New Surfactant-based Dressing Product to Improve Wound Closure Rates of Nonhealing Wounds: A European Multicenter Study Including 1036 Patients

Objective. A new surfactant-based biomaterial containing the antimicrobial 1% silver sulfadiazine (SSD) was developed at the University of Virginia (Charlottesville, VA) to improve outcomes for nonhealing wounds. This study’s objective was to clinically test the wound care outcomes of the new surfactant-based antimicrobial wound dressing (SAWD) in a multicenter trial. Methods and Materials. This cohort study enrolled 1036 patients with any nonhealing wound of > 3 months duration not responding to standard-of-care treatments from 10 wound care centers in 7 European countries. The SAWD was used for all wound types at all stages of complexity, healing, and severity. Data collection ranged from 6 months to 2 years and measured the percentage of patients achieving wound closure and time to complete closure. Results. Of the 1036 patients, 70% achieved wound closure, 24.6% were still in treatment at data collection, and 5.4% had a therapy change. The majority (56%) of these non-healing wounds achieved wound closure within 11 weeks. Patients were treated with the SAWD for 3 weeks to more than 1 year with no complications or adverse effects from long-term SSD antimicrobial use. Conclusion. Ten centers concluded that the new SAWD provided positive results (improved wound closure rates, reduction of inflammation, pain, and odor), improvements in clinical application (faster and easier dressing change), and improved patient compliance.

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Nonhealing wounds are responsible for a significant economic burden and an increase in morbidity and mortality for patients.^1,2 These wounds, along with myriad dressing and medication choices, are the subject of intensive research. In addition, an extensive number of protocols exists for managing these debilitating wounds. Nevertheless, rates of clinical wound closure remain unacceptably low, and the burden of disease is rising.³

Physicians and scientists at the University of Virginia (Charlottesville, VA) developed a new surfactant-based biomaterial containing 1% silver sulfadiazine (SSD) to improve outcomes for chronic wounds. The aim of this study was to clinically test the wound care outcomes of the new surfactant-based antimicrobial wound dressing (SAWD) in a multicenter setting.

Materials. The SAWD (PluroGel with 1% silver sulfadiazine, PluroGen Therapeutics, Norristown, PA) was applied as a primary dressing in all wounds. It was used in conjunction with the existing standard of wound care products and treatment procedures at each of the participating centers in order to limit variability and facilitate adoption. Materials used were simple, inexpensive nonwoven or gauze materials, and inexpensive moisture barrier covers.

The surfactant used in the SAWD is built with 2 monomer chains, 1 hydrophilic and 1 hydrophobic. This polymer can be formed into spherical micelles with the hydrophilic component on the outside surface of the micelle and the hydrophobic component oriented to the sphere’s interior (Figure 1). The surfactant-based micelles are further cross-linked, utilizing water to form a matrix (PluroGel Micelle Matrix, PluroGen Therapeutics, Norristown, PA). The spaces between the micelles, in addition to carrying the water component of the matrix, may carry water-soluble materials, while the hydrophobic center of the micelles may carry oil-soluble materials. This micelle matrix forms a water-based emulsion with the hydrophilic/hydrophobic structure of the micelles establishing biocompatible, biomaterial surfactant properties.⁴ 

Wound exudate and debris become relatively solubilized in the SAWD’s micelle matrix structure, allowing for increased ease of wound cleaning. Further, as the SAWD’s micelle matrix structure warms, the micelles exhibit greater attraction for each other than for the water surrounding them, resulting in a more rigid structure and a more viscous product at body temperature, to help the SAWD stay on the wound. By contrast, cooling to room temperature increases the micelles’ attraction for the water, resulting in a less rigid structure, promoting easier rinsing of the wound and minimizing the need for mechanical scraping or debridement of the wound bed.

Relevant additional biophysical properties of the SAWD’s micelle matrix structure include its promotion of a moist, oxygenated wound healing environment and its capability of plugging leaky cell membranes to minimize cell necrosis and apoptosis.⁵ The SAWD matrix exhibits the capacity for reducing inflammation (thought to be both because extravasation of intracellular components into the wound bed is minimized, and because bradykinins and other inflammatory cytokines are bound by the matrix, reducing their pro-inflammatory properties).^6,7 Microcirculation may be enhanced by the SAWD micelle matrix structure, as its surfactant effect can help prevent clot formation and obstruction of the microvasculature in the presence of wound debris.⁸ Finally, the SAWD’s micelle matrix structure has the ability to disrupt and penetrate the biofilm encapsulation present in many chronic wounds, maximizing the antimicrobial effect in multiple-agent formulations.⁹

Methods. Ten experienced wound care centers in 7 European countries participated in this multicenter study. Institutional Review Board approval was obtained in all centers independently. All 10 centers reported results for patients being treated with the new SAWD up to May 1, 2013 when the data was to be collected. Data collection time ranged from 6 months to 2 years depending on the center. To provide a better understanding of the expected results using the SAWD in everyday clinical practice, each wound care center collected the data through its normal patient data collection system. To ensure data and results were reliable, each wound care center first reviewed its own results, and then an external reviewer reviewed the results.

One center, a university hospital, focused on the use of the SAWD on complex chronic wounds or complicated postoperative wounds that could not be closed by any of the methods previously used (ie, treatment of the cause, best modern local wound treatment, extracorporeal shock wave therapy for wounds, electrostimulation, surgical debridement, and, if necessary, split skin grafting).  Clinical wound closure had not been achieved in this population for durations ranging from 3 months to more than 1 year despite the use of adequate multiple products and therapies. The remaining 9 centers used the SAWD for all wound types and for wounds at all stages of complexity, severity, and healing. For the 10 centers, a cohort study design was used because this design provides a better understanding of the results that can be expected in using the SAWD in everyday clinical practice. Modern wound care according to the principals of wound bed preparation was the standard of care at each wound care center.¹⁰ The inclusion criterion consisted of any nonhealing wound not responding to standard-of-care treatments.

The SAWD was used in all stages of wound healing; all centers followed a similar protocol: 

• A wound care follow-up file was maintained (measuring size, amount of exudate, infection, pain, odor, and perilesional skin state), and photographs of the patient’s progress were obtained. Wound cleaning or debridement of necrotic tissue was performed as required; and
• A non-water soluble skin protectant, such as petrolatum, was applied to the wound border where appropriate.

The SAWD was applied as follows:

1. Spread with a spatula over a piece of nonwoven material or gauze, which was then laid over the complete wound surface, and usually over-covered with a moisture barrier; or
2. Directly placed in the wound by a spatula, after which the wound was covered with appropriate nonwoven material or gauze and a moisture barrier over-cover;
3. The entire wound surface was covered with the SAWD; and
4. No healthy tissue was covered with the SAWD.

Other protocols included:

• Use of additional therapies and products (eg, compression, negative pressure wound therapy, hyperbaric chamber) occurred as dictated by wound status and as clinically necessary, and
• Dressing changes according to the patient’s needs and type of wound occurred at frequencies ranging from twice daily to 1-3 times/w performed as dictated by wound status and as clinically necessary.

The primary outcome parameter was the number of patients achieving wound closure. Wound closure was defined as complete and stable reepithelialization of the wound. The wound closure progress was defined as > 40% wound area reduction within 4 weeks.^11-15 Wound closure progress was used for those patients who had not achieved complete wound closure at the time the study was concluded. 

Patients. In this cohort study any patient with a chronic wound > 3 months duration not responding to the standard of care was enrolled. A total of 1036 patients with all types of nonhealing wounds were treated at 10 centers. The types of ulcers treated were diabetic, arterial, venous, mixed, hypertensive, vasculitic, and pressure. Infected wounds, posttraumatic/postoperative wounds, and burns were also included in this study. 

The duration of the study and the number of patients enrolled at each center is reported in Table 1. The table also documents 56 patients (5.4%) who were withdrawn due to a change of procedure; and 68 patients (6.6%) withdrawn due to being lost to follow-up. Patients withdrawn due to change in procedure, as well as patients lost to follow-up, were not included in an intention-to-treat analysis for several reasons: first, the number of patients in each group was small; second, the change in procedure was not equal to treatment failure but often caused by regimen change in other institutions; third, the loss to follow-up was only 6%, a figure found in most contemporary analyses of cohort studies; last, but not least, the analysis of almost 90% of the total patient population (1036) represents a real-world setting and allows the objective judgment of therapy success in the average clinical setting. 

All 10 centers focused on achieving wound closure and wound progress using the SAWD. Results for the 10 centers are summarized in Table 2. The SAWD was used to treat 1036 patients. At the time of data reporting (excluding patients lost to follow-up), 70% of patients (n = 678) achieved wound closure, while 24.2% (n = 234) showed dramatic wound closure progress and were still in treatment. Note: 5.4% of patients (n = 56) required a change of procedure for reasons that included skin graft, difficult infection, or allergy. 

Four centers reported their time to wound closure in Table 3. One center documented 54.1% of wounds closing within 30 days and 82.9% closing within 60 days of treatment. The other 3 centers that monitored time to wound closure recorded their results during the first 180 days. In these 3 centers, for those wounds that closed, 65.2% closed by day 75 with an additional 34.8% closing within 180 days. According to these results, for those wounds that closed, the majority of nonhealing wounds treated with the SAWD (80.5%) closed within 11 weeks. 

Clinical observations about wound conditions and handling characteristics for the SAWD for all 10 centers are reported in Table 4. The centers’ clinical observations were noted in contrast to their expected results using their normal standard-of-care products and procedures. 

The use of the SAWD in 1036 patients resulted in a closure rate of 70%. In all 10 of the centers, they reported reduced patient pain, decreased inflammation in wound site and in perilesional skin, reduced wound size, decreased infection rates, and decreased exudate.  Further, in all 10 of the centers, dressing changes were reported to be easier and quicker for the clinician and less painful for the patient. Dressing change interval may be modified to suit the stage of wound healing, and the SAWD can be used across all stages of wound healing. No center reported complications from long-term use of the SAWD containing 1% SSD.

This multicenter cohort study reports results for 1036 patients from 10 experienced wound care centers in 7 European countries. The cohort design provides a better understanding of results that can be expected in using the new product in everyday clinical practice; therefore this study compared the unchanged standard-of-care practices in 10 experienced wound care centers to the same centers’ use of the SAWD. The only change in patient treatment reported in this study for these 10 centers was the use of the SAWD, and it was compared directly to the 10 centers usual standard-of-care practice. Because 10 centers reported results from their standard-of-care practice, a broad array of products and clinical practices were included in the results reported here. This broad array was representative of standard-of-care practices in the general treatment population, and with the single change to standard of care being the SAWD the cohort design used for this study provides a better understanding of the results that can be expected in using the new product in everyday clinical practice.

Wound closure rates for the SAWD dressing were compared with baseline results expected when standard products and treatments (standard of care) are used for this type of patient population. A recent meta-analysis of the wound care literature recognized the complexity of the research landscape for chronic wounds, which contributes to the lack of large, well-designed studies from which to draw representative or comparative data.¹⁶ Therefore, 5 smaller published trials^17-21 were utilized to establish the baseline results, or control data, for the standard of care. These 5 published trials^17-21 were selected because they were randomized, controlled trials (RCTs) reporting peer-reviewed results on wound closure for both standard-of-care treatments and new experimental treatments intended to improve results beyond standard-of-care treatments as reported in Table 5. Use of these 5 trials provided a scientifically reviewed broad baseline of performance comparison for the SAWD. These new experimental treatments included granulocyte macrophage colony stimulating factor, porcine small intestine submucosa extracellular matrix graft, mesenchymal stem cell, molecular pathogen diagnostic implementation and 2 versions of a formulated collagen gel. 

To compare the 5 published trials to the SAWD, the mean cross-trial wound closure rate was calculated and compared to the mean wound closure rate calculated for the 10 centers in this study. Standard-of-care wound closure rates were used as control and compared to wound closure rates for the new experimental treatments and the SAWD. The mean cross-trial standard-of-care wound closure rate was 43.8% (n = 645), while the mean cross-trial wound closure rate for the new experimental treatments was 58.9% (n = 727).^17-21 In comparison, the new surfactant-based dressing studied in this multicenter trial showed a mean wound closure rate of 70% (n = 968). The SAWD provided a 60% increase in wound closure over the reported wound closure rate from standard of care. Use of the SAWD demonstrated a 19% increase in wound closure over that obtained from the 5 new experimental treatments.

Clinicians reported that the properties and characteristics of the SAWD included ease and speed of dressing change, less tissue damage on dressing change, flexibility of spacing between dressing changes, and suitability for use through all phases of wound closure.

The strengths of this study include the large number of patients (> 1000), the prospective data collection, the real-world setting of a multicenter study, and the thorough follow-up. However, 2 limitations with this research should be noted. 1) The treatment with SAWD was not randomly tested with standard-of-care wound therapy because the best standard-of-care treatments had already been carried out previously and did not induce healing. Therefore, comparison of historical data in similar patients was the best comparator possible. For this reason, instead of random testing, 5 published trials^17-21 were utilized to establish the baseline expectations for standard-of-care and experimental therapies compared to the SAWD results. Furthermore, with the very encouraging immediate results of the SAWD treatment, the researchers were reluctant to randomize patients to the standard-of-care treatment modalities because they were already shown to be less successful. 2) The relatively low number of patients in some centers may have resulted from the limited number of patients available for the study inclusion criteria at the time of the study.

The SAWD is a positive new approach for the treatment of nonhealing wounds of all types. Clinicians’ reports affirm the product’s ease and flexibility of use, reveal good wound closure rates, reduction in pain, improvement in quality of life, and patient compliance and acceptance. Further studies in each of these areas for this new product are suggested.

Affiliations: Azienda Ospedaliera Universitaria, Policlinico Paolo Giaccone di Palermo, Department of Geriatric Surgery, Palermo, Sicily, Italy; Wound Healing School of Medicine, Cardiff University, Cardiff, UK; Vascular Surgery Unit, A.O.G. Salvini, Garbagnate Milanese, Italy; Ambulatorien der Steiermärkischen Gebietskrankenkasse, Fachärztezentrum Graz, Austria; Diabetologe DDG, Wound Care Centre, Städt Krankenhaus Offenbach, Germany; Private Practice, Specialist in Dermatologie und Venerologie, Wien, Austria; Wound Care Centre, AZ St. Elisabeth Zottegem; Wondzorg De Parel Zorg-en Dienstencentrum, Hillegem, Belgium; Vulnologic Center and Second Unit of General Surgery, Villa Fiorita Surgical Clinic, Prato, Italy; and Clinic for Cardiovascular Surgery, University Hospital of Zurich, Zurich, Switzerland

Correspondence:
Francesco Paolo Palumbo, MD
Division of Surgery
Via di Cantagallo, 56
Prato, Italy, 59100
drpalumbo.studio@gmail.com  

Disclosure: PluroGen Therapeutics, Norristown, PA provided test material and editorial assistance.