The Transport of Insulin-Like Growth Factor through Cartilage - Porous Media: Applications in Biological Systems and Biotechnology - page 403

in the form of supramolecular aggregates; other newly synthesized aggrecan
monomers may be lost from the tissue by diffusion along a chemical potential
gradient [20]. Finally under normal turnover conditions, a small population of
newly synthesized and/or preexisting aggrecan are degraded, predominantly
by one of the aggrecanases [21]. These aggrecan molecules are soluble and
mobile in interstitial fluid, and may be transported through the ECM [22-24].
The newly synthesized aggrecans need to be transported away from chondro-
cytes after secretion and ultimately incorporated into the tissue matrix, while
degraded aggrecans may find their way out of the cartilage ECM and are dis-
charged into the synovial fluid. The turnover rate of proteoglycan in normal
rabbit cartilage is around 21 days [25], however, the half-life of proteoglycan
in vivo is much longer in human cartilage (estimated to be approximately 3.4
years) [26]. Additional complexity arises because cell responses are mediated
via intracellular signaling pathways [27], which then lead to protein produc-
tion. To “top it all off” many of these key processes are linked via feedback
loops at a variety of length and time scales. The list of possible components
and processes involved is truly daunting. Tackling problems of this complex-
ity require multiscale hierarchical modeling approaches, and multiple models
that suit the questions being investigated. Here we have begun the process of
building a continuum reactive-transport poroelastic model at the tissue level.
Clearly, this can be extended in the future.
We specifically focus on only two questions. First, what processes are
involved in the transport of large molecules like growth factors into cartilage?
The absence of blood and lymph vessels in cartilage implies that diffusive
transport must play an important role in delivering nutrients and growth fac-
tors to chondrocytes. However, proteins such as growth factors are usually
large molecules that do not diffuse easily. How might cartilage regulate its
exposure to growth factors, and can we devise strategies to increase chondro-
cytes exposure to these molecules? Second, we build a model to investigate
the interplay between two key stimulators of aggrecan production: IGF-I and
cyclic mechanical loading. In doing so, we will describe a model framework
that could be expanded naturally in a variety of ways.
In the next section a coupled solute transport and mechanical deformation
model for articular cartilage [28] is presented, and this model is employed
to examine the effect of advection on growth factor transport. This initial
model will form the basis of a series of model “extensions” encompassing an
increasing array of complex processes. Wherever possible, currently available
experimental data [29-32] is used to validate the models.
More specifically in Section 11.3.2, the model is extended to incor-
porate reversible time-dependent binding of IGF to an IGFBP [33]. In
Section 11.4.1.1, the model is extended to include a family of six IGFBPs
in two functional groups to understand the effect of competitive binding on
IGF-I transport in both normal and diseased cartilage [34]. In Section 11.4.2
a competitor growth factor is introduced into the transport model [34]. The
models developed in Sections 11.4-11.5 are then used to describe the chem-
ical microenvironment of chondrocytes in an aggrecan biosynthesis model