Recapitulating atherogenic flow disturbances and vascular inflammation in a perfusable 3D stenosis model
Recapitulating atherogenic flow disturbances and vascular inflammation in a perfusable 3D stenosis model
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DOI：
10.1088/1758-5090/aba501
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发表时间：
2020-07
期刊：
影响因子：
9
通讯作者：
N. Menon;Chengxun Su;K. Pang;Zhai Juan Phua;H. Tay;R. Dalan;Xiaomeng Wang;King Ho Holden Li;H. Hou
中科院分区：
文献类型：
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作者：
N. Menon;Chengxun Su;K. Pang;Zhai Juan Phua;H. Tay;R. Dalan;Xiaomeng Wang;King Ho Holden Li;H. Hou
血管狭窄和动脉闭塞是动脉粥样硬化的病理特征，其涉及血流动力学紊乱、内皮功能障碍和炎症级联反应的复杂相互作用。在此，我们报告了一种新的环形微流体狭窄模型，概括了致动脉粥样硬化流动介导的内皮功能障碍和血液内皮细胞（EC）的相互作用在体外。使用3D打印制造具有不同收缩几何形状的2D和3D狭窄微通道，以研究在不同严重程度的闭塞和壁剪切应力（100至2000 dynecm-2）下的流动扰动。实验和流体模拟结果证实了狭窄区域中存在病理性剪切应力，以及狭窄后的再循环流。由此产生的病理性流动曲线诱导促炎和促血栓形成EC状态，如通过正交EC对齐、狭窄处血小板粘附增强和狭窄后异常白细胞-EC相互作用所证明的。通过分别测试阿司匹林和二甲双胍的抗血栓形成和免疫调节功效来进一步研究血管模型的临床效用。总体而言，该平台能够对关键的致动脉粥样硬化事件进行多因素分析，包括内皮功能障碍、血小板和白细胞粘附，并可进一步开发为用于心血管风险分层的液体活检工具。
Blood vessel narrowing and arterial occlusion are pathological hallmarks of atherosclerosis, which involves a complex interplay of perturbed hemodynamics, endothelial dysfunction and inflammatory cascade. Herein, we report a novel circular microfluidic stenosis model that recapitulates atherogenic flow-mediated endothelial dysfunction and blood-endothelial cell (EC) interactions in vitro. 2D and 3D stenosis microchannels with different constriction geometries were fabricated using 3D printing to study flow disturbances under varying severity of occlusion and wall shear stresses (100 to 2000 dynecm−2). Experimental and fluid simulation results confirmed the presence of pathological shear stresses in the stenosis region, and recirculation flow post stenosis. The resultant pathological flow profile induced pro-inflammatory and pro-thrombotic EC state as demonstrated by orthogonal EC alignment, enhanced platelet adhesion at the stenosis, and aberrant leukocyte-EC interactions post stenosis. Clinical utility of the vascular model was further investigated by testing anti-thrombotic and immunomodulatory efficacy of aspirin and metformin, respectively. Overall, the platform enables multi-factorial analysis of critical atherogenic events including endothelial dysfunction, platelets and leukocyte adhesion, and can be further developed into a liquid biopsy tool for cardiovascular risk stratification.