Multi‐Modal, Surface‐Focused Anticoagulation Using Poly‐2‐methoxyethylacrylate Polymer Grafts and Surface Nitric Oxide Release

Abstract

and platelet activation on the surfaces of these devices lead to clot formation. This, in turn, causes device failure and thromboembolic complications. The most common solution to this problem is systemic anticoagulation, but this leads to bleeding complications that can also contribute to patient morbidity and mortality. [ 1-3 ] Anticoagulation that is limited only upon device surfaces could remedy these shortcomings. Two methods of surface focused anticoagulation have demonstrated some promise in reducing coagulation: surface coatings designed to limit nonspecifi c protein adsorption and anti-platelet surface NO release. Surface coatings only reduce coagulation in the device and thus have no systemic anticoagulant effect. Various commercial anti-thrombogenic coatings have shown better preservation of platelet counts than the uncoated control surface [ 4,5 ] during short-term applications. However, these surface coatings have not yet proven suffi cient to allow the elimination of systemic anticoagulation or long-term use of high surface area artifi cial organs without signifi cant decrease in systemic platelet concentration. [ 6,7 ] Nitric oxide is released from biomaterials into fl owing blood, [ 8-12 ] but has a short half-life of 2-5 seconds [ 8 ] in blood prior to being scavenged. Thus, its systemic effects are minor, and it has been examined as a means to focus anticoagulation at biomaterials' surfaces rather than systemically. Several means of supplying surface NO fl ux have been tested. They include NO release from a stored pool in the biomaterial, NO generation from endogenous sources in blood, and NO delivery via the gas fl ow in artifi cial lungs. [ 9-12 ] Early studies examining the latter approach were largely unsuccessful. These studies did not quantify surface NO fl ux, and it was likely insuffi cient. [ 13 ] More recent studies with proven, endothelial levels of NO fl ux (>2 × 10 −10 mol/min/cm 2) have been successful, reducing platelet adhesion in tubing and catheters by approximately 40%, [ 9,10 ] and markedly reducing coagulation and increasing longevity in artifi cial lungs. [ 12 ] Although positive, these studies were all for a period of 4 hours. Longer-term effectiveness in these settings is unknown. Additionally, use of NO in high surface area artifi cial organs could lead to excessive generation of methemoglobin in the blood, limiting the possible fl ux rates, and anticoagulation. In this study, we hypothesize that the combination of antiadsorptive coatings and surface NO fl ux will lead to more This study examines platelet adhesion on surfaces that combine coatings to limit protein adsorption along with "anti-platelet" nitric oxide (NO) release. Uncoated and poly-2-methoxyethylacrylate (PMEA) coated, gas permeable polypropylene (PP) membranes were placed in a bioreactor to separate plasma and gas fl ows. Nitrogen with 100/500/1000 ppm of NO was supplied to the gas side as a proof of concept. On the plasma side, platelet rich plasma (PRP, 1 × 108 cell/mL) was recirculated at low (60)/high ...

Multimodal, Biomaterial‐Focused Anticoagulation via Superlow Fouling Zwitterionic Functional Groups Coupled with Anti‐Platelet Nitric Oxide Release

“…These results compare favorably a similar study of this nature involving PMEA‐coated polypropylene and NO release . While PMEA coating reduced platelet adsorption to 82.6% ± 9.2% of uncoated control, pCB coating studied here reduced platelet adsorption to 23.3% ± 7.4% of uncoated.…”

“…The combination of pCB coating with the same 100 ppm NO flow (NO flux = 1.03 ± 0.41 × 10 −10 mol min −1 cm −2 ) reduced platelet adsorption to 6.90% ± 1.30% of uncoated control. With PMEA coating, it is estimated that it would require 200 ppm of NO flow and an NO flux of 2.40 ± 1.63 × 10 −10 mol min −1 cm −2 to achieve similar results . Thus, pCB allows for lower NO levels to be used without sacrificing biocompatibility and lowers the risk of elevated methemoglobin concentrations (metHb).…”

“…These findings led us to explore other anti‐fouling coatings, which may exhibit a higher anti‐fouling property. Published studies have demonstrated a lesser amount of protein fouling with polycarboxybetaine (pCB) than PMEA coating . We thus hypothesized that paring pCB with NO concentrations would lead to less platelet binding and that this might allow for the use of lower NO surface flux.…”

“…Surfaces modified for NO release alone (1) will not be able to resist protein adsorption, have to compete with procoagulant proteins including the adsorption of fibrinogen, which is shown to increase on NO releasing surfaces . Surfaces modified with protein adsorption resistant coatings alone (2) will require very high, uniform graft densities to remain nonfouling.…”

“…Prior to this paper, we studied how surface NO flux and PMEA coatings synergistically affect platelet adsorption . It was concluded in that paper that the PMEA significantly inhibits adsorption.…”