In silico particle margination in blood flow

A profound knowledge of margination, the migration of blood components to the vessel wall in blood flow, is required in order to understand the genesis of various diseases, as e.g., cardiovascular diseases or bleeding disorders. Margination of particles is a pre-condition for potential adhesion. Adhesion to the vessel wall is required for platelets, the protein von Willebrand factor (VWF), but also for drug and imaging agent carriers in order to perform their particular tasks. In the haemostasis, a process to prevent blood loss in case of an injury, platelets adhere to the injured vessel wall in order to close a lesion by a blood clot. In regions, where high shear rates prevail, platelet adhesion is mediated by the large multimeric VWF, which, if stretched, provides binding sites for platelets. However, the triggers for VWF stretching are still not fully understood. Moreover, malfunction of this process and alteration of involved blood components might lead on the one hand to undesirable blood clots and subsequently to stroke or heart attack and, on the other hand, to severe bleeding disorders. Furthermore, the delivery of imaging agents and drugs via targeted carriers provides a promising strategy for early detection and therapy of diseases, for instance cancer. In this work, the dependence of margination on system parameters such as the volume faction of red blood cells (RBCs), shear rate, channel size, and particle deformability, size, and shape is examined, in order to shed light on the relevant physical mechanisms. Methodological, margination is investigated by means of computer simulations. Therefore, two mesoscopic hydrodynamic particle-based simulation approaches, the dissipative particle dynamics (DPD) method and the smoothed dissipative particle dynamics (SDPD) method, are employed. Furthermore, two-dimensional (2D) and three-dimensional (3D) mesoscopic models for RBCs, platelets, carriers, and the VWF are employed to study blood flow in microcirculation in a simplified geometry. For high enough shear rates and volume faction of RBCs (hematocrit), the investigated particles become quasi-trapped in the RBC-free-layer (RBC-FL), a region depleted of RBCs, which originates from a repulsive hydrodynamic lift of RBCs from the wall. With increasing hematocrit, the margination probability increases. The margination of deformable particles is also markedly influenced by the shear rate. With increasing shear rate and deformability, the margination decreases. Furthermore, the study indicates that micron-particles with an ellipsoidal shape and high aspect ratio, such as platelets, are favourable for drug carriers, rather than nano-carriers or considerably larger particles. Large particles might be moved away from the wall by RBCs and also nano-carriers show less margination into regions close to the wall. Moreover, the rotational dynamics and different studies of particle adhesion lead to a preference of an ellipsoidal shape over a spherical one. In addition, margination has been found to be most efficient in narrow channels. For wide channels, the RBC-FL thickness is too large to promote a high enough fraction of particles to be close to the wall. Furthermore, with increasing channel size, increasing hematocrit, or decreasing carrier size, an increase of carrier concentration is observed. Concerning the margination process, hydrodynamic interactions have been shown to slow down the shear-induced migration away from the RBC-FL, and to speed up the migration from the center to the RBC-FL. However, the shape of the particle distribution is mainly determined by excluded-volume interactions and collisions with RBCs. Regarding the VWF, strong attractive interactions between monomers of a polymer model lead not only to a globule stretching transition at a critical shear rate, as observed for the VWF in experiments, but also to a sufficient margination. Furthermore, adhesion of the VWF to the wall is identified as an additional trigger for stretching, since adhesion of one end of the polymer to the wall decreases the critical shear rate by an order of magnitude and leads to more extended conformations. Additionally, the adhesion of a platelet leads to even further stretching. All these conclusions are drawn by a combined interpretation of 2D and 3D simulations, since the margination in 2D and 3D has been shown to be qualitatively comparable.