Biofunctional textiles

Biofunctional Textiles Manuel J Lis1*; Meritxell Martí2; Luisa Coderch2; Cristina Alonso2; Fabricio M Bezerra3; Ana P Immich4; José A Tornero1 1INTEXTER-UPC, Colon, 15. 08222 Terrassa. Barcelona. Spain. 2Institute of Advanced Chemistry of Catalonia (IQAC-CSIC). Jordi Girona 18-26. 08034 Barcelona, Spain 3Textile Engineering, Federal University of Technology – Paraná, 635 Marcilio Dias St., Apucarana, 86812-60,Parana, Brazil 4Universidade Federal de Santa Catarina, Departamento das Engenharias, Campus Blumenau, SC – Brasil *Correspondence to: Manuel J Lis, INTEXTER-UPC, Colon, 15. 08222 Terrassa. Barcelona. Spain Email: [email protected] Chapter 1 Advances in Textile Engineering Abstract  Theaimofthechapteristostatedifferentnewpossibilitiesthattextile substratesofferformorespecializedfunctionsasBiomedicaldevices,Cosmetics,Skintreatment,andwhicharethemechanismsinvolvedinsuchnew applications.Howtoquantifythetransportphenomenafromthesubstrateto theskin,ortosurroundingdifferentmedium,inwhichtheyhavetobeused.  Textilesarecovering80%ofthehumanbodyandabigpercentageof thatisinclosecontactwithskin.Ifthesystemofvehiculizationoftheactive principlesis,carefully,designed,thereservoireffectofthepolymericchains offiberscanplayaveryinterestingroleinthedeliveryoftheactiveprinciple.  Microencapsulation, lipidic aggregates and nanofibers, have shown verypromisingexperimentalresults.Theseresultswillhelptootherresearcherstodevelop,moreaccuratesystems,whichwillvalorizetextilesubstrates, fibersandtissuesfortheuseinmoresophisticatedfields. 2 www.openaccessebooks.com AdvancesinTextileEngineering Lis MJ 1. Introduction 1.1. Textile substrates, as “active systems”  Biofunctionaltextilesarethetextileswithsmartandnewpropertiesandaddedvalue, especiallyrelatedtocomfortorspecificfunctions.Suchtextilesconstitutethebasisforthe deliverysystemofcosmeticorpharmaceuticalsubstanceswhenthetextilecomesintocontact withtheskin.Asmostofthehumanbodyiscoveredwithsomesortoftextile,thepotentialof biofunctionaltextilesisconsiderable.Textilesthathavefunctionalpropertiesfortheskinhave beenstudiedandpatentedinrecentyears[1,2].  Sincetimeimmemorial,textilefabricshavebeenimprovedtoassistskinfunctionby ensuringhomeostasisofthewholebody.Practicalfunctionsofclothingincludeprovidingthe humanbodywithprotectionagainsttheweather–strongsunlight,extremeheatorcold,and rainorsnow–andagainstinsects,noxiouschemicalsandcontactwithabrasivesubstances. Clothingoffersprotectionagainstanythingthatmightinjurethenakedhumanbody.Thisis becausetextileshavealwaysbeenconsideredasa“second skin”forhumanbeings.  Asaresultofnewtechnologies,technicalbioactiveorbiofunctionaltextilesarecurrently beingproduced.Suchfabricsareabletoabsorbsubstancesfromtheskinorreleasetherapeutic orcosmeticcompoundstoit.Thetextileindustrytogetherwithmedicalknowledgehaspaved thewayforenrichingtheuseoftextilefabricsbecauseoftheirinteractionwiththeskin[3].  Percutaneousabsorptionisaninterdisciplinarysubjectthatisrelevanttoanumberof widelydivergentfields.Transdermaldevicesmaybeconsideredasoneoftheprecursorsof biofunctionaltextilesgiventhattheydeliveracompoundwithatherapeuticeffectintothe body[4,5].  Bioactivetextilesarenew,innovativetextileproductsthatarepushingbacktheboundaries oftextileapplications.Theycanactas“reservoirsystems”andareabletocontinuallyrelease controlleddosesofactivesubstancesfromthetextiletotheskin.Severalactivecompounds havebeenappliedontotextilesusingdifferentvehiclesasmicroornanocapsulesin order toimprovethefixationonthefabricandtheprogressiveandeffectivereleaseoftheactive principleintothedifferentskinlayers(stratum corneum,epidermisordermis). 1.2. Mechanisms involved and their quantification 1.2.1. Transdermal drug release into the skin  Transdermaldrugreleaseisaviableadministrationrouteforpowerful,low-molecularweighttherapeuticagentsthatmustbepreciseinitscontrolofdrugadministration.Thesystem shouldensuretherequireddosesandavoidtheminimumtoxicconcentration[6].Thisstrategy 3 AdvancesinTextileEngineering isespeciallyrecommended for many drugsthatare difficult to takebecausethey must be deliveredslowlyoveraprolongedperiodtohaveabeneficialeffect.Forinstance,thedrug releasemodellingofbiodegradablepolymericsystemsasencapsulationtechnologiesintextiles hasnotyetprogressedappreciablyduetoitshighcomplexity.  Transdermaladministrationalsocantakeadvantageofchemicalandphysicalstrategies that can improve skin permeability and allow for drug penetration [7-14]. Specifically, transdermal drug delivery is a viable administration route for powerful, low-molecularweighttherapeuticagentsthateithercanorcannotwithstandthehostileenvironmentofthe gastrointestinaltract[6].Regardlessofthenecessityforphysical-chemicalenhancement,for the reliable and effective design of transdermal delivery systems, knowledge of the skin’s structure(seeFigure 1)anditspropertiesisfundamental[9].  Empiricalanalysisofthepermeationofdrugsthroughtheskinisbasedonapproaches suchasaneuralnetworkmodellingtopredictthepermeabilityofskin[15-22].  GuyandHadgraft[23]developedamathematicalmodelforinvestigatingtheeffectof thevariationinthicknessduringdrugreleasethroughtheskin.Accordingly,theexperimental permeation data are fitted by the following equation, which suitable for describing the permeationofadrugthroughathinmembrane: (1)  whereMtisthetotalamountofdrugthatpassesthroughthelayersofskin,Ls is the thicknessofthestratum corneumandL0theformulationthicknessoverperiodt.Ds is the diffusioncoefficientofthedrugthroughthedifferentskinlayers,andKisapartitioncoefficient Figure 1: Schematicrepresentationofthetransportprocessesinvolvedindrugreleasefromtheformulationuptoits uptakethroughthedermalcapillaries[6]. 4 AdvancesinTextileEngineering betweentheskinlayersandthedrugformulation(typicallyK=concentrationinskinlayer/ concentrationinvehicle). 1.2.2. Release mechanisms from vehicles and substrates  Thereleaseofanactiveagentinanon-erodiblecore-shellsystemcanshowdifferent profilesofdelivery.InFigure2,fourpossibletheoreticalcurves(A,B,CandD)showthe globalbehaviorsofthereleasephenomenaindifferentsituations.  CurveAshowsaperfectreleaseprofile.Itshowsasystemwheretherateofdeliveryis controlledbythediffusionoftheactiveagentmoleculesthroughtheexternalmembrane.The rateofreleasedependsstronglyontheinternal-externalconcentrationgradient.  If there exist some molecules that are retained in the shell, then a lag-time on the releasewillbeobtained.Then,therewillbetwocontrollingstepsanddiffusionwillundergoa transitionalintermediatestate.CurveAinFigure2displaysasystemwithnolag-time.When theencapsulatedmaterialmigratestotheexternalmembraneofthemicrocapsule,therewill bea“burst-effect,”asshownbylineB.  Ifthemicrocapsuleactsasamicrosphere(theentireamountofactiveagentisdistributed inthepolymermatrix),theHiguchiequationisusefulupto60%release.Inthiscase,aplot ofpercentreleasedversussquarerootoftimeislinear,asshownbylineC.First-orderrelease isrepresentedbycurveD.ThecurvewillbelinearwhentheLogofthepercentageofcore materialremaininginthecapsuleisplottedversustime[25].  Themainaimistoapplyamathematicmodelbasedonthephenomenologyinvolved,to explainin vitropermeationexperimentswithabiofunctionaltextileusingdifferentmolecules, astracers.  TheKorsenmeyer-Peppas,equation(2),canbeusedtoaccountforthecoupledeffectsof Figure 2: Theoretical release curves expected for different types of non-erodible delivery systems.A, Membrane reservoir-typefreeoflagtimeandbursteffects;B,sameasA,withbursteffects;C,matrixormonolithicspherewith squareroottime-release;D,systemwithfirst-orderrelease[24]. 5 AdvancesinTextileEngineering Fickiandiffusionandviscoelasticrelaxationinpolymersystemsbyincludingbothprocesses:     (2)  WhereMtistheamountofdrugreleasedattimet,M∞isthemaximalamountofthe releaseddrugatinfinite time, kistherateconstantofdrugrelease, and nisadiffusional exponentthatdependsonthesystemgeometry,andthevalueofnisindicativeoftherelease mechanismoftheactiveagent. Eq(2)hasbeenusedfrequentlyintheliteraturetodescribetherelativeimportanceof transportmechanismsasshowninTable1[26-32].  Historically,thefirstmathematicalmodelofdrugpermeationthroughtheskinwasthat proposedbyHiguchi.Sincetheestablishmentofthemodel,manyotherauthorshaveconducted excellentresearchstudiesonthistopic,developingseveralmodelsbasedonchangesinactive principleconcentrations  ThetransportinpolymericorganizedsystemscanbedescribedbyFick’ssecondLaw,so thediffusionoftheactiveagentcanbeassumedasaplanesurfaceforshorttimesofliberation, usingtheHiguchiequation(eq.4)fortocalculatetheapparentdiffusioncoefficient,usingthe approximationofeq.(3),whereDistheapparentdiffusioncoefficientofdrugrelease,andδis thewidthoftheplanarmatrix. (3)  Themostwidelyusedmodeltodescribedrugreleasefrommatricesisderivedfrom Higuchiforaplanegeometry,whichisapplicableforsystemsofdifferentshapesaswell. (4) 2. Active Principles used in Micro/Nanoencapsulation for textiles 2.1. Polymers  Encapsulationisoneofthetechniquesusedtoapplysubstancestotextiles[33,34]. Biodegradablepolymermicro-ornanoparticlesareofgreatinterestasdrugdeliverysystems becauseoftheirabilitytobereabsorbedbythebody.Syntheticaliphaticlinearpolyesters, suchaspoly-ε-caprolactone(PCL),areoftenusedinbiomedicalapplications[35]because n Drug Delivery Systems n≤0.5 FickianDiffusionMechanism 0.5<n<1 AnomalousDiffusion n≥1 Non-FickianDiffusionMechanism(zero-ordermodel) Table 1: Drugdeliverymodelsbasedontheparametern. 6 AdvancesinTextileEngineering theyarebiocompatible,non-toxicandhavecertainadvantagesoverotherpolymerssuchas PLA(polylacticacid):(a)thepolymersaremorestableunderambientconditions;(b)theyare significantlylessexpensiveand,(c)theyarereadilyavailableinlargequantities[36]. 2.2. Ibuprofen  Ibuprofen was used as active principle-tracer. Ibuprofen is an anti-inflammatory steroid.Itisusedtorelievesymptomsofarthritis,primarydysmenorrhoea,fever,andasan analgesic,especiallywherethereisaninflammatorycomponent.Ibuprofenappearstohavethe lowestincidenceofgastrointestinalreactionsadverseofallnon-selectivenon-steroidalantiinflammatorydrugs(NSAIDs).However,thisonlyoccursatlowerdosesofibuprofenbecause theusuallyadvisablemaximumdailydoseis1,200mg.Adverseeffectsincludedyspepsia, nausea,ulcers/bleedinggastrointestinal,increasedhepaticenzymes,diarrhoea,constipation, epistaxis,headache,dizziness,priapism,rash,saltandfluidretention,andhypertension. 2.3. Caffeine  Caffeineisotheractiveprincipleusedtopreparebiofunctionalcottontextiles.Caffeine wasselectedgivenitsuseinseveralspecifictherapiesanditswidespreaduseincosmetics becauseofitsstimulatingactivityonfatmetabolism(anti-celluliteaction)[37-39].Especial emphasiswasplacedonthereleaseofthisactiveprinciplefromtheformulationsandfromthe cottonfabricsandonitstransdermaldeliveryinordertoreachthetargetcompartmentofthe skin. 2.4. Gallic Acid (GA)  GAwasselectedandincorporatedintopolyamide(PA)throughmicrospheresprepared frompoly-ε-caprolactone(PCL).Gallicacid(GA)waschosenastheactiveagenttoobtaina biofunctionaltextilewithantioxidantproperties.Antioxidantsarenaturalagentsthatareused topreventtheexternalaggressionofoxidativestressinhumanbeings.Theroutetoapply different compounds is clearly through the skin.When topically applied, these exogenous antioxidantshavebeendemonstratedtodiminishtheeffectsoffreeradicalsbyusingdefense mechanismssimilarorcomplementarytothoseofendogenousantioxidants[40-41]. 2.5. In vitro drug release experimental results  AfterGAencapsulationandapplicationontocotton(CO)andpolyamide(PA)fabrics, theresultsobtainedareshowninFigure 3. 7 AdvancesinTextileEngineering Figure 3: SEMmicrographsofPCL-MicrosphereswithGA.A)Cottonfabric(x1000).B)Polyamidefabric(x1000) COfibersallowthemicrospherestobeplacedincornersandspaceswhichcreatea properfiberstructureandPAacceptsthemicrospheresbetweenfibers.Visually,PAretains moremicrospheresthanCO.Thisisinaccordancewiththehigheramountofdryproduct presentinthePAfabric.  Toperformtheanalysisofthemechanismofthedrugdeliverysystem,thetreatedfabric samplesweresubmergedintoasemi-infinitebathofphysiologicalsaline,andeveryxminutes, abathaliquotewaspickedupandanalysedbyHPLC. InFigure 4,itcanbeseenthatPAreleasesGAmorequicklythanCO,andPAreaches equilibriumbeforeCO.  UsingEq.(2)onthevaluesofthefirststeps(Figure 4),theexponentnisobtained, whichisindicativeofthedrugdeliverymechanism(Table 2). 3. Lípids as Vehicles for Skin Treatment  Liposomes are vesicles made up of lipids that can encapsulate different compounds forapplicationontotextiles.Liposomeshavebeenusedasmodelsforcomplexbiological membranes in biophysical and medical research owing to their lipid bilayer structural Figure 4: KineticreleaseofGA(M)appliedontextilefabricsinabathofserumat37°C. Table 2: nvaluesobtainedfromfittingdrugreleaseexperimentaldatabyequation2. n Drug delivery system COfabric 0.46 Fickiandiffusion PAfabric 0.63 Anomalousdiffusion 8 AdvancesinTextileEngineering similarity.Moreover,theyhavebeenthesubjectofnumerousstudiesgiventheirimportance asmicroencapsulationdevicesfordrugdeliveryandtheirapplicationsincosmetics[41-45]. Inrecentyears,liposomeshavebeenusedinthetextileindustryasdyeingauxiliaries,mainly forwooldyeing[46,47]orasadispersingauxiliaryfordispersedyes[48,49].  Woolisakeratinizedtissuewhoseinternallipidshavebeenextractedandanalyzed. Theselipidsarerichincholesterol,freefattyacids,cholesterolsulphateandceramidesandthey resemblethosefoundinmembranesofotherkeratinizedtissuessuchashumanhairorstratum corneumfromskin,becauseoftheircapacitytoformstablebilayerstructures.Accordingly, IWLcouldberegardedasanewandnaturalformtoencapsulatedifferentactiveagentsoras activeagentsforskincare[50,52]. 3.1. In vitro percutaneous absorption experiments (Franz diffusion cells) and cutaneous effectivity  Forthesestudies,pigskinwasusedwithathicknessofapproximately500±50μm. Skindiscswitha2.5cminnerdiameterwerepreparedandfittedintostaticFranz-typediffusion cells.  Acontrolskindisc(withoutproductapplicationontheskinsurface)wasusedtorule outpossibleinterferencesintheanalysisbyHPLC-UV.AccordingtotheOECDmethodology [5],theskinpenetrationstudieswereperformedfor24hofclosecontactbetweenthetextile andtheskin.Toincreasethecontactpressurebetweenthetextilefabricandskin,permeation experimentswerealsocarriedoutbyplacingasteelcylinderonthetextile-skinsubstrateat aconstantpressureinaccordancewithstandardconditions(125g/cm2)(ISO105-E04,1996) (seeFigure 5).  Aftertheexposuretime,thereceptorfluidwascollected,thefabricswereremovedfrom theskinsurfaceandcollectedtogetherwiththetopofthecell.Thestratum corneumoftheskin wasremovedusingadhesive.Theepidermiswasseparatedfromthedermisafterheatingthe skin[53].  The efficacy of the biofunctional textiles in close contact with skin was studied by Figure 5:Diagramofin vitropercutaneousabsorptionexperiments. 9 AdvancesinTextileEngineering measuringchangesintransepidermalwaterloss(TEWL)asanindexofskinbarrierrepair, whereasthewater-holdingcapacitywasmeasuredaschangesinskincapacitance[54].  Skintapestrippingisanin vivomethodologyusedtodemonstratethepenetrationof theprincipleintotheoutermostlayersofvolunteerforearmskin[55,56].Thisisaminimally invasive technique to sequentially remove SC by the repeated application of appropriate adhesivetapes[57].  Usingthesemethodologies,itwasconcludedthatliposomes,especiallythoseprepared withIWL,weresuitablevehiclesforapplyingagivenactiveprincipleontotextiles. 3.2. Gallic Acid (GA) encapsulated in lipid structures  GAwasencapsulatedintoliposomesandappliedtodifferentfabrics,cotton,polyamide, polyester,acrylicandwool,usingbathexhaustionandthepad-dryprocesses.GAabsorptiondesorptionbehaviorofthedifferenttextileswascomparedusingthetwomethodologies(by weightdifferenceandbyextractionanddetection).  Also,GAwasencapsulatedinliposomesandinmixedmicellesforapplicationtocotton andpolyamide.GAabsorption-desorptionbehaviorofthetextileswasalsodeterminedusing thetwoimpregnationmethods. 3.2.1. Liposome/Mixed Micelle Preparation for Gallic Acid  Liposomesof4%ofEmulmetik900(PC)and2%GAwerepreparedusingthefilm hydrationmethodreportedelsewhere[58].Mixedmicelles(30wt%ofsurfactant,4wt%of PCand2wt%GA)werepreparedsolubilizingallcompoundsindistilledwater;solubilisation wasperformedbygentlyshakinguntilclearsolutionswereobtained.  ParticlesizesofliposomesandmixedmicellesweremeasuredbyusingDynamicLight Scattering(DLS),todeterminesizedistribution,polydispersityindexandzetapotentialofthe twolipidicstructures.  ToquantifytheGAentrappedinthevesicles,liposomeformulationwasprecipitated andseparatedfromthesupernatantbycentrifugation.Theefficacyentrapmentpercentageof GAinliposomeswasdeterminedwiththeamountoftheactiveprinciplepresentinthewhole liposomesolutionaswellasinthesupernatant,usingaGAcalibrationcurve. 3.2.2. Textile application and absorption/desorption process.  Theapplicationofliposomesorthemixedmicellesontothefabricswasperformedby bathexhaustionandthefoulardpaddingprocess[59]. 16 AdvancesinTextileEngineering  TheelectrospunPLAmembraneswereshowntoprovideausefulmechanicalsupportfor thedrug.Theinitialstudiesonthesandwichmodelalsorevealedthatthismodelprovidesan elegantmeanstokineticallycontrolthewateruptakebythedrug.AlthoughthePLAmembrane isbiodegradableorerodible(i.e.,asystemthatdisintegratesovertime),thisphenomenoncan beirrelevantwhentheentiredrugisreleasedbeforethedissolutionofthepolymerbecomes important.Therefore,themembranescouldbeconsiderednon-erodible.  Therefore,thisnewsystemcanbedirectlyusedintheprophylacticperiodofpatients whorecentlyunderwentanoperation,whenin situapplicationisrequired.Insomecases, thisparticularmembranecanactnotonlyasacarrierbutalsoascavityfillerwiththerapeutic agents.  Here,thepolymericsolutionusedtoproducenanofiberswasobtainedbydissolving 10%ofthesolutionweightofpoly(lacticacid)indichloromethaneunderconstantmagnetic agitationandataconstantroomtemperatureof23-25°C.Themagneticagitationremained constantuntilthePLAwascompletelydissolved,whichwasindicatedbythesolutionbecoming translucentand whennosolidparticlesweredetected.Completedissolutionwasachieved after1hourofagitation.  Toconducttheexperiment,ahighvoltagepowersupply,aspinneret(acapillarytube withverysmalldiameter)andagroundedcollectorplate(aplateusuallycomposedofmetal) wererequired,asseeninFigure 6. Duringtheelectrospinningprocess,astrongelectrostaticfieldisappliedtoapolymer solutionheldinasyringewithacapillaryoutlet.Apendent-shapeddropletofthepolymer solutionfromthecapillaryoutletisdeformedintoaTaylorcone[80]bytheelectrostaticfield. Whenthevoltagesurpassesathresholdvalue,theelectricforceovercomesthesurfacetension ofthedropletandachargedjetofthesolutionisejectedfromthetipoftheTaylorcone.As thejetmovestowardacollectingmetalscreen(counterelectrode),thesolventevaporatesand anon-wovenfabricmatisformedonthescreen[81].TheprocesscanbeseeninFigure 7. Figure 6: Electrospinningdevicecontainingallessentialelements:highvoltage,spinneret,metalcollector 17 AdvancesinTextileEngineering 4.2. Experimental results of Nanofibers formation  When applying the former conditions specified, PLA nanofibers are formed, as the followingfiguresshow. Figure 7: ElectrospinningofPLAunderoptimalconditions Figure 8:SEMofPLAfibersunderoptimalhighvoltageconditions(orderofmagnitude1000x). Figure 9: SEMofPLAwithbeaddefects;orderofmagnitude250x Figure 10:SEMofPLAfiberswithincreasingflowrate;orderofmagnitude4000x. 18 AdvancesinTextileEngineering 4.3. Sandwich configuration with Ibuprofen or Caffeine  Ibuprofen, or caffeine, was placed between two adjacent layers of the polymeric membranes.Whenthefirstlayeroftheelectrospunmembranewasdriedandsolidified,the drug,which was in adriedmedium, was evenly dispersedon the membrane surface.The amount of drug was controlled using an analytical balance.After placing the drug on the membranesurface,asecondmembranelayerwaselectrospunoverthefirstlayertocoverthe drug[82]. 4.4. Drug-Delivery Mechanisms  Thecapabilityofthepolymericmembranetodeliverthedrugwasdeterminedthrough triplicatemeasurementsofthedrugreleasekineticsintoafluidphase.  Thedrugreleasekineticsweredeterminedusingbatchmethodsformembranesoperating indifferentconditions,suchasmembranesobtainedafterdifferentelectrospinningperiods(5, 10and20minutes)andsandwichmembraneswithdifferentdrugamounts(5,10and15mg). Foreachoperatingcondition,theexperimentwasrepeated3times.  Toperformtheexperiment,thesandwichmembraneswereplacedbetweenconcentric ringsinametallictamboursystem,asshowninFigure13,toensureuniformmasstransfer along thesurfaceofthemembranefromthesolidphasetothefluidphaseandtosoavoid bendingstress. Figure 11:SEMofporousPLAfiberduetohighroomhumidity Figure 12: SEMofnanofibersproducedbyoptimizedelectrospinningprocess;orderofmagnitude15000x. 19 AdvancesinTextileEngineering Afteradjustingthesandwichmembranesinthemetallictamboursystem,theywereplaced inacoveredcontainerwith100mLofphysiologicalserumasthefluidphase,withapH7.4. Thecontainerspreparedfortheanalysesweremaintainedinabathwithaconstanttemperature of37°C.Thesamplesweretakenforanalysisatregulartimeintervals,andtheconcentrations ofdrugreleasedintothefluidphaseweredeterminedthroughspectrophotometrictechniques inaShimadzuUV-2401PCUV-visspectrophotometerwithawavelengthof263nm. 4.5. Controlled Drug Release Mathematical Modeling  Theresultsobtainedfromthekineticstestswereusedforthemathematicalmodelingof thecontrolleddrugrelease,followingtheapproachexplainedbeforeinImmichetal.[83]and in1.2.2. 4.6. Scanning Electron Microscopy (SEM)  The surface morphologies and thicknesses (δ) of the polymeric membranes were examinedusingascanningelectronmicroscope(JEOL/JSM-5610).Afterthesampleswere driedovernightatroomtemperature,eachspecimenwassputtered-coatedwithgoldpowder beforebeingexaminedwiththeSEM.Forthethicknessmeasurement,3differentregionsofthe transversalareaofthemembraneweremeasured,andtheaveragevalueofthesemeasurements wasused.  The membrane thickness was determined for the PLA membranes obtained after 5, 10and20minutesofelectrospinningwithdifferentamountsofibuprofen.Theresultsare presentedinTable 9. Figure 13:Masstransferconfigurationdeviceonthedrug-deliveryexperiment 20 AdvancesinTextileEngineering  ThedifferencesinthemorphologiesofthePLAmembraneswithdifferentelectrospinning time intervals were analyzed and the difference in the amount of fibers in each obtained membraneisnoticeable.InthePLAmembraneobtainedafter5minutesofelectrospinning,it canbeseenemptyspacesamongthefibers.Theseemptyspacesfacilitatemasstransferenceof thefluidphasethroughthemembrane,whichisreadilyconducivetodrugrelease.Whenthere isanincreaseintheamountoffibersandconsequently,areductionintheamountofempty space,themolecularmobilitybecomesdifficultandconsequently,itreducesmasstransport throughthemembrane.  Thediameterofthefiberinapuremembraneobtainedafter20minutesofelectrospinning (withoutthedrug)wasalsomeasuredusingSEM,andtheaveragediameterisapproximately 150nmwhendisregardingthebeadeffect. 4.7. Ibuptofen delivery from PLA electrospun membrane  Theinfluenceofthemembranethicknessonthereleasekineticsofibuprofenthrough PLAmembraneswasstudiedataninitialdrugamountof5mg(Figure 14).  AlthoughthePLAmembraneisbiodegradableorerodible,inthisstudy,thephenomenon Table 9: ThicknessofPLAmembranesfordifferentibuprofenamounts. Electrospinning time(min) Ibuprofen amount (mg) Membrane thickness (mm) 5 5 0.0662 5 10 0.0926 5 15 0.1190 10 5 0.0927 10 10 0.1130 10 15 0.1423 20 5 0.1192 20 10 0.1424 20 15 0.1655 Figure 14: KineticsofibuprofendeliveryfromPLAmembranesafter5minuteselectrospinningAftertheinitialburst, thepolymerstructureswells,stabilizesandtrapsthedrug.Theresultisacontinuousandslowersustainedreleaseprocess. 21 AdvancesinTextileEngineering wasnegligiblebecausetheentiredrughadalreadybeenreleasedbeforethedissolutionofthe polymerbecameimportant.Therefore,themembraneswereconsideredtobenon-erodible. Figure14presentskineticsbehaviorwithamoreintenseinitialburst,whichleadstoarelease ofapproximately0.05g/Lofibuprofen(100%ofinitialdrugconcentration)duringthefirst stageofthedrugdelivery.  MorecontrolledreleaseprocessesareobservedinkineticspresentedinFigures15and 16,withalessintensebursteffectandaninitialdrugreleaseofapproximately0.03g/L(30% ofinitialdrugconcentration)and0.02g/L(13%ofinitialdrugconcentration),respectively. Thisdecreaseinthebursteffectintensityisduetoanincreaseinmembranethicknessafter10 and20minutesofelectrospinning,whichdelayedmasstransferencethroughthepolymeric membranetotheexternalfluidphase. Inadditiontothedecreaseofthebursteffectindrugreleaseforthemembraneobtained after20minutesofelectrospinning,anincreaseinthepseudo-equilibriumtimeoftotaldrug releasewasalsoobservedduetothemembranethickness,whichisconsiderablygreaterthan thatofthemembraneobtainedafter5minutesofelectrospinning.Thisthickermembranealso restrainsandcontrolsdrugmobilityandtransportthroughthemembrane. Figure 15:KineticsofIbuprofendeliveryfromPLAmembranesafter10minuteselectrospinning Figure 16:KineticsofibuprofendeliveryfromPLAmembranesafter20minuteselectrospinning 22 AdvancesinTextileEngineering  Theamountofibuprofenwithinthemembraneisalsoimportantwhendeterminingthe timerequiredforthetotalreleaseofthedrug.Whentheamountofibuprofenincreasesfrom5 to10mg,thetimerequiredforthetotalreleaseofthedrugincreasesby72%onaverage.There isnosignificantincreaseintimeforthetotalreleaseofthedrugwhentheamountofibuprofen increasesfrom10to15mg.Membraneswith10and15mgofibuprofenhavesimilarbehavior duringthereleasingprocess.  Becausethekineticscurvesforthereleaseofibuprofen,whichareillustratedinFigures 14,15and16,exhibitthetypicalbehaviorforreservoir-typemembranes,itcanbeassumed thatthedrugtransportmechanismthroughthesemembranesisusuallyasolution-diffusion mechanism.Though,thisisnotsufficienttoprovethemechanismofdrugrelease.Forthat reason,thereleasingmechanism(n)ofibuprofenwascalculated,accordingtoPowerLaw equation(2)[83]. ThereleasingmechanismpresentedinTable 10,forpolymericmembranesobtained after5minutesofelectrospinning,donotdescribeanyestablishedmechanismofdrugrelease. Itmeansthemechanismofreleaseisneitheradiffusion-controlleddrugrelease(n=0.5)nora swelling-controlleddrugrelease(n=1),wheretherelaxationprocessofthemacromolecules occurringuponwaterimbibitionintothesystemistheratecontrollingstep.Here,thereason forthereleaseofibuprofenmustbethelargeporosityofthethin5minutemembranethatdoes notrestrictthemoleculesofibuprofenfrompassingthrough.  However, for membranes obtained after 10 and 20 minutes of electrospinning, the exponentntakesavalueof0.5orverycloseto0.5.Itindicatesthatdiffusionisthemechanism controlling the release of ibuprofen.Therefore, drug transport initially occurs through the dissolutionofthedrugthroughthemembrane,whichisfollowedbydiffusionthroughthe samemembraneanddesorptiontotheothersideofthemembrane.Consideringthattherelease ofibuprofeniscontrolledbydiffusion,itispossibletoapplytheclassicalHiguchiequation (eq.3),todeterminethemasstransportcoefficient,andthentheapproachofFick’ssecondlaw Table 10: MechanismofdrugreleaseforPLAmembranes. Electrospinning time (min) Ibuprofen amount (mg) n (releasing mechanism) 5 5 0.18 5 10 0.30 5 15 0.31 10 5 0.22 10 10 0.50 10 15 0.50 20 5 0.25 20 10 0.40 20 15 0.40 23 AdvancesinTextileEngineering todeterminetheapparentdiffusivityofibuprofenthroughthePLAmembranesobtainedafter 10and20minutesofelectrospinning. ThedatapresentedinTable 11showsthatthemasstransportcoefficient,KH,(equation (4))forthereleaseofibuprofenthroughelectrospinningmembranes,decreasedwhenmembrane thicknessisincreased(from10to20min.electrospinning).Thisresultisduetothereinforcement offibers,whichbecomedenserandnoteasilypenetrable.Thisfiberreinforcementreduces theemptyspacesavailableforibuprofenparticlemobility,whichrestrainsitstransferenceto theexternalmedium.Increasingthedrugconcentrationfurtherdecreasestheavailableempty spacesformasstransference,whichconsequentlydecreasesthemasstransportcoefficient.  Table11alsoshowsthediffusivity(D)values,whichappeartoincreaseforthe10min. electrospinningmembranewhentheinitialdrugconcentrationisincreased.  Increasingtheelectrospinningtimefrom10to20min.producesevendensermembranes that are full of fibers with a compact internal structure and less empty spaces for particle mobilityandtransport.Therefore,increasingtheibuprofenconcentrationfillsevenmoreof theemptyspacesinthemembrane,whichdecreasesthepossibilityofinternaltransportand consequentlydecreasesthemasstransportcoefficientandrestrainsthedrugdelivery,asshown inTable 11.  Unlikethe10min.electrospinningmembrane,thediffusivityofibuprofenthroughthe 20min.electrospinningmembraneispracticallyconstantwithincreasingdrugconcentration, as the variation in the diffusivity values is insignificant. This is due to the uniformity of membranethickness.Theminorvariationindiffusivityshownforthe20min.electrospinning membranecouldbeattributedtotheoreticalfittinguncertainty.Here,itispossibletomaintain thepercentageofdrugreleasedisregardingtheamountofdruginthereservoir.Theaverage valueofdiffusivityshowninTable 11is2.5E-08cm2/s,inaccordancewiththecommonrange ofdrugdiffusivitiesinvariousmembranes[84,85]. Table 11: DrugreleaseparametersforPLAmembranesobtainedafter10and20minutesofelectrospinning. Electrospinning time (min) Ibuprofen amount (mg) KHDiffusivity (cm2/s) 10 5 0.033 1.8395E-08 10 10 0.030 2.2564E-08 10 15 0.029 3.3436E-08 20 5 0.028 2.1899E-08 20 10 0.026 2.6895E-08 20 15 0.023 2.8468E-08 24 AdvancesinTextileEngineering 5. 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