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1 Biomaterials Research (2010) 14(2) : Biomaterials Research 7 The Korean Society for Biomaterials jm ù œw Fabrication of Chitosan Nanofiber Scaffold and Their Biomedical Applications wùáá«* Ha Na Park, Jung Bok Lee, and Il Keun Kwon* Š tš Department of Maxillofacial Biology and Institute of Oral Biology, School of Dentistry, Kyunghee University, Seoul , Korea (Received May 10, 2010/Acccepted May 12, 2010) Functional biomaterial research has been directed toward the development of improved scaffolds for tissue engineering. Many biodegradable and biocompatible polymers both synthetic polymers and natural polymers have been used to make scaffolds. Among the naturally derived polymers, chitosan which is deacetylated derivative of chitin, is widely used for biomedical applications such as tissue engineering scaffolds, drug delivery, and wound dressing due to their unique biological properties such as biocompatibility, biodegradability, anti-bacterial, and non-toxicity. In the recent years, electrospinning has been used to be a novel technique to fabricate nano/micro fibers. These nano/micro fibers have been applied in biomedical fields as tissue engineering scaffold because of their high surface area and porosity. In this reason, there has been a growing interest in electrospinning using chitosan in order to improve similarities to natural tissue. This article reviews the recent and relevant reports of the chitosan nanofibers fabricated by electrospinning and their biomedical applications. Key words: chitosan, electrospinning, nanofiber scaffold, tissue engineering lšh (Tissue engineering)f fdš l Œ f fš ilf f gš eš thšf f fdš llt(scaffold) Š Œ lš f. il gf ilšh h f,, gš f llt, ilf gš f fff Šd Š, j ti l hšš if eš fhf dlf i f Š f jd f. 1) f llt f r, l, Œ f Š, f Œ f ihf Š, llt hfš xv,, f f. 2) u h(electrospinning, ELSP)f fdš f lf l e Š ilf ECM i eš Œf l llt hfš f. h f 1882 Lord Rayleigh Š tf Š fh ff hhf gf Š f f, 1934 ff A. Formhals fš f. h f f} f lf l *sfhf: kwoni@khu.ac.kr ef hff Š, hf hf e e Š f e l hf d } eš df f Š f } ƒlf l ff, ilš llt fd f. 3-5) hf fdf d f lf Š Š, 10~50 kvf hf l fš 10~25 cmf h f l f ef hf f Š l df eœ~ lš, ef lf Œ~ fh, l l ff,,, l f h f i f, fš dff ihš eš Œ ~f hff Š. jm(chitosan) g e ~f Š lltf hf d f d eš, j g f d f t hš f poly (L-lactic acid) (PLLA), poly (LA-co-GA) (PLGA), poly (ε-caprolactone) (PCL), poly (L-lactic-coε-caprolactone) (PLCL) f Š f z, h, ~ f s f f f. j ~ 95

2 96 ŠÁfhÁf Figure 1. (a) ~ (b) ~ f ŒŠ i. (Poly-(1Á4)-2-amino-2-deoxy-β-D-glucose)f z f fl ~ (f d, vf, f f ig)f ~ Œ(deacetylation, DA)Š l t f, z z f fl f ff(figure 1). ~ f Œ h z z f h ef l, f - ƒ, d Š f ~ f f ƒf ih. ~ e f Š (Acid dissociation constant)f pka ~ Œf h, fœ f hš jœ fš h, Œf h 50% tšl f, h j Œ fd Š e pka f e. f f t ff d f dš~. f f t ff d f ff ghf Œ fdšf ff r fš lf Š f ~. ~ f jdš ƒf f d Š f dš h l hf., ef f, zf f ~ f ešh lf f Œ Š h h d f j zf ef t f } ~ f. 6) fš ƒf l ~ f Šhf g, Š, Še, t hšf dš 7) d Š, Š e hi ef fdf Š f, vx h, ˆ th, 8) r x 9,10) h t 11) Š il Šh fdf f ) jm ù ~ e ~ f dš thšf l f fdš ilšh fdf ff, hf Š e hf Š Šf fš f ) ~ f e Š f z unit f Šf fhff f, f f Šf fe f f f. f e d l ~ Š, ~ f f l pka 6.3 f primary amine groups fš Š f ph 6.0 fšf d. 20) 2004 Min f ~ f vz ŠjŠ (depolymerization)š, dš l ~ f 1,1,1,2,2,2- hexafluoro-2-propanol (HFIP) hf ƒ hfš. hf ~ ƒ 40% aq NaOH df f dš 60 o C 100 o C ~ ŒŠ Š ~ ƒ ~ f xœš, FT-IR WAXD Š ih f Œ ŒfŠf hf ~ ƒ hff f ŒfŠ. 21) Geng f ~ f ~ Œ h f, d dš ƒf df g h whš, SEMf Š ~ ef Œ~ ŒfŠ. ff Š ff ~ f fdš h Š e hfš. f ff ~ f wt.%f } } (bead) ŒŠ ef f Š f ŒfŠf, f f f ~ f wt.% df d Š d e hf f Š f ŒfŠ. ff, 106,000 g/mol f ff l ~ f fdš wt.%f f fš e ŒŠ f Šf, f ff ~ f Š lf e ŒŠl Š fe ~ f l f fš f hš f f Š. 17) Ohkawa f Š ~ f f df fdš h ŠŠ eš methanol, ethanol, 1,4-dioxane, dichloromethane (DCM) f Ž e d, N,Ndimethylformamide (DMF), dimethylsulfoxie (DMSO) f f d (aprotic solvent), Acetic acid, HCl f d f ŒŠ d fdšf, d j Trifluoroacetic acid (TFA) fdšf d ~ f l e ŒŠ Š. 22) ff ~ / TFAdf hš, ~ f 6wt.% fšf d e Š f Œ(Figure 2(a), (b)), chitosanf 7wt.% f, e dš Œf ŒfŠ(Figure 2(c), (d)). Š fš Œ~ l ~ e 8wt.% f Œ f ŒfŠ(Figure 2(e), (f)). Biomaterials Research 2010

a) jœs Šhf ~ e, b) 5 M NaOH fdš jœs Š f ~ e, c) 5 M Na 2 CO 3 fdš jœsš f ~ e.

3 ~ e lltf hf tšh fd 97 Figure 2. TFA d fdš ~ h. ~ f h ~ ef SEM fl: a) 5 wt.%, b) 6wt.%, c) 7wt.%, d) 7wt.% e) 8wt.% f) 8wt.%. Figure 3. TFA DCMf ŒŠ ed fdš hf Š hfš ~ ef SEM fl. ~ f 7 wt.% TFA/DCM (70/30 v/v%) ŒŠ ed f. a) jœs Šhf ~ e, b) 5 M NaOH fdš jœs Š f ~ e, c) 5 M Na 2 CO 3 fdš jœsš f ~ e. Ohkawa f TFA d dšf d, hf ~ f h fl f, tm, ~ f TFA f ŒŠ, f fš ~ ff Š Šf z h Š Šj, m, TFAf Š Žf ~ /TFA df h fhf fdš ff f Œ. 22) ~ f hš e hfš eš TFA DCMf dš f. Sangsanoh ftfa/ DCM(70:30)f d Š hfš ~ e ƒ (Figure 3(a)) h dš jœ hf ŠdŠf fl Vol. 14, No. 2

4 98 ŠÁfhÁf Figure 4. a) NaOH b) Na 2 CO 3 fš ~ f jœ h. Š, NaOH Na 2 CO 3 df fdš 3 jœ s Š. 19) 5M NaOH df sš ~ e ƒ tf ei elšl Šf(Figure 3(b)), Na 2 CO 3 df sš d, tf fiber i elš f df ŒfŠ vhf f Š ih f jœ flf flš. NaOH Na 2 CO 3 f Š ~ f jœ hf (Figure 4) ~. fš ~ f hf fdš e f g } h hh fš e l f ~ f f hf, h Š ~ e hfš eš ~ df h ihš f ŠdŠ. f x s Š Šf Š 24). ~ x s Š ~ f tff Š fš l ff Š, h Š hhš h l ~ df d fš. jm w ù chitosanf acetic acid f d dš ƒf e ŒŠ f. Šl f hi ~ ft hfš f hf, f ŠŠ eš PEO, PVA, PLA, silk fibroin, collagen f Š Œf sff ŒŠf fdš e hfš f. 25) ~ e hfš eš h i ŒŠf hš(table 1) ~. ~ e hfš eš g f d f PVA bone implant, f g f fšhf Š fd f. Xu f enzyme immobilizationf eš hš chitosan e PVAf ŒŠf fdš hfš. 26) ff chitosan PVAf ŒŠdf e NaOH s Š e f PVA h Š hš i l chitosan ef ŒŠ. ef PVAf h ff f TEMf Š ŒfŠ(Figure 5(b)). PVAf h fš Š ~ ef ff f enzyme loading, immobilized lipasef hg enzyme immobilizationf eš hš i hš fff Š. ~ PVA ŒŠŠ antibacterial activity l ~ e ƒ wound healing h dš. 27) ff quaternized ~ (QCS) PVA ŒŠŠ df hš Staphylococcus aureus Escherichia coli Š hšf l ƒ hfš. polyampholyte (N-carboxyethyl chitosan) fœl f }f(poly acrylamide) ŒŠŠ df h fš, f l fš dš ~ e hfš. 28) ~ e hfš eš f ~ (4-6 wt.%) PEO 2:1 1:1f e ŒŠŠ d e hfš. 29,30) PEO thšf if, 31) r h, 32) il g 33) f d f d f. Kriegel f ~ PEO 3:1f e ŒŠŠ f f d e hfš. 34) f Biomaterials Research 2010

~ e lltf hf tšh fd 99 Table 1. l ed ff ŒŠf fdš ~ ef hf Blended polymer Molecular weight DDA [%] Solvent Surfactant Ref. CS/PLLA-CL PLA 50 mol% 60 HFIP, TFA 57 CS/CL I CL-I 0.

5 ~ e lltf hf tšh fd 99 Table 1. l ed ff ŒŠf fdš ~ ef hf Blended polymer Molecular weight DDA [%] Solvent Surfactant Ref. CS/PLLA-CL PLA 50 mol% 60 HFIP, TFA 57 CS/CL I CL-I Da 85 HFIP, TFA 58 HFIP, TFA, MC 40 CS g/mol, PEO g/mol 82 AA 59 CS 190 kda, PEO 900 kda 85 AA, DMSO Triton PEO g/mol CS/PEO CS , , g/mol AA 63 PEO 600, 1500, 2300, 4000 kda, CS 654 kda 90 AA 29 CS 1400, 100 kda, PEO 900 kda 80, 70, 60 / 83 AA 35 α-cs/ PEO α-cs 1000 kda, PEO 900 kda 80 AA SDS, Brij 35, DTAB 61 CS/UHMWPEO UHMWPEO > Da 85 AA, DMSO 64 CS/PVA CS/PEO/PVA/ PAA/PAAm CS 1600 kda, PVA kda 82.5 AA 60 PEO g/mol CS Mw 82.5 AAc 66 CS 405, 40, 89 kda PAA 450 kda PEO 100 kda PAAm 10, kda, PVA kda CS/PAAm/AMPS/PVA CS g/mol 80 acrylic acid 28 PLGA/PVA-CS CS Da 90 THF, DMF, AA 62 CS/PET - 85 HFIP, TFA 67 *DDA : degree of deacetylation, SDS : Anionic sodium dodecyl sulfate, Brij 35 : nonionic, polyoxyethylene glycol (23) lauryl ether, DTAB : cationic dodecyltrimethylammoniumbromide CL : collagen, UHMWPEO : ultra high molecular weigh PEO (poly ethylene oxide) PVA : poly vinyl alcohol, PAA : poly acrylic acid, PAAm : poly acrylamide, CS : chitosan, AA : acetic acid, AAc : acrylic acid, DMSO : dimethyl sulfoxide, AMPS : 2-acryloylamido-2-methylpropanesulfonic acid, MC : Methylene chloride, PET : poly (ethylene terephthalate) Figure 5. ~ /PVA f fdš e. a) h jœs hf e b) 0.5 M NaOH sš f ~ e. (Œ : PVA h f pore). ŒŠd nonionic, ionic, cationic surfactant tš d, Š }f d e f f. h h f-d, f-f f h, h, g f df ƒf g jdš dff fdš, Œh Š hhh Œfdf i hš Šf Š. PEO fdš ~ e hfš d ~ f ef lš ef lf Š. 29,35) Bhattarai f ~ /PEO 9/1f e Š i~ g elš (chondrocyte) (osteoblast)f hrf g ellt hfš ilš(bone tissue engineering) fdš. 36) Vol. 14, No. 2

6 100 ŠÁfhÁf PVA PEO d PET (poly ethylene terpthalate), collagen, silk fibroin f Š f ŒŠŠ e hfš ff, u 37-43) derivated ~ ff ŒŠ df fdš h f. 27,44-47) jm (modification) mw w w» ~ f Š if side chainf ~Šf dš f f eš ƒf ff Š fš (biomedical engineering) d Š fdf f. lf Š ~ f l ƒf tl, ~ f thš, Š, Š, rxe, mucoadhesivity f Šh ƒ(biological properties)f elš f. ~ f f ff Š ŒŠh i f(figure 1(b)) etherification, esterification, cross-linking, graft copolymerization f f ff Š. 20) acetylation, quaternization, aldehyde ketone f f, alkylation, grafting, chelation of metals f Œ Šh ff Š ff, Š r Š(cross-link)f Š diisocyanate, Resimene, 48) N,N-disuccinimidyl suberate, 49) epichlorohydrin, 50) genipin, 51) hexamethylene 1,6-di (aminocarboxysulfonate) f f ŠŠ 52) ff, l f O-acetylation, gratfing, eff H-bonding f Š ff Š f. il Šh hdf eš ~ f l(modification)f Š f ƒh f(specific recognition)f. Š f ~ f Šf j fš ƒ h, f, f f, DDS (drug delivery system), gene therapy, ilš. Li f D-, L- fucose, lectin ƒhš Šf f f f Š f ~ f Š Š Š. 53) PLGA-~ /PVAf Š ƒ f embryo skin fibroblast ~d hšš, 63) ~, PEO, Triton X-100 f ŒŠŠ d(~ /PEO = 9/1,w/w), Š i elš f f rf ll~. 54,55) Jiang f hf fdš ibuprofenf ~g f PLGA/PEG-g-chitosanŒŠ ƒ hfš. ff PEGg-chitosan fdš PLGA ƒ t f v f jf, PEG-g-chitosanf 2j f ibuprofen Šf elš f Šf u h 56) f fdš hfš e ƒ hhš h Š hff h. ~ f thš, Š, Š f dš Šh ƒ Š, f dš f df f Š ilšh hdf e h f f l Š f. Šl ff Œ Œf f ŒŠ f Š h dfš Š ff, f fdš h ~ e hfš f. u f fdš f f. e h hfš f j Šf hf h, l l ff, df jf f df f, h, h, g Š d jdš dff fdš, ƒ f f f l ff d ŒŠ f ff, f ff f lf } e ŒŠ hf fdš ~ f fdf hf Š eš f ŒŠ e, d Š h i f hhš g f g jdš. hhš if ŒŠ h, rx f fšhf hd df hf ~ f ƒ f fd f f. uf ll(b ) es ( )f le fš fhf f. šx 1. I. O. Smith, X. H. Liu, Smith LA, P. X. Ma, Nanostructured polymer scaffolds for tissue engineering and regenerative medicine, Wiley Interdiscip Rev Nanomed Nanobiotechnol., 1, (2009). 2. B. S. Kim, D. J. Mooney, Development of biocompatible synthetic extracellular matrices for tissue engineering. TIBTECH, 16, 224 (1998). 3. R. Casarano, R. Bentini, V. B. Bueno, T. Iacovella, F. B. F. Monteiro, F. A. S. Iha, A. Campa, D. F. S. Petri, M. Jaffe, L. H. Catalani, Enhanced fibroblast adhesion and proliferation on electrospun fibers obtained from poly (isosorbide succinate-b-l-lactide) block copolymers, Polymer., 50, (2009). 4. S. Madduri, M. PapaloÁzos, B. Gander, Trophically and topographically functionalized silk fibroin nerve conduits for guided peripheral nerve regeneration,á Biomaterials., 31, (2010). 5. H. R. Jung, D. H. Ju, W. J. Lee, X. Zhang, R. Kotek, Electrospun hydrophilic fumed silica/polyacrylonitrile nanofiber-based composite electrolyte membranes, Electrochimica Acta., 54, (2009). 6. E. Guibal, Heterogeneous catalysis on chitosan-based materials : a review, Prog. Polym. Sci., 30, (2005). 7. K. MNVR, A review of chitin and chitosan applications, React Funct Polym., 46, 1-27 (2000). 8. S. W. Ko, Y. W. Cho, Chitin (or Chitosan) Blends and Their Applications, Polymer Science and Technology., 8, (1997). 9. S. Hirano, C. Itakura, H. Seino, Y. Akiyama, I. Nonaka, N. Biomaterials Research 2010

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Biomaterials Research (2007) 11(3) : 96-101 Biomaterials Research 7 The Korean Society for Biomaterials w jm /v -w qk p w œ p Porous Structure and Characteristic of Protein Release on Biodegradable Chitosan/Fibroin-Hydroxyapatite