Synthesis Of Cysteine-hyaluronic Acid Conjugate And Its Applications For Injectable And In-situ Formed Hydrogels

Hyaluronic acid is a biocompatible and biodegradable linear polysaccharide polymer, widely distributed in various parts of the body, plays an important physiological role in the human body. In our study, we described a novel, efficient and mild approach to functionalize the hyaluronic acid via its hydroxyl groups and obtained a cysteine-hyaluronic acid conjugate through a stable ether bond linkage.For the first time, we utilized tetrabutylammonium hydroxide (TBAH) as a co-solvent and catalyst for the modification of the polysaccharide, leading to significantly improve the solubility of hyaluronic acid and functionalization level in aqueous solution. This discovery overcame the solubility problem of hyaluronic acid in aqueous solution and opened a new avenue to the functionalization of polysaccharides. Additionally, the cysteine-functionalized hyaluronic acid conjugate with thiol group can be further modified to prepare a variety of functionalized hyaluronic acid conjugates for biomedical applicationsIn this research, two kinds of covalently cross linked hydrogels were formed using synthesized Cys-HA conjugates through Michael addition and Native chemical ligation (NCL), respectively. The Theological results of these hydrogel formation and the formed hydrogels showed that the hydrogels formed within10min and the formed gels were highly visoelastic and covalently cross-linked.The cysteine-hyaluronic acid conjugate could be used to prepare in situ-formed, injectable and covalently cross linked hydrogels, to extend the residence time of hyaluronic acid, to apply to the body in a minimally invasive way without surgery to fill any shape defects, to be mixed with drugs for controlled drug delivery, to be mixed with cells for cell transplantation, tissue engineering and repairing.