Microcirculatory blood flow in sickle cell disease

镰状细胞病（SCD）是一种红血球疾病，影响了大约10万美国人，尤其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，红细胞随着年龄的增长而变硬，通常呈镰刀状。SCD的急性症状出现时，患病的红细胞阻塞小血管，由于镰状形状和硬度增加，导致局部血液流动受限。然而，长期的问题也出现了，这些问题在过去很少受到关注。血管周围的细胞在大多数循环区域变得功能失调，尤其是在大脑中，血管损伤与中风的风险增加有关，中风是导致SCD死亡的主要原因之一，但人们对中风的了解最少。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。该项目将使用详细的血流数学模型模拟，以更好地理解镰状细胞特性的改变是如何导致血管壁损伤的。特别注意的是在大脑中发现的蛇形血管和相关形状的血管。SCD患者的病变细胞比健康红细胞（红细胞）更小、更硬。这两种特征都增加了细胞靠近血管壁的倾向，这种现象被称为边缘现象。过去在理想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，主要居住在血管壁附近的无细胞层，从而产生物理相互作用，如大的剪切应力波动和机械接触，破坏血管内皮细胞。该项目将从理想化的系统转移到生理相关条件和复杂性，解决镰状细胞病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)预测细胞特性的影响，包括形状、大小、刚度、黏附性和多分散性对流动过程中空间分布和细胞壁相互作用的影响，以及(2)从机制上确定血管几何和血流动力学对SCD红细胞边缘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)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本科生参与研究，以及(3)一门服务学习课程，在该课程中，工程本科学生开发基于项目的流体力学课程，并与来自服务不足的少数民族的儿童分享。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.