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Emerging Treatments and Technologies

O R I G I N A L

A R T I C L E

Human Epidermal Growth Factor


Enhances Healing of Diabetic Foot Ulcers
MAN WO TSANG, MD1
WAN KEUNG R. WONG, PHD2
CHI SANG HUNG, MD1
KWOK-MAN LAI, DPODM3
WEGIN TANG, BSC3
ELAINE Y.N. CHEUNG, MD1

GRACE KAM, MD1


LEO LEUNG, BSC1
CHI WAI CHAN, MD4
CHUNG MIN CHU, MD1
EDWARD K.H. LAM, PHD2

From the 1Diabetes Ambulatory Care Center, Department of Medicine & Geriatrics, United Christian
Hospital, Hong Kong, China; the 2Department of Biochemistry, Hong Kong University of Science and
Technology, Clear Water Bay, Kowloon, Hong Kong, China; the 3Podiatry Department, United Christian
Hospital, Hong Kong, China; and the 4Department of Orthopaedics and Traumatology, United Christian
Hospital, Hong Kong, China.
Address correspondence and reprint requests to Man Wo Tsang, Diabetes Ambulatory Care Center,
Department of Medicine & Geriatrics, 130 Hip Wo St., Kwun Tong, Hong Kong SAR, China. E-mail:
mwtsang@ha.org.hk.
Received for publication 12 October 2002 and accepted in revised form 22 February 2003.
Abbreviations: ABI, ankle-brachial index; EGF, epidermal growth factor; hEGF, human EGF; FGF,
fibroblast growth factor; PDGF, platelet-derived growth factor.
A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
factors for many substances.
2003 by the American Diabetes Association.

iabetic foot ulcer is a major complication of diabetes. People with diabetes show a 5- to 50-fold higher
risk of nontraumatic amputation compared with individuals who do not suffer
from diabetes (1). Between 1996 and
1998, diabetic patients accounted for
47% of all the lower-limb amputations
performed in our hospital (M.W.T., K.M.L., G.K., unpublished data), comparable to published data (2). The major risk
factor leading to diabetic foot ulcer is poor
diabetes control, which results in neuropathic and vascular changes. In general,
diabetic foot ulcers are difficult to heal
and frequently lead to amputation if complicated by infection and gangrene. Several new treatment modalities, such as
exposure to an oxygen chamber, the use
of platelet-derived growth factor (PDGF),
and the application of various local dressings, have produced various degrees of
success. Currently, there are only a few
interventions in which randomized control trials have documented efficacy.
Among these is the use of PDGF, and the
Food and Drug Administration has approved Becaplermin gel as an adjuvant
therapy in diabetes foot ulcer management (3).
Physiologically, wound healing can
be divided into three stages: inflammation, proliferation, and remodeling
(4). Wound repair is characterized by a
series of complex cellular and molecular
events. Numerous growth factors are involved in these processes and act by stimulating chemotaxis, cellular proliferation,
extracellular matrix formation, and angiogenesis, with contraction and reestablishment of cellular integrity. Both in vivo
and in vitro data have demonstrated the
efficacy of growth factors in enhancing
wound healing. The most studied growth
factors are PDGF, fibroblast growth factor
(FGF), transforming growth factor-1,
and epidermal growth factor (EGF) (57).
Early experimental studies have shown
the potential of EGF in promoting wound
healing. EGF clearly stimulates epidermal
repair in animal excisional and thermal
injury models and may also stimulate dermal repair (8). Nanney (9), using a pig
partial thickness wound model, reported

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DIABETES CARE, VOLUME 26, NUMBER 6, JUNE 2003

OBJECTIVE To study the healing effect of recombinant human epidermal growth factor
(hEGF) on diabetic foot ulcers.
RESEARCH DESIGN AND METHODS A total of 127 consecutive patients were
screened and 61 diabetic subjects were recruited into this double-blind randomized controlled
study. Predetermined criteria were used for diagnosis and classification of the diabetic wound.
The patients were randomized into three groups. All patients attended our Diabetes Ambulatory
Care Center every other week for joint consultation with the diabetologist and the podiatrist.
Group 1 (control) was treated with Actovegin 5% cream (Actovegin), group 2 with Actovegin
plus 0.02% (wt/wt) hEGF, and group 3 with Actovegin plus 0.04% (wt/wt) hEGF. The study end
point was the complete closure of the wound. Failure to heal was arbitrarily defined as incomplete healing after 12 weeks.
RESULTS Final data were obtained from 61 patients randomly assigned into three groups.
The mean ages of the patients, wound sizes, wound duration, metabolic measurements, and
comorbidities were comparable within groups, except that group 3 had more female patients.
Mean follow-up for the patients was 24 weeks. Data were cutoff at 12 weeks, and results were
analyzed by intention to treat. After 12 weeks, in group 1 (control) eight patients had complete
healing, two patients underwent toe amputation, and nine had nonhealing ulcers. In group 2
(0.02% [wt/wt] hEGF) 12 patients experienced wound healing, 2 had toe amputations, and 7
had nonhealing ulcers. Some 20 of 21 patients in group 3 (0.04% [wt/wt] hEGF) showed
complete wound healing. Healing rates were 42.10, 57.14, and 95% for the control, 0.02%
(wt/wt) hEGF, and 0.04% (wt/wt) hEGF groups, respectively. Kaplan-Meier survival analysis
suggested that application of cream with 0.04% (wt/wt) hEGF caused more ulcers to heal by 12
weeks and increased the rate of healing compared with the other treatments (log-rank test, P
0.0003).
CONCLUSIONS Our data support the contention that application of hEGF-containing
cream, in addition to good foot care from a multidisciplinary team, significantly enhances
diabetic foot ulcer wound healing and reduces the healing time.
Diabetes Care 26:1856 1861, 2003

Tsang and Associates

Figure 1Step 1: foot ulceration is documented by digital camera. Step 2: the image is
processed by Adobe Photoshop version 5.0.
Step 3: the wound and the standard square (1
cm2) are painted black. The target region of
the image is identified by Matrox Inspector
version 2.1, which turns the color photo to
black and white. Step 4: the black areas are
calculated in pixels, and the standard square
and wound are compared.

a dose-dependent increase in the thickness of granulation tissue and epithelization with EGF. By means of Northern
hybridization specific for the content of
mRNA of type I and III procollagens,
Laato et al. (10) confirmed that EGF is a
potent dose-dependent mitogen for the
granulation fibroblast. However, early
clinical studies provided mixed data on
the utility of exogenous growth factors in
chronic wound healing. In a small study
published in 1993, Lev-Ran and Hwang
(11) reported an elevation of PDGF and
EGF in the plasma of diabetic subjects
compared with control subjects. However, Cooper et al. (12) showed that a
number of growth factors were markedly
reduced in wound fluid from chronic
wounds compared with acute wounds.
Bennett and Schultz (13) postulated increased destruction or inhibition of
growth factors by elevated levels of proinflammatory cytokines and metallomatrix
protein following repeated trauma and infection. In the current study, we postulated that there was a relative deficiency of
growth factors in chronic wounds such as
diabetic foot ulcers and aimed to determine whether local application of a high
concentration of human EGF (hEGF)
might be effective in promoting wound
healing of diabetic foot ulcers.
DIABETES CARE, VOLUME 26, NUMBER 6, JUNE 2003

RESEARCH DESIGN AND


METHODS A randomized doubleblind controlled trial was used to study
the efficacy of hEGF in promoting healing
of diabetic foot ulcers. Between September 2000 and August 2002, 127 patients
from our Diabetes Ambulatory Care center were screened. Predetermined criteria
used for patient selection were 1) ulcer
with grade I or II, as defined by the Wagner Classification (grade I, superficial ulcer; grade II, deep ulcer to tendon,
capsule, or bone; grade III, deep ulcer
with abscess, osteomyelitis, or joint sepsis; grade IV, localized gangrene of forefoot or heel; and grade V; gangrene of
entire foot) (14), 2) ulcer located below
the ankle, and 3) ulcer with adequate perfusion, as indicated by an ankle-brachial
index (ABI) 0.7. Patients were excluded
if they had very poor sugar control (HbA1c
12%) or had ulcers with severity equal
to or greater than grade III. The patients
were seen in the designated multidisciplinary diabetes foot clinic in our diabetes
center. We accepted referral of new patients from the medical, orthopedic, and
podiatrist clinics in our hospital and other
hospitals in our region. Diabetes control
was maximized by the diabetologist.
Comprehensive foot assessment was carried out by the podistrist, including deter-

mination of ABI, vibration perception


threshold, and 10-g monofilament and
pin prick tests. Standard wound care consisted of debridement of necrotic tissue
and reduction of callus. Wound parameters such as exudates, signs of infection,
combined with granulation of tissues, and
eschar were documented on each visit,
and complete healing was defined as full
epithelialization of the wound with absence of discharge. Wound swabs were
taken if infection was suspected, and antibiotics were prescribed based on clinical
judgment or on positive wound bacterial
cultures.
After the initial consultation, patients
were then evaluated 2 weeks later with a
view to their inclusion in the trial. In the
second consultation, we excluded patients whose ulcers healed 25% with
conventional foot ulcer care. Informed
consent was obtained, and randomization
was performed by drawing envelopes. Patients were randomly assigned into three
groups: group 1 (treated with Actovegin
5% cream only), (Actovegin is a protein
free calf blood extract manufactured by
NYCOMED Austria [Linz Austria]. It is
claimed to improve the utilization of oxygen and to promote the uptake of nutrient media into the cell. It is indicated for
varicose ulcer and for any ulcers with a
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hEGF and diabetic foot ulcers

Figure 2Diagram showing the


flow of participants through the randomized control study.

smeary coat.) group 2 (treated with Actovegin plus 0.02% [wt/wt] hEGF), and
group 3 (treated with Actovegin plus
0.04% [wt/wt] hEGF). The study protocol
and consent form were approved by the
ethics committee of the United Christian
Hospital.
Throughout the study, ulcerated areas were overlaid with gridded paper for
size reference in photography. The digital
pictures were processed with Adobe Photoshop version 5.0, and the ulcerated areas were compared with reference areas.
The sizes of the ulcerated areas were then
calculated using Matrox Inspector version
2.1 (Matrox Electronic System) (Fig. 1).
The cream under study was applied
locally and covered with sterile gauze. Patients were instructed to continue with
the normal daily saline dressing, combined with local application of the cream,
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either in the government outpatient clinic


or with the aid of the community nurse
who provided home care for patients with
ambulatory problems. The pharmacy department of our hospital prepared the
creams, and both patients and physicians
were blind to the hEGF concentrations.
Wound measurement and validation
A foot model was used to create 12 superficial wounds over the big toe, second toe,
dorsum, sole, and heel regions to compare data from measurements by digital
imaging and tracing. The Spearman range
correlation coefficient was 0.858, comparable to that in an earlier study (15).
Statistical analysis
Analysis was based on intention to treat. A
t test for continuous data and a KruskalWallis test and 2 test for categorical data

were used for comparison of baseline


characteristics among the three groups. A
Kaplan-Meier plot was used to examine
the time to complete healing in each
group. Data were censored at 12 weeks. A
log-rank test was used to compare the
time to complete healing among the different groups.
RESULTS A total of 127 patients
were screened between September 2000
and August 2002. Sixty-six patients were
excluded for various reasons: 19 had ABI
0.7, 6 had high-grade foot ulcers, 9 refused to participate in the study, and 2
had ulcers above the malleoli. Some 30
patients were not included in the study
because, under conventional treatment,
their ulcers healed by 25% by the second visit. A flow chart of the experimental
protocol is shown (Fig. 2).
DIABETES CARE, VOLUME 26, NUMBER 6, JUNE 2003

Tsang and Associates

Table 1Baseline characteristics of the study population

n
Sex (M/F)
Age (years)
ABI
Vibration threshold
25
25
10-g monofilament test
Normal
Abnormal
Ulcer area (cm2)
Site (distribution of ulcer)
Sole
Toe
Ankle
Others
Duration of ulcer (weeks)
History of diabetes (years)
HbA1c (%)
BMI (kg/m2)
Use of insulin
Use of oral OHA
Serum creatinine 2 mg
Diabetic nephropathy
(proteinuria 300 mg/day)
Diabetic retinopathy
Comorbidities

Group 1:
control

Group 2:
0.02% (wt/wt)
hEGF

Group 3:
0.04% (wt/wt)
hEGF

19
10/9
64.37 11.67
0.99 0.16

21
13/8
68.76 10.45
1.03 0.22

21
6/15
62.24 13.68
1.05 0.19

NS
0.03*
NS
NS

6
13

6
14

8
13

NS
NS

13
6
3.48 0.82

11
10
2.78 0.82

11
10
3.40 1.1

NS
NS
NS

2
11
2
4
12.00 15.47
10.11 8.29
7.97 1.81
25.69 5.21
9
9
3
12

3
11
5
2
8.24 5.55
9.85 7.79
8.69 1.99
23.33 3.11
7
9
2
16

6
10
4
1
11.48 14.68
9.05 6.19
8.5 1.34
23.83 3.17
9
11
3
12

NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS

9
17

12
16

16
19

NS
NS

Data are means SE. *Sex distribution between groups 2 and 3; including hypertension, coronary heart disease, and hyperlipidemia. OHA, oral hypoglycemic
agent; NS, not significant.

A total of 61 patients, 57 with type 2


and 4 with type 1 diabetes, were enrolled
in the study and randomly assigned into
the three groups defined above. The end
point of treatment was defined as complete closure of the wound, whereas failure to heal was defined as incomplete
closure after 12 weeks of treatment.
The baseline profile of the three
groups was similar in regard to age, duration of diabetes, HbA1c, BMI, wound size,
duration of ulcer, distribution of ulcer, vibration threshold, monofilament test results, and diabetic comorbidities, as
shown in Table 1. The use of oral hypoglycemic agents and insulin was comparable in all groups. There was a difference
in sex distribution (P 0.03) between
group 2 and group 3. However, there was
no difference in median healing time between the two sexes.
Wound healing, by the Kaplan-Meier
survival plot, is shown in Fig. 3. Data were
DIABETES CARE, VOLUME 26, NUMBER 6, JUNE 2003

analyzed at a 12-week cutoff. As indicated, 20 of 21 patients (95.3%) in the


0.04% (wt/wt) hEGF group achieved
complete healing, which is a significantly
higher value than those obtained for the
0.02% (wt/wt) hEGF and placebo groups
in post hoc analysis. Patients in the 0.04%
(wt/wt) hEGF group also healed more
quickly than those in the other groups.
The median time to complete healing in
the 0.04% (wt/wt) hEGF group was 6 1
weeks (CI 4.227.78) (log-rank test, P
0.0003) (Fig. 2). Healing rates were 42.10
and 57.14% for the control and the 0.02%
(wt/wt) hEGF groups, respectively. There
was no significant difference in healing
time between the 0.02% (wt/wt) hEGF
and control groups. As there was a sex
difference between the 0.02 and 0.04%
group, we therefore also analyzed the
healing times of the two sexes. At 12
weeks, 21 female and 18 male patients
had healed ulcers. The median healing

times were 8 and 12 weeks, with a P value


of 0.599, for women and men, respectively. The mean follow-up time was 24
weeks. As depicted in Fig. 2, more ulcers
healed with time: seven more patients
from the placebo group and five more patients from the 0.02% (wt/wt) hEGF
group had healed ulcers. The fact that
most of the ulcers from the 0.04% (wt/wt)
hEGF groups healed with a median healing time of 6 weeks supports the efficacy
of 0.04% (wt/wt) hEGF in enhancing
wound healing. As the extend of healing
between the placebo and the 0.02% (wt/
wt) hEGF group was of no statistical significance, despite a mean follow-up study
of 24 weeks, there may exist a threshold
for hEGF action. However, it must
be pointed out that the original design
was a randomized double-blind 12-week
study, and after 12 weeks, the study was
open and further conclusions therefore
must be cautiously drawn.
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hEGF and diabetic foot ulcers

Figure 3Ulcer healing among different groups with respect to time (in weeks). Solid line, 0.04%
(wt/wt) hEGF; interrupted line, 0.02% (wt/wt) hEGF; and dotted line, placebo (P 0.0003).

CONCLUSIONS The main conclusion of this study is that 20 of 21 diabetic foot ulcers healed with daily
application of 0.04% (wt/wt) hEGF for 12
weeks under the management of a multidisciplinary team. The difference in healing rate compared with that seen without
the hEGF cream was statistically significant, and the curve from control diverged
at the beginning of the fourth week. The
healing with 0.04% (wt/wt) hEGF was accompanied by a significant reduction in
median healing time.
A Medline search using the key
phrases epidermal growth factor and
clinical study did not yield a placebo
control study with EGF for the management of diabetic foot ulcers. To our
knowledge, this is the first study to demonstrate a significant and positive effect of
hEGF in the healing of diabetic foot ulcers
in a randomized double-blind controlled
trial. However, our data suggest that
hEGF at 0.02% (wt/wt) in cream does not
offer significant benefits over conventional foot care practice (Fig. 2). The dose
sensitivity observed in our study is in accordance with a requirement for the sustained presence of EGF in the promotion
of wound repair and reports of a dosedependent effect of EGF on the formation
of granulation tissue (7,16). Also, in a recent study on the effects of PDGF on neu1860

ropathic diabetic foot ulcers, a statistically


significant improvement in ulcer healing
was shown with a cream with 100 g/g in
PDGF but not when the cream contained
30 g/g of the peptide (17). We suggest
that the threshold effect for growth factor
action seen in these studies may reflect the
presence of growth factor inhibitors, or
proteases, in the wound microenvironment, or that higher levels of the factors
recruit other cytokines required to promote wound healing.
The reported diabetic ulcer healing
rates ranged from 33 to 57.5% at a cutoff
time of 1220 weeks, when the growth
factors PDGF or FGF were used in controlled trials (17,18). In a small pilot randomized double-blind study reported by
Richard et al. (18), nine chronic neuropathic plantar foot ulcers (Wegner grade
IIII) were treated with topical FGF for a
total of 18 weeks. The healing rates for the
treated and placebo group were 33 and
63%, respectively, with no statistically
significant difference. In a large multicenter study, PDGF, at a concentration of
100 g/g in cream, gave a better healing
rate (50%) than the placebo group (35%)
in a 20-week study (P 0.007) (17). In
an open-label study, Embil et al. (19) reported a complete healing rate of 57.5%,
with a daily local application of PDGF
cream, in chronic diabetic foot ulcer pa-

tients. The wide healing ranges shown


above probably reflect differences in
study design, duration of study, and patient and ulcer characteristics. It is difficult to compare these studies with our
work. Our study included all patients
with ulcers from the malleoli to toe apices.
All patients in our study had an ABI 0.7,
and the vibration threshold varied between 11 and 55 V. We excluded those
with wound healing of 25% during the
run-in period and thus deliberately selected relatively difficult cases. On the
whole, the pretrial durations of ulcers in
our study (20 weeks), were shorter than
those in the reported cases.
We suggest that a possible explanation for the successful use of hEGF in our
study is due to the fact that we used a
hEGF concentration higher than that
used in earlier studies. In general, the
dose of growth factors employed topically
in previous studies was 1100 g/g (20).
Another explanation may lie in differences in the sources and hence the potencies of the hEGF samples. The average
time required for healing of ulcers in our
work is shorter than that seen in other
reported studies (17,20,21). It should be
noted, however, that the average BMI of
our patients was lower than those patients
in other studies, and thus the average
pressure on the ulcers was less. Most of
our patients were ambulatory. No offloading or total contact casting was prescribed in this study, but bespoke insoles
were prescribed when appropriate.
It must be stressed that meticulous
wound care such as debridement, callus
reduction, and control of infection also
played a vital role in promoting wound
healing. Debridement enabled removal of
necrotic tissue, maintained drainage, and
allowed better surface contact with hEFG.
Callus reduction also helped to reduce excess pressure on the wound. Antibiotics
were prescribed upon clinical suspicion
of infection or positive culture results.
However, even with all these measures,
two patients from each of the placebo and
the 0.02% EGF group had either toe or
ray amputation as a result of chronic osteomyelitis or gangrene, which may partly
reflect the limitation of the Wagner classification of foot ulcer.
There are several limitations to the
present study. First, the small sample size
limits significance. Second, the diabetic
ulcers were heterogeneous in nature. Although ABI in our patients is 0.7, due to
DIABETES CARE, VOLUME 26, NUMBER 6, JUNE 2003

Tsang and Associates

the high prevalence of medial calcinosis


in diabetic vessel, this value may not be
reliable in ruling out cases of peripheral
vascular disease. Third, some 50% of our
patients had toe ulcers. It is generally appreciated that ulcers in different regions
may have different etiologies or aggravating factors, making comparison between
studies difficult. Lastly, this is a single
center study and needs validation with a
multicenter study.
In conclusion, our data support the
contention that hEGF application, in addition to good foot care with a multidisciplinary team approach, enhances
diabetic ulcer wound healing and significantly reduces the healing time. Further
study is required to define the optimal
hEGF dose, the optimal frequency of application, and potential interaction of
hEGF with other growth factors, such as
PDGF, in promoting wound healing. It
will also be important to study the cost
implications in the context of wound
healing and amputation prevention in the
future.
Acknowledgments We thank Dr. Jim
Hackett for his critical review of the manuscript. rhEGF was generously provided by BioClick Technologies Ltd., Hong Kong.

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