The Transport of Insulin-Like Growth Factor through Cartilage - Porous Media: Applications in Biological Systems and Biotechnology - page 415

Gardiner et al. [28] went on to state that before cyclic loading can signif-
icantly enhance solute transport by advection, there needs to be a so-called
“symmetry breaking” mechanism, otherwise solutes are just advectively trans-
ported into and out of the cartilage within each loading cycle with equal facil-
ity. That is, there needs to be a directional bias imposed on the solute trans-
port before cyclic fluid motion can enhance transport. Diffusion provides one
symmetry breaking mechanism, as concentration gradient provides a bias to
the transport. Solutes can then be transported into the cartilage under advec-
tion and diffusion in one half of the loading cycle, but in the other half of the
loading cycle advection and diffusion are in opposite directions. This cyclic
advection plus diffusive transport still provides enhanced solute uptake com-
pared to diffusion only transport, as advection allows solute to reach cartilage
at deeper layers sooner (although this may potentially flatten the concentra-
tion gradient). Hence for diffusion to act as a symmetry breaking mechanism,
to significantly enhance transport, large concentration gradients are required.
Using their model Gardiner et al. [28] showed that enhanced transport was
only observed at early times near the surface of the cartilage when the solute
concentration gradient was the steepest and colocalized with maximum Darcy
velocities.
One of the more promising other potential symmetry breaking mechanisms
is the “capture” of solute to the cartilage matrix (by binding to the solid
phase), so that they are not released when fluid moves back out of the cartilage.
To work effectively, this requires a matching of timescales of cyclic loading to
the association/dissociation rates of the capture process. If the timescale of
capture is too slow or if release is too quick, relative to the loading cycle
frequency, solute capture cannot operate as an effective symmetry breaking
mechanism. In the case of IGF-I there is a range of IGFBPs contained within
the cartilage matrix which may perform this symmetry breaking function.
Here we will develop a model of this process by extending the model equations
developed in the previous section.

11.3.1.1 The Effect of IGF Binding on IGF Transport

in Cartilage

A family of at least six IGFBPs regulates the bioavailability of IGFs in carti-
lage [64]. It is suggested that the major functions of these binding proteins are
to prolong the half-life of IGFs in cartilage and to regulate the bioavailability
of IGFs in their interaction with cell surface receptors [65-67]. In addition,
IGFBPs may also exert IGF-independent effects by transcriptional activation
of genes by IGFBPs transported into the nucleus via their nuclear localization
signal [64]. However, the actual mechanisms are far from clear.
There are relatively few studies that experimentally and theoretically
investigate the effect of IGF binding to its binding proteins on IGF transport
in cartilage. Bhakta et al . [29] conducted a series of experiments to study
the effect of graded levels of unlabeled IGFs competing with radio-labeled