Hyaluronan based biomaterial for antiadhesion and thermosensitive hyaluronan lanthanide complexes

Hyaluronan (HA) is a naturally-occurring polysaccharide abundant in the extracellular matrix (ECM). The unique physicochemical properties and biological functions of HA make it suitable for applications in drug delivery, anti-adhesion and tissue engineering. Studying new HA properties and developing novel HA based biomaterials will contribute to medical and pharmaceutical applications. HA-lanthanide complexes were discovered to exhibit thermosensitive properties. Addition of trivalent lanthanide salts to solutions of HA resulted in an unexpected reverse-temperature phase transition (RTPT), i.e., the complexes were soluble when cooled but precipitated when warmed. A unique lower critical solution transition temperature (LCST) was observed for each lanthanide in the order (increasing LCST) Eu3+ < Nd3+< Ce3+ < Gd3+ < La3+ < Tb3+ < Dy3+ < Yb3+ < Lu3+ for high molecular weight HA. Moreover, the LCST values increased as the molecular weight of the HA decreased from 1730 kDa to 190 kDa. The precipitation-dissolution behavior was fully reversible in a cyclical fashion; a lag in redissolution was observed as the temperature was lowered, and longer incubation times at each temperature minimized this lag. The RTPT behavior could be ablated by titration with 8 kDa HA to produce complexes soluble at ambient temperature. This is the first description of RTPT behavior in a biologically important glycosaminoglycan (GAG). A novel HA material was developed with significant anti-adhesion efficacy. Mitomycin C (MMC) was modified with acryloyl chloride and covalently conjugated to a thiolated HA derivative. The HA-thiopropanoyl hydrazide-MMC derivative (HA-DTPH-MMC) was cross-linked with poly(ethylene glycol)-diacrylate (PEGDA) and evaporated into a film. MMC was released from the film by hydrolysis. The films with different MMC loadings had similar releasing kinetics and released MMC was proportional to the MMC loading. To evaluate the efficacy in reducing postoperative adhesion formation, the film was applied in a rat uterine horn adhesion model. The extent and severity of adhesions was greatly reduced in a dose-dependent way by HA-DTPH-MMC-PEGDA barriers. In vivo biocompatibility studies showed that MMC coupling did not evoke a severe peritoneal fluid leukocyte response through day 3 after film insertion. This film was demonstrated to be an attractive biomaterial for anti-adhesion usage.