Bone Healing and Failure - Engineered Bone: Tissue Engineering Intelligence Unit - page 54

The condition of the limb prior to fracture is particularly relevant, preexisting vascular
disease, ulceration, previous trauma, edema, radiation or neurological impairment pose signifi-
cant impairment to successful fracture healing. Those that affect the vascular bed and conse-
quent availability of progenitor cells are especially important.
The degree of energy imparted to the limb at the time of injury has significant conse-
quences. High energy fractures result in comminution of the fracture and disruption of the soft
tissue envelope. The association between high energy and retarded bony healing has been long
recognized this is exacerbated if the fracture is open, 122,123 or if there is an associated neurovas-
cular injury 124-126 or compartment syndrome. 127-129 Fracture location is also important. Meta-
physeal fractures heal more readily than those involving the diaphysis. 130 Fractures with a sur-
rounding bulky soft tissue envelop are more likely to heal than those covered by only skin and
subcutaneous tissue e.g., middle third tibial diaphyseal fractures.
Surgical insult may, in some cases, be the final sequence in a series of events that contribute
to failure of bone repair. Additional soft tissue injury and periosteal stripping may disrupt
blood supply even further. Surgical strategies must be cognizant of this and aim to avoid exac-
erbating soft tissue injury. Fracture fixation has important consequences that are not always
beneficial. Fracture gap and segmental defects following fixation is an important concept. It
has been stated that a gap of greater than 2 mm may adversely affect healing. 131 Fixation
method becomes important in these situations as this determines the degree of interfragmentary
motion, shear and stress. As previously outlined, complete elimination of interfragmentary
motion results in primary bone healing via intramembraneous ossification. Cutting cones are
important in this process. For these to function there must be interfragmentary contact. 3 If a
fracture gap exists in the presence of rigid internal fixation then failure of bone healing is likely
to occur. Interfragmentary motion is beneficial to fracture healing up to a point. 3-5 The degree
of motion at the fracture site affects the differentiation of mesenchymal cells either towards
osteogenic or chondrogenic pathways. Creating a stable mechanical environment decreases the
overall amount of cartilage that forms at the fracture site. So called micromotion at the fracture
site stimulates chondrogenesis and subsequent endochondral ossification. However excessive
motion disrupts this process and results in fibrous nonunion. The exact mechanism whereby
this occurs is not fully understood. Le et al 132 have demonstrated that mesenchymal cells in the
callus commit to a chondrogenic or osteogenic fate during the initial stages of healing and this
is influenced by the mechanical environment of the fracture site. For example, by day 4.5 of
nonstabilized fracture repair mesenchymal cells in the callus had begun to express indian hedge-
hog, (ihh, a regulator of chondrocyte maturation during skeletogenesis) indicating their differ-
entiation along a chondrogenic lineage. However, in stabilized fractures this was not detected
until day 7. This would suggest that mechanical environment influences cell differentiation at
an early stage of fracture healing. It has been postulated the mechanical forces may influence
mesenchymal differentiation by either preventing or facilitating vascular ingrowth into the
fracture sire. Hypovascularity and alterations in pH may stimulate cartilage formation. 6,132
Aspenberg et al 133 demonstrated reduced expression of BMP-3 due to mechanical loading and
suggested a link between mechanical stimuli and tissue differentiation. It would therefore ap-
pear that temporal or spatial presence or absence of certain signaling proteins may be affected
by the mechanical environment of the fracture and this in turn may influence the conversion of
cell from osteogenic to chondrogenic or fibroblastic phenotypes. However other authors have
failed to demonstrate altered expression of growth factors or their receptors in either animal 134
or human nonunions. 135
The exact cellular pathophysiology of bone repair failure remains undiscovered. However, a
complete understanding of this process is now closer that ever before. Modulation of the repair
process using exogenously applied growth factors is a clinical reality. The most efficient way to
use this technology in the setting of fracture nonunion remains unresolved. However, it is
conceivable that during the present decade nonunion will no longer exist as a clinical problem.