Biomedical Engineering Reference
In-Depth Information
(a)
(b)
Figure 17.1.
Modes of action of growth factors (a) and the concept of
growth factor immobilization(b).
signal transduction in the cell. These complexes are then internal-
ized, partially decomposed by lysosomes, and partially recycled to
thecellmembrane.Thus,internalizationofthereceptor/growthfac-
tor complexes reduces their number at the cell membrane, which
leadstothedesensitizationofcells(down-regulation)andreduction
ofexcessiveresponseandoverstimulation.Incontrast,somegrowth
factors are known to act in a nondiffusible manner by being present
at the cell surface (juxtacrine) or by associating with specific sub-
stances,suchastheECM(matricrine).Thenondiffusiblemechanism
was elucidated by the discovery of cell membrane-bound growth
factors in the 1990s,
5
,
6
which include heparin-binding-epidermal
growth factor (HB-EGF), transforming growth factor-
β
(TGF-
β
),
tumor necrosis factor-
α
(TNF-
α
), colony stimulating factor 1 (CSF-
1),andthec-kitligand.Thesegrowthfactorsarehardlyinternalized
butexhibitlong-termactivitywithoutdown-regulation.
The immobilization or high-a
nity binding approach is consid-
ered as the means of choice to mimic the nondiffusible action of
growth factors (Fig. 17.1b). Chemically immobilized growth factors
were devised and investigated in the 1990s by our group, and later
by other researchers, as reviewed recently by Ito.
7
,
8
These growth
factorswerecovalentlycross-linkedtoartificialmaterialsandexhib-
ited long-lasting activity, which suggests that internalization and
down-regulation were blocked or retarded. The procedure of cross-
linking is simple and applicable to various growth factors, with-
out a need for prior modification of the growth factors themselves,
although cross-linked molecules are randomly oriented on the
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