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The splenic interendothelial slits fulfill the essential function of continuously filtering red blood cells (RBCs) from the bloodstream to eliminate abnormal and aged cells. To date, the process by which 8 $\mathrm{\mu }$m RBCs pass through 0.3 $\mathrm{\mu }$m-wide slits remains enigmatic. Does the slit caliber increase during RBC passage as sometimes suggested? Here, we elucidated the mechanisms that govern the RBC retention or passage dynamics in slits by combining multiscale modeling, live imaging, and microfluidic experiments on an original device with submicron-wide physiologically calibrated slits. We observed that healthy RBCs pass through 0.28 $\mathrm{\mu }$m-wide rigid slits at 37 °C. To achieve this feat, they must meet two requirements. Geometrically, their surface area-to-volume ratio must be compatible with a shape in two tether-connected equal spheres. Mechanically, the cells with a low surface area-to-volume ratio (28% of RBCs in a 0.4 $\mathrm{\mu }$m-wide slit) must locally unfold their spectrin cytoskeleton inside the slit. In contrast, activation of the mechanosensitive PIEZO1 channel is not required. The RBC transit time through the slits follows a $-$1 and $-$3 power law with in-slit pressure drop and slip width, respectively. This law is similar to that of a Newtonian fluid in a two-dimensional Poiseuille flow, showing that the dynamics of RBCs is controlled by their cytoplasmic viscosity. Altogether, our results show that filtration through submicron-wide slits is possible without further slit opening. Furthermore, our approach addresses the critical need for in vitro evaluation of splenic clearance of diseased or engineered RBCs for transfusion and drug delivery. 

Computational modeling and simulations can tackle a broad range of morphological, mechanical, and rheological problems relevant to blood and blood cells. Here, we review some continuum-based and particle-based computational approaches towards the modeling of healthy and diseased red blood cells (RBCs) with focus on the most recent contributions, including the three-level multiscale RBC model coupled with the boundary integral method of surrounding flows and two-component RBC models with explicit descriptions of lipid bilayer, cytoskeleton, and transmembrane proteins.