Abstract
Wound repair process is initiated immediately after injury by releasing a variety of growth factors. It is known that basic fibroblast growth factor (bFGF) promoted fibroblasts migration, proliferation and effective helped skin wound healing. However, the use of bFGF is limited by two drawbacks, which are its short half-life and easily degraded by enzymes. In this study, we fabricate fucoidan-modified chitosan/alginate (F-CS/Alg) scaffold to protect and control release bFGF to regulate fibroblast migration activity. The experimental results show that oversulfated fucoidan was successfully prepared, with 43% sulfation degree. The 43% sulfated fucoidan (F43) exhibited effective DPPH scavenging activity, good biocompatibility and protected bFGF from trypsin degradation. The F43-CS/Alg scaffold could maintain bFGF activity and control its release, reaching 2.52 ng/mL for 10 h releasing. In vitro cell studies demonstrate that F43-CS/Alg scaffold showed a considerable elevation in cell viability and promoted L929 fibroblasts migration efficiently. In brief, bFGF loaded F43-CS/Alg scaffold effectively accelerating fibroblast migration for wound repair and could have a great potential in clinical applications in the future.
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References
Werner S, Grose R (2003) Regulation of wound healing by growth factors and cytokines. Physiol Rev 83(3):835–870. https://doi.org/10.1152/physrev.00031.2002
Martin P (1997) Wound healing--aiming for perfect skin regeneration. Science 276(5309):75–81
Freedberg IM, Tomic-Canic M, Komine M, Blumenberg M (2001) Keratins and the keratinocyte activation cycle. J Invest Dermatol 116(5):633–640. https://doi.org/10.1046/j.0022-202x.2001.doc.x
Hantash BM, Zhao L, Knowles JA, Lorenz HP (2008) Adult and fetal wound healing. Front Biosci 13:51–61
Raja SK, Garcia MS, Isseroff RR (2007) Wound re-epithelialization: modulating keratinocyte migration in wound healing. Front Biosci 12:2849–2868
N. Scott Adzick MD (1997) The molecular and cellular biology of wound repair, 2nd edn. Academic Press, London
Grayson LS, Hansbrough JF, Zapata-Sirvent RL, Dore CA, Morgan JL, Nicolson MA (1993) Quantitation of cytokine levels in skin graft donor site wound fluid. Burns 19(5):401–405
Edmonds M, Bates M, Doxford M, Gough A, Foster A (2000) New treatments in ulcer healing and wound infection. Diabetes Metab Res Rev 16(Suppl 1):S51–S54
Harris IR, Yee KC, Walters CE, Cunliffe WJ, Kearney JN, Wood EJ, Ingham E (1995) Cytokine and protease levels in healing and non-healing chronic venous leg ulcers. Exp Dermatol 4(6):342–349
Shankaran V, Brooks M, Mostow E (2013) Advanced therapies for chronic wounds: NPWT, engineered skin, growth factors, extracellular matrices. Dermatol Ther 26(3):215–221. https://doi.org/10.1111/dth.12050
DiGabriele AD, Lax I, Chen DI, Svahn CM, Jaye M, Schlessinger J, Hendrickson WA (1998) Structure of a heparin-linked biologically active dimer of fibroblast growth factor. Nature 393(6687):812–817. https://doi.org/10.1038/31741
Sperinde GV, Nugent MA (1998) Heparan sulfate proteoglycans control intracellular processing of bFGF in vascular smooth muscle cells. Biochemistry 37(38):13153–13164. https://doi.org/10.1021/bi980600z
Pieper JS, Hafmans T, van Wachem PB, van Luyn MJ, Brouwer LA, Veerkamp JH, van Kuppevelt TH (2002) Loading of collagen-heparan sulfate matrices with bFGF promotes angiogenesis and tissue generation in rats. J Biomed Mater Res 62(2):185–194. https://doi.org/10.1002/jbm.10267
Losi P, Briganti E, Errico C, Lisella A, Sanguinetti E, Chiellini F, Soldani G (2013) Fibrin-based scaffold incorporating VEGF- and bFGF-loaded nanoparticles stimulates wound healing in diabetic mice. Acta Biomater 9(8):7814–7821. https://doi.org/10.1016/j.actbio.2013.04.019
Xie JL, Bian HN, Qi SH, Chen HD, Li HD, Xu YB, Li TZ, Liu XS, Liang HZ, Xin BR, Huan Y (2008) Basic fibroblast growth factor (bFGF) alleviates the scar of the rabbit ear model in wound healing. Wound Repair Regen 16(4):576–581. https://doi.org/10.1111/j.1524-475X.2008.00405.x
Ayvazyan A, Morimoto N, Kanda N, Takemoto S, Kawai K, Sakamoto Y, Taira T, Suzuki S (2011) Collagen-gelatin scaffold impregnated with bFGF accelerates palatal wound healing of palatal mucosa in dogs. J Surg Res 171(2):e247–e257. https://doi.org/10.1016/j.jss.2011.06.059
Huang YC, Yang YT (2016) Effect of basic fibroblast growth factor released from chitosan-fucoidan nanoparticles on neurite extension. J Tissue Eng Regen Med 10(5):418–427. https://doi.org/10.1002/term.1752
Nimni ME (1997) Polypeptide growth factors: targeted delivery systems. Biomaterials 18(18):1201–1225
Freeman I, Kedem A, Cohen S (2008) The effect of sulfation of alginate hydrogels on the specific binding and controlled release of heparin-binding proteins. Biomaterials 29(22):3260–3268. https://doi.org/10.1016/j.biomaterials.2008.04.025
Schultz V, Suflita M, Liu X, Zhang X, Yu Y, Li L, Green DE, Xu Y, Zhang F, DeAngelis PL, Liu J, Linhardt RJ (2017) Heparan sulfate domains required for fibroblast growth factor 1 and 2 signaling through fibroblast growth factor receptor 1c. J Biol Chem 292(6):2495–2509. https://doi.org/10.1074/jbc.M116.761585
Wenk E, Murphy AR, Kaplan DL, Meinel L, Merkle HP, Uebersax L (2010) The use of sulfonated silk fibroin derivatives to control binding, delivery and potency of FGF-2 in tissue regeneration. Biomaterials 31(6):1403–1413. https://doi.org/10.1016/j.biomaterials.2009.11.006
Casu B, Lindahl U (2001) Structure and biological interactions of heparin and heparan sulfate. Adv Carbohydr Chem Biochem 57:159–206
Li YC, Ho IH, Ku CC, Zhong YQ, Hu YP, Chen ZG, Chen CY, Lin WC, Zulueta MM, Hung SC, Lin MG, Wang CC, Hsiao CD (2014) Interactions that influence the binding of synthetic heparan sulfate based disaccharides to fibroblast growth factor-2. ACS Chem Biol 9(8):1712–1717. https://doi.org/10.1021/cb500298q
Nagumo T, Iizima-Mizui N, Fujihara M, Himeno J, Komiyama K, Umezawa I (1988) Separation of sulfated, fucose-containing polysaccharides from the brown seaweed Sargassum Kjellmanianum and their heterogeneity and antitumor activity. Kitasato Arch Exp Med 61(1):59–67
Chizhov AO, Dell A, Morris HR, Haslam SM, McDowell RA, Shashkov AS, Nifant'ev NE, Khatuntseva EA, Usov AI (1999) A study of fucoidan from the brown seaweed Chorda Filum. Carbohydr Res 320(1–2):108–119
Huang YC, Liu TJ (2012) Mobilization of mesenchymal stem cells by stromal cell-derived factor-1 released from chitosan/tripolyphosphate/fucoidan nanoparticles. Acta Biomater 8(3):1048–1056. https://doi.org/10.1016/j.actbio.2011.12.009
Chen M, Song K, Rao N, Huang M, Huang Z, Cao Y (2011) Roles of exogenously regulated bFGF expression in angiogenesis and bone regeneration in rat calvarial defects. Int J Mol Med 27(4):545–553. https://doi.org/10.3892/ijmm.2011.619
Kim BS, Park JY, Kang HJ, Kim HJ, Lee J (2014) Fucoidan/FGF-2 induces angiogenesis through JNK- and p38-mediated activation of AKT/MMP-2 signalling. Biochem Biophys Res Commun 450(4):1333–1338. https://doi.org/10.1016/j.bbrc.2014.06.137
Park JH, Choi SH, Park SJ, Lee YJ, Park JH, Song PH, Cho CM, Ku SK, Song CH (2017) Promoting wound healing using low molecular weight fucoidan in a full-thickness dermal excision rat model. Mar Drugs 15(4). https://doi.org/10.3390/md15040112
Dai M, Zheng X, Xu X, Kong X, Li X, Guo G, Luo F, Zhao X, Wei YQ, Qian Z (2009, 2009) Chitosan-alginate sponge: preparation and application in curcumin delivery for dermal wound healing in rat. J Biomed Biotechnol:595126. https://doi.org/10.1155/2009/595126
Lai HL, Abu'Khalil A, Craig DQ (2003) The preparation and characterisation of drug-loaded alginate and chitosan sponges. Int J Pharm 251(1–2):175–181
Wang J, Liu L, Zhang Q, Zhang Z, Qi H, Li P (2009) Synthesized oversulphated, acetylated and benzoylated derivatives of fucoidan extracted from Laminaria Japonica and their potential antioxidant activity in vitro. Food Chem 114(4):1285–1290. https://doi.org/10.1016/j.foodchem.2008.10.082
Terho TT, Hartiala K (1971) Method for determination of the sulfate content of glycosaminoglycans. Anal Biochem 41(2):471–476. https://doi.org/10.1016/0003-2697(71)90167-9
Kusaykin M, Bakunina I, Sova V, Ermakova S, Kuznetsova T, Besednova N, Zaporozhets T, Zvyagintseva T (2008) Structure, biological activity, and enzymatic transformation of fucoidans from the brown seaweeds. Biotechnol J 3(7):904–915. https://doi.org/10.1002/biot.200700054
Li B, Lu F, Wei X, Zhao R (2008) Fucoidan: structure and bioactivity. Molecules 13(8):1671–1695
Ale MT, Mikkelsen JD, Meyer AS (2011) Important determinants for fucoidan bioactivity: a critical review of structure-function relations and extraction methods for fucose-containing sulfated polysaccharides from brown seaweeds. Mar Drugs 9(10):2106–2130. https://doi.org/10.3390/md9102106
Matthaus B (2002) Antioxidant activity of extracts obtained from residues of different oilseeds. J Agric Food Chem 50(12):3444–3452
Huang YC, Li RY (2014) Preparation and characterization of antioxidant nanoparticles composed of chitosan and fucoidan for antibiotics delivery. Mar Drugs 12(8):4379–4398. https://doi.org/10.3390/md12084379
Palanisamy S, Vinosha M, Marudhupandi T, Rajasekar P, Prabhu NM (2017) Isolation of fucoidan from Sargassum Polycystum Brown algae: structural characterization, in vitro antioxidant and anticancer activity. Int J Biol Macromol 102:405–412. https://doi.org/10.1016/j.ijbiomac.2017.03.182
Machova E, Bystricky S (2013) Antioxidant capacities of mannans and glucans are related to their susceptibility of free radical degradation. Int J Biol Macromol 61:308–311. https://doi.org/10.1016/j.ijbiomac.2013.07.016
Tsiapali E, Whaley S, Kalbfleisch J, Ensley HE, Browder IW, Williams DL (2001) Glucans exhibit weak antioxidant activity, but stimulate macrophage free radical activity. Free Radic Biol Med 30(4):393–402
Mak W, Hamid N, Liu T, Lu J, White WL (2013) Fucoidan from New Zealand Undaria pinnatifida: monthly variations and determination of antioxidant activities. Carbohydr Polym 95(1):606–614. https://doi.org/10.1016/j.carbpol.2013.02.047
Yan JK, Wang WQ, Ma HL, Wu JY (2012) Sulfation and enhanced antioxidant capacity of an exopolysaccharide produced by the medicinal fungus Cordyceps sinensis. Molecules 18(1):167–177. https://doi.org/10.3390/molecules18010167
Tabata Y, Hijikata S, Ikada Y (1994) Enhanced vascularization and tissue granulation by basic fibroblast growth factor impregnated in gelatin hydrogels. J Control Release 31(2):189–199. https://doi.org/10.1016/0168-3659(94)00035-2
Chabut D, Fischer AM, Colliec-Jouault S, Laurendeau I, Matou S, Le Bonniec B, Helley D (2003) Low molecular weight fucoidan and heparin enhance the basic fibroblast growth factor-induced tube formation of endothelial cells through heparan sulfate-dependent alpha6 overexpression. Mol Pharmacol 64(3):696–702. https://doi.org/10.1124/mol.64.3.696
Ud-Din S, Bayat A (2016) Non-invasive objective devices for monitoring the inflammatory, proliferative and remodelling phases of cutaneous wound healing and skin scarring. Exp Dermatol 25(8):579–585. https://doi.org/10.1111/exd.13027
Kong Y, Xu R, Darabi MA, Zhong W, Luo G, Xing MM, Wu J (2016) Fast and safe fabrication of a free-standing chitosan/alginate nanomembrane to promote stem cell delivery and wound healing. Int J Nanomedicine 11:2543–2555. https://doi.org/10.2147/IJN.S102861
Lin HY, Yeh CT (2010) Alginate-crosslinked chitosan scaffolds as pentoxifylline delivery carriers. J Mater Sci Mater Med 21(5):1611–1620. https://doi.org/10.1007/s10856-010-4028-2
Zhang JD, Cousens LS, Barr PJ, Sprang SR (1991) Three-dimensional structure of human basic fibroblast growth factor, a structural homolog of interleukin 1 beta. Proc Natl Acad Sci U S A 88(8):3446–3450
Kanazawa S, Fujiwara T, Matsuzaki S, Shingaki K, Taniguchi M, Miyata S, Tohyama M, Sakai Y, Yano K, Hosokawa K, Kubo T (2010) bFGF regulates PI3-kinase-Rac1-JNK pathway and promotes fibroblast migration in wound healing. PLoS One 5(8):e12228. https://doi.org/10.1371/journal.pone.0012228
Jastrebova N, Vanwildemeersch M, Lindahl U, Spillmann D (2010) Heparan sulfate domain organization and sulfation modulate FGF-induced cell signaling. J Biol Chem 285(35):26842–26851. https://doi.org/10.1074/jbc.M109.093542
Acknowledgments
The authors would like to thank the National Science Council of the Republic of China, Taiwan for financially supporting this research under Contract No. MOST 104-2221-E-017-MY3. Thanks to Ms. C.Y. Chien of Ministry of Science and Technology for the assistance in SEM experiments. Wallace Academic Editing is appreciated for editorial assistance.
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Zeng, HY., Huang, YC. Basic fibroblast growth factor released from fucoidan-modified chitosan/alginate scaffolds for promoting fibroblasts migration. J Polym Res 25, 83 (2018). https://doi.org/10.1007/s10965-018-1476-8
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DOI: https://doi.org/10.1007/s10965-018-1476-8