title: Thermogelling and Chemoselectively Cross-Linked Hydrogels with Controlled Mechanical Properties and Degradation Behavior.
abstract: Chemoselectively cross-linked hydrogels have recently gained increasing attention for the development of novel, injectable biomaterials given their limited side reactions. In this study, we compared the properties of hydrogels obtained by native chemical ligation (NCL) and its recently described variation termed oxo-ester-mediated native chemical ligation (OMNCL) in combination with temperature-induced physical gelation. Triblock copolymers consisting of cysteine functionalities, thermoresponsive N-isopropylacrylamide (NIPAAm) units and degradable moieties were mixed with functionalized poly(ethylene glycol) (PEG) cross-linkers. Thioester or N-hydroxysuccinimide (NHS) functionalities attached to PEG reacted with cysteine residues of the triblock copolymers via either an NCL or OMNCL pathway. The combined physical and chemical cross-linking resulted in rapid network formation and mechanically strong hydrogels. Stiffness of the hydrogels was highest for thermogels that were covalently linked via OMNCL. Specifically, the storage modulus after 4 h reached a value of 26 kPa, which was over a 100 times higher than hydrogels formed by solely thermal physical interactions. Endothelial cells showed high cell viability of 98 ± 2% in the presence of OMNCL cross-linked hydrogels after 16 h of incubation, in contrast to a low cell viability (13 ± 7%) for hydrogels obtained by NCL cross-linking. Lysozyme was loaded in the gels and after 2 days more than 90% was released, indicating that the cross-linking reaction was indeed chemoselective as the protein was not covalently grafted to the hydrogel network. Moreover, the degradation rates of these hydrogels under physiological conditions could be tailored from 12 days up to 6 months by incorporation of a monomer containing a hydrolyzable lactone ring in the thermosensitive triblock copolymer. These results demonstrate a high tunability of mechanical properties and degradation rates of these in situ forming hydrogels that could be used for a variety of biomedical applications.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University , P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: Kristel W M
authors.initials: KW
authors.lastname: Boere
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University , P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: van den Dikkenberg
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University , P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Orthopaedics, University Medical Center Utrecht , P.O. Box 85500, 3508 GA Utrecht, The Netherlands.
authors.forename: Jetze
authors.initials: J
authors.lastname: Visser
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University , P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University , P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: Tina
authors.initials: T
authors.lastname: Vermonden
mesh_terms: D000178:Acrylamides / Q000737:chemistry*; D000818:Animals; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000737:chemistry*; D020100:Hydrogels / Q000737:chemistry*; D008422:Materials Testing; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D000178:Acrylamides; D003432:Cross-Linking Reagents; D020100:Hydrogels; D011092:Polyethylene Glycols; C067295:N-isopropylacrylamide; C000595209:polyethylene glycol 1000