Computational Biorheology of Human Blood Flow in Health and Disease

Hematologic disorders arising from infectious diseases, hereditary factors and environmental influences can lead to, and can be influenced by, significant changes in the shape, mechanical and physical properties of red blood cells (RBCs), and the biorheology of blood flow. Hence, modeling of hematologic disorders should take into account the multiphase nature of blood flow, especially in arterioles and capillaries. We present here an overview of a general computational framework based on dissipative particle dynamics (DPD) which has broad applicability in cell biophysics with implications for diagnostics, therapeutics and drug efficacy assessments for a wide variety of human diseases. This computational approach, validated by independent experimental results, is capable of modeling the biorheology of whole blood and its individual components during blood flow so as to investigate cell mechanistic processes in health and disease. DPD is a Lagrangian method that can be derived from systematic coarse-graining of molecular dynamics but can scale efficiently up to arterioles and can also be used to model RBCs down to the spectrin level. We start from experimental measurements of a single RBC to extract the relevant biophysical parameters, using single-cell measurements involving such methods as optical tweezers, atomic force microscopy and micropipette aspiration, and cell-population experiments involving microfluidic devices. We then use these validated RBC models to predict the biorheological behavior of whole blood in healthy or pathological states, and compare the simulations with experimental results involving apparent viscosity and other relevant parameters. While the approach discussed here is sufficiently general to address a broad spectrum of hematologic disorders including certain types of cancer, this paper specifically deals with results obtained using this computational framework for blood flow in malaria and sickle cell anemia.National Institutes of Health (U.S.)Singapore-MIT Alliance for Research and Technology (SMART)United States. Dept. of Energy. Collaboratory on Mathematics for Mesoscopic Modeling of MaterialsUnited States. Dept. of Energy (INCITE Award

Multi-Scale Modeling of Soft Matter: Gas Vesicles and Red Blood Cells

Modeling of soft matter, nowadays, became an extremely active research field due to the advancement in computational power and theoretical physics. Not only because we can access and study larger length scales and longer time scales, but also, the ability to model more complex systems. In this dissertation, we utilized the state-of-the-art computational and theoretical tools to model and study two systems. The first system is gas vesicles, a proteineous organelle that exist in microorganisms such as archea and bacteria. The structure and assembly process of gas vesicles have received significant attention in recent decades, although relatively little is still known. In this work we develop a model for the major gas vesicle protein, GvpA, and explore its structure within the assembled vesicle. Elucidating this protein's structure has been challenging due to its adherent and aggregative nature, which has so far precluded in-depth biochemical analyses. Moreover, GvpA has extremely low similarity with any known protein structure, which renders homology modeling methods ineffective. Thus, alternate approaches were used to model its tertiary structure. Starting with the sequence from haloarchaeon Halobacterium sp.NRC-1, we performed ab-initio modeling and threading to acquire a multitude of structure decoys, which were equilibrated and ranked using molecular dynamics and mechanics, respectively. The highest ranked predictions exhibited an $alpha;-$beta;-$beta;-$alpha; secondary structure in agreement with earlier experimental findings, as well as with our own secondary structure predictions. Afterwards, GvpA subunits were docked in a quasi-periodic arrangement to investigate the assembly of the vesicle wall and to conduct simulations of contact-mode atomic force microscopy imaging, which allowed us to reconcile the structure predictions with the available experimental data. Finally, the GvpA structure for two representative organisms, Anabaena flos-aquae and Calothrix sp. PCC 7601, was also predicted, which reproduced the major features of our GvpA model, supporting the expectation that homologous GvpA sequences synthesized by different organisms should exhibit similar structures. The second system studied in this dissertation is red blood cells and their hemolytic processes. Due to the significant progress that has been achieved in the treatment of patients with cardiovascular diseases, procedures such as heart valve replacements, either with mechanical or biological substitutes, have become routine operations. However, despite this progress, the use of cardiovascular implants always results in changes to the blood fluid dynamics, such that undesired damage to red blood cells (hemolysis) occurs. This type of damage, which can also be brought about by certain medical procedures, such as dialysis, reduces the ability of the circulatory system to transport oxygen and carbon dioxide. To gain a deeper understanding of the conditions leading to hemolysis and to aid in the design of low-hemolysis cardiovascular implants, this document proposes the development of a coarse-grained dynamics model to simulate red blood cells, which will be integrated into a computational fluid dynamics solver and packaged into an integrated software tool. A novel aspect of the proposed model will be its ability to reproduce interactions between different red blood cells in large scale simulations, as well as hemolysis at the single-cell level due to the stresses imparted by the fluid. The model will be validated against previous experiments reported in the literature and will also be used to simulate model biodevices

Multiscale Molecular Simulation of Nanostructured Systems

2008/2009Computational materials science based on multiscale approach is very promising in the domain of nanoscience. It gives the modeler a route from the atomistic description of the system to a trust-worthy estimate of the properties of a material, obtained from the underlying molecules in a quantifiable manner. In this thesis we discuss general guidelines for its implementation in the field of nanomaterials and propose an alternative pathway to link effectively atomistic to mesoscopic scale and this, in turn, to the macroscopic scale. As proofs of concept for the reliability of the proposed approach, we consider several systems of industrial interest, ranging from polymeric nanocomposite materials, to epoxy resins, block copolymers, and gels for biomedical applications. In this context, we ascertain that multiscale molecular modelling can play a crucial role in the design of new materials whose properties are influenced by the structure at nanoscale. The results suggest that the combination of simulations at multiple scales can unleash the power of modeling and yield important insights.Le tecniche computazionali fondate su un approccio multiscala costituiscono uno strumento molto promettente nel campo della nanoscienza e dei nanomateriali. Esse forniscono al modellatore un percorso quantitativo che parte dalla descrizione atomistica fino alle proprietà finali del materiale. In questo lavoro di tesi sono discusse le linee guida per l’implementazione della modellistica multiscala nel settore dei nanomateriali ed è proposta una strategia alternativa alle soluzioni attualmente esistenti per collegare la scala atomistica alla mesoscala e, successivamente, la mesoscala alla scala macroscopica. Per dimostrare la validità del metodo proposto, sono stati presi in esame differenti sistemi di interesse industriale, i quali comprendono materiali nanocompositi polimerici, resine epossidiche, copolimeri a blocchi, e gel per applicazioni biomediche. In questo contesto, si è evidenziato come la modellistica multiscala possa svolgere un ruolo cruciale nella progettazione di nuovi materiali le cui proprietà sono influenzate dalla struttura a scala nanometrica. I risultati suggeriscono che la combinazione di simulazioni su scale multiple amplifica sinergicamente la potenza della modellazione e può fornire importanti intuizioni.XXII Ciclo197

Multiscale Modelling Of Platelet Aggregation

During clotting under flow, platelets bind and activate on collagen and release autocrinic factors such ADP and thromboxane, while tissue factor (TF) on the damaged wall leads to localized thrombin generation. Toward patient-specific simulation of thrombosis, a multiscale approach was developed to account for: platelet signaling (neural network trained by pairwise agonist scanning, PAS-NN), platelet positions (lattice kinetic Monte Carlo, LKMC), wall-generated thrombin and platelet-released ADP/thromboxane convection-diffusion (PDE), and flow over a growing clot (lattice Boltzmann). LKMC included shear-driven platelet aggregate restructuring. The PDEs for thrombin, ADP, and thromboxane were solved by finite element method using cell activation-driven adaptive triangular meshing. At all times, intracellular calcium was known for each platelet by PAS-NN in response to its unique exposure to local collagen, ADP, thromboxane, and thrombin. The model accurately predicted clot morphology and growth with time on collagen/TF surface as compared to microfluidic blood perfusion experiments. The model also predicted the complete occlusion of the blood channel under pressure relief settings. Prior to occlusion, intrathrombus concentrations reached 50 nM thrombin, ~1 μM thromboxane, and ~10 μM ADP, while the wall shear rate on the rough clot peaked at ~1000-2000 sec-1. Additionally, clotting on TF/collagen was accurately simulated for modulators of platelet cyclooxygenase-1, P2Y1, and IP-receptor. The model was then extended to a rectangular channel with symmetric Gaussian obstacles representative of a coronary artery with severe stenosis. The upgraded stenosis model was able to predict platelet deposition dynamics at the post-stenotic segment corresponding to development of artery thrombosis prior to severe myocardial infarction. The presence of stenosis conditions alters the hemodynamics of normal hemostasis, showing a different thrombus growth mechanism. The model was able to recreate the platelet aggregation process under the complex recirculating flow features and make reasonable prediction on the clot morphology with flow separation. The model also detected recirculating transport dynamics for diffusible species in response to vortex features, posing interesting questions on the interplay between biological signaling and prevailing hemodynamics. In future work, the model will be extended to clot growth with a patient cardio-vasculature under pulsatile flow conditions

Modelling of red blood cell morphological and deformability changes during in-vitro storage

© 2020 by the authors. Storage lesion is a critical issue facing transfusion treatments, and it adversely affects the quality and viability of stored red blood cells (RBCs). RBC deformability is a key indicator of cell health. Deformability measurements of each RBC unit are a key challenge in transfusion medicine research and clinical haematology. In this paper, a numerical study, inspired from the previous research for RBC deformability and morphology predictions, is conducted for the first time, to investigate the deformability and morphology characteristics of RBCs undergoing storage lesion. This study investigates the evolution of the cell shape factor, elongation index and membrane spicule details, where applicable, of discocyte, echinocyte I, echinocyte II, echinocyte III and sphero-echinocyte morphologies during 42 days of in-vitro storage at 4 °C in saline-adenine-glucose-mannitol (SAGM). Computer simulations were performed to investigate the influence of storage lesion-induced membrane structural defects on cell deformability and its recoverability during optical tweezers stretching deformations. The predicted morphology and deformability indicate decreasing quality and viability of stored RBCs undergoing storage lesion. The loss of membrane structural integrity due to the storage lesion further degrades the cell deformability and recoverability during mechanical deformations. This numerical approach provides a potential framework to study the RBC deformation characteristics under varying pathophysiological conditions for better diagnostics and treatments

Cellular Level In-silico Modeling of Blood Rheology with An Improved Material Model for Red Blood Cells

Many of the intriguing properties of blood originate from its cellular nature. Therefore, accurate modeling of blood flow related phenomena requires a description of the dynamics at the level of individual cells. This, however, presents several computational challenges that can only be addressed by high performance computing. We present Hemocell, a parallel computing framework which implements validated mechanical models for red blood cells and is capable of reproducing the emergent transport characteristics of such a complex cellular system. It is computationally capable of handling large domain sizes, thus it is able to bridge the cell-based micro-scale and macroscopic domains. We introduce a new material model for resolving the mechanical responses of red blood cell membranes under various flow conditions and compare it with a well established model. Our new constitutive model has similar accuracy under relaxed flow conditions, however, it performs better for shear rates over 1,500 s−1. We also introduce a new method to generate randomized initial conditions for dense mixtures of different cell types free of initial positioning artifacts

Shapes and Dynamics of Blood Cells in Poiseuille and Shear Flows

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

Computational Study of Cell Mobility and Transport Phenomena Through Textile Vascular Grafts Using a Multi-Scale Approach

Textile vascular grafts are biomedical devices that serve as partial replacement of damaged arterial vessels, prevent aneurysms rupture and restore normal blood flow -- It is believed that the success of a textile vascular graft, in the healing process after implantation, is due to the porous micro-structure of the wall -- Among the key properties that take part in the tissue repair process are the type of fabric and degree of porosity and permeability, defining the ability of a well-controlled environment for the neovascularization, nutrient supply, and cellular transport -- Although the transport of fluids through textiles is of great technical interest in biomedical applications, little is known about predicting the micro-flow pattern and the transport and deposition of individual platelets, related with the graft occlusion -- Often, this information is difficult to obtain experimentally both in vivo and in vitro, representing a great deal of research efforts -- The aim of this work is to investigate how the type of fabric, permeability and porosity affect both the local fluid dynamics at several scales and the fluid-particle interaction among platelets in textile grafts with an anastomosis of end-to-end configuration -- Two types of samples were analyzed: woven and electrospun, this last one has been manufactured -- This study involves both experimental and computational tests -- The experimental tests were performed to characterize the permeability and porosity under static conditions -- The computational tests are based on a multiscale approach where the fluid flow was solved with the Finite Element Method and the discrete particles were solved with the Molecular Dynamic Method -- The fluid-particle interaction was accomplished in one-, two-, and four-ways, where the blood was considered as a suspension of platelets in plasma -- The textile wall was considered as a porous media with two scales of length: straight tubular structure with porous walls for the macro-domain and representative unit cells of fabric for the micro-domain. Additionally, it presents the implementation of a numerical case that includes one of the main applications of textile vascular grafts to repair Abdominal Aortic Aneurysms (AAA) -- The results have shown that the type of fabric in textile vascular grafts and the degree of porosity and permeability affect the local fluid dynamics and the level of penetration of platelet particles through the graft wall at several length scales, thus indicating their importance as design parameters -- It was found that the permeability is strongly depends on the micro-structure of the fabric, changing the local fluid dynamics and the time of residence of platelets inside the wall -- Moreover, the porous walls cause deviations from Poiseuille flow due to leakage flow through the wall from a macroscopic viewpoint -- Lastly, it was possible to observe that the textile wall with different porosities, acting like a barrier between the blood and an aneurysmal zone, affects the flow pattern, the number of platelets adhered to the artificial surface and the time of residence of platelets into the aneurysmal zone -- In conclusion, predicting the flow pattern and the mobility of blood cells through the textile wall before the graft is manufactured, the development of new textile grafts can be improve