Nitric Oxide-Generating Silicone As a Blood-Contacting Biomaterial

Abstract

Coagulation upon blood-contacting biomaterials remains a problem for short and long-term clinical applications. This study examined the ability of copper(II)-doped silicone surfaces to generate nitric oxide (NO) and locally inhibit coagulation. Silicone was doped with 3-micron copper (Cu(0)) particles yielding 3 to 10 weight percent (wt%) Cu in 70-μm thick Cu/Silicone polymeric matrix composites (Cu/Si PMCs). At 3, 5, 8 and 10 wt% Cu doping, the surface expression of Cu was 12.1 ± 2.8%, 19.7 ± 5.4%, 29.0 ± 3.8%, and 33.8 ± 6.5% respectively. After oxidizing Cu(0) to Cu(II) by spontaneous corrosion, NO flux, JNO (mol*cm−2*min−1), as measured by chemiluminescence, increased with surface Cu expression according to the relationship JNO =(1.63 %SACu −0.81) ×10−11, R2 = 0.98 where %SACu is the percentage of surface occupied by Cu. NO flux at 10 wt% Cu was 5.35± 0.74 ×10−10 mol*cm−2*min−1. The clotting time of sheep blood exposed to these surfaces was 80 ± 13s with pure silicone and 339 ± 44s when 10 wt% Cu(II) was added. SEMs of coatings showed clots occurred away from exposed Cu-dendrites. In conclusion, Cu/Si PMCs inhibit coagulation in a dose-dependent fashion related to the extent of copper exposure on the coated surface.

Fabrication and in vivo thrombogenicity testing of nitric oxide generating artificial lungs

“…Therefore, as the same amount of Cu (10 wt% of Cu/polymer matrix) was added to fibers and to tubing, both surfaces had similar catalytic activity on NO donors and thus similar rate of NO release per unit area. Previous 10 wt% surfaces with either 3 μm [19] and 50 nm [21] copper particles produced 9 × 10 −10 and 15 × 10 −10 mol cm −2 min −1 , respectively, under identical in vitro conditions. Due to the NO flux, the NOgen ECC lungs were less thrombogenic than their non NOgen controls.…”

“…The NOgen shunts were coated tip-to-tip with either the two-part silicone or with10 wt% of 50 nm Cu(II) oxide particles (Sigma Aldrich, St Louis MO, Product number 544868) in tygon polymer. NO-gen silicone was used to coat the angiocaths and connectors in either silicone using the synthesis procedure described previously [19]. To coat tubing, tygon pellets chopped up from tygon tubing were dissolved in tetrahydrofuran (THF) (Sigma Aldrich, St Louis MO) at, using 1g pellets per 3mL THF by vortexing the mixture for 30 minutes.…”

“…NO generation was measured from 1 cm long tubing samples (NOgen and non-NOgen surfaces, N=5 ea), and from 1 cm long fibers (NOgen and non-NOgen, N=5 ea) using a Seivers nitric oxide analyzer (NOA), model 280 (Boulder, CO) according to previously described methods [19]. In brief, S-nitrosoglutathione (GSNO, 1 μM), 30 mM glutathione and 5 mM Ethylenediaminetetraacetic acid, all purchased from Sigma Aldrich, were added to an amber reaction vessel containing phosphate-buffered saline (PBS, pH= 7.34) at 37°C.…”

“…The Cu particles catalyze NO formation in blood via decomposition of circulating s-nitrosothiols via the mechanism in Figure 1A [16-18]. NO generation and clotting have both been shown to be linearly related to surface expression of Cu [19]. These fibers were incorporated in miniature artificial lungs, which were inserted into a circuit that was similarly coated tip-to-tip with the NOgen material.…”

Catalytic Formation of Nitric Oxide Mediated by Ti–Cu Coatings Provides Multifunctional Interfaces for Cardiovascular Applications

“…Copper‐containing materials such as polyurethane loaded with copper nanoparticles can also continuously generate nitric oxide by the catalytic decomposition of blood RSNO . Amoako et al have reported that Cu‐mediated NO‐generating silicone has the ability to catalyze nitric oxide formation and reduce blood coagulation . Cu–SNAP composites, fabricated by incorporating copper nanoparticles onto the SNAP films, provide controlled NO release and reduced platelet adhesion .…”