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Correction published on 17 March 2014, see J. Funct. Biomater. 2014, 5(1), 27-28.

Open AccessArticle
J. Funct. Biomater. 2013, 4(3), 162-177; doi:10.3390/jfb4030162

Epoxy Cross-Linked Collagen and Collagen-Laminin Peptide Hydrogels as Corneal Substitutes

Integrative Regenerative Medicine Center, Department of Physics, Chemistry and Biology, Linköping University, SE 581 83 Linköping, Sweden
Swedish Nanoscience Center, Karolinska Institute, 171 77 Stockholm , Sweden
Integrative Regenerative Medicine Center & Department of Clinical and Experimental Medicine, Cell Biology Building, Linköping University, SE 581 85 Linköping, Sweden
Ottawa Hospital Research Institute, University of Ottawa Eye Institute, 501 Smyth Rd. Ottawa, ON K1H 8L6, Canada
Center for Biomimetic Sensor Science, Nanyang Technological University, Singapore
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Received: 7 April 2013 / Revised: 3 July 2013 / Accepted: 6 August 2013 / Published: 28 August 2013
(This article belongs to the Special Issue Advances in Ophthalmic Biomaterials)
View Full-Text   |   Download PDF [574 KB, 2 September 2013; original version 28 August 2013]   |  


A bi-functional epoxy-based cross-linker, 1,4-Butanediol diglycidyl ether (BDDGE), was investigated in the fabrication of collagen based corneal substitutes. Two synthetic strategies were explored in the preparation of the cross-linked collagen scaffolds. The lysine residues of Type 1 porcine collagen were directly cross-linked using l,4-Butanediol diglycidyl ether (BDDGE) under basic conditions at pH 11. Alternatively, under conventional methodology, using both BDDGE and 1-Ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS) as cross-linkers, hydrogels were fabricated under acidic conditions. In this latter strategy, Cu(BF4)2·XH2O was used to catalyze the formation of secondary amine bonds. To date, we have demonstrated that both methods of chemical cross-linking improved the elasticity and tensile strength of the collagen implants. Differential scanning calorimetry and biocompatibility studies indicate comparable, and in some cases, enhanced properties compared to that of the EDC/NHS controls. In vitro studies showed that human corneal epithelial cells and neuronal progenitor cell lines proliferated on these hydrogels. In addition, improvement of cell proliferation on the surfaces of the materials was observed when neurite promoting laminin epitope, IKVAV, and adhesion peptide, YIGSR, were incorporated. However, the elasticity decreased with peptide incorporation and will require further optimization. Nevertheless, we have shown that epoxy cross-linkers should be further explored in the fabrication of collagen-based hydrogels, as alternatives to or in conjunction with carbodiimide cross-linkers.
Keywords: biomimetic materials; cross-linking; collagen; cornea; tissue engineering biomimetic materials; cross-linking; collagen; cornea; tissue engineering
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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    A correction was published on 17 March 2014 (

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MDPI and ACS Style

Koh, L.B.; Islam, M.M.; Mitra, D.; Noel, C.W.; Merrett, K.; Odorcic, S.; Fagerholm, P.; Jackson, W.B.; Liedberg, B.; Phopase, J.; Griffith, M. Epoxy Cross-Linked Collagen and Collagen-Laminin Peptide Hydrogels as Corneal Substitutes. J. Funct. Biomater. 2013, 4, 162-177.

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