Mathematical Modelling of Regeneration of a Tissue-Engineered Trachea - Computational Modeling in Tissue Engineering - page 395

An important first step in the therapy is to decellularise the donor trachea. This
is done to prevent rejection by the host and has the potential advantage over
synthetic tracheal prostheses of presenting cells with the appropriate guidance
clues for growth and differentiation. Decellularisation removes all the cells from
the trachea while leaving the extra-cellular matrix (ECM) components largely
intact [ 36 ]. Then the donor trachea is seeded with correct types of cells from the
patient, crucially EPCs to regenerate the lining of the tracheal lumen and MSC-
derived chondrocytes to regenerate the cartilage ring [ 26 ]. Decellularised tracheas
implanted into laboratory animals without both cell types present have been shown
to fail [ 66 ]. Seeding of the trachea is performed so as to direct each type of cell
into the appropriate layer of the trachea. For the first tracheal operation this was
done ex vivo using a special bioreactor [ 4 ] to distribute the cells through the
trachea mechanically.
A different approach can be used whereby MSCs are applied to the exterior of
the scaffold in situ [ 54 ] along with appropriate growth factors [ 6 ]. This technique
aims to harness the reparative potential of MSCs, which have been shown to be
able to invade cartilage and differentiate into chondrocytes [ 62 ]. The contrast
between the two approaches is similar to that between 'dynamic seeding' and
'static seeding' of tissue engineering scaffolds. Static seeding, where cells are
applied to the exterior surface of the scaffold, can be problematic because of the
time it takes for cells to migrate through the scaffold. A mathematical modelling
study by our group of the differences between the two approaches is described in
[ 45 ]. In terms of revascularisation of the tissue-engineered trachea, where blood
vessels grow from surrounding tissue into the implant, such a delay could lead to
failure of the graft if the seeded cells react adversely to the hypoxic conditions
within the trachea [ 20 ]; mathematical modelling of the problem of vascularisation
of porous biomaterials by our group is described in [ 43 ].
The different types of cells that participate in the regeneration must be rapidly
directed to the correct layer within the tracheal cross section (Fig. 1 b) and this
layering must be maintained indefinitely. A pertinent question is: to what extent
does morphogenesis during development relate to the process of regeneration? The
growth of some embryonic tissues are guided by global polarity signals so it is
interesting to speculate as to whether such clues persist in the adult trachea to
maintain its shape and structure. On the other hand, the layered structure of the
trachea and the presence of certain growth factors within the underlying ECM,
established during development, may serve as a template to guide the positioning
of cells during episodes of healing in the adult tissue. The mechanical environment
experienced by cells in situ will also serve as a guide for cell positioning: for
example EPCs favour a fluid-air interface [ 90 ], which makes them preferentially
grow to cover the lining of the tracheal lumen.
Pathological states can arise after implantation of the trachea, which are
characterised by fibrotic growth (excessive proliferation of fibroblasts and pro-
duction of ECM in the submucosa) and malacia (softening of the cartilage rings)
[ 10 , 26 ], resulting in the initially normal structure of the donor trachea or graft to
be overrun and destroyed. The presence of both EPCs and MSCs appear to be