Abstract
Hydrogels are extensively studied as carrier matrices for the controlled release of bioactive molecules. The aim of this study was to design gelatin-based hydrogels crosslinked with genipin and study the impact of crosslinking temperature (5, 15 or 25°C) on gel strength, microstructure, cytocompatibility, swelling and drug release. Gels crosslinked at 25°C exhibited the highest Flory–Rehner crosslink density, lowest swelling ratio and the slowest release of indomethacin (Idn, model anti-inflammatory drug). Diffusional exponents (n) indicated non-Fickian swelling kinetics while drug transport was anomalous. Hydrogel biocompatibility, in vitro cell viability, cell cycle experiments with AH-927 and HaCaT cell lines indicated normal cell proliferation without any effect on cell cycle. Overall, these results substantiated the use of genipin-crosslinked hydrogels as a viable carrier matrix for drug release applications.
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References
Pal K, Banthia AK, Majumdar DK. Preparation and characterization of polyvinyl alcohol–gelatin hydrogel membranes for biomedical applications. AAPS Pharm Sci Technol. 2007;8:E142–6.
Madhumathi K, Shalumon KT, Divya Rani VV, Tamura H, Furuike T, Selvamurugan N, Nair SV, Jayakumar R. Wet chemical synthesis of chitosan hydrogel–hydroxyapatite composite membranes for tissue engineering applications. Int J Biol Macromol. 2009;45:12–5.
Kim UJ, Park J, Li C, Jin HJ, Valluzzi R, Kaplan DL. Structure and properties of silk hydrogels. Biomacromolecules. 2004;5:786–92.
Berger J, Reist M, Mayer JM, Felt O, Peppas NA, Gurny R. Structure and interactions in covalently and ionically crosslinked chitosan hydrogels for biomedical applications. Eur J Pharm Biopharm. 2004;57:19–34.
Bigi A, Cojazzi G, Panzavolta S, Rubini K, Roveri N. Mechanical and thermal properties of gelatin films at different degrees of glutaraldehyde crosslinking. Biomaterials. 2001;22:763–8.
Nickerson MT, Farnworth R, Wagar E, Hodge SM, Rousseau D, Paulson AT. Some physical and microstructural properties of genipin-crosslinked gelatin–maltodextrin hydrogels. Int J Biol Macromol. 2006;38:40–4.
Jin J, Song M, Hourston DJ. Novel chitosan-based films cross-linked by genipin with improved physical properties. Biomacromolecules. 2004;5:162–8.
Liang HC, Chang WH, Lin KJ, Sung HW. Genipin-crosslinked gelatin microspheres as a drug carrier for intramuscular administration: in vitro and in vivo studies. J Biomed Mater Res A. 2003;65A:271–82.
Muzzarelli RAA. Genipin-crosslinked chitosan hydrogels as biomedical and pharmaceutical aids. Carbohydr Polym. 2009;77:1–9.
Gupta P, Vermani K, Garg S. Hydrogels from controlled release to pH-responsive drug delivery. Drug Discov Today. 2002;7:569–79.
Chiono V, Pulieri E, Vozzi G, Ciardelli G, Ahluwalia A, Giusti P. Genipin-crosslinked chitosan/gelatin blends for biomedical applications. J Mater Sci Mater Med. 2008;19:889–98.
Young S, Wong M, Tabata Y, Mikos AG. Gelatin as a delivery vehicle for the controlled release of bioactive molecules. J Control Release. 2005;109:256–74.
Yao CH, Liu BS, Chang CJ, Hsu SH, Chen YS. Preparation of networks of gelatin and genipin as degradable biomaterials. Mater Chem Phys. 2004;83:204–8.
Briones V, Aguilera VJM, Brown C. Effect of surface topography on color and gloss of chocolate samples. J Food Eng. 2006;77:776–83.
Silva SS, Motta A, Rodrigues MT, Pinheiro AFM, Gomes ME, Mano JF, Reis RL, Migliaresi C. Novel genipin cross-linked chitosan-silk fibroin sponges for cartilage engineering strategies. Biomacromolecules. 2008;9:2764–74.
Yuan Y, Chesnutt BM, Utturkar G, Haggard WO, Yang Y, Ong JL, Bumgardner JD. The effect of cross-linking of chitosan microspheres with genipin on protein release. Carbohydr Polym. 2007;68:561–7.
Mi FL. Synthesis and characterization of a novel chitosan–gelatin bioconjugate with fluorescence emission. Biomacromolecules. 2005;6:975–87.
Chen H, Ouyang W, Lawuyi B, Prakash S. Genipin cross-linked alginate-chitosan microcapsules: membrane characterization and optimization of cross-linking reaction. Biomacromolecules. 2006;7:2091–8.
Sungthongjeen S, Sriamornsak P, Puttipipatkhachorn S. Design and evaluation of floating multilayer coated tablets based on gas formation. Eur J Pharm Biopharm. 2008;69:255–63.
Brannon-Peppas L, Peppas NA. Equilibrium swelling behaviour of dilute ionic hydrogels in electrolytic solutions. J Control Release. 1991;16:319–30.
Sen M, Yakar A, Güven O. Determination of average molecular weight between cross-links (Mc) from swelling behaviors of diprotic acid-containing hydrogels. Polymer. 1999;40:2969–74.
Sen M, Güven O. Prediction of the swelling behaviour of amphiphilic hydrogels and the determination of average molecular weight between crosslinks. Comput Theor Polym Sci. 2000;11:475–82.
Peppas NA, Bures P, Leobandung W, Ichikawa H. Hydrogels in pharmaceutical formulations. Eur J Pharm Biopharm. 2000;50:27–46.
Ofner CM III, Bubnis WA. Chemical and swelling evaluations of amino group crosslinking in gelatin and modified gelatin matrices. Pharm Res. 1996;13:1821–7.
Rajvaidya S, Bajpai R, Bajpai AK. Effect of gamma irradiation on the interpenetrating networks of gelatin and polyacrylonitrile: aspect of crosslinking using microhardness and crosslink density measurements. J Appl Polym Sci. 2006;101:2581–6.
Çaykara T, Kantoğlu Ö. Thermal behavior and network structure of poly(N-vinyl-2-pyrrolidone-crotonic acid) hydrogels prepared by radiation-induced polymerization. Polym Adv Technol. 2004;15:134–9.
Ritger P, Peppas N. A simple equation for description of solute release II. Fickian and anomalous release from swellable devices. J Control Release. 1987;5:37–42.
Ritger P, Peppas N. A simple equation for description of solute release I. Fickian and non-Fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J Control Release. 1987;5:23–36.
Costa P, Lobo JMS. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001;13:123–33.
Lara MG, Bentley MVLB, Collett JH. In vitro drug release mechanism and drug loading studies of cubic phase gels. Int J Pharm. 2005;293:241–50.
Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Method. 1983;65:55–63.
Touyama R, Takeda Y, Inoue K, Kawamura I, Yatsuzuka M, Ikumoto T, Shingu T, Yokoi T, Inouye H. Studies on the blue pigments produced from genipin and methylamine I. Structures of the brownish-red pigments, intermediates leading to the blue pigments. Chem Pharm Bull. 1994;42:668–73.
Sell SA, Francis MP, Garg K, McClure MJ, Simpson DG, Bowlin GL. Cross-linking methods of electrospun fibrinogen scaffolds for tissue engineering applications. Biomed Mater. 2008;3:045001–11.
Sung HW, Huang RN, Huan LLH, Tsai CC, Chiu CT. Feasibility study of a natural crosslinking reagent for biological tissue fixation. J Biomed Mater Res. 1998;42:560–7.
Chen HM, Wei OY, Bisi LY, Martoni C, Prakash S. Reaction of chitosan with genipin and its fluorogenic attributes for potential microcapsule membrane characterization. J Biomed Mater Res A. 2005;75:917–27.
Chatterjee S, Bohidar HB. Effect of cationic size on gelation temperature and properties of gelatin hydrogels. Int J Biol Macromol. 2005;35:81–8.
Liu H, Ge Z, Wang Y, Toh SL, Sutthikhum V, Goh JCH. Modification of sericin-free silk fibers for ligament tissue engineering application. J Biomed Mater Res B Appl Biomater. 2007;82:129–38.
Yung CW, Wu LQ, Tullman JA, Payne GF, Bentley WE, Barbari TA. Transglutaminase crosslinked gelatin as a tissue engineering scaffold. J Biomed Mater Res A. 2007;83:1039–46.
Wang XH, Li DP, Wang WJ, Feng QL, Cui FZ, Xu YX, Song XH, van der Werf M. Crosslinked collagen/chitosan matrix for artificial livers. Biomaterials. 2003;24:3213–20.
Martínez-Ruvalcaba A, Sánchez-Díaz JC, Becerra F, Cruz-Barba LE, González-Álvarez A. Swelling characterization and drug delivery kinetics of polyacrylamide-co-itaconic acid/chitosan hydrogels. Express Polym Lett. 2009;3:25–32.
Lee PI. Kinetics of drug release from hydrogel matrices. J Control Release. 1985;2:277–88.
Zhang Y, Chu CC. The effect of molecular weight of biodegradable hydrogel components on indomethacin release from dextran and poly(DL)lactic acid based hydrogels. J Bioact Compat Polym. 2002;17:65–85.
Morimoto K, Nagayasu A, Fukanoki S, Morisaka K, Hyon SH, Ikada Y. Evaluation of poly(vinyl alcohol) hydrogel as a sustained-release vehicle for rectal administration. Pharm Res. 1989;6:338–44.
Kallinteri P, Antimisiaris SG. Solubility of drugs in the presence of gelatin: effect of drug lipophilicity and degree of ionization. Int J Pharm. 2001;221:219–26.
Ng KW, Hutmacher DW, Schantz MD, Ng CS, Too HP, Lim TC, Phan TT, Teoh SH. Evaluation of ultra-thin poly(caprolactone) films for tissue-engineered skin. Tissue Eng. 2001;7:441–5.
Dash BC, Mandal BB, Kundu SC. Silk gland sericin protein membranes: fabrication and characterization for potential biotechnological applications. J Biotechnol. 2009;144:321–9.
Kenchington AW, Ward AG. The titration curve of gelatin. Biochem J. 1954;58:202–7.
Acknowledgments
Funding from the Natural Science and Engineering Research Council of Canada (NSERC) is acknowledged. Author Thakur acknowledges Sutapa Mukherjee, Joydip Kundu, Pallab Dutta, Shubhadeep Banerjee and Sanat Dey of Indian Institute of Technology Kharagpur and Muhammad Ali Naqvi, Renuka Gupta, Roomana Aafaqi of Ryerson University for their technical assistance. He is also thankful to Dr. Mahitosh Mandal for access to cell culture facilities.
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Thakur, G., Mitra, A., Rousseau, D. et al. Crosslinking of gelatin-based drug carriers by genipin induces changes in drug kinetic profiles in vitro. J Mater Sci: Mater Med 22, 115–123 (2011). https://doi.org/10.1007/s10856-010-4185-3
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DOI: https://doi.org/10.1007/s10856-010-4185-3