Multiscale Modeling in Vascular Disease and Tissue Engineering - Multiscale Computer Modeling in Biomechanics and Biomedical Engineering - page 239

such multiscale modelling approaches whereby FEM was used to quantify the
mechanical stimuli at the tissue level and CA and ABM were utilised to capture the
cell level events.
In the following chapter, a review will be presented of some relevant studies
reported in literature which have used multiscale modelling approaches to elucidate
the growth and remodelling mechanisms underlying vascular diseases, such as
atherosclerosis, in-stent restenosis and intimal hyperplasia.
2 Multiscale Models of Vascular Disease
2.1 Atherosclerosis
It has been shown that atherosclerosis usually occurs in locations where blood flow
perturbations, i.e. low and oscillatory wall shear stress, take place such as at, or near,
bifurcations. Damage to the endothelium can also increase penetration of low density
lipoproteins (LDL) into the intima and lead to accumulation of macrophages and
subsequently foam cells in the arterial wall and its chronic inflammation [ 16 - 18 ].
This chronic inflammation can lead to dedifferentiation of SMCs and their
chemotactic migration and proliferation from the media to the intima and formation
of atherosclerotic plaques. As such the events involved in the onset and progression
of atherosclerosis are intrinsically multiscale chemo-mechano-biological events.
To-date models of atherosclerosis have been developed at the cell level using
ABM, for example (SimAthero, [ 3 ]). Models such as SimAthero consider the
biological variables that play the most important role in atherogenesis and its
induced immune response, i.e., LDL, ox-LDL, chitotriosidase and the foam cells
generated in the artery wall. Pappalardo et al. [ 3 ] analysed four different classes of
patients to show how SimAthero could be used to analyse and predict the effects of
various LDL levels in a diverse group of patients over a time scale of two years,
namely (i) patients with an LDL level considered normal, where no foam cells
were formed, (ii) patients with a high level of LDL with delayed drug treatment,
(iii) patients with high LDL levels, treated with specific drugs aimed at reducing
total LDL (statins), and (iv) patients with specific lifestyle conditions that
increased the risk of LDL oxidation such as smoking. As with other ABM or
multiscale models, the underlying cell rules described by the model in the virtual
patients were tuned against human data, thereby providing a means of ensuring
realistic behavioural outcomes. Whilst ABM of this nature can provide insights
into individualised drug treatment and the underlying biology of diseases such as
atherosclerosis, the inherent mechano-biological interaction driving many vascular
diseases cannot be modelled by such a framework.
A multiscale model of early stage atherosclerotic plaque formation has recently
been developed in order to integrate the various mechano-biological phenomena
leading to fatty streak formation [ 19 ]. The different scales considered in this model