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

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

Effective balance equations for poroelastic composites

We derive the quasi-static governing equations for the macroscale behaviour of a linear elastic porous composite comprising a matrix interacting with inclusions and/or fibres, and an incompressible Newtonian fluid flowing in the pores. We assume that the size of the pores (the microscale) is comparable with the distance between adjacent subphases and is much smaller than the size of the whole domain (the macroscale). We then decouple spatial scales embracing the asymptotic (periodic) homogenization technique to derive the new macroscale model by upscaling the fluid–structure interaction problem between the elastic constituents and the fluid phase. The resulting system of partial differential equations is of poroelastic type and encodes the properties of the microstructure in the coefficients of the model, which are to be computed by solving appropriate cell problems which reflect the complexity of the given microstructure. The model reduces to the limit case of simple composites when there are no pores, and standard Biot’s poroelasticity whenever only the matrix–fluid interaction is considered. We further prove rigorous properties of the coefficients, namely (a) major and minor symmetries of the effective elasticity tensor, (b) positive definiteness of the resulting Biot’s modulus, and (c) analytical identities which allow us to define an effective Biot’s coefficient. This model is applicable when the interactions between multiple solid phases occur at the porescale, as in the case of various systems such as biological aggregates, constructs, bone, tendons, as well as rocks and soil

Periodic rhomboidal cells for symmetry-preserving homogenization and isotropic metamaterials

In the design and analysis of composite materials based on periodic arrangements of sub-units it is of paramount importance to control the emergent material symmetry in relation to the elastic response. The target material symmetry plays also an important role in additive manufacturing. In numerous applications it would be useful to obtain effectively isotropic materials. While these typically emerge from a random microstructure, it is not obvious how to achieve isotropy with a periodic order. We prove that arrangements of inclusions based on a rhomboidal cell that generates the Face-Centered Cubic lattice do in fact preserve any material symmetry of the constituents, so that spherical inclusions of isotropic materials in an isotropic matrix produce effectively isotropic composites.Comment: 8 pages; 1 figur

Homogenized balance equations for nonlinear poroelastic composites

Within this work, we upscale the equations that describe the pore-scale behaviour of nonlinear porous elastic composites, using the asymptotic homogenization technique in order to derive the macroscale effective governing equations. A porous hyperelastic composite can be thought of as being comprised of a matrix interacting with a number of subphases and percolated by a fluid flowing in the pores (which is chosen to be Newtonian and incompressible here). A general nonlinear macroscale model is derived and is then specified for a particular choice of strain energy function, namely the de Saint-Venant function. This leads to a macroscale system of PDEs, which is of poroelastic type with additional terms and transformations to account for the nonlinear behaviour of the material. Our new porohyperelastic-type model describes the effective behaviour of nonlinear porous composites by prescribing the stress balance equations, the conservation of mass and Darcy’s law. The coefficients of these macroscale equations encode the detailed microstructure of the material and are to be found by solving pore-scale differential problems. The model reduces to the following limit cases of (a) linear poroelastic composites when the deformation gradient approaches the identity, (b) nonlinear composites when there are no pores and (c) nonlinear poroelasticity when only the matrix–fluid interaction is considered. This model is applicable when the interactions between various hyperelastic solid phases occur at the pore-scale, as in biological tissues such as artery walls, the myocardium, lungs and liver

Double poroelasticity derived from the microstructure

We derive the balance equations for a double poroelastic material which comprises a matrix with embedded subphases. We assume that the distance between the subphases (the local scale) is much smaller than the size of the domain (the global scale). We assume that at the local scale both the matrix and subphases can be described by Biot’s anisotropic, heterogeneous, compressible poroelasticity (i.e. the porescale is already smoothed out). We then decompose the spatial variations by means of the two-scale homogenization method to upscale the interaction between the poroelastic phases at the local scale. This way, we derive the novel global scale model which is formally of poroelastic-type. The global scale coefficients account for the complexity of the given microstructure and heterogeneities. These effective poroelastic moduli are to be computed by solving appropriate differential periodic cell problems. The model coefficients possess properties that, once proved, allow us to determine that the model is both formally and substantially of poroelastic-type. The properties we prove are a) the existence of a tensor which plays the role of the classical Biot’s tensor of coefficients via a suitable analytical identity and b) the global scale scalar coefficient M¯ is positive which then qualifies as the global Biot’s modulus for the double poroelastic material

Micromechanical analysis of the effective stiffness of poroelastic composites

Within this work we investigate the role that the microstructure of a poroelastic material has on the resulting elastic parameters. We are considering the effect that multiple elastic and fluid phases at the same scale (LMRP model (L. Miller and R. Penta, 2020)) have on the estimation of the materials elastic parameters when compared with a standard poroelastic approach. We present a summary of both the LMRP model and the comparable standard poroelastic approach both derived via the asymptotic homogenization approach. We provide the 3D periodic cell problems with associated boundary loads that are required to be solved to obtain the effective elasticity tensor for both model setups. We then perform a 2D reduction of the cell problems, again presenting the 2D boundary loads that are required to solve the problems numerically. The results of our numerical simulations show that whenever investigating a poroelastic composite material with porosity exceeding 5% then the LMRP model should be considered more appropriate in incorporating the structural details in the Young’s moduli E1 and E3 and the shear C44. Whenever the porosity exceeds 20% it should also be used to investigate the shear C66. We find that for materials with less than 5% porosity that the voids are so small that a standard poroelastic approach or the LMRP model produce the same results

The Latin Leaflet

In the present work, we apply the asymptotic homogenization technique to the equations describing the dynamics of a heterogeneous material with evolving micro-structure, thereby obtaining a set of upscaled, effective equations. We consider the case in which the heterogeneous body comprises two hyperelastic materials and we assume that the evolution of their micro-structure occurs through the development of plastic-like distortions, the latter ones being accounted for by means of the Bilby–Kröner–Lee (BKL) decomposition. The asymptotic homogenization approach is applied simultaneously to the linear momentum balance law of the body and to the evolution law for the plastic-like distortions. Such evolution law models a stress-driven production of inelastic distortions, and stems from phenomenological observations done on cellular aggregates. The whole study is also framed within the limit of small elastic distortions, and provides a robust framework that can be readily generalized to growth and remodeling of nonlinear composites. Finally, we complete our theoretical model by performing numerical simulations

Effective properties of hierarchical fiber-reinforced composites via a three-scale asymptotic homogenization approach

The study of the properties of multiscale composites is of great interest in engineering and biology. Particularly, hierarchical composite structures can be found in nature and in engineering. During the past decades, the multiscale asymptotic homogenization technique has shown its potential in the description of such composites by taking advantage of their characteristics at the smaller scales, ciphered in the so-called effective coefficients. Here, we extend previous works by studying the in-plane and out-of-plane effective properties of hierarchical linear elastic solid composites via a three-scale asymptotic homogenization technique. In particular, the approach is adjusted for a multiscale composite with a square-symmetric arrangement of uniaxially aligned cylindrical fibers, and the formulae for computing its effective properties are provided. Finally, we show the potential of the proposed asymptotic homogenization procedure by modeling the effective properties of musculoskeletal mineralized tissues, and we compare the results with theoretical and experimental data for bone and tendon tissues