Biomedical Engineering Reference
In-Depth Information
The structural geometry of the callus may
also depend on the muscular anatomy or vas-
cularization of the tissue and on the biome-
chanical environment at the site of injury. The
latter seems to be particularly important. When
bending and shear loading were introduced at
an osteotomy site, osteogenesis was favored
over chondrogenesis [
skeletal-cell lineages. Of particular interest is
the fact that some factors act at several stages
during skeletal-cell lineage progression. For
example, BMPs not only are associated with
MSC lineage commitment but also are involved
in cellular expansion. In contrast, the scope
of morphogens such as VEGF and the Wnts
appears to be more restricted, with their pre-
dominant effect on proliferative lineage expan-
sion or survival. Members of the TNF-
]. Other studies have
similarly shown that mechanical instability
leads to persistence of cartilage tissue at the
fracture site. This involves up-regulation of
molecular signals such as Ihh that regulate
chondrogenesis [
42
family,
which are part of the immune response to
injury, regulate the initial stages of MSC recruit-
ment and cell survival during the infl ammatory
stage and re-emerge at the end of the MSC cycle
to control apoptosis during tissue remodeling.
Finally, factors such as the FGFs control the rate
or timing of entry and exit of committed cells
during their period of proliferative expansion.
The functional contribution of specifi c cyto-
kines and morphogens during fracture healing
is presented in Fig.
α
]. How morphogenetic
fi elds are established and how biomechanical
factors direct tissue differentiation and the
geometry of the regenerative process are ques-
tions of considerable importance, because the
answers may identify the signal molecules and
relate them to the origins of MSCs. Defi ning
how the morphogenetic fi elds are established
also has clinical importance, since the thera-
peutic responses to bioactive factors may
depend on whether they are correctly directed
to the morphogenetic fi eld.
124
. These factors are
expressed during different phases of fracture
healing and therefore may vary in the roles
they play during healing. For example, TGF-
2
.
3
β
2
,
TGF-
show peak mRNA expres-
sion during chondrogenic differentiation and
as the endochondral phases develop. This sug-
gests that the two factors are functionally
restricted to the periods in which chondrogen-
esis takes place.
Understanding the temporal pattern and
molecular nature of the factors as they are
expressed during bone healing can allow
targeting and modifi cation of their actions to
lead to better fracture healing. Knowing the
spatial nature of the morphogenetic fi elds
during the temporal processes of fracture
healing has clinical importance because the
therapeutic responses to bioactive factors may
be infl uenced by the moment in time when they
contact the correct morphogenetic fi eld. Such
knowledge will help to develop therapeutic
agents to treat osteoporosis and can equally
well be applied to the development of therap-
eutic agents that promote bone formation.
Table
β
3
, and GDF-
5
2.4 Bone Repair Is
Dependent upon
Multiple Cellular and
Molecular Signals
The cellular and molecular processes that
govern bone repair after injury have many fea-
tures that are similar to what occurs in a growth
plate during embryonic and postnatal skeletal
development. As reviewed earlier, fracture
healing involves several stages and is mediated
by very different biological processes. Figure
2
presents the stages and progression of MSC
differentiation into cartilage and bone as the
skeleton is formed.
Figure
.
2
also shows the stages at which
various morphogens and cytokines become
active and regulate MSC and skeletal-cell dif-
ferentiation. In addition the fi gure lists the spe-
cifi c transcription factors (Runx
2
.
2
lists the biological processes and
approaches that can be modifi ed in coupled
bone remodeling, either to impede bone loss or
to promote bone regeneration. The table also
lists approaches that could enhance the rate or
quality of bone healing.
2
.
1
2
, Osterix, and
Sox
]) involved in lineage commitment
and identifi es stage-specifi c markers for the two
9
[
117
