Computational Mechanobiology in Cartilage and Bone Tissue Engineering: From Cell Phenotype to Tissue Structure - Computational Modeling in Tissue Engineering - page 340

Fig. 2 Regulation of tissue
differentiation by substrate
stiffness and oxygen tension.
Cartilage forms in a low
oxygen environment and
turns into calcified cartilage
(CC) in close proximity to
bone. MSCs will differentiate
to form marrow (stroma and
adipogenesis), fibrous tissue
or bone when attached to soft,
medium or stiff extracellular
materials, respectively.
Colour version available
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substrate stiffness
soft stiff

marrow

bone

cc

low pO 2

cartilage

high pO 2

fibrous tissue

oxygen tension

oxygen concentration results in cartilage formation. Thus, the effect of deformation
on stem cell fate is more indirect. Rather than responding to external strain, the cells
are assumed to actively probe the ECM in order to determine its stiffness and dif-
ferentiate accordingly.
Like several other theories, this regulatory model has successfully captured many
of the key stages of fracture healing [ 12 ]. This illustrates that the corroboration of one
hypothesis in a simulation does not allow one to reject others. Extensive assessment
of the efficacy of a proposed theory via the simulation of a broad range of experiments
is needed to further corroborate the proposed hypothesis.

3.3 Accounting for Tissue Architecture During Skeletal
Regeneration

A tissue's structure is crucial for its mechanical fitness. Understanding how the
structure evolves during development and regeneration can have important
implications for how tissue engineering protocols, scaffolds and bioreactors are
designed in order to mimic a desired tissue architecture. The extension of the
predictive power of tissue differentiation models to include anisotropy will benefit
the investigation of specifically those healing processes and tissue engineering
strategies where recapitulating normal tissue architecture is important. For
example chondral and osteochondral defect repair critically depends on achieving
a native-like zonal structure within the cartilage tissue so that the tissue can endure
in-vivo loads.
Cullinane et al. [ 25 , 26 ] have demonstrated that the mechanical environment
during bone defect healing can influence both tissue differentiation and the
molecular organisation (collagen fibre architecture) of the repair tissue. They
showed that cyclic bending applied daily to an experimental mid-femoral defect