Biofunctional TextilesManuel 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
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Abstract
TheaimofthechapteristostatedifferentnewpossibilitiesthattextilesubstratesofferformorespecializedfunctionsasBiomedicaldevices,Cos-metics,Skintreatment,andwhicharethemechanismsinvolvedinsuchnewapplications.Howtoquantifythetransportphenomenafromthesubstratetotheskin,ortosurroundingdifferentmedium,inwhichtheyhavetobeused.
Textilesarecovering80%ofthehumanbodyandabigpercentageofthatisinclosecontactwithskin.Ifthesystemofvehiculizationoftheactiveprinciplesis,carefully,designed,thereservoireffectofthepolymericchainsoffiberscanplayavery interesting role in thedeliveryof theactiveprin-ciple.
Microencapsulation, lipidic aggregates and nanofibers, have shownverypromisingexperimentalresults.Theseresultswillhelptootherresearch-erstodevelop,moreaccuratesystems,whichwillvalorizetextilesubstrates,fibersandtissuesfortheuseinmoresophisticatedfields.
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AdvancesinTextileEngineeringLi
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1. Introduction
1.1. Textile substrates, as “active systems”
Biofunctionaltextilesarethetextileswithsmartandnewpropertiesandaddedvalue,especiallyrelatedtocomfortorspecificfunctions.Suchtextilesconstitute thebasisfor thedeliverysystemofcosmeticorpharmaceuticalsubstanceswhenthetextilecomesintocontactwiththeskin.Asmostofthehumanbodyiscoveredwithsomesortoftextile,thepotentialofbiofunctionaltextilesisconsiderable.Textilesthathavefunctionalpropertiesfortheskinhavebeenstudiedandpatentedinrecentyears[1,2].
Sincetimeimmemorial,textilefabricshavebeenimprovedtoassistskinfunctionbyensuringhomeostasisofthewholebody.Practicalfunctionsofclothingincludeprovidingthehumanbodywithprotectionagainsttheweather–strongsunlight,extremeheatorcold,andrainorsnow–andagainstinsects,noxiouschemicalsandcontactwithabrasivesubstances.Clothingoffersprotectionagainstanythingthatmightinjurethenakedhumanbody.Thisisbecausetextileshavealwaysbeenconsideredasa“second skin”forhumanbeings.
Asaresultofnewtechnologies,technicalbioactiveorbiofunctionaltextilesarecurrentlybeingproduced.Suchfabricsareabletoabsorbsubstancesfromtheskinorreleasetherapeuticorcosmeticcompoundstoit.Thetextileindustrytogetherwithmedicalknowledgehaspavedthewayforenrichingtheuseoftextilefabricsbecauseoftheirinteractionwiththeskin[3].
Percutaneousabsorptionisaninterdisciplinarysubjectthatisrelevanttoanumberofwidelydivergentfields.Transdermaldevicesmaybeconsideredasoneoftheprecursorsofbiofunctional textilesgiven that theydeliveracompoundwitha therapeuticeffect into thebody[4,5].
Bioactivetextilesarenew,innovativetextileproductsthatarepushingbacktheboundariesoftextileapplications.Theycanactas“reservoirsystems”andareabletocontinuallyreleasecontrolleddosesofactivesubstancesfromthetextiletotheskin.Severalactivecompoundshave been applied onto textiles using different vehicles asmicro or nanocapsules in ordertoimprovethefixationonthefabricandtheprogressiveandeffectivereleaseoftheactiveprincipleintothedifferentskinlayers(stratum corneum,epidermisordermis).
1.2. Mechanisms involved and their quantification
1.2.1. Transdermal drug release into the skin
Transdermaldrugreleaseisaviableadministrationrouteforpowerful,low-molecular-weighttherapeuticagentsthatmustbepreciseinitscontrolofdrugadministration.Thesystemshouldensuretherequireddosesandavoidtheminimumtoxicconcentration[6].Thisstrategy
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is especially recommended formany drugs that are difficult to take because theymust bedeliveredslowlyoveraprolongedperiodtohaveabeneficialeffect.Forinstance, thedrugreleasemodellingofbiodegradablepolymericsystemsasencapsulationtechnologiesintextileshasnotyetprogressedappreciablyduetoitshighcomplexity.
Transdermaladministrationalsocantakeadvantageofchemicalandphysicalstrategiesthat can improve skin permeability and allow for drug penetration [7-14]. Specifically,transdermal drug delivery is a viable administration route for powerful, low-molecular-weighttherapeuticagentsthateithercanorcannotwithstandthehostileenvironmentofthegastrointestinaltract[6].Regardlessofthenecessityforphysical-chemicalenhancement,forthe reliable and effective design of transdermal delivery systems, knowledge of the skin’sstructure(seeFigure 1)anditspropertiesisfundamental[9].
Empiricalanalysisofthepermeationofdrugsthroughtheskinisbasedonapproachessuchasaneuralnetworkmodellingtopredictthepermeabilityofskin[15-22].
GuyandHadgraft[23]developedamathematicalmodelforinvestigatingtheeffectofthevariationinthicknessduringdrugreleasethroughtheskin.Accordingly,theexperimentalpermeation data are fitted by the following equation, which suitable for describing thepermeationofadrugthroughathinmembrane:
(1)
whereMt is thetotalamountofdrugthatpassesthroughthelayersofskin,Ls is the thicknessof thestratum corneum andL0 the formulation thicknessoverperiod t.Ds is the diffusioncoefficientofthedrugthroughthedifferentskinlayers,andKisapartitioncoefficient
Figure 1: Schematicrepresentationofthetransportprocessesinvolvedindrugreleasefromtheformulationuptoitsuptakethroughthedermalcapillaries[6].
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betweentheskinlayersandthedrugformulation(typicallyK=concentrationinskinlayer/concentrationinvehicle).
1.2.2. Release mechanisms from vehicles and substrates
Thereleaseofanactiveagentinanon-erodiblecore-shellsystemcanshowdifferentprofilesofdelivery.InFigure2,fourpossibletheoreticalcurves(A,B,CandD)showtheglobalbehaviorsofthereleasephenomenaindifferentsituations.
CurveAshowsaperfectreleaseprofile.Itshowsasystemwheretherateofdeliveryiscontrolledbythediffusionoftheactiveagentmoleculesthroughtheexternalmembrane.Therateofreleasedependsstronglyontheinternal-externalconcentrationgradient.
If there exist somemolecules that are retained in the shell, then a lag-time on thereleasewillbeobtained.Then,therewillbetwocontrollingstepsanddiffusionwillundergoatransitionalintermediatestate.CurveAinFigure2displaysasystemwithnolag-time.Whentheencapsulatedmaterialmigratestotheexternalmembraneofthemicrocapsule,therewillbea“burst-effect,”asshownbylineB.
Ifthemicrocapsuleactsasamicrosphere(theentireamountofactiveagentisdistributedinthepolymermatrix),theHiguchiequationisusefulupto60%release.Inthiscase,aplotofpercentreleasedversussquarerootoftimeislinear,asshownbylineC.First-orderreleaseisrepresentedbycurveD.ThecurvewillbelinearwhentheLogofthepercentageofcorematerialremaininginthecapsuleisplottedversustime[25].
Themainaimistoapplyamathematicmodelbasedonthephenomenologyinvolved,toexplainin vitropermeationexperimentswithabiofunctionaltextileusingdifferentmolecules,astracers.
TheKorsenmeyer-Peppas,equation(2),canbeusedtoaccountforthecoupledeffectsof
Figure 2: Theoretical release curves expected for different types of non-erodible delivery systems.A,Membranereservoir-typefreeoflagtimeandbursteffects;B,sameasA,withbursteffects;C,matrixormonolithicspherewithsquareroottime-release;D,systemwithfirst-orderrelease[24].
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Fickiandiffusionandviscoelasticrelaxationinpolymersystemsbyincludingbothprocesses:
(2)
WhereMtistheamountofdrugreleasedattimet,M∞isthemaximalamountofthereleased drug at infinite time, k is the rate constant of drug release, and n is a diffusionalexponentthatdependsonthesystemgeometry,andthevalueofnisindicativeofthereleasemechanismoftheactiveagent.
Eq(2)hasbeenusedfrequentlyintheliteraturetodescribetherelativeimportanceoftransportmechanismsasshowninTable1[26-32].
Historically,thefirstmathematicalmodelofdrugpermeationthroughtheskinwasthatproposedbyHiguchi.Sincetheestablishmentofthemodel,manyotherauthorshaveconductedexcellentresearchstudiesonthistopic,developingseveralmodelsbasedonchangesinactiveprincipleconcentrations
ThetransportinpolymericorganizedsystemscanbedescribedbyFick’ssecondLaw,sothediffusionoftheactiveagentcanbeassumedasaplanesurfaceforshorttimesofliberation,usingtheHiguchiequation(eq.4)fortocalculatetheapparentdiffusioncoefficient,usingtheapproximationofeq.(3),whereDistheapparentdiffusioncoefficientofdrugrelease,andδisthewidthoftheplanarmatrix.
(3)
Themostwidelyusedmodel todescribedrugrelease frommatrices isderivedfromHiguchiforaplanegeometry,whichisapplicableforsystemsofdifferentshapesaswell.
(4)
2. Active Principles used in Micro/Nanoencapsulation for textiles
2.1. Polymers
Encapsulation isoneof the techniquesused to apply substances to textiles [33,34].Biodegradablepolymermicro-ornanoparticlesareofgreatinterestasdrugdeliverysystemsbecauseof theirability tobe reabsorbedby thebody.Syntheticaliphatic linearpolyesters,suchaspoly-ε-caprolactone (PCL), areoftenused inbiomedical applications [35]because
n Drug Delivery Systems
n≤0.5 FickianDiffusionMechanism
0.5<n<1 AnomalousDiffusion
n≥1 Non-FickianDiffusionMechanism(zero-ordermodel)
Table 1: Drugdeliverymodelsbasedontheparametern.
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theyarebiocompatible,non-toxicandhavecertainadvantagesoverotherpolymerssuchasPLA(polylacticacid):(a)thepolymersaremorestableunderambientconditions;(b)theyaresignificantlylessexpensiveand,(c)theyarereadilyavailableinlargequantities[36].
2.2. Ibuprofen
Ibuprofen was used as active principle-tracer. Ibuprofen is an anti-inflammatorysteroid.Itisusedtorelievesymptomsofarthritis,primarydysmenorrhoea,fever,andasananalgesic,especiallywherethereisaninflammatorycomponent.Ibuprofenappearstohavethelowestincidenceofgastrointestinalreactionsadverseofallnon-selectivenon-steroidalanti-inflammatorydrugs(NSAIDs).However,thisonlyoccursatlowerdosesofibuprofenbecausetheusuallyadvisablemaximumdailydose is1,200mg.Adverseeffects includedyspepsia,nausea,ulcers/bleedinggastrointestinal, increasedhepaticenzymes,diarrhoea,constipation,epistaxis,headache,dizziness,priapism,rash,saltandfluidretention,andhypertension.
2.3. Caffeine
Caffeineisotheractiveprincipleusedtopreparebiofunctionalcottontextiles.Caffeinewasselectedgivenitsuse inseveralspecific therapiesanditswidespreaduse incosmeticsbecauseofitsstimulatingactivityonfatmetabolism(anti-celluliteaction)[37-39].Especialemphasiswasplacedonthereleaseofthisactiveprinciplefromtheformulationsandfromthecottonfabricsandonitstransdermaldeliveryinordertoreachthetargetcompartmentoftheskin.
2.4. Gallic Acid (GA)
GAwasselectedandincorporatedintopolyamide(PA)throughmicrospherespreparedfrompoly-ε-caprolactone(PCL).Gallicacid(GA)waschosenastheactiveagenttoobtainabiofunctionaltextilewithantioxidantproperties.Antioxidantsarenaturalagentsthatareusedtoprevent the external aggressionofoxidative stress inhumanbeings.The route to applydifferent compounds is clearly through the skin.When topically applied, these exogenousantioxidantshavebeendemonstratedtodiminishtheeffectsoffreeradicalsbyusingdefensemechanismssimilarorcomplementarytothoseofendogenousantioxidants[40-41].
2.5. In vitro drug release experimental results
AfterGAencapsulationandapplicationontocotton(CO)andpolyamide(PA)fabrics,theresultsobtainedareshowninFigure 3.
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Figure 3: SEMmicrographsofPCL-MicrosphereswithGA.A)Cottonfabric(x1000).B)Polyamidefabric(x1000)
COfibersallow themicrospheres tobeplaced incornersandspaceswhichcreateaproperfiberstructureandPAaccepts themicrospheresbetweenfibers.Visually,PAretainsmoremicrospheres thanCO.This is in accordancewith thehigher amountofdryproductpresentinthePAfabric.
Toperformtheanalysisofthemechanismofthedrugdeliverysystem,thetreatedfabricsamplesweresubmergedintoasemi-infinitebathofphysiologicalsaline,andeveryxminutes,abathaliquotewaspickedupandanalysedbyHPLC.
InFigure 4,itcanbeseenthatPAreleasesGAmorequicklythanCO,andPAreachesequilibriumbeforeCO.
UsingEq.(2)on thevaluesof thefirststeps(Figure 4), theexponentn isobtained,whichisindicativeofthedrugdeliverymechanism(Table 2).
3. Lípids as Vehicles for Skin Treatment
Liposomes are vesiclesmade up of lipids that can encapsulate different compoundsfor applicationonto textiles.Liposomeshavebeenused asmodels for complexbiologicalmembranes in biophysical and medical research owing to their lipid bilayer structural
Figure 4: KineticreleaseofGA(M)appliedontextilefabricsinabathofserumat37°C.
Table 2: nvaluesobtainedfromfittingdrugreleaseexperimentaldatabyequation2.
n Drug delivery systemCOfabric 0.46 FickiandiffusionPAfabric 0.63 Anomalousdiffusion
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similarity.Moreover,theyhavebeenthesubjectofnumerousstudiesgiventheirimportanceasmicroencapsulationdevicesfordrugdeliveryandtheirapplicationsincosmetics[41-45].Inrecentyears,liposomeshavebeenusedinthetextileindustryasdyeingauxiliaries,mainlyforwooldyeing[46,47]orasadispersingauxiliaryfordispersedyes[48,49].
Wool isakeratinized tissuewhose internal lipidshavebeenextractedandanalyzed.Theselipidsarerichincholesterol,freefattyacids,cholesterolsulphateandceramidesandtheyresemblethosefoundinmembranesofotherkeratinizedtissuessuchashumanhairorstratum corneumfromskin,becauseoftheircapacitytoformstablebilayerstructures.Accordingly,IWLcouldberegardedasanewandnaturalformtoencapsulatedifferentactiveagentsorasactiveagentsforskincare[50,52].
3.1. In vitro percutaneous absorption experiments (Franz diffusion cells) and cutaneous effectivity
Forthesestudies,pigskinwasusedwithathicknessofapproximately500±50μm.Skindiscswitha2.5cminnerdiameterwerepreparedandfittedintostaticFranz-typediffusioncells.
Acontrolskindisc(withoutproductapplicationontheskinsurface)wasusedtoruleoutpossibleinterferencesintheanalysisbyHPLC-UV.AccordingtotheOECDmethodology[5],theskinpenetrationstudieswereperformedfor24hofclosecontactbetweenthetextileandtheskin.Toincreasethecontactpressurebetweenthetextilefabricandskin,permeationexperimentswerealsocarriedoutbyplacingasteelcylinderonthetextile-skinsubstrateataconstantpressureinaccordancewithstandardconditions(125g/cm2)(ISO105-E04,1996)(seeFigure 5).
Aftertheexposuretime,thereceptorfluidwascollected,thefabricswereremovedfromtheskinsurfaceandcollectedtogetherwiththetopofthecell.Thestratum corneumoftheskinwasremovedusingadhesive.Theepidermiswasseparatedfromthedermisafterheatingtheskin[53].
The efficacy of the biofunctional textiles in close contactwith skinwas studied by
Figure 5:Diagramofin vitropercutaneousabsorptionexperiments.
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measuringchangesintransepidermalwaterloss(TEWL)asanindexofskinbarrierrepair,whereasthewater-holdingcapacitywasmeasuredaschangesinskincapacitance[54].
Skintapestrippingisan in vivomethodologyusedtodemonstratethepenetrationoftheprincipleintotheoutermostlayersofvolunteerforearmskin[55,56].Thisisaminimallyinvasive technique to sequentially remove SC by the repeated application of appropriateadhesivetapes[57].
Usingthesemethodologies,itwasconcludedthatliposomes,especiallythosepreparedwithIWL,weresuitablevehiclesforapplyingagivenactiveprincipleontotextiles.
3.2. Gallic Acid (GA) encapsulated in lipid structures
GAwasencapsulatedintoliposomesandappliedtodifferentfabrics,cotton,polyamide,polyester,acrylicandwool,usingbathexhaustionandthepad-dryprocesses.GAabsorption-desorptionbehaviorofthedifferenttextileswascomparedusingthetwomethodologies(byweightdifferenceandbyextractionanddetection).
Also,GAwasencapsulatedinliposomesandinmixedmicellesforapplicationtocottonandpolyamide.GAabsorption-desorptionbehaviorofthetextileswasalsodeterminedusingthetwoimpregnationmethods.
3.2.1. Liposome/Mixed Micelle Preparation for Gallic Acid
Liposomesof4%ofEmulmetik900 (PC)and2%GAwerepreparedusing thefilmhydrationmethodreportedelsewhere[58].Mixedmicelles(30wt%ofsurfactant,4wt%ofPCand2wt%GA)werepreparedsolubilizingallcompoundsindistilledwater;solubilisationwasperformedbygentlyshakinguntilclearsolutionswereobtained.
ParticlesizesofliposomesandmixedmicellesweremeasuredbyusingDynamicLightScattering(DLS),todeterminesizedistribution,polydispersityindexandzetapotentialofthetwolipidicstructures.
Toquantify theGAentrappedin thevesicles, liposomeformulationwasprecipitatedandseparatedfromthesupernatantbycentrifugation.TheefficacyentrapmentpercentageofGAinliposomeswasdeterminedwiththeamountoftheactiveprinciplepresentinthewholeliposomesolutionaswellasinthesupernatant,usingaGAcalibrationcurve.
3.2.2. Textile application and absorption/desorption process.
Theapplicationofliposomesorthemixedmicellesontothefabricswasperformedbybathexhaustionandthefoulardpaddingprocess[59].
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Liposomes and mixed micelles were also applied to textiles in triplicate with bathexhaustion, liquor ratio1/5,at60ºCfor60minwithmanual stirringevery10minutes.Toquantifytheamountofliposomesormixedmicellesabsorbedintothefabrics,thedrysampleswereweightedbeforeandafter24happlicationunderstandardambientconditions(20±2ºCand65±5%relativehumidity).
Treated fabrics were washed in three different water baths at room temperature. Inallcases,thedrysampleswereweightedbeforeandafter24hofthewashingprocessunderstandardambientconditions.Thefirstwashingstepwasperformedwithdeionisedwater(1/5liquorratio)for5minwithmagneticstirring.Asecondwashwascarriedoutwithdeionisedwater(1/10liquorratio)for5minwithmagneticstirring,andthethirdwash,withdeionisedwater(1/25liquorratio)for5minwithmagneticstirring.Particlesizeandzetapotentialweremeasuredinthebathsaftertheexhaustiontreatmentandinthebathsafterthefirstandthirdwashingsasdescribedfortheinitialformulations.
ThehighersubstantivityofthephospholipidliposomesforsomefiberslikePAC,PAandWOwasclearlydemonstratedbyanabsorptionlevelhigherthan15%forallthesefibers.Desorptionwithwaterwas also evaluated for all the treated fabrics.Results of remainingliposomeinpercentagearealsodescribedinTable 3.
Asinthecaseofthepaddingprocess,thehighestdesorptionwasobtainedforthemostsyntheticPACandPESfabrics, followedbyCOandWO.Thehighest retainedamountofliposomeswasobtainedforthePAfabric.
Bothliposomesandthetextilefibersareusuallyelectricallycharged.Theyaresurroundedbyacloudofionswhichcarryanequalandoppositecharge.Thezetapotentialisthevoltagedifference between the droplet surface and the liquid beyond the charge cloud. InitialGAliposomeformulationappliedtotextileshasanacidicpHof3.3withazetapotentialof-4mV.However, in thewashingbaths thepHrises toaround5.0and thezetapotential toaround-50mV.Theincreaseinthewaterlayersaroundanegativechargeduetodilutionrendersthezetapotentialmorenegative.Moreover,thenatureofthechemicaldissociablegroupsinthetextilefibersurfaceinducesanegativezetapotentialofthefibers,seeTable4[60,61].
Table 3: Percentageofliposomeabsorbedanddesorbedonthedifferentfabrics,CO,PA,PES,PACandWOusingthebathexhaustionmethodology.(%owf:percentageoverweightoffiber)
Ini. weightg Fin. weight % owf Weight 1st washing % owf Weight total washing % owf
CO 2.00±0.01 10.99±0.39 7.32±2.43 5.58±0.39
PA 2.05±0.04 16.34±1.23 12.73±1.94 7.31±0.64
PES 2.07±0.01 14.05±1.15 9.64±1.53 2.05±0.50
PAC 1.98±0.06 17.44±1.09 13.20±0.93 4.25±0.33
WO 2.04±0.04 17.15±0.90 12.95±1.05 6.17±0.51
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COisthemosthydrophilicfiber,itshigherswellingcapacityyieldingtosmallerzetapotentialvalues than the hydrophobic fibers. PAC and, especially PES fibers contain sulfonic andcarboxylicgroups,respectively,contributingtothemostnegativezetapotential.BecauseWOhas carboxylic and amino groups near the surface, negative or positive zeta potentials arefoundwhenthepHisoverorunderitsisoelectricpoint3.5.PAhasamoderatehydrophilicity,inferiortocottonbutsuperiortoPESandPAC.Moreover,itsweaklybasicaminogroupsandweaklyacidiccarboxylicacidgroupsgiverisetotheionicpropertiessimilartoWO.
IntheabsorptionprocessatpH3.3,mostofthefabricshaveaneutralorcationiccharacterwiththeresultthatabsorptionissimilar.InthewashingbathsatpH≈5andmorenegativezetapotential,textilesalsohavehighernegativevalues.ThedesorptionofthePESandPAC(thefiberswiththemostnegativezetapotential)isthereforeabout85%and75%,respectively.Bycontrast,desorptionofWO,PAandCO(thefiberswiththeleastnegativezetapotential)isabout65%,55%and50%,respectively.ThehighestfixationpropertiesdemonstratedbythelowestdesorptionofPAandCO,togetherwiththehighestcomfortpropertiesofthesefiberswhenincontactwiththeskin,endorsetheirapplicationascosmeticbiofunctionaltextiles.
In mixed micelles, the two constituent phospholipids and the surfactant agent arestructuredtogetherinsmallmicelles,givingrisetoatransparentsolution.However,dilutionofmixedmicellespromotestheseparationofthesurfactantandthephospholipidswithformationofliposomes.Thisresultsinalargeincreaseinsize,givingrisetoaturbidsolution[62].Theabsorptionofmicellesbytextilescouldbemaintainedafterawashingprocessbecauseofanexpectedincreaseinsizeofthevehiclesinsidethefiber.Thiscouldenhancethefixationintextileswithlessdesorptionasoccursintheskin[63,64].
Thiswasexpected,owingtoliposomeformationwithdilution.Besides,zetapotentialisalwaysnegativewithsmallvaluesforthetwoconcentratedformulationsaround-4mV(Table5).They increasewith dilution in absolute value to -20mV for themixedmicelles and to-50mVforliposomes.Theseincreasesinnegativelychargedareduetotherepulsionchargesinthedilutions,whichincreasethecolloidstability.
Table 4:Z-potentialsoftextilefibersinaqueousneutralmedia(83).
CO PA PES PAC WO
PotZ.(mV) -33 -42 -74 -47 -45
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Asintheliposomeformulation,theapplicationoftheactiveagentvehiculizedinmixedmicelles(36%ofdryproductand2%GA)tothetextilesubstrates,COandPAwasperformedbythefoulardprocessinanattempttoachieveapick-upofapproximately90-100%.
Whenmixedmicelleswereappliedtothefabrics,thereweredifferencesofabout35%betweenthecalculatedamountofproductimpregnated(34-35%)andtheproductfoundinthefabricafterheatingattheStenter(22-23%).Thiscouldmeanthatthesurfactant,whichisthemaincomponentofthemixedmicelles,hashighersubstantivityforwaterthanforthetextiles.COandPAincorporatealmostthesameamountofproduct(about23%)whichismuchhigherthantheamountofproductabsorbedwithliposomes(seeTable 3).Desorptionwithwaterwasalsoevaluatedforthetwofabrics.ResultsofremainingmixedmicellesinpercentagearealsodescribedinTable 6andaregraphicallyrepresentedinFigure6.Forcomparison,theresultsobtainedwithliposomesarealsoshown.
ThesamemixedmicellesformulationwasappliedtocottonandPAbybathexhaustionasdescribedintheexperimentalsection.TheinitialweightswiththepercentagesofdryproductcalculatedbyweightdifferencebetweendryinitialfabricanddryfabricafterbathexhaustionareshowninTable 7.
Table 5: Meansize,polydispersityindexandZpotentialofinitialliposomeandmixedmicelleformulationsandtheirdilutions.
Formulation Mean Size (nm) Polydispers. Index Z-Potential (mV)
Liposome4%PC 717.40±56.25 0.74±0,03 -4.3±0.30
Liposome0.4%PC 407.47±24.07 0.79±0,03 -46.3±1.08
Liposome0.2%PC 367.80±8.51 0.84±0,10 -49.2±0.90
Liposome0.1%PC 395.07±28.84 0.60±0,14 -57.1±0.20
Mix.Micelle4%PC 8.05±0.08 0.13±0.02 -4.07±0.01
Mix.Micelle0.4%PC 8.23±0.17 0.10±0,01 -8.69±1.28
Mix.Micelle0.2%PC 10.53±0.06 0.14±0.05 -20.47±1.17
Mix.Micelle0.1%PC 55.35±0.08 0.09±0.01 -19.13±0.29
Table 6: Percentage(%owf)ofmixedmicellesabsorbedanddesorbedonCOandPAusingthefoulardprocess.
Ini. weight g Pick-uptot.% lip%
Fin. weight% owf
Weight 1st washing.% owf
Weight total washings.% owf
CO 2.01±0.10 95.28±3.2234.3 22.23±1.50 7.07±1.0 1.11±0.13
PA 2.06±0.01 97.6±0.535.1 23.05±0.63 7.44±0.6 0.26±0.17
Table 7: PercentageofmixedmicellesabsorbedanddesorbedonCOandPAusingthebathexhaustionmethodology.
Ini. weightg
Fin. weight%
Weight 1st w.%
Weight total w.%
CO 2.05±0.04 35,43±2.73 12.72±0.44 2.42±0.06
PA 2.08±0.02 40,14±4.23 18.29±1.98 3.91±0.11
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Whenmixedmicelleswereappliedtothefabricsbybathexhaustion,asintheliposometreatments, higher absorptionwasobtained for the two fabricswith respect to thepad-dryprocess,withhighersubstantivityforPA.Thehighertemperatureofbathexhaustion(60ºC)withrespecttothefoulardprocess(30ºC)couldaccountforthis.Desorptionwithwaterwasalsoevaluatedforallfabrics.ResultsofremainingmixedmicellesinpercentagearealsodescribedinTable 7andarerepresentedinFigure 6includingtheresultsobtainedwithliposomes.
Asinthecaseofthefoulardprocess,despitethehighabsorption,considerablyhigherdesorptionwasobtainedforthemixedmicellestreatedfabricswithrespecttotheliposometreatedfabrics.Moreover,PApresentshigherabsorptionandlessdesorptionthanCOinthecaseof liposomesandmixedmicelles treatments. Interactionof lecithinwithCOhasbeenreported to bemainly at the surface through a coating layer,whereas interactionwith PAoccursintheinteriorofthefiber[65].
ThehigherabsorptionofmixedmicellesinCOandespeciallyinPAcouldbeduetothepresenceofOramix in30%.The increase inparticle sizewithdilution in thewashingbaths,whichcouldattain50-100nm,doesnotpreventdesorption.Bycontrast,alargeamountofdesorptionoccurs inmixedmicelles treatedfabrics.DesorptionofPAandCOliposometreatedfiberswasabout50%,whereasdesorptionofPAandCOmixedmicellestreatedfibersattained90%.Thesizeofthelipidstructuresofliposomesandmixedmicelleswasevaluatedintheinitialandwashingbathsoftheexhaustiontreatments(Table 8)todetermineitspossibleinfluenceonproductdesorption.
Figure 6: Absorptionanddesorptionoftotalproduct(GAinliposomeormixedmicelles)appliedtocottonandpolyamidebybathexhaustion.
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Theincreaseinparticlesizeofthesestructures(seeTable8)didnotpreventtheirexitfromthefiberswithlessdesorptionasexpected.Bycontrast,desorptionwasmaximum.Thiscouldbeduetoahigherpermeabilityoftextilescomparedwithhumanskininwhichthiseffectwasnotobserved[63,64].
TheloweramountofGA,bothrealandtheoretical,inCOandPAtreatedwithmixedmicelleswith respect to those treatedwith liposomesshouldbenoted.The realamountofGAevaluatedbyHPLCinCOfibersisalwayslowerforthetwovehiclesthantheamountcalculated.ThisisnotthecaseforthePAfiber.Thesephenomenasuggestalowsubstantivity
Table 8: Size(Z-Average)andPolydispersityIndex(Pdl)ofdifferentbathsofCOandPAsubjectedtobathexhaustionwithliposomesandmixedmicelles.
Treatment Analyzed BathSize (Z-Average) Diameter (nm)
PdI
Cotton/Liposomes
InitialBath 525.6±26.1 0.68±0.03
Bathafterexhaustiontreatment 375.3±64.6 0.51±0.12
Bathafter1stwaterwashing(10ml) 474.3±32.2 0.68±0.20
Bathafter3rdwaterwashing(50ml) 623.5±18.8 0.52±0.03
Cotton/Mixed Micelles
InitialBath 6.9±0.8 0.98±0.04
Bathafterexhaustiontreatment 102.2±30.9 0.98±0.03
Bathafter1stwaterwashing(10ml) 206.7±76.5 0.34±0.12
Bathafter3rdwaterwashing(50ml) 211.0±38.2 0.31±0.02
Polyamide/Liposomes
InitialBath 525.6±26.0 0.68±0.03
Bathafterexhaustiontreatment 460.6±76.4 0.45±0.01
Bathafter1stwaterwashing(10ml) 510.0±53.2 0.88±0.21
Bathafter3rdwaterwashing(50ml) 660.3±31.9 0.49±0.04
Polyamide/Mixed Micelles
InitialBath 6.6±0.8 0.97±0.04
Bathafterexhaustiontreatment 157.2±81.7 0.62±0.17
Bathafter1stwaterwashing(10ml) 257.6±97.9 0.05±0.12
Bathafter3rdwaterwashing(50ml) 166.9±89.5 0.34±0.07
Figure 4: RealandtheoreticalGApercentagesoftreatedandwashedtextiles.
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fortheGAforcottonandamuchgreatersubstantivityforPA.ItcanthereforebeconcludedthatthevehiculizationefficiencyofliposomeswithrespecttomixedmicellesisalwaysgreaterforpolyamidethanforCO.Thusabiofunctionaltextilewithmorethan5%ofGAisobtainedevenafterthreeconsecutivewashings.
4. Electrosupun Nanofibers as Biomedical Devices
4.1. Introduction
Overthepast20years,theinteractionsofthefieldsofpolymerandmaterialssciencewith the pharmaceutical industry have resulted in the development ofwhat are known asdrugdeliverysystems(DDSs),orcontrolled-releasesystems[66-69].Drugdeliverysystemscanbeclassifiedaccordingtothemechanismthatcontrolsthereleaseofthedrug[70],suchas diffusion-controlled systems, chemically controlled systems, solvent-activated systems,modulated-releasesystemsandbioerodible-releasesystems[69-74].
Oneofthemostpromisingbiodegradablepolymersforuseinbioerodible-releasesystemsispoly(lacticacid)(PLA),Fig5,becauseofitsmechanicalandbiologicalproperties.
PLAisathermoplasticpolyesterderivedfromrenewableresources,suchascornstarch.PLAhasahydrolyticdegradationmechanism,anditiscapableofdegradingintoinnocuouslacticacidandthenintoCO2andwater,whichareabsorbedbythebody.PLAisusedinmedicalimplantsintheformofscrews,pins,rodsandasamesh[75-77].Dependingontheexacttypeused,PLAdegradesinthebodywithin6monthsto2years[77].Thisgradualdegradationisdesirableforasupportstructurebecauseitgraduallytransferstheloadtothebodyastheorganheals.
Here, the properties of a different drug-delivery system,which consists of differentnanofibermembraneconfigurations,wereexamined.Themembraneconfigurationwasbasedon sandwiching the drug between two adjacent layers of electrospun PLAmembranes todetermine themass transport behavior of the drug through different polymericmembraneconfigurations.
SimilarstudieshavebeenconductedbyFiedetal.[78]withthepurposeofdevelopingultrafiltrationmembranes. Tiemessen et al. [79] have also described a so-called occlusionsimulation model based on sandwiching the stratum corneum between sticky siliconemembranestoprovideameansforsimulatingskinpenetrationunderocclusion.
Figure 5:ChemicalstructureofPLA
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TheelectrospunPLAmembraneswereshowntoprovideausefulmechanicalsupportforthedrug.Theinitialstudiesonthesandwichmodelalsorevealedthatthismodelprovidesanelegantmeanstokineticallycontrolthewateruptakebythedrug.AlthoughthePLAmembraneisbiodegradableorerodible(i.e.,asystemthatdisintegratesovertime),thisphenomenoncanbeirrelevantwhentheentiredrugisreleasedbeforethedissolutionofthepolymerbecomesimportant.Therefore,themembranescouldbeconsiderednon-erodible.
Therefore,thisnewsystemcanbedirectlyusedintheprophylacticperiodofpatientswho recentlyunderwent anoperation,when in situ application is required. In somecases,thisparticularmembranecanactnotonlyasacarrierbutalsoascavityfillerwiththerapeuticagents.
Here, thepolymeric solutionused toproducenanofiberswasobtainedbydissolving10%ofthesolutionweightofpoly(lacticacid)indichloromethaneunderconstantmagneticagitationandataconstantroomtemperatureof23-25°C.ThemagneticagitationremainedconstantuntilthePLAwascompletelydissolved,whichwasindicatedbythesolutionbecomingtranslucent andwhenno solid particleswere detected.Complete dissolutionwas achievedafter1hourofagitation.
Toconducttheexperiment,ahighvoltagepowersupply,aspinneret(acapillarytubewithverysmalldiameter)andagroundedcollectorplate(aplateusuallycomposedofmetal)wererequired,asseeninFigure 6.
Duringtheelectrospinningprocess,astrongelectrostaticfieldisappliedtoapolymersolutionheld inasyringewithacapillaryoutlet.Apendent-shapeddropletof thepolymersolutionfromthecapillaryoutletisdeformedintoaTaylorcone[80]bytheelectrostaticfield.Whenthevoltagesurpassesathresholdvalue,theelectricforceovercomesthesurfacetensionofthedropletandachargedjetofthesolutionisejectedfromthetipoftheTaylorcone.Asthejetmovestowardacollectingmetalscreen(counterelectrode),thesolventevaporatesandanon-wovenfabricmatisformedonthescreen[81].TheprocesscanbeseeninFigure 7.
Figure 6: Electrospinningdevicecontainingallessentialelements:highvoltage,spinneret,metalcollector
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4.2. Experimental results of Nanofibers formation
When applying the former conditions specified, PLA nanofibers are formed, as thefollowingfiguresshow.
Figure 7: ElectrospinningofPLAunderoptimalconditions
Figure 8:SEMofPLAfibersunderoptimalhighvoltageconditions(orderofmagnitude1000x).
Figure 9: SEMofPLAwithbeaddefects;orderofmagnitude250x
Figure 10:SEMofPLAfiberswithincreasingflowrate;orderofmagnitude4000x.
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4.3. Sandwich configuration with Ibuprofen or Caffeine
Ibuprofen, or caffeine, was placed between two adjacent layers of the polymericmembranes.Whenthefirstlayeroftheelectrospunmembranewasdriedandsolidified,thedrug,whichwas in a driedmedium,was evenly dispersed on themembrane surface.Theamount of drugwas controlled using an analytical balance.After placing the drug on themembranesurface,asecondmembranelayerwaselectrospunoverthefirstlayertocoverthedrug[82].
4.4. Drug-Delivery Mechanisms
Thecapabilityofthepolymericmembranetodeliverthedrugwasdeterminedthroughtriplicatemeasurementsofthedrugreleasekineticsintoafluidphase.
Thedrugreleasekineticsweredeterminedusingbatchmethodsformembranesoperatingindifferentconditions,suchasmembranesobtainedafterdifferentelectrospinningperiods(5,10and20minutes)andsandwichmembraneswithdifferentdrugamounts(5,10and15mg).Foreachoperatingcondition,theexperimentwasrepeated3times.
Toperformtheexperiment,thesandwichmembraneswereplacedbetweenconcentricringsinametallictamboursystem,asshowninFigure13,toensureuniformmasstransferalong thesurfaceof themembranefromthesolidphase to thefluidphaseand tosoavoidbendingstress.
Figure 11:SEMofporousPLAfiberduetohighroomhumidity
Figure 12: SEMofnanofibersproducedbyoptimizedelectrospinningprocess;orderofmagnitude15000x.
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Afteradjustingthesandwichmembranesinthemetallictamboursystem,theywereplacedinacoveredcontainerwith100mLofphysiologicalserumasthefluidphase,withapH7.4.Thecontainerspreparedfortheanalysesweremaintainedinabathwithaconstanttemperatureof37°C.Thesamplesweretakenforanalysisatregulartimeintervals,andtheconcentrationsofdrugreleasedintothefluidphaseweredeterminedthroughspectrophotometrictechniquesinaShimadzuUV-2401PCUV-visspectrophotometerwithawavelengthof263nm.
4.5. Controlled Drug Release Mathematical Modeling
Theresultsobtainedfromthekineticstestswereusedforthemathematicalmodelingofthecontrolleddrugrelease,followingtheapproachexplainedbeforeinImmichetal.[83]andin1.2.2.
4.6. Scanning Electron Microscopy (SEM)
The surface morphologies and thicknesses (δ) of the polymeric membranes wereexaminedusingascanningelectronmicroscope(JEOL/JSM-5610).Afterthesamplesweredriedovernightatroomtemperature,eachspecimenwassputtered-coatedwithgoldpowderbeforebeingexaminedwiththeSEM.Forthethicknessmeasurement,3differentregionsofthetransversalareaofthemembraneweremeasured,andtheaveragevalueofthesemeasurementswasused.
Themembrane thicknesswas determined for the PLAmembranes obtained after 5,10 and20minutes of electrospinningwithdifferent amounts of ibuprofen.The results arepresentedinTable 9.
Figure 13:Masstransferconfigurationdeviceonthedrug-deliveryexperiment
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ThedifferencesinthemorphologiesofthePLAmembraneswithdifferentelectrospinningtime intervals were analyzed and the difference in the amount of fibers in each obtainedmembraneisnoticeable.InthePLAmembraneobtainedafter5minutesofelectrospinning,itcanbeseenemptyspacesamongthefibers.Theseemptyspacesfacilitatemasstransferenceofthefluidphasethroughthemembrane,whichisreadilyconducivetodrugrelease.Whenthereisanincreaseintheamountoffibersandconsequently,areductionintheamountofemptyspace,themolecularmobilitybecomesdifficultandconsequently,itreducesmasstransportthroughthemembrane.
Thediameterofthefiberinapuremembraneobtainedafter20minutesofelectrospinning(withoutthedrug)wasalsomeasuredusingSEM,andtheaveragediameterisapproximately150nmwhendisregardingthebeadeffect.
4.7. Ibuptofen delivery from PLA electrospun membrane
TheinfluenceofthemembranethicknessonthereleasekineticsofibuprofenthroughPLAmembraneswasstudiedataninitialdrugamountof5mg(Figure 14).
AlthoughthePLAmembraneisbiodegradableorerodible,inthisstudy,thephenomenon
Table 9: ThicknessofPLAmembranesfordifferentibuprofenamounts.
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: KineticsofibuprofendeliveryfromPLAmembranesafter5minuteselectrospinningAftertheinitialburst,thepolymerstructureswells,stabilizesandtrapsthedrug.Theresultisacontinuousandslowersustainedreleaseprocess.
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wasnegligiblebecausetheentiredrughadalreadybeenreleasedbeforethedissolutionofthepolymerbecameimportant.Therefore, themembraneswereconsidered tobenon-erodible.Figure14presentskineticsbehaviorwithamoreintenseinitialburst,whichleadstoareleaseofapproximately0.05g/Lofibuprofen(100%ofinitialdrugconcentration)duringthefirststageofthedrugdelivery.
MorecontrolledreleaseprocessesareobservedinkineticspresentedinFigures15and16,withalessintensebursteffectandaninitialdrugreleaseofapproximately0.03g/L(30%ofinitialdrugconcentration)and0.02g/L(13%ofinitialdrugconcentration),respectively.Thisdecreaseinthebursteffectintensityisduetoanincreaseinmembranethicknessafter10and20minutesofelectrospinning,whichdelayedmasstransferencethroughthepolymericmembranetotheexternalfluidphase.
Inadditiontothedecreaseofthebursteffectindrugreleaseforthemembraneobtainedafter20minutesofelectrospinning,anincreaseinthepseudo-equilibriumtimeoftotaldrugreleasewasalsoobservedduetothemembranethickness,whichisconsiderablygreaterthanthatofthemembraneobtainedafter5minutesofelectrospinning.Thisthickermembranealsorestrainsandcontrolsdrugmobilityandtransportthroughthemembrane.
Figure 15:KineticsofIbuprofendeliveryfromPLAmembranesafter10minuteselectrospinning
Figure 16:KineticsofibuprofendeliveryfromPLAmembranesafter20minuteselectrospinning
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Theamountofibuprofenwithinthemembraneisalsoimportantwhendeterminingthetimerequiredforthetotalreleaseofthedrug.Whentheamountofibuprofenincreasesfrom5to10mg,thetimerequiredforthetotalreleaseofthedrugincreasesby72%onaverage.Thereisnosignificantincreaseintimeforthetotalreleaseofthedrugwhentheamountofibuprofenincreasesfrom10to15mg.Membraneswith10and15mgofibuprofenhavesimilarbehaviorduringthereleasingprocess.
Becausethekineticscurvesforthereleaseofibuprofen,whichareillustratedinFigures14,15and16,exhibitthetypicalbehaviorforreservoir-typemembranes,itcanbeassumedthat thedrug transportmechanismthrough thesemembranes isusuallyasolution-diffusionmechanism.Though, this isnotsufficient toprovethemechanismofdrugrelease.Forthatreason, the releasingmechanism(n)of ibuprofenwascalculated,according toPowerLawequation(2)[83].
The releasingmechanismpresented inTable 10, forpolymericmembranesobtainedafter5minutesofelectrospinning,donotdescribeanyestablishedmechanismofdrugrelease.Itmeansthemechanismofreleaseisneitheradiffusion-controlleddrugrelease(n=0.5)noraswelling-controlleddrugrelease(n=1),wheretherelaxationprocessofthemacromoleculesoccurringuponwaterimbibitionintothesystemistheratecontrollingstep.Here,thereasonforthereleaseofibuprofenmustbethelargeporosityofthethin5minutemembranethatdoesnotrestrictthemoleculesofibuprofenfrompassingthrough.
However, for membranes obtained after 10 and 20 minutes of electrospinning, theexponentntakesavalueof0.5orverycloseto0.5.Itindicatesthatdiffusionisthemechanismcontrolling the release of ibuprofen.Therefore, drug transport initially occurs through thedissolutionof thedrug through themembrane,which is followedbydiffusion through thesamemembraneanddesorptiontotheothersideofthemembrane.Consideringthatthereleaseofibuprofeniscontrolledbydiffusion,itispossibletoapplytheclassicalHiguchiequation(eq.3),todeterminethemasstransportcoefficient,andthentheapproachofFick’ssecondlaw
Table 10: MechanismofdrugreleaseforPLAmembranes.
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
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todeterminetheapparentdiffusivityofibuprofenthroughthePLAmembranesobtainedafter10and20minutesofelectrospinning.
ThedatapresentedinTable 11showsthatthemasstransportcoefficient,KH,(equation(4))forthereleaseofibuprofenthroughelectrospinningmembranes,decreasedwhenmembranethicknessisincreased(from10to20min.electrospinning).Thisresultisduetothereinforcementoffibers,whichbecomedenserandnoteasilypenetrable.Thisfiber reinforcementreducestheemptyspacesavailableforibuprofenparticlemobility,whichrestrainsitstransferencetotheexternalmedium.Increasingthedrugconcentrationfurtherdecreasestheavailableemptyspacesformasstransference,whichconsequentlydecreasesthemasstransportcoefficient.
Table11alsoshowsthediffusivity(D)values,whichappeartoincreaseforthe10min.electrospinningmembranewhentheinitialdrugconcentrationisincreased.
Increasingtheelectrospinningtimefrom10to20min.producesevendensermembranesthat are full of fiberswith a compact internal structure and less empty spaces for particlemobilityandtransport.Therefore,increasingtheibuprofenconcentrationfillsevenmoreoftheemptyspacesinthemembrane,whichdecreasesthepossibilityofinternaltransportandconsequentlydecreasesthemasstransportcoefficientandrestrainsthedrugdelivery,asshowninTable 11.
Unlikethe10min.electrospinningmembrane,thediffusivityofibuprofenthroughthe20min.electrospinningmembraneispracticallyconstantwithincreasingdrugconcentration,as the variation in the diffusivity values is insignificant. This is due to the uniformity ofmembranethickness.Theminorvariationindiffusivityshownforthe20min.electrospinningmembranecouldbeattributedtotheoreticalfittinguncertainty.Here,itispossibletomaintainthepercentageofdrugreleasedisregardingtheamountofdruginthereservoir.TheaveragevalueofdiffusivityshowninTable 11is2.5E-08cm2/s,inaccordancewiththecommonrangeofdrugdiffusivitiesinvariousmembranes[84,85].
Table 11: DrugreleaseparametersforPLAmembranesobtainedafter10and20minutesofelectrospinning.
Electrospinning time (min)
Ibuprofen amount (mg) KH Diffusivity (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
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