Non-invasive assessment for intratumoural distribution of interstitial fluid flow

Interstitial fluid plays a vital role in drug delivery and tumour treatment.However,few non-invasive measurement methods are available for measuring low-velocity biological fluid flow.Therefore,this study aimed to develop a novel technology called interstitial flow velocity-MRI.The interstitial flow velocity-MRI sequence consists of a dual inversion recovery preparation and an improved stimulated echo sequence(ISTE)combined with phase-contrast MRI.A homemade flow phantom was used to assess the feasibility and sensitivity of interstitial flow velocity-MRI.In addition,xenografts of female BALB/c mouse models of 4T1 breast cancer administered losartan(40 mg/kg)or saline(n?6)were subjected to imaging on a 7.0 T scanner to assess the in vivo interstitial fluid flow velocity.The results showed a significant correlation(P<0.001)between the theoretical velocities and velocities measured using the flow phantom.Interstitial flow velocity-MRI could detect a velocity as low as 10.21±2.65 mm/s with a spatial resolution of 0.313 mm.The losartan group had a lower mean interstitial fluid velocity than the control group(85±16 vs 113±24 mm/s).In addition,compared to the saline treatment,losartan treatment reduced the proportion of collagen fibres by 10%and 12%in the Masson and Sirius red staining groups,respectively.Interstitial flow velocity-MRI has the potential to determine interstitial fluid flow velocity non-invasively and exhibits an intuitive velocity map.

Role of interstitial flow in tumor migration through 3D ECM

Cancer invasion in tissue is simultaneously regulated by chemical and mechanical cues.Evidences suggest that interstitial flow plays a critical role in tumor metastasis.On one hand,the distribution of chemokines around cell is influenced by flow.On the other hand,interstitial flow may reconfigure the alignment of fiber matrix,which greatly changes the contact force between cell and extracellular matrix.In this study,we have upgraded a model by which we can quantitatively investigate the influence of flow on tumor cell migration.A hydrodynamic analysis of shear stress on a slender body is introduced to simulate the fiber realignment.Factors such as subtle flow and cell-matrix interaction which dominate tumor migration are integrated in this novel model.Simulation results show interstitial flow facilitates tumor cell migration in the flow direction.Moreover,the flow-related chemical and mechanical cues have a synergistic effect on the migration.This model provides better understanding on cancer metastasis and helps design vitro experiment precisely.

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.

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 ceils. 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.

Fundamental kinematics laws of interstitial fluid flows on vascular walls

In the previous studies,the phenomenon that the interstitial fluid(ISF)can flow along tunica adventitia of the arteries and veins in both human and animal bodies was reported.On the basis of these studies,this paper aims to:(i)summarize the basic properties of the ISF flows in the walls of arteries and veins,(ii)combine the basic properties with axiomaticism and abstract the axiom for ISF flows,and(iii)propose three fundamental laws of the ISF flow,(i.e.,the existence law,the homotropic law and the reverse law).The three laws provide solid theoretical basement for exploring the kinematic patterns of interstitial fluid flow in the cardiovascular system.

Modeling Tracer Flow Characteristics in Different Types of Pores: Visualization and Mathematical Modeling

Structure of porous media and fluid distribution in rocks can significantly affect the transport characteristics during the process of microscale tracer flow.To clarify the effect of micro heterogeneity on aqueous tracer transport,this paper demonstrates microscopic experiments at pore level and proposes an improved mathematical model for tracer transport.The visualization results show a faster tracer movement into movable water than it into bound water,and quicker occupancy in flowing pores than in storage pores caused by the difference of tracer velocity.Moreover,the proposed mathematical model includes the effects of bound water and flowing porosity by applying interstitial flow velocity expression.The new model also distinguishes flowing and storage pores,accounting for different tracer transport mechanisms(dispersion,diffusion and adsorption)in different types of pores.The resulting analytical solution better matches with tracer production data than the standard model.The residual sum of squares(RSS)from the new model is 0.0005,which is 100 times smaller than the RSS from the standard model.The sensitivity analysis indicates that the dispersion coefficient and flowing porosity shows a negative correlation with the tracer breakthrough time and the increasing slope,whereas the superficial velocity and bound water saturation show a positive correlation.

Analytic solutions of the interstitial fluid flow models

In this paper, we present the analytic solutions of several continuum porous media models that describe the interstitial fluid flow in the interosseous membrane. We first compare the results of the Brinkman, Stokes and Darcy systems in describing the isotropic interstitial fluid flows. Our calculations show that the Stokes equations can well approximate the Brinkman equations when the Darcy number Da 〉 0.2, while the Darcy model is an appropriate approximation to the Brinkman model in the interosseous membrane when Da 〈 2 × 10-4. Yet, in most cases, the anisotropy dominates the interstitial fluid. Therefore, we build an anisotropic Darcy model and show that an isotropic model can be used as a suitable approximation when the ratio between the transverse and longitudinal permeabilities is no larger than 20. Lastly, we take the blood flow in capillaries into consideration as well and introduce the coupled Stokes-Darcy system to describe the cases comprising both the capillary and the interstitial domain. Our results reveal that the profile of the interface exchange flow is not exactly in the linear form as was widely adopted in the numerical simulation, instead, the flux near the artery and the vein is more significant, which in turn results in the increase of the maximum horizontal velocity in the interstitial space while the outflow rate remains the same.

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 interstitiM 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.

Dynamics of Calcium Signal and Leukotriene C_(4) Release in Mast Cells Network Induced by Mechanical Stimuli and Modulated by Interstitial Fluid Flow

Mast cells(MCs)play an important role in the immune system.Through connective tissues,mechanical stimuli activate intracellular calcium signaling pathways,induce a variety of mediators including leukotriene C4(LTC4)release,and affect MCs’microenvironment.This paper focuses on MCs’intracellular calcium dynamics and LTC4 release responding to mechanical stimuli,explores signaling pathways in MCs and the effect of interstitial fluid flow on the transport of biological messengers and feedback in the MCs network.We use a mathematical model to show that(i)mechanical stimuli including shear stress induced by interstitial fluid flow can activate mechano-sensitive(MS)ion channels on MCs’membrane and allow Ca^(2+)entry,which increases intracellular Ca^(2+)concentration and leads to LTC4 release;(ii)LTC4 in the extracellular space(ECS)acts on surface cysteinyl leukotriene receptors(LTC4R)on adjacent cells,leading to Ca^(2+)influx through Ca^(2+)release-activated Ca^(2+)(CRAC)channels.An elevated intracellular Ca^(2+)concentration further stimulates LTC4 release and creates a positive feedback in the MCs network.The findings of this study may facilitate our understanding of the mechanotransduction process in MCs induced by mechanical stimuli,contribute to understanding of interstitial flow-related mechanobiology in MCs network,and provide a methodology for quantitatively analyzing physical treatment methods including acupuncture and massage in traditional Chinese medicine(TCM).

A three-dimensional biomimetic microfluidic chip to study the behavior of hepatic stellate cell under the tumor microenvironment

In this paper, we designed a three-dimensional cell co-cultured microfluidic chip, which generated interstitial flow and oxygen gradient to simulate the complex tumor microenvironment. It consisted of five parallel cell culture channels and one hypoxic channel. These channels were constructed for the culture of mouse liver tumor cells(Hepa1-6), mouse liver stellate cells(JS-1), the simulation of extracellular matrix, complex biochemical factors(hypoxia and interstitial flow), and the supply of cellular nutrients. The 3D-interstitial flow-hypoxia model was used to study the behavior of JS-1 cells under the effect of tumor microenvironment(TME). The results showed that by co-cultured with Hepa1-6 cells, hypoxia of Hepa1-6 cells, and adding TGF-β1 by interstitial flow, the migration of JS-1 cells could be promoted. Similarly,activated JS-1 cells could led to the epithelial-mesenchymal transformation in co-cultured Hepa1-6 cells,which secreted more TGF-β 1.