High-throughput Imaging-integrated Vascular Model for Understanding Thromboembolism and Therapeutics Screening

摘要 血栓形成，即由于血管中凝块的形成而导致的血流阻塞，占1/4 全球死亡。特别是，静脉血栓最常发生在腿部或手臂的深静脉中， 通常称为深静脉血栓形成（DVT）。DVT和肺栓塞统称为 静脉血栓栓塞（VTE），其中部分静脉血栓脱落，进入肺部，并且 停留在肺动脉中。VTE是全球心血管相关死亡的第三大原因， 据估计，美国每年有超过50万人死亡。据报道，静脉血栓栓塞是导致 住院患者失能调整生命年损失。 尽管在药物开发上投入了大量的资本，但最终被证明有用的药物却寥寥无几 在人类身上。如此低的产量主要是因为平面细胞培养和用于测试药物的动物模型 通常不能反映人类生理学/病理学。相比之下，三维（3D）人类细胞为基础的， 越来越多地采用体外模型来通过再现生理和生理学特性来改进药物测试， 人类的病理参数。除了开发工程化的人类- 基于微组织，实时，原位，非侵入性体积监测的行为的工程 血管模型及其对病毒感染/药物治疗的反应是实现以下目标的关键能力： 高（更）通量和准确的体外筛选有前途的候选药物。 在这里，我们建议利用我们在体外工程人类血管组织模型方面的独特专长， 血栓形成的高速无标记成像，并得到临床血液学丰富经验的进一步帮助， 患者的抗凝治疗。我们将共同创造一个有利的和第一个同类的高（呃）， 用于研究血栓形成和潜在血栓形成的通量实时成像集成芯片模型 治疗药物，以严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）感染为 及时的例子，以指导未来对流行病和其他血管疾病的准备。

Abstract Thrombosis, the obstruction of blood flow due to the formation of clot in blood vessels, accounts for 1 in 4 deaths worldwide. In particular, venous thrombi occur in deep veins most often in the legs or arms and is commonly known as deep vein thrombosis (DVT). DVT and pulmonary embolism are collectively referred to as venous thromboembolism (VTE) in which a part of the venous thrombus breaks off, travel to the lungs, and lodge in pulmonary arteries. VTE is the 3rd leading cause of cardiovascular-related deaths globally with estimates of >500,000 deaths in the United States every year. VTE is reported to be the leading cause of disability-adjusted life years lost in hospitalized patients. Despite the large amount of capital invested in drug development, very few drugs are ultimately proven useful in humans. Such a low yield occurs largely because planar cell culture and animal models for testing the drugs oftentimes fail to reflect human physiology/pathology. In contrast, three-dimensional (3D) human cell-based in vitro models have been increasingly adopted to improve drug testing by recapitulating physiological and pathological parameters of their human counterparts. In addition to the development of engineered human- based microtissues, real-time, in situ, non-invasive volumetric monitoring of the behaviors of the engineered vascular models and their responses towards viral infection/drug treatment is a key capacity to achieve high(er)-throughput and accurate in vitro screening of promising drug candidates. Here we propose to harness our unique expertise in engineered in vitro human vascular tissue models and high-speed label-free imaging of thrombosis with further aid by strong experiences in clinical hematology and anticoagulation management in patients. Together, we will create an enabling and first-of-its-kind high(er)- throughput real-time imaging-integrated thrombosis-on-chip model to study thrombosis and potential therapeutic agents, taking severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as a timely example to instruct future preparedness for pandemics and other vascular disorders.