Thermoresponsive Injectable Hydrogels Cross-Linked
by Native Chemical Ligation
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Abstract
Temperature-induced
physical gelation was combined with native chemical ligation (NCL)
as a chemical cross-linking mechanism to yield rapid network formation
and mechanically strong hydrogels. To this end, a novel monomer <i>N</i>-(2-hydroxypropyl)methacrylamide-cysteine (HPMA-Cys) was
synthesized that copolymerizes with <i>N</i>-isopropylacrylamide
(NIPAAm) to yield thermoresponsive polymers decorated with cysteine
functionalities. Triblock copolymers consisting of a poly(ethylene
glycol) (PEG) middle block flanked by random blocks of NIPAAm and
HPMA-Cys were successfully synthesized and characterized. Additionally,
thioester cross-linkers were synthesized based on PEG and hyaluronic
acid, respectively. Upon mixing the thermoresponsive polymer with
PEG or hyaluronic acid cross-linker, cysteine and thioester functionalities
react under physiological conditions to generate a native peptide
bond. An immediate physical network was formed after elevation of
the temperature to 37 °C due to the self-assembly of the pNIPAAm
chains. This network was stabilized in time by covalent cross-linking
due to NCL reaction between thioester and cysteine functionalities,
resulting in hydrogels with up to 10 times higher storage moduli than
without chemical cross-links. Finally, a collagen mimicking peptide
sequence was successfully ligated to this hydrogel using the same
reaction mechanism, showing the potential of this hydrogel for tissue
engineering applications