13 research outputs found

    Deformability-induced effects of red blood cells in flow

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    To ensure a proper health state in the human body, a steady transport of blood is necessary. As the main cellular constituent in the blood suspension, red blood cells (RBCs) are governing the physical properties of the entire blood flow. Remarkably, these RBCs can adapt their shape to the prevailing surrounding flow conditions, ultimately allowing them to pass through narrow capillaries smaller than their equilibrium diameter. However, several diseases such as diabetes mellitus or malaria are linked to an alteration of the deformability. In this work, we investigate the shapes of RBCs in microcapillary flow in vitro, culminating in a shape phase diagram of two distinct, hydrodynamically induced shapes, the croissant and the slipper. Due to the simplicity of the RBC structure, the obtained phase diagram leads to further insights into the complex interaction between deformable objects in general, such as vesicles, and the surrounding fluid. Furthermore, the phase diagram is highly correlated to the deformability of the RBCs and represents thus a cornerstone of a potential diagnostic tool to detect pathological blood parameters. To further promote this idea, we train a convolutional neural network (CNN) to classify the distinct RBC shapes. The benchmark of the CNN is validated by manual classification of the cellular shapes and yields very good performance. In the second part, we investigate an effect that is associated with the deformability of RBCs, the lingering phenomenon. Lingering events may occur at bifurcation apices and are characterized by a straddling of RBCs at an apex, which have been shown in silico to cause a piling up of subsequent RBCs. Here, we provide insight into the dynamics of such lingering events in vivo, which we consequently relate to the partitioning of RBCs at bifurcating vessels in the microvasculature. Specifically, the lingering of RBCs causes an increased intercellular distance to RBCs further downstream, and thus, a reduced hematocrit.Um die biologischen Funktionen im menschlichen Körper aufrechtzuerhalten ist eine stetige Versorgung mit Blut notwendig. Rote Blutzellen bilden den Hauptanteil aller zellulären Komponenten im Blut und beeinflussen somit maßgeblich dessen Fließeigenschaften. Eine bemerkenswerte Eigenschaft dieser roten Blutzellen ist ihre Deformierbarkeit, die es ihnen ermöglicht, ihre Form den vorherrschenden Strömungsbedingungen anzupassen und sogar durch Kapillaren zu strömen, deren Durchmesser kleiner ist als der Gleichgewichtsdurchmesser einer roten Blutzelle. Zahlreiche Erkrankungen wie beispielsweise Diabetes mellitus oder Malaria sind jedoch mit einer Veränderung dieser Deformierbarkeit verbunden. In der vorliegenden Arbeit untersuchen wir die hydrodynamisch induzierten Formen der roten Blutzellen in mikrokapillarer Strömung in vitro systematisch für verschiedene Fließgeschwindigkeiten. Aus diesen Daten erzeugen wir ein Phasendiagramm zweier charakteristischer auftretender Formen: dem Croissant und dem Slipper. Aufgrund der Einfachheit der Struktur der roten Blutzellen führt das erhaltene Phasendiagramm zu weiteren Erkenntnissen über die komplexe Interaktion zwischen deformierbaren Objekten im Allgemeinen, wie z.B. Vesikeln, und des sie umgebenden Fluids. Darüber hinaus ist das Phasendiagramm korreliert mit der Deformierbarkeit der Erythrozyten und stellt somit einen Eckpfeiler eines potentiellen Diagnosewerkzeugs zur Erkennung pathologischer Blutparameter dar. Um diese Idee weiter voranzutreiben, trainieren wir ein künstliches neuronales Netz, um die auftretenden Formen der Erythrozyten zu klassifizieren. Die Ausgabe dieses künstlichen neuronalen Netzes wird durch manuelle Klassifizierung der Zellformen validiert und weist eine sehr hohe Übereinstimmung mit dieser manuellen Klassifikation auf. Im zweiten Teil der Arbeit untersuchen wir einen Effekt, der sich direkt aus der Deformierbarkeit der roten Blutzellen ergibt, das Lingering-Phänomen. Diese Lingering-Ereignisse können an Bifurkationsscheiteln zweier benachbarter Kapillaren auftreten und sind durch ein längeres Verweilen von Erythrozyten an einem Scheitelpunkt gekennzeichnet. In Simulationen hat sich gezeigt, dass diese Dynamik eine Anhäufung von nachfolgenden roten Blutzellen verursacht. Wir analysieren die Dynamik solcher Verweilereignisse in vivo, die wir folglich mit der Aufteilung von Erythrozyten an sich gabelnden Gefäßen in der Mikrovaskulatur in Verbindung bringen. Insbesondere verursacht das Verweilen von Erythrozyten einen erhöhten interzellulären Abstand zu weiter stromabwärts liegenden Erythrozyten und damit einen reduzierten Hämatokrit

    Effect of Cell Age and Membrane Rigidity on Red Blood Cell Shape in Capillary Flow

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    Blood flow in the microcirculatory system is crucially affected by intrinsic red blood cell (RBC) properties, such as their deformability. In the smallest vessels of this network, RBCs adapt their shapes to the flow conditions. Although it is known that the age of RBCs modifies their physical properties, such as increased cytosol viscosity and altered viscoelastic membrane properties, the evolution of their shape-adapting abilities during senescence remains unclear. In this study, we investigated the effect of RBC properties on the microcapillary in vitro flow behavior and their characteristic shapes in microfluidic channels. For this, we fractioned RBCs from healthy donors according to their age. Moreover, the membranes of fresh RBCs were chemically rigidified using diamide to study the effect of isolated graded-membrane rigidity. Our results show that a fraction of stable, asymmetric, off-centered slipper-like cells at high velocities decreases with increasing age or diamide concentration. However, while old cells form an enhanced number of stable symmetric croissants at the channel centerline, this shape class is suppressed for purely rigidified cells with diamide. Our study provides further knowledge about the distinct effects of age-related changes of intrinsic cell properties on the single-cell flow behavior of RBCs in confined flows due to inter-cellular age-related cell heterogeneity

    Red blood cells under flow: blood rheology and effect of vascular endothelial cells on haemodynamics in vitro

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    Understanding rheological properties and flow behavior of human blood is the object of a large body of literature related to both biomedical and clinical field of cardiovascular disorders as well as to the development of microfluidic platforms for blood testing. Although hemorheology and haemodynamics would seem to have the potential to describe complex physiological phenomena, there is still uncertainty regarding the exact applicability to specific issues. Here, an extensive rheological characterization under both continuous and oscillatory conditions is presented, demonstrating that human blood shows a peculiar viscoelastic behavior. In particular, the viscous character prevails over the elastic one even if the latter gives a significant contribution to the mechanical spectra. In addition, the effects of increasing red blood cells (RBC) volume fraction and of the addition of dextran, an aggregating agent, has been studied, showing a gel-like response. Regarding haemodynamics, blood flow in human body shows uncommon phenomena compared to other fluids. In vitro models that mimic human vasculature and the study of the interaction between endothelial cells and RBC are the main topics which have not been deeper investigated. Moreover, the properties and the role of endothelial glycocalyx (GCX), a negatively charged hairy layer of proteoglycans and glycoproteins located on the inner surface of the vascular endothelium, is far from being fully elucidated. In this work, the study of blood flow in microchannels lined with endothelial cells, including the GCX, has been proposed. Microchannels dimensions and flow conditions have been chosen to mimic big arterioles and venules regions. Velocity profiles of RBC in endothelialized microchannel have been compared with bare ones, suggesting a marginal role of the endothelial layer. Moreover, the electronegativity of endothelial GCX seems not to influence RBC flow. A case study that uses the mentioned approach is addressed to the analysis of malaria infected RBC by Plasmodium falciparum parasite. Indeed, the pathogenicity of Plasmodium parasite results from its ability to adhere to endothelium during its life cycle, preventing removal by the spleen. Preliminary results regarding dynamics of a single RBC are in good agreement with previous numerical simulation works, while the cytoadhesion has shown that both healthy and infected RBC adhere on endothelial cells. These findings could be useful for a deep understanding of the human blood flow behavior. In particular, viscoelastic characterization could help in elucidating the role of hemorheological alteration in pathologies such as myocardial infarction, hypertension, and diabetes. On the other hand, RBC-endothelial cell flow assay can serve as starting point to design blood-on-chip platforms aimed to study drug transport in blood stream

    Biophysical Regulation of in vitro Gastrulation using Human Induced Pluripotent Stem Cells

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    Embryogenesis is a complex process orchestrated through local morphogen gradients and physical constraints that give rise to the three germ layers. In vitro models of embryogenesis have been demonstrated by treating pluripotent stem cells in adherent or suspension culture with soluble morphogens and small molecules, which leads to tri-lineage differentiation. However, treatment with exogenous agents override the subtle spatiotemporal changes observed in vivo that ultimately underly the human body plan. In this thesis, we demonstrate how deformable hydrogels for pluripotent stem cell culture catalyse gastrulation-like events using materials alone. Micro-confinement through soft lithography enhances cell-cell adhesion and proliferation within the colony, where stress at the interface leads to mechanosensing mediated nuclear shape changes, epithelial to mesenchymal transition, and emergence of defined patterns of primitive streak containing SOX17+ T/BRACHYURY+ cells. Immunofluorescence staining, transcript analysis, and the use of pharmacological modulators reveal a role for mechanotransduction-coupled non-canonical wingless-type (Wnt) signalling and YAP1 signalling dynamics in promoting epithelial to mesenchymal transition at the interface, and multilayered organization within the colonies. These microscale gastruloids were removed from the substrate and grown in suspension culture. Rather than uniform growth as observed using traditional embryoid body culture, the gastruloids undergo multi-lobed outgrowth with evidence of further differentiation both in vitro and in vivo. Encapsulating the gastruloids into several hydrogel biomaterials indicates that materials properties will influence the interfacial positioning of primitive streak, which may prove a useful strategy to further direct differentiation. Together, this thesis demonstrates how materials alone can nurture embryonic gastrulation, with defined microenvironmental cues that mimic pre-streak events, thereby providing an in vitro model of early development. This work provides a new tool to link the biophysical and biochemical parameters of the local microenvironment to cell and tissue morphogenesis for fundamental studies. Using materials to guide morphogenesis in the laboratory provides an approach for directing differentiation, towards new materials-directed organoid models for tissue engineering and regenerative medicine

    The role of space, dispersal and active movement in fungal community assembly

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    Most of the theory of community ecology has been developed studying the unitary organisms. Therefore, the applicability of established theory to modular organisms remains unclear. Here we present theoretical developments that allow the community ecology of modular organisms to be firmly embedded within the established community ecology frameworks of modern coexistence theory and movement ecology. Within modular organisms, our primary focus is on filamentous fungi. The interplay of space and movement of organisms is critical for community assembly and species coexistence. Several research areas such as metacommunity theory, modern coexistence theory, and movement ecology aim to describe this interplay for animals and plants. These disciplines have assembled theoretical knowledge about the persistence and dynamics of biological diversity that is intended to be universally applicable to living systems. Applying theoretical concepts largely developed for unitary macro-organisms to filamentous fungi is challenging given their modular, network-like body structure. Here, we reviewed relevant knowledge from modern coexistence theory, movement ecology, and fungal ecology and developed two concepts that enable the application of established community ecology to filamentous fungi. We named these concepts unit of community interactions (UCI) and active movement of fungi. The first concept provides an operational definition of individual and population that is central to modern coexistence theory, but is problematic for clonal/modular life forms. This concept is introduced in the first chapter of this thesis along with modern coexistence theory applied to fungal systems. In the second chapter, we introduce the concept of active movement in fungi, demonstrating how the framework of movement ecology can be applied to filamentous fungi at all relevant spatial scales. We show that in modular organisms, physiological and morphological movements have a coupled ecological function and can thus influence community assembly via processes predicted by movement ecology. We further demonstrate this in the third chapter, where we describe the development of an agent-based model of hyphal dispersal in micro-structured environments and provide an initial evaluation of the model

    Modeling and Simulation of Lipid Membranes

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    Cell membranes are complex structures able to contain the main elements of the cell and to protect them from the external surroundings, becoming the most fundamental interface in Biology. The main subject of this book is the study of the structure and characteristics of lipid membranes in a wide variety of environments, ranging from simple phospholipid membranes to complex systems including proteins, peptides, or oncogenes as well as the analysis of the interactions of the membrane components with small molecules and drugs. The scope of this book is to provide recent developments on membrane structure, composition and function by means of theoretical and experimental techniques, some of them combining computer simulations with available data obtained at the laboratory.This Special Issue aims to report brand new key contributions to the field and also to give an overview about the connection between experiments and computer simulations, addressing fundamental aspects and applied research in biological membranes, with particular attention paid to the applications of computer modeling and simulation to medicine

    Modelling the dynamics of cellular membranes

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    [eng] Membranes are present in all cells, in some viruses, and are involved in all kinds of biological functions. The goal of this thesis is to expand our knowledge of this element, in hope that this -on top of all the other knowledge of biology and physics- can help someday improve people's life. With this aim, what I tried to do was to understand how cells react when things happen to them. This is the drive behind the two different research paths written in this thesis: membranes inside a fluid flow, and membranes during topological transitions and fluctuations. For the first research path -on membranes inside a flow- while this is not a new topic we wanted to start by making it more approachable. That has been achieved by introducing a new methodology to couple membranes and flows by using the stream function and the vorticity to solve the Navier Stokes equation. This approach creates a model derived straight from the hydrodynamic equations and grounded on the physics of the system rather than other more complex approaches. With this model we tried to study the effects of confinement for membranes inside a Poiseuille flow. We mainly tried to replicate red blood cell shapes as it is a very researched case and there is plenty of experimental data on them. First starting with cells inside channels slightly bigger than their diameter, which is known to give a set of shapes named parachutes and slippers. We use this knowledge to prove the validity of our model. For very wide channels, the low confinement Poiseuille flows have shown a different meta-stable shape which we named anti-parachute. Moreover, tumbling can be produced by introducing a different viscosity for the cell fluid, higher than the surrounding fluid. In very narrow super-confined channels we have a Poiseuille flow where the cell is much bigger than the channel and gives very different shapes. However, the model is capable of studying other flows rather than Poiseuille. Couette flow has been studied, where one can see a lift perpendicular to the flow that depends on the reduced volume of the cell as well as the viscosity contrast. The most important thing has been leaving behind a methodology ready for expansion to time-dependent flows, inertial flows, or to generalize to 3 dimensions. For the second research path --on topological transitions-- we have implemented the Gaussian curvature energy term to the membrane model, to allow study of fission and fusion. With this methodology we study fission of tubes with the use of the spontaneous curvature, which deforms a membrane tube into a pearled tube. This pearled tube formed by an array of spheres connected through membrane tethers undergoes fission if the Gaussian rigidity is negative and high enough. A phase diagram of what happens depending on the values of Gaussian and bending rigidity is obtained. Then we expand to study geometries less helpful for fission, such as a flat planar membrane. It will not matter how big is the spontaneous curvature of the Gaussian rigidity, as a perfectly flat membrane is a meta-stable shape. This is due the fact that to start the fission process we need an area with enough curvature so that the spontaneous curvature can kick-off the membrane budding process. To solve this, we added a white noise to mimic temperature. This noise makes each point of the membrane position to fluctuate. There is a phase transition between a flat membrane that is not undergoing fission and one that does.[cat] Les membranes estan presents a totes les cèl·lules, en alguns virus, i estan implicades en tot tipus de funcions biològiques. L'objectiu d'aquesta tesi és ampliar el nostre coneixement d'aquest element, amb l'esperança que això –junt amb tots els altres coneixements de biologia i física– pugui ajudar algun dia a millorar la vida de les persones. Amb aquest objectiu, el que vaig intentar va ser entendre com reaccionen les cèl·lules quan els passen coses. Aquest és el objectiu de les dues parts en les que està dividida la recerca en aquesta tesi: membranes dins d'un flux de fluids i membranes durant transicions topològiques. Per a la primera part de la recerca –sobre membranes dins d'un flux–, tot i que no és un tema extremadament nou, hem volgut començar per fer-lo més accessible. Això s'ha aconseguit introduint una nova metodologia per acoblar membranes i fluxos. Amb aquest model hem intentat estudiar els efectes del confinament de les membranes dins d'un flux. Tanmateix, el més important ha estat deixar enrere una metodologia preparada per a l'expansió a fluxos dependents del temps, fluxos inercials o per expandir-se a 3 dimensions. Per a la segona part de la recerca –sobre transicions topològiques– hem implementat el terme d'energia de curvatura gaussiana al model de membrana, per permetre l'estudi de la fissió i la fusió. Amb això s'estudia la fissió de tubs amb l'ús de la curvatura espontània. A partir d'això ens expandim per estudiar geometries menys tolerants per a la fissió, com ara una membrana plana plana. Afegint una temperatura a les simulacions s'estudia com en funció de la temperatura es pot promoure fins i tot una membrana amb geometria difícil per generar vesícules

    Physical properties of red blood cells in aggregation

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    Red blood cells (RBC) are micron-sized biological objects and the main corpuscular constituent of blood. It flows from larger arteries to very small capillaries. Utilizing a physical approach, this work aims to assess properties that govern blood flows and in particular the disaggregation and aggregation mechanisms of RBC at a single cell level. The interactions of RBCs are thus, investigated experimentally by measuring adhesive forces in the pN range in various model solutions thanks to optical tweezers. While two models for aggregation have been proposed: bridging and depletion, experimental evidence is still lacking to decide which mechanism prevails. The research presented here provides a new insight on the aggregation of RBCs and shows that the two models may not be exclusive. A complete 3-dimensional phase diagram of doublets has been established and confirmed by experiments by varying the adhesive forces and reduced cell volumes. Besides, the effect of aggregation was studied in vitro in a bifurcating microcapillary network and the distribution of aggregates and their stability in such a geometry are reported. Finally, experiments in flow allowed the characterization of the flow field around single RBCs at different velocities. Interesting vortical fluid structures have been also observed thanks to tracer nanoparticles.Rote Blutkörperchen (Erythrozyten) sind biologische Objekte im Mikrometerbereich und der korpuskuläre Hauptbestandteil des Blutes. Es fließt aus größeren Arterien in sehr kleine Kapillaren. Unter Verwendung eines physikalischen Ansatzes zielt diese Arbeit darauf ab, die Eigenschaften zu bewerten, die den Blutfluss und insbesondere die Disaggregations- und Aggregationsmechanismen der RBC auf Einzelzellebene regeln. Die Interaktionen der Erythrozyten werden daher experimentell untersucht, indem Adhäsionskräfte im pN-Bereich in verschiedenen Modelllösungen mit Hilfe einer optischen Pinzette gemessen werden. Während mit Bridging und Depletion zwei Modelle für die Aggregation vorgeschlagen wurden, fehlen noch experimentelle Beweise, um zu entscheiden, welcher Mechanismus vorherrscht. Die hier vorgestellte Forschung liefert neue Erkenntnisse über die Aggregation von RBCs und zeigt, dass die beiden Modelle möglicherweise nicht exklusiv sind. Es wurde ein vollständiges dreidimensionales Phasendiagramm von Dubletten erstellt und experimentell durch Variation der Adhäsionskräfte und reduzierte Zellvolumina bestätigt. Außerdem wurde der Effekt der Aggregation in vitro in einem sich gabelförmigen Mikrokapillarnetz untersucht, und es wird über die Verteilung der Aggregate und ihre Stabilität in einer solchen Geometrie berichtet. Schließlich erlaubten Strömungsexperimente die Charakterisierung des Strömungsfeldes um einzelne RBCs bei unterschiedlichen Geschwindigkeiten. Dank Tracer-Nanopartikeln konnten auch interessante wirbelartige Fluidstrukturen beobachtet werden

    The effect of red blood cell deformability on microscale blood flows

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    The non-Newtonian nature of blood arises from the presence of suspended formed elements which are the red blood cells (RBCs), white blood cells (WBCs) and platelets. Red blood cells or erythrocytes are the predominant constituent elements of blood, hence their role on haemodynamics is of great importance. Their remarkable deformability enables their flow in microvessels and is vital to oxygen delivery to tissue. Different diseases, such as malaria, sickle cell anaemia, diabetes etc. affect the mechanical properties and mainly the deformability of RBCs leading to pathological conditions and disorders in the microcirculation. However, the exact role of RBC deformability in microvascular flows has not been established hitherto. In this study, the role of red blood cell deformability on microscale haemodynamics was examined by perfusing artificially hardened RBCs in straight and bifurcating microchannels mimicking the microvasculature. RBC microchannel flows were resolved using brightfield micro-PIV methods. Advanced image processing routines were implemented in MATLAB to simultaneously determine the velocity and haematocrit distributions for a range of flow rates and feed haematocrit conditions. At low feed haematocrits (5%) hardened RBCs were found to be more dispersed in the straight microchannel flows compared to healthy RBCs, consistent with reports of decreased migration of hardened cells. At high haematocrits (25%) hardened RBCs produced less blunted velocity profiles compared to healthy RBCs, implying a reduction in the shear thinning behaviour of the suspensions. However, the haematocrit profiles appeared to also be sharper indicating some complex interactions between hardened cells. These findings were supported by cell tracking experiments which produced similar cell distributions for fluorescent hardened RBCs in a hardened RBC suspension, in contrast to observed margination of the same cells when suspended in healthy RBCs suspensions. Experiments with higher aspect microchannels confirmed the same trends, indicating that the latter were not due to confinement. The extent of RBC aggregation – indicated by the bluntness of the velocity and haematocrit profiles as well as the standard deviation of the image intensity – was found to be decreased in flows of hardened RBCs, compared to healthy ones in the whole range of the measured flow rates. RBC flows showed a higher level of heterogeneity in the bifurcating microchannels with both haematocrit and velocity profiles downstream of the T-junction bifurcation, exhibiting skewness the extent of which depended on the flow ratio between branches and RBC properties. RBC aggregation appeared to affect the non-uniformity of the haematocrit and velocity distributions downstream the bifurcation to a larger extent than RBC hardening which showed smaller variations compared to healthy non-aggregated RBC suspensions. Finally, the parent branch flow rate affected the redistribution of RBCs downstream of the bifurcation producing less skewed distributions with increasing flow rate. The thesis elucidated the physics of RBCs flows with impaired deformability providing thus the fundamental knowledge that is required for the development of medical diagnostic tools able to capture and assess the severity of diseases associated with impaired RBC deformability

    Shapes and Dynamics of Blood Cells in Poiseuille and Shear Flows

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    The dynamics, shape, deformation, and orientation of red blood cells in microcirculation affect the rheology, flow resistance and transport properties of whole blood. This leads to important correlations of cellular and continuum scales. Furthermore, the dynamics of RBCs subject to different flow conditions and vessel geometries is relevant for both fundamental research and biomedical applications (e.g drug delivery). In this thesis, the behaviour of RBCs is investigated for different flow conditions via computer simulations. We use a combination of two mesoscopic particle-based simulation techniques, dissipative particle dynamics and smoothed dissipative particle dynamics. We focus on the microcapillary scale of several μm. At this scale, blood cannot be considered at the continuum but has to be studied at the cellular level. The connection between cellular motion and overall blood rheology will be investigated. Red blood cells are modelled as viscoelastic objects interacting hydrodynamically with a viscous fluid environment. The properties of the membrane, such as resistance against bending or shearing, are set to correspond to experimental values. Furthermore, thermal fluctuations are considered via random forces. Analyses corresponding to light scattering measurements are performed in order to compare to experiments and suggest for which situations this method is suitable. Static light scattering by red blood cells characterises their shape and allows comparison to objects such as spheres or cylinders, whose scattering signals have analytical solutions, in contrast to those of red blood cells. Dynamic light scattering by red blood cells is studied concerning its suitability to detect and analyse motion, deformation and membrane fluctuations. Dynamic light scattering analysis is performed for both diffusing and flowing cells. We find that scattering signals depend on various cell properties, thus allowing to distinguish different cells. The scattering of diffusing cells allows to draw conclusions on their bending rigidity via the effective diffusion coefficient. The scattering of flowing cells allows to draw conclusions on the shear rate via the scattering amplitude correlation. In flow, a RBC shows different shapes and dynamic states, depending on conditions such as confinement, physiological/pathological state and cell age. Here, two essential flow conditions are studied: simple shear flow and tube flow. Simple shear flow as a basic flow condition is part of any more complex flow. The velocity profile is linear and shear stress is homogeneous. In simple shear flow, we find a sequence of different cell shapes by increasing the shear rate. With increasing shear rate, we find rolling cells with cup shapes, trilobe shapes and quadrulobe shapes. This agrees with recent experiments. Furthermore, the impact of the initial orientation on the dynamics is studied. To study crowding and collective effects, systems with higher haematocrit are set up. Tube flow is an idealised model for the flow through cylindric microvessels. Without cell, a parabolic flow profile prevails. A single red blood cell is placed into the tube and subject to a Poiseuille profile. In tube flow, we find different cell shapes and dynamics depending on confinement, shear rate and cell properties. For strong confinements and high shear rates, we find parachute-like shapes. Although not perfectly symmetric, they are adjusted to the flow profile and maintain a stationary shape and orientation. For weak confinements and low shear rates, we find tumbling slippers that rotate and moderately change their shape. For weak confinements and high shear rates, we find tank-treading slippers that oscillate in a limited range of inclination angles and strongly change their shape. For the lowest shear rates, we find cells performing a snaking motion. Due to cell properties and resultant deformations, all shapes differ from hitherto descriptions, such as steady tank-treading or symmetric parachutes. We introduce phase diagrams to identify flow regimes for the different shapes and dynamics. Changing cell properties, the regime borders in the phase diagrams change. In both flow types, both the viscosity contrast and the choice of stress-free shape are important. For in vitro experiments, the solvent viscosity has often been higher than the cytosol viscosity, leading to a different pattern of dynamics, such as steady tank-treading. The stress-free state of a RBC, which is the state at zero shear stress, is still controversial, and computer simulations enable direct comparisons of possible candidates in equivalent flow conditions
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