Zilberman-Rudenko Jevgenia, Sylman Joanna L, Lakshmanan Hari H S, McCarty Owen J T, Maddala Jeevan
Biomedical Engineering, School of Medicine, Oregon Health and Science University, Portland, OR.
Chemical and Biomedical Engineering, West Virginia University, Morgantown, WV.
Cell Mol Bioeng. 2017 Feb;10(1):16-29. doi: 10.1007/s12195-016-0470-7. Epub 2016 Oct 20.
The reaction dynamics of a complex mixture of cells and proteins, such as blood, in branched circulatory networks within the human microvasculature or extravascular therapeutic devices such as extracorporeal oxygenation machine (ECMO) remains ill-defined. In this report we utilize a multi-bypass microfluidics ladder network design with dimensions mimicking venules to study patterns of blood platelet aggregation and fibrin formation under complex shear. Complex blood fluid dynamics within multi-bypass networks under flow were modeled using COMSOL. Red blood cells and platelets were assumed to be non-interacting spherical particles transported by the bulk fluid flow, and convection of the activated coagulation factor II, thrombin, was assumed to be governed by mass transfer. This model served as the basis for predicting formation of local shear rate gradients, stagnation points and recirculation zones as dictated by the bypass geometry. Based on the insights from these models, we were able to predict the patterns of blood clot formation at specific locations in the device. Our experimental data was then used to adjust the model to account for the dynamical presence of thrombus formation in the biorheology of blood flow. The model predictions were then compared to results from experiments using recalcified whole human blood. Microfluidic devices were coated with the extracellular matrix protein, fibrillar collagen, and the initiator of the extrinsic pathway of coagulation, tissue factor. Blood was perfused through the devices at a flow rate of 2 µL/min, translating to physiologically relevant initial shear rates of 300 and 700 s for main channels and bypasses, respectively. Using fluorescent and light microscopy, we observed distinct flow and thrombus formation patterns near channel intersections at bypass points, within recirculation zones and at stagnation points. Findings from this proof-of-principle ladder network model suggest a specific correlation between microvascular geometry and thrombus formation dynamics under shear. This model holds potential for use as an integrative approach to identify regions susceptible to intravascular thrombus formation within the microvasculature as well as extravascular devices such as ECMO.
在人体微血管内的分支循环网络中，诸如血液这样由细胞和蛋白质构成的复杂混合物的反应动力学，或者在诸如体外膜肺氧合机（ECMO）等血管外治疗设备中的反应动力学，仍然不清楚。在本报告中，我们利用一种多旁路微流控梯形网络设计，其尺寸模仿微静脉，以研究复杂剪切力作用下血小板聚集和纤维蛋白形成的模式。使用COMSOL对流动状态下多旁路网络内复杂的血液流体动力学进行建模。红细胞和血小板被假定为通过总体流体流动运输的非相互作用球形颗粒，并且假定活化凝血因子II（凝血酶）的对流受传质控制。该模型作为预测由旁路几何形状决定的局部剪切速率梯度、驻点和再循环区域形成的基础。基于这些模型的见解，我们能够预测设备中特定位置的血凝块形成模式。然后，我们使用实验数据来调整模型，以考虑血栓形成在血流生物流变学中的动态存在。然后将模型预测结果与使用重新钙化的全人血进行实验的结果进行比较。微流控设备涂有细胞外基质蛋白、纤维状胶原蛋白以及凝血外源性途径的启动子组织因子。以2微升/分钟的流速将血液灌注通过这些设备，这分别转化为主通道和旁路生理相关的初始剪切速率300和700秒⁻¹。使用荧光显微镜和光学显微镜，我们在旁路点的通道交叉处附近、再循环区域内和驻点处观察到了不同的流动和血栓形成模式。这个原理验证梯形网络模型的研究结果表明，微血管几何形状与剪切力作用下血栓形成动力学之间存在特定的相关性。该模型具有作为一种综合方法的潜力，用于识别微血管以及诸如ECMO等血管外设备中易发生血管内血栓形成的区域。
