Injectable polysaccharide hydrogels as localized nitric oxide delivery formulations

Abstract

A series of injectable polysaccharide hydrogels are prepared with oxidized dextran and diethylenetriamine-modified carboxymethylcellulose (CMC) or hyaluronic acid (HA). Rheological evaluation reveals that CMC-based hydrogels achieve storage moduli >1 kPa when prepared from 5 wt% solutions, while storage moduli >100 Pa are achievable from solutions with concentrations as low as 2 wt%. HA-based hydrogels demonstrate smaller storage moduli but have swelling ratios more than four-fold that of CMC systems at equal concentrations. The incorporation of N-diazeniumdiolate nitric oxide (NO) donors into the hydrogels results in reduced hydrogel storage moduli as a function of NO donor concentration. The impact of the hydrogel architecture on NO-release kinetics proves dependent on the identity of the NO donor. Hydrogel degradation over 14 d indicates that HA-based hydrogels degrade more rapidly than CMC hydrogels and that the addition of NO to the hydrogels increases the rate at which they degrade. In vitro cytotoxicity of hydrogel extracts is minimal, with toxicity observed only at high NO-donor concentrations for select cell lines. The diverse properties, versatility, and nontoxic characteristics of these injectable hydrogels should facilitate local delivery of nitric oxide for a range of biomedical applications.