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 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 × 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 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.

Polydopamine/poly(sulfobetaine methacrylate) Co-deposition coatings triggered by CuSO4/H2O2 on implants for improved surface hemocompatibility and antibacterial activity

“…Based on the above description, we know that the construction of a material with both antibacterial and anticoagulant is of great significance in clinical applications. Although the emerging applications of nitric oxide release have been extensively studied in overcoming anti-thrombotic and anti-bacterial medical devices, there are still problems such as short lifetime and poor blood compatibility [ [34] , [35] , [36] , [37] , [38] , [39] ]. In contrast, the use of copper ions and zwitterionic polymers to modify implant materials has unparalleled advantages.…”

Nitric oxide and viral infection: Recent developments in antiviral therapies and platforms

“…3 b). Studies such as these have been mostly relegated to in vitro models of viral infection [59 , 64 , 70 , [119] , [120] , [121] , [122] ; however, SNAP and various other RSNO derivatives have also shown promising antibacterial, anti-thrombotic, and non-cytotoxic results in other in vivo models of blood circulation and urinary tract infection [12 , 14 , 123] . These applications incorporated NO donors such as SNAP or S -nitrosoglutathione (GSNO) into medical grade polymers, polysaccharides, and various macromolecular scaffolds via covalent modifications (see Fig.…”

“…As a result, researchers at the turn of the century began to use antiviral NO-based therapeutics through three different strategies: 1) compounds that modulate endogenous production of NO, 2) gaseous NO (gNO) inhalation, and 3) direct NO donor compounds. More recently, NO-releasing and catalytic NO-generating surfaces have been developed for blood-contacting and other indwelling medical devices to combat bacterial infection and prevent blood thrombus formation that are often associated with urinary/vascular catheters, mechanical ventilators, and ex vivo blood circulation in dialysis and extracorporeal membrane oxygenation (ECMO) [12] , [13] , [14] .…”

S‐Nitrosoglutathione‐Based Nitric Oxide‐Releasing Nanofibers Exhibit Dual Antimicrobial and Antithrombotic Activity for Biomedical Applications

“…These results are consistent with previous studies utilizing GSNO-incorporated materials to reduce the viability of bacteria with different biomaterials. [61][62][63] It should be noted that while NO reduces the viability of pathogens attached to the surface, it does not reduce the number of bacteria adhered to the surface. However, NO donors have also been combined with other agents such as liquid-infused surfaces, hydrophilic top coats, and zwitterionic surfaces to amplify resistance of bacterial contamination of different polymers.…”