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7
Therapeutic
Approaches - 3
Growth
Factors
The paradigm that normal healing is regulated by the co-ordinate actions
of cytokine growth factors and that such regulation is disordered in
the chronic wound led to the concept that intervention with exogenous
growth factors may stimulate healing (Bennet, 1993)). Implementation
of this strategy was made possible by the availability of an increasing
number of recombinant human growth factors with functions known to be
important in healing. Key examples that have been evaluated in human
clinical studies are presented below.
Platelet
Derived Growth Factor (PDGF)
PDGF plays a central role to initiate healing after its release from
platelets aggregating at the site of tissue injury. It acts as a chemoattractant
stimulating the directed migration of neutrophils, macrophages and fibroblasts;
it activates macrophages to synthesise and release other growth factors
and stimulates production of fibronectin, hyaluronan and proteases by
fibroblasts. Early studies of treatment of DFU with platelet releasate
indicated accelerated wound closure by comparison to placebo (Steed
1992). Platelet releasate is essentially the cytoplasmic contents of
homologous platelets and whilst containing PDGF also contains other
growth factors such as EGF, TGF and FGF (Steed, 1992). However the beneficial
effect of topically applied recombinant PDGF was later confirmed in
treatment of DFU (Steed, 1995). In this 20 week study 48% of wounds
treated with PDGF achieved complete wound healing compared to 25% in
the placebo group with mean 98.8% and 82.1% wound area reductions in
each group respectively. Recombinant PDGF has been licensed for treatment
of DFU and whilst not 100% effective in all cases has been demonstrated
in cost effectiveness analyses to result in 26 fewer ulcer days per
patient (Sibbald, 2003).
Granulocyte-Monocyte
Colony Stimulating Factor (GM-CSF)
GM-CSF is produced by T-lymphocytes and macrophages following their
activation. It was originally named because it was found to stimulate
proliferation of granulocyte and monocyte progenitor cells. As with
most growth factors it is multifunctional and in the context of wound
healing those properties that may be important include attraction and
differentiation of neutrophils and macrophages with a consequential
enhancement of their microbicidal capacity. It is an important mediator
for regulation of inflammatory responses and synergises with other cytokines.
Additionally it is chemotactic for keratinocytes, modulates fibroblast
function and stimulates endothelial proliferation.
With such
an impressive array of healing related effects it is not surprising
that GM-CSF has been evaluated for the treatment of human chronic wounds.
As with other growth factors a positive effect was found but no study
has demonstrated a result approaching 100% efficacy. Subsets of refractory
chronic wounds have been demonstrated to respond rapidly (Malik, 1998),
an improvement from 19% of placebo to 57% or 61% healed VLU depending
on GM-CSF dose (Da Costa, 1999).
Transforming
Growth Factor beta (TGF-b)
TGFb exists as three isoform (TGF-b1, TGF-b2,
TGF-b3) and can be produced by all cells
in the wound environment suggesting a multiplicity of functions including
chemotaxis of leucocytes and stimulation of angiogenesis. Additionally
it is essential for wound maturation and strength as it stimulates fibroblast
production of collagen, fibronectin and glycosaminoglycans. These properties
led to its proposal as a wound healing agent (Amento, 1991). Published
evidence of efficacy in chronic wounds is limited although there is
some evidence of an early stimulation of healing in pressure ulcers.
However this effect did not result in a difference in overall healing
rates compared to placebo at the end of a 16 week study (Hirshberg,
2001). There is some evidence that TGF-b2
may accelerate normal incisional healing (Wright, 2000) and act synergistically
with PDGF in healing experimental diabetic wounds (Brown, 1994).
Keratinocyte
Growth Factor-2 (KGF-2)
KGF-2 is a member of the Fibroblast Growth Factor family (FGF-10). It
is synthesised by fibroblasts and stimulates proliferation of the majority
of keratinocytes. This mode of action has been demonstrated to accelerate
healing in animal models of normal (Soler, 1999) and impaired (Xia,
1999) healing. Application to human wounds did not demonstrate such
a positive effect with little difference between KGF-2 treated and placebo
in numbers of VLU achieving closure within 12 weeks. However, an increased
rate of area decrease was observed in the KGF-2 group with the treatment
being more effective with long standing smaller ulcers (Robson, 2001).
A partial
response to therapy after application of a single type of growth factor
is not surprising considering that healing follows a temporal sequence
of growth factor gene expression. It may be that optimal dosing regimens
will have to be derived that apply different combinations of growth
factors in an appropriate order (Robson, 2000). Proteolytic degradation
of applied growth factors may also negate their effect and it has been
suggested that there may be a requirement for co-administration of a
protease inhibitor to protect the therapeutic agent (Trengrove, 1999).
Finally, to compensate for the heterogeneity of response to growth factor
therapy, consideration has to be given to development of a diagnostic
system that will predict the appropriate factor(s) requirement for each
wound.
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