In vitro modeling of the microvascular occlusion and thrombosis that occur in hematologic diseases using microfluidic technology
In vitro modeling of the microvascular occlusion and thrombosis that occur in hematologic diseases using microfluidic technology
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DOI：
10.1172/jci58753
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发表时间：
2012-01-01
影响因子：
15.9
通讯作者：
Lam, Wilbur A.
中科院分区：
文献类型：
--
作者：
Tsai, Michelle;Kita, Ashley;Lam, Wilbur A.
在血液病中，如镰状细胞病（SCD）和溶血性尿毒症综合征（HUS），血细胞、内皮细胞和可溶性因子之间的病理性生物物理相互作用导致微血管闭塞和血栓形成。在这里，我们报告了一个体外“内皮化”微流体微血管模型，概括和整合这一合奏的病理生理过程。在受控流动条件下，该模型能够定量研究血液病中的生物物理学改变如何共同导致微血管闭塞和血栓形成。使用SCD患者的血液样本，我们研究了药物羟基脲如何定量影响SCD中的微血管阻塞，这是一个尚未解决的问题，对于了解其在此类患者中的临床疗效至关重要。此外，我们证明了我们的微系统可以作为HUS的体外模型，并表明剪切力影响微血管血栓形成/阻塞和药物依替巴肽的疗效，该药物可降低血小板聚集，在HUS的背景下。这些实验建立了我们的微血管芯片模型作为血液病理生理学的生物物理测定以及药物发现平台的多功能性和临床相关性。
In hematologic diseases, such as sickle cell disease (SCD) and hemolytic uremic syndrome (HUS), pathological biophysical interactions among blood cells, endothelial cells, and soluble factors lead to microvascular occlusion and thrombosis. Here, we report an in vitro "endothelialized" microfluidic microvasculature model that recapitulates and integrates this ensemble of pathophysiological processes. Under controlled flow conditions, the model enabled quantitative investigation of how biophysical alterations in hematologic disease collectively lead to microvascular occlusion and thrombosis. Using blood samples from patients with SCD, we investigated how the drug hydroxyurea quantitatively affects microvascular obstruction in SCD, an unresolved issue pivotal to understanding its clinical efficacy in such patients. In addition, we demonstrated that our microsystem can function as an in vitro model of HUS and showed that shear stress influences microvascular thrombosis/obstruction and the efficacy of the drug eptifibatide, which decreases platelet aggregation, in the context of HUS. These experiments establish the versatility and clinical relevance of our microvasculature-on-a-chip model as a biophysical assay of hematologic pathophysiology as well as a drug discovery platform.