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

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 the 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 the adhered bacterial viability and the occurrence of thrombosis for the first time in an animal model. A Cu GSNO-coated material demonstrated a nitric oxide (NO) release flux ranging from an initial flux of 6.3 +/- 0.9 x 10(-10) mol cm(-2) min(-1) to 7.1 +/- 0.4 x 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 x 10(-10) mol cm(-2) min(-1) to 2.3 +/- 0.2 x 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 Staphylococcus aureus and 1-log reduction in Pseudomonas aeruginosa were 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 toward 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 toward mammalian cells.