Tailored hyaluronic acid hydrogels through hydrophilic prepolymer cross-linkers

Despite its enormous biological importance, a lack of mechanical stability and fast degradability often hampers more intense application of hyaluronic acid (HA) for biomedical applications. We present a method to prepare hyaluronic acid based hydrogels with tailored stability, degradability and porosity by cross-linking with functional 18 kDa six arm star shaped poly(ethylene oxide-stat-propylene oxide) (sP(EO-stat-PO)) prepoylmers in aqueous solutions. In the case of NCO groups at the distal ends of the arms, cross-linking occurs through reaction with OH groups of the HA resulting in urethane bridges between star molecules and HA. In parallel, slow hydrolysis of isocyanates to amines that subsequently rapidly aminolyze other isocyanate groups and lead to urea bridges between prepolymers occurs as a side reaction. Overall, this process leads to cross-linking within 5 to 15 min depending on the molar ratios of NCO-sP(EO-stat-PO) to HA. A chemically orthogonal way of cross-linking can be achieved with acrylate functional prepolymers and thiolated HA where cross-linking exclusively results from Michael-type addition of the thiol to the acrylate groups. This process also results in gelation times of 5 to 15 min. The two mechanisms are compared and the resulting gels are analyzed regarding chemical composition, equilibrium water content, degree of sol-content, porosity, mechanical stability and resistance towards enzymatic degradation by hyaluronidase.