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Nitric oxide-releasing injectable hydrogels with high antibacterial activity through in situ formation of peroxynitrite.

Abstract：

:Nitric oxide (NO) is an endogenous molecule with many critical biological functions that depend on its concentration. At high levels, NO provides broad-spectrum antibacterial effects through both its pathogen inhibition and killing abilities. However, its short half-life has been a great challenge to its clinical application in pharmaceutical forms. In this study, we incorporated the NO donor S-nitrosothiolated gelatin (GelSNO) into injectable gelatin-based hydrogels (GHs) to controllably release NO. Under catalysis by horseradish peroxidase, H2O2 oxidizes phenol moieties functionalized on gelatin to quickly form phenol-phenol crosslinks that encapsulate GelSNO. Through thermal, visible light, and oxidizing agent-driven mechanisms, NO is released from the GH/GelSNO hydrogels. By varying the GelSNO concentration, the release of NO was controllable in a wide range, 0.054-2.050 μmol/mL, for up to 14 days. In addition, NO release was fine-tunable as a function of H2O2 concentration. Notably, the in situ formation of peroxynitrite (ONOO-) that produces potent antibacterial effects originated from H2O2 residues and nitrous acid formed by NO and oxygen in aqueous solution. The Kirby-Bauer method indicated that there was an inhibition zone against both Escherichia coli and Staphylococcus aureus incubated with GH/GelSNO hydrogels. The AlarmaBlue assay showed that E. coli and S. aureus were completely killed at NO concentrations of 0.39 and 0.58 μmol/mL. Cytotoxicity tests of GH/GelSNO hydrogels on human dermal fibroblasts at the indicated bactericidal NO concentrations induced no cell toxicity. In summary, GH/GelSNO hydrogels may provide a new platform for topical delivery of NO in treating wound infections and for various biomedical applications. STATEMENT OF SIGNIFICANCE:NO is an effective antibacterial agent even in cases of antibiotic-resistant bacteria. Moreover, its intermediate, peroxynitrite, has been reported to have a much higher ability to kill bacteria. In this study, we utilized injectable GH/GelSNO hydrogels formed by HRP/H2O2 reaction not only to control NO release but also to generate peroxynitrite in situ from released NO and H2O2 residues. The GH/GelSNO hydrogels showed significant antibacterial ability on both gram-positive and negative bacteria, while no cytotoxicity was induced on human dermal fibroblasts. In addition, their tunable chemico-physical properties and controllable NO release within a wide range but narrow scale will make the hydrogels useful in various biomedical applications.

journal_name

Acta Biomater

journal_title

Acta biomaterialia

authors

Hoang Thi TT,Lee Y,Le Thi P,Park KD

doi

10.1016/j.actbio.2017.12.005

subject

Has Abstract

pub_date

2018-02-01 00:00:00

pages

66-78

eissn

1742-7061

issn

1878-7568

pii

S1742-7061(17)30761-4

journal_volume

pub_type

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Nitric oxide-releasing injectable hydrogels with high antibacterial activity through in situ formation of peroxynitrite.