Research Article Preparation of Biodegradable Silk...

Hindawi Publishing CorporationAdvances in Materials Science and EngineeringVolume 2013 Article ID 412458 6 pageshttpdxdoiorg1011552013412458

Research ArticlePreparation of Biodegradable Silk FibroinAlginate Blend Filmsfor Controlled Release of Antimicrobial Drugs

Yaowalak Srisuwan and Yodthong Baimark

Biodegradable Polymers Research Unit Department of Chemistry and Center of Excellence for Innovation in ChemistryFaculty of Science Mahasarakham University Mahasarakham 44150 Thailand

Correspondence should be addressed to Yodthong Baimark yodthongbmsuacth

Received 6 May 2013 Revised 29 July 2013 Accepted 15 August 2013

Academic Editor Jie Dai

Copyright copy 2013 Y Srisuwan and Y Baimark This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Silk fibroin (SF)alginate blend films have been prepared for controlled release of tetracycline hydrochloride an antimicrobialmodel drug The blend films were analysed by Fourier transform infrared (FTIR) spectroscopy scanning electron microscopy(SEM) and UV-vis spectroscopy The functional groups of the SFalginate blends were monitored from their FTIR spectra Thehomogeneity of the blend films was observed from SEM imagesThe dissolution and film transparency of the blend films dependedon the SFalginate blend ratio The in vitro drug release profile of the blend films was determined by plotting the cumulative drugrelease versus time It was found that the drug release significantly decreased as the SFalginate blend ratio increased The resultsdemonstrated that the SFalginate blend films should be a useful controlled-release delivery system for water-soluble drugs

1 Introduction

Controlled-release drug delivery is a term referring to drugdelivery in response to time Prolonged release sustainedrelease and delayed release are terms used to identify drugdelivery systems that are designed to deliver a precise amountof a drug at a preprogrammed rate in order to achieve thedrug level necessary for treatment after administration ofa single dose [1] Controlled-release drug delivery not onlyprolongs the action thus reducing the frequency of drugadministration but also attempts to maintain drug levelswithin the therapeutic window to avoid potentially haz-ardous peaks in drug concentration following injection oringestion and to maximise therapeutic efficiency Varioustypes of controlled-release drug delivery system have beenprepared such as films particles gels and fibres Polymericmaterials have been widely investigated for use as matri-ces of drug delivery systems The drug delivery systemsobtained from biodegradable polymers have the advantageover nonbiodegradable polymers in that the removal ofthese devices at the completion of therapy is not requiredThe biodegradable polymers consist of natural type suchas silk fibroin chitosan starch and alginate and synthetic

type such as polylactic acid polyglycolic acid and poly(120576-caprolactone) Usually the natural biodegradable polymersare less expensive

Silk fibroin (SF) obtained from Bombyx mori silkwormis a protein polymer [2] SF has been widely studied foruse in tissue engineering [3] and drug delivery applications[4 5] SF in film fibre tube gel and particle forms hasbeen prepared for these purposes SF has two conformationalforms water-soluble (random coil) and water-insoluble (120573-sheet) The conformational transition of SF from the randomcoil form to the 120573-sheet form can be done by treatment withalcohol heat cross-linker and polymeric blending [2]

Alginates are natural polysaccharides that havemany usesin biomedical and pharmaceutical applications due to theirlow toxicity biocompatibility and biodegradability [6 7]Alginate-based devices have been widely used as drug car-riers for controlled release due to their low immunogenicityand mucoadhesive properties [8ndash10] However alginate iseasily dissolved in aqueous media Cross-linking of alginatewith Ca2+ ions has been used to reduce their swelling anddissolution [8]

In the present study SFalginate blend films containinga model drug were prepared by the solvent evaporation

2 Advances in Materials Science and Engineering

O

O

O

O

O

O

NH

NH

NH

NH

NH

NH

CH3CH3

OH

n

(a)

O

OO

O

OH

HOH

HOCO2Na

CO2Na

(b)

OOO

NHHCH3CH3

OH

OHOH HO

HOH3C

NH2 middot HCl

(c)

Figure 1 Chemical structures of (a) silk fibroin (b) alginate and (c) tetracycline hydrochloride

method The influence of SFalginate blend ratio on filmcharacteristics and drug release behaviour was determinedTetracycline hydrochloride was chosen as an antimicrobialmodel drug due to its good water solubility SF alginateand drug were blended in an aqueous medium before filmcasting Tetracycline hydrochloride has been shown to beclinically effective in the treatment of periodontal infection[11] The chemical structures of SF alginate and tetracyclinehydrochloride are illustrated in Figure 1

2 Materials and Methods

21 Materials Silk fibroin (SF) aqueous solution was pre-pared as follows Briefly cocoons of B mori gifted from theSilk Innovation Centre MahasarakhamUniversityThailandwere degummed by boiling twice in 05 (wv) Na

2CO3

solution at 95∘C for 1 h followed by rinsing thoroughlywith distilled water to remove sericin before drying at roomtemperature [12] Degummed SF fibres were dissolved inthe ternary solvent system CaCl

2-ethanol-water (molar ratio

= 1 2 8) by stirring at 85∘C for 2 h The resultant SFsolution was then dialysed in a dialysis tube (molecularweight cutoff 6000ndash8000Da) for 3 days in distilled waterThe distilled water was changed every day The SF solutionwas filtered before adjusting to 1 (wv) with distilled waterSodium alginate ((C

6H7O6Na)119899 pharmaceutical grade) was

purchased from Carlo Erba The intrinsic viscosity of thesodium alginate measured in 01M NaCl water solution at25∘C using an Ubbelohde viscometer was 850mLg Tetracy-cline hydrochloride (C

22H24N2O8sdot HCl 99) was used as

a water-soluble model drug and purchased from Sigma The1 (wv) alginate solution was prepared using distilled wateras the solvent

22 Preparation of Drug-Loaded Blend Films SFalginateblend films containing the model drug were prepared bythe solvent evaporation method Appropriate volumes of1 (wv) SF and 1 (wv) alginate solutions were blendedtogether by magnetic stirring for 30min The total volumeof the blend solution was kept constant at 20mL The modeldrug (2mg) was completely dissolved in the blend solution

600800100012001400160018002000

1247

1247

1248

12461244

T(

)

Wavenumber (cmminus1)

(a)

(b)

(c)

(d)

(e)

(f)

Figure 2 FTIR spectra of drug-loaded blend films with SFalginateblend ratios of (a) 01 (b) 11 (c) 21 (d) 41 (e) 81 and (f) 10 (ww)

before film casting on polystyrene dishes SFalginate blendratios of 81 41 21 and 11 (ww) were investigated Plain SFand alginate filmswere also prepared for comparisonThe (SF+ alginate)drug ratio was kept constant at 1001 (ww) Theblend solution was dried at 40∘C for 48 h The obtained filmswere kept in a desiccator before property characterisation anddrug release testing

23 Characterisation of Drug-Loaded Blend Films Chemicalfunctional groups of the blend films were analysed by Fouriertransform infrared (FTIR) spectroscopy using a Perkin-Elmer Spectrum GX FTIR spectrophotometer A resolutionof 4 cmminus1 and 32 scans were employed The morphologyof the blend films was determined by scanning electronmicroscopy (SEM) using a JEOL JSM-6460LV SEM Theblend film samples were coated with gold to enhance thesurface conductivity before the scan Film transparency wasmeasured from the percentage of transmittance at 660 nm(T660

) [13] by UV-vis spectrophotometry using a Perkin-Elmer Lambda 25 UV-vis spectrophotometer Dissolutionof the films (sim10mg) was tested in 2mL of distilled waterat 37∘C for 24 h under shaking The remaining film was

Advances in Materials Science and Engineering 3

(a) (b)

(c) (d)

(e) (f)Figure 3 SEMmicrographs of surfaces of drug-loaded blend films with SFalginate blend ratios of (a) 01 (b) 11 (c) 21 (d) 41 (e) 81 and(f) 10 (ww) All bars = 1 120583m

collected by centrifugation and freeze-dried before weighingThe dissolution was calculated from the following

Dissolution () = [(119860 minus 119861)119860

] times 100 (1)

where 119860 and 119861 are the weights of the starting and remainingfilms respectively

24 In Vitro Drug-Release Test An in vitro drug-releasetest was performed in 1mM PBS buffer (pH 74) at 37∘Cunder shaking The drug-loaded blend films (sim10mg) wereimmersed in 2mL of buffer At the desired time 1mL ofdrug solution was collected after centrifugation at 5000 rpmfor 5min The 1mL of fresh buffer was then replaced Thedrug release was determined by UV-vis spectrophotometry

at 120582max = 360 nm and compared to a standard curve of drugsolution Cumulative drug release was calculated in terms ofthe ratio of the cumulativemass of the released drug at a giventime against the initial drug loading in the film sample Invitro drug release tests were run in triplicate (119899 = 3)

3 Results and Discussion

31 FTIR of Blend Films FTIR spectra were used to deter-mine the chemical functional groups and molecular inter-actions between SF and alginate as shown in Figure 2 TheFTIR spectrum of the alginate film in Figure 2(a) showstwo distinctive absorption bands at around 1600 cmminus1 and1418 cmminus1 relative to both asymmetric and symmetric C=Ostretching absorptions of the carboxylic acid salts [14] Theabsorption band at 1000ndash1200 cmminus1 is attributed to the


(a) (b)

(c) (d)

(e) (f)Figure 4 SEM micrographs of cross-sections of drug-loaded blend films with SFalginate blend ratios of (a) 01 (b) 11 (c) 21 (d) 41 (e)81 and (f) 10 (ww) All bars = 10120583m

characteristic saccharide absorptions of polysaccharides [1516]The FTIR spectrum of the SF film in Figure 2(f) exhibitedabsorption bands at 1641 cmminus1 (amide I) 1551 cmminus1 (amideII) and 1244 cmminus1 (amide III) which are assigned to thepredominantly random coil form [17 18] The characteristicabsorption bands of both SF and alginate characters werefound in the FTIR spectra of all the blend films As wouldbe expected the band intensities of the alginatersquos distinc-tive absorptions (C=O symmetric stretching and saccharidebands) significantly decreased as the SFalginate blend ratioincreased as shown in Figures 2(b)ndash2(e)The band intensitiesof SF amide III seem similar to those of the 81 41 and 21(ww) SFalginate blend films This is due to the fact that SFis dominant in these blend films However the band intensityof SF amide III significantly decreased as the SFalginateblend ratio decreased to 11 (ww) as shown in Figure 2(b)

The band intensities of SF and alginate depended on the blendratio In addition the amide III bands of the SF componentshifted to a higher wavenumber after blending with alginatesuggesting interactions between the SF and alginate in theblend films These interactions may be the hydrogen bondsbetween the carbonyl groups of SF and hydroxyl groups ofalginate

32 Morphology and Transparency of Blend Films Figures3 and 4 show SEM micrographs of the film surface andcross-section respectively Film thicknesses observed fromFigure 4 were in the range of 40ndash60120583m It can be seen thatboth film surfaces and cross-sections of the SF alginate andtheir blend films were homogeneous For the blend filmsphase separation was not observed in all of the blend ratiosThis is due to the fact that both the SF and alginate are


108141211101SFalginate blend ratio (ww)

100

80

60

40

20

0

T660

()

Figure 5 T660

of drug-loaded blend films with different SFalginateblend ratios


100

80

60

40

20

0

Diss

olut

ion

()

Figure 6 Dissolution of drug-loaded blend films with differentSFalginate blend ratios

hydrophilic polymers and are miscible in aqueous mediabefore film casting

The SF and blend films were highly transparent whereasthe alginate film was slightly opaque Film transparencieswere compared from their T

660values A higher T

660

value indicates higher film transparency Figure 5 shows theT660

of the SF alginate and their blend films The T660

values of the SF and alginate films were 91 and 75respectively that is the SF film showed higher transparencythan that of the alginate film The film transparency of theblend films slightly decreased as the SFalginate blend ratiodecreased The film transparency results supported the factthat the blend films consisted of different SFalginate blendratios as according to the FTIR results

33 Dissolution of Blend Films Figure 6 shows the dissolu-tion behaviour in distilled water of SF alginate and theirblend films The dissolutions of SF and alginate films were13 and 84 respectively The low dissolution of the SF filmmay be due to the SF containing strong hydrogen bondsThe dissolution of the blend films was lower than that ofthe alginate film and decreased as the SFalginate blend ratioincreased This result indicates that the dissolution of theblend films can be controlled with the SFalginate blend ratio

34 Drug Release of Blend Films Figure 7 shows the in vitrodrug release profiles of the film samples in phosphate buffer

Release time (h)2520151050

Dru

g re

leas

e (

)

120

100

80

60

40

20

0

Figure 7 In vitro drug release profiles of blend films withSFalginate blend ratios of (◼) 01 (⧫) 11 (998771) 21 (◻) 41 (loz) 81and (998779) 10 (ww)

solution (pH = 74) at 37∘C for 24 h In the case of the alginatefilm (SFalginate ratio = 01) around 95 of the loaded drugwas released within 3 h due to the fast dissolution of thealginate film matrix The SF film (SFalginate ratio = 10)showed the lowest drug release which might be due to thelowest dissolution of the SF filmmatrix For all the SFalginateblend films a sustained drug release can be observed ForSFalginate blend ratios of 01 11 21 41 81 and 10 (ww)the drug release levels at 24 h were 95 90 85 8271 and 64 respectively This result revealed that thedrug release steadily decreased as the SFalginate blend ratioincreased The lower dissolution of SF provided a decreaseddrug release level of the blend films as previously described

4 Conclusions

In this research the drug-loaded SFalginate blend films wereprepared by the simple solvent evaporation method Thedrug SF and alginate were blended in an aqueous mediumbefore film casting SEM images reveal that the drug-loadedblend films for all SFalginate blend ratios are homogeneousThe transparency and dissolution of the blend films stronglydepend on SFalginate blend ratio The drug release profilescan be adjusted by varying the SFalginate blend ratio TheseSFalginate blend films are potential as controlled-releasedelivery media for water-soluble drugs

Acknowledgments

The authors gratefully acknowledge Mahasarakham Uni-versity for financial support The Center of Excellence forInnovation in Chemistry (PERCH-CIC) Office of theHigherEducation Commission Ministry of Education Thailand isalso acknowledged

References

[1] V Kumar S K Prajapati G C Soni M Singh and N KumarldquoSustained release matrix type drug delivery system a reviewrdquoWorld Journal of Pharmacy and Pharmaceutical Sciences vol 1pp 934ndash960 2012


[2] GH Altman F Diaz C Jakuba et al ldquoSilk-based biomaterialsrdquoBiomaterials vol 24 no 3 pp 401ndash416 2003

[3] L Meinel R Fajardo S Hofmann et al ldquoSilk implants for thehealing of critical size bone defectsrdquoBone vol 37 no 5 pp 688ndash698 2005

[4] A S Lammel XHu S-H ParkD L Kaplan andT R ScheibelldquoControlling silk fibroin particle features for drug deliveryrdquoBiomaterials vol 31 no 16 pp 4583ndash4591 2010

[5] E M Pritchard C Szybala D Boison and D L Kaplan ldquoSilkfibroin encapsulated powder reservoirs for sustained release ofadenosinerdquo Journal of Controlled Release vol 144 no 2 pp 159ndash167 2010

[6] K Y Lee andD JMooney ldquoAlginate properties and biomedicalapplicationsrdquo Progress in Polymer Science vol 37 no 1 pp 106ndash126 2012

[7] H Wu C Liao Q Jiao Z Wang W Cheng and Y Wan ldquoFab-rication of core-shell microspheres using alginate and chitosan-polycaprolactone for controlled release of vascular endothelialgrowth factorrdquo Reactive Functional Polymers vol 72 pp 427ndash437 2012

[8] A Shilpa S S Agrawal and A R Ray ldquoControlled delivery ofdrugs from alginate matrixrdquo Journal of Macromolecular ScienceC vol 43 no 2 pp 187ndash221 2003

[9] J K Oh D I Lee and J M Park ldquoBiopolymer-basedmicrogelsnanogels for drug delivery applicationsrdquo Progress inPolymer Science vol 34 no 12 pp 1261ndash1282 2009

[10] C A Garcıa-Gonzalez M Alnaief and I Smirnova ldquoPolysa-ccharide-based aerogelsmdashpromising biodegradable carriers fordrug delivery systemsrdquo Carbohydrate Polymers vol 86 no 4pp 1425ndash1438 2011

[11] S P Vyas V Sihorkar and V Mishra ldquoControlled and targeteddrug delivery strategies towards intraperiodontal pocket dis-easesrdquo Journal of Clinical Pharmacy and Therapeutics vol 25no 1 pp 21ndash42 2000

[12] J Zhou C Cao X Ma L Hu L Chen and C Wang ldquoIn vitroand in vivo degradation behavior of aqueous-derived electro-spun silk fibroin scaffoldsrdquo Polymer Degradation and Stabilityvol 95 no 9 pp 1679ndash1685 2010

[13] Y Baimark N Niamsa N Morakot J Threeprom and Y Sri-suwan ldquoPreparation and morphology study of biodegrad-able chitosanmethoxy poly(ethylene glycol)-b-poly(120576-capro-lactone) nanocomposite filmsrdquo International Journal of PolymerAnalysis and Characterization vol 12 no 6 pp 457ndash467 2007

[14] A Joshi R Keerthiprasad R D Jayant and R SrivastavaldquoNano-in-micro alginate based hybrid particlesrdquo CarbohydratePolymers vol 81 no 4 pp 790ndash798 2010

[15] R C Mundargi N B Shelke A P Rokhade S A Patil andT M Aminabhavi ldquoFormulation and in-vitro evaluation ofnovel starch-based tableted microspheres for controlled releaseof ampicillinrdquo Carbohydrate Polymers vol 71 no 1 pp 42ndash532008

[16] A Roy J Bajpai and A K Bajpai ldquoDynamics of controlledrelease of chlorpyrifos from swelling and eroding biopolymericmicrospheres of calcium alginate and starchrdquo CarbohydratePolymers vol 76 no 2 pp 222ndash231 2009

[17] Y Srisuwan P Srihanam and Y Baimark ldquoPreparation of silkfibroin microspheres and its application to protein adsorptionrdquoJournal of Macromolecular Science A vol 46 no 5 pp 521ndash5252009

[18] Y Hu Q Zhang R You L Wang and M Li ldquoThe relationshipbetween secondary structure and biodegradation behavior

of silk fibroin scaffoldsrdquo Advances in Materials Science andEngineering vol 2012 Article ID 185905 5 pages 2012

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Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research



MetallurgyJournal of


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MaterialsJournal of


Nano

materials


Journal ofNanomaterials


O

O

O

O

O

O

NH

NH

NH

NH

NH

NH

CH3CH3

OH

n

(a)

O

OO

O

OH

HOH

HOCO2Na

CO2Na

(b)

OOO

NHHCH3CH3

OH

OHOH HO

HOH3C

NH2 middot HCl

(c)

Figure 1 Chemical structures of (a) silk fibroin (b) alginate and (c) tetracycline hydrochloride

method The influence of SFalginate blend ratio on filmcharacteristics and drug release behaviour was determinedTetracycline hydrochloride was chosen as an antimicrobialmodel drug due to its good water solubility SF alginateand drug were blended in an aqueous medium before filmcasting Tetracycline hydrochloride has been shown to beclinically effective in the treatment of periodontal infection[11] The chemical structures of SF alginate and tetracyclinehydrochloride are illustrated in Figure 1

2 Materials and Methods

21 Materials Silk fibroin (SF) aqueous solution was pre-pared as follows Briefly cocoons of B mori gifted from theSilk Innovation Centre MahasarakhamUniversityThailandwere degummed by boiling twice in 05 (wv) Na

2CO3

solution at 95∘C for 1 h followed by rinsing thoroughlywith distilled water to remove sericin before drying at roomtemperature [12] Degummed SF fibres were dissolved inthe ternary solvent system CaCl

2-ethanol-water (molar ratio

= 1 2 8) by stirring at 85∘C for 2 h The resultant SFsolution was then dialysed in a dialysis tube (molecularweight cutoff 6000ndash8000Da) for 3 days in distilled waterThe distilled water was changed every day The SF solutionwas filtered before adjusting to 1 (wv) with distilled waterSodium alginate ((C

6H7O6Na)119899 pharmaceutical grade) was

purchased from Carlo Erba The intrinsic viscosity of thesodium alginate measured in 01M NaCl water solution at25∘C using an Ubbelohde viscometer was 850mLg Tetracy-cline hydrochloride (C

22H24N2O8sdot HCl 99) was used as

a water-soluble model drug and purchased from Sigma The1 (wv) alginate solution was prepared using distilled wateras the solvent

22 Preparation of Drug-Loaded Blend Films SFalginateblend films containing the model drug were prepared bythe solvent evaporation method Appropriate volumes of1 (wv) SF and 1 (wv) alginate solutions were blendedtogether by magnetic stirring for 30min The total volumeof the blend solution was kept constant at 20mL The modeldrug (2mg) was completely dissolved in the blend solution

600800100012001400160018002000

1247

1247

1248

12461244

T(

)

Wavenumber (cmminus1)

(a)

(b)

(c)

(d)

(e)

(f)

Figure 2 FTIR spectra of drug-loaded blend films with SFalginateblend ratios of (a) 01 (b) 11 (c) 21 (d) 41 (e) 81 and (f) 10 (ww)

before film casting on polystyrene dishes SFalginate blendratios of 81 41 21 and 11 (ww) were investigated Plain SFand alginate filmswere also prepared for comparisonThe (SF+ alginate)drug ratio was kept constant at 1001 (ww) Theblend solution was dried at 40∘C for 48 h The obtained filmswere kept in a desiccator before property characterisation anddrug release testing

23 Characterisation of Drug-Loaded Blend Films Chemicalfunctional groups of the blend films were analysed by Fouriertransform infrared (FTIR) spectroscopy using a Perkin-Elmer Spectrum GX FTIR spectrophotometer A resolutionof 4 cmminus1 and 32 scans were employed The morphologyof the blend films was determined by scanning electronmicroscopy (SEM) using a JEOL JSM-6460LV SEM Theblend film samples were coated with gold to enhance thesurface conductivity before the scan Film transparency wasmeasured from the percentage of transmittance at 660 nm(T660

) [13] by UV-vis spectrophotometry using a Perkin-Elmer Lambda 25 UV-vis spectrophotometer Dissolutionof the films (sim10mg) was tested in 2mL of distilled waterat 37∘C for 24 h under shaking The remaining film was


(a) (b)

(c) (d)




] times 100 (1)







(a) (b)

(c) (d)







100

80

60

40

20

0

T660

()

Figure 5 T660



100

80

60

40

20

0

Diss

olut

ion

()





660







Dru

g re

leas

e (

)

120

100

80

60

40

20

0



4 Conclusions


Acknowledgments


References




























CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




(a) (b)

(c) (d)




] times 100 (1)







(a) (b)

(c) (d)







100

80

60

40

20

0

T660

()

Figure 5 T660



100

80

60

40

20

0

Diss

olut

ion

()





660







Dru

g re

leas

e (

)

120

100

80

60

40

20

0



4 Conclusions


Acknowledgments


References




























CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




(a) (b)

(c) (d)







100

80

60

40

20

0

T660

()

Figure 5 T660



100

80

60

40

20

0

Diss

olut

ion

()





660







Dru

g re

leas

e (

)

120

100

80

60

40

20

0



4 Conclusions


Acknowledgments


References




























CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials





100

80

60

40

20

0

T660

()

Figure 5 T660



100

80

60

40

20

0

Diss

olut

ion

()





660







Dru

g re

leas

e (

)

120

100

80

60

40

20

0



4 Conclusions


Acknowledgments


References




























CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials





























CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials



Research Article Preparation of Biodegradable Silk...

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