John P. Ward

Mathematical modelling of drug transport in tumour multicell spheroids and monolayer cultures.

In this paper we adapt an avascular tumour growth model to compare the effects of drug application on multicell spheroids and on monolayer cultures. The model for the tumour is based on nutrient driven growth of a continuum of live cells, whose birth and death generates volume changes described by a velocity field. The drug is modelled as an externally applied, diffusible material capable of killing cells, both linear and Michaelis-Menten kinetics for drug action on cells being studied. Numerical solutions of the resulting system of partial differential equations for the multicell spheroid case are compared with closed form solutions of the monolayer case, particularly with respect to the effects on the cell kill of the drug dosage and of the duration of its application. The results show an enhanced survival rate in multicell spheroids compared to monolayer cultures, consistent with experimental observations, and indicate that the key factor determining this is drug penetration. An analysis of the large time tumour spheroid response to a continuously applied drug at fixed concentration reveals up to three stable large time solutions, namely the trivial solution (i.e. a dead tumour), a travelling wave (continuously growing tumour) and a sublinear growth case in which cells reach a pseudo-steady-state in the core. Each of these possibilities is formulated and studied, with the bifurcations between them being discussed. Numerical solutions reveal that the pseudo-steady-state solutions persist to a significantly higher drug dose than travelling wave solutions.

Individual differences in students' use of optional learning resources

We investigated ways in which undergraduates use optional learning resources in a typical blended learning environment. Specifically, we recorded how often students attended live face-to-face lectures, accessed online recorded lectures, and visited a mathematics learning support centre during a multivariate calculus course. Four distinct study strategies emerged, but surprisingly none involved making heavy use of more than one resource. In contrast with some earlier research, the general strategy a student adopted was related to their academic achievement, both in the multivariate calculus course, and in their degree programme more widely. Those students who often accessed online lectures had lower attainment than those who often attended live lectures or the support centre. We discuss the implications of these findings and suggest that ‘blended teaching environments’ may be a more accurate description for what have previously been called ‘blended learning environments’.

Mathematical Modelling of the Effects of Mitotic Inhibitors on Avascular Tumour Growth

In this paper we build on the mathematical model of Ward and King (1998) to study the effects of high molecular mass mitotic inhibitors released at cell death. The model assumes a continuum of living cells which, depending on the concentration of a generic nutrient, generate movement (described by a velocity field) due to the changes in volumes caused by cell birth and death. The necrotic material is assumed to consist of two diffusible materials: I) basic cellular material which is used by living cells as raw material for mitosis; 2) a generic non-utilisable material which may inhibit mitosis. Numerical solutions of the resulting system of partial differential equations show all the main features of tumour growth and heterogeneity. Material 2) is found to act in an inhibitive fashion in two ways: i) directly, by reducing the mitotic rate and ii) indirectly, by occupying space, thereby reducing the availability of the basic cellular material. For large time the solutions to the model tend either to a steady-state, reflecting growth saturation, or to a travelling wave, indicating continual linear growth. The steady-state and travelling wave limits of the model are derived and studied, the regions of existence of these two types of long-time solution being explored in parameter space using numerical methods.

Numerical Modelling of Effects of Biphasic Layers of Corrosion Products to the Degradation of Magnesium Metal In Vitro

Magnesium (Mg) is becoming increasingly popular for orthopaedic implant materials. Its mechanical properties are closer to bone than other implant materials, allowing for more natural healing under stresses experienced during recovery. Being biodegradable, it also eliminates the requirement of further surgery to remove the hardware. However, Mg rapidly corrodes in clinically relevant aqueous environments, compromising its use. This problem can be addressed by alloying the Mg, but challenges remain at optimising the properties of the material for clinical use. In this paper, we present a mathematical model to provide a systematic means of quantitatively predicting Mg corrosion in aqueous environments, providing a means of informing standardisation of in vitro investigation of Mg alloy corrosion to determine implant design parameters. The model describes corrosion through reactions with water, to produce magnesium hydroxide Mg(OH)2, and subsequently with carbon dioxide to form magnesium carbonate MgCO3. The corrosion products produce distinct protective layers around the magnesium block that are modelled as porous media. The resulting model of advection–diffusion equations with multiple moving boundaries was solved numerically using asymptotic expansions to deal with singular cases. The model has few free parameters, and it is shown that these can be tuned to predict a full range of corrosion rates, reflecting differences between pure magnesium or magnesium alloys. Data from practicable in vitro experiments can be used to calibrate the model’s free parameters, from which model simulations using in vivo relevant geometries provide a cheap first step in optimising Mg-based implant materials.

A mathematical model for the human menstrual cycle

A simple mathematical model framework is developed to describe the hormonal interactions of the human menstrual cycle along the hypothalamus-pituitary-ovaries axis. The framework is designed so that it can be readily extended to model processes that disrupt the normal functioning cycle. The model in its most basic formulation exhibits multiple periodic solutions, one of which shows the key characteristics of a menstrual cycle, while the others indicate possible abnormalities sometimes observed in women of reproductive age. The basic model is extended to encompass receptor down-regulation as a mechanism to describe the desensitization of the pituitary to continuous stimulation of hypothalamic hormone, a hormonal therapy that is commonly prescribed prior to the surgical procedure for the removal of uterine myomas. Though the mechanisms for desensitization are likely to be more complex, the model results are in good qualitative agreement with physiological observations.

Timescale analysis of a mathematical model of acetaminophen metabolism and toxicity.

Acetaminophen is a widespread and commonly used painkiller all over the world. However, it can cause liver damage when taken in large doses or at repeated chronic doses. Current models of acetaminophen metabolism are complex, and limited to numerical investigation though provide results that represent clinical investigation well. We derive a mathematical model based on mass action laws aimed at capturing the main dynamics of acetaminophen metabolism, in particular the contrast between normal and overdose cases, whilst remaining simple enough for detailed mathematical analysis that can identify key parameters and quantify their role in liver toxicity. We use singular perturbation analysis to separate the different timescales describing the sequence of events in acetaminophen metabolism, systematically identifying which parameters dominate during each of the successive stages. Using this approach we determined, in terms of the model parameters, the critical dose between safe and overdose cases, timescales for exhaustion and regeneration of important cofactors for acetaminophen metabolism and total toxin accumulation as a fraction of initial dose.

Modelling The Effect of Cell Shedding on Avascular Tumour Growth

Earlier mathematical models of the authors which describe avascular tumour growth are extended to incorporate the process of cell shedding, a feature known to affect the growth of multicell spheroids. A continuum of live cells is assumed within which, depending on the concentration of a generic nutrient, movement (described by a velocity field) occurs due to volume changes caused by cell birth and death. The necrotic material is assumed to contain a mixture of basic cellular material (assumed necessary for creating new cells) and a non-utilisable material which may inhibit mitosis. The rate of cell shedding is taken to be proportional to the mitotic rate, with constant of proportionality θ. Numerical solutions of the resulting system of partial differential equations indicate that, depending on θ and the initial conditions, the solution may either tend to the trivial state in finite time (by which we mean complete death of the tumour), or to one of two non-trivial states, namely a steady-state (indicating growth saturation) or a travelling wave (indicating continual linear growth). These long time outcomes are explored by deriving the travelling wave and steady-state limits of the model. Numerical solutions demonstrate that there are two branches of solutions, which we have termed the ′Major′ and ′Minor′ branches, consisting of both travelling waves and steady-states. The behaviour of the solutions along each branch is discussed, with those of the Major branch expected to be stable. Beyond some critical θ,where the Major and Minor branches merge, the spheroid ultimately vanishes whatever the initial tumour size due to the effects of cell shedding being too strong for it to survive. The regions of existence of the two long time outcomes are investigated in parameter space, cell shedding being shown to expand significantly the parameter ranges within which growth saturation occurs.

Modelling the influence of foot-and-mouth disease vaccine antigen stability and dose on the bovine immune response

Foot and mouth disease virus causes a livestock disease of significant global socio-economic importance. Advances in its control and eradication depend critically on improvements in vaccine efficacy, which can be best achieved by better understanding the complex within-host immunodynamic response to inoculation. We present a detailed and empirically parametrised dynamical mathematical model of the hypothesised immune response in cattle, and explore its behaviour with reference to a variety of experimental observations relating to foot and mouth immunology. The model system is able to qualitatively account for the observed responses during in-vivo experiments, and we use it to gain insight into the incompletely understood effect of single and repeat inoculations of differing dosage using vaccine formulations of different structural stability.

Modelling Foot-and-Mouth Disease Virus Dynamics in Oral Epithelium to Help Identify the Determinants of Lysis

Foot-and-mouth disease virus (FMDV) causes an economically important disease of cloven-hoofed livestock; of interest here is the difference in lytic behaviour that is observed in bovine epithelium. On the skin around the feet and tongue, the virus rapidly replicates, killing cells, and resulting in growing lesions, before eventually being cleared by the immune response. In contrast, there is usually minimal lysis in the soft palate, but virus may persist in tissue long after the animal has recovered from the disease. Persistence of virus has important implications for disease control, while identifying the determinant of lysis in epithelium is potentially important for the development of prophylactics. To help identify which of the differences between oral and pharyngeal epithelium are responsible for such dramatically divergent FMDV dynamics, a simple model has been developed, in which virus concentration is made explicit to allow the lytic behaviour of cells to be fully considered. Results suggest that localised structuring of what are fundamentally similar cells can induce a bifurcation in the behaviour of the system, explicitly whether infection can be sustained or results in mutual extinction, although parameter estimates indicate that more complex factors may be involved in maintaining viral persistence, or that there are as yet unquantified differences between the intrinsic properties of cells in these regions.

A mathematical model of the in vitro keratinocyte response to chromium and nickel exposure.

A mathematical model describing the main mechanistic processes involved in keratinocyte response to chromium and nickel has been developed and compared to experimental in vitro data. Accounting for the interactions between the metal ions and the keratinocytes, the law of mass action was used to generate ordinary differential equations which predict the time evolution and ion concentration dependency of keratinocyte viability, the amount of metal associated with the keratinocytes and the release of cytokines by the keratinocytes. Good agreement between model predictions and existing experimental data of these endpoints was observed, supporting the use of this model to explore physiochemical parameters that influence the toxicological response of keratinocytes to these two metals.