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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 52  |  Issue : 2  |  Page : 52-56

A randomized clinical trial comparing a collagen-based composite dressing versus topical antibiotic ointment on healing full-thickness skin wounds to promote epithelialization


1 Department of Surgery, Taichung Hospital, Ministry of Health and Welfare; Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
2 Department of Surgery, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan
3 Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan

Date of Submission30-May-2018
Date of Decision05-Aug-2018
Date of Acceptance18-Nov-2018
Date of Web Publication18-Apr-2019

Correspondence Address:
Dr. Hsin-Chung Tsai
Department of Surgery, Taichung Hospital, Ministry of Health and Welfare, 199 San Min Rd., Sec. 1, Taichung
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/fjs.fjs_58_18

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  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


How to cite this article:
Tsai HC, Shu HC, Huang LC, Chen CM. A randomized clinical trial comparing a collagen-based composite dressing versus topical antibiotic ointment on healing full-thickness skin wounds to promote epithelialization. Formos J Surg 2019;52:52-6

How to cite this URL:
Tsai HC, Shu HC, Huang LC, Chen CM. A randomized clinical trial comparing a collagen-based composite dressing versus topical antibiotic ointment on healing full-thickness skin wounds to promote epithelialization. Formos J Surg [serial online] 2019 [cited 2019 Nov 19];52:52-6. Available from: http://www.e-fjs.org/text.asp?2019/52/2/52/256533


  Introduction Top


Traumatic acute full-thickness skin wounds are usually large, deep, and difficult to suture which generally necessitates the secondary intention healing process. The secondary intention healing process is characterized by regenerated granulation tissue and keloid tissue that 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],[4],[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 Top


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 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 neomycin containing antibiotic ointment covered with sterile gauzes. Both kinds of dressings were replaced daily. Patients with contact dermatitis discontinued participation in this trial.

Data collection and analysis

Wounds were photographed weekly and the wound areas were calculated using ImageJ software to evaluate the wound healing rate. Participants' demographic data, including age, gender, and wound area, were recorded, assessed, and analyzed blindly by a surgical team whose members include three surgeons, nurses, and research assistants. The Chi-square and Student's t-test with 95% confidence intervals were applied to compare the statistical differences between experimental and control groups.


  Results Top


The biological characteristics of participants in this trial were summarized and are as shown in [Table 1]. Of note, there were no significant differences regarding all of the patients' characteristics. Here, we selected a representative case from each group as shown in [Figure 1] to illustrate the recovery process with or without the multi-layered collagen-based dressing. In [Figure 1]a, a 35-year-old female patient was injured in a traffic accident, leading to full-thickness wounds on her right ankle with the depth of about 1.5 cm. Following cleaning and debridement of the wound, this patient received the collagen-based dressings as the major treatment. By day 28 of treatment, her wounds were not measurable and became nearly recovered. In addition, a 29-year-old male was injured in a traffic accident and received multiple abrasions and full-thickness wounds on his knee. [Figure 1]b depicts the wound status at days 0 and 28 of treatment with the antibiotic ointment gauze.
Table 1: Patient characteristics and wound-related information

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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

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We then compared the wounds' healing rates between experimental and control groups. The initial average of wound areas was 5.89 ± 4.23 cm2 and 6.15 ± 3.85 cm2, respectively. The weekly healing rate was defined as the wound area from each week divided by that of the previous week. These figures were converted to percentages and results are shown in [Figure 2]. Overall, the wound recovery rate in the experimental cohort was faster than in the control group. We further analyzed the healing data between the two cohorts by calculating statistical significance with the Student t-test and found that the two-tailed P value reached 0.0247, indicating that there was a significant difference between the two treatments for full-thickness wounds. Hence, patients that received treatments with the collagen-based dressings exhibited better and faster healing rates than those treated with traditional neomycin-containing antibiotic ointment gauzes. Our results clearly reveal that collagen along with the silver-containing layer could be considered for application in treating full-thickness wounds and that the recovery rate appeared to be superior to traditional ointment and gauze.
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

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  Discussion Top


Despite the sufficiency of conventional methods (dry or hydrocolloid dressings) in dealing with the majority of acute skin injuries, there is still room for improvement while treating deep, acute wounds. New advances in developing more adequate and effective dressings are applied toward improving the efficacy of traditional wound dressings. For example, hydrocolloid and hydrogel can be biosynthetic dressings that create an ideal moist environment for deep and full-thickness wound recovery. However, second intention healing remains an issue for patients due to the protracted healing process and the need for frequent daily wound care over a long period, greatly reducing the life quality of patients. In some cases, delayed intervention operations, such as split thickness skin grafts, could be needed for wound healing at the final stage.

It is easy to ignore the importance of epithelization while applying traditional wound healing dressings. Previously, an animal study regarding the application of collagen and the process of epithelialization showed that epithelial cells began migrating over the bovine collagen matrix by day 2 of treatment, while the untreated sites had delayed epithelial cell migration as well as a decrease in cells that descended into the granulation tissue and traveled over the wound surface. A bovine collagen matrix may stimulate more rapid wound healing with minimal to no side effects and high patient satisfaction, as described by Kolenik et al.[10] From our past experience applying these advanced dressings, including silver dressings, collagen-based dressings, and foam type dressings, we found that these dressings better 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 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 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.

 
  References Top

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Smith KJ, Skelton HG, Barrett TL, Welch M, Beard J. Histologic and immunohistochemical features in biopsy sites in which bovine collagen matrix was used for hemostasis. J Am Acad Dermatol 1996;34:434-8.  Back to cited text no. 15
    
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Motta G, Ratto GB, De Barbieri A, Corte G, Zardi L, Sacco A, et al. Can heterologous collagen enhance the granulation tissue growth? An experimental study. Ital J Surg Sci 1983;13:101-8.  Back to cited text no. 16
    
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