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43]

Original Article

A randomized clinical trial comparing a collagen‑based

composite dressing versus topical antibiotic ointment
on healing full‑thickness skin wounds to promote
epithelialization
Hsin‑Chung Tsai1,2, Hui-Ching Shu1, Li-Chuan Huang1, Chuan‑Mu Chen2
1
Department of Surgery, Taichung Hospital, Ministry of Health and Welfare, 2Department of Life Sciences, National Chung Hsing University,
Taichung, Taiwan

Abstract Background: Acute traumatic wounds are a common and distressing event for patients presenting to
plastic surgery clinics. There are no definitive conclusions regarding the benefits of collagen‑based wound
care products toward the application on full‑thickness wounds compared to traditional ointment or gauze
care. In this clinical trial, we aimed to define the potential benefits of collagen‑based dressings on healing
through the comparison of collagen‑based composite dressings with antibiotic ointment dressings.
Methods: This was a randomized two‑tailed controlled clinical trial. The acute full‑thickness wounds
underwent wound cleansing, debridement, and were secured with different dressings in both experimental
and control groups. The wounds were subsequently photographed weekly, and the wound areas were
calculated using ImageJ software to evaluate wound healing rate.
Results: The results demonstrate that the collagen‑based triple layer composite dressings which consisted of
silver sheet, collagen sponge, and foam films promoted better epithelialization and healing than antibiotic
ointment treatment. Collagen supplementation improved wound healing and epithelialization by providing
a dry environment during the late stage of wound healing.
Conclusion: We demonstrated that the collagen‑based triple layer wound dressing could potentially increase
the healing rate when used for traumatic full‑thickness wound care compared to the conventional antibiotic
ointment dressing, providing a new prospective in the future applications of wound care.

Keywords: Acute traumatic wound, composite dressing, epithelialization, ointment dressing

Address for correspondence: Dr. Hsin‑Chung Tsai, Department of Surgery, Taichung Hospital, Ministry of Health and Welfare, 199 San Min Rd., Sec. 1,
Taichung, Taiwan.
E‑mail: prch1212@gmail.com
Received: 30‑May‑2018, Revised: 05‑Aug‑2018, Accepted: 18‑Nov‑2018

INTRODUCTION necessitates the secondary intention healing process.

The secondary intention healing process is characterized
Traumatic acute full‑thickness skin wounds are usually by regenerated granulation tissue and keloid tissue that
large, deep, and difficult to suture which generally
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How to cite this article: Tsai HC, Shu HC, Huang LC, Chen CM.
DOI: A randomized clinical trial comparing a collagen‑based composite dressing
10.4103/fjs.fjs_58_18 versus topical antibiotic ointment on healing full‑thickness skin wounds to
promote epithelialization. Formos J Surg 2019;52:52-6.

52 © 2019 Formosan Journal of Surgery | Published by Wolters Kluwer ‑ Medknow

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Tsai, et al.: Collagen-based dressing potentially promotes epithelialization of full-thickness wound
replenishes or covers the wound before epithelialization can
be initiated.[1,2] Epithelialization is a crucial stage during the
wound healing process, creating a denuded surface on the
wound which is the loss of the epithelial layer.[3‑5] However,
when wounds are too large in size, the secondary intention
is not a feasible method as the wounds could fail to heal or
the healing process is prolonged, subsequently leading to
patient distress and remarkable degradation of life quality.
By convention, appropriate debridement to remove necrotic
tissues and maintaining a moist wound environment can
facilitate and promote wound healing. [6] As a result,
traditional artificial skin dressings containing antibiotic
ointment or hydrophilic material are commonly applied
to full‑thickness wounds to enhance tissue‑granulation
and prevent bacterial contamination. While these
traditional dressings appear to be beneficial when applied
to partial thickness wounds, they are not as effective on
full‑thickness wounds. That is, they could reversely prolong
wound epithelialization, causing excessive proliferation of
granulation resulting in hypertrophic keloid formation in
the full‑thickness wounds. Therefore, an alternative wound
dressing which can shorten the healing period and induce
adequate epithelialization and granulation in full‑thickness
skin wounds is required.
To date, plenty of alternative wound care products on
the market, such as collagen dressings, hydrogels, hydro
foams, hydrocolloid, or growth factors, can be utilized to
enhance epithelization and granulation for full‑thickness
wounds. In addition, chitosan hydrogels‑based dressings
have been tested in animal experiments,[7,8] and microskin
grafts have also been reported to promote the healing
of full‑thickness skin wounds.[9] However, few studies
have tested the benefits of collagen‑based dressing on
full‑thickness wounds. Haycocks et al. found that a collagen
matrix could enhance wound healing in the diabetic foot by
modulating the wound environment, but may not promote
epithelialization.[8] Little is known whether a collagen matrix
dressing could stimulate epithelialization in full‑thickness
wounds, so we aimed to compare the collagen‑based
advanced dressing versus traditional antibiotic ointment
gauze, generating more clinical evidence to validate the
benefits of collagen on acute wounds.
 METHODS
Experimental design
This study is a randomized controlled trial which was
approved by the Institutional Review Board of Jianan
Psychiatric Center, Ministry of Health and Welfare,
Taiwan (Approval IRB No. 14‑013). The data throughout
Formosan Journal of Surgery | Volume 52 | Issue 2 | March-April 2019 53
this study were conducted in the outpatient plastic surgery
department of Taichung Hospital in Taiwan according to
approved protocols.
Participants
A total of thirty‑three volunteers were enrolled in
experimental (n  =  16) and control groups  (n  =  17) and
consented to participate in this investigation. Enrolled
patient criteria were as follows. (1) patients suffered from
physician‑confirmed acute full‑thickness wounds which
failed to heal for more than 7 days and their ages were
between 20 and 49 years old (2) No signs of infections
of wounds  (3) Patients did not take any anti‑coagulant
medications at least one month before enrolling into this
study and were willing to comply the related regulations
and medical orders during the trial.
Conversely, patients with following conditions were
excluded from this study.  (1) Patients with infected
wounds, whose wounds were over 20 cm2 in size, and
whose personal identification was potentially revealed
(2) Coagulation disorders (i.e., blood platelet count was less
than 150,000/UL or prothrombin time was <11 or more
than 16 s), ongoing medical treatments (i.e. anticoagulant
medication, long course use of steroid‑containing drugs,
or steroid cream in the wound vicinity), comorbidity
(i.e., leukemia, sepsis, any blood‑related diseases, diabetes
mellitus, uremia, or peripheral vascular diseases).
Volunteer informed consent was required for participation
in this trial. Patients were randomly assigned into
experimental and control groups in which the collagen‑based
dressing or traditional antibiotic ointment gauze was
administered, respectively. Randomized group assignment
was implemented by outpatient nurses and using the
RANDBETWEEN function of Microsoft Excel to
randomly assign participants a number of either 0 or 1.
Patients with the number 0 were assigned to the control
group, while those with the number 1 belonged to the
experimental group.
Wound treatment and dressings
Acute full‑thickness wounds in the experimental and
control groups received the same wound cleansing and
debridement procedures before applying wound dressings.
In the experimental group, we applied the combinatorial
collagen‑based dressings including silver‑impregnated
dressing from Atrauman Ag ® (Paul Hartmann AG,
Germany) as the inner layer, type‑I collagen dressing from
Collawound®  (Collamatrix, Taiwan) as the middle layer,
and sponge dressing from Mepilex® (Moleke, Sweden) as
the outer layer. Participants in the control group received
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Tsai, et al.: Collagen-based dressing potentially promotes epithelialization of full-thickness wound

neomycin containing antibiotic ointment covered with Table 1: Patient characteristics and wound‑related information
sterile gauzes. Both kinds of dressings were replaced daily. Characteristics n (%) or mean±SD P
(two‑tail)
Patients with contact dermatitis discontinued participation Experimental Control
group group
in this trial.
Sex†
Male 7 (43.8) 11 (68.8) 0.154
Data collection and analysis Female 9 (56.2) 5 (31.2)
Wounds were photographed weekly and the wound Age (years)‡ 26.06±5.98 26.50±4.55 0.817
Full‑thickness wound area (cm2)‡ 5.89±4.23 6.15±3.85 0.853
areas were calculated using ImageJ software to evaluate
Wound location†
the wound healing rate. Participants’ demographic data, Knee 3 (18.8) 8 (50.0) 0.336
including age, gender, and wound area, were recorded, Ankle 4 (25.0) 4 (25.0)
Instep 5 (31.3) 2 (12.6)
assessed, and analyzed blindly by a surgical team whose
Leg 3 (18.7) 1 (6.2)
members include three surgeons, nurses, and research Hand 1 (6.2) 1 (6.2)
assistants. The Chi‑square and Student’s t‑test with 95% *P<0.05, †χ2 analysis, ‡Independent sample t‑test. SD: Standard deviation
confidence intervals were applied to compare the statistical
differences between experimental and control groups. traditional neomycin‑containing antibiotic ointment gauzes.
Our results clearly reveal that collagen along with the
RESULTS silver‑containing layer could be considered for application
in treating full‑thickness wounds and that the recovery rate
The biological characteristics of participants in this trial appeared to be superior to traditional ointment and gauze.
were summarized and are as shown in Table 1. Of note,
there were no significant differences regarding all of the DISCUSSION
patients’ characteristics. Here, we selected a representative
case from each group as shown in Figure 1 to illustrate Despite the sufficiency of conventional methods
the recovery process with or without the multi‑layered (dry or hydrocolloid dressings) in dealing with the majority
collagen‑based dressing. In Figure  1a, a 35‑year‑old of acute skin injuries, there is still room for improvement
female patient was injured in a traffic accident, leading to while treating deep, acute wounds. New advances in
full‑thickness wounds on her right ankle with the depth of developing more adequate and effective dressings are
about 1.5 cm. Following cleaning and debridement of the applied toward improving the efficacy of traditional
wound, this patient received the collagen‑based dressings as wound dressings. For example, hydrocolloid and hydrogel
the major treatment. By day 28 of treatment, her wounds can be biosynthetic dressings that create an ideal moist
were not measurable and became nearly recovered. In environment for deep and full‑thickness wound recovery.
addition, a 29‑year‑old male was injured in a traffic accident However, second intention healing remains an issue for
and received multiple abrasions and full‑thickness wounds patients due to the protracted healing process and the need
on his knee. Figure 1b depicts the wound status at days 0 for frequent daily wound care over a long period, greatly
and 28 of treatment with the antibiotic ointment gauze. reducing the life quality of patients. In some cases, delayed
intervention operations, such as split thickness skin grafts,
We then compared the wounds’ healing rates between could be needed for wound healing at the final stage.
experimental and control groups. The initial average of
wound areas was 5.89 ± 4.23 cm2 and 6.15 ± 3.85 cm2, It is easy to ignore the importance of epithelization while
respectively. The weekly healing rate was defined as applying traditional wound healing dressings. Previously,
the wound area from each week divided by that of the an animal study regarding the application of collagen and
previous week. These figures were converted to percentages the process of epithelialization showed that epithelial cells
and results are shown in Figure  2. Overall, the wound began migrating over the bovine collagen matrix by day 2
recovery rate in the experimental cohort was faster than of treatment, while the untreated sites had delayed epithelial
in the control group. We further analyzed the healing cell migration as well as a decrease in cells that descended
data between the two cohorts by calculating statistical into the granulation tissue and traveled over the wound
significance with the Student t‑test and found that the surface. A bovine collagen matrix may stimulate more rapid
two‑tailed P value reached 0.0247, indicating that there wound healing with minimal to no side effects and high
was a significant difference between the two treatments patient satisfaction, as described by Kolenik et al.[10] From
for full‑thickness wounds. Hence, patients that received our past experience applying these advanced dressings,
treatments with the collagen‑based dressings exhibited including silver dressings, collagen‑based dressings, and
better and faster healing rates than those treated with foam type dressings, we found that these dressings better
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Tsai, et al.: Collagen-based dressing potentially promotes epithelialization of full-thickness wound
Figure 1: The representative cases in the experimental and control
groups (a) a 35‑year‑old female patient acquired multiple full‑thickness
wounds in a traffic accident and received the collagen‑based treatments
for up to 28 days (b) a 29‑year‑old male with full‑thickness wounds
on the knee resulting from a traffic collision was treated with antibiotic
ointment gauze
promoted wound healing in both acute wounds and chronic
ulcers despite lack of clinical data. Among these advanced
dressings, type I porcine collagen comprises 97% of the
collagen‑based dressing implemented in our trial and can
serve as a scaffold and substrate for keratinocytes and
matrix metalloproteinases (MMPs). This collagen dressing
product can alternatively combine with antibacterial silver
sheets or external coverings to absorb more exudates,
enabling the collagen‑based dressing to be a better
replacement for traditional secondary intention methods
with delayed epithelialization.
Most advanced wound care products, such as hydrocolloid
dressings, tend to focus on addressing the macro
environment of wounds, maintaining a moist wound
environment, managing exudates, and controlling
transpiration of wound fluids.[11] However, these occlusive
dressings are more suitable for application on partial
thickness wounds than on full‑thickness wounds as
hydrocolloid has been implicated in the induction of
excessive granulation tissue without establishing good
epithelialization, potentially leading to formation of
keloids. [12] Newer biomaterials and wound‑healing
agents, such as collagen and growth factors, however,
seem to able to target specific defects in the chronic
wound environment,[13] but still play a limited role in
the epithelialization process. The mechanisms by which
heterologous collagen matrices assist wound healing
including hemostatic, spatial, nutritional, and chemotactic
effects remain unclear. Nevertheless, the use of porcine
collagen matrix as a support scaffold for human epidermal
cells appears to be a reasonable concept as the collagen
Formosan Journal of Surgery | Volume 52 | Issue 2 | March-April 2019 55
Figure 2: The weekly trend of wound healing rates between the
experimental and control groups. Weekly healing rate was defined as
the percentage of wound area change within two 2 weeks from both
groups. The data are presented as a mean ± SD standard deviation.
Statistical significance was considered when P value is under 0.05 and
is indicated by a star symbol (*P<0.05). The Student t-test was applied
to calculate the significant significance
generated from dermal fibroblasts could resemble and
organize into the architecture of human skin.[14] This
architectural scaffold could also be used for aggregation of
platelets and coagulation factors to improve hemostasis.[15]
Meanwhile, the scaffold was able to support the preparation
of epithelialization. Orderly mechanical support could
readily organize fibroblasts and newly‑formed collagen
fibers into a regular network and serve as a nutrient
substitute in the metabolic activity of granulation tissue.[16]
Other benefits might follow collagen dressing application:
inhibiting or deactivating MMP, increasing fibroblast
production and permeation, aiding in the uptake and
bioavailability of fibronectin, helping to preserve leukocytes,
macrophages, fibroblasts, and epithelial cells, and assisting in
the maintenance of the wound’s chemical and thermostatic
microenvironment.[17,18] Wound contraction was observed
to be significantly reduced by collagen matrix application
but was not altered by the occlusive dressings described
by Leipziger et al. The aforementioned authors also found
that the collagen matrix increased fibronectin binding sites
and subsequently increased fibronectin binding, ultimately
stimulated migration of fibroblasts.[19]
Heretofore, the use of collagen was limited only to
the promotion of granulation tissues due to their easy
degradation by exudates. To avoid this circumstance, we
used a silver‑impregnated sheet to separate the collagen
from the direct exudate. The silver sheet can also reduce the
possibility of infection. In clinical practice, the inner silver
film can last for at least 2–3 weeks without being changed
before the infection becomes a concern, while the outer
layer foam only needs occasional changing.
In our study, the experimental group exhibited faster weekly
healing rates compared to the traditional group. Based on
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Tsai, et al.: Collagen-based dressing potentially promotes epithelialization of full-thickness wound
our data, we believe these multi‑layered collagen‑based
dressings could accelerate the wound healing rate and
minimize the exudates. However, a large, controlled,
multicenter clinical trial of a bovine collagen matrix is
warranted in addition to this pilot study.
Acknowledgment
The authors greatly appreciates Dr.  Chiang‑Hung
Chou  (Gene BioDesign Co., Ltd) and Jong‑Liang,
Jeng  (Taichung Hospital) for valuable advice regarding
the experimental direction and drafting as well as
Dr.  Shih‑Chao Lin  (George Mason University) and
Christopher Lien  (American Type  Culture Collection)
for reviewing, and editing this manuscript to improve the
quality of article.
Declaration of patient consent
The authors certify that they have obtained all appropriate
patient consent forms. In the form the patients have given
their consent for their images and other clinical information
to be reported in the journal. The patients understand
that their names and initials will not be published and due
efforts will be made to conceal their identity, but anonymity
cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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