Suspension physics govern the multiscale dynamics of blood flow in sickle cell disease

In diseases from diabetes to malaria, blood dynamics are significantly altered, resulting in poor clinical outcomes. However, the multiscale mechanisms that determine blood flow in the microcirculation in health and disease are undefined, largely owing to the difficulty in directly linking cell properties to whole-blood rheology. Here, we overcome these difficulties by developing a microfluidic platform to measure red blood cell properties and flow dynamics in the same blood samples from donors. We focus on sickle cell disease (SCD), a genetic disorder that causes red blood cells to stiffen in deoxygenated conditions, with disease pathology driven by oxygen-dependent blood rheology. Our linked cell and whole-blood measurements establish that increases in effective resistances in heterogeneous suspensions are driven by increases in the proportion of stiff cells, similar macroscopically to the behavior of rigid-particle suspensions. Furthermore, by combining simulations with spatially resolved measurements of cell dynamics, we show how the spatio-temporal organization of stiff and deformable cells determines blood rheology and drives disease pathophysiology. In the presence of deformable cells, the stiffened cells marginate towards channel walls, increasing effective wall friction. In fully deoxygenated conditions in which all cells are stiffened, significant heterogeneity in cell volume fraction along the direction of flow causes localized jamming, drastically increasing effective viscous flow resistance. Our work defines the relevant suspension physics required to understand pathological blood rheology in SCD and other diseases affecting red blood cell properties. More broadly, we reveal the multiscale processes that determine emergent rheology in heterogeneous particle suspensions.