In Situ Cross-Linkable Hydrogel of Hyaluronan Produced via Copper-Free Click Chemistry

Abstract

Injectable hydrogels are useful in biomedical applications. We have synthesized hyaluronic acids chemically modified with azide groups (HA-A) and cyclooctyne groups (HA-C), respectively. Aqueous HA-A and HA-C solutions were mixed using a double-barreled syringe to form a hydrogel via strain-promoted [3 + 2] cycloaddition without any catalyst at physiological conditions. The hydrogel slowly degraded in PBS over 2 weeks, which was accelerated to 9 days by hyaluronidase, while it rapidly degraded in a cell culture media with fetal bovine serum within 4 days. Both HA-A and HA-C showed good biocompatibility with fibroblast cells in vitro. They were administered using the double-barreled syringe into mice subcutaneously and intraperitoneally. Residue of the hydrogel was cleared 21 days after subcutaneous administration, while it was cleared 7 days after intraperitoneal administration. This injectable HA hydrogel is expected to be useful for tissue engineering and drug delivery systems utilizing its orthogonality.

Cytocompatible in situ forming chitosan/hyaluronan hydrogels via a metal-free click chemistry for soft tissue engineering

“…The in vitro gelation, morphologies, equilib- 34 rium swelling, compressive modulus and degradation of the composite hydrogels were examined. The 35 potential of the metal-free hydrogel as a cell scaffold was demonstrated by encapsulation of human adi- 36 pose-derived stem cells (ASCs) within the gel matrix in vitro. Cell culture showed that this metal-free 37 hydrogel could support survival and proliferation of ASCs.…”

“…Presently, the SPPC has been employed to graft bioactive 86 peptides to PEG hydrogels for molecular patterning [33,34]. Also, 87 Takahashi et al chemically modified hyaluronan with azide and 88 cyclooctyne groups to prepare an in situ crosslinked hyaluronan 89 hydrogel [35]. Although the formed hydrogel was biocompatible, 90 it showed fast hydrolytic degradation that may prevent its use in 91 tissue engineering.…”

Recent Advances in 3D Tissue Models

“…Recently, the even more selective native chemical ligation which involves a thioesther and an N -terminal cysteine has been used for the formation of hydrogels [ 102 ]. Also copper free click-reactions are now being developed, which have a good substrate specifi city and improved reaction kinetics [ 103 ]. Alternatively, enzymatic reactions which are known to have a very high substrate specifi city have been used to form hydrogels [ 102 ] being highly compatible with the preservation of active growth factors.…”

Tunable and modular assembly of polypeptides and polypeptide-hybrid biomaterials

“…By chemical modi cation, polymers can be crosslinked to form large polymeric networks, 14,106,123,124 or conjugated with other functional molecules that e.g. provide self-assembling properties, 75,110,111 or increase their bioactivity.…”