The immobilization of a direct thrombin inhibitor to a polyurethane as a nonthrombogenic surface coating for extracorporeal circulation.
The immobilization of a direct thrombin inhibitor to a polyurethane as a nonthrombogenic surface coating for extracorporeal circulation.
复制标题
将直接凝血酶抑制剂固定在聚氨酯上，作为体外循环的非血栓形成表面涂层。
DOI：
10.1039/c5tb02419f
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发表时间：
2016-04-07
期刊：
影响因子：
--
通讯作者：
Major T
中科院分区：
文献类型：
--
作者：
Yu J;Brisbois E;Handa H;Annich G;Meyerhoff M;Bartlett R;Major T
具有抗凝血酶和抗血小板特性的生物材料是体外循环（ECC）中使用的理想表面，因为它同时靶向纤维蛋白生成和血小板粘附。血液相容性表面涂层通过在聚合物-血液界面处提供局部抗凝作用而避免了对全身抗凝的需要。先前的工作已经证明了阿加曲班（一种直接凝血酶抑制剂）作为体外装置的非血栓形成材料的潜在用途。本文报告的工作重点是阿加曲班与聚硅氧烷聚合物CarboSil®连接的表征。评价化学固定、阿加曲班的量、孵育时间和饱和点以在聚合物表面实现最大抗凝血酶活性。制备并测试与10和30 μ mol阿加曲班反应的交联聚合物涂层。这些涂层导致阿加曲班活性水平分别为0.131 µM和0.446 µM。在改进交联过程后，阿加曲班活性增加了约3.6倍。还评价了活性的保持和从聚合物表面的浸出。使用将阿加曲班连接到聚合物的精制工艺，将所得聚合物作为表面涂层施加到聚（氯乙烯）ECC回路管的内腔，并使用4小时兔ECC模型评价其抗凝血酶作用。血液暴露4小时后，阿加曲班回路显示出与对照CarboSil®涂层相比显著更少的血栓形成，对照涂层的血栓平均面积为4.1 cm 2，而阿加曲班涂层的血栓平均面积为1.2 cm 2（n=4）。使用阿加曲班涂层回路的动物血浆中凝血酶时间相对于基线无显著变化，t=0时凝血酶时间为16.2 s，4 h后为14.5 s。这些结果证明了固定化阿加曲班作为体外生命支持装置的血液相容性生物材料的潜在功效。
A biomaterial with both antithrombin and antiplatelet properties is the ideal surface for use in extracorporeal circulation (ECC) as it targets both fibrin generation and platelet adhesion. A hemocompatible surface coating avoids the need for systemic anticoagulation by providing a local anticoagulant effect at the polymer-blood interface. Previous work has demonstrated the potential use of argatroban, a direct thrombin inhibitor, as a nonthrombogenic material for extracorporeal devices. The work reported here focuses on the characterization of argatroban linked to a polyurethane-silicone polymer, CarboSil®. Chemical immobilization, the amount of argatroban, incubation times, and saturation point were evaluated to achieve maximal antithrombin activity at the polymer surface. Cross-linked polymer coatings reacted with 10 and 30 µmole of argatroban were prepared and tested. These coatings resulted in argatroban activity levels of 0.131 µM and 0.446 µM, respectively. After refining the cross-linking process, argatroban activity increased by approximately 3.6 fold. Maintenance of activity and leaching from the polymer surface were also evaluated. Using the refined process for linking argatroban to polymer, the resulting polymer was applied as a surface coating to the inner lumen of poly(vinyl chloride) ECC circuit tubing and its antithrombin effect evaluated using a 4 h rabbit ECC model. Following 4 h of blood exposure, the argatroban circuit demonstrated significantly less thrombus formation compared to the control CarboSil® coating with a 4.1 cm2 thrombus average area for the control coating compared to 1.2 cm2 for the argatroban coating (n=4). There was no significant change in thrombin time from baseline in plasma from animals in which the argatroban coated circuit was used, with a thrombin time of 16.2 s at t=0 and 14.5 s after 4 h. These results demonstrate the potential efficacy of immobilized argatroban as a hemocompatible biomaterial for extracorporeal life support devices.