Endogenous Nitric Oxide-Releasing Microgel Coating Prevents Clot Formation on Oxygenator Fibers Exposed to In Vitro Blood Flow

Abstract

Background: Clot formation on foreign surfaces of extracorporeal membrane oxygenation systems is a frequent event. Herein, we show an approach that mimics the enzymatic process of endogenous nitric oxide (NO) release on the oxygenator membrane via a biomimetic, non-fouling microgel coating to spatiotemporally inhibit the platelet (PLT) activation and improve antithrombotic properties. This study aims to evaluate the potential of this biomimetic coating towards NO-mediated PLT inhibition and thereby the reduction of clot formation under flow conditions. Methods: Microgel-coated (NOrel) or bare (Control) poly(4-methyl pentene) (PMP) fibers were inserted into a test channel and exposed to a short-term continuous flow of human blood. The analysis included high-resolution PLT count, pooled PLT activation via β-Thromboglobulin (β-TG) and the visualization of remnants and clots on the fibers using scanning electron microscopy (SEM). Results: In the Control group, PLT count was significantly decreased, and β-TG concentration was significantly elevated in comparison to the NOrel group. Macroscopic and microscopic visualization showed dense layers of stable clots on the bare PMP fibers, in contrast to minimal deposition of fibrin networks on the coated fibers. Conclusion: Endogenously NO-releasing microgel coating inhibits the PLT activation and reduces the clot formation on PMP fibers under dynamic flow.

Bioimpedance Analysis as Early Predictor for Clot Formation Inside a Blood-Perfused Test Chamber: Proof of Concept Using an In Vitro Test-Circuit

“…Moreover, heparin positively modulates the interactions of von Willebrand factor with the platelet GPIb/V/IX complex, also leading to the inhibition of platelet aggregation [ 33 ]. In previous in vitro studies, β-TG was a reliable marker for platelet activation and subsequent clot formation, matching the findings of this study [ 34 ]. The initial higher values of β-TG in both the clotting group and the control group could be explained by the fact that the baseline values were measured from the samples directly drawn from the volunteers, thus representing the in vivo concentration.…”

A dual‐action nitric oxide‐releasing slippery surface for extracorporeal organ support: Dynamic in vitro hemocompatibility evaluation

“…A strategy to apply LINO to membrane oxygenators has yet to be developed; however, recent studies suggest that NO-release modifications can be applied to the polymethyl pentene fibers that compose the membrane lung gas exchange fibers. 33 Further, early evidence is suggesting that administration of NO gas into the oxygenator sweep gas may be a viable alternative for NO-release in membrane lungs versus polymer modifications. [34][35][36] In vivo multi-day animals studies utilizing fullscale ECLS devices and conducted under clinically relevant conditions for multi-day duration will be essential to ascertain whether the hemocompatibility benefit observed here will translate to a clinically meaningful benefit.…”

“…Extending the study duration introduces the variable of blood viability in the ex vivo setting; thus, future testing in vivo on a multi‐day time frame will be necessary and is planned in our laboratory. A strategy to apply LINO to membrane oxygenators has yet to be developed; however, recent studies suggest that NO‐release modifications can be applied to the polymethyl pentene fibers that compose the membrane lung gas exchange fibers 33 . Further, early evidence is suggesting that administration of NO gas into the oxygenator sweep gas may be a viable alternative for NO‐release in membrane lungs versus polymer modifications 34–36 .…”

Polymeric Membranes for Biomedical Applications

“…Normally, in order to avoid the formation of clots in the oxygenation installation, they administer anticoagulant drugs, such as heparin. Unfortunately, this method has the disadvantage of the possibility of severe bleeding [ 186 , 187 , 188 , 189 ]. Another limitation of the ECMO system is the adherence of various biomolecules on the surface, which can be overcome by incorporating small molecules, such as heparin, in the coating of the ECMO system surface [ 190 ].…”