Biomedical Engineering Reference
In-Depth Information
in the acute phase following a fracture, a series of inflammatory mediators are present and
initiate the repair process at the various sites, namely, periosteum, bone marrow, and surround-
ing soft tissue. These factors are important in regulating cell proliferation, differentiation of
committed mesenchymal stem cells, chemotaxis and angiogenesis. 3,10,11
Angiogenesis is an essential component of successful bone repair and numerous angiogenic
factors have been identified that have roles in both normal and pathological processes. 12 Wound
angiogenesis is initiated by the early rapid release of stored growth factors such as FGF-2 (basic
FGF) and several studies have demonstrated its role in bone healing. 13-16 Endothelial cell growth
factor (ECGF) has been shown to enhance angiogenesis and osteogenesis in a rat model. 17
Vascular endothelial growth factor (VEGF) has been widely studied and has been shown to
be an important stimulator of angiogenesis. VEGF is produced by osteoblastic cell lines in
vitro, 18 a process that is stimulated by insulin-like growth factor I (IGF-I) 19 and bone morpho-
genetic proteins (BMPs). 20 Sustained delivery of recombinant VEGF in rabbits stimulated
neovascularization and DNA synthesis in endothelial cells. 21 Gene therapy techniques leading
to VEGF expression has resulted in local neoangiogenesis in mice 22 and revascularization of
avascular muscle in a rabbit model. 23
Vascular invasion brings pericytes that function as mesenchymal stem cells that also pro-
duce various growth factors. There is evidence to show that following fracture, periosteal
microvessel endothelial cells and pericytes increase in number and are transformed to mesen-
chymal stem cells that subsequently develop into chondroblasts. 6
As outlined above the bone marrow is the first local tissue to react to a fracture and it has
been shown that within 24 hours of injury that cells in the areas of high cellular density un-
dergo differentiation and take on an osteoblastic phenotype. In addition to changes in the bone
marrow, osteoblasts lining the cortical bone surface are activated, and adjacent periosteal cam-
bium derived preosteoblasts divide and begin differentiating. These resident and differentiat-
ing osteoblasts lay down new bone via an intramembraneous pathway and form woven bone
(hard callus) adjacent to the fracture site. This process of early intramembraneous ossification
can be detected in experimental models of fracture healing by studying the expression of
osteoclacin and type I collagen which indicate osteoblastic activity. 11 Expression occurs as early
as 24 hours post injury and continues for the first 7 to 10 days of fracture healing, as evident
with the formation of woven bone opposed to the cortex within a few millimeters from the site
of the fracture on either side. 3,11 Proliferation in this region disappears by day 14 however
osteoblastic activity continues beyond this time point
In secondary fracture healing, however, endochondral ossification provides the most im-
portant source of new bone formation. This process occurs in various stages, the acute inflam-
matory stage, as outlined, is the important first step. Mesenchymal cell proliferation can be
detected as early as day 3 post fracture and remains high for several days. 11 The subsequent
chondrogenesis by these mesenchymal cells and the proliferation of new chondrocytes contin-
ues from day 7 to day 21, leading to the formation of a cartilaginous callus (soft callus) that
bridges the fracture site and provides initial stabilization. This chondrogenic phase is hall-
marked by the expression of collagen types II and X which peaks at day 7. 11 As endochondral
ossification progresses type II collagen expression subsides more rapidly than type X collagen
expression. The sequence of events that culminates in endochondral ossification is very similar
to the events in the proliferative zone of the growth plate. By day 9 post fracture the chondrocytes
of the soft callus adjacent to the woven bone of the hard callus begin to elongate, form elabo-
rate vesicular structures and turn off type II collagen and aggrecan expression characteristic of
maturing chondrocytes. 11 These chondrocytes undergo hypertrophy and display the character-
istic expression of type X collagen typical of hypertrophic chondrocytes of the growth plate. In
addition, these cells produce and release neutral proteases that begin breaking down the carti-
laginous matrix, including proteoglycans, in preparation for calcification. 11 The mineralization
of soft callus proceeds in a spatially organized manner with hypertrophy of chondrocytes and
calcification beginning at the interface between the maturing cartilage and newly formed woven
 
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