Multiscale Modeling in Vascular Disease and Tissue Engineering - Multiscale Computer Modeling in Biomechanics and Biomedical Engineering - page 242

intracellular level leading to phenotype modulation and changes in cellular
behaviour which ultimately emerge at the tissue level as intimal hyperplasia and loss
of vessel patency. Clearly, in order to develop effective treatment strategies for
in-stent restenosis, a mechanistic understanding of the mechanisms and interactions
at different length scales is required. From a modelling perspective, this can be
realised by means of multiscale modelling strategies rather than single-scale
phenomenological models. One other important advantage of such in-silico models
is that whilst in-vivo and in-vitro models generally enable studying the role of single
parameters at a time, multiscale mechanistic in-silico models can provide a systems
approach to the role of several different parameters and their interactions in the onset
and prognosis of pathologies.
Multiscale approaches which have been adopted to model in-stent restenosis
include those using agent based models to describe SMC proliferation governed by
local fluid flow, structural stress and anti-proliferative drug concentration eluting
from the stent [ 4 ], and lattice based CA models of SMC phenotypic modulation,
proliferation and migration governed by arterial damage at the organ level [ 6 , 7 ].
The authors have recently developed a mechanobiological modelling framework
by coupling a FEM, that simulates strut-artery interaction, with a lattice-free ABM
that simulates the key responses of VSMCs to mechanical damage [ 58 ]. In this
model, the stresses induced within the arterial wall were quantified and related to a
damage scale of [0-1] within each element. The ABM was superimposed on the
finite element mesh whereby the level of damage at the location of each VSMC
could be apraised. Damage upregulated MMP synthesis by VSMCs and resulted in
the degradation of the collagen matrix surrounding each VSMC. Endothelial dam-
age and degradation of the collagen matrix were then used as the main regulators of
VSMC activation. As such, degradation of the collagen matrix and lack of nitric
oxide (NO) signalling due to endothelial damage led to migration and proliferation
of VSMCs and ultimately intimal growth and lesion formation, see Fig. 2 .
Using this model, collagen matrix turnover following stent induced arterial
injury could be evaluated quantitatively. Given that the collagen matrix is a key
regulator of VSMC activation and phenotypic modulation this enabled the influence
of design parameters, such as stent deployment diameter and strut geometry, on the
level of in-stent restenosis to be investigated using this multiscale framework, see
Fig. 3 .
The model predicted that synthesis of MMP-2 reaches its maximum one week
following stent deployment. As a result, the amount of collagen per VSMC drops
33 % from its initial state in the vicinity of the stent strut after 2 weeks. VSMCs
were also activated due to the degradation of the collagen matrix and their numbers
started to increase 2 days post stent deployment. After reaching its maximum
concentration one week post-deployment, MMP concentration subsequently began
to recess to normal levels, decreasing 80 % of the maximum level by the end of day
14. This was found to be consistent with the outcome of organ culture experiments
conducted on damaged human saphenous veins [ 34 ], see Fig. 4 .