Biomedical Engineering Reference
In-Depth Information
In our tests of the effect of the viscosity ratio, we found that a given epithe-
lially generated force could cause very different amounts of deformation in a
given time period, depending on how viscous was the material in which it was
embedded. The major developmental conclusion we can draw from our results is
this: any experiment in which the mesenchyme of a clefting rudiment is replaced
by a gel of a different viscosity is
not
mechanically equivalent to an experiment
with epithelium embedded in intact mesenchyme. Most crucially, the time
course of a thin-ECM clefting will be substantially faster than a viscous-ECM
clefting. By analogy, a hand can very easily move in water, but very slowly if
embedded in clay, and hardly at all in plaster. In particular, we cannot conclude
from mesenchyme-free experiments (40,46,48) that the clefting force of branch-
ing morphogenesis comes solely from the epithelium
unless
the gel is of the
same viscosity as the tissue it replaces
and
the time course of clefting is the
same in mesenchyme-free rudiments and intact rudiments. In short, until me-
chanical measurements are made of the tissues and gels involved, we cannot
conclude from mesenchyme-free experiments that branching morphogenesis is
driven solely by forces of epithelial origin.
The model described in this chapter has been very useful in answering a few
questions, but others cannot be answered with these modeling tools. For exam-
ple, clefts are known to be filled with collagen fibers (19,43,44), and the mesen-
chyme close to a branched epithelium is denser than that far away, yet the
epithelial and mesenchymal theories could both explain these phenomena. As
we showed in the case of tumor encapsulation, a dense layer of tissue can be
formed equally well by contractility from outside or by suction from inside (36).
The right model can clarify the implications of a hypothesis while suggesting
refinements to a theory and also suggesting more rigorous experimental frame-
works.
There is ample work still to be done to understand the mechanical aspects of
branching morphogenesis. The model described in this chapter is extremely
simple, and focused on understanding a single aspect of branching—the me-
chanical implications of being surrounded by mesenchyme or surrounded by a
collagen gel. The conclusion is clear: pushing against a soft material is easier
than pushing against a firm material. Mesenchyme provides more resistance
than a typical collagen gel. To move the mesenchyme requires its cooperation.
What the model presented in this chapter does not address is whether or not
the mesenchyme can generate enough force to create a cleft. It also assumes that
the viscosities of the epithelium and mesenchyme are constant. An alternative
hypothesis of the mechanical aspects of branching morphogenesis would assume
that the mesenchyme is remaining passive, but is not resisting deformation
nearly as much as we suppose, because the epithelium is in a sense melting it
away with collagenases as it expands. These collagenases would have to be lo-
calized in the proliferating tips, because it has been shown (24) that collagenases
added to the culture medium inhibit branching by preventing cleft formation.
