTs)isanalyzedwithtransmissionelectronmicroscopes
(TEM).ScientistsusingtheTEMmeasureandexaminethethermalvibrationsatbothendsofthetubes.Asaresult
ofthestrengthoftheatomicbondsincarbonnanotubes,theynotonlycanwithstandhightemperaturesbutalso

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havebeenshowntobeverygoodthermalconductors.Theycanwithstandupto750Catnormaland2,800Cin
vacuumatmosphericpressures.Thetemperatureofthetubesandtheoutsideenvironmentcanaffectthethermal
conductivityofcarbonnanotubes[8].Someofthemajorphysicalpropertiesofcarbonnanotubesaresummarized
inTable2.

Table2
Thephysicalpropertiesofcarbonnanotubes

Synthesis
ThereareseveraltechniquesthathavebeendevelopedforfabricatingCNTstructureswhichmainlyinvolvegas
phaseprocesses.Commonly,threeproceduresarebeingusedforproducingCNTs:(1)thechemicalvapor
deposition(CVD)technique[12,13],(2)thelaserablationtechnique[3,9],and(3)thecarbonarcdischarge
technique[1416](Table3).Hightemperaturepreparationtechniquesforexamplelaserablationorarcdischarge
werefirstusedtosynthesizeCNTs,butcurrently,thesetechniqueshavebeensubstitutedbylowtemperature
chemicalvapordeposition(CVD)methods(<800C),sincethenanotubelength,diameter,alignment,purity,
density,andorientationofCNTscanbeaccuratelycontrolledinthelowtemperaturechemicalvapordeposition
(CVD)methods[17].

Table3
SummaryandcomparisonofthreemostcommonCNTsynthesismethods

Electricarcdischarge

Arcdischargetechniqueuseshighertemperatures(above1,700C)forCNTsynthesiswhichtypicallycausesthe
expansionofCNTswithfewerstructuraldefectsincomparisonwithothermethods.Themostutilizedmethodsuse
arcdischargebetweenhighpuritygraphite(6to10mmopticaldensity(OD))electrodesusuallywatercooled
electrodeswithdiametersbetween6and12mmandseparatedby1to2mminachamberfilledwithhelium
(500torr)atsubatmosphericpressure(heliumcanbereplacedbyhydrogenormethaneatmosphere)[10].The
chambercontainsagraphitecathodeandanodeaswellasevaporatedcarbonmoleculesandsomeamountofmetal
catalystparticles(suchascobalt,nickel,and/oriron).Directcurrentispassedthroughthecamber(arcingprocess),
andthechamberispressurizedandheatedtoapproximately4,000K.Inthecourseofthisprocedureandarcing,
abouthalfoftheevaporatedcarbonsolidifiesonthecathode(negativeelectrode)tip,andadepositformsatarate
of1mm/minwhichiscalledcylindricalharddepositorcigarlikestructure,whereastheanode(positiveelectrode)
isconsumed.Theremainingcarbon(ahardgrayshell)depositedontheperipheryandcondensesintochamber
sootnearbythewallsofthechamberandcathodesootonthecathode.Theinnercore,cathodesootandchamber
soot,whicharedarkandsoft,yieldeithersinglewalledormultiwalledcarbonnanotubesandnestedpolyhedral
grapheneparticles.Byusingscanningelectronmicroscopy(SEM),twodifferenttexturesandmorphologiescanbe
observedinstudyingofthecathodedepositthedarkandsoftinnercoredepositsconsistofbundlelikestructures,
whichcontainrandomlyarrangednanotubesandthegrayoutershell,whichiscomposedofcurvedandsolid
graphemelayers.

InthearcdischargedepositionandsynthesisofCNTs,therearetwomaindifferentways:synthesiswithuseof
differentcatalystprecursorsandwithoutuseofcatalystprecursors.Generally,synthesisofMWNTscouldbedone
withoutuseofcatalystprecursorsbutsynthesisofsinglewallnanotubes(SWNTs)utilizesdifferentcatalyst
precursorsand,forexpansioninarcdischarge,utilizesacomplexanode,whichismadeasacompositionof
graphiteandametal,forexample,Gd[11],Co,Ni,Fe,Ag,Pt,Pd,etc.,ormixturesofCo,Ni,andFewithother
elementslikeCoPt,CoRu[18],NiY,FeNi,CoNi,CoCu,NiCu,FeNo,NiTi,NiY,etc.Studieshaveshown
NiYgraphitemixturescanproducehighyields(<90%)ofSWNTs(averagediameterof1.4nm)[19],and
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nowadays,thismixtureisusedworldwideforcreationofSWNTsinhighyield.Themainadvantageofarc
dischargetechniqueisabilityandpotentialforproductionofalargequantityofnanotubes.Ontheotherhand,the
maindisadvantageofthismethodisrelativelylittlecontroloverthealignment(i.e.,chirality)ofthecreated
nanotubes,whichisimportantfortheircharacterizationandrole.Additionally,becauseofthemetalliccatalyst
neededforthereaction,purificationoftheobtainedproductsisessential.

Laserablationmethod

Byusingofhighpowerlaservaporization(YAGtype),aquartztubecontainingablockofpuregraphiteisheated
insideafurnaceat1,200C,inanAratmosphere[12].Theaimofusinglaserisvaporizingthegraphitewithinthe
quartz.AsdescribedaboutthesynthesisofSWNTbyusingarcdischargemethod,forgeneratingofSWNTs,using
thelasertechniqueaddingofmetalparticlesascatalyststothegraphitetargetsisnecessary.Studieshaveshownthe
diameterofthenanotubesdependsuponthelaserpower.Whenthelaserpulsepowerisincreased,thediameterof
thetubesbecamethinner[13].Otherstudieshaveindicatedultrafast(subpicosecond)laserpulsesarepotentialand
abletocreatelargeamountsofSWNTs[14].Theauthorsrevealedthatitisnowpromisingtocreateupto1.5g/hof
nanotubematerialusingthelasertechnique.

ManyparameterscanaffectthepropertiesofCNTssynthesizedbythelaserablationmethodsuchasthestructural
andchemicalcompositionofthetargetmaterial,thelaserproperties(peakpower,cwversuspulse,energyfluence,
oscillationwavelength,andrepetitionrate),flowandpressureofthebuffergas,thechamberpressureandthe
chemicalcomposition,thedistancebetweenthetargetandthesubstrates,andambienttemperature.Thismethodhas
apotentialforproductionofSWNTswithhighpurityandhighquality.Theprinciplesandmechanismsoflaser
ablationmethodaresimilartothearcdischargetechnique,butinthismethod,theneededenergyisprovidedbya
laserwhichhitapuregraphitepelletholdingcatalystmaterials(frequentlycobaltornickel).

Themainadvantagesofthistechniqueconsistofarelativelyhighyieldandrelativelylowmetallicimpurities,since
themetallicatomsinvolvedhaveatendencytoevaporatefromtheendofthetubeonceitisclosed.Onotherhand,
themaindisadvantageisthattheobtainednanotubesfromthistechniquearenotnecessarilyuniformlystraightbut
insteaddocontainsomebranching.

Unfortunately,thelaserablationmethodisnoteconomicallyadvantageousbecausetheprocedureencompasses
highpuritygraphiterods,thelaserpowersrequiredaregreat(insomecasestwolaserbeamsarerequired),andthe
quantityofnanotubesthatcanbesynthesizedperdayisnotashighasarcdischargetechnique.

Chemicalvapordeposition

OneofstandardmethodsforproductionofcarbonnanotubesischemicalvapordepositionorCVD.Thereare
manydifferenttypesofCVDsuchascatalyticchemicalvapordeposition(CCVD)eitherthermal[20]orplasma
enhanced(PE)oxygenassistedCVD[5],waterassistedCVD[2123],microwaveplasma(MPECVD)[24],
radiofrequencyCVD(RFCVD)[25],orhotfilament(HFCVD)[26,27].Butcatalyticchemicalvapordeposition
(CCVD)iscurrentlythestandardtechniqueforthesynthesisofcarbonnanotubes.

ThistechniqueallowsCNTstoexpandondifferentofmaterialsandinvolvesthechemicalbreakdownofa
hydrocarbononasubstrate.Themainprocessofgrowingcarbonnanotubesinthismethodassameasarc
dischargemethodalsoisexcitingcarbonatomsthatareincontactwithmetalliccatalystparticles.

Forallintentsandpurposes,tubesaredrilledintosiliconandalsoimplantedwithironnanoparticlesatthebottom.
Afterthat,ahydrocarbonsuchasacetyleneisheatedanddecomposedontothesubstrate.Sincethecarbonisable
tomakecontactwiththemetalparticlesimplantedintheholes,itinitiatestocreatenanotubeswhichareatemplate
fromtheshapeofthetunnel.Withusingoftheseproperties,thecarbonnanotubescangrowverywellalignedand
verylong,intheangleofthetunnel.InCVDprocessing,alayerofmetalcatalystparticlesprepareandprocessa
substrateatapproximately700C.Mostcommonly,metalcatalystparticlesarenickel,cobalt[28],iron,ora
combination[29].TheaimofusingthemetalnanoparticlesincombinationwithacatalystsupportsuchasMgOor
Al2O3istodevelopthesurfaceareaforhigherbyproductofthecatalyticreactionofthepurecarbonwiththe
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metalparticles.Inthefirststepofnanotubeexpansion,twotypesofgasesfueledthereactor(themostwidelyused
reactorisfluidizedbedreactor[30,31]):acarboncontaininggas(suchasethylene,acetylene,methane,orethanol)
andaprocessgas(suchasnitrogen,hydrogen,orammonia).Atthesurfaceofthecatalystparticle,thecarbon
containinggasisbrokenapartandsothecarbonbecamevisibleattheedgesofthenanoparticlewherethe
nanotubescanproduce.Thismechanismisstillunderdiscussion[32].Studieshaveshowntheconventionally
acceptedmodelsarebasegrowthandtipgrowth[33].Dependingontheadhesionandattachmentbetweenthe
substrateandthecatalystparticle,thecatalystparticlescanremainatthenanotubebaseornanotubeduringgrowth
andexpansion[34].

Ascomparedwithlaserablation,CCVDisaneconomicallypracticalmethodforlargescaleandquitepureCNT
productionandsotheimportantadvantageofCVDarehighpurityobtainedmaterialandeasycontrolofthe
reactioncourse[35].

Nanotubepurification
Dependingontechniqueofcarbonnanotubesynthesis,therearemanydifferentmethodsandprocedurefor
purification.Allpurificationprocedureshavethefollowingmainsteps:deletionoflargegraphiteparticlesand
aggregationswithfiltration,dissolutioninappropriatesolventstoeliminatecatalystparticles(concentratedacidsas
solvent)andfullerenes(useoforganicsolvents),andmicrofiltrationsandchromatographytosizeseparationand
removetheamorphouscarbonclusters[35].PurificationofMWNTsproducedbyarcdischargetechniquescanbe
donebyusingoxidationtechniqueswhichcantakeapartMWNTsfrompolyhedralgraphitelikeparticles[10].

Themaindisadvantagesofthismethodarelowpurity,highdestroyingrateofstartingmaterials(95%),aswellas
highreactivityoftheremainingnanotubesatendofprocessduetoexistenceofdanglingbonds(anunsatisfied
valence)[36]andforeliminationofsuchdanglingbondsisnecessarytousehightemperatureannealing(2,800
C).

ThenondestructivemethodsforseparatingCNTscouplewelldispersedcolloidalsuspensionsoftubes/particles
withmaterialswhichpreventaggregationsuchassurfactants,polymers,orothercolloidalparticles[37].Theother
methodasaimofsizeexclusionnanotubesusessizeexclusionchromatographyandporousfilters[37]aswellas
ultrasonicallyassistedmicrofiltrationwhichpurifiesSWNTsfromamorphouscarbonandcatalyticparticles[38].

StudieshaveshowntheboilingofSWNTsinnitricacid[39]orhydrofluoricacid[40]aqueoussolutionsfor
purificationofSWNTsandremovingamorphouscarbonandmetalparticlesasanefficientandsimpletechnique.

Forthepurificationofcarbontubules,scientistpreferstousesonicationofnanotubeindifferentmediaand
afterwardthermaloxidationofSWNTmaterial(at470C)aswellashydrochloricacidtreatments[41].Another
wayforoxidizingunsatisfiedcarbonaceousparticlesisuseofgoldclusters(OD20nm)togetherwiththethermal
oxidationofSWNTsat350C[42].

Huangetal.introduceanewwayforseparationofsemiconductingandmetallicSWNTsbyusingofsizeexclusion
chromatography(SEC)ofDNAdispersedcarbonnanotubes(DNASWNT),whichhavethehighestresolution
lengthsorting[43].ThedensitygradientultracentrifugationhasbeenusedforseparationofSWNTbasedon
diameter[44].Combinationofionexchangechromatography(IEC)andDNASWNT(IECDNASWNT)has
alsobeenusedforpurificationofindividualchiralities.Inthisprocess,specificshortDNAoligomerscanbeusedto
separateindividualSWNTchiralities.Scientistshaveusedfluorinationandbrominationprocessesaswellasacid
treatmentsofMWNTandSWNTmaterialwiththeaimsofpurifying,cutting,andsuspendingthematerials
uniformlyincertainorganicsolvents[45,46].

Asdiscussedabove,dependingonnanotubesynthesisway,therearemanydifferentmethodsforpurificationof
carbonnanotubes,andtherefore,existenceofmethodswhicharesinglestepprocessesandunaffectedonproperties
ofcarbonnanotubeproductsisessentialforproducingcleannanotubesandshouldbetargetedinthefuture.

Biomedicalapplications
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Thepropertiesofnanotubesarecertainlyamazinginthelastfewyears,manystudieshavesuggestedpotential
applicationsofCNTsandhaveshowninnumerableapplicationsthatcouldbepromisingwhenthesenewly
determinedmaterialsarecombinedwithtypicalproducts[36,4751].ProductionofnanorodsusingCNTsas
reactingtemplates[5155].

Applicationsfornanotubesencompassmanyfieldsanddisciplinessuchasmedicine,nanotechnology,
manufacturing,construction,electronics,andsoon.Thefollowingapplicationcanbenoted:highstrength
composites[54,5661],actuators[62],energystorageandenergyconversiondevices[63],nanoprobesandsensors
[61],hydrogenstoragemedia[64],electronicdevices[65],andcatalysis[66].However,thefollowingsections
detailexistingapplicationsofCNTsinthebiomedicalindustryexclusively.Beforeuseofcarbonnanotubein
biologicalandbiomedicalenvironments,therearethreebarrierswhichmustbeovercome:functionalization,
pharmacology,andtoxicityofCNTs.Oneofthemaindisadvantagesofcarbonnanotubesisthelackofsolubilityin
aqueousmedia,andtoovercomethisproblem,scientistshavebeenmodifyingthesurfaceofCNTs,i.e.,
fictionalizationwithdifferenthydrophilicmoleculesandchemistriesthatimprovethewatersolubilityand
biocompatibilityofCNT[67].

Anotherbarrierwithcarbonnanotubeisthebiodistributionandpharmacokineticsofnanoparticleswhichare
affectedbymanyphysicochemicalcharacteristicssuchasshape,size,chemicalcomposition,aggregation,solubility
surface,andfictionalization.StudieshaveshownthatwatersolubleCNTsarebiocompatiblewiththebodyfluids
anddonotanytoxicsideeffectsormortality.

AnotherimportantbarrieristoxicityofCNTs.Generally,thecombinationofthehighsurfaceareaandtheintrinsic
toxicityofthesurfacecanberesponsiblefortheharmfuleffectsofnanoparticles.

ThetoxicityofCNTscanbeaffectedbythesizeofnanotubes.Theparticlesunder100nmhavepotentialharmful
propertiessuchasmorepotentialtoxicitytothelung,escapefromthenormalphagocyticdefenses,modificationof
proteinstructure,activationofinflammatoryandimmunologicalresponses,andpotentialredistributionfromtheir
siteofdeposition.

Artificialimplants
Nanomaterialsshowprobabilityandpromiseinregenerativemedicinebecauseoftheirattractivechemicaland
physicalproperties[68].Generally,rejectimplantswiththepostadministrationpain,andtoavoidthisrejection,
attachmentofnanotubeswithproteinsandaminoacidshasbeenpromising.Carbonnanotube,bothsingleand
multiWNT,canbeemployedasimplantsintheformofartificialjointsandotherimplantswithouthostrejection
response.Moreover,becauseofuniquepropertiessuchashightensilestrength,CNTscanactasbonesubstitutes
andimplantsiffilledwithcalciumandshaped/arrangedinthebonestructure[69,70].

IthasbeeninvestigatedthecellularadhesionandproliferationcanenhancewithSWCNTandMWCNT
composites,andtherefore,thesenanotubeshavebeenintegratedintonaturalandsyntheticmaterialstogenerate
nanocomposites.SomenanotubeapplicationsasartificialimplantsaresummarizedinTable4.

Table4
Applicationofnanotubeasartificialimplants

Tissueengineering

Theaimoftissueengineeringistosubstitutedamagedordiseasedtissuewithbiologicalternatesthatcanrepairand
preservenormalandoriginalfunction.Majoradvancesintheareasofmaterialscienceandengineeringhave
supportedinthepromisingprogressoftissueregenerativemedicineandengineering.Carbonnanotubescanbe
usedfortissueengineeringinfourareas:sensingcellularbehavior,celltrackingandlabeling,enhancingtissue
matrices,andaugmentingcellularbehavior[78].Celltrackingandlabelingistheabilitytotrackimplantedcellsand

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toobservetheimprovementoftissueformationinvivoandnoninvasively.Labelingofimplantedcellsnotonly
facilitatesevaluatingoftheviabilityoftheengineeredtissuebutalsoassistsandfacilitatesunderstandingofthe
biodistribution,migration,relocation,andmovementpathwaysoftransplantedcells.Becauseoftimeconsuming
andchallengeofhandlinginusingoftraditionalmethodssuchasflowcytometry,noninvasivemethodsare
incomingpopularmethods.Itisshowncarbonnanotubescanbefeasibleasimagingcontrastagentsformagnetic
resonance,optical,andradiotracermodalities.

Anotherimportantapplicationofcarbonnanotubesintissueengineeringisitspotentialformeasureof
biodistributionandcanalsobemodifiedwithradiotracersforgammascintigraphy.Singhetal.boundSWNTswith
[79].InandadministeredtoBALB/cmicetoevaluatethebiodistributionofnanotubes[80].Thedesignofbetter
engineeredtissuesenhancesandfacilitateswiththebettermonitorofcellularphysiologysuchasenzyme/cofactor
interactions,proteinandmetabolitesecretion,cellularbehavior,andiontransport.Nanosensorspossiblywillbe
utilizedtomakeavailableconstantmonitoringoftheperformanceoftheengineeredtissues.Carbonnanotubes
presentnumerouspopularfeaturesthatmakethemidealelementsfornanosensorsincludingtheirlargesurfacearea
andcapacitytoimmobilizeDNAorotherproteins,andelectricalproperties.Thecarbonnanotubehasunique
electronicstructureswhichascarbonnanotubeelectrochemicalsensorprobabilitymakessimplertheinvestigation
ofredoxactiveproteinsandaminoacidsallowingcellmonitoringinengineeredtissues.Inonestudy,MWNTs
wereconjugatedwithplatinummicroparticlesandwereabletosensethiolsincludingaminoacidssuchas
glutathioneandLcysteineinrat[81].

Thematrixofcellsplaysanimportantroleintissueengineering.Whileacceptedsyntheticpolymers,forexample,
PLGAandPLAhavebeenemployedfortissueengineering,theylacktherequiredmechanicalstrengthandcannot
simplybefunctionalizedincontradictionofcarbonnanotubeswhichcanbevoluntarilyfunctionalized.Thus,
carbonnanotubeshavepotentialforuseastissuescaffoldsandcanprovidetherequiredstructuralreinforcement,
butthemaindisadvantageofcarbonnanotubesisthattheyarenotbiodegradable.Combinationofpolymerby
dissolvingadesiredportionofcarbonnanotubesintoapolymer,significantenhancementsinthemechanical
strengthofthecompositehasbeendetected.MWNTscombinedwithchitosanillustratedsignificantadvancementin
mechanicalpropertiescomparedwithonlychitosan[82].TheSWNTblendedcollagenimprovessmoothmuscle
cellgrowth[8389].

Cancercellidentification
Nanodevicesarebeingcreatedthathaveapotentialtodevelopcancertreatment,detection,anddiagnosis.
Nanostructurescanbesosmall(lessthan100nm)thatthebodypossiblywillclearthemtooquicklyforthemtobe
efficientinimagingordetectionandsocanentercellsandtheorganellesinsidethemtointeractwithDNAand
proteins.Castilloetal.,byusingapeptidenanotubefolicacidmodifiedgrapheneelectrode,improvedetectionof
humancervicalcancercellsoverexpressingfolatereceptors[9096].

Sincealargeamountofcancersareasymptomaticthroughouttheirearlystageanddistinctmorphologic
modificationsareabsentinthemajorityofneoplasticdisordersinearlystage,consequentlytraditionalclinical
cancerimagingmethods,forexample,Xray,CT,andMRI,donotacquireadequatespatialresolutionfordetection
ofthediseaseinearlystage.TheimagingstudieswithSWCNTshavethrivedoverthepastfewyears.Hongetal.
[97]evaluatedthemolecularimagingwithSWNTsandevaluatedthecombinedGd3+functionalizedSWCNTs
whenappliedtoMRI,andhighresolutionandgoodtissuepenetrationwereachieved.

CombinationofradioisotopeslabeledSWCNTswithradionuclidebasedimagingtechniques(PETandSPECT)
canimprovethetissuepenetration,sensitivity,andmediumresolution.

Therearemanycharacteristicproteinbiomarkerswhichoftenareoverexpressedincancercells,andtheyprovide
anopeninggateforearlydiagnosis,prognosis,maintainingsurveillancefollowingcurativesurgery,monitoring
therapyinadvanceddisease,andpredictingtherapeuticresponse.Manyimportanttumormarkershavebeen
extensivelyappliedandusedinthediagnosisofhepatocellularcarcinoma,colorectalcancer,pancreaticcancer,
prostatecancers,epithelialovariantumorsuchascarbohydrateantigen199(CA199),alphafetoprotein(AFP),
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141964/ 8/16
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carcinoembryonicantigen(CEA),carcinomaantigen125(CA125),humanchorionicgonadotropin(hCG),and
prostatespecificantigen(PSA).SomeofthecancerbiomarkerswhicharedetectedbyCNTbaseddetection
systemsaresummarizedinTable5.

Table5
Exampleofdetectionofcancerbiomarkerbycarbonnanotubes

DrugandgenedeliverybyCNTs
Therearemanybarrierswithconventionaladministrationofchemotherapeuticagentssuchaslackofselectivity,
systemictoxicity,poordistributionamongcells,limitedsolubility,inabilityofdrugstocrosscellularbarriers,and
lackofclinicalproceduresforovercomingmultidrugresistant(MDR)cancer[112,113].Researchershave
introducedawiderangeofdifferenttypesofdrugdeliverysystemstoovercometheseproblemssuchaspolymers,
silicananoparticles,quantumdots,emulsions,dendrimers,liposomes,molecularconjugates,andmicelles[114].As
mentionedabove,CNTshavetheuniquepropertiessuchasultrahighsurfaceareawhichmakethemaspromising
potentialfordeliveryofdrugs,peptides,andnucleicacids(Table6).Thespecificdrugorgenecanbeintegratedto
wallsandtipsofCNTsandrecognizecancerspecificreceptorsonthecellsurface,bythesemeansCNTscancross
themammaliancellmembranebyendocytosisorothermechanisms[115]andcarrytherapeuticdrugsorgenes
moresafelyandefficientlyinthecellsthatarepreviouslyinaccessible[116].Morerecently,researchershave
developedanovelandmoreefficientSWNTbasedtumortargeteddrugdeliverysystem(DDS)whichconsistsof
tumortargetingligands,anticancerdrugs,andfunctionalizedSWNTs.Ifthissysteminteractswithcancercells,then
itcaninducereceptormediatedendocytosisbyrecognizingcancerspecificreceptorsonthesurfaceofcancercells
andsoefficientlyandspecificallyreleasechemotherapeuticagents.

Table6
Exampleofdrugsandnucleicacidswhichweredeliveredbycarbon
nanotubes

Conclusions Goto:

Nanomaterialsexplainprobabilityandpromiseinregenerativemedicineforthereasonthatoftheirattractive
chemicalandphysicalproperties.

Carbonnanotubes(purified/modified)haveahighpotentialoffindinguniqueapplicationsinwideareasof
medicine.Moreover,theencapsulationofothermaterialsinthecarbonnanotubeswouldopenupaprospectfor
theirbioapplicationsinmedicine.

Thereremainsamountofessentialissuesthatrequiretoberesolved,ontheotherhand,suchashomogeneityofthe
materialthatcontainswidedistributionofthenanotube'sdiameters,unlikenanostructures,presenceofresidual
metalsdivisionoftheindividualnanotubesandasensitivitytothedifferentgasesandspecies[126139].

Competinginterests Goto:

Theauthorsdeclarethattheyhavenocompetinginterests.

Authorscontributions Goto:

AE,HK,andNZconceivedofthestudyandparticipatedinitsdesignandcoordination.AA,MK,andSWJ
assistedinthenumericalcalculations.HD,MA,andYHparticipatedinthesequencealignmentanddraftedthe
manuscript.SWJsupervisedthewholestudy.Allauthorsreadandapprovedthefinalmanuscript.

Acknowledgements
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141964/ 9/16
3/7/2017 Carbonnanotubes:properties,synthesis,purification,andmedicalapplications

Acknowledgements Goto:

TheauthorsthanktheDepartmentofMedicalNanotechnology,andBiotechnologyFacultyofAdvancedMedical
ScienceofTabrizUniversityforallsupportsprovided.ThisworkisfundedbytheGrant20110014246ofthe
NationalResearchFoundationofKorea.

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