Colorado State University, 301 West Pitkin Street, Fort Collins, Colorado 80523, United States.
Autonomous Reanimation and Evacuation Research Program, The Geneva Foundation, 2509 Kennedy Circle, San Antonio, Texas 78259, United States.
ACS Biomater Sci Eng. 2022 Aug 8;8(8):3438-3449. doi: 10.1021/acsbiomaterials.2c00492. Epub 2022 Jul 1.
Medical devices that require substantial contact between blood and a foreign surface would be dramatically safer if constructed from materials that prevent clot formation and coagulation disturbance at the blood-biomaterial interface. Nitric oxide (NO), an endogenous inhibitor of platelet activation in the vascular endothelium, could provide anticoagulation at the blood-surface interface when applied to biomaterials. We investigated an application of a copper-based metal-organic framework, H[(CuCl)(BTTri)-(HO)]·72HO where HBTTri = 1,3,5-tris(1-1,2,3-triazole-5-yl)benzene] (CuBTTri), which has been shown to be an effective catalyst to generate NO from -nitrosothiols that are endogenously present in blood. A method was developed to apply a CuBTTri composite coating to Tygon medical tubing used for extracorporeal lung support devices. The stability and activity of the coating were evaluated during 72 h dynamic saline flow testing (1.5-2.5 L/min, = 3) with scanning electron microscopy imaging and inductively coupled mass-spectroscopy analysis. Compatibility of the coating with whole blood was assessed with a panel of hemocompatibility tests during 6 h circulation of swine donor blood in an ex vivo circulation loop constructed with CuBTTri tubing or unmodified Tygon (1.5 L/min blood flow rate, = 8/group). Thrombus deposition and catalytic activity of the CuBTTri tubing were assessed following blood exposure. The coating remained stable during 72 h saline flow experiments at clinically relevant flow rates. No adverse effects were observed relative to controls during blood compatibility testing, to include no significant changes in platelet count ( = 0.42), platelet activation indicated by P-selectin expression ( = 0.57), coagulation panel values, or methemoglobin fraction ( = 0.18) over the 6 h circulation period. CuBTTri within the coating generated NO following blood exposure in the presence of biologically relevant concentrations of an NO donor. CuBTTri composite coating was stable and blood compatible in this pilot study and requires further investigation of efficacy using in vivo models conducted with clinically relevant blood flow rates and study duration.
如果医疗器械与血液和外来表面之间需要大量接触，那么由能够防止血液-生物材料界面处血栓形成和凝血紊乱的材料制成的医疗器械将显著更安全。一氧化氮（NO）是血管内皮中血小板激活的内源性抑制剂，当应用于生物材料时，它可以在血液-表面界面提供抗凝作用。我们研究了一种铜基金属有机骨架 H[(CuCl)(BTTri)-(HO)]·72HO 的应用，其中 HBTTri = 1,3,5-三(1-1,2,3-三唑-5-基)苯]（CuBTTri），已证明它是一种有效的催化剂，可以从血液中内源性存在的 -亚硝基硫醇生成 NO。开发了一种将 CuBTTri 复合涂层施加到用于体外肺支持设备的 Tygon 医疗管的方法。通过扫描电子显微镜成像和电感耦合质谱分析，在 72 小时动态盐水流动测试（1.5-2.5 L/min， = 3）中评估了涂层的稳定性和活性。通过在体外循环回路中用 CuBTTri 管或未改性的 Tygon（1.5 L/min 血流速率， = 8/组）循环猪供体血液 6 小时，用一系列血液相容性测试评估了涂层与全血的相容性。暴露于血液后评估了 CuBTTri 管的血栓沉积和催化活性。在临床相关流速的盐水流动实验中，涂层在 72 小时内保持稳定。在血液相容性测试中与对照相比，没有观察到任何不良反应，包括血小板计数无显著变化（ = 0.42）、血小板激活（ = 0.57）、凝血谱值或高铁血红蛋白分数（ = 0.18）在 6 小时循环期间。在存在生物相关浓度的 NO 供体的情况下，暴露于血液后，涂层内的 CuBTTri 生成了 NO。在这项初步研究中，CuBTTri 复合涂层是稳定的且与血液相容的，需要进一步研究使用具有临床相关血流速率和研究持续时间的体内模型的功效。
