Computational Mechanobiology in Cartilage and Bone Tissue Engineering: From Cell Phenotype to Tissue Structure - Computational Modeling in Tissue Engineering - page 339

Several comparison studies between the various algorithms named above have
been performed with no full corroboration achieved for any of them [ 35 , 49 , 50 ]
although the influence of torsional loading on fracture healing could only be
captured by considering fluid flow and shear strain as regulators of MSC differ-
entiation [ 49 ]. Further reviews of in silico approaches to regenerative medicine,
namely for bone and wound healing, can be found elsewhere in the literature
[ 10 , 38 ].
3.2 MSC Differentiation Regulated by Substrate Stiffness
As outlined in Sect. 2 , the profound effect of substrate stiffness on cells including
the stiffness-dependent differentiation of mesenchymal stem cells into various
lineages [ 31 ] has attracted considerable attention and is an important factor in the
choice of an appropriate biomaterial carrier for tissue engineering applications.
Cells furthermore depend on the supply of oxygen and nutrients and different
phenotypes thrive under different ambient oxygen tensions. Perhaps most impor-
tantly, oxygen tension itself has been shown to be a regulator of stem cell fate
[ 105 ]. In regenerative events or during progenitor cell based tissue engineering,
osteogenesis, for example, relies heavily on sufficient vascular supply, while
chondrogenesis has been shown to be favoured under low oxygen conditions [ 76 ].
Various tissue differentiation models therefore include an angiogenic component
[ 19 , 37 , 107 ].
A recent mechanoregulation model for tissue differentiation [ 12 ] developed in
our lab is based on two fundamental components: The influence of substrate
stiffness and oxygen tension. The model relies on a four-step analysis approach:
1. MSC infiltration into the regenerating tissue is modelled as a diffusive process.
2. A biphasic analysis is performed to evaluate the mechanical environment
throughout the regenerating domain.
3. Angiogenesis is modelled as a mechanoregulated diffusive process where the
formation of new capillaries is inhibited in regions of high shear strain as
determined in analysis step 2.
4. Based on the vascular supply another diffusion analysis additionally accounts
for cellular consumption and determines the levels of oxygen tension in the
regenerating tissue.
Based on the current distribution of tissues, information on both the local oxygen
tension and substrate stiffness is now available in each point. This information is used
to predict the cell phenotypes for the next iteration based on the theory described in
Fig. 2 . The mechanical properties, state of vascular and cellular infiltration as well as
oxygen perfusion can now be updated for the next time increment of the analysis. In
contrast to most mechanoregulation models, mechanical stimuli such as strain, stress
or fluid flow do not exert their influence on MSC differentiation directly in this model.
Instead, neovascularisation is inhibited in regions of high strain and the resulting low