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An “occlusive thrombosis-on-a-chip” microfluidic device for investigating the effect of anti-thrombotic drugs
Lab on a Chip ( IF 6.1 ) Pub Date : 2021-08-12 , DOI: 10.1039/d1lc00347j
Jess Berry 1 , François J Peaudecerf 2 , Nicole A Masters 3 , Keith B Neeves 3 , Raymond E Goldstein 4 , Matthew T Harper 1
Affiliation  

Cardiovascular disease remains one of the world's leading causes of death. Myocardial infarction (heart attack) is triggered by occlusion of coronary arteries by platelet-rich thrombi (clots). The development of new anti-platelet drugs to prevent myocardial infarction continues to be an active area of research and is dependent on accurately modelling the process of clot formation. Occlusive thrombi can be generated in vivo in a range of species, but these models are limited by variability and lack of relevance to human disease. Although in vitro models using human blood can overcome species-specific differences and improve translatability, many models do not generate occlusive thrombi. In those models that do achieve occlusion, time to occlusion is difficult to measure in an unbiased and objective manner. In this study we developed a simple and robust approach to determine occlusion time of a novel in vitro microfluidic assay. This highlighted the potential for occlusion to occur in thrombosis microfluidic devices through off-site coagulation, obscuring the effect of anti-platelet drugs. We therefore designed a novel occlusive thrombosis-on-a-chip microfluidic device that reliably generates occlusive thrombi at arterial shear rates by quenching downstream coagulation. We further validated our device and methods by using the approved anti-platelet drug, eptifibatide, recording a significant difference in the “time to occlude” in treated devices compared to control conditions. These results demonstrate that this device can be used to monitor the effect of antithrombotic drugs on time to occlude, and, for the first time, delivers this essential data in an unbiased and objective manner.

中文翻译:

用于研究抗血栓药物效果的“闭塞性血栓芯片”微流控装置

心血管疾病仍然是世界上最主要的死亡原因之一。心肌梗塞(心脏病发作)是由富含血小板的血栓(凝块)阻塞冠状动脉引发的。预防心肌梗塞的新型抗血小板药物的开发仍然是一个活跃的研究领域,并且依赖于对血栓形成过程的准确建模。闭塞性血栓可以在一系列物种体内产生,但这些模型受到变异性的限制并且与人类疾病缺乏相关性。尽管使用人血的体外模型可以克服物种特异性差异并提高可转化性,但许多模型不会产生闭塞性血栓。在那些确实实现遮挡的模型中,遮挡时间很难以公正且客观的方式测量。在这项研究中,我们开发了一种简单而可靠的方法来确定新型体外微流体测定的闭塞时间。这凸显了血栓微流体装置通过异位凝血发生闭塞的可能性,从而掩盖了抗血小板药物的作用。因此,我们设计了一种新型闭塞性血栓芯片微流控装置,该装置通过淬灭下游凝血,在动脉剪切速率下可靠地产生闭塞性血栓。我们通过使用已批准的抗血小板药物依替巴肽进一步验证了我们的设备和方法,记录了与对照条件相比,处理设备的“闭塞时间”的显着差异。这些结果表明,该设备可用于监测抗血栓药物对闭塞时间的影响,并且首次以公正和客观的方式提供这一重要数据。
更新日期:2021-09-15
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