TY - JOUR
T1 - Thermogelling and chemoselectively cross-linked hydrogels with controlled mechanical properties and degradation behavior
AU - Boere, Kristel W. M.
AU - Van Den Dikkenberg, Joep
AU - Gao, Yuan
AU - Visser, Jetze
AU - Hennink, Wim E.
AU - Vermonden, Tina
PY - 2015/9/14
Y1 - 2015/9/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84941712118&partnerID=8YFLogxK
U2 - 10.1021/acs.biomac.5b00802
DO - 10.1021/acs.biomac.5b00802
M3 - Article
C2 - 26237583
AN - SCOPUS:84941712118
SN - 1525-7797
VL - 16
SP - 2840
EP - 2851
JO - Biomacromolecules
JF - Biomacromolecules
IS - 9
ER -