Mechanical Modulation of Fracture Healing and Implications for Skeletal Tissue Engineering - Engineered Bone: Tissue Engineering Intelligence Unit - page 84

Transduction Mechanisms
The effects of different mechanical conditions at the fracture site have been discussed in
relation to the material properties of the matrices of the range of connective tissues that are
induced and differentiate in the process of indirect bone repair as a consequence of fracture or
osteotomy. Indeed increasingly the effect of periods of cyclical mechanical strain are being
found to modified the various tissues that also appear in bone healing. For instance the devel-
opment of sutures, which are fibrous joints between some of the bones of the skull, is modified
by cyclical strain which significantly enhanced sutural growth. 47 However, the connective tis-
sue matrices are produced, maintained or modified as a function of cell activity. The cells
respond to mechanical cues or signals which are related to the loading of the limb and local
material conditions of the adjacent matrix.
The transduction mechanisms for both mechanical and biological cell signalling provide
potential pathways to modify the process of healing in a controlled manner, for example in
limb lengthening where soft tissue extension requires long periods of slow distraction that are
impeded by the potential for osteotomies to heal. For instance, it may be possible to superim-
pose a cyclical micro-movement regimen that reduces the rate of healing during the distraction
phase.
Direct deformation of cells can induce changes in cell metabolism. Various studies in vitro
have shown that different magnitudes of strain will influence proliferation and cell metabo-
lism. 59 This group also demonstrated that the response of bone cells to direct strain in vitro was
modulated in skeletal conditions that also down-regulated the response of the skeleton to me-
chanical loading in vivo. They found that osteoblasts from osteoporotic patients responded to
in vitro cyclical strain with a reduced proliferation and TGF β synthesis compared to osteo-
blasts from normal subjects (Neidlinger-Wilke et al, 1995) 58 suggesting that in vitro response
to direct mechanical stimulation is representative of the whole body response. The cells may
also respond to fluid shear stresses and the electrical effects of streaming potentials as ionic
fluids flow both within the cells and matrix as a consequence of mechanical deformation of
skeletal structures. 52,46 The effect of high rate micro-motion could therefore be a direct effect
of strain at the cellular level or alternatively mediated indirectly as a consequence of fluid
movement and streaming potentials.
The transduction pathway of mechanical strain in bone has been shown to involve the
prostaglandins, 81 inhibitors of prostaglandin synthesis such as indomethacin which blocks both
constitutive and inducible cyclo-oxygenases down-regulate the adaptive response of bone to
mechanical stimulation. 60,65 The prostaglandins also play a role in bone repair, the effects of
mechanical stimulation using applied cyclical inter-fragmentary micromotion involve the pres-
ence of endogenous prostaglandins. Different regimens of micro-motion were shown to be
associated with different levels of prostaglandins in the callus at a very early stage of the repair
process, 30 this may also indicate the importance of providing an appropriate mechanical stimu-
lus in the early stages of the repair process. The role of prostaglandins in bone repair should also
be considered with respect to the inhibitors of cyclo-oxygenases that might be used clinically
and could have an adverse impact on healing by blocking an important transduction pathway
in the critical stages of healing. 24
Recently it has been found that mechanical strain acts via the estrogen receptor and thus
this receptor provides a common pathway for mechanical and hormonal activation of bone
cells. 21,41 Estrogen receptor mRNA has also been found in fracture callus 5 and thus could
represent part of the transduction pathway for mechanical modulation of bone healing. Fur-
ther, evidence suggests that estrogen receptors are only found in the callus tissues present in the
early stages of healing and absent in the latter stages. 56 This may also be related to the impor-
tance of imposing the correct mechanical stimulus in the early stages of repair. Thus manipula-
tion of estrogen related pathways also has the potential to modulate the progression of bone
healing.