Synthesis of enzyme-degradable, peptide-cross-linked dextran hydrogels.
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.
Lévesque
Stéphane G
SG
Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario M5S 3E5.
Shoichet
Molly S
MS
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*
D003485:Cyanates; D003911:Dextrans; D020100:Hydrogels; D008301:Maleimides; D010455:Peptides; C082056:4-maleimidophenyl isocyanate; D020778:Matrix Metalloproteinase 2