New strategy for chemical modification of hyaluronic acid: Preparation of functionalized derivatives and their use in the formation of novel biocompatible hydrogels

TLDR

Biodegradable materials for spatially and temporally controlled delivery of bioactive agents such as drugs, growth factors, or cytokines are key to facilitating tissue repair. The authors developed a versatile method for chemical crosslinking high‑molecular‑weight hyaluronic acid under physiological conditions to yield biocompatible and biodegradable hydrogels. They introduced functional groups onto hyaluronic acid via active‑ester chemistry, generating amino or aldehyde derivatives that were crosslinked with bifunctional crosslinkers or mixtures to form hydrogels, which were then evaluated for biodegradability, biocompatibility, and ectopic bone formation. Size analysis confirmed that chemical modification preserved hyaluronic acid integrity, and the resulting hydrogels supported cell infiltration and chondro‑osseous differentiation with BMP‑2, promoted cartilage formation when combined with IGF‑1, and induced rapid bone replacement when combined with TGF‑β and BMP‑2. © 1999 John Wiley & Sons, Inc., J Biomed Mater Res 47:152–169.

Abstract

Biodegradable materials for spatially and temporally controlled delivery of bioactive agents such as drugs, growth factors, or cytokines are key to facilitating tissue repair. We have developed a versatile method for chemical crosslinking high-molecular-weight hyaluronic acid under physiological conditions yielding biocompatible and biodegradable hydrogels. The method is based on the introduction of functional groups onto hyaluronic acid by formation of an active ester at the carboxylate of the glucuronic acid moiety and subsequent substitution with a side chain containing a nucleophilic group on one end and a (protected) functional group on the other. We have formed hyaluronic acid with amino or aldehyde functionality, and subsequently hydrogels with these hyaluronic acid derivatives and bifunctional crosslinkers or mixtures of the hyaluronic acid derivatives carrying different functionalities using active ester- or aldehyde-mediated reactions. Size analysis of the hyaluronic acid derivatives showed that the chemical modification did not lead to fragmentation of the polysaccharide. Hydrogels formed with hyaluronic acid derivatized to a varying degree and crosslinked with low- or high-molecular-weight crosslinkers were evaluated for biodegradability by digestion with hyaluronidase and for biocompatibility and ectopic bone formation by subcutaneous implantation in rats. Several hydrogel formulations showed excellent cell infiltration and chondro-osseous differentiation when loaded with bone morphogenetic protein-2 (BMP-2). Synergistic action of insulin-like growth factor-1 with BMP-2 promoted cartilage formation in this model, while addition of transforming growth factor-β and BMP-2 led to rapid replacement of the matrix by bone. © 1999 John Wiley & Sons, Inc. J Biomed Mater Res, 47, 152–169, 1999.