Bone Healing and Failure - Engineered Bone: Tissue Engineering Intelligence Unit - page 46

occurs beneath the periosteum but its ability to cross the fracture gap is limited. 4 This response
is enhanced by motion and increases in interfragmentary strain. 4,5 The response is retarded by
rigid internal fixation. 4,5 McKibbin, in his classical article on fracture healing describes four
types of fracture repair. 4 The primary callus response is: periosteal, rapid, very tolerant to both
motion and rigidity, with limited ability to bridge gaps. External bridging callus forms rela-
tively rapidly, has considerable ability to bridge gaps, is tolerant to movement, but inhibited by
rigidity. Late medullary, or internal callus, forms at a slower rate, is best at bridging gaps, and is
moderately tolerant to both motion and rigidity. Primary cortical repair, as outlined above, is
the slowest form of fracture healing, and is unable to bridge gaps, completely intolerant to
motion and will only occur in the presence of total rigidity. 4
Two types of bone formation occur during fracture healing and will be discussed in greater
detail below: intramembraneous ossification forms bone directly without first forming carti-
lage, resulting in “hard callus” formation, while endochondral ossification involves bone for-
mation via a cartilage anlage.
The bone marrow response to fracture is rapid, within a few hours there is loss of normal
architecture of the bone marrow elements, disappearance of blood vessels in the region adja-
cent to the fracture clot and a reorganization of the cellular complement of the bone marrow
into regions of high and low cellular density. Within 24 hours of fracture, polymorphic cells
that have transformed form endothelial cells in the cellular areas of the bone marrow express
osteoblastic phenotype and begin to form bone. It would appear from this that the bone mar-
row has an important function in the early phase of fracture healing. 5
The external soft tissue is the final vital component for successful fracture healing. Rapid
cellular activity occurs early in the repair process and results in the development of an early
bridging external callus. This response is stimulated by motion and its prime objective is to
achieve early fracture stability to enable the repair process to continue unimpeded. 5 This pro-
cess may be negatively influenced by significant soft tissue trauma, excessive soft tissue strip-
ping during surgery, and rigid internal fixation. The external “soft callus” formed subsequently
becomes bone through the process of endochondral ossification. 3
The Sequence of Fracture Healing
Secondary fracture healing thus involves a combination of intramembraneous and endoch-
ondral ossification. However the formation of bone via these pathways is both spatially and
temporally different. The overall sequence of events in fracture healing includes, the immediate
response to injury, intramembraneous bone formation, chondrogenesis, endochondral bone
formation, and bone remodeling.
Endochondral ossification occurs through a series of steps as follows: Initial or inflamma-
tory stage, angiogenesis and initial cartilage formation, cartilage calcification, cartilage removal
and bone formation, and finally, bone remodeling.
Bone formation through the intramembraneous ossification pathway occurs earlier in the
fracture repair process from committed osteoprogenitor cells.
The various stages of fracture healing result from a complex interplay of cellular compo-
nents with an array of pro-inflammatory cytokines and growth factors. The earliest event in the
healing process is the formation of a fracture hematoma and it would appear that this is an
important source of signaling molecules that have the capacity to initiate the cascades of cellu-
lar events that are critical to fracture healing. 3,7 The first detectable inflammatory factors fol-
lowing fracture include platelet derived growth factor (PDGF) and transforming growth factor
beta (TGF- β ) released by degranulating platelets. 7,8 This is closely followed by infiltrating
macrophages and other inflammatory cells that secrete fibroblast growth factor (FGF) and
additional PDGF and TGF- β . 7,8 The pro-imflammatory cytokines interleukin-1 and -6 (IL-1
and IL-6) are thought to play an important role also and are presumably secreted at this time. 8,9
Their exact role remains to be elucidated. Peak expression of both IL-2 and IL-6 occurs on day
1 post fracture and declines rapidly until day 3 when levels are barely detectable. 8,10,11 Therefore,