Research Supplement to Promote Diversity Supplement for the ECMO without Anticoagulation

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Nitric Oxide (NO) is a gaseous radical continuously produced by the endothelial nitric oxide synthase (eNOS) enzyme within the walls of the blood vessels and is an essential molecule to maintain homeostasis and prevent blood clot formation. NO is an extremely reactive molecule with only 2 ms half-life and can form various metabolites in the blood. The artificial surfaces of blood contacting devices can activate platelets and induce thrombus formation. This is a not desired side effect of Extracorporeal Life Support (ECLS) circuits and is typically prevented by systemic anticoagulation, which however increases the risk of hemorrhagic complications. Hence, there is an effort to create more biocompatible artificial surfaces that obviate the need for systemic anticoagulation. NO emitting artificial surfaces offer attractive solution to this problem. However, the NO payload of such surfaces is inherently limited. In this research supplement we would like to explore an alternative approach, where the available NO payload is circulating within the blood in the form of NO metabolites (e.g., nitrite, small and large molecular weight S-nitroso thiols) as reservoirs and is released upon contact with the chemically modified artificial surface of the biomedical device. We would like to achieve this goal through the following aims: Aim 1: Develop analytical methods to measure circulating NO donors in the blood. Selective analytical methods will be developed to quantify potential circulating NO donors (nitrite, small and large molecular weight S-nitroso thiols) in the blood. Aim 2: Modulate concentration of circulating NO reservoirs in the blood. This aim is to assess the effect of the delivered NO gas on the quantity of individual NO metabolites within the blood. NO gas will be delivered to pre-conditioned blood via an in vitro membrane oxygenator setup. This will allow for precise control of the delivery of NO to the blood (partial pressure of NO and O2, flow rate of sweep gas and blood). Aim 3: Modify EC surfaces that can induce NO release from circulating NO reservoirs. We will coat PVC tubing with a polymer coating doped/covalently modified with divalent metal ions (Cu2+) and assess its ability to induce NO release from the circulating NO reservoirs and to prevent blood clot formation in vitro in Chandler loop model.