The role of the microvascular network structure on diffusion and consumption of anticancer drugs

We investigate the impact of microvascular geometry on the transport of drugs in solid tumors, focusing on the diffusion and consumption phenomena. We embrace recent advances in the asymptotic homogenization literature starting from a double Darcy—double advection-diffusion-reaction system of partial differential equations that is obtained exploiting the sharp length separation between the intercapillary distance and the average tumor size. The geometric information on the microvascular network is encoded into effective hydraulic conductivities and diffusivities, which are numerically computed by solving periodic cell problems on appropriate microscale representative cells. The coefficients are then injected into the macroscale equations, and these are solved for an isolated, vascularized spherical tumor. We consider the effect of vascular tortuosity on the transport of anticancer molecules, focusing on Vinblastine and Doxorubicin dynamics, which are considered as a tracer and as a highly interacting molecule, respectively. The computational model is able to quantify the treatment performance through the analysis of the interstitial drug concentration and the quantity of drug metabolized in the tumor. Our results show that both drug advection and diffusion are dramatically impaired by increasing geometrical complexity of the microvasculature, leading to nonoptimal absorption and delivery of therapeutic agents. However, this effect apparently has a minor role whenever the dynamics are mostly driven by metabolic reactions in the tumor interstitium, eg, for highly interacting molecules. In the latter case, anticancer therapies that aim at regularizing the microvasculature might not play a major role, and different strategies are to be developed

The asymptotic homogenization elasticity tensor properties for composites with material discontinuities

The classical asymptotic homogenization approach for linear elastic composites with discontinuous material properties is considered as a starting point. The sharp length scale separation between the fine periodic structure and the whole material formally leads to anisotropic elastic-type balance equations on the coarse scale, where the arising fourth rank operator is to be computed solving single periodic cell problems on the fine scale. After revisiting the derivation of the problem, which here explicitly points out how the discontinuity in the individual constituents’ elastic coefficients translates into stress jump interface conditions for the cell problems, we prove that the gradient of the cell problem solution is minor symmetric and that its cell average is zero. This property holds for perfect interfaces only (i.e., when the elastic displacement is continuous across the composite’s interface) and can be used to assess the accuracy of the computed numerical solutions. These facts are further exploited, together with the individual constituents’ elastic coefficients and the specific form of the cell problems, to prove a theorem that characterizes the fourth rank operator appearing in the coarse-scale elastic-type balance equations as a composite material effective elasticity tensor. We both recover known facts, such as minor and major symmetries and positive definiteness, and establish new facts concerning the Voigt and Reuss bounds. The latter are shown for the first time without assuming any equivalence between coarse and fine-scale energies (Hill’s condition), which, in contrast to the case of representative volume elements, does not identically hold in the context of asymptotic homogenization. We conclude with instructive three-dimensional numerical simulations of a soft elastic matrix with an embedded cubic stiffer inclusion to show the profile of the physically relevant elastic moduli (Young’s and shear moduli) and Poisson’s ratio at increasing (up to 100 %) inclusion’s volume fraction, thus providing a proxy for the design of artificial elastic composites

Natural Right, Providence, and Order: Frédéric Bastiat's Laissez-Faire

The paper suggests that Bastiat’s theory of interests, harmony, and the State is rooted in a particular conception of Natural Right, in which the Lockeans and thomistic streams of thought meet. But it also suggests that Bastiat’s interpretation of the role that Providence plays in human events is not able to give a sustainable theory of liberal order. The paper also considers the criticisms to Bastiat’s economic and political theory coming from exponents of classical liberalism, from the Austrians, and from Catholic thinkers of that time, such as L. Taparelli d’Azeglio and M. Liberatore. The conclusion is that although the economic theory of Bastiat is by now obsolete from the conceptual point of view, his political theory and his criticism of the state do remain extraordinarily topical. Cet article suggère que les théories des intérêts, de l’harmonie et de l’Etat de Bastiat sont ancrées dans une conception particulière du droit naturel au confluent des pensées lockéenne et thomiste. Cependant, il suggère aussi que l’interprétation que donne Bastiat du rôle de la Providence dans les affaires humaines ne débouche pas sur une théorie recevable de l’ordre libéral. L’article examine aussi les critiques qu’adressent les partisans du libéralisme classique-tels que les économistes autrichiens, les penseurs catholiques de l’époque comme L. Taparelli d’Azeglio et M. Liberatore-à l’égard des théories économiques et politiques de Bastiat. L’article conclut que le caractère obsolète des théories de Bastiat d’un point de vue conceptuel ne remet pas en cause la singulière actualité de sa théorie politique et de sa critique de l’Etat

Homogenized modeling for vascularized poroelastic materials

A new mathematical model for the macroscopic behavior of a material composed of a poroelastic solid embedding a Newtonian fluid network phase (also referred to as vascularized poroelastic material), with fluid transport between them, is derived via asymptotic homogenization. The typical distance between the vessels/channels (microscale) is much smaller than the average size of a whole domain (macroscale). The homogeneous and isotropic Biot’s equation (in the quasi-static case and in absence of volume forces) for the poroelastic phase and the Stokes’ problem for the fluid network are coupled through a fluid-structure interaction problem which accounts for fluid transport between the two phases; the latter is driven by the pressure difference between the two compartments. The averaging process results in a new system of partial differential equations that formally reads as a double poroelastic, globally mass conserving, model, together with a new constitutive relationship for the whole material which encodes the role of both pore and fluid network pressures. The mathematical model describes the mutual interplay among fluid filling the pores, flow in the network, transport between compartments, and linear elastic deformation of the (potentially compressible) elastic matrix comprising the poroelastic phase. Assuming periodicity at the microscale level, the model is computationally feasible, as it holds on the macroscale only (where the microstructure is smoothed out), and encodes geometrical information on the microvessels in its coefficients, which are to be computed solving classical periodic cell problems. Recently developed double porosity models are recovered when deformations of the elastic matrix are neglected. The new model is relevant to a wide range of applications, such as fluid in porous, fractured rocks, blood transport in vascularized, deformable tumors, and interactions across different hierarchical levels of porosity in the bone