Blood viscosity decreases with shear stress, a property essential for an efficient perfusion of the vascular tree. Shear thinning is intimately related to the dynamics and mutual interactions of RBCs, the major component of blood. Because of the lack of knowledge about the behavior of RBCs under physiological conditions, the link between RBC dynamics and blood rheology remains unsettled. We performed experiments and simulations in microcirculatory flow conditions of viscosity, shear rates, and volume fractions, and our study reveals rich RBC dynamics that govern shear thinning. In contrast to the current paradigm, which assumes that RBCs align steadily around the flow direction while their membranes and cytoplasm circulate, we show that RBCs successively tumble, roll, deform into rolling stomatocytes, and, finally, adopt highly deformed polylobed shapes for increasing shear stresses, even for semidilute volume fractions of the microcirculation. Our results suggest that any pathological change in plasma composition, RBC cytosol viscosity, or membrane mechanical properties will affect the onset of these morphological transitions and should play a central role in pathological blood rheology and flow behavior.

A recent study of red blood cells (RBCs) in shear flow [Lanotte et al., Proc. Natl. Acad. Sci. U.S.A. 113, 13289 (2016)PNASA60027-842410.1073/pnas.1608074113] has demonstrated that RBCs first tumble, then roll, transit to a rolling and tumbling stomatocyte, and finally attain polylobed shapes with increasing shear rate, when the viscosity contrast between cytosol and blood plasma is large enough. Using two different simulation techniques, we construct a state diagram of RBC shapes and dynamics in shear flow as a function of shear rate and viscosity contrast, which is also supported by microfluidic experiments. Furthermore, we illustrate the importance of RBC shear elasticity for its dynamics in flow and show that two different kinds of membrane buckling trigger the transition between subsequent RBC states.

The motion of red blood cells (RBCs) in microchannels is important for microvascular blood flow and biomedical applications such as blood analysis in microfluidics. The current understanding of the complexity of RBC shapes and dynamics in microchannels is mainly based on several simulation studies, but there are a few systematic experimental investigations. Here, we present a combined study that systematically characterizes RBC behavior for a wide range of flow rates and channel sizes. Even though simulations and experiments generally show good agreement, experimental observations demonstrate that there is no single well-defined RBC state for fixed flow conditions but rather a broad distribution of states. This result can be attributed to the inherent variability in RBC mechanical properties, which is confirmed by a model that takes the variation in RBC shear elasticity into account. This represents a significant step toward a quantitative connection between RBC behavior in microfluidic devices and their mechanical properties, which is essential for a high-throughput characterization of diseased cells.

Light scattering is a well-established experimental technique, which gains more and more popularity in the biological field because it offers the means for non-invasive imaging and detection. However, the interpretation of light-scattering signals remains challenging due to the complexity of most biological systems. Here, we investigate static and dynamic scattering properties of red blood cells (RBCs) using two mesoscopic hydrodynamics simulation methods—multi-particle collision dynamics and dissipative particle dynamics. Light scattering is studied for various membrane shear elasticities, bending rigidities, and RBC shapes (e.g., biconcave and stomatocyte). Simulation results from the two simulation methods show good agreement, and demonstrate that the static light scattering of a diffusing RBC is not very sensitive to the changes in membrane properties and moderate alterations in cell shapes. We also compute dynamic light scattering of a diffusing RBC, from which dynamic properties of RBCs such as diffusion coefficients can be accessed. In contrast to static light scattering, the dynamic measurements can be employed to differentiate between the biconcave and stomatocytic RBC shapes and generally allow the differentiation based on the membrane properties. Our simulation results can be used for better understanding of light scattering by RBCs and the development of new non-invasive methods for blood-flow monitoring.

The dynamics and deformation of red blood cells (RBCs) in microcirculation affect the flow resistance and transport properties of whole blood. One of the key properties that can alter RBC dynamics in flow is the contrast λ (or ratio) of viscosities between RBC cytosol and blood plasma. Here, we study the dependence of RBC shape and dynamics on the viscosity contrast in tube flow, using mesoscopic hydrodynamics simulations. State diagrams of different RBC dynamical states, including tumbling cells, parachutes, and tank-treading slippers, are constructed for various viscosity contrasts and wide ranges of flow rates and tube diameters (or RBC confinements). Despite similarities in the classification of RBC behavior for different viscosity contrasts, there are notable differences in the corresponding state diagrams. In particular, the region of parachutes is significantly larger for λ=1 in comparison to λ=5. Furthermore, the viscosity contrast strongly affects the tumbling-to-slipper transition, thus modifying the regions of occurrence of these states as a function of flow rate and RBC confinement. Also, an increase in cytosol viscosity leads to a reduction in membrane tension induced by flow stresses. Physical mechanisms that determine these differences in RBC dynamical states as a function of λ are discussed.

The motion of red blood cells (RBCs) in microchannels is important for microvascular blood flow and biomedical applications such as blood analysis in microfluidics. The current understanding of the complexity of RBC shapes and dynamics in microchannels is mainly based on several simulation studies, but there are a few systematic experimental investigations. Here, we present a combined study, which systematically characterizes RBC behavior for a wide range of flow rates and channel sizes. Even though simulations and experiments generally show good agreement, experimental observations demonstrate that there is no single well-defined RBC state for fixed flow conditions, but rather a broad distribution of states. This result can be attributed to the inherent variability in RBC mechanical properties, which is confirmed by a model that takes the variation in RBC shear elasticity into account. This represents a significant step toward a quantitative connection between RBC behavior in microfluidic devices and their mechanical properties, which is essential for a high-throughput characterization of diseased cells. STATEMENT OF SIGNIFICANCEThe ability to change shape is crucial for the proper functioning of red blood cells under harsh conditions in the microvasculature, since their shapes strongly affect the flow behavior of whole blood. Our results from simulations and systematic experiments reveal the shapes and dynamics of red blood cells for different flow conditions and channel dimensions, generally in good agreement. However, in the experiments, cells do not exhibit a single well-defined shape for fixed flow conditions. We show that this distribution of shapes can be attributed to the variability in mechanical properties of red blood cells.

The dynamics and deformation of red blood cells (RBCs) in microcirculation affect the flow resistance and transport properties of whole blood. One of the key properties that can alter RBC dynamics in flow is the contrast λ (or ratio) of viscosities between RBC cytosol and blood plasma. Here, we study the dependence of RBC shape and dynamics on the viscosity contrast in tube flow, using mesoscopic hydrodynamics simulations. State diagrams of different RBC dynamical states, including tumbling cells, parachutes, and tank-treading slippers, are constructed for various viscosity contrasts and wide ranges of flow rates and tube diameters (or RBC confinements). Despite similarities in the classification of RBC behavior for different viscosity contrasts, there are notable differences in the corresponding state diagrams. In particular, the region of parachutes is significantly larger for λ = 1 in comparison to λ = 5. Furthermore, the viscosity contrast strongly affects the tumbling-to-slipper transition, thus modifying the regions of occurrence of these states as a function of flow rate and RBC confinement. Also, an increase in cytosol viscosity leads to a reduction in membrane tension induced by flow stresses. Physical mechanisms that determine these differences in RBC dynamical states as a function of λ are discussed.

by internal/external stimuli, epithelial cells adopt a variety of shapes that affect their packing and the properties of the tissue and its morphology. In this context, the accepted view was that when tissues bend, cells change theirs shape from columnar (prism) to a ''bottle shape'' (frustum) hence assuming that the 3D packing properties remain unchanged along the apicobasal axis. In order to characterize and investigate the 3D packing and the shapes of cells in curved epithelia we mimicked computationally the architecture of tissues using computational geometry methods (Voronoi tessellation). To confirm the predictions of our model, we have investigated by microscopy means the 3D packing of the salivary gland of Drosophila (a model extensively used for tubulogenesis) as well as other tissues in different organisms. Finally, we have also developed a theoretical model based on energetic considerations to understand the biophysical origin of the 3D cellular organization. Our computational model predicts, and our experiments confirm, that, as the curvature of the tissue increases, prisms and frusta are not the only cell shapes that develop and reveals a previously undescribed geometrical shape: the scutoid. As a consequence, the apical and basal surfaces may have different packing topologies showing a neighbor interchange between cells along their apicobasal. Our energetics analysis reveals that scutoids allow tissues to minimize the packing energy and we propose that such geometrical shape is nature's solution to epithelial bending. 1) Scutoids are a geometrical solution to three-dimensional packing of epithelia, P. Gómez-Ghlvez et al.Integrin-mediated adhesions are essential for multicellular life because of their ability to both apply force to and sense the mechanical properties of the extracellular matrix. These effects are attributed to the ''focal adhesion clutch'', in which moving actin filaments transmit force to integrins via dynamic protein interactions. To understand mechanotransduction through integrins, we simultaneously measured force on talin together with rates of actin flow by combining a previously developed talin FRET tension sensor with quantitative actin speckle microscopy. While force on talin in small lamellipodial adhesions correlated with actin flow, force on talin in large adhesions in the lamella was mainly flow-independent. Stopping actin flow blocked force transmission in lamellipodia but not lamellar adhesions. This indicates there are two unique types of force transfer in integrin based adhesions, one that is actin flow-dependent and one that is actin flow-independent. Flowdependent force transfer required talin's C-terminal actin binding site, ABS3, whereas flow-independent force transfer required vinculin and the central actin binding site, ABS2. Mutation of these sites identified distinct functions in force transmission, cell spreading and mechanosensing. Together, these results revealed that the focal adhesion clutch is a transient structure that mediates events at the cell edge p...