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86 B. Cheng and X. Fu
Cytokines
GM-CSF GM-CSF is a family of specific cytokines. Not only can it promote the
proliferation of cutaneous repaired cells through autocrine, it also plays a role in
promoting wound healing by mediating several other cytokines or growth factors
under paracrine. Granulocyte–macr
a cytokine released by T and B lymphocytes, macrophages, endothelial cells and
fibroblasts, and it induce s proliferation and activity of polymorphonuclear cells,
monocyte migration and differentiation in macrophages to injured tissue, activation
of antigen-presenting cells. As it could causes local recruitment of inflammatory
cells, and induces keratinocyte proliferation and migration. It also activates
mononuclear phagocytes, further regulates cytokine production. Therefore,
recombinant human granulocyte–macrophage colony-stimulating factors also were
used in accelerating healing of chronic wounds (Groves and Schmidt-Lucke 2000;
Brem
al. 2018).
et
In 1992, Kaplan first introduce GM-CSF treated acute skin wounds. It was
proved that rhGM-CSF injection could promote wound healing (Kaplan et al.
1992). Other studies have shown that the different evidence grades and expert
recommendations of GM-CSF to promote wound healing in different types of
wounds (Li et al. 2020). However, it has previously been demonstra ted that
rhGM-CSF could not have a significant effect on healthy wounds (Ure et al. 1998).
In
7 and 1999, two double-blind, randomized, placebo-controlled trials were
199
nt t
releva
o chronic venous leg ulcers treated with topically administered GM-CSF.
These studies were a series study conducted by rhe same center. Da Costa found
400 µg of rhuGM-CSF appears to heal faster than 200 µg. A key point of treating
venous ulcers is rapid healing, and better economic outcome could be acquired (Da
et al. 1999; Marques et al. 1997). Another two RCT studies were done by Robson
and Payne (Robson et al. 2000). These were relevant to pressure ulcers (grade
also treated with topically administered GM-CSF or growth factors. The
III/IV)
Payne’s study was the extension of the Robson’s, and the data were integrated with
the him (Robson et al. 2000; Payne et al. 2001). The study for meta-analysis.
Long-term outcome was better in this cytokin/growth factor (GM-CSF, bFGF, or
sequential GM-CSF/bFGF) trial than with surgical or standard non-operative
therapy of pressure ulcers. When patients receiving exogenous cytokines/growth
factors might achieved over 85% closure during the treatment phase of the trial, the
excellent long-term outcome appears attributable to the cytokine/growth factor
therapy. In the open clinical studi
reports reported a total of 93 patients with chronic leg ulcers were treated with
GM-CSF, by perilesional injection (Da et al.
1998; Cianfarani et al. 2006) or sprinkling on wound bed, the encouraging reports
on the use of topical recombinan t GM-CSF for rapid healing of nonpainful ulcers
have been described. Bianchi performed an additional study to test the usefulness of
recombinant human GM-CSF (rHuGM-CSF), local ly applied, for the treatment of
venous and diabetic chronic lower extremity wounds. Before 2008, GM-CSF had
been applied mainly by injection as a general clinical drug for more than ten years.
ophage colony stimulating factor (GM-CSF), as
es and case reports, 4 clinical studies and 2 case
Arnold et al. 1995; Malik et al.
1994;
Biologic Transducers in Wound Healing 87
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Subsequently, recombinant human GM-CSF (rhGM-CSF) gel was developed and
applied to clinical acute and chronic wound therapy. In these trials, in agreement
with previously reported experiences, provides further information on the safety,
efficacy, time dependence and size dependence of topical rHuGM-CSF as an
alternative choice for treating difficult to cure neuropathic diabetic and vascular leg
ulcers (Bianchi et al. 2002
). Almost all the studies reported favorable effect of
GM-CSF had beneficial effect on chronic venous ulcer and other cutaneous ulcers
except in in pressure ulcers. There were obvious heterogeneity in the groups. The
pooled effect was still in favor of the positive effect of GM-CSF for the treatment of
chronic ulcers, but was not significant. The rest of the 14 studies also reported
positive effect of topical administration of GM-CSF for chronic ulcers ofdiverse
etiology (i
ncluding chronic venous ulcers, pressure ulcers, erythropathy-associated
ulcers, neutrophil dysfunction-associated chronic ulcers, immunodeficiencyassociated ulcers, leprosy ulcers and refractory wounds in patients with cancer).
The side effects of topically administered GM-CSF were imperceptible in all the
studies (Hu et al.
2011).
See Table 1 for the clinical observation of GM-CSF promoting wound healing.
In 2014, Huang and colleagues (Huang et al. 2014) evaluated the clinical effec-
tiveness of the combined application of alginate and recombinant human granulocyte–macrophage colony-stimulating factor (rhGM-CSF) on the healing of
refractory skin and soft tissue ulcers. As a single center, three arm, randomized
study, it was performed at Jinan Central Hospital, Shandong province, China. A total
of 60 patients with refractory chronic skin ulcers (contains pressure ulcerssores,
venous leg ulcers and diabetic fo
four weeks, were e
nrolled and randomly divided into one of the following three
ot ulcers), which treatment continued for more than
groups: alginate dressing/rhGM-CSF group (group A), rhG M-CSF only group
(group B) and conventional (vaseline dressing) group (group C). The wound healing
rate was measured, granulation growing state and wound color were observed and
pain was evaluated. The data were summarized and statistical analysis was performed. The results demonstrated that group A exhibited a significantly accelerating
wound healing rate and reducing pain score compared with the others (p < 0.01). In
a word, the combined application of alginate dressing and rhGM-CSF for the
treatment of refractory chronic skin ulcers demonstrated significant advantages. It
promoted the growth of granulation tissue, accelerated re-epithelialization and also
significantly relieved wound pain, and thus improved the quality of life for the
patient. This article give some proposal that the combined application of alginate and
rhGM-CSF may be an effective therapeutic means for the clinical treatment of
refractory chronic skin and soft tissue ulcers.
Growth Factors
PDGF
PDGF possesses a wide range of biological activities. It acts on the membrane
receptors of target cells, producing a series of biological effects that play an
88 B. Cheng and X. Fu
(continued)
changes in the hematological and biochemical
parameters studied.GM-CSF seems a very
The number of healed wounds in the placebo
and the treated arms were significantly different
(p = 0.05), with 4 of 21 (19%) in the first
group having healed at week 13, as compared
to 12 of 21 (57%) and 11 of 18 (61%), in the
200 microg and the 400 microg groups,
respectively. There were only minor
side-effects attributable to the treatment, and
the reobservation at 6 months showed that
none of the treated ulcers recurred during that
period. We conclude that granulocyte–
macrophage colony stimulating factor injected
perilesionally may be a useful drug for the
treatment of chronic venous leg ulcers
Treated patients fared much better than
controls, prompting an early termination of the
study: of 16 GM-CSF treated patients, 3 (19%)
had their ulcers healed by week 1; 8 (50%)
were healed by week 8; only 1 of 9 controls
had the ulcer healed by week 1 (11%), and that
was the only ulcer of the group that healed at
useful drug for the healing of leg ulcers
all. We observed no significant side effects or
Therapeutic method Results/Conclusions
Placebo (drug vehicle), 200 µg or 400 µgof
Experimental
method
year
1999 Double-blind,
Author Particular
Da et al.
Disease
species
Table 1 Clinical observation of GM-CSF promoting wound healing
Chronic
rhuGM-CSF (Leucomax, Schering-Plough,
Brinny, Ireland) were administered in four
perilesional subcutaneousinjections totaling
0.5 ml and given 0.5 cm from thewound edge’
randomized,
placebo-controlled
study
(1999)
venous leg
ulcers
Patients received a single perilesional injection
of GM-CSF, the effect of which was observed
weekly and compared with that of a placebo
injection in a control group
randomized
placebo-controlled
trial
1997 Double-blind
Marques
et al.
(1997)
Chronic
venous leg
ulcers
Biologic Transducers in Wound Healing 89
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(continued)
Ulcers treated with cytokines had greater
closure than those in placebo-treated patients.
Patients treated with bFGF alone did the best,
followed by the GM-CSF/bFGF
GM-CSF topically applied daily
2
for 35 days; 5.0 mg/cm2 bFGF topically
Therapeutic method Results/Conclusions
Experimental
method
year
applied daily for 35 days; 2.0 mg/cm2
Randomized to one of four treatment regimens:
2.0 mg/cm
randomized,
placebo-controlled
trial
2000 A double-blind,
group. Patients treated with GM-CSF or bFGF
had higher levels of their respective cytokine
after treatment
bFGF; or the comparative
2
GM-CSF applied for 10 days, followed
sequentially by 25 days of topically applied
5.0 mg/cm
Fifty-four of 61 patients completed the
follow-up period with 68.5% of the patients
placebos, applied daily for 35 days
Follow-up data were serially collected as part
of a fourarm, blinded, randomized, pressure
placebo-controlled
2001 Blinded,
(37 of 54) being healed after 1 year. Of
patients healing > or = 85% during the active
ulcer clinical trial comparing sequential topical
CM-CSF/bFGF therapy with each cytokine
cytokine clinical
trial
treatment phase, 84.6% were healed after
1 year compared with 61% of those that
alone and with a placebo over a 35-day period
Complete resolution of the ulcers was seen
healed < 85% during treatment (P < 0.05)
(Leucomax) were subcutaneously injected into
1994 Case report Total doses of 400 flg of molgramostim
four injection sites, in approximately equal
amounts, in the four quadrants of each wound.
The puncture sites were about 0–5 cm away
from the limits of the open wound, and the
injection needle, tilted 45° from the
surface of the leg, penetrated only 0–5cm
deep. We found it very difficult to inject the
drug into the perilesional tissue, which had a
very hard consistency, and effort had to be
exerted to inject the liquid
Payne
et al.
Author Particular
Robson
et al.
(2000)
Disease
species
Pressure
Table 1 (continued)
ulcers
(2001)
Pressure
ulcers
(1994)
Leg ulcers Da et al.
90 B. Cheng and X. Fu
Fifty-four of 61 patients completed the
follow-up period with 68.5% of the patients
(37 of 54) being healed after 1 year. Of
patients healing > or = 85% during the active
treatment phase, 84.6% were healed after
1 year compared with 61% of those that
healed < 85% during treatment (P < 0.05)
subcutaneous injection of a single dose of
GM-CSF may induce healing in refractory
chronic wounds. Trials are necessary to
validate these initial observations and to decide
the optimal dose and route, and whether any
additional benefit may be derived from
repeated injections
increased in the ulcer bed following GM-CSF
treatment. VEGF transcripts were localized in
keratinocytes at the ulcer margin both before
and after GM-CSF treatment, whereas a VEGF
hybridization signal was evident within the
ulcer bed only following administration. PlGF
mRNA was barely detectable in keratinocytes
at the ulcer margin and was not visibly
increased after treatment. Unlike VEGF, a
specific PlGF hybridization signal could not be
detected in cells within the ulcer following
GM-CSF administration.
Blood vessel density was significantly
Monocytes/macrophages were the main cell
(continued)
Therapeutic method Results/Conclusions
Subcutaneous injection of GM-CSF around
Experimental
method
year
1995 Comparison before
Author Particular
Arnold
Disease
species
Table 1 (continued)
Vascular
ulcer
and after treatment
et al.
(1995)
leg ulcers
GM-CSF 10 microg/cm2 was injected
subcutaneously along the edges and base of the
and after treatment
1998 Comparison before
Malik et al.
(1998)
Chronic
wounds
wound. The treatment was given only once and
patients were followed weekly for a minimum
of six weeks
Patients with nonhealing venous leg ulcers
were treated with intradermal injection of
recombinant human GM-CSF
and after treatment
2006 Comparison before
Cianfarani
et al.
(2006)
Chronic
venous
ulcers
Biologic Transducers in Wound Healing 91
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(continued)
population transcribing VEGF after GM-CSF
treatment. In vitro analysis demonstrated that
VEGF transcription can be directly stimulated
by GM-CSF in a differentiated monocytic cell
line, but not in keratinocytes. Data show that
increased vascularization is associated with
GM-CSF treatment of chronic venous ulcers
and indicate that inflammatory cell-derived
VEGF may act as an angiogenic mediator of
the healing effect of GM-CSF in chronic ulcers
Pathogenesis, size and duration of the ulcers
seemed to be the most important parameters
regarding wound repairing capability of
rHuGM-CSF. None of the ulcers increased in
size and none of the patients developed clinical
side-effects or peripheral blood cell count
abnormalities during the treatment. All the
results described were stable after 6 months of
follow up. The absence of peripheral leucocyte
count variation and the size-dependent
therapeutic effect indicate that the drug
exercises local rather than systemic actions
The overall effects of rhGM-CSF on the
healing of wound are diverse. Topically
applied rhGM-CSF is beneficial for deep
partial-thickness burn wounds, chronic leg
ulcers, and leprosy ulcers. rhGM-CSF may
Therapeutic method Results/Conclusions
Experimental
method
year
Author Particular
Disease
species
Table 1 (continued)
One patient had a neuropathic-diabetic ulcer,
and four had long-standing vascular leg ulcers.
and after treatment
2002 Comparison before
Bianchi
et al.
Chronic
cutaneous
Ulcers were cleansed with 0.9% sodium
chloride solution and sprinkled with 1–2mLof
(2002)
leg ulcers
the rHuGM-CSF working solution. The
working solution was applied three times a day
for the first week then daily for the remainder
of the treatment period. The wounds were
covered with non-adhesive simple dressing
changed every day
To evaluate the effect of the rhGM-CSF on
wound healing, 8 RCT studies and 23 clinical
review
2011 A systematic
Hu et al.
(2011)
The
wound
studies and case reports are collected for
analysis of the evidence
healing
92 B. Cheng and X. Fu
for generalised use at present. rhGM-CSF is
suggested have no accelerating effect on the
related ulcers, but the evidence is not sufficient
healing of healthy wounds or surgical incisions
have a positive effect on other type of chronic
ulcers such as pressure ulcers and cancer
Therapeutic method Results/Conclusions
Experimental
method
year
Author Particular
Disease
species
Table 1 (continued)
Biologic Transducers in Wound Healing 93
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important role in the physiological and pathological processes of tissue repair. They
include chemotaxis of inflammatory cells (such as neutrophils and monocytes) and
recruitment repaired cell s to the wound, promotin
g the mitosis of VECs, fibroblasts,
SMCs and keratinocytes, regulating the synthesis and remodeling of extracellular
matrix (ECM), contribute to angiogenesis, granulation tissue forming, and
re-epithelialization of the wound site. The grades of evidence and expert recommendations for PDGF to promote wound healing in different types of wounds,
especially chronic ulcers.
In the 1980s, PDGF became the first growth factor that was isolated and purified
to homogeneity. The first human experience of PDGF using in chronic wound,
published as a preliminary report in the Lancet in 1992 and based on preclinical
results, reported the use of exogenous PDGF-BB in the treatment of pressure ulcers
(Robson et al. 1992a). Soon afterwards, a more detailed report of that phase I/II
trial was published in the Annals of Plastic Surgery. Total three dose levels of
PDGF (1 lg/ml, 10 lg/ml, and 100 lg/ml) were used and compared with a placebo. rPDGF-BB topically used in chronic pressure ulcers, which can promote
wound closure compared with that in a similarly managed placebo control group. In
addition, this article indicated the effective doses of wound-healing with PDGF are
about 10–20 pg/cm
2
, similar to the total dose delivered in the patients who received
100 µg/ml.
In 1997, rhPDGF-BB was approved by the American FDA for the therapy of
chronic lower extremity diabetic neuropathic ulcers, it became the first pharmacological agent approved for treatment of a chronic ulcer condition. The recombinant growth facto r is loaded in a aqueous-based sodium carboxymethylcellulose
(NaCMC) gel and is marketed as Regranex®. The local used for diabetic foot ulcers
that could arrived to the subcutaneous tissue and supplied adequate blood flow.
Steed reported the therapeutic efficacy of rhPDGF-BB gel accelerating healing of
lower extremity diabetic ulcers, he used a multi-center, randomized, prospective,
double-blind, parallel-group, placebo-controlled clinical trial in 1995. This Phase II
trial was the first to investigate PDGF in human diabetic ulcers and recruited 118
patients. The results illustrate that rhPDGF-BB gel is safety profile of repeated,
once-daily, topical application, and could easily be employed. And there was a
statistically significant difference in both the number of patients healed and the
healing rates in diabetic patients with chronic ulcers treated topically with
rhPDGF-BB gel (Steed 1995). In 2006, Steed again evaluated the safety and efficacy of rhPDGF therapy for the treatment of diabetic foot ulcers. It was effective of
rhPDGF applied once daily on healing chronic diabetic foot ulcers, but shoul d be
used in conjunction with good wound care. There was a trend toward more
recurrences in the placebo contr ol group than in the rhPDGF treatment group, it was
not statistically significant, no difference between these two groups in the incidence
of adverse events (Steed 2006).
A multicenter, double-blind, placebo-controlled, Phase III trial assigned 382
patients to becaplermin gel (30 and 100 lg/g) and placebo gel treatment groups (the
control. The becaplermin treated wounds had higher incidences of complete healing
over the study period, but only the 100 lg/g becaplermin dose yielded statistically
94 B. Cheng and X. Fu
significant results when compared to placebo gel (50% vs. 35%, p = 0.01). In order
to ensure efficacy of topical becaplermin gel, the treatment process must be
administered along with a standardized regimen of good wound care, which consisted of twice-daily dressing changes, debridement to remove nonviable tissue,
systemic control of infection (Wieman et al. 1998). Therefore, the utility of using
becaplermin therapy earlier in those
patients with wounds at high risk for failure,
such as large foot ulcers (Wieman 2005). In a word, rhPDGF is a safe and effective
treatment for lower-extremity diabetic neuropathic ulcers.
Robson et al. also performed a meta-analysis after the Phase IV trial to integrate
those results with the previous RCTs. In spite of the phase IV study itself did not
showing statistical significance results, the overall meta-analysis results did not
deviate remarkably from that of the RCTs (Robson et al. 2005).
A few authorities recommend becaplermin as an adjuvant treatment for diabetic
foot ulcers that do not respond acceptably to optimized standard strategies. The
scholars suggest that ulcer wound thera py would be more readily add becaplermin
in the case of aged patients. As there are likely more senescent cells and a relative
growth factor deficiency that may derive more benefit from exogenous growth
factor supplementation (Fang and Galiano 2008).
In 2014, Zhao and his colleagues systematically reviewed and meta analyzed
about topical recombinant human platelet-derived growth factor treating diabetic
lower-extremity ulcers. A total of 6 randomized controlled trials including 992
s w
patient
ere selected from 173 identified studies. The studies compared rhPDGF
treatment in the context of standard of care (SOC) to placebo or SOC alone. In the
absence of study heterogeneity, a fixed-effects model was performed, and the
combined odds ratio (OR) indicated a significantly greater complete healing rate in
patients treated with rhPDGF compared to placebo or SOC alone. The ORs ranged
from 0.58 to 2.77, with a combined OR of 1.53 (95% CI = 1.14– 2.04, p = 0.004).
A sensiti
vity analysis (leave-one-out method) indicated good study reliability, and a
funnel plot with Egger test showed no publication bias. The results showed that
rhPDGF is useful for treating diabetic lower-extremity ulcers (Zhao et al. 2014).
Another systematic reviews has reported that employing of rhPDGF (becaplermin)
combined with good wound management was cost effective in many developed
country, such as United States, Canada, the United Kingdom, Switzerland, and
Sweden, etc. (Zhao et al.
Langer and Rogowski 2009
2014;
).
FGF
FGF is a very important of significant growth factors in body. It has a wide range of
biological effects on tissues and cells (fibroblasts, vascular endothelial cells,
epithelial cells, etc.) derived from mesoderm and neuroectoderm, and is involved in
wound healing. In the family of FGFs, topical bFGF and aFGF have been used
widely. The possible biological functions of exogenous FGF for promoting wound
healing are as follows. (1) FGF can observably promote angiogenesis, exert
chemotaxis of various cells involved in angiogenesis, and promote their proliferation and migration, which is one of the main angiogenetic factors.
(2) Injury-induced FGF promotes the aggregation of monocytes, neutrophils,
Biologic Transducers in Wound Healing 95
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macrophages and fibroblasts via chemotaxis to injured tissue sites. It can also
promote mitogenic activity, which mainly demonstrates could be promote cell
proliferation and division. The evidence grades and wound expert recommendations
for FGF to prom ote the healing of kinds of wounds (Fu et al. 1998; Ohura et al.
2011; Hong et al. 2004).
Robson’s group (Robson et al. 1992b) fi rstly reported the randomized, blinded,
placebo-controlled phase I/II clinical trials for recombinant bFGF. All patients with
stage III/IV pressure ulcers were treated with eight different dosage regimens of
three different bFGF concentrations (1.0 lg/cm
2
, 5.0 lg/cm2,10lg/cm2). There
was a significantly tendency to accelerate healing in six of eight groups treated with
topical bFGF, compared with the vehicle-treated groups. All patients receiving
bFGF at the two institutional sites were combined as a group, the difference
between the slopes of the treated and placebo curves was significant (p < 0.05).
When the data were analyzed in terms of the number of patients achieving a 69%
volume reduction, compared with 59% for the control group. This outcome was
significantly different when analyzed by the Fisher's exact test (p = 0.047). This
first human trial suggests that topically applied recombinant bFGF is safe, and may
be effective in the treatment of chronic wounds, especially pressure sores.
In 1995, Richard et al. (1995) assessed the efficacy and safety of topical
recombinant human basic fibroblast growth factor (rh-bFGF) on the healing of
diabetic foot neurotrophic ulcers. Cases inclusion criteria were a typical neuropa thic
ulcer of Wagner grade I-III, more than 0.5 cm in the largest diameter, with an
abnormally high vibration perception threshold in the absence of significant
peripheral vascular disease or wound infection. Rh-bFGF or placebo (normal saline) was applied once a day during the first 6 weeks, then twice a week last
12 weeks. Changes of ulcer size was assessed through weekly clinical examination
and computerized photographs. This pilot (phase I and II), randomized,
double-blind, placebo-controlled study showed there was not significantly different,
repartition in Wagner's classification was similar in both groups at the end of the
clinical trails. The weekly reduction in ulcer perimeter and area was identical in
both groups, as was the rate of linear advance from entry to the 6th week of
treatment (bFGF: 0.053 ± 0.048 mm vs. normal saline: 0.116 ± 1.129 mm): the
same result was obtained at the 11th week. Moreover, percent healed area at the end
of the study did not differ significantly. In addition, this study indicate that topical
rh-bFGF application was well tolerated; the clinical studies observed no clinical
drug-related adverse events or abnormalities in hematological or biochemical data.
In a word, topical application recombinant human bFGF has no advantage over
placebo for healing chronic neuropathic ulcer of the diabetic foot. The authors
inferenced that using a single recombinant growth factor might be insufficient to
accelerate wound closure of diabetic ulcers.
EGF
EGF is found in almost all kinds of body fluids, secretions and most tissues. EGF
receptor (EGFR) is mainly expressed by keratinocytes. Other EGFR-expressing
cells include normal fibroblasts , Vascular endothelial cells, smooth muscle cells
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