Biomedical Engineering Reference
In-Depth Information
fi nd a mathematical relationship to solve this
observational enigma. A large number of
studies, primarily performed during the
similar to fracture healing and distraction
osteogenesis, when early-loading protocols are
used [
s,
were undertaken to examine the local mechan-
ical responses of mineralized tissues during
fracture healing. These studies attempted to
develop a physical rule to explain the link
between callus formation and functional
stresses at different stages of healing.
During the healing process, many factors,
including the sex, genotype, and age of an
individual and the presence of chemical and
physical stimuli, infl uence the gene/protein
expression of cells and thus affect the outcome
of regeneration [
1980
]. Taken together, these observations
indicate that there is a therapeutic benefi t of
functional loading prior to the postspurt RAP,
e.g., to stimulate healing tissue to produce bone
faster and to maintain osteoblastic cells in
highly active and mitogenic states.
In intact bone, the pathway for transducing
mechanical signals in bone cells includes an
increase of the mRNA level of the protooncogene
c-fos
and of the bone matrix proteins collagen
and ALP [
112
]. In addition, several other genes/
proteins have been shown to be altered by
mechanical stimuli. Similar fi ndings were
reported in a healing scaffold as a result of
loading the
97
]. The degree of
infl uence depends on the local bone quality,
which governs cell activities and determines
the degree of maturation possible. The sequen-
tial expression of tissue-specifi c genes encod-
ing collagens, proteoglycans, and other
noncollagenous ECM proteins provides pat-
terning for the development of new ECM.
An ordered sequence of cell differentiation
and mRNA expression of bone-matrix proteins
governs the evolving histological changes
observed during fracture healing [
15
,
44
,
46
,
47
8
-week healed implant [
86
]. Further,
Ziros et al. [
as a
target for mechanotransduction in human peri-
odontal ligament osteoblastic fi broblast-cell
culture. Following mechanical stretch, both
Runx
128
] identifi ed Runx-
2
/Cbfa-
1
m R NA a nd protei n s were up -re g-
ulated. The authors reported that MAPK could
physically interact with and phosphorylate
Runx
2
/Cbfa-
1
2
/Cbfa-
1
. Other physical stimuli, such as a
6
,
63
,
102
,
shock wave [
], have
also been shown to infl uence the phosphoryla-
tion of various genes, such as Runx
119
,
120
] and ultrasound [
105
126
]. The expression of markers of osteoblast
activity during bone healing follows a temporal
pattern that is similar to the adolescence growth
curve. It contains a lag phase (prespurt) fol-
lowed by a spurt and then a decline (postspurt).
During the spurt stage, the cells secrete pro-
foundly more ECM than does unwounded,
normal bone. This overexpression of genes/
proteins may facilitate a rapid mineralization
during healing and was termed the regional
acceleratory phenomenon (RAP) by Frost in
1986
.
Thus, the more recent studies have taken into
account that mechanical signal transduction is
par t of t he regenerative ef fects of late R AP.
During the accelerated regenerative stage
(prespurt or spurt) of fracture healing, distrac-
tion osteogenesis, and endosteal implantation,
the mechanical response of osteoblastic cells,
has been shown to produce more ECM than
that evoked during the subsided RAP (post-
spurt) [
2
/Cbfa-
1
]. Frost postulated that the RAP healing
process is controlled predominantly by biologi-
cal factors (cells and molecules) released at
sites of injury, and that this phase is insensitive
to other physical stimuli, such as stresses and
strains. He implied that accelerated ossifi cation
is controlled by specifi c genes. In contrast to
this idea, a signifi cant body of histomorpho-
metric research has shown that early weight
bearing (loading
[
37
]. This fi nding contradicts Frost's
hypothesis that RAP is not affected by physical
stimulation. A decrease of cellular activity
during the late healing stage may result in cells
being less responsive to mechanical stimuli. If
this were the case, the situation would be anal-
ogous to that in intact, disused bone in which
bone cells resist gene regulation, and the result
is decreased bone formation [
44
,
68
].
Questions exist as to whether the accelerated
molecular expression during early healing ele-
vates tissue sensitivity to mechanical stimula-
tion, and whether the enhanced osteoblastic
bioactivity suppresses osteoclastic resorption
and callus shrinkage. Other questions concern
the role of apoptosis of osteoblasts that occurs
during the late healing stage [
23
,
30
,
50
,
77
,
109
days after fracture) can
enhance both endochondral and intramembra-
nous ossifi cation during fracture healing [
2
to
7
24
,
44
]. Distracted motion perpendicu-
lar to an osteotomized bone section has also
been shown to stimulate profound bone forma-
tion. In addition, osseous implants show evi-
dence of an improved osseointegration effect,
,
81
,
92
,
104
78
,
103
].
