Towards whole-organ modelling of tumour growth

Multiscale approaches to modelling biological phenomena are growing rapidly. We present here some recent results on the formulation of a theoretical framework which can be developed into a fully integrative model for cancer growth. The model takes account of vascular adaptation and cell-cycle dynamics. We explore the effects of spatial inhomogeneity induced by the blood flow through the vascular network and of the possible effects of p27 on the cell cycle. We show how the model may be used to investigate the efficiency of drug-delivery protocols

Numerical solution of the two-phase tumour growth model with moving boundary

A novel numerical technique has been proposed to solve a two-phase tumour growth model in one spatial dimension without needing to account for the boundary dynamics explicitly. The equivalence to the standard definition of a weak solution is proved. The method is tested against equations with analytically known solutions, to illustrate the advantages over the existing techniques. The tumour growth model is solved using the new procedure and showed to be consistent with results available in the literature.Comment: 11 pages, 3 figures, CTAC 2018 conference proceedings (submitted to ANZIAM J

Multiphase modelling of tumour growth and extracellular matrix interaction: mathematical tools and applications

Resorting to a multiphase modelling framework, tumours are described here as a mixture of tumour and host cells within a porous structure constituted by a remodelling extracellular matrix (ECM), which is wet by a physiological extracellular fluid. The model presented in this article focuses mainly on the description of mechanical interactions of the growing tumour with the host tissue, their influence on tumour growth, and the attachment/detachment mechanisms between cells and ECM. Starting from some recent experimental evidences, we propose to describe the interaction forces involving the extracellular matrix via some concepts coming from viscoplasticity. We then apply the model to the description of the growth of tumour cords and the formation of fibrosis

A two-fluid model for tissue growth within\ud a dynamic flow environment

We study the growth of a tissue construct in a perfusion bioreactor, focussing on its response to the mechanical environment. The bioreactor system is modelled as a two-dimensional channel containing a tissue construct through which a flow of culture medium is driven. We employ a multiphase formulation of the type presented by G. Lemon, J. King, H. Byrne, O. Jensen and K. Shakesheff in their study (Multiphase modelling of tissue growth using the theory of mixtures. J. Math. Biol. 52(2), 2006, 571–594) restricted to two interacting fluid phases, representing a cell population (and attendant extracellular matrix) and a culture medium, and employ the simplifying limit of large interphase viscous drag after S. Franks in her study (Mathematical Modelling of Tumour Growth and Stability. Ph.D. Thesis, University of Nottingham, UK, 2002) and S. Franks and J. King in their study (Interactions between a uniformly proliferating tumour and its surrounding: Uniform material properties. Math. Med. Biol. 20, 2003, 47–89).\ud \ud The novel aspects of this study are: (i) the investigation of the effect of an imposed flow on the growth of the tissue construct, and (ii) the inclusion of a mechanotransduction mechanism regulating the response of the cells to the local mechanical environment. Specifically, we consider the response of the cells to their local density and the culture medium pressure. As such, this study forms the first step towards a general multiphase formulation that incorporates the effect of mechanotransduction on the growth and morphology of a tissue construct. The model is analysed using analytic and numerical techniques, the results of which illustrate the potential use of the model to predict the dominant regulatory stimuli in a cell population

A novel model for one-dimensional morphoelasticity. Part I - Theoretical foundations

While classical continuum theories of elasticity and viscoelasticity have long been used to describe the mechanical behaviour of solid biological tissues, they are of limited use for the description of biological tissues that undergo continuous remodelling. The structural changes to a soft tissue associated with growth and remodelling require a mathematical theory of ‘morphoelasticity’ that is more akin to plasticity than elasticity. However, previously-derived mathematical models for plasticity are difficult to apply and interpret in the context of growth and remodelling: many important concepts from the theory of plasticity do not have simple analogues in biomechanics.\ud \ud In this work, we describe a novel mathematical model that combines the simplicity and interpretability of classical viscoelastic models with the versatility of plasticity theory. While our focus here is on one-dimensional problems, our model builds on earlier work based on the multiplicative decomposition of the deformation gradient and can be adapted to develop a three-dimensional theory. The foundation of this work is the concept of ‘effective strain’, a measure of the difference between the current state and a hypothetical state where the tissue is mechanically relaxed. We develop one-dimensional equations for the evolution of effective strain, and discuss a number of potential applications of this theory. One significant application is the description of a contracting fibroblast-populated collagen lattice, which we further investigate in Part II

Lattice and Continuum Modelling of a Bioactive Porous Tissue Scaffold

A contemporary procedure to grow artificial tissue is to seed cells onto a porous biomaterial scaffold and culture it within a perfusion bioreactor to facilitate the transport of nutrients to growing cells. Typical models of cell growth for tissue engineering applications make use of spatially homogeneous or spatially continuous equations to model cell growth, flow of culture medium, nutrient transport, and their interactions. The network structure of the physical porous scaffold is often incorporated through parameters in these models, either phenomenologically or through techniques like mathematical homogenization. We derive a model on a square grid lattice to demonstrate the importance of explicitly modelling the network structure of the porous scaffold, and compare results from this model with those from a modified continuum model from the literature. We capture two-way coupling between cell growth and fluid flow by allowing cells to block pores, and by allowing the shear stress of the fluid to affect cell growth and death. We explore a range of parameters for both models, and demonstrate quantitative and qualitative differences between predictions from each of these approaches, including spatial pattern formation and local oscillations in cell density present only in the lattice model. These differences suggest that for some parameter regimes, corresponding to specific cell types and scaffold geometries, the lattice model gives qualitatively different model predictions than typical continuum models. Our results inform model selection for bioactive porous tissue scaffolds, aiding in the development of successful tissue engineering experiments and eventually clinically successful technologies.Comment: 38 pages, 16 figures. This version includes a much-expanded introduction, and a new section on nonlinear diffusion in addition to polish throughou

In silico investigations of intratumoral heterogeneous interstitial fluid pressure

Recent preclinical studies have shown that interstitial fluid pressure (IFP) within tumors can be heterogeneous Andersen et al. (2019). In that study tumors of two xenograft models, respectively, HL-16 cervical carcinoma and Panc-1 pancreatic carcinoma, were investigated. Significant heterogeneity in IFP was reported and it was proposed that this was associated with division of tissue into compartments separated by thick connective tissue bands for the HL-16 tumors and with dense collagen-rich extracellular matrix for the Panc-1 tumors. The purpose of the current work is to explore these experimental observations by using in silico generated tumor models. We consider a mathematical multiphase model which accounts for tumor cells, fibroblasts and interstitial fluid. The model has been trained to comply with experimental in vitro results reported in Shieh et al. (2011) which has identified autologous chemotaxis, ECM remodeling, and cell-fibroblast interaction as drivers for invasive tumor cell behavior. The in silico model is informed with parameters that characterize the leaky intratumoral vascular network, the peritumoral lymphatics which collect the fluid, and the density of ECM as represented through the hydraulic conductivity of the interstitial space. Heterogeneous distribution of solid stress may result in heterogeneous compression of blood vessels and, thus, heterogeneous vascular density inside the tumor. To mimic this we expose the in silico tumor to an intratumoral vasculature whose net effect of density of blood vesssels and vessel wall conductivity is varied through a 2D Gaussian variogram constrained such that the resulting IFPs lie within the range as reported from the preclinical study. The in silico cervical carcinoma model illustrates that sparse ECM was associated with uniform intratumoral IFP in spite of heterogeneous microvascular network, whereas compartment structures resulted in more heterogeneous IFP. Similarly, the in silico pancreatic model shows that heterogeneity in the microvascular network combined with dense ECM structure prevents IFP to even out and gives rise to heterogeneous IFP. The computer model illustrates how a heterogeneous invasive front might form where groups of tumor cells detach from the primary tumor and form isolated islands, a behavior which is natural to associate with metastatic propensity. However, unlike experimental studies, the current version of the in silico model does not show an association between metastatic propensity and elevated IFP.publishedVersio