Multiscale Modeling of Thrombus Initiation in Cardiovascular Prostheses

描述（由申请人提供）：将开发一个多尺度模型，以物理精确的方式描述血液流经狭窄几何形状时的动力学。这项研究很重要，因为在心血管假体（心脏瓣膜、支架和心室辅助装置）中，这种狭窄的几何形状（狭窄的泄漏间隙、铰链）是高流体剪切应力可能导致血小板损伤的位置；血小板活化和碰撞可触发聚集和随后的血栓形成。这一建议背后的关键思想是，导致血栓形成的现象本质上是多尺度的。装置的尺寸为~厘米，而收缩的几何形状为~100微米宽，血细胞的大小为微米数量级。流经100微米缝隙的血液不能被视为均匀流体，血小板也不能被视为被动点颗粒。事实上，较大的、可变形的、数量相对较多的红细胞在血小板的机制中起着至关重要的作用。因此，一个物理上正确的剪切诱导血小板活化（SIPA）模型必须考虑到血细胞的动力学、流动几何形状和血浆的流动。为了更好地理解导致SIPA的微观尺度相互作用，并指导更好的假肢设计，通过收缩和扭曲的微观几何形状进行精确的血流计算建模将非常有用。建模的挑战在于，即使在狭窄的微观几何形状中，也有数百万个血细胞，因此，目前还无法进行高精度的3-D计算。因此，所提出的多尺度模型：(1)将是二维的，(2)将把红细胞和血小板的全分辨率微尺度模型与粗粒度中尺度模型结合起来，以便能够跟踪大量（~104）个细胞。为了确保物理有效性，模型预测（例如细胞轨迹、细胞间相互作用和流场特征）将与串联微粒子图像测速（m-PIV）实验进行比较。此外，将在m-PIV可视化中跟踪血小板，并采用生物测定来确定血小板的活化和聚集水平。通过计算和实验的紧密结合，我们试图获得：(1)血细胞微观力学的清晰图像；(2)局部剪切应力和剪切梯度与血小板表现出标志血栓形成信号的趋势之间的定量相关性。这项工作极具挑战性，它将通过以下方式推进最先进的技术：(1)计算沉浸在血流中的大量细胞的动力学；(2)设计将信息从完全分辨的微观尺度传递到粗粒度的中尺度计算的技术；(3)紧密结合实验和计算研究来理解微观尺度动力学；(4)发展执行真正大规模并行计算的能力，广泛应用于各种生物医学系统。这些尖端技术将为血细胞的微动力学以及微观几何形状和血流模式对血栓形成的影响提供前所未有的定量信息。

DESCRIPTION (provided by applicant): A multiscale model will be developed to describe in a physically accurate manner the dynamics of blood as it flows through constricted geometries. This study is important because in cardiovascular prostheses (heart valves, stents, and ventricular assist devices) such constricted geometries (narrow leakage gaps, hinges) are locations where platelet damage can be caused by high fluid shear stresses; platelet activation and collisions can then trigger aggregation and subsequent thrombus formation. The key idea underlying this proposal is that the phenomena that lead to thrombus initiation are intrinsically multiscale in nature. Device scales are ~centimeters, while the constricted geometries are ~100 microns wide and the blood cells are order of microns in size. Blood flowing through 100 micron gaps cannot be treated as a homogeneous fluid and platelets cannot be treated as passive point particles. In fact, the larger, deformable and relatively numerous red blood cells play a crucial role in the mechanics of platelets. Therefore, a physically correct model of shear-induced platelet activation (SIPA) must account for the dynamics of blood cells, the flow geometry and the flow of plasma. To better understand the micro-scale interaction that leads to SIPA and to guide beter design of prostheses, accurate computational modeling of blood flow through constricted and contorted micro-geometries will be extremely useful. The challenge for modeling is that even in constricted micro-geometries there are millions of blood cells, thus well resolved 3-D computations are presently infeasible. Therefore, the proposed multiscale model: (1) will be 2-dimensional and (2) will couple fully resolved micro-scale models of red blood cells and platelets with coarse-grained meso-scale models in order to make possible the tracking of multitudes of (~104) cells. To ensure physical validity, model predictions (for example cell trajectories, cell-cell interactions and flow field characteristics) will be compared with tandem micro-particle image velocimetry (m-PIV) experiments. Furthermore, platelets will be tracked in the m-PIV visualizations and biological assays will be employed to determine the levels of activation and aggregation of platelets. By intimately combining computations and experiments, we seek to obtain: (1) a clear picture of the micro-mechanics of blood cells and (2) quantitative correlation between local shear stresses and shear gradients and the tendency of platelets to exhibit the signals that mark thrombus initiation. The work is highly challenging and it will advance the state-of-the-art by: (1) computing the dynamics of large numbers of cells immersed in blood flow; (2) devising techniques for transferring information from fully-resolved micro-scale to coarse-grained meso-scale calculations; (3) intimately coupling experimental and computational studies to understand micro-scale dynamics; and (4) developing the ability to perform truly large scale parallel computations with broad application to a variety of biomedical systems. These cutting-edge techniques will provide unprecedented quantitative information on the micro-dynamics of blood cells and the impact of micro-geometry and flow patterns on thrombus initiation. PUBLIC HEALTH RELEVANCE: This proposal seeks to develop multiscale computational models of blood flow in specific regions of cardiovascular prostheses (heart valves, stents, ventricular assist devices) that are implicated in initiation of potentially dangerous thrombi. By advancing the understanding of and the ability to model the mechanics of blood cells under thrombogenic conditions, the proposed work will not only further our understanding of the pathology, but also develop predictive capabilities that can be used in designing safer prostheses.