Multiscale Modeling in Vascular Disease and Tissue Engineering - Multiscale Computer Modeling in Biomechanics and Biomedical Engineering - page 240

are in both the spatial domain (from cellular to organism level) and the time
domain (from seconds to months). At the cell level, the transport and chemical
interactions of low-density lipoproteins (LDL) and other agents were modelled.
This was linked to arterial thickening and mean LDL level at the organ level in a
stenosed artery whilst the critical factors for atherosclerotic formation at the organ
level were chosen to be mean LDL and flow induced endothelial wall shear stress.
In this study, it was observed that plaque location was dependent on WSS and that
plaque size, number, and growth were also dependent on mean blood LDL levels.
Whilst the simulation results from these models compared favourably with some
well-established biological hypotheses for atherosclerosis in terms of plaque
location, number, size, and rate of formation, the most significant potential of the
models is their ability to be highly individualised. Multiscale patient-specific
models can take the anatomies of individual patients into account, but they can
also include cell and molecular level information by considering individual
baseline LDL levels and plaque growth rates.
2.2 In-Stent Restenosis
In-stent restenosis, or re-blockage of a vessel following stent implantation, is a
vascular disease which is linked with mechanical injury at the tissue level induced
by the stent which can dramatically alter the microenvironment of SMCs at the
cellular level. After stent deployment, vessel injury by the stent struts leads to
modulation of the medial SMCs' phenotype to a synthetic phenotype. This change
of phenotype is followed by migration and proliferation of dedifferentiated medial
SMCs towards the lumen and lesion formation, see Fig. 1 [ 20 - 23 ].
The changes in the microenvironment of cells, specifically the extracellular
matrix (ECM) changes following vessel injury have been shown to regulate
VSMC activation [ 24 ]. An intact and mature collagen type IV matrix has been
shown to promote a quiescent and contractile phenotype, whereas its degradation
leads to VSMC activation [ 25 - 28 ]. In addition, degradation of collagen types I and
III which maintain the mechanical integrity and stability of arteries promotes a
synthetic VSMC phenotype [ 28 ]. As such, basement membrane-degrading matrix
metalloproteinase, i.e. MMP-2 and MMP-9, which can degrade collagen type IV
[ 29 ], and fibrilar collagen types I and III [ 29 , 30 ] are also strongly implicated in
activation of VSMCS following arterial damage. Mechanical injury to the arterial
wall has been shown to upregulate MMP-2 production [ 31 - 34 ], as does
mechanical stretch [ 35 , 36 ]. A study by Asanuma et al. [ 35 ] showed that the
application of a constant mechanical stretch increased MMP expression in cultured
human VSMCs. Therefore, long-term strain imposed by stents, hypertension or
atherosclerosis may lead to enhanced matrix degradation by VSMCs.
Clearly therefore, during in-stent restenosis mechanical perturbations at the tissue
level, due to stent implantation, lead to dramatic changes in the microenvironment of
cells. Subsequently, these cell level changes initiate a cascade of event at the