Mechanical Modulation of Fracture Healing and Implications for Skeletal Tissue Engineering - Engineered Bone: Tissue Engineering Intelligence Unit - page 74

This chapter will review the interaction of mechanical environment and the bone repair
process together with the implications for in vivo regeneration of specific connective tissues
using mechanical cues.
Adaptation of the Skeleton to Changes in Mechanical Conditions
Since the observations of Wolff, Culman, von Meyer and others, leading to the concepts
that bone as a structure responds to mechanical loading to optimise mass and architecture,
techniques to quantify the effects of load on the skeleton have only been developed relatively
recently. Lanyon (1971) 48 and van Cochran succeeded in transferring engineering technology
to enable bone strain to be measured in the living skeleton. Direct measurement of loads and
stresses within the skeleton is not possible. However, the consequence of applying a load to a
structure, is the deformation of that structure. The degree of deformation depends upon the
magnitude of load and the structural and material properties of the bone. The ability to mea-
sure bone deformation not only in cadaveric bone in the laboratory but also in the living
skeleton during functional loading was enabled by the advent of the cyano-acrylate adhesives
that allowed foil strain gauges to be bonded to the bone surface in the living skeleton. This
technique made it possible to quantify both the magnitude and direction of principal surface
strains both during physiological activities and also during the magnitude and distribution of
strains associated with imposed loading regimens to enable the investigation of the effects of
specific loading regimens on tissue and structural morphology.
Following this breakthrough many experiments have been performed in which loads have
been applied to the skeleton to perturb normal strain patterns and to relate the imposed strains
to changes in bone tissue from the structural level of whole bones down to changes in gene
expression in the bone cell populations of bone tissue in response to specific mechanical condi-
tions.
The skeleton responds to changes in strain and adjusts mass and distribution of bone to
restore the customary strain levels. Increase strains provoke an osteogenic response to increase
skeletal mass and thus restore the optimal strain environment. Conversely, a reduction in strain
evokes a cellular response that induces the removal of bone again to adjust the mass and struc-
ture of the bone to restore the optimal strain. This adaptive response, initially observed in
qualitative terms, has now been validated experimentally and also modelled mathemati-
cally. 8,35,40,50,72
The cascade of events following an episode of osteogenic cyclical strain has been elucidated
in terms of effects on both the bone matrix and cell populations.
Initial responses to mechanical stimulation occur very rapidly in both the matrix following
as few as 50 cycles of loading. There are changes in the orientation of proteoglycans that remain
for twenty four hours after the imposition of the single train of loading cycles. This has been
suggested as a “strain memory”. 74 There is a concurrent change in metabolism of the osteocytes
with elevation of G6PD levels and mRNA synthesis with changes in mediators such as
prostanoids and nitric oxide occurring within a few minutes of the application of the stimulus.
This is followed after a few hours by activation of the surface lining osteoblasts. Activation of
gene expression and synthesis of bone matrix components by osteoblasts occurs within 24
hours. 66,75
The coordination of the response of bone tissue to changes in loading is now known to be
via the osteocyte cell population. These cells are well placed to respond to local changes in
environment and to communicate not only with other osteocytes but also with the surface
lining cells and active osteoblasts. The osteoblast has been shown to signal the osteoclasts and
participate in the control of coupling between the two processes of bone resorption and bone
formation that effect the changes in mass and distribution of matrix that are required to ac-
commodate alterations in mechanical loading. This coupling is mediated by the RANK, RANKL
and osteoprotegerin (OPG) system. 77