Biomedical Engineering Reference
In-Depth Information
flow, including the high sensitivity of osteocytes to strain. Several different stretch devices have
been used. Most devices apply stretch to a membrane or flexible culture dish on which the cells
are cultured. The applied stretch can be uniaxial (the membrane is stretched in one direction)
or biaxial (where the membrane is stretched in all directions simultaneously). In the latter case
a circular membrane is usually used that is stretched in all directions. The disadvantage of such
a system is that the applied strain is not homogeneous in size and direction. Other systems use
four-point bending of plastic or glass coverslips on which cells are cultured. 26,85-87 See Brown 88
and Basso and Heersche 89 for reviews of the mechanical loading devices used to apply me-
chanical loads to cells in vitro. In addition, 3-dimensional collagen culture models were used to
evaluate the response of fibroblasts or osteoblasts to stretch. 90-92 It was found that collagen
fiber and cell alignment depended on the applied force. Many different responses to mechani-
cal stretch have been reported. These include synthesis of active regulatory molecules (growth
factors, hormones, etc.), 93,94 changes in matrix synthesis, 41,95 cell alignment, 44,45,96 and en-
zyme release. 42 However, the mechanisms involved in mechano-sensing are still ambiguous.
Modulation of cytosolic free calcium, 97 stretch-sensitive ion channels, 87,98 or integrin-cytoskeletal
interactions 73,99-101 have all been suggested to play a role.
The advantage of cell straining via the cell culture substratum is, that this technique allows
to precisely determine the amount of cell strain that is applied, provided that the cell does not
modulate it's attachment to the substratum during stretching. Cell strain in vitro can therefore
be matched to bone tissue strain in vivo during exercise. Compared with physiological strains
in bone, relatively high strains are necessary to evoke cell responses. 78,85 It should be noted that
the application of mechanical strain in vitro is always accompanied by another mechanical
stimulus; fluid flow. Stretch of the substrate will inevitably cause movement of the medium
with respect to the substrate and thus fluid shear. Two independent studies concluded that the
actual physical cell stimulus during substratum-mediated cell stretching is the flow of culture
medium over the cell surface. 26,78 When this medium fluid flow was prevented, 10% cell stretch
was needed to induce increase of cell calcium levels. 78 You et al 78 suggest that bone cell
mechanotransduction may involve two distinct pathways relating to two different events. One
is the mechanical adaptation of intact bone that occurs throughout life mediated by canalicular
loading-induced fluid flow derived from small bone strains of the order of 0.1%. The other
relates to fracture healing, when large cell deformations of the order of 10% can be expected.
Such large cell deformations are also applied during DOG and in orthodontic tooth displace-
ment, where rapid activation of osteoprogenitor cells occurs. 102 It seems therefore that
osteoprogenitor cells are activated to express their osteoblastic phenotype when they experi-
ence large strains in biological processes related to rapid bone healing. However the more
subtle effects of physiological bone loading seem to be mediated by fluid flow in the osteocyte
network in intact bone.
Relation of Cellular Responses in Vitro with Mechanobiology
of Bone in Vivo
After evaluating the effects of fluid shear stress and cell strectching in vitro, we will now
return to the intact bone tissue. Can we link the cellular responses as observed in bone cell
cultures to the behavior of bone tissue during adaptive remodeling or DOG? The former para-
graphs have shown the intrinsic differences between these two processes. Here we will discuss
the concept that fluid shear stress applied to bone cells in vitro mimics the canalicular fluid
shear stress of osteocytes in remodeling bone. Stretching of bone cells in vitro however likely
mimics the osteogenic stimulus in the fibrous central zone during DOG.
Fluid Shear Stress and Adaptive Bone Remodeling
We recently described a link between local strains around a remodeling (hemi-)osteon and
the activation of osteoclasts and osteoblasts. 103 A finite element analysis of the deformation of
the bone tissue around a progressing BMU showed opposite strain fields around the cutting
and closing cone. These opposite strains appeared both under compressive and tensile axial
 
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