In situ forming hydrogels by tandem thermal gelling and Michael addition reaction between thermosensitive triblock copolymers and thiolated hyaluronan

This study reports on the synthesis, characterization and peptide release behavior of an in situ physically and chemically cross-linking hydrogel. (Meth)acrylate bearing ABA-triblock copolymers consisting of a poly(ethylene glycol) (PEG) middle block, flanked by thermosensitive blocks of random N-isopropylacrylamide (pNIPAm)/N-(2-hydroxypropyl) methacrylamide dilactate (pHPMAmlac2) and exhibiting lower critical solution temperature behavior in aqueous solution were synthesized. Upon body temperature induced physical gelation, these polymers were cured by Michael type addition reaction with thiolated hyaluronic acid (HA-SH) to yield injectable in situ gelling, biodegradable but structurally stable and biocompatible hydrogels. These stable and elastic networks were prepared by mixing (meth)acrylated ABA-triblock copolymers and thiolated hyaluronic acid at a ratio thiol/(meth)acrylate groups of 1/1. The simultaneous physical and chemical gelation kinetics, investigated by rheological measurements, demonstrated that the physical networks were progressively stabilized as the Michael addition reaction between (meth)acrylate and thiol groups proceeded and that acrylated thermosensitive polymers had a higher reactivity with thiol groups, as compared to methacrylate analogues, resulting in a faster gel formation. The networks, characterized by a remarkable initial structural stability, degraded in time at physiological conditions. The degradability is ensured by the presence of hydrolytically sensitive ester bonds in the cross-links, as well as in the lactate side chains and between PEG and thermosensitive blocks. Methacrylated polymer gels loaded with a model peptide (bradykinin), showed a diffusion controlled release of this peptide, tailorable by the polymer concentration. This tandem system, displaying in situ physical and chemical gelation has a high potential for biomedical applications, such as delivery of peptide and protein biopharmaceuticals. © 2010 American Chemical Society.