The impact of vascular volume fraction and compressibility of the interstitial matrix on vascularised poroelastic tissues.

In this work we address the role of the microstructural properties of a vascularised poroelastic material, characterised by the coupling between a poroelastic matrix and a viscous fluid vessels network, on its overall response in terms of pressures, velocities and stress maps. We embrace the recently developed model (Penta and Merodio in Meccanica 52(14):3321-3343, 2017) as a theoretical starting point and present the results obtained by solving the full interplay between the microscale, represented by the intervessels' distance, and the macroscale, representing the size of the overall tissue. We encode the influence of the vessels' density and the poroelastic matrix compressibility in the poroelastic coefficients of the model, which are obtained by solving appropriate periodic cell problem at the microscale. The double-poroelastic model (Penta and Merodio 2017) is then solved at the macroscale in the context of vascular tumours, for different values of vessels' walls permeability. The results clearly indicate that improving the compressibility of the matrix and decreasing the vessels' density enhances the transvascular pressure difference and hence transport of fluid and drug within a tumour mass after a transient time. Our results suggest to combine vessel and interstitial normalization in tumours to allow for better drug delivery into the lesions.

Effective Governing Equations for Viscoelastic Composites.

We derive the governing equations for the overall behaviour of linear viscoelastic composites comprising two families of elastic inclusions, subphases and/or fibres, and an incompressible Newtonian fluid interacting with the solid phases at the microscale. We assume that the distance between each of the subphases is very small in comparison to the length of the whole material (the macroscale). We can exploit this sharp scale separation and apply the asymptotic (periodic) homogenization method (AHM) which decouples spatial scales and leads to the derivation of the new homogenised model. It does this via upscaling the fluid-structure interaction problem that arises between the multiple elastic phases and the fluid. As we do not assume that the fluid flow is characterised by a parabolic profile, the new macroscale model, which consists of partial differential equations, is of Kelvin-Voigt viscoelastic type (rather than poroelastic). The novel model has coefficients that encode the properties of the microstructure and are to be computed by solving a single local differential fluid-structure interaction (FSI) problem where the solid and the fluid phases are all present and described by the one problem. The model reduces to the case described by Burridge and Keller (1981) when there is only one elastic phase in contact with the fluid. This model is applicable when the distance between adjacent phases is smaller than the average radius of the fluid flowing in the pores, which can be the case for various highly heterogeneous systems encountered in real-world (e.g., biological, or geological) scenarios of interest.

Effective Properties of Homogenised Nonlinear Viscoelastic Composites.

We develop a general approach for the computation of the effective properties of nonlinear viscoelastic composites. For this purpose, we employ the asymptotic homogenisation technique to decouple the equilibrium equation into a set of local problems. The theoretical framework is then specialised to the case of a strain energy density of the Saint-Venant type, with the second Piola-Kirchhoff stress tensor also featuring a memory contribution. Within this setting, we frame our mathematical model in the case of infinitesimal displacements and employ the correspondence principle which results from the use of the Laplace transform. In doing this, we obtain the classical cell problems in asymptotic homogenisation theory for linear viscoelastic composites and look for analytical solutions of the associated anti-plane cell problems for fibre-reinforced composites. Finally, we compute the effective coefficients by specifying different types of constitutive laws for the memory terms and compare our results with available data in the scientific literature.

Investigating the effects of microstructural changes induced by myocardial infarction on the elastic parameters of the heart.

Within this work, we investigate how physiologically observed microstructural changes induced by myocardial infarction impact the elastic parameters of the heart. We use the LMRP model for poroelastic composites (Miller and Penta in Contin Mech Thermodyn 32:1533-1557, 2020) to describe the microstructure of the myocardium and investigate microstructural changes such as loss of myocyte volume and increased matrix fibrosis as well as increased myocyte volume fraction in the areas surrounding the infarct. We also consider a 3D framework to model the myocardium microstructure with the addition of the intercalated disks, which provide the connections between adjacent myocytes. The results of our simulations agree with the physiological observations that can be made post-infarction. That is, the infarcted heart is much stiffer than the healthy heart but with reperfusion of the tissue it begins to soften. We also observe that with the increase in myocyte volume of the non-damaged myocytes the myocardium also begins to soften. With a measurable stiffness parameter the results of our model simulations could predict the range of porosity (reperfusion) that could help return the heart to the healthy stiffness. It would also be possible to predict the volume of the myocytes in the area surrounding the infarct from the overall stiffness measurements.

Optimal heat transport induced by magnetic nanoparticle delivery in vascularised tumours.

We describe a novel mathematical model for blood flow, delivery of nanoparticles, and heat transport in vascularised tumour tissue. The model, which is derived via the asymptotic homogenisation technique, provides a link between the macroscale behaviour of the system and its underlying, tortuous micro-structure, as parametrised in Penta and Ambrosi (2015). It consists of a double Darcy's law, coupled with a double advection-diffusion-reaction system describing heat transport, and an advection-diffusion-reaction equation for transport and adhesion of particles. Particles are assumed sufficiently large and do not extravasate to the tumour interstitial space but blood and heat can be exchanged between the two compartments. Numerical simulations of the model are performed using a finite element method to investigate cancer hyperthermia induced by the application of magnetic field applied to injected iron oxide nanoparticles. Since tumour microvasculature is more tortuous than that of healthy tissue and thus suboptimal in terms of fluid and drug transport, we study the influence of the vessels' geometry on tumour temperature. Effective and safe hyperthermia treatment requires tumour temperature within certain target range, generally estimated between 42 °C and 46 °C, for a certain target duration, typically 0.5h to 2h. As temperature is difficult to measure in situ, we use our model to determine the ranges of tortuosity of the microvessels, magnetic intensity, injection time, wall shear stress rate, and concentration of nanoparticles required to achieve given target conditions.

Multi-scale modelling of nanoparticle delivery and heat transport in vascularised tumours.

We focus on modelling of cancer hyperthermia driven by the application of the magnetic field to iron oxide nanoparticles. We assume that the particles are interacting with the tumour environment by extravasating from the vessels into the interstitial space. We start from Darcy's and Stokes' problems in the interstitial and fluid vessels compartments. Advection-diffusion of nanoparticles takes place in both compartments (as well as uptake in the tumour interstitium), and a heat source proportional to the concentration of nanoparticles drives heat diffusion and convection in the system. The system under consideration is intrinsically multi-scale. The distance between adjacent vessels (the micro-scale) is much smaller than the average tumour size (the macro-scale). We then apply the asymptotic homogenisation technique to retain the influence of the micro-structure on the tissue scale distribution of heat and particles. We derive a new system of homogenised partial differential equations (PDEs) describing blood transport, delivery of nanoparticles and heat transport. The new model comprises a double Darcy's law, coupled with two double advection-diffusion-reaction systems of PDEs describing fluid, particles and heat transport and mass, drug and heat exchange. The role of the micro-structure is encoded in the coefficients of the model, which are to be computed solving appropriate periodic problems. We show that the heat distribution is impaired by increasing vessels' tortuosity and that regularization of the micro-vessels can produce a significant increase (1-2 degrees) in the maximum temperature. We quantify the impact of modifying the properties of the magnetic field depending on the vessels' tortuosity.

Mathematical Modelling of Residual-Stress Based Volumetric Growth in Soft Matter.

Growth in nature is associated with the development of residual stresses and is in general heterogeneous and anisotropic at all scales. Residual stress in an unloaded configuration of a growing material provides direct evidence of the mechanical regulation of heterogeneity and anisotropy of growth. The present study explores a model of stress-mediated growth based on the unloaded configuration that considers either the residual stress or the deformation gradient relative to the unloaded configuration as a growth variable. This makes it possible to analyze stress-mediated growth without the need to invoke the existence of a fictitious stress-free grown configuration. Furthermore, applications based on the proposed theoretical framework relate directly to practical experimental scenarios involving the "opening-angle" in arteries as a measure of residual stress. An initial illustration of the theory is then provided by considering the growth of a spherically symmetric thick-walled shell subjected to the incompressibility constraint.

The role of malignant tissue on the thermal distribution of cancerous breast.

The present work focuses on the integration of analytical and numerical strategies to investigate the thermal distribution of cancerous breasts. Coupled stationary bioheat transfer equations are considered for the glandular and heterogeneous tumor regions, which are characterized by different thermophysical properties. The cross-section of the cancerous breast is identified by a homogeneous glandular tissue that surrounds the heterogeneous tumor tissue, which is assumed to be a two-phase periodic composite with non-overlapping circular inclusions and a square lattice distribution, wherein the constituents exhibit isotropic thermal conductivity behavior. Asymptotic periodic homogenization method is used to find the effective properties in the heterogeneous region. The tissue effective thermal conductivities are computed analytically and then used in the homogenized model, which is solved numerically. Results are compared with appropriate experimental data reported in the literature. In particular, the tissue scale temperature profile agrees with experimental observations. Moreover, as a novelty result we find that the tumor volume fraction in the heterogeneous zone influences the breast surface temperature.

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.