Catalyzed Nitric Oxide Release Via Cu Nanoparticles Leads to an Increase in Antimicrobial Effects and Hemocompatibility for Short Term Extracorporeal Circulation.

ABSTRACT

Devices used for extracorporeal circulation are met with two major medical concerns thrombosis and infection. A device that allows for anticoagulant-free circulation while reducing risk of infection has yet to be developed. We report the use of a copper nanoparticle (Cu NP) catalyst for the release of nitric oxide (NO) from the endogenous donor S-nitrosoglutathione (GSNO) in a coating applied to commercial Tygon S3™ E-3603 poly(vinyl chloride) tubing in order to reduce adhered bacterial viability and the occurrence thrombosis for the first time in an animal model. Cu GSNO coated material demonstrated a nitric oxide (NO) release flux ranging from an initial flux of 6.3 ± 0.9 ×10-10 mol cm-2 min-1 to 7.1 ± 0.4 ×10-10 mol cm-2 min-1 after 4 h of release, while GSNO loops without Cu NPs only ranged from an initial flux of 1.1 ± 0.2 ×10-10 mol cm-2 min-1 to 2.3 ± 0.2 ×10-10 mol cm-2 min-1 after 4 h of release, indicating that the addition of Cu NPs can increase NO flux up to five times in the same 4 h period. Additionally, a 3-log reduction in S. aureus and 1-log reduction in P. aeruginosa was observed in viable bacterial adhesion over a 24 h period compared to control loops. A Cell Counting Kit-8 (CCK-8) assay was used to validate no overall cytotoxicity towards 3T3 mouse fibroblasts. Finally, extracorporeal circuits were coated and exposed to 4 h of blood flow under an in vivo rabbit model. The Cu GSNO combination was successful in maintaining 89.3% of baseline platelet counts, while the control loops were able to maintain 67.6% of the baseline. These results suggest that the combination of Cu NPs with GSNO increases hemocompatibility and antimicrobial properties of ECC loops without any cytotoxic effects towards mammalian cells.