Computational Modeling of Mass Transport and Its Relation to Cell Behavior in Tissue Engineering Constructs - Computational Modeling in Tissue Engineering - page 88

Fig. 1 Fibrous matrix remodeling is triggered by cell proteolytic activity. Transport of various
solutes drives specific cell behavior during the different stages of new tissue formation (e.g.,
differentiation and apoptosis) and is strongly influenced by changes in carrier components (e.g.,
new matrix production by differentiated cells or release of matrix-bound soluble factors). Adapted
from [ 50 ]

of about 40 lm and was present at the construct periphery (Fig. 3 b). To account
for this in the model a heterogeneous proliferation rate was implemented, with fast
cell proliferation at the construct surface-its value being determined by means of a
dedicated experiment-and slow proliferation inside the construct.
The model predicted the highest cell density in the outer layer (i.e., multilay-
ered cell sheet), which was about 30 times higher than the maximum density in the
rest of the gel (Fig. 4 a). This led to the highest volumetric oxygen consumption
rate and the highest gradient in oxygen tension in this outer layer. (Fig. 4 b).
However, this was not the primary cause of hypoxic regions detected within the
hydrogel center, as the surface region only accounted for 2.3 % of the total
decrease in oxygen tension compared to a decrease of 16.5 % in the rest of the
hydrogel. This finding was further confirmed in a model parameter sensitivity
analysis in which (reasonable) changes in cell sheet thickness did not have a
significant influence on the occurrence of tissue hypoxia. On the contrary, varia-
tions in cellular oxygen consumption and oxygen diffusivity in the hydrogel region
had a major effect on total construct hypoxia, making both governing factors for
design and upscaling of static in vitro cultured hydrogel-based constructs.
As a second application we consider the development of TE pancreatic sub-
stitutes. In this field the use of mouse insulinoma bTC3 cells has since long been
investigated for the long-term treatment of insulin dependent diabetes mellitus
(IDDM) [ 28 ]. Reports on the insulin secretory capacities of these cells have
indicated a strong reduction in secretion as the available oxygen tension drops
below 10 lM[ 98 ]. This observation has therefore strong implications for the
functioning of the substitute in vitro and in vivo, a problem that has been assessed
using diffusion-reaction models for oxygen transport in the carrier [ 44 ]. By
combining

experimental measurements with the steady-state solutions of a