Dermatol Ther (Heidelb) (2020) 10:1075–1088

https://doi.org/10.1007/s13555-020-00432-5

ORIGINAL RESEARCH

Evaluation of BepanGel Hydrogel Efficacy

and Tolerability Using an Abrasive Wound Model
in a Within-Person, Single-Center, Randomized,
Investigator-Blind Clinical Investigation
Lei Zhang . Raffaella de Salvo . Sonja Trapp . Walter Wigger-Alberti .
Ragna Williams . Lucie Delcour . Bart Rossel . Maarten T. Huisman

Received: June 29, 2020 / Published online: August 2, 2020

Ó The Author(s) 2020

ABSTRACT subjects, two small superficial wounds were

induced on the non-dominant forearms.
Introduction: Over the last few years, it has Wounds were treated with BepanGel and cov-
been demonstrated that a moist environment ered with a standard semi-occlusive wound
enhances the healing process and reduces scar plaster or covered with a plaster alone for
formation of wounds. Such moist conditions 11 consecutive days. Wound healing efficacy,
can be created and maintained using hydrogels. cooling effect, and tolerability of the treatment
The aim of this study was to evaluate wound were assessed over 12 investigational days.
healing, cooling efficacy, local tolerability, and During follow-up at day 31, the cosmetic
cosmetic appearance of abrasive wounds treated appearance of the wounds was evaluated.
with BepanGel wound care hydrogel. Results: On day 12, the test field treated with
Methods: This study was designed as a within- BepanGel was completely healed in nearly all
person, single-center, randomized, investigator- subjects (97.0%) in contrast with the test field
blind clinical investigation comparing a treated with a plaster alone (18.2%, AUCdays 2–12
hydrogel-treated test field with an untreated p \ 0.0001) as assessed by a blinded investiga-
test field in an abrasive wound model. In 33 tor. Two-thirds of the unblinded subjects indi-
cated an immediate cooling effect of the
Digital Features To view digital features for this article hydrogel (p = 0.0555). At the end of the inves-
go to https://doi.org/10.6084/m9.figshare.12696644. tigation, the cosmetic appearance of the
Electronic supplementary material The online
BepanGel-treated test fields scored superior to
version of this article (https://doi.org/10.1007/s13555- the fields treated with a plaster alone as evalu-
020-00432-5) contains supplementary material, which is ated by a blinded investigator (p = 0.0005) and
available to authorized users.
the unblinded subjects (p = 0.0078). The
hydrogel was generally well tolerated and no
L. Zhang
R. de Salvo
S. Trapp
signs of infection or adverse events (AEs) related
Bayer Consumer Care AG, Peter Merian-Strasse 84,
4002 Basel, Switzerland to the treatment were observed.
Conclusion: This evaluation shows that treat-
W. Wigger-Alberti
R. Williams ment of superficial cutaneous wounds with
Bioskin GmbH, Messberg 4, 20095 Hamburg,
Germany BepanGel results in improved wound healing as
demonstrated by faster wound closure and a
L. Delcour
B. Rossel
M. T. Huisman (&) considerably better cosmetic appearance, while
Oystershell Laboratories, Nijverheidsweg 10, 9820
Merelbeke, Belgium
providing immediate cooling.
e-mail: [email protected]
1076 Dermatol Ther (Heidelb) (2020) 10:1075–1088

Trial Registration Number: EUDAMED-No.: of the normal anatomic epidermal structure and
CIV-19-09-029744. function. Usually, healing of superficial wounds
proceeds in a complex orderly and timely
Keywords: Abrasive wound model; BepanGel; reparative process that completely restores the
Cooling; Cosmetic appearance; Efficacy; affected tissue and function, although forma-
Flamozil; Hydrocolloid; Hydrogel; Tolerability; tion of scars might be possible [1]. Standard
Zoralan treatment for such typical everyday minor
wounds consists of thorough cleansing with tap
water or saline followed by the use of plasters
Key Summary Points that are able to provide a barrier against dirt,
contamination, and external influences and as
Why carry out this study? such protect the wound and improve healing.
Superficial minor wounds are standardly Research over the last few years demonstrates
treated by cleansing with tap water or that one of the main external factors responsi-
saline and use of a plaster, while there is ble for optimal wound healing is hydration [2].
growing evidence available reporting Creation of a moist wound environment, e.g.,
enhanced healing of wounds and reduced with ointments, results in improved and accel-
scarring when healing in a moist erated healing, reduces pain, and probably also
environment. restricts scar formation in comparison with
conventional wound treatment [3, 4].
The current clinical investigation Hydrogels provide such a moist environ-
evaluated the healing efficacy, cooling ment. Hydrogels are water-based polymers
effect, and cosmetic outcome of abrasive designed to prevent wounds from drying out in
wounds treated with a moisturizing order to stimulate wound healing, decrease
hydrogel. granulation and subsequent scarring, prevent
What was learned from the study? cracking of the wound, and form a barrier
against dirt, contamination, and external
BepanGel (Flamozil, Zoralan Wound) influences. The beneficial effects of hydrogels
wound care hydrogel clearly demonstrates have been demonstrated in several types of
a superior effect over the standard wounds, including necrotic and sloughy
treatment (plaster) as shown by higher re- wounds, chronic skin wounds, corneal wounds,
epithelialization rates, an improved and burn wounds [5–9]. BepanGel wound care
cosmetic outcome, and a slight cooling hydrogel, also known as Flamozil or Zoralan
effect in superficial abrasive wounds. Wound, is a paraben-free, unmedicated, acidi-
A moist wound environment increases fied hydrogel that forms a semi-occlusive,
healing efficacy and outcomes of small breathable protective film on the wound. The
superficial wounds, without posing any hydrogel is composed of a dispersion of an
additional risk in comparison with the acidic carbomer in water, stabilized by carno-
standardly used plaster. sine, a basic dipeptide naturally present in the
skin. It also contains a certain percentage of
fatty substances which help to reduce the
evaporation of water. Presence of the carbomer
results in the principal mode of action of the
hydrogel by ensuring optimal hydration for
INTRODUCTION both dry and wet wounds. The activity of the
carbomer depends on the circumstances: in dry
Minor superficial acute wounds such as abra- wounds it gives off moisture to prevent cracking
sions, lacerations, and incisions as well as of the wound and formation of a scab. In wet
superficial thermal wounds are part of our wounds it absorbs the excess of wound exu-
everyday life. Such wounds result in disruption dates. In addition, the acidity of the carbomer
Dermatol Ther (Heidelb) (2020) 10:1075–1088 1077

polymer keeps the pH of the wound environ- nurse who regularly treated the induced
ment low, thus preventing (in a natural, physi- wounds needed to be informed about which
cal way) microbial growth. BepanGel has been wounds to treat. To keep the blinding, the
CE marked as a medical device and marketed investigator was not involved in treatment
since 2007. Over two million units have been procedures and the study nurse was not
put on the market. involved in clinical assessments. The clinical
The objective of this study was to assess the investigation was conducted in accordance with
wound healing properties of BepanGel hydrogel local law, the Declaration of Helsinki 1964 and
on small everyday epidermal wounds in com- its later amendments, and ISO 14155:2011.
parison with the standard treatment (wound Written informed consent was obtained for all
plaster) in a controlled clinical setting. The included subjects. This study is registered at
primary objectives were to evaluate wound BfArM and EC (EUDAMED-No.: CIV-19-09-
healing—based on re-epithelialization proper- 029744). The study was approved by the ethics
ties—and cooling properties. The secondary committee of the medical association in Ham-
objective was to assess the local tolerability of burg (Ethik-Kommission der Ärztekammer
the hydrogel. In addition, the cosmetic Hamburg, Weidestraße 122b, 22083 Hamburg,
appearance of healed wounds was evaluated; Germany).
lastly, the product performance and acceptance
as experienced by the subjects were assessed. Study Participants and Sample Size
In order to realize these objectives, the
abrasive wound model was selected on the basis A total of 40 healthy volunteers (at least
of its (1) reflection of small epidermal wounds 18 years old, male and female) were screened
obtained by minor accidents, (2) relevance for with the goal of including 33 eligible subjects
the evaluation of healing properties of different and expectation of at least 27 evaluable sub-
products for superficial wounds, (3) ability to jects, which was considered to be sufficient to
significantly detect differences in wound heal- meet the primary and secondary objectives of
ing properties of test products, and (4) stan- the clinical investigation. The sample size was
dardization and clinical validation of this not based on a formal sample size calculation,
method [10]. In the abrasive wound model, but defined according to the Guidance for
small superficial abrasions are induced on the Industry on Skin Irritation and Sensitization
forearms of subjects by repeatedly scrubbing the Testing of Generic Transdermal Drug Products
skin with a surgical brush until the first signs of as advised by the FDA [11]. According to FDA
uniform glistening and punctuate bleeding are guidance 30 subjects would have been suffi-
observed. cient. On top of this an additional dropout rate
of 10% was considered; therefore, 33 subjects
METHODS were randomized.
Subjects were eligible at screening if they
Clinical Study presented with healthy skin on the forearms,
determined by a physical examination and
demonstrated by the absence of disease findings
This study was designed as a within-person,
unless the investigator considered an abnor-
single-center (bioskin Research Center Derma-
mality to be irrelevant to the outcome of the
tology (RCD), Hamburg, Germany), random-
clinical investigation. As dark-skinned persons
ized, investigator-blind clinical investigation.
tend to develop hyperpigmentation after
The investigational design was blinded for the
wound healing, only skin types I to III (Fitz-
investigator who performed the clinical assess-
patrick scale) were included in the investiga-
ments, but could not be blinded for the subjects
tion. Written informed consent was obtained
and study nurse. Since the study was designed
for all included subjects.
as a within-person investigation, subjects were
aware of the treatment allocation. The study
1078 Dermatol Ther (Heidelb) (2020) 10:1075–1088

Abrasive Wound Model standard semi-occlusive wound plasters (Han-

saplast Sensitive wound plaster) for protection.
The standardized abrasive wound model is ideal This routine was repeated daily over the test
to assess healing properties of products inten- period by an unblinded study nurse at bioskin
ded for superficial wounds and was performed RCD in Hamburg, Germany.
as originally described by Wigger-Alberti et al.
[10]. In brief, two small superficial, abrasive Wound Healing Efficacy, Cooling,
wounds (approximately 1.2 cm in diameter) Tolerability, and Cosmetic Appearance
were induced on the respective non-dominant Evaluation
forearm of each subject using a sterile surgical
hand brush. Before wounding, the forearms Wound healing efficacy assessments as well as
were disinfected with a standard alcohol-based the clinical assessment of tolerability and eval-
antiseptic. Epidermal abrasive wounds were uation of signs of infection were performed by a
induced under visual control by the same blinded investigator on days 2, 6, 8, 10, and 12,
trained study nurse, who repeatedly scrubbed while cooling property (day 1), product perfor-
the skin with a sterile surgical hand brush using mance, and product traits (day 12) were assessed
moderate pressure until first signs of uniform by the unblinded subjects. Global assessment of
glistening and punctuate redness were local tolerability and the cosmetic outcome
observed. Thus, it could be ensured that the were evaluated both by the blinded investigator
wounds only reached the uppermost dermis but and the unblinded subjects throughout the
did not involve deeper layers. A distance investigation (days 2, 6, 8, 10, and 12) and
between the wounds of at least 5 cm was during follow-up at the end of the investigation
respected. The procedure caused only minor (day 31), respectively.
pain, so no anesthetic was necessary.
Assessment of Wound Healing
Study Products, Dosage,
and Administration
Wound healing efficacy of both test sites was
evaluated by a blinded investigator by scoring
The test product, BepanGel wound care hydro- using a 6-point re-epithelialization scale
gel (Flamozil, Zoralan Wound), is classified as a (0 = 0% healing; 1 = 1–25% re-epithelialization;
IIb Medical Device (with CE mark) and meets 2 = 26–50% re-epithelialization; 3 = 51–75% re-
requirements of the European Council Directive epithelialization; 4 = over 75% but not com-
93/42 EEC. BepanGel is composed of acidic plete re-epithelialization; 5 = 100% complete
colloidal carbomer, carnosine, water, and healing). A global assessment of wound healing
preservative (sodium benzoate, potassium sor- was performed by the blinded investigator on
bate) and is manufactured by Oystershell Lab- the basis of a 5-point scale (0 = very good;
oratories (Merelbeke, Belgium). BepanGel is 1 = good; 2 = acceptable; 3 = poor; 4 = very
available in a plastic tube of 20 g and 50 g sizes. poor). Also, the total time until complete heal-
In this clinical investigation, 50 g plastic tubes ing for both test fields was evaluated, as deter-
were used. The test fields were randomly mined by the first day after wound induction
assigned in all subjects with the hydrogel kept with a re-epithelialization score of 5. Addition-
at room temperature before application. It was ally, the presence of crusts was assessed (yes/no)
topically applied (approximately 0.2 g Bepan- for the two test fields.
Gel for a single dosage) for a 12-day treatment
period, covering 11 treatments (approximately
Assessment of Cooling Effect
2.2 g BepanGel in total). The hydrogel was
carefully distributed over the test field, but not
rubbed in. The other test field remained On day 1 of the clinical investigation, the
untreated. Both test fields were covered with cooling effect in the two test fields was assessed
by the unblinded subjects using a visual
Dermatol Ther (Heidelb) (2020) 10:1075–1088 1079

analogue scale (VAS) of 100 mm length, rang- unblinded subjects using a 7-tiered rating scale
ing from 0 (no cooling) to 100 (extremely (1 = strongly agree; 2 = moderately agree;
cooling), 20 ± 5 s after application of Bepan- 3 = slightly agree; 4 = neither agree nor dis-
Gel, but prior to application of the protective agree; 5 = slightly disagree; 6 = moderately dis-
wound plaster. The assessment was performed agree; 7 = strongly disagree) on day 12 of the
for the untreated test field as well. A VAS is investigation.
commonly used to measure pain, itching, and
other subjective responses and has been proven Safety Evaluation
to have a high reliability and concurrent
validity [12, 13]. Specifically, VAS have also The abrasive wound test model did not pose a
been used in assessing thermal perception for relevant risk for the subjects, as demonstrated
decades [14, 15]. by past experiences with the induction of small
superficial wounds that usually heal with no
Assessment of Tolerability consequences. Small scars may occur as a result
of injury to the dermis [16]. For the test product,
The clinical tolerability was assessed by a blin- all required quality, safety, and efficacy issues
ded investigator by scoring using a 5-point are addressed and evaluated on the basis of the
erythema scale on healthy skin in close prox- documentation essential to fulfil the require-
imity to the two test fields (0 = no reaction; ments of the European Council Directive 93/42
1 = slight uniform or spotty erythema or slight EEC. According to the Risk Management Pro-
diffuse, partial or follicular erythema; 2 = clear, cedure for the medical device in compliance
sharply demarcated erythema; 3 = severe ery- with ISO 14971, no unacceptable risks were
thema with infiltrate; 4 = severe erythema with identified.
infiltrate and/or epidermal defect [blisters, Serious adverse events (SAEs) were reported
blebs, erosions]). Additionally, the tolerability within 24 h from the acknowledgement to the
was globally assessed by the blinded investiga- sponsor. Spontaneously noted complaints were
tor and the unblinded subject by means of a recorded as AEs with duration, intensity, and
5-point scale (0 = very good; 1 = good; 2 = ac- probability of a correlation with the test
ceptable; 3 = poor; 4 = very poor). product.
Furthermore, signs of infection were assessed
for both test fields by the blinded investigator Data Analysis and Statistics
by answering a closed question (yes/no), con-
sidering the following parameters: erythema, The statistical evaluation was performed at
pain, malodor, delayed wound healing, exces- bioskin GmbH using the software program SAS
sive exudate, and heat. (Statistical Analysis System, SAS Inc., Cary, NC)
and data were analyzed by a statistician
Assessment of Cosmetic Outcome according to the International Conference on
and Acceptance Harmonization (ICH) E9 Note for Guidance on
Statistical Principles for Clinical Trials [17].
The cosmetic outcome/acceptance was assessed For the re-epithelialization score and global
on day 31 by the blinded investigator and the assessment of wound healing efficacy scores,
unblinded subject by means of a VAS of the area under the curve (AUC) was calculated
100 mm length, ranging from 0 (poor) to 100 using the trapezoid formula and compared by
(excellent) for each of the test fields. means of a paired t test. For the assessment of
cooling properties by subject on VAS (day 1)
Product Performance and global tolerability (days 2, 6, 8, 10, and 12),
mean scores over day 1 or all visits, respectively,
Twelve questions related to product perfor- were presented descriptively by treatment.
mance and product traits were filled out by all
1080 Dermatol Ther (Heidelb) (2020) 10:1075–1088

RESULTS investigation process is shown in Fig. 1. Subject

demographics and baseline characteristics are
Baseline Data Clinical Trial summarized in Table 1.

The clinical investigation was carried out Wound Healing Efficacy

between January and February 2020. In total, 40
healthy volunteers were screened for eligibility Already starting on day 6 after wound induc-
and 33 subjects were included. Seven subjects tion, the hydrogel-treated test fields showed a
were not randomized: six subjects were allo- significantly faster onset of wound closure as
cated as backup subjects in case of need for demonstrated by wound re-epithelialization. As
replacements and one subject had schedule such, re-epithelialization scores were consis-
problems. The two induced wounds on each tently higher in the hydrogel-treated test fields
subject were randomly treated with one of the at all time points in comparison with the test
two treatment regimens (BepanGel wound care fields treated with a plaster alone, as demon-
hydrogel covered with standard semi-occlusive strated in Table 2 and Fig. 2. At the end of the
wound plaster or only covered with standard investigation on day 12, the BepanGel-treated
semi-occlusive wound plaster without hydrogel) test field was completely healed in nearly all
for 11 consecutive days. In total, 32 subjects subjects (97.0%). In the test fields treated with a
completed the study according to protocol. In plaster alone, only six subjects demonstrated
one subject, two SAEs unrelated to the hydrogel complete healing (18.2%). Increased re-epithe-
or the study procedures were reported and lialization after treatment with the hydrogel
finally led to premature subject discontinua- was also reflected by a significantly larger mean
tion. The last visit of this subject was on day 12; AUCdays 2–12 for the hydrogel-treated test fields
hence, the subject was included in the analyses, in comparison with test fields treated with a
but missed the follow-up visit. A CONSORT plaster alone as shown in Table 2. The higher re-
flowchart providing an overview of the clinical epithelialization rate in the BepanGel-treated
test fields was accompanied by a reduced time
to complete healing in comparison with the test
fields treated with the plaster alone as illustrated
in Fig. 3 (18 BepanGel-treated test fields were
completely healed by day 10, and a further 14

Table 1 Subject demographics and baseline characteristics

Number of subjects 33
Age (mean ± SD) 55.6 ± 10.8 (years)
Sex
Male 18 (55%)
Female 15 (45%)
Skin type (Fitzpatrick)
I–III 33 (100%)
IV–VI 0 (0%)
Race
Caucasian 33 (100%)

Fig. 1 CONSORT flowchart (within-person trials)

Dermatol Ther (Heidelb) (2020) 10:1075–1088 1081

Table 2 Mean re-epithelialization values of test fields treated with BepanGel and plaster or plaster alone
Re-epithelialization Day 2 Day 6 Day 8 Day 10 Day 12 AUCdays 2–12
(man – SD) (mean – SD) (mean – SD) (mean – SD) (mean – SD)
BepanGel ? plaster 0.0 ± 0.0 1.6 ± 0.6 2.8 ± 0.8 4.4 ± 0.7 5.0 ± 0.2 24.2 ± 3.5 ***
(n = 33)
Plaster (n = 33) 0.0 ± 0.0 0.9 ± 0.3 1.6 ± 0.7 3.0 ± 1.1 4.0 ± 0.7 16.0 ± 4.4
AUC area under the curve
***p \ 0.0001

by day 12. Over 75% but not complete re-ep- Safety Assessment
ithelialization was noted in the remaining one
subject. In comparison, when treated with a During the investigation, no wound gel-related
plaster alone, four test fields were healed by (S)AEs were reported. One subject reported two
days 10 and a further two by day 12; 27 test SAEs (rupture quadriceps tendon right side and
fields were partially healed by day 12). rupture quadriceps tendon left side on day 11
In addition, the investigator assessed the and day 27, respectively), which led to prema-
global wound healing as predominantly ‘‘very ture discontinuation of the investigation. Both
good’’ at each assessment point in the hydrogel- SAEs were recovering/resolving at the end of
treated test fields. In the test fields treated with this clinical investigation. No other serious or
the plaster alone, the global wound healing was non-serious AEs or any device deficiencies were
assessed as ‘‘very good’’ in fewer subjects at each reported. In addition, no signs of infection were
assessment point. This resulted in a significantly reported by the investigator in any of the two
smaller AUCdays 2–12 in the hydrogel-treated test test fields over the entire investigation period.
fields (0.3 ± 1.1) in comparison to the test fields
treated with the plaster alone (3.3 ± 2.7, Tolerability Assessment
p \ 0.0001), again confirming better healing
efficacy of the wounds treated with BepanGel.
Generally, BepanGel wound care hydrogel
Crust formation was observed in only 2 of 33
demonstrated an excellent local tolerability
subjects (6.1%) in both test fields.
when applied to standardized, artificially
induced abrasive wounds. The clinical assess-
Cooling Properties ment by the investigator showed that there was
no local reaction on healthy skin in close
Immediately after the first administration of the proximity to the two test fields at day 2 in
hydrogel, about half of the subjects (48.5%) approximately two-thirds of the subjects after
assessed a slight cooling effect for BepanGel on treatment with BepanGel and plaster alone. In
the VAS (mean 9.7 ± 20.5). Fewer subjects the remaining subjects, a slight erythema was
(39.4%) assessed a cooling effect in the noted for both test fields (11 BepanGel-treated
untreated test field (mean 4.5 ± 11.4), although test fields and 9 test fields treated with plaster
this did not achieve statistical significance alone demonstrated slight erythema). At the
(p = 0.1441) in comparison with the hydrogel- other time points, no reaction was seen in either
treated test field. of the test fields except for one or two subjects
At day 12 of the investigation, two-thirds of presenting with slight erythema. There was no
the subjects strongly, moderately, or slightly significant difference in general clinical tolera-
agreed that BepanGel provides an immediate bility between the hydrogel and plaster (mean
cooling effect when answering the question- sum 0.5 ± 0.7) or plaster alone (mean sum
naire (p = 0.0555). 0.4 ± 0.5) over the 12 investigation days.
1082 Dermatol Ther (Heidelb) (2020) 10:1075–1088
 Dermatol Ther (Heidelb) (2020) 10:1075–1088 1083

b Fig.2 Example of wound healing assessment of induced can be found in Table S1 in the Electronic
abrasive wounds by means of a 6-point-re-epithelialization Supplementary Material.
scale. a Score 0 = 0% healing; score 1 = 1–25% re- In addition, no signs of infection were
epithelialization; score 2 = 26–50% re-epithelialization; observed throughout the total investigational
score 3 = 51–75% re-epithelialization; score 4 = over 75% period of 31 days.
but not complete re-epithelialization; score 5 = 100%
complete healing. b Visual illustration of re-epithelializa-
Cosmetic Appearance and Acceptance
tion of abrasive wound test fields treated with BepanGel in
comparison with test fields treated with a plaster alone
over a treatment period of 12 days. ***p \ 0.0001 The cosmetic appearance of the test fields was
evaluated both by the subjects and the blinded
investigator on day 31 of the clinical investiga-
tion through VAS assessments. The subjects
The global tolerability rated by the subjects
rated the cosmetic appearance of the hydrogel-
for both test fields was overall ‘‘very good’’ and
treated test field on average 81.9 ± 18.9 in
‘‘good’’ over all time points for both test fields
comparison with 71.5 ± 22.8 for the test field
with scores increasing over time. No statistical
treated with a plaster alone (p = 0.0078). These
difference was observed between the two test
results were similar to the rating of the blinded
fields, although slightly better results were
investigator, who rated the BepanGel-treated
obtained with BepanGel (mean sum 2.1 ± 2.5
test field on average 83.6 ± 17.6 and the plaster-
for the BepanGel-treated test field and mean
treated test field 72.3 ± 21.2 (p = 0.0005).
sum 2.7 ± 3.0 for the test field treated with a
plaster alone) over the total investigation per-
iod. As for the blinded investigator, global tol- Product Performance and Product Traits
erability was scored predominantly ‘‘very good’’
for both test fields during the study. The global Lastly, the effect of BepanGel on the test fields
tolerability was statistically similar between the was evaluated by the subjects on performance
test product (mean sum 0.2 ± 0.6) and the test and traits through a questionnaire. In general,
field treated with the plaster alone (mean sum 87.9% of the subjects were of the opinion that
0.2 ± 0.5). An overview of the tolerability the gel has a pleasant texture and 51.5% mod-
results is provided in Fig. 4 and further details erately to strongly agreed that BepanGel pro-
vides immediate pain relief. As such, at least

Fig. 3 Graph demonstrating the time to complete healing of induced abrasive wounds after BepanGel treatment and
treatment with a plaster alone
1084 Dermatol Ther (Heidelb) (2020) 10:1075–1088

Fig. 4 Tolerability assessments by the blinded investigator plaster alone. c Global tolerability evaluation by the
and the unblinded subjects. a Clinical tolerability evalu- investigator of the BepanGel-treated test fields in combi-
ation of the BepanGel-treated test field and the plaster- nation with a plaster in comparison with a plaster alone
treated test fields by the investigator. b Global tolerability
evaluation by the subjects of the BepanGel-treated test
field in combination with a plaster in comparison with a

three-quarters of the study population clinical application was as soft contact lenses in
acknowledged a reduced pain sensation during 1960 after these water-based polymers were
and after application with the hydrogel as well discovered in 1936 by DuPont (du Pont de
as when the bandage was changed. Finally, Nemours 1936) [19]. Since then, hydrogel
90.91% of the subjects agreed that the hydrogel technologies have been widely used for several
speeds up the healing process. Results of the purposes including hygiene products, drug
questionnaire, limited to the questions relevant delivery systems, sealing, pharmaceuticals,
for the current investigation, are provided in biomedical applications, tissue engineering,
Table 3. regenerative medicines, and wound dressings
[20]. As a result of their structure, hydrogels
possess many desired characteristics to effec-
DISCUSSION tively treat wounds, including cleansing of dry
wounds by providing a moist environment,
Hydrogels are three-dimensional polymer net- providing permeability towards metabolites,
works capable of holding large amounts of and their ability to cool the surface of the
water which makes them very appealing for all wound leading to an immediate relief of pain
kinds of biological applications [18]. Their first [6, 21, 22]. In addition, the hydrogel forms a
Dermatol Ther (Heidelb) (2020) 10:1075–1088 1085

Table 3 BepanGel product performance and product traits questionnaire

Question N N agreement % agreement p valuea
The gel has a pleasant texture 33 32 96.97 \ 0.0001
The gel provides immediate cooling effect 33 22 66.67 0.0555
The gel provides immediate pain relief 33 21 63.64 0.1172
The gel reduces sensation of pain during application 33 26 78.79 0.0009
The gel reduces sensation of pain after application 33 27 81.82 0.0003
The gel speeds up healing time 33 30 90.91 \ 0.0001
No pain while changing bandage 33 31 93.94 \ 0.0001
The questions provided in the table are a selection of the complete questionnaire. The questions and respective answers
presumed most relevant to the investigation are provided
a
p value from a two-sided binomial test for null hypothesis proportion p0 = 0.5 to test if the agreement level differs from
50% with (nominal) significance level of 5%

physical barrier preventing contamination and investigation. These results were confirmed by a
potential infection of the wound. larger AUCdays 2–12 (p \ 0.0001) regarding re-
BepanGel (Flamozil, Zoralan Wound) is a epithelialization for the test field treated with
wound care hydrogel that promotes wound the hydrogel and a significantly better scoring
healing by regulating the microenvironment of of global wound healing by the blinded inves-
the wound and serving as a barrier between the tigator. An earlier closure of wounds is of clini-
healing wound and external factors. Presence of cal relevance as it minimizes the risk of
the carbomer polymer ensures optimal hydra- secondary infections.
tion—and subsequently optimal conditions for In general, it should be considered that both
healing—of wounds at all times by releasing test fields were covered with a standard semi-
moisture into the wound bed of dry wounds occlusive wound dressing which mostly alone
and taking up moisture (exudates) of wet results in a better wound healing outcome than
wounds. In this way, BepanGel serves as an ideal under uncovered, dry conditions. Therefore, the
treatment for several types of wounds including difference in wound healing of the covered
superficial burns, grazed skin, abrasions and BepanGel-treated test field to a fully unpro-
cuts, surgical wounds, bedsores, and open leg tected, untreated test field might be expected to
sores. In addition, the low pH of the hydrogel be even more pronounced.
prevents microbial growth in a natural way. Despite previously proven cooling properties
The current investigation clearly substanti- of hydrogel due to their high water content, no
ates the beneficial effects of BepanGel on heal- statistical significance was reached in the cur-
ing of everyday superficial wounds in a clinical rent clinical evaluation in regard to cooling
setting in comparison with the standard treat- properties of the hydrogel. It should be noted,
ment consisting of wound plasters. First and however, that at the end of the study about two-
foremost, complete wound healing as assessed thirds of the subjects agreed that BepanGel
by re-epithelialization of the wounds was noted provides an immediate cooling effect
in 97.0% of all hydrogel-treated test fields (of (p = 0.0555). The lack of remarkable cooling
which 54.5% of the test fields were already experience is probably due to the small size of
completely healed by day 10). This was only the the wounds, making it nearly impossible to
case for 18.2% of the test fields treated with become aware of temperature differences. One
standard plasters alone at the end of the way to test this hypothesis is to treat a larger test
1086 Dermatol Ther (Heidelb) (2020) 10:1075–1088

wound surface area with the hydrogel; however, CONCLUSION

that would not have been ethically justifiable.
During follow-up of the investigation on The results of this clinical investigation clearly
day 31, both the unblinded study population demonstrate that there is a relevant benefit of
and the blinded investigator rated the cosmetic using BepanGel wound care hydrogel for the
appearance of the test field treated with hydro- daily treatment of small epithelial wounds over
gel better than treatment with the plaster alone plaster alone. The hydrogel is easy in use and
(p = 0.0005 and p = 0.0078, respectively). These improves wound healing efficacy by enhanced
findings are consistent with the beneficial re-epithelialization, leading to a better cosmetic
wound healing properties of the hydrogel outcome while providing a slight cooling effect
speeding up the healing process by promoting upon application. BepanGel is well tolerated by
wound epithelialization and wound closure, all study subjects to the same extent as standard
and subsequently reduce scarring. treatment with a plaster alone.
It is important to note that the hydrogel’s
performance was very positively rated by the
study population—and potential end users of
the marketed test product—with regard to tex-
ACKNOWLEDGEMENTS
ture and provision of pain relief during and
after application, as well as when changing the
Funding. Oystershell Laboratories spon-
bandage.
sored this study and is also the manufacturer of
Lastly, BepanGel demonstrated excellent
the investigational product. Study funding and
local tolerability when applied to standardized,
the journal’s rapid service fee were funded by
artificially induced abrasive wounds, while no
Oystershell Laboratories and Bayer Consumer
AEs associated with the use of the hydrogel were
Care AG. The sponsor was involved in the study
reported over those already known and
planning as well as in the decision to publish,
described.
but was not involved in data collection, data
A limitation of the current study is a com-
analysis, and data interpretation. All authors
parison of BepanGel-treated wounds with a test
had full access to all data in this study and take
field without any covering of the wound. The
complete responsibility for the integrity of the
reason for this decision is threefold: (1) the
data and accuracy of the data analysis.
standard of care of small, everyday epidermal
wounds currently consists of a semi-occlusive Authorship. All named authors meet the
plaster and hence serves as a relevant control, International Committee of Medical Journal
(2) if BepanGel-treated test fields remain Editors (ICMJE) criteria for authorship for this
uncovered, this will most likely result in article, take responsibility for the integrity of
removal of the wound hydrogel by scrubbing the work as a whole, and have given their
against clothes or obstacles, leaving the wounds approval for this version to be published.
with an insufficient amount of BepanGel, and
(3) covering of the BepanGel-treated test fields Medical Writing and Other Assis-
limits the evaporation of water from the tance. Oystershell Laboratories engaged bioskin
hydrogel, ensuring optimal treatment condi- GmbH to independently design and perform the
tions. Another limitation is the small surface clinical investigation. Writing of the manuscript
(1.2 cm diameter) of the induced wounds which was performed by an independent, external
might explain the absence of a significant consultant, Leni Vandekerckhove (email: leni-
cooling effect and difference in cosmetic [email protected]). We thank all
appearance of the wounds. However, a larger subjects for participating in the clinical trial.
test field area would not be in line with ethical
considerations. Disclosures. Lei Zang, Raffaella de Salvo,
and Sonja Trapp are employees of Bayer Con-
sumer Care AG, which partially funded this
Dermatol Ther (Heidelb) (2020) 10:1075–1088 1087

study. Walter Wigger-Alberti and Ragna Wil- healing between acute wounds, chronic wounds
liams are employees of bioskin GmbH, which and wounds in the aged. World Wide Wounds
2004. http://www.worldwidewounds.com/2004/
performed the study. Lucie Delcour, Bart Rossel, august/Enoch/Pathophysiology-Of-Healing.html.
and Maarten Huisman are employees of Oys- Accessed 30 July 2020.
tershell Laboratories, which is the developer of
the test product and partially funded this study. 2. Atiyeh BS, Ioannovich J, Al-Amm CA, El-Musa KA.
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14155:2011. Written informed consent was tance of wound healing in a moist environment.
obtained for all included subjects. The study J Eur Acad Dermatol Venereol. 2011;25(2):130–7.
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medical association in Hamburg (Ethik-Kom-
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