Flowing blood displays a phenomenon called margination, in which leukocytes and platelets are preferentially found near blood vessel walls, while erythrocytes are depleted from these regions. Here margination is investigated using direct hydrodynamic simulations of a binary suspension of stiff (s) and floppy (f) capsules, as well as a stochastic model that incorporates the key particle transport mechanisms in suspensions-wall-induced hydrodynamic migration and shear-induced pair collisions. The stochastic model allows the relative importance of these two mechanisms to be directly evaluated and thereby indicates that margination, at least in the dilute case, is largely due to the differential dynamics of homogeneous (e.g. s-s) and heterogeneous (s-f) collisions.
Leukocytes normally marginate toward the vascular wall in large vessels and within the microvasculature. Reversal of this process, leukocyte demargination, leads to substantial increases in the clinical white blood cell and granulocyte count and is a welldocumented effect of glucocorticoid and catecholamine hormones, although the underlying mechanisms remain unclear. Here we show that alterations in granulocyte mechanical properties are the driving force behind glucocorticoid-and catecholamine-induced demargination. First, we found that the proportions of granulocytes from healthy human subjects that traversed and demarginated from microfluidic models of capillary beds and veins, respectively, increased after the subjects ingested glucocorticoids. Also, we show that glucocorticoid and catecholamine exposure reorganizes cellular cortical actin, significantly reducing granulocyte stiffness, as measured with atomic force microscopy. Furthermore, using simple kinetic theory computational modeling, we found that this reduction in stiffness alone is sufficient to cause granulocyte demargination. Taken together, our findings reveal a biomechanical answer to an old hematologic question regarding how glucocorticoids and catecholamines cause leukocyte demargination. In addition, in a broader sense, we have discovered a temporally and energetically efficient mechanism in which the innate immune system can simply alter leukocyte stiffness to fine tune margination/demargination and therefore leukocyte trafficking in general. These observations have broad clinically relevant implications for the inflammatory process overall as well as hematopoietic stem cell mobilization and homing. cellular mechanics | leukocyte deformability | demargination | microfluidics | atomic force microscopy L eukocyte margination within the microvasculature and in larger blood vessels is an integral part of the inflammatory process and innate immune system (1, 2). This margination phenomenon is twofold, involving sequestration of leukocytes in the capillary bed (3, 4) as well as movement of leukocytes toward the blood vessel wall (Fig. 1A) (5, 6). Recent experimental and computational data, including our own, indicate that the mechanical properties of leukocytes play a major role in margination and are sufficient to drive leukocytes in whole blood toward the vessel wall (7-12).What is not known is whether leukocyte softening can cause the reversal of leukocyte margination, which would indicate that leukocyte stiffness may be modulated by the immune system as an additional biophysical means to mediate leukocyte trafficking. To that end, we explored whether leukocyte stiffness alterations play a role in leukocyte demargination induced by glucocorticoid and catecholamine hormones. Although this phenomenon, which causes significant increases in the white blood cell (WBC) count within the clinical complete blood count (CBC) and specifically involves the granulocyte subpopulation of leukocytes, has been well documented from a clinical perspective for deca...
The effects of particle size and rigidity on segregation behaviour in confined simple shear flow of binary suspensions of fluid-filled elastic capsules are investigated in a model system that resembles blood. We study this problem with direct simulations as well as with a master equation model that incorporates two key sources of wall-normal particle transport: wall-induced migration and hydrodynamic pair collisions. The simulation results indicate that, in a mixture of large and small particles with equal capillary numbers, the small particles marginate, while the large particles antimarginate in their respective dilute suspensions. Here margination refers to localization of particles near walls, while antimargination refers to the opposite. In a mixture of particles with equal size and unequal capillary number, the stiffer particles marginate while the flexible particles antimarginate. The master equation model traces the origins of the segregation behaviour to the size and rigidity dependence of the wall-induced migration velocity and of the cross-stream particle displacements in various types of collisions. In particular, segregation by rigidity, especially at low volume fractions, is driven in large part by heterogeneous collisions, in which the stiff particle undergoes larger displacement. In contrast, segregation by size is driven mostly by the larger wall-induced migration velocity of larger particles. Additionally, a non-local drift-diffusion equation is derived from the master equation model, which provides further insights into the segregation behaviour.
Spatial segregation in the wall normal direction is investigated in suspensions containing a binary mixture of neo-Hookean capsules subjected to pressure driven flow in a planar slit. The two components of the binary mixture have unequal membrane rigidities. The problem is studied numerically using an accelerated implementation of the boundary integral method. The effect of a variety of parameters was investigated, including the capillary number, rigidity ratio between the two species, volume fraction, confinement ratio, and number fraction of the more floppy particle Xf in the mixture. It was observed that in suspensions of pure species, the mean wall normal positions of the stiff and the floppy particles are comparable. In mixtures, however, the stiff particles were found to be increasingly displaced toward the walls with increasing Xf, while the floppy particles were found to increasingly accumulate near the centerline with decreasing Xf. This segregation behavior was universally observed independent of the parameters. The origin of this segregation is traced to the effect of the number fraction Xf on the localization of the stiff and the floppy particles in the near wall region--the probability of escape of a stiff particle from the near wall region to the interior is greatly reduced with increasing Xf, while the exact opposite trend is observed for a floppy particle with decreasing Xf. Simple model studies on heterogeneous pair collisions involving a stiff and a floppy particle mechanistically explain the contrasting effect of Xf on the near wall localization of the two species. The key observation in these studies is that the stiff particle experiences much larger cross-stream displacement in heterogeneous collisions than the floppy particle. A unified mechanism incorporating the wall-induced migration of deformable particles away from the wall and the particle fluxes associated with heterogeneous and homogeneous pair collisions is presented.
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