Hematocrit,viscosity and velocity distributions of aggregating and non-aggregating blood in a bifurcating microchannel

Microscale blood flow is characterised by heterogeneous distributions of hematocrit, viscosity and velocity. In microvascular bifurcations, cells are unevenly distributed between the branches, and this effect can be amplified in subsequent branches depending on a number of parameters. We propose an approach to infer hematocrit profiles of human blood flowing through a bifurcating microchannel. The influence of aggregation, induced by the addition of Dextran 2000 to the samples, is also considered. Averaged values indicate plasma skimming, particularly in the presence of red blood cell (RBC) aggregation. Using an empirical model, the hematocrit profiles are used to estimate local relative viscosity distributions. Simulations are used to predict how the non-uniform viscosity influences the velocity profiles. Comparing these data to velocity profiles of RBCs measured using particle image velocimetry provides validation of the model. It is observed that aggregation blunts velocity profiles after a long straight section of channel. Downstream of the bifurcation, skewing of the velocity profiles is detected, which is enhanced by aggregation. The proposed methodology is capable of providing hitherto unreported information on important aspects of microscale blood rheology.     

Estimation of hematocrit profile symmetry recovery length downstream from a bifurcation

Downstream from a microvascular bifurcation the distribution of blood cells in the vessel lumen is not symmetric. A diffusion process is used to model the rearrangement of red cells as blood flows between junctions in the microcirculation. A Fourier series approach is used to solve the model diffusion convection equation in slit geometry. Both flat and parabolic velocity profiles are considered. The eigenvalues, found using the Rayleigh-Ritz method, are used to find an upper bound on distance required for a symmetric red cell distribution to be obtained. The method has also been applied to cylindrical geometry and the computed symmetry recovery lengths are compared to distances between bifurcations measured in vivo. These estimates indicate that red cell distributions are frequently asymmetric in the microcirculation. Such asymmetries can have a strong effect on plasma skimming and material balance calculations.     

Inflow/Outflow Boundary Conditions for Particle-Based Blood Flow Simulations: Application to Arterial Bifurcations and Trees

When blood flows through a bifurcation, red blood cells (RBCs) travel into side branches at different hematocrit levels, and it is even possible that all RBCs enter into one branch only, leading to a complete separation of plasma and RBCs. To quantify this phenomenon via particle-based mesoscopic simulations, we developed a general framework for open boundary conditions in multiphase flows that is effective even for high hematocrit levels. The inflow at the inlet is duplicated from a fully developed flow generated in a pilot simulation with periodic boundary conditions. The outflow is controlled by adaptive forces to maintain the flow rate and velocity gradient at fixed values, while the particles leaving the arteriole at the outlet are removed from the system. Upon validation of this approach, we performed systematic 3D simulations to study plasma skimming in arterioles of diameters 20 to 32 microns. For a flow rate ratio 6:1 at the branches, we observed the “all-or-nothing” phenomenon with plasma only entering the low flow rate branch. We then simulated blood-plasma separation in arteriolar bifurcations with different bifurcation angles and same diameter of the daughter branches. Our simulations predict a significant increase in RBC flux through the main daughter branch as the bifurcation angle is increased. Finally, we demonstrated the effectiveness of the new methodology in simulations of blood flow in vessels with multiple inlets and outlets, constructed using an angiogenesis model.     

A numerical study of the shape of the surface separating flow into branches in microvascular bifurcations.

The shape of the separating surface formed by the streamlines entering the branches of microvascular bifurcations plays a major role in determining the distribution of red blood cells and other blood constituents downstream from the bifurcation. Using the finite element method, we determined the shape of the surface through numerical solution of three dimensional Navier-Stokes equations for fluid flow at low Reynolds numbers in a T-type bifurcation of circular tubes. Calculations were done for a wide range of daughter branch to parent vessel diameter ratios and flow ratios. The effect of Reynolds number was also studied. Our numerical results are in good agreement with previously reported experimental data of Rong and Carr (Microvascular Research, Vol. 39, pp. 186-202, 1990). The numerical results of this study will be used to predict the concentration of blood constituents downstream from microvascular bifurcations providing that the inlet concentration profile is known.     

Dynamics of blood flow: modeling of the Fåhræus–Lindqvist effect

To model the Fåhræus–Lindqvist effect, Haynes’ marginal zone theory is used, following previous works, i.e., a core layer of uniform red blood cells (RBCs) is assumed to be surrounded by an annular plasma layer in which no RBCs are present. A simplified trial-and-error solution procedure is provided to determine the size of the core region and the hematocrit level in that zone in addition to the apparent viscosity, given the (upstream) large vessel hematocrit level and the average hematocrit level in the (downstream) small vessel. To test the model, a set of experimental data is selected to provide not only apparent viscosity data but also the average hematocrit levels in small tubes of different diameters. The results are found to support Haynes’ marginal theory, with no fitting parameters used in the computations. Viscous dissipation is determined. The use of the mechanical energy balance is found to lead to results that are consistent with those based on the momentum balance, while leaving the average hematocrit level undetermined and required by either experimental data or an additional equation based on further theoretical work. The present analysis is used to model bifurcation using published empirical correlations quantifying the Fåhræus effect and phase separation. The model equations are extended to microvascular networks with repeated bifurcations.     

Liposomes - a selective drug delivery system for the topical route of administration I. Lotion dosage form

The applicability of liposomes as drug carriers for the topical route of administration was investigated using triamcinolone as a model drug. The liposomal encapsulation favourably altered the drug dipposition; the concentration of the drug decreased at the site of its adverse effects and increased at the site where its activity is desired.     

Two-dimensional lattice Boltzmann study of red blood cell motion through microvascular bifurcation: cell deformability and suspending viscosity effects

Red blood cell (RBC) motion and trajectories in bifurcated microvessels are simulated using a two-dimensional immersed boundary-lattice Boltzmann method (IB-LBM). A RBC is modeled as a capsule with viscous interior fluid enclosed by a flexible membrane. For the symmetric bifurcation model employed, the critical offset position in the mother branch, which separates the RBC flux toward the two branches, has been calculated. The RBC flux and the hematocrit partitioning between the two daughter branches have also been studied. Effects of the flow-rate ratio, cell deformability and suspending viscosity have been examined. Simulation results indicate that increased cell rigidity and suspending viscosity have counter effects on cell trajectory through a bifurcation: the cell trajectory shifts toward the low flow-rate branch for less deformable cells, and toward the high flow-rate branch for more viscous plasma. These results imply that a higher cell rigidity would reduce the regular phase separation of hematocrit and plasma skimming processes in microcirculation, while an increased viscosity has the opposite effect. This has implications for relevant studies in fundamental biology and biomedical applications.     

Photometric assay for measuring the intracellular concentration of branched-chain amino acids in bacteria

The changes in intracellular pool of branched-chain amino acids (BCAA) regulate different physiological processes in bacteria. Up to date, the only available photometric test for measuring BCAA concentration was adapted for blood and plasma samples in diagnostic purposes. We have modified this method for use on bacterial cells, and tested its applicability on several model organisms: Lactococcus lactis, Bacillus subtilis and Escherichia coli.     

Venular endothelium-derived NO can affect paired arteriole: a computational model

Venular endothelial cells can release nitric oxide (NO) in response to intraluminal flow both in isolated venules and in vivo. Experimental studies suggest that venular endothelium-released NO causes dilation of the adjacent paired arteriole. In the vascular wall, NO stimulates its target hemoprotein, soluble guanylate cyclase (sGC), which relaxes smooth muscle cells. In this study, a computational model of NO transport for an arteriole and venule pair was developed to determine the importance of the venular endothelium-released NO and its transport to the adjacent arteriole in the tissue. The model predicts that the tissue NO levels are affected within a wide range of parameters, including NO-red blood cell reaction rate and NO production rate in the arteriole and venule. The results predict that changes in the venular NO production affected not only venular endothelial and smooth muscle NO concentration but also endothelial and smooth muscle NO concentration in the adjacent arteriole. This suggests that the anatomy of microvascular tissue can permit the transport of NO from arteriolar to venular side, and vice versa, and may provide a mechanism for dilation of proximal arterioles by venules. These results will have significant implications for our understanding of tissue NO levels in both physiological and pathophysiological conditions.     

内皮抑素及其在抗肿瘤中的应用

内皮抑素是一种抗血管生成的抑制因子,它特异性地作用于新生微血管的内皮细胞,其水平与肿瘤血管生成有着明显的相关性。体内外的研究均表明,内皮抑素具有无毒副作用、不容易产生耐药性和易达到有效药物浓度等优点。我们简要综述了内皮抑素的特性、作用机制,及其在抗肿瘤应用等方面的研究进展。     

Investigation of the Spatiotemporal Responses of Nanoparticles in Tumor Tissues with a Small-Scale Mathematical Model

The transport and accumulation of anticancer nanodrugs in tumor tissues are affected by many factors including particle properties, vascular density and leakiness, and interstitial diffusivity. It is important to understand the effects of these factors on the detailed drug distribution in the entire tumor for an effective treatment. In this study, we developed a small-scale mathematical model to systematically study the spatiotemporal responses and accumulative exposures of macromolecular carriers in localized tumor tissues. We chose various dextrans as model carriers and studied the effects of vascular density, permeability, diffusivity, and half-life of dextrans on their spatiotemporal concentration responses and accumulative exposure distribution to tumor cells. The relevant biological parameters were obtained from experimental results previously reported by the Dreher group. The area under concentration-time response curve (AUC) quantified the extent of tissue exposure to a drug and therefore was considered more reliable in assessing the extent of the overall drug exposure than individual concentrations. The results showed that 1) a small macromolecule can penetrate deep into the tumor interstitium and produce a uniform but low spatial distribution of AUC; 2) large macromolecules produce high AUC in the perivascular region, but low AUC in the distal region away from vessels; 3) medium-sized macromolecules produce a relatively uniform and high AUC in the tumor interstitium between two vessels; 4) enhancement of permeability can elevate the level of AUC, but have little effect on its uniformity while enhancement of diffusivity is able to raise the level of AUC and improve its uniformity; 5) a longer half-life can produce a deeper penetration and a higher level of AUC distribution. The numerical results indicate that a long half-life carrier in plasma and a high interstitial diffusivity are the key factors to produce a high and relatively uniform spatial AUC distribution in the interstitium.     

Significance of plasma skimming and plasma volume expansion.

The organs associated with plasma volume expansion, i.e., the red bone marrow, the enlarged spleen, and the uteroplacental complex, are arteriovenous shunts with an interposed sinusoidal stroma able to skim off plasma-rich blood. In the spleen, plasma separation is an integral part of the hemoconcentration. In the red bone marrow, plasma skimming might provide a washout mechanism for the many newly formed erythrocytes and platelets from the sinusoids to the peripheral blood circulation. In the uteroplacental complex, skimming of plasma-rich blood is beneficial in increasing blood flow in the myometrium, kidneys, and skeletal musculature. The hypervolemic status with anemia will simulate a negative iron balance, which speeds up the absorption of iron. Thus a conceptual unit seems to exist in which rheological factors influence such functions as transport of newly formed blood cells into the circulation (in the red bone marrow), hemoconcentration (in the spleen), and iron balance during pregnancy (in the uteroplacental complex).     

通络救脑注射液对脑微血管内皮细胞活性影响的特征

目的：观察通络救脑注射液对培养的正常及缺血脑微血管内皮细胞的活性影响。揭示其通络作用的效应靶点与特征。方法：原代培养大鼠脑皮质微血管内皮细胞,传至第三代。分为正常及拟缺血组,采用培养基氧糖刺夺（OGD）法建立拟缺血模型。通过四甲基偶氮唑盐（MTT）比色分析法测定不同浓度的通络救脑注射液对正常及OGD内皮细胞的活性影响。结果：通络救脑注射液作用于正常脑微血管内皮细胞,与未加药组比较,小剂量药物抑制细胞活性趋势,大剂量促进细胞活性趋势,剂量总趋势呈反抛物线形;通络救脑注射液作用于OGD组脑微血管内皮细胞,小剂量范围促进内皮细胞的增殖活性,呈显著和极显著差异,而大剂量组则抑制细胞活性,剂量总趋势呈抛物线形。结论：通络救脑注射液对正常及缺血脑微血管内皮细胞具有双向调节作用,药物剂量与细胞增殖活性呈非线性关系。天剂量与小剂量可能是不同的作用机制,反映了中药复方药效的多维性。     

Surface charge of nanoparticles determines their endocytic and transcytotic pathway in polarized MDCK cells

A major challenge in drug delivery is the internalization through the apical plasma membrane of the polarized epithelial cells lining organs facing the external environment, e.g., lungs and the gastrointestinal tract. The reduced permeation of drugs entering through this pathway is in part due to the mucosal barrier and low rate of endocytosis at these membranes. We investigated the possible role of nanoparticle surface charge on its entry through the apical plasma membrane and its intracellular pathway. We found that both cationic and anionic nanoparticles are targeted mainly to the clathrin endocytic machinery. A fraction of both nanoparticle formulations is suspected to internalize through a macropinocytosis-dependent pathway. A significant amount of nanoparticles transcytose and accumulate at the basolateral membrane. Some anionic but not cationic nanoparticles transited through the degradative lysosomal pathway. Taken together, these observations indicate that cationic nanoparticles, in addition to their potential for drug delivery to epithelia, may be promising carriers for transcytosing drugs to the blood stream.     

Application of the Convection–Dispersion Equation to Modelling Oral Drug Absorption

Models of systemic drug absorption after oral administration are frequently based on a direct or a delayed first-order rate process. In practice, the use of the first-order approach to predict drug concentrations in blood plasma frequently yields a considerable mismatch between predicted and measured concentration profiles. This is particularly true for the upswing of the plasma concentration after oral administration. The current investigation explores an alternative model to describe the absorption rate based on the convection–dispersion equation describing the transport of chemicals through the GI tract. This equation is governed by two parameters, transport velocity and dispersion coefficient. One solution of this equation for a specific set of initial and boundary conditions was used to model absorption of paracetamol in a 22-year-old man after oral administration. The GI-tract passage rate in this subject was influenced by co-administration of drugs that stimulate or delay gastric emptying. The transport-limited absorption function is more accurate in describing the plasma concentration versus time curve after oral administration than the first-order model. Additionally, it provides a mechanistic explanation for the observed curve through the differences in GI-tract passage rate.     

Effect of nonaxisymmetric hematocrit distribution on non-Newtonian blood flow in small tubes

Hematocrit distribution and red blood cell aggregation are the major determinants of blood flow in narrow tubes at low flow rates. It has been observed experimentally that in microcirculation the hematocrit distribution is not uniform. This nonuniformity may result from plasma skimming and cell screening effects and also from red cell sedimentation. The goal of the present study is to understand the effect of nonaxisymmetric hematocrit distribution on the flow of human and cat blood in small blood vessels of the microcirculation. Blood vessels are modeled as circular cylindrical tubes. Human blood is described by Quemada's rheological model, in which local viscosity is a function of both the local hematocrit and a structural parameter that is related to the size of red blood cell aggregates. Cat blood is described by Casson's model. Eccentric hematocrit distribution is considered such that the axis of the cylindrical core region of red cell suspension is parallel to the axis of the blood vessel but not coincident. The problem is solved numerically by using finite element method. The calculations predict nonaxisymmetric distribution of velocity and shear stress in the blood vessel and the increase of apparent viscosity with increasing eccentricity of the core.     

Ascorbate prevents microvascular dysfunction in the skeletal muscle of the septic rat.

Septic patients have low plasma ascorbate concentrations and compromised microvascular perfusion. The purpose of the present experiments was to determine whether ascorbate improves capillary function in volume-resuscitated sepsis. Cecal ligation and perforation (CLP) was performed on male Sprague-Dawley rats. The concentration of ascorbate in plasma and urine, mean arterial blood pressure, and density of continuously perfused capillaries in the extensor digitorum longus muscle were measured 24 h after surgery. CLP caused a 50% decrease (from 56 +/- 4 to 29 +/- 2 microM) in plasma ascorbate concentration, 1,000% increase (from 46 +/- 13 to 450 +/- 93 microM) in urine ascorbate concentration, 20% decrease (from 115 +/- 2 to 91 +/- 2 mmHg) in mean arterial pressure, and 30% decrease (from 24 +/- 1 to 17 +/- 1 capillaries/mm) in the density of perfused capillaries, compared with time-matched controls. A bolus of intravenous ascorbate (7.6 mg/100 g body wt) administered immediately after the CLP procedure increased plasma ascorbate concentration and restored both blood pressure and density of perfused capillaries to control levels. In vitro experiments showed that ascorbate (100 microM) inhibited replication of bacteria and prevented hydrogen peroxide injury to cultured microvascular endothelial cells. These results indicate that ascorbate is lost in the urine during sepsis and that a bolus of ascorbate can prevent microvascular dysfunction in the skeletal muscle of septic animals. Our study supports the view that ascorbate may be beneficial for patients with septic syndrome.     

Multiple equilibrium states in a micro-vascular network

We use a simple model of micro-vascular blood flow to explore conditions that give rise to multiple equilibrium states in a three-node micro-vascular network. The model accounts for two primary rheological effects: the Fåhræus-Lindqvist effect, which describes the apparent viscosity of blood in a vessel, and the plasma skimming effect, which governs the separation of red blood cells at diverging nodes. We show that multiple equilibrium states are possible, and we use our analytical and computational tools to design an experiment for validation.     

Quantification of kinetic rate constants for transcytosis of polymeric nanoparticle through blood-brain barrier

Background

Polymeric nanoparticles (PNP) have received significant amount of interests for targeted drug delivery across the blood-brain barrier (BBB). Experimental studies have revealed that PNP can transport drug molecules from microvascular blood vessels to brain parenchyma in an efficient and non-invasive way. Despite that, very little attention has been paid to theoretically quantify the transport of such nanoparticles across BBB.