Nitric Oxide-Releasing Hyaluronic Acid as an Antibacterial\nAgent for Wound Therapy

Abstract

Taking\nadvantage of their respective wound-healing roles in physiology,\nthe dual activity of hyaluronic acid (HA) and nitric oxide (NO) was\ncombined to create a single-agent wound therapeutic. Carboxylic acid\ngroups of HA (6 and 90 kDa) were chemically modified with a series\nof alkylamines via carbodiimide chemistry to provide secondary amines\nfor subsequent <i>N</i>-diazeniumdiolate NO donor formation.\nThe resulting NO-releasing HA derivatives stored 0.3–0.6 μmol\nNO mg^–1 and displayed diverse release kinetics (5–75\nmin NO-release half-lives) under physiological conditions. The 6 kDa\nHA with terminal primary amines and intermediate release kinetics\nexhibited broad-spectrum bactericidal activity against common wound\npathogens, including planktonic methicillin-resistant Staphylococcus aureus as well as planktonic and biofilm-based\nmultidrug-resistant Pseudomonas aeruginosa. The treatment of infected murine wounds with NO-releasing HA facilitated\nmore rapid wound closure and decreased the quantity of the P. aeruginosa genetic material in the remaining wound\ntissue. Hyaluronidase readily degraded the HA derivatives, indicating\nthat NO donor modification did not prohibit endogenous biodegradation\npathways.