Microcirculatory blood flow in sickle cell disease

镰状细胞病（SCD）是一种红细胞疾病，影响约10万美国人，特别是那些祖先来自撒哈拉以南非洲或拉丁美洲的人。在这种疾病中，红细胞会随着年龄的增长而变硬，并通常呈镰刀形状。当患病的红细胞由于镰状形状和增加的硬度而阻塞小血管时，就会出现SCD的急性症状，导致局部血流受限。 然而，长期问题也出现了，这些问题在过去得到的关注较少。在循环的大多数区域，尤其是在大脑中，血管内的细胞变得功能障碍，其中血管损伤与中风风险增加有关，中风是SCD死亡率的主要但最不了解的原因之一。此外，疾病控制和预防中心报告说，患有SCD会增加患COVID-19严重疾病的风险。该项目将使用血流的详细数学模型的模拟，以更好地了解镰状细胞的改变特性如何导致血管壁损伤。将特别注意在大脑中发现的蛇形和相关形状的血管。 SCD患者的红细胞比健康的红细胞（RBC）更小且更硬。这两个特征都增加了细胞驻留在血管壁附近的倾向，这种现象称为边缘化。过去在理想化系统中的实验和计算工作支持这样的假设，即病变细胞强烈边缘化，主要驻留在血管壁附近的无细胞层中，从而产生物理相互作用，例如大的剪切应力波动和机械接触，这些物理相互作用会损坏排列在血管中的内皮细胞。该项目将从理想化的系统转移到生理相关的条件和复杂性，解决有关镰状细胞病的流体力学的重要问题。详细的模拟和简化的机制模型将用于（1）预测细胞特性（包括形状、大小、刚度、弹性和多分散性）对流动过程中空间分布和壁相互作用的影响，以及（2）从机制上确定血管几何形状和血液动力学对SCD RBC边缘化和细胞壁相互作用的影响，特别是在脑微循环的分支和蛇形血管几何特征中。 该项目的更广泛影响包括：（1）其重点是将基础生物力学和流体动力学与医学中的一个重要问题联系起来，（2）本科生，特别是那些来自代表性不足的少数民族的学生参与研究，以及（3）服务学习课程，其中本科工程学生开发项目-该奖项反映了NSF的法定使命，并通过使用基金会的智力价值进行评估，被认为值得支持和更广泛的影响审查标准。

Sickle cell disease (SCD) is a disorder of red blood cells that affects about 100,000 Americans, particularly those whose ancestors came from sub-Saharan Africa or Latin America. In the disorder, red blood cells stiffen as they age and often take on a sickle shape. Acute symptoms of SCD arise when diseased red blood cells obstruct small blood vessels due to the sickled shape and increased stiffness, resulting in restricted local blood flow. However, chronic issues arise as well, and these have received less attention in the past. The cells that line blood vessels become dysfunctional in most regions of the circulation, and especially in the brain, where blood vessel damage is associated with increased risk of stroke, one of the leading yet least understood causes of mortality in SCD. Additionally, the Centers for Disease Control and Prevention reports that having SCD increases the risk of severe illness from COVID-19. This project will use simulations of a detailed mathematical model of blood flow to gain a better understanding of how the altered properties of sickle cells may lead to damage of blood vessel walls. Particular attention will be paid to blood vessels of serpentine and related shapes that are found in the brain. Diseased cells of a SCD patient are smaller and stiffer than healthy red blood cells (RBCs). Both of these features increase the propensity for cells to reside near blood vessel walls, a phenomenon called margination. Past experimental and computational work in idealized systems supports the hypothesis that diseased cells strongly marginate, residing primarily in the cell-free layer near blood vessel walls, thereby generating physical interactions such as large shear stress fluctuations and mechanical contacts that damage the endothelial cells that line the vessels. This project will move from idealized systems to physiologically relevant conditions and complexities, addressing important questions about the fluid mechanics of sickle cell disease. Detailed simulations and simplified mechanistic models will be used to (1) Predict the effects of cell properties, including shape, size, stiffness, adhesiveness and polydispersity on spatial distributions and wall interactions during flow, and (2) Mechanistically determine the effects of blood vessel geometry and hemodynamics on SCD RBC margination and cell-wall interactions, particularly in branched and serpentine blood vessel geometries characteristic of the brain microcirculation. Broader impacts of the project include (1) its focus on connecting fundamental biomechanics and fluid dynamics to an important problem in medicine, (2) involvement of undergraduate students, especially those from underrepresented minorities, in research, and (3) a service learning course in which undergraduate engineering students develop project-based lessons in fluid mechanics and share them with children from underserved minority populations.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.