Quantitative prediction of flow dynamics and mechanical retention of surface-altered red blood cells through a splenic slit

Abstract

Normal red blood cells (RBCs) have remarkable properties of deformability, which enable them to squeeze through tiny splenic inter-endothelial slits (IESs) without any damage. Decreased surface-area-to-volume (SA/V) ratio through the loss of membrane surface is a key determinant of splenic entrapment of surface-altered RBCs due to cell aging or disease. Here, we investigate the flow dynamics and mechanical retention of the surface-altered RBCs with different extents of surface area loss, using a multiscale RBC (MS-RBC) model implemented in dissipative particle dynamics (DPD). We show that the DPD-based MS-RBC simulations can accurately reproduce the ex vivo experimentally measured rate of RBC mechanical retention when we take into account the distribution of RBC surface area (i.e., the size difference within the RBC population). We also examine the cumulative effect of the cell surface area loss on the traversal dynamics of the surface-altered RBCs, where we found that the final values of cell surface area (or the SA/V ratio) play a key role in determining the RBC traversal dynamics, regardless of the loss pathway of cell surface area. Taken together, these simulation results have implications for understanding the sensitivity of the splenic IESs to retain and clear the surface-altered RBCs with increased surface area loss, providing an insight into the fundamental flow dynamics and mechanical clearance of the surface-altered RBCs by the human spleen.

How the spleen reshapes and retains young and old red blood cells: A computational investigation

“…As RBCs age, their deformability decreases primarily due to reduced S/V [82], increased membrane stiffness [83] and increased ratio of internal viscosity to external viscosity [84], see recent review in [85]. A number of experimental [29,86] and computational studies [14,48,50,51,87] have demonstrated that S/V plays a much more important role in dictating the passage or retention of RBCs through narrow slit than the other two factors. In particular, a recent ex vivo experimental study [86] reported that a solo increase in membrane stiffness of diamide-treated RBCs without decreasing their S/V was not associated with mechanical retention in the human spleen.…”

“…In addition, prior studies on the traversal of RBCs through IES mainly look into the RBC deformation dynamics and the conditions for RBC retention or passage without considering the alterations of retained RBCs at IES.In this work, we perform a systematic computational study to simulate the passage of RBCs at different stages of their lifespan through IES in the spleen, the most stringent challenge on RBCs' integrity and deformability in the human circulation. Different from prior computational work [14,[48][49][50][51], we primarily focus on simulating the alterations of reticulocytes and senescent RBCs when traversing IES, such as pitting, vesiculation and lysis, and explore the mechanism of the spleen in facilitating the maturation of reticulocytes as well as to examine the emerging hypothesis of intrasplenic hemolysis triggered by mechanical trapping of aged RBCs [34].…”

Recent Advances in Computational Modeling of Biomechanics and Biorheology of Red Blood Cells in Diabetes

“…While in the particle-based methods, such as dissipative particle dynamics (DPD), blood cell models are constructed using DPD particles and thus are naturally assimilated with the background flow, continuum-based RBC models often implemented a boundary integral algorithm or the immersed boundary method (IBM) to couple RBC models with the background flow, which are solved using different solvers, including the finite volume method, the finite element method and the lattice Boltzmann method [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Motivated by experimental studies, recent progress in computational modeling has enabled simulations of fluid dynamics and cell aggregation dynamics under physiological and pathological states [ 10 , 27 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ], which has provided insight into the pathogenesis of the disease as well as facilitated the development of therapeutic treatments [ 51 , 52 ]. For example, RBC models developed using DPD are widely applied to simulate the deformation and aggregation of healthy RBC doublets [ 42 ] together with their effects on the blood cell dynamics in stenosed microvessels [ 43 ].…”

Physical mechanisms of red blood cell splenic filtration

“…Stacks of beads may provide slits of less than 1 μm in width but do not allow controlled and extensive studies (14). Recent numerical and/or theoretical approaches have suggested that the spleen may play an important role in defining the surface area-to-volume ratio of the RBCs circulating in the microvascular system (19–24), but, so far, numerical approaches are not quantitatively validated by experiments and no experimental direct observation of RBCs flowing in splenic-like slits supports this hypothesis. Moreover, observations (25, 26) also suggest that slit caliber may vary over time leading to the hypothesis and modeling (27) that it is modulated by stress fiber contraction in human endothelial cells.…”

“…Stacks of beads may provide slits 36 of less than 1 µm in width but do not allow controlled and 37 extensive studies (14). Recent numerical and/or theoretical 38 approaches have suggested that the spleen may play an impor-39 tant role in defining the surface area-to-volume ratio of the 40 RBCs circulating in the microvascular system (19)(20)(21)(22)(23)(24), but, so…”