Effect of TLC-NOSF Dressing on Epithelization of Diabetic Wounds: A Pilot Clinical Trial
Article information
Abstract
Background
The positive effects of technology-lipid-colloid (TLC) dressings impregnated with nano-oligosaccharide factors (NOSF) have been well documented. However, there is insufficient study on the specific impact of TLC-NOSF dressings on epithelization in patients with diabetes who have partial-thickness wounds. This article presents the results of a pilot clinical trial conducted to address the aforementioned issue.
Methods
Twenty patients with diabetes who underwent split-thickness skin grafting were enrolled in this study. Half of the donor site was covered with a TLC-NOSF dressing, whereas the other half was covered with a TLC dressing. The ratio of complete epithelialization within 14 days postoperatively was compared between the two groups. Furthermore, progress of epithelialization was assessed to determine whether the TLC or TLC-NOSF dressing promoted more rapid epithelialization.
Results
Seventeen patients completed the study. The percentages of complete epithelialization in the TLC and TLC-NOSF dressing groups were 41% (7/17) and 53% (9/17), respectively (P = 0.49). Regarding the degree of epithelialization, the differences between the TLC-NOSF and TLC dressing were not statistically significant. The TLC-NOSF dressing was superior in nine patients, while the TLC dressing was superior in two patients. Six patients demonstrated “no significant difference” (P = 0.11).
Conclusion
Based on the current results alone, it is difficult to definitively conclude that TLC-NOSF dressings are superior to TLC dressings. However, these findings suggest a potential positive effect of TLC-NOSF dressings. Further large-scale studies are required to validate these results.
Introduction
Wound healing in patients with diabetes is frequently impeded by several factors. Delays or failures in healing are common even in partial-thickness wounds. Such failure of a partial-thickness wound to heal within a reasonable timeframe may lead to worsening and progression to a more severe condition. In partial-thickness skin graft donor sites, delayed wound healing may lead to increased pain, discomfort, and an elevated risk of infection [1]. Consequently, demand exists for more effective therapies that promote and accelerate wound healing.
In patients with diabetes, proper wound bed preparation including debridement and the selection of appropriate dressings are essential to facilitate successful wound healing [2]. For full-thickness wounds, the healing process involves three mechanisms: epithelialization, growth of granulation tissue, and wound contraction. Conversely, for partial-thickness wounds, the primary mode of healing is epithelization, with less emphasis on formation of granulation tissue and wound contraction [3]. Dressings that enhance keratinocyte migration and proliferation could effectively expedite early epithelization and through this quicken the total wound healing process in these partial-thickness wounds, especially in patients with diabetes.
One innovation in dressing materials is technology-lipidcolloid (TLC) dressings impregnated with a nano-oligosaccharide factor (NOSF). The application of NOSF diminishes the activity of matrix metalloproteinases (MMPs) and has been proven to enhance wound healing [4]. When integrated into a lipido-colloid dressing, NOSF forms a matrix that is then released into the wound microenvironment upon contact with wound exudate [5]. Several studies have highlighted the positive effects of TLC-NOSF (sucrose octasulfate) dressings in the therapy of venous leg and diabetic foot ulcers [5-7].
However, studies specifically examining the effect of TLC-NOSF dressings on epithelialization in patients with diabetes who have partial-thickness wounds are lacking. We have therefore conducted a pilot clinical study to investigate the potential impact of a TLC-NOSF dressing on the epithelialization of skin graft donor sites in patients with diabetes, and hereby present the findings.
Methods
Patients
The study protocol was approved by the Institutional Review Board of Korea University Guro Hospital (No. 2023GR0049). All participants provided written informed consent. A total of 20 patients were recruited between March 2023 and February 2024. The major inclusion criteria included individuals aged 19 years or older with diabetes, who were scheduled to receive split-thickness skin grafts, and were exhibiting no signs of systemic or local infection upon enrollment. The major exclusion criteria were conditions that markedly affected wound healing, such as connective tissue disease, sickle cell disease, or chemotherapy.
Design and procedures
Each patient underwent a skin grafting procedure in the operating room, where an Electric Dermatome (Zimmer) was used to harvest a 13/1,000-inch thickness of skin from the lateral upper thigh area. The donor site was split into two halves, with one half covered by a TLC-NOSF dressing (Urgostart, Laboratoires Urgo) and the other half covered by a TLC dressing (UrgoTul, Laboratoires Urgo). Ten patients received the TLC-NOSF dressing on the distal portion of the donor site, whereas the remaining patients received the same dressing on the proximal portion. The dressings were replaced every 1–3 days, depending on the amount of exudate from the donor site. At every dressing change, wounds were cleaned and irrigated with normal saline. Throughout the study period, up until the postoperative day (POD) 14, the donor site was photographed after each dressing change. On POD14, two blinded plastic surgeons assessed the degree of epithelialization on each side of the donor site clinically through visual inspection based on the amount of exudates absorbed by the dressings.
The comparison of levels of epithelialization between the two groups involved the assessment of two parameters. First, the ratio of complete epithelialization within 14 days after surgery was compared between the two groups. Second, the progression of epithelialization on POD14 was evaluated in each patient to determine whether the TLC dressing or the TLC-NOSF dressing facilitated more rapid epithelialization. A clinical assessment by visual inspection was conducted to compare which side had achieved more epithelialization. Additionally, the amount of exudate absorbed by the removed dressings was compared. In this context, the degree of epithelialization at the donor site and the amount of exudate in both dressings were compared to determine if either dressing was superior in promoting healing or if no notable difference was observed. In cases where the opinions of the two evaluators were not aligned, they were categorized as “no significant difference.”
Statistical analyses
Pearson chi-square test was used to compare the ratio of completed epithelialization within 14 days to the progression of epithelialization. Statistical significance was set at P<0.05. Statistical analyses were performed using the SPSS for Windows (version 12.0; SPSS Inc.).
Results
Seventeen patients (13 men, 4 women) with a mean age of 60.1±9.7 years (range, 37–79 years) successfully completed the study. The other three patients were excluded from the study: one due to the absence of a diabetes diagnosis, and two were lost to follow-up. The TLC-NOSF dressing was applied to the proximal half of the wound in eight patients and to the distal half in nine patients.
The TLC-NOSF dressing exhibited a higher ratio of complete epithelialization within 14 days after surgery (Figs. 1, 2). The ratios for the TLC and TLC-NOSF dressing groups were 41% (7/17) and 53% (9/17), respectively. However, this difference did not reach statistical significance according to Pearson chi-square test (P=0.49, degree of freedom=1). Regarding the degree of epithelialization, the TLC-NOSF dressing demonstrated faster healing compared to the TLC dressing in nine patients, while the TLC dressing showed faster healing compared to the TLC-NOSF dressing in two patients. Additionally, six patients exhibited “no significant difference” according to the Pearson chi-square test (P=0.11, degree of freedom=2) (Table 1).
A representative case. (A) Partial-thickness wound resulting from split-thickness skin harvesting on the lateral side of the thigh. (B) The donor site is managed with a technology-lipid-colloid (TLC) foam dressing on the proximal (left side in the photo) half and a TLC dressing impregnated with nano-oligo-saccharide factor (NOSF) dressing on the distal (right side in the photo) half of the wound. (C) Fourteen days postoperative. The area treated with TLC-NOSF dressing was completely epithelialized, whereas the other half treated with TLC dressing did not achieve complete epithelialization.
A second representative case. (A) Split-thickness graft donor site on the day of operation. The donor site is managed with a technology-lipid-colloid (TLC) dressing impregnated with nano-oligo-saccharide factor (NOSF) dressing on the proximal (left side in the photo) half and a TLC foam dressing on the distal (right side in the photo) half of the wound. (B) Eleven days postoperative. (C) Fourteen days postoperative. The area treated with TLC-NOSF dressing exhibited superior epithelialization compared to that of the area treated with TLC dressing.
Comparison of epithelialization levels between the two groups
No adverse events or complications were noted in any of the participants.
Discussion
This pilot clinical trial supports the feasibility of conducting a main study to confirm the effect of TLC-NOSF dressings on the healing process of partial-thickness wounds in patients with diabetes. Several studies have demonstrated the positive effects of TLC-NOSF dressings on chronic ulcers, but there is a lack of research specifically examining the effect of TLC-NOSF dressings on the epithelization of partial-thickness wounds. As far as we know, this pilot clinical trial is the first study designed to highlight the potential benefits of TLC-NOSF dressings in promoting the epithelialization of wounds in diabetes.
Neutral TLC dressings have been widely used by healthcare professionals for a decade, and their efficacy has been extensively studied in trials across a range of medical conditions [8,9]. Furthermore, data from in vitro studies indicated that TLC may enhance fibroblast growth and the production of extracellular matrix compounds [10].
Although neutral TLC dressings offer several advantages, integrating NOSF could potentially amplify the efficacy of the dressings in fostering wound healing. In experimental cell culture models, NOSF has been demonstrated to reduce MMP activity, with a notable impact on MMP-1. Octasulfate, the potassium salt in sucrose, acts as an inhibitor of excess MMPs. Additionally, octasulfate engages with growth factors, aiding in the recovery of biological functions, and thereby contributing to the formation of new tissues [11,12]. A recent in vitro study [13] exploring the TLC-NOSF dressing used in the present study revealed diminished activity of gelatinase (MMP-2 and MMP-9) and collagenase (MMP-1 and MMP-8) functions in a dermal equivalent comprised of normal human dermal fibroblasts embedded in a collagen matrix. When incorporated into a lipido-colloid dressing, NOSF can generate a matrix that is subsequently dispersed into the wound microenvironment upon contact with wound exudates [5]. These results indicate that the integration of NOSF into a lipido-colloid matrix enhances the clinical advantages previously noted in the treatment of both acute and chronic wounds [8,14]. Moreover, as discussed earlier, the incorporation of the NOSF compound into the lipido-colloid matrix not only provides potential antiinflammatory effects by isolating surplus MMPs from chronic wound exudate but also contributes to the overall healing process [15].
The effect of TLC-NOSF dressings has been well-investigated in chronic venous leg ulcers. Schmutz et al. [5] reported a notable augmentation in the healing efficacy, which was especially evident in the NOSF matrix group compared with that in the control group. Meaume et al. [16] conducted a randomized, controlled, double-blind trial to assess the effects of TLC and TLC-NOSF dressings on individuals with chronic venous leg ulcers. The results demonstrated that the TLC-NOSF dressing achieved a 26.7% larger decrease in the median wound area and displayed an accelerated healing rate compared to those observed with the TLC dressing.
Several studies have highlighted the benefits of TLC-NOSF dressings for wound healing in diabetes. In the Explorer randomized clinical trial, Edmonds et al. [6] documented accelerated wound healing in non-infected neuro-ischemic diabetic foot ulcers following 20 weeks of sucrose octasulfate dressing therapy. Additionally, Meloni et al. [7] also highlighted the potential advantages of sucrose octasulfate for the therapy of neuro-ischemic diabetic heel foot ulcers.
In the context of diabetic foot ulcers, the specific advantages of TLC-NOSF dressings can be elucidated by the following mechanisms. Diabetic foot ulcers manifest as an extended inflammatory phase marked by fibroblast dysfunction, compromised neovascularization, and heightened concentrations of MMPs [17,18]. Furthermore, MMPs hinder the wound healing process by degrading growth factors and contributing to the breakdown of the extracellular matrix [18,19]. At the tissue level, the potassium salt of sucrose octasulfate can inhibit excessive MMPs. Moreover, the distinctive structure of the potassium salt of sucrose octasulfate facilitates interactions with growth factors, thereby encouraging the recovery of their biological functions and aiding in tissue formation [11,12].
While the positive effects of TLC-NOSF dressings on venous leg and diabetic foot ulcers are primarily focused on chronic wound healing, there are also studies exploring the mechanisms that aid in superficial wound healing. Multiple studies have suggested that the topical application of sucralfate has demonstrated benefits in wound healing and epithelialization, even when not in the form of a TLC-NOSF dressing. Based on clinical evidence, the use of sucralfate in various formulations appears to offer potential benefits in addressing burns, cutaneous erosions, and ulcerations, as well as in the management of non-healing venous stasis ulcers [20]. Banati et al. [21] explored the topical application of sucralfate for the treatment of burn wounds in 60 patients. Their study demonstrated that in comparison to alternative topical agents, sucralfate cream enhanced epithelialization and accelerated the development of healthy granulation tissue in second- and third-degree burns at an earlier stage.
These outcomes were attributed to the interactions facilitated by sucralfate with various growth factors that are critical for epithelial wound healing. Sucralfate increases the concentration of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) in wounds [22]. The heightened activity of FGF appears to be pivotal in the mechanism of action of sucralfate [11,23]. FGFs play a vital role in all phases of healing thanks to their mitogenic activity in endothelial cells, chondrocytes, and fibroblasts [24]. Additionally, bFGF promotes the development of small blood vessels and activates the proliferation of fibroblasts and epidermal cells. In experimental investigations involving sucralfate, cultured dermal fibroblasts, and keratinocytes, sucralfate stimulated growth in the resting cultures of both dermal fibroblasts and keratinocytes. Furthermore, daily use of sucralfate on full-thickness wounds in rats augmented granulation tissue thickness, as noted on day 12 [25]. The modulatory effect of EGF and bFGF is likely to play a key role in the epithelialization of superficial wound healing.
In this study, the TLC-NOSF dressing exhibited a higher ratio of complete epithelialization compared to the TLC dressing. Additionally, the TLC-NOSF dressing demonstrated more rapid epithelialization in nine patients, whereas the TLC dressing showed more rapid results in two patients. However, due to the lack of statistical significance, it is difficult to conclude that the TLC-NOSF dressing is superior to the TLC dressing.
This study has several limitations. The sample size for analysis of the outcome was insufficient to draw substantial conclusions. However, it is noteworthy that this was a feasibility study aimed at piloting a main clinical trial to confirm the effect of TLC-NOSF dressing on the healing process of partial-thickness wounds in patients with diabetes. Therefore, rigorously planned prospective studies with large participant cohorts are essential to establish the effectiveness of TLC-NOSF dressings. Additionally, the lack of blinding among the clinicians responsible for administering the dressings could be considered another shortcoming. Also, based on the study’s protocol, the frequency of dressing change varied between 1 to 3 days. Unnecessarily frequent changes of the donor site dressing can cause pain and discomfort to the patient and may impede epithelialization. Therefore, we aimed to minimize the number of dressing changes in the clinical research protocol to prevent harm to patients. However, the inconsistency in the frequency and number of dressing changes may have affected the healing results. Lastly, degree of epithelialization on POD14 was assessed subjectively by two blinded observers after the dressings had been removed. The assessment lacked objectivity as it did not employ quantification methods such as ImageJ analysis or photometric techniques.
In conclusion, this pilot clinical trial aimed to investigate the feasibility of integrating NOSF into a TLC wound dressing to improve epithelialization in diabetic wounds. The TLC-NOSF dressing exhibited a higher ratio of complete epithelialization compared to the TLC dressing. Additionally, the TLC-NOSF dressing demonstrated a higher ratio of faster healing than the TLC dressing. However, the differences in both parameters did not reach statistical significance. Therefore, based on the current results alone, it is difficult to definitively conclude that the TLC-NOSF dressing is superior to the TLC dressing. Instead, the study’s findings suggest a potential positive effect of the TLC-NOSF dressing. Further large-scale studies are required to validate these results.
Notes
This study was supported by a grant from Bom Medical (Seoul, South Korea), a company that distributes and sells TLC dressings (UrgoTul, Laboratoires Urgo, Paris, France) and TLC-NOSF dressings (Urgostart, Laboratoires Urgo). No other potential conflicts of interest relevant to this article were reported.