title: Synthesis of enzyme-degradable, peptide-cross-linked dextran hydrogels.
abstract: Hydrogels derived from synthetic polymers have been previously engineered to degrade under the activity of matrix metalloproteinases (MMPs). It is believed that these systems can act as extracellular-matrix (ECM) equivalents mimicking the degradation and remodeling of the ECM through the activity of cell-secreted enzymes. In this study, MMP-sensitive hydrogels derived from dextran were developed. In order to avoid the incorporation of hydrolyzable esters often introduced in dextran modification strategies, the polysaccharide was modified with p-maleimidophenyl isocyanate (PMPI) thereby introducing maleimide functionalities in the backbone and resulting in dextran derivatized with p-maleimidophenyl isocyanate (Dex-PMPI). This strategy was favored to separate out the effects of random hydrolysis and enzymatic digestion in the degradation of the dextran hydrogels. A peptide cross-linker, derived from collagen and susceptible to gelatinase A (MMP-2) digestion, was synthesized with bifunctional cysteine termini and used to cross-link the Dex-PMPI. These hydrogels were found to be hydrolytically stable for more than 200 days yet degraded either within 30 h when exposed to bacterial collagenase or within 16 days when exposed to human MMP-2, demonstrating enzymatic-mediated digestion of the peptide cross-links. Further modification of the cross-linked hydrogels with laminin-derived peptides enhanced cell adhesion and survival, demonstrating the potential of these materials for use in tissue engineering applications.
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario M5S 3E5.
authors.forename: Stéphane G
authors.initials: SG
authors.lastname: Lévesque
authors.forename: Molly S
authors.initials: MS
authors.lastname: Shoichet
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003485:Cyanates / Q000737:chemistry; D003911:Dextrans / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D020100:Hydrogels / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006868:Hydrolysis; D008301:Maleimides / Q000737:chemistry; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry*; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010455:Peptides / Q000737:chemistry*
chemical_list: D003485:Cyanates; D003911:Dextrans; D020100:Hydrogels; D008301:Maleimides; D010455:Peptides; C082056:4-maleimidophenyl isocyanate; D020778:Matrix Metalloproteinase 2