Biomedical Engineering Reference
In-Depth Information
is presented, in the form of a set of coupled partial differential equations (PDEs), to
describe how the densities of the different types of cells and the concentrations of
ECM and cytokines vary in space and time through the trachea as regeneration
proceeds. The model results demonstrate that stenosis of the implant is minimised
when the lining of the lumen of the trachea is seeded with EPCs and MSCs are
applied to the external surface, as compared to when either or both of these cells
are excluded (see Fig. 5 and Table 1 ). This strategy works because the EPCs and
MSCs synergistically damp down the inflammation that causes excess secretion of
collagen in the submucosa resulting in stenosis, and the MSCs regenerate the
chondrocytes so as to maintain the GAGs in the cartilage thereby preventing
airway stenosis due to malacia.
The modelling results accord qualitatively with observed experimental out-
comes but in view of the many simplifying steps taken in the modelling, to what
extent does the model reflect the processes of tracheal regeneration as they occur
in living tissue? Some of the mechanisms crucial to the regeneration of the trachea,
particularly the revascularisation, have been excluded. Such an omission means
that the model cannot be used to provide a complete prognosis. Instead the model
is concerned with the processes of inflammation, particularly how inflammation in
the submucosa affects the regeneration of the cartilage and how chondrogenesis
and MSC infiltration affect inflammation in the submucosa. However the inflam-
matory cytokines included in the model (IL-10, TGF-b1 and TNF-a) are only a
few of those that form part of the highly complicated signalling network governing
inflammation of epithelial tissues.
As is typically the case with complex biological systems, there is an incomplete
knowledge of the biology underlying the mechanisms contributing to the regen-
eration process. This is particularly the case with understanding what factors
determine the differentiation fate of MSCs. Although an extensive knowledge has
been built up in recent years of the different chemical and mechanical signals that
guide MSC migration and their differentiation into chondrocytes, the complete
picture is still unclear. Yet such knowledge is key to harnessing effectively the
power of MSCs for regenerative medicine, and its absence is a barrier to devel-
oping effective mathematical models. The advantage of using donor trachea rather
than an artificial matrix is that the former is a more natural environment for
guiding the migration of the MSCs into the cartilage ring and for encouraging
them to differentiate into chondrocytes. This motivated the simplified approach
taken in the modelling whereby MSCs were assumed to differentiate directly into
chondrocytes within the cartilage but not within the submucosa. An extension of
the model could be to allow MSCs in the submucosa to differentiate into myofi-
broblasts where they could potentially have a pro-fibrotic effect [ 16 , 72 ].
The complex and incomplete knowledge of the biology of tracheal regeneration
warranted extensive use of such simplifications to keep the number of equations
and parameters in the model to a tractable level. The guiding principle was to use
the smallest possible set of tissue components that could be assembled to form a
realistic model. This represents a top-down approach to the biomedical modelling
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