Microcirculatory blood flow in sickle cell disease

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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.