Biomedical Engineering Reference
In-Depth Information
bone. Following closely after hypertrophic chondrocyte mineralization of the matrix is angio-
genesis, and the formation of new vascular structures which infiltrate along with accompany-
ing osteoblasts. The resident hypertrophic chondrocytes begin to undergo programmed cell
death, or apoptosis, and the mineralized matrix is replaced by woven bone laid down by the
incoming osteoblasts. 3 This new bone will subsequently be remodeled by coordinated osteo-
blastic/osteoclastic activity in response to the mechanical stresses peculiar for that bone.
As outlined previously, the mechanical environment that a healing fracture is exposed to
significantly influences the differentiation of mesenchymal tissue into bone, cartilage, or fi-
brous tissue. 5 Cyclic motion resulting in shear stresses cause cell proliferation and the produc-
tion of a large callus in the early phases of fracture healing. Low stress and strain at the fracture
site is associated with direct intramembraneous bone formation. Low to moderate tensile strain
and hydrostatic tensile stress may stimulate intramembraneous ossification. This is dependent
on vascularity, with low vascularity promoting chondrogenesis. Hydrostatic compressive forces
stimulate chondrogenesis whereas high tensile strain results in a net production of fibrous
tissue. Tensile strain with a superimposed hydrostatic compressive stress will stimulate the de-
velopment of fibrocartilage. 5
The process of fracture healing is well described and universally accepted. The precise mecha-
nisms whereby the different cellular events are initiated and controlled have been investigated
in detail. While not fully understood, these processes involve a complex series of inflammatory
mediators, growth factors, and signaling proteins, many of which have been isolated. The tem-
poral expression of these factors in fracture healing has become clearer.
The Role of Pro-Inflammatory Cytokines in Fracture Healing
The initial inflammatory phase of fracture healing is a vital stage in the repair process.
Influx of macrophages and other inflammatory cells leads to a secretion of an array of
pro-inflammatory cytokines. IL-1 and IL-6 are accepted as being ubiquitous to tissue injury,
including fracture healing, other cytokines such as the TNF family are also important. Both
IL-1 and TNF- α have been shown to have important regulatory roles in bone remodeling and
homeostasis. 24-29 Through a variety of mechanisms these factors regulate osteoclastic activ-
ity. 30,31 TNF- α participates in the cellular response to trauma by inducing acute phase proteins
and increasing adhesiveness of leukocytes on vascular endothelial surfaces. It is a primary me-
diator of immune responses. A novel member of the TNF receptor family, osteoprotegrin (OPG),
and its specific ligand receptor activator of NK- κ B ligand (RANKL) in conjunction with mac-
rophage colony stimulating factor (M-CSF) have been shown to be key regulators in the con-
trol of bone mass through their modulation of the bone resorptive cycle. 32-34 OPG is a secreted
soluble TNF receptor family member that binds to RANKL and prevents it from stimulating
osteoclastogenesis. RANKL up-regulation is an important component of the bone repair pro-
cess. It is responsible for osteoclast mediated activities including; removal of devascularized
bone, any remodeling that may occur during fracture repair, and ultimately for callus remodel-
ing along the lines of stress, once union is achieved.
The role of these factors in the response to skeletal injury has become somewhat clearer in
recent times.
Kon et al 11 have studied the expression of IL-1 ( α and β ), TNF- α , and their receptors, and,
OPG, RANKL, and M-CSF. OPG was expressed in unfractured bones but had two distinct
phases of increased expression following fracture. The first phase was within 24 hours of frac-
ture and the second occurred at day 7 which is the time of peak cartilage production. RANKL
was almost undetectable in unfractured bones but was strongly induced throughout the period
of fracture healing with maximum expression on days 3 and 14. M-CSF followed the temporal
profile of RANKL but had higher expression in unfractured bones.
TNF- α , IL-1 α and IL-1 β all showed peaks in expression within the first 24 hours following
fracture, depressed levels during cartilage formation, and, a second increase in expression on
days 21 and 28 when bone remodeling was initiated. TNF- α and IL-1 α expression was seen in
 
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