Biomedical Engineering Reference
In-Depth Information
8.2 Bone Healing
factor (PDGF), transforming growth factor
β
(TGF-
), fi broblast growth factor (FGF), and
epidermal growth factor (EGF) [
β
]. These
secreted growth factors play important roles in
the proliferation and differentiation of “stem-
like” cells at the healing site.
22
Bone regeneration is often associated with
wound repair, which involves complex bio-
chemical interactions among cells and associ-
ated factors. Research targeted at understanding
modulation of tissue development and early
embryogenesis has contributed to the fi eld of
wound healing, because similar molecules,
common cell types including “stemlike” cells,
and parallel processes are involved [
8.2.1.2 Reparative Phase
As the MSCs begin to differentiate, a loose,
unorganized callus is formed. This phase
requires the presence of collagens and many
noncollagenous proteins, including bone mor-
phogenetic protein (BMP), osteopontin (OPN),
osteocalcin (OCN), alkaline phosphatase (ALP),
and bone sialoprotein (BSP), along with several
others. Collagen provides a protein bed (osteoid)
for biomineralization to occur. Some noncol-
lagenous proteins serve as adhesive molecules
that immobilize cells. Others are enzymes that
activate the binding sites in the collagen through
phosphorylation/dephosphorylation. Still others
play a role as carriers to deliver calcium and
phosphate ions to supersaturated loci for apatite
nucleation. Table
13
,
22
,
32
,
33
]. In both cases, mesenchymal “stem-
like” cells migrate to and aggregate within the
matrix core and begin to proliferate and dif-
ferentiate in order to form the required tissues.
Injured bone attracts platelets, growth factors,
and blood capillaries to the local site, and this
process allows for recruitment of mesenchymal
stem cells (MSCs) to form the matrix. When the
MSCs differentiate, they produce cartilaginous
or osseous tissues, depending on whether they
are forming endochondral bone (cartilage to
bone, e.g., long bone) or intramembranous
bone (does not form cartilage fi rst, e.g., cal-
varium, periodontal wound healing). Bone
healing is functionally divided into three
phases: the infl ammatory phase, the reparative
phase, and the remodeling phase [
,
34
,
52
lists the putative roles of
selected proteins involved in regulating osteo-
blast activity and biomineralization.
Linked with expression of these proteins are
transcriptional factors, including osterix and
Runx-
8
.
1
79
].
, which have been identifi ed as
key factors required for osteoblast differentia-
tion and skeletal development. The
cis
-binding
element (OSE
2
/Cbfa-
1
8.2.1. Three Phases Of Bone Healing
has been
identifi ed in various osteoblast-specifi c genes,
including type I collagen, BSP, OPN, OCN, and
ALP. Binding of Runx
2
) for Runx
2
/Cbfa-
1
8.2.1.1 Inflammatory Phase
The infl ammatory phase begins at the onset of
bone damage. As blood vessels in the damaged
region rupture and clot formation is initiated,
they signal the body to dispatch macrophages
to the wounded area [
site
regulates the expression of transcripts encod-
ing these proteins [
2
/Cbfa-
1
to the OSE
2
]. A key result defi ning
the critical role of Runx
128
]. These macrophages
absorb and break down necrotic or damaged
tissues, and in turn lure osteoclasts, which
debride broken bone fragments. Whether the
next two phases of bone healing are activated is
contingent upon whether both the macrophages
and the osteoclasts can “clean up” the fi eld of
biological debris. In the meantime, granuloma
tissue, a repair blastema, is formed to provide
structural support in this vulnerable area, while
endothelial cells form capillaries that provide
basic nutrition and also deliver cells to the
healing site. Growth factors are released from
the local environment; these include insulin-
like growth factor (IGF), vascular endothelial
growth factor (VEGF), platelet-derived growth
108
expression
during skeletal development was the observa-
tion of the absence of mineralized bone in mice
with homogyzous deletion of the Runx
2
/Cbfa-
1
2
/Cbfa-
1
gene [
119, 120
]. Therefore, any factors that
infl uence Run
and osterix expression
of these transcription factors may affect this
phase of healing.
There are two types of reparative cascades:
one involves a phase of chondrogenesis (carti-
lage formation) fi rst a nd t hen conver ts to osteo-
genesis (bone formation), a process that occurs
primarily in appendicular bone and vertebrae
(endochondral bone formation). In the second
type, intramembranous bone formation, bone
is formed directly without a cartilage template.
2
/Cbfa-
1
