Numerical simulation of blood flow and interstitial fluid pressure in solid tumor microcirculation based on tumor-induced angiogenesis

A coupled intravascular–transvascular–interstitial fluid flow model is developed to study the distributions of blood flow and interstitial fluid pressure in solid tumor microcirculation based on a tumor-induced microvascular network. This is generated from a 2D nine-point discrete mathematical model of tumor angiogenesis and contains two parent vessels. Blood flow through the microvascular network and interstitial fluid flow in tumor tissues are performed by the extended Poiseuille’s law and Darcy’s law, respectively, transvascular flow is described by Starling’s law; effects of the vascular permeability and the interstitial hydraulic conductivity are also considered. The simulation results predict the heterogeneous blood supply, interstitial hypertension and low convection on the inside of the tumor, which are consistent with physiological observed facts. These results may provide beneficial information for anti-angiogenesis treatment of tumor and further clinical research. The project supported by the National Natural Science Foundation of China (10372026).     

Numerical Investigation of Magnetic Nanoparticles Distribution Inside a Cylindrical Porous Tumor Considering the Influences of Interstitial Fluid Flow

A numerical simulation of interstitial fluid flow and blood flow and diffusion of magnetic nanoparticles (MNPs) are developed, based on the governing equations for the fluid flow, i.e., the continuity and momentum and mass diffusion equations, to a tissue containing two-dimensional cylindrical tumor. The tumor is assumed to be rigid porous media with a necrotic core, interstitial fluid and two capillaries with arterial pressure input and venous pressure output. Blood flow through the capillaries and interstitial fluid flow in tumor tissues are carried by extended Poiseuille’s law and Darcy’s law, respectively. Transvascular flows are also described using Starling’s law. MNPs diffuse by interstitial fluid flow in tumor. The finite difference method has been used to simulate interstitial fluid pressure and velocity, blood pressure and velocity and diffusion of MNPs injected inside a biological tissue during magnetic fluid hyperthermia (MFH). Results show that the interstitial pressure has a maximum value at the center of the tumor and decreases toward the first capillary. The reduction continues between two capillaries, and interstitial pressure finally decreases in direction of the tumor perimeter. This study also shows that decreasing in intercapillary distance may cause a decrease in interstitial pressure. Furthermore, multi-site injection of nanoparticles has better effect on MFH.     

3D numerical study of tumor blood perfusion and oxygen transport during vascular normalization

The changes of blood perfusion and oxygen transport in tumors during tumor vascular normalization are studied with 3-dimensional mathematical modeling and numerical simulation. The models of tumor angiogenesis and vascular-disrupting are used to simulate "un-normalized" and "normalized" vasculatures. A new model combining tumor hemodynamics and oxygen transport is developed. In this model, the intravasculartransvascular-interstitial flow with red blood cell(RBC) delivery is tightly coupled, and the oxygen resource is produced by heterogeneous distribution of hematocrit from the flow simulation. The results show that both tumor blood perfusion and hematocrit in the vessels increase, and the hypoxia microenvironment in the tumor center is greatly improved during vascular normalization. The total oxygen content inside the tumor tissue increases by about 67%, 51%, and 95% for the three approaches of vascular normalization,respectively. The elevation of oxygen concentration in tumors can improve its metabolic environment, and consequently reduce malignancy of tumor cells. It can also enhance radiation and chemotherapeutics to tumors.     

MASS TRANSPORT IN SOLID TUMORS (Ⅰ)──FLUID DYNAMICS

A three-porous-medium model for transvascular exchange and extravascular transport of fluid and macromolecules in a spherical solid tumor is developed. The microvasculature, lymphatics, and tissue space are each treated as a porous medium with the flow of blood. lymph, and interstitial fluid obeying Darcy’s law and Starling’s assumption. In this part, the role of interstitial pressure and fluid convection are studited. The analytical soiutions are obtained for foe isolated tumor and the normal-tissue-surrounded tumor respectively. The calculated interstitial pressure profue are consistent with the experimental observation that the elevated interstitial pressure is a major barrier in the penetration of macromolecular drug into tumors. The factors which may reduce the interstitial pressure are analyzed in details.     

MASS TRANSPORT IN SOLID TUMORS (Ⅰ)──FLUID DYNAMICS

I.IntroductionCancerhasbeenthekillerinmanywesterncountriesonlysecondtothecardiovasculardiseaseformanyyears.Ditficultiesinearlydiagnosisisoneofthemajorobstaclesincancertreatment.However,recentlyitisreportedthatthetumorphysiologicalbarrier,whichpreventsdrugsfrompenetratingintothecoreoftumor,'mayconstituteanothermajorobstacleinkillingcancercallseffectivelyl'].Therefore,tostudythemasstransp.ortprocessintumorbecomesimportantinthatitmayprovidesomecriteriafordrugdesignanddrug-giningstrategies.Tradit…     

利用血管生成模型计算实体肿瘤内的血液动力学

肿瘤血管生成(Tumor-induced Angiogenesis)是指在实体肿瘤细胞诱导下毛细血管的生长以及肿瘤中血液微循环的建立。肿瘤内血液、组织液等流体流动在肿瘤药物输运过程中扮演着重要作用,而这些流动受到肿瘤内微血管网络结构的直接影响。目前要获得精确的肿瘤内外的毛细血管拓扑结构存在一定困难,因此给肿瘤内的血液动力学研究带来困难。本文根据肿瘤内外的复杂生理特性,建立肿瘤内外血管生成的二维离散模型,在获得相对真实的毛细血管网络拓扑结构基础上对肿瘤内的血液动力学进行初步计算,数值计算的结果加深了对肿瘤的复杂生理特性的理解,同时也给肿瘤内的药物输运给予一定的提示。     

MASS TRANSPORT IN SOLID TUMORS(Ⅱ)──DRUG DELIVERY

Based on the flow field solution of the three-porous-medium model for tumor microcirculation, the diffusion-convection equations are solved with various initial and boundary conditions using finite element method. The concentration profile of two therapeutic agents: immunoglobulin G (IgG) and its antigen-binding fragment (Fab) in blood, lymph and interstitial fluid are obtained for normal-tissue-surrounded tumor. The effect of tumor microvasculature, lymph function, drug injection mode, the molecular weight and binding kinetics of the drug on the distribution in tumors are also considered.     

An analytical poroelastic model for laboratorial mechanical testing of the articular cartilage (AC)

The articular cartilage (AC) can be seen as a biphasic poroelastic material. The cartilage deformation under compression mainly leads to an interstitial fluid flow in the porous solid phase. In this paper, an analytical poroelastic model for the AC under laboratorial mechanical testing is developed. The solutions of interstitial fluid pressure and velocity are obtained. The results show the following facts. (i) Both the pressure and fluid velocity amplitudes are proportional to the strain loading amplitude. (ii) Both the amplitudes of pore fluid pressure and velocity in the AC depend more on the loading amplitude than on the frequency. Thus, in order to obtain the considerable fluid stimulus for the AC cell responses, the most effective way is to increase the loading amplitude rather than the frequency. (iii) Both the interstitial fluid pressure and velocity are strongly affected by permeability variations. This model can be used in experimental tests of the parameters of AC or other poroelastic materials, and in research of mechanotransduction and injury mechanism involved interstitial fluid flow.     

Numerical simulation of solid tumor angiogenesis with Endostatin treatment： a combined analysis of inhibiting effect of anti-angiogenic factor and micro mechanical environment of extracellular matrix

To investigate the influence of anti-angiogenesis drug Endostatin on solid tumor angiogenesis, a mathematical model of tumor angiogenesis was developed with combined influences of local extra-cellular matrix mechanical environment, and the inhibiting effects of Angiostatin and Endostatin. Simulation results show that Angiostatin and Endostatin can effectively inhibit the process of tumor angiogenesis, and decrease the number of blood vessels in the tumor. The present model could be used as a valid theoretical method in the investigation of anti-angiogenic therapy of tumors.     

Interstitial fluid flow: simulation of mechanical environment of cells in the interosseous membrane

In vitro experiments have shown that subtle fluid flow environment plays a significant role in living biological tissues,while there is no in vivo practical dynamical measurement of the interstitial fluid flow velocity.On the basis of a new finding that capillaries and collagen fibrils in the interosseous membrane form a parallel array,we set up a porous media model simulating the flow field with FLUENT software,studied the shear stress on interstitial cells’ surface due to the interstitial fluid flow,and analyzed the effect of flow on protein space distribution around the cells.The numerical simulation results show that the parallel nature of capillaries could lead to directional interstitial fluid flow in the direction of capillaries.Interstitial fluid flow would induce shear stress on the membrane of interstitial cells,up to 30 Pa or so,which reaches or exceeds the threshold values of cells’ biological response observed in vitro.Interstitial fluid flow would induce nonuniform spacial distribution of secretion protein of mast cells.Shear tress on cells could be affected by capillary parameters such as the distance between the adjacent capillaries,blood pressure and the permeability coefficient of capillary’s wall.The interstitial pressure and the interstitial porosity could also affect the shear stress on cells.In conclusion,numerical simulation provides an effective way for in vivo dynamic interstitial velocity research,helps to set up the vivid subtle interstitial flow environment of cells,and is beneficial to understanding the physiological functions of interstitial fluid flow.     

Ramp loading in Russian doll poroelasticity

Aporoelastic model for porous materials with a nested pore space structure is developed to represent the interstitial fluid flow in bone tissue. The nested porosity model is applied to the problem of determining the exchange of pore fluid between the vascular porosity (PV) and the lacunar-canalicular porosity (PLC) in bone tissue in a ramp loading in the case where the fluid and solid constituents are assumed to be compressible. The compressibility assumption is appropriate for hard tissues while the incompressibility assumption is appropriate for soft tissues. The influence of blood pressure in the PV is included in the analysis. A formula for the fluid that moves between the two porosities is developed. The analysis showed the coupling of the two porosities and their influence on each other and concluded that the PV pore pressure has an influence less than 3% on the PLC pore pressure while the absence of the PV pore pressure will affect the fluid exchange between the PV and PLC by less than 6% (the blood pressure range is 40-60 mmHg). Also the analysis has shown that the draining time of the PLC is inversely proportional to its permeability. The significance of the result is basic to the understanding of interstitial flow in bone tissue that, in turn, is basic to understanding of nutrient transport from the vasculature to the bone cells buried in the bone tissue and to the process of mechanotransduction by these cells.     

Fluid flow and fluid shear stress in canaliculi induced by external mechanical loading and blood pressure oscillation

The paper studies the problem of fluid flow and fluid shear stress in canaliculi when the osteon is subject to external mechanical loading and blood pressure oscillation. The single osteon is modeled as a saturated poroelastic cylinder. Solid skeleton is regarded as a poroelastic transversely isotropic material. To get near-realistic results, both the interstitial fluid and the solid matrix are regarded as compressible. Blood pressure oscillation in the Haverian canal is considered. Using the poroelasticity theory, an analytical solution of the pore fluid pressure is obtained. Assuming the fluid in canaliculi is incompressible, analytical solutions of fluid flow velocity and fluid shear stress with the Navier-Stokes equations of incompressible fluid are obtained. The effect of various parameters on the fluid flow velocity and fluid shear stress is studied.     

Squeeze flow of interstitial Herschel–Bulkley fluid between two rigid spheres

Interaction between two spheres with an interstitial fluid is crucial in discrete element modeling for simulating the behaviors of ‘wet’ particulate materials. The normal viscous force of squeeze flow between two arbitrary rigid spheres with an interstitial Herschel–Bulkley fluid was studied on the basis of Reynolds’ lubrication theory, resulting in analytical integral expressions of pressure distribution and the viscous force between the two spheres. According to the variation of shear stress, the fluid was divided into yielding and unyielding regions, followed by a discussion on the thickness of the two regions. The result of this paper could be reduced to either the power-law fluid or the Bingham fluid case.     

含液颗粒材料液固耦合分析的离散颗粒模型及特征线SPH法

对含液颗粒材料流固耦合分析建议了一个基于离散颗粒模型与特征线SPH法的显式拉格朗日-欧拉无网格方案。在已有的用以模拟固体颗粒集合体的离散颗粒模型[1]基础上,将颗粒间间隙内的流体模型化为连续介质,对其提出并推导了基于特征线的SPH法。数值例题显示了所建议方案在模拟颗粒材料与间隙流相互作用的能力和性能以及间隙流体对颗粒结构承载能力及变形的影响。     

恶性肿瘤研究新进展——生理屏障的发现

近年来发明的生物疗法,如单克隆抗体(Mabs),增长因子(GFs)等,由于它们在体外对癌细胞有效的杀伤能力而被称为“突破性药物”,“神奇炮弹”.但当这些药物用于病人体内时则疗效较差.从事肿瘤结构研究达15年之久的Jain博士最近指出,药物在体内疗效不好的原因是肿瘤内部产生了三个生理屏障:①非均匀的血液供给;②组织间隙中的高压;③组织间隙中的大传质距离.这些屏障使药物很难到达肿瘤内核区.尤其是对于从人体免疫系统提取的象单克隆抗体这类药物更严重,因为免疫系统的细胞和分子比一般药物分子大得多.因此,要使治癌药物在体内完成预期医疗效果,必须发展克服生理屏障的方法. 本文对生理屏障进行了全面描述,希望引起我国癌症研究者的注意和生物力学工作者的兴趣.      

Flow of a biomagnetic viscoelastic fluid: application to estimation of blood flow in arteries during electromagnetic hyperthermia,a therapeutic procedure for cancer treatment

The paper deals with the theoretical investigation of a fundamental problem of biomaguetic fluid flow through a porous medium subject to a magnetic field by using the principles of biomagnetic fluid dynamics （BFD）. The study pertains to a situation where magnetization of the fluid varies with temperature. The fluid is considered to be non-Newtonian, whose flow is governed by the equation of a second-grade viscoelastic fluid. The walls of the channel are assumed to be stretchable, where the surface velocity is proportional to the longitudinal distance from the origin of coordinates. The problem is first reduced to solving a system of coupled nonlinear differential equations involving seven parameters. Considering blood as a biomagnetic fluid and using the present analysis, an attempt is made to compute some parameters of the blood flow by developing a suitable numerical method and by devising an appropriate finite difference scheme. The computational results are presented in graphical form, and thereby some theoretical predictions are made with respect to the hemodynamical flow of the blood in a hyperthermal state under the action of a magnetic field. The results clearly indicate that the presence of a magnetic dipole bears the potential so as to affect the characteristics of the blood flow in arteries to a significant extent during the therapeutic procedure of electromagnetic hyperthermia. The study will attract the attention of clinicians, to whom the results would be useful in the treatment of cancer patients by the method of electromagnetic hyperthermia.     

基于Starling假设新发现的组织流场模拟

根据微血管壁渗流的Starling假设新发现,对人体骨间膜的组织液流动进行数值模拟,讨论 了组织间隙蛋白质非均匀分布对流动的影响. 结果发现血管壁中对蛋白质有渗透屏障作用的 纤维基质层, 导致了组织空间蛋白质非均匀分布. 靠近动脉端,高静水压引起毛细血管内液体 的净流出,使组织蛋白无法扩散到血管壁附近;在静脉端,由于毛细血管内静水压较低,蛋 白质可以扩散到血管壁附近. 将组织空间蛋白质非均匀分布与传统的Starling模型假设的蛋 白质浓度定常的数值模拟结果对比发现,两者组织液流动的速度有较大的差异,前者的最大 速度是后者的一半,非均匀分布模型的模拟结果更符合实验观察的现象,说明组织间隙蛋白 质的非均匀分布对组织液的流动很重要.     

一种骨小管中液体流动产生的流量及切应力模型

骨组织受力变形后其内部液体就会流动,同时在其微观结构——骨单元壁中扩散,并进一步产生一系列与骨液流动相关的物理效应,如流体剪切应力、流动电位等,这些物理效应被细胞感知并做出破骨或成骨等反应,来使骨适应外部载荷环境.鉴于骨组织产生的内部液体流动很难实验测定,理论模拟是目前的主要研究手段.基于骨单元的多孔弹性性质建立了骨小管内部液体的流动模型,该模型将骨单元所受的外部载荷与骨小管内部液体的压力、流速、流量和切应力联系起来,并进一步可以研究其力传导与力电传导机制.骨小管模型的建立分别基于中空和考虑哈弗液体的骨单元模型,并考虑了骨单元外壁的弹性约束和刚性位移约束两种边界条件.最终得到骨单元在外部轴向载荷作用下,骨小管内部液体的流量及流体切应力的解析解.结果表明:骨小管中的液体流量与流体切应力都正比于应变载荷幅值和频率,并由载荷的应变率决定.因此应变率可以作为控制流量和流体切应力的一种生理载荷因素.流量随着骨小管半径的增大而非线性增大,而流体切应力则随着骨小管半径的增大而线性增大.此外,在相同的载荷下,含哈弗液体的骨单元的模型中,骨小管中液体的流量和切应力均大于中空骨单元模型.     

On the permeability of fibre-reinforced porous materials

Biological tissues can be considered as composite materials comprised of a porous matrix filled with interstitial fluid and reinforced by impermeable collagen fibres. Motivated by studies on fluid flow in articular cartilage, we would like to quantify the undeformed configuration permeability of fibre-reinforced composite materials. If there is a sufficient scale separation between the internal structure of the porous matrix and the arrangement of the fibres, the matrix can be taken as a porous continuum at the fibre scale. In this case, the fibres can be treated as inclusions in a porous continuum, and the overall permeability of the composite can be evaluated using homogenisation procedures. For an isotropic homogeneous matrix, the symmetry of the system is governed by the orientation of the fibres. Here, we propose to retrieve the overall permeability through geometrical considerations and directional averaging methods. The special case of transverse isotropy is discussed in detail, with particular attention to the sub-cases of aligned fibres and fibres lying on a plane.     

Investigation of turbulence and skin friction modification in particle-laden channel flow using lattice Boltzmann method

Interaction between turbulence and particles is investigated in a channel flow. The fluid motion is calculated using direct numerical simulation (DNS) with a lattice Boltzmann (LB) method, and particles are tracked in a Lagrangian framework through the action of force imposed by the fluid. The particle diameter is smaller than the Kolmogorov length scale, and the point force is used to represent the feedback force of particles on the turbulence. The effects of particles on the turbulence and skin friction coefficient are examined with different particle inertias and mass loadings. Inertial particles suppress intensities of the spanwise and wall-normal components of velocity, and the Reynolds shear stress. It is also found that, relative to the reference particle-free flow, the overall mean skin-friction coefficient is reduced by particles. Changes of near wall turbulent structures such as longer and more regular streamwise low-speed streaks and less ejections and sweeps are the manifestation of drag reduction.