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.     

实体肿瘤血管生成和肿瘤生长的耦合研究

研究宏观尺度上肿瘤向外浸润式生长的动态变化对微观尺度上肿瘤内部微血管网生成过程产生的影响。建立肿瘤组织生长动力学模型与促血管生成的二维离散数学模型,模型考虑促血管生成因子诱导下血管内皮细胞的随机性、趋化性和趋触性运动以及血管内皮细胞与胞外基质的相互作用,并且肿瘤组织的生长满足经典的Compertz函数形式,通过耦合研究模拟了肿瘤组织动态生长过程中微脉管系统生成的时空演化,数值生成肿瘤动态生长下内外异构的微血管网和肿瘤内部分层的网络结构。该模型可以产生相对真实的具有接近肿瘤病理生理特性的血管网,为临床研究提供有益的信息。     

Numerical modeling of a mechano-chemical theory for wound contraction analysis

Wound contraction due to traction forces exerted by cells on the underlying extracellular matrix (ECM) brings the wound edges together, effectively reducing the wound size and aiding its healing. It occurs on deep wounds and burns only and plays a central role on fibroplasia related pathologies. In this work, we present a novel model based on the work of Olsen et al. [Olsen, L., Sherratt, J.A., Maini, P.K., 1995. A mechanochemical model for adult dermal wound contraction and the permanence of the contracted tissue displacement profile. Journal of Theoretical Biology 177 (2), 113–128] in which we incorporate a cell differentiation mechanical signaling, a cell mechanical sensing and transmission of traction forces to the ECM and a dynamical change of the ECM mechanical properties with collagen deposition. Along with the mathematical model, we propose a numerical solution of the nonlinearly coupled convection–diffusion-reaction equations based on a finite element analysis with a Newton–Raphson solver and rigorous linearizations of the nonlinear terms. We investigate the effect of wound morphology on the contraction process and analyze the influence of the strength of the dermal attachment to the underlying tissue on contraction.     

Numerical simulation of inhibiting effects on solid tumour cells in anti-angiogenic therapy: application of coupled mathematical model of angiogenesis with tumour growth

To investigate the inhibiting effects of the anti-angiogenic factor andostatin and the anti-angiogenic drug endostatin on tumour angiogenesis and tumour cells, a coupled mathematical model of tumor angiogenesis with tumour growth and blood perfusion is developed. Simulation results show that angiostatin and endostatin can improve the abnormal microenvironment inside the tumour tissue by effectively inhibiting the process of tumor angiogenesis and decreasing tumour cells. The present model can be used as a valid theoretical method in the investigation of the tumour anti-angiogenic therapy.     

Mathematical modeling of anisotropic avascular tumor growth

Cancer represents one the most challenging problems in medicine and biology nowadays, and is being actively addressed by many researchers from different areas of knowledge. The increasing development of sophisticated mathematical models and computer-based procedures has had a positive impact on our understanding of cancer-related mechanisms and the design of anticancer treatment strategies. However, further investigation and experimentation are still required to completely elucidate the tumor-associated mechanical responses, as well as the effect of mechanical forces on the net tumor growth. In this work we develop a theoretical framework in the context of continuum mechanics to investigate the anisotropic growth of avascular tumor spheroids. To that end, a specific anisotropic growth deformation tensor is considered, which also describes an isotropic growth law as a particular case. Mixtures theory and the notion of multiple natural configurations are then used to formulate a mathematical model of avascular tumor growth. More precisely, mass, momentum balance and nutrients diffusion equations are derived, where solid tumors are assumed as hyperelastic and compressible materials. Moreover, mechanical interactions with a rigid extracellular matrix (ECM) are considered, and the mechanical modulation of growing tumors in a rigid surrounding tissue is investigated by means of numerical simulations. Finally, the model results are compared with experimental data previously reported in the literature.     

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。     

Two-dimensional discrete mathematical model of tumor-induced angiogenesis

A 2D discrete mathematical model of a nine-point finite difference scheme is built to simulate tumor-induced angiogenesis. Nine motion directions of an individual endothelial cell and two parent vessels are extended in the present model. The process of tumor-induced angiogenesis is performed by coupling random motility, chemotaxis, and haptotaxis of endothelial cell in different mechanical environments inside and outside the tumor. The results show that nearly realistic tumor microvascular networks with neoplastic pathophysiological characteristics can be generated from the present model. Moreover, the theoretical capillary networks generated in numerical simulations of the discrete model may provide useful information for further clinical research.     

Numerical simulation of avascular tumor growth based on p27 gene regulation

A multi-scale continuous-discrete model based on the effects of the p27 gene control is built to simulate the avascular tumor growth. At the tissue level, the continuous Eulerian model is adopted to determine the distribution of the concentration of oxygen, the extracellular matrix (ECM), and the matrix-degradative enzyme (MDE). At the cellular level, the discrete Lagrangien model is adopted to determine the movement, the proliferation, and the death of single tumor cells (TCs). At the genetic level, whether a cell is committed to mitosis is determined by solving a set of equations modeling the effects of the p27 gene control. The avascular morphological evolution of the solid tumor growth is simulated, including the radius of the solid tumor, the number of the TCs, the oxygen distribution over time, and the inhibiting effect of the up-regulating p27 gene expression.     

Measurement of Mechanical Properties of Soft Tissues In Vitro Under Controlled Tissue Hydration

Alterations in tissue hydration that accompany inflammation or chronic remodeling of the Extracellular Matrix (ECM) have significant impact on the biomechanics of vascular tissue in health and disease. Examination of tissue behavior under controlled hydration in vitro could be helpful in better understanding the effects of tissue water content on its mechanical properties where in vivo tissue conditioning could not be possible. This study explains a multistage experimental protocol that allows both to prepare the tissue specimens with specific water content and to measure their mechanical behavior while maintaining the water content constant during the laboratory experimentation. Stress relaxation behaviors of the bovine aortic specimens–extracted from native, collagen-denatured and elastin-isolated tissues–were obtained within a water content range of 100–400 %. Using this method, distinct relaxation behaviors were obtained from tissue specimens with changing ECM treatments and hydration levels. The relaxation behavior was found to conform to a 4-parameter linear-viscoelastic macromechanical model consisting of two Maxwell components in parallel. The macromechanical model was able to distinguish between the morphological mechanisms associated with ECM elastin and collagen.     

浮式垂直轴风机的动力学建模、仿真与实验研究

考虑气动力和水动力的耦合研究浮式垂直轴风机系统的运动响应,将固定式垂直轴风机的气动载荷计算方法进一步推广到海上浮式垂直轴风机的气动载荷计算.考虑阻尼力、波浪力、风载荷、系泊力等,建立了浮式垂直轴风机系统的纵荡-垂荡-纵摇运动方程.考虑动态失速和浮式基础运动,基于双致动盘多流管理论,推导了风机叶片气动载荷计算公式,编制了数值计算程序.以Sandia 17 m风机为例,验证了气动载荷计算程序的正确性.最后进行了模型实验,其中模型的风机为Φ型达里厄垂直轴风机,支撑基础为桁架式Spar型浮式基础,将模型实验结果与数值计算结果进行了对比,验证了耦合计算程序.结果表明,数值计算得到的风机系统的垂荡、纵摇运动的RAO(幅值响应算子)曲线与模型实验结果吻合较好,验证了耦合程序的正确性.然而,由于数值计算与模型实验在运动自由度、阻尼、风载荷等方面存在差别,数值计算结果与模型实验结果仍有一定的差异.     

A numerical and experimental hybrid approach for the investigation of aerodynamic forces on stay cables suffering from rain-wind induced vibration

The aerodynamic forces on a stay cable under a rain-wind induced vibration (RWIV) are difficult to measure directly in a wind tunnel test. This paper presents a hybrid approach that combines an experiment with computational fluid dynamics (CFD) for the investigation on aerodynamic forces of a stay cable under a RWIV. The stay cable and flow field were considered as two substructures of the system. The oscillation of the stay cable was first measured by using a wind tunnel test of a RWIV under an artificial rainfall condition. The oscillation of the cable was treated as a previously known moving boundary condition and applied to the flow field. Only the flow field with the known moving cable boundary was then numerically simulated by using a CFD method (such as Fluent 6.3). The transient aerodynamic forces of the stay cable with a predetermined cable oscillation were obtained from numerical calculations. The characteristics of the aerodynamic forces in the time domain and frequency domain were then analysed for various cases. To verify the feasibility and accuracy of the proposed hybrid approach, the transient aerodynamic forces were applied to a single-degree-of-freedom model (SDOF) of the stay cable to calculate the RWIV of the cable. A comparison was performed between the oscillation responses of the stay cable obtained from the calculated (SDOF model) and experimental results, and the results indicate that the hybrid approach accurately simulates the transient aerodynamic forces of the stay cable. The equivalent damping ratios induced by the aerodynamic forces were obtained for various wind speeds. Furthermore, a nonlinear model of the aerodynamic force is proposed based on the calculation results, and the coefficients in the model were identified by a nonlinear least-squares technique.     

Some basic questions on mechanosensing in cell–substrate interaction

Cells constantly probe their surrounding microenvironment by pushing and pulling on the extracellular matrix (ECM). While it is widely accepted that cell induced traction forces at the cell–matrix interface play essential roles in cell signaling, cell migration and tissue morphogenesis, a number of puzzling questions remain with respect to mechanosensing in cell–substrate interactions. Here we show that these open questions can be addressed by modeling the cell–substrate system as a pre-strained elastic disk attached to an elastic substrate via molecular bonds at the interface. Based on this model, we establish analytical and numerical solutions for the displacement and stress fields in both cell and substrate, as well as traction forces at the cell–substrate interface. We show that the cell traction generally increases with distance away from the cell center and that the traction-distance relationship changes from linear on soft substrates to exponential on stiff substrates. These results indicate that cell adhesion and migration behaviors can be regulated by cell shape and substrate stiffness. Our analysis also reveals that the cell traction increases linearly with substrate stiffness on soft substrates but then levels off to a constant value on stiff substrates. This biphasic behavior in the dependence of cell traction on substrate stiffness immediately sheds light on an existing debate on whether cells sense mechanical force or deformation when interacting with their surroundings. Finally, it is shown that the cell induced deformation field decays exponentially with distance away from the cell. The characteristic length of this decay is comparable to the cell size and provides a quantitative measure of how far cells feel into the ECM.     

PREDICTIVE APPROACH TO FAILURE OF COMPOSITE LAMINATES WITH EQUIVALENT CONSTRAINT MODEL

<正>This work established a new analytical model based upon the equivalent constraint model(ECM)to constitute an available predictive approach for analyzing the ultimate strength and simulating the stress/strain response of general symmetric laminates subjected to combined loading,by taking into account the effect of matrix cracking.The ECM was adopted to mainly predict the in-plane stiffness reduction of the damaged laminate.Basic consideration that progressive matrix cracking provokes a re-distribution of the stress fields on each lamina within laminates, which greatly deteriorates the stress distributed in the primary load-bearing lamina and leads to the final failure of the laminates,is introduced for the construction of the failure criterion. The effects of lamina properties,lay-up configurations and loading conditions on the behaviors of the laminates were examined in this paper.A comparison of numerical results obtained from the established model and other existed models and published experimental data was presented for different material systems.The theory predictions demonstrated great match with the experimental observations investigated in this study.     

Effect of the deformation in the inertia forces on the inverse dynamics of planar flexible mechanical systems

The inverse dynamics problem for articulated structural systems such as robotic manipulators is the problem of the determination of the joint actuator forces and motor torques such that the system components follow specified motion trajectories. In many of the previous investigations, the open loop control law was established using an inverse dynamics procedure in which the centrifugal and Coriolis inertia forces are linearized such that these forces in the flexible model are the same as those in the rigid body model. In some other investigations, the effect of the nonlinear centrifugal and Coriolis forces is neglected in the analysis and control system design of articulated structural systems. It is the objective of this investigation to study the effect of the linearization of the centrifugal and Coriolis forces on the nonlinear dynamics of constrained flexible mechanical systems. The virtual work of the inertia forces is used to define the complete nonlinear centrifugal and Coriolis force model. This nonlinear model that depends on the rate of the finite rotation and the elastic deformation of the deformable bodies is used to obtain the solution of the inverse dynamics problem, thus defining the joint torques that produce the desired motion trajectories. The effect of the linearization of the mass matrix as well as the centrifugal and Coriolis forces on the obtained feedforward control law is examined numerically. The results presented in this investigation are obtained using a slider crank mechanism with a flexible connecting rod.     

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).     

水荷载引起混凝土重力坝位移的理论研究

基于多孔连续介质模型,从理论上探讨了作用在地基上的水荷载作为渗流体荷载时引起混凝土重力坝的位移,导出了均质各向同性地基在渗流体荷载作用下的应力解答和位移解答.通过理论分析得到:(1)由于渗流体荷载引起上游地基下沉,下游地基上抬,从而使地基转动,导致坝体向上游位移.(2)作用在地基上的水荷载按面荷载分析的位移大于按渗流体荷载分析的位移,但它们都引起坝体向上游位移.     

An expanding cavity model incorporating strain-hardening and indentation size effects

An expanding cavity model (ECM) for determining indentation hardness of elastic strain-hardening plastic materials is developed. The derivation is based on a strain gradient plasticity solution for an internally pressurized thick-walled spherical shell of an elastic power-law hardening material. Closed-form formulas are provided for both conical and spherical indentations. The indentation radius enters these formulas with its own dimensional identity, unlike that in classical plasticity based ECMs where indentation geometrical parameters appear only in non-dimensional forms. As a result, the newly developed ECM can capture the indentation size effect. The formulas explicitly show that indentation hardness depends on Young’s modulus, yield stress, strain-hardening exponent and strain gradient coefficient of the indented material as well as on the geometry of the indenter. The new model reduces to existing classical plasticity based ECMs (including Johnson’s ECM for elastic–perfectly plastic materials) when the strain gradient effect is not considered. The numerical results obtained using the newly developed model reveal that the hardness is indeed indentation size dependent when the indentation radius is very small: the smaller the indentation, the larger the hardness. Also, the indentation hardness is seen to increase with the Young’s modulus and strain-hardening level of the indented material for both conical and spherical indentations. The strain-hardening effect on the hardness is observed to be significant for materials having strong strain-hardening characteristics. In addition, it is found that the indentation hardness increases with decreasing cone angle of the conical indenter or decreasing radius of the spherical indenter. These trends agree with existing experimental observations and model predictions.     

DETERMINATION OF QUADRICEPS FORCES IN SQUAT AND ITS APPLICATION IN CONTACT PRESSURE ANALYSIS OF KNEE JOINT

While the quadriceps muscles of human body are quite important to the daily activities of knee joints,the determination of quadriceps forces poses significant challenges since it cannot be measured in ...     

A three-dimensional,higher-order,elasticity-based micromechanics model

The three-dimensional (3D) version of a new homogenization theory [A Two-Dimensional, Higher-Order, Elasticity-Based Micromechanics Model, in print] is presented. The 3D theory utilizes a higher-order, elasticity-based cell model (ECM) analysis for a periodic array of 3D unit cells. The unit cell is discretized into eight subregions or subcells. The displacement field within each subcell is approximated by a (truncated) eigenfunction expansion of up to fifth order. The governing equations are developed by satisfying the pointwise governing equations of geometrically linear continuum mechanics exactly up through the given order of the subcell displacement fields. The specified governing equations are valid for any type of constitutive model used to describe the behavior of the material in a subcell. The specialization of the theory to lower orders and to two-dimeinsions (2D) and to the exact one-dimensional (1D) theory is discussed.Since the proposed 3D homogenization theory correctly reduces to both 2D and 1D the validation process applied to the 2D theory [A Two-Dimensional, Higher-Order, Elasticity-Based Micromechanics Model, in print] directly applies to the current formulation. Additional comparisons of the predicted responses obtained from the 3D ECM theory with existing published results are conducted. The good agreement obtained shows that the current theory represents a viable 3D homogenization tool. The improved agreement between the current theory results and published results as compared to the comparison of the MOC results and the published results is due to the correct incorporation of the coupling effects between the local fields. Additional results showing the convergence behavior of the average fields as a function of the order of the analysis is presented. These results show that the 1st order theory may not accurately predict the local averages but that consistent and converged behavior is obtained using the higher order ECM theories.The proposed theory represents the necessary theoretical foundations for the development of exact homogenization solutions of generalized, three-dimensional microstructures.     

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.