Introduction
Wounds involving the deep dermis of the skin inevitably result in scar formation. The wound healing process progresses through inflammatory, proliferative, and remodeling phases, during which excessive local expression of transforming growth factor-beta promotes fibroblast differentiation into myofibroblasts and induces abnormal collagen deposition, leading to hypertrophic scars and keloids [1-5].
These pathologic scars not only cause cosmetic deformities but also produce functional impairment, pain, pruritus, and persistent heat sensation [1,4]. Conventional silicone gel sheets and silicone ointments are currently regarded as the standard non-invasive treatment for hypertrophic scars. Silicone maintains hydration of the stratum corneum through occlusive effects and regulates fibroblast activity and collagen synthesis. However, prolonged occlusion frequently aggravates local heat sensation and pruritus, thereby decreasing patient compliance [6].
Transient receptor potential melastatin 8 (TRPM8) is a cold-sensitive ion channel activated by low temperatures and cooling compounds such as menthol and eucalyptol [7-9]. Activation of TRPM8 induces cooling sensation and modulates neural pathways associated with itching and discomfort without significantly lowering actual skin temperature.
The purpose of this study was to evaluate the cooling effect, pruritus mitigation, patient compliance, and scar prevention efficacy of a novel topical anti-scarring composition consisting of 20% silicone with 0.4% eucalyptol, a relatively non-irritating TRPM8 agonist that has been extensively studied [10].
Methods
Silicone ointment composition
Eucalyptol was selected after screening commercially available topical cooling agents, including TRPM8 agonists such as menthol, eucalyptol, WS-3, and icilin. Formulation stability, homogeneity, cooling effect, and irritation potential were evaluated. The concentration of 0.4% was selected based on a preliminary dosage study performed at our institution, in which eucalyptol concentrations ranging from 0.1% to 1.0% were evaluated on the skin of 30 healthy subjects. 0.4% was the minimum concentration required to produce a cooling sensation without causing irritation symptoms such as pain or discomfort.
The two ointments used in this study were prepared as a moisturizing cream base to facilitate active massage by patients. A 20% concentration of silicone was selected for both, based on the concentrations (10–60 wt%) reported in previously patented medical silicone gel products [11,12]. Silicone polymer was heated to 80 °C and homogenized, to which hydrophilic components including purified water, glycerin, and niacinamide were added and again homogenized. For the eucalyptol group, eucalyptol was added at a concentration of 0.4% (w/w).
These creams were packaged in ointment tubes and stored at room temperature until use. To minimize bias, both the silicone-only formulation and the eucalyptol-containing formulation were packaged in the same type of tube with identical appearance.
Physicochemical stability evaluation
The formulations were visually inspected for appearance, color, and impurities. Viscosity was measured using a Brookfield viscometer under standardized conditions. Acidity (pH) and specific gravity were assessed, and accelerated stability testing was conducted at 5 °C, 25 °C, and 40 °C for 48 hours to evaluate phase separation. All ointments appeared as homogeneous white cream preparations without visible impurities. No phase separation or instability was observed during accelerated stability testing under temperatures ranging from 5 °C to 40 °C for 48 hours.
Patient inclusion criteria and allocation
A prospective comparative pilot study was performed in a total of 30 adult patients with donor-site scars following split-thickness skin graft (STSG). Inclusion criteria were patients aged 19 or older who had STSGs harvested from their thigh areas. STSGs were performed by a single surgeon who used a Zimmer pneumatic dermatome for 0.25 mm to 0.50 mm thick grafts. Patients were randomly assigned by lottery to either a 20% silicone-only group or a 20% silicone plus 0.4% eucalyptol group. Application of the cream began at 2 to 4 weeks after complete epithelialization of the donor site. Immediately after epithelization, the epithelium is quite thin and may be vulnerable to friction applied during massage. Therefore, a 2- to 4-week interval allowed the donor-site skin to become sufficiently mature and mechanically stable before initiation of topical scar treatment.
Exclusion criteria were systemic comorbidities such as renal failure, diabetes, autoimmune diseases, malignancies, peripheral artery disease, or neuropathy. Administration of antihistamines or steroids for other causes was also criteria for exclusion. Patients who sustained infection signs on their donor sites, along with subjects who did not complete the 3-month follow-up period, were also excluded.
Evaluation parameters
The first application of the cream was done by the surgeon during outpatient follow-up, lightly applying a layer of the cream over the entirety of the donor scar. Patients were informed beforehand to report when any cooling sensation was perceived, which was timed with a stopwatch by the outpatient clinic nurse. Patients were revisited at 5 minutes and asked to report a subjective degree of how much the cooling sensation had decreased. Patients were also asked to report any pain, stinging, discomfort or irritation.
Patients were educated to apply the cream twice daily, every single day, for the following 3 months, and told to check how many times they missed application to report at their regular outpatient visits. Visits were scheduled on different intervals depending on the requirement of the other wounds, but were usually once every 2 weeks.
At the 3-month visit, patients were independently evaluated by two blinded medical doctors using the Vancouver Scar Scale (VSS). The average score of the two assessments was used for statistical analysis. VSS consists of the variables vascularity, pigmentation, pliability, and height and has a total score of 0 to 13, with higher scores implying a higher degree of hypertrophy and visibility [13]. Patients were asked to fill out the Visual Analog Scale (VAS) for subjective pruritus evaluation. The pruritus VAS is a visual linear scale from 0 (no itching) to 10 (worst imaginable itching) [14]. The primary outcome measure was the pruritus VAS score at 3 months. Secondary outcomes included cooling sensation, treatment adherence, adverse effects, and VSS scores.
Statistical analysis
Continuous variables are presented as mean±standard deviation (SD). Comparisons between the silicone-only group and the combined ointment group were performed. Continuous variables were analyzed using the Mann-Whitney U test, whereas categorical variables were analyzed using the chi-square test. A P-value <0.05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics version 26.0 (IBM Corp.).
Results
A total of 30 patients with thigh STSG donor-site scars were enrolled in the study. Patients were randomly assigned by lottery to either the 20% silicone-only group or the 20% silicone plus 0.4% eucalyptol group. Fifteen patients were allocated to the 20% silicone-only group, and 15 patients were in the 20% silicone and 0.4% eucalyptol group. Baseline demographic characteristics, including age and sex distribution, did not significantly differ between the two groups. The silicone-only group had a mean age of 46.8±12.1 years and consisted of eight male and seven female patients, whereas the silicone and eucalyptol group had a mean age of 44.9±11.4 years and consisted of nine male and six female patients.
Seven patients required coverage of flap donor sites with exposed muscle fascia or subcutaneous tissue. Three patients required burn reconstruction and three patients needed coverage for oncological skin defects, while 17 patients required coverage for lower extremity trauma wounds.
Immediate (<30 seconds) cooling sensation was perceived by all 15 patients in the 20% silicone and 0.4% eucalyptol-combined ointment upon initial application. Most reported cooling at 5 seconds after the cream had contacted their scar. At 5 minutes after application, the patients reported a 50% decrease of the intensity of cooling, with no patients reporting irritation, stinging, discomfort or pain. None of the patients in the 20% silicone-only group described perception of cooling, and none described irritation, stinging, discomfort or pain either.
At 3 months, total VSS scores evaluated by two blinded medical doctors were as follows: the total score for the silicone-only group was 4.3±1.2 (mean±SD), and 4.0±1.1 for the silicone–eucalyptol group (P=0.412). The mean difference between groups was 0.3 points (95% confidence interval [CI], −0.52 to 1.12), indicating no statistically significant difference in scar outcomes (Figs. 1, 2). For individual VSS parameters, vascularity scores were 1.1±0.5 and 1.0±0.4 (P=0.538), pigmentation scores were 0.8±0.4 and 0.7±0.5 (P=0.621), pliability scores were 1.6±0.7 and 1.4±0.6 (P=0.447), and height scores were 0.8±0.5 and 0.9±0.4 (P=0.732) in the silicone-only group and the combination group, respectively. Demographic characteristics and clinical outcomes are summarized in Table 1.
The pruritus VAS score was 5.1±1.4 for the silicone-only group, whereas it was 2.8±1.0 for the silicone–eucalyptol group (P=0.003). The mean difference between groups was 2.3 points (95% CI, 1.43–3.17), demonstrating a significant reduction in pruritus in the combined ointment group. In some cases, the patients had inadvertently scratched their wounds, resulting in disruption of the healing process and crust formation (Fig. 2). Patient compliance was assessed based on self-reported missed cream applications during outpatient follow-up visits. Treatment adherence was significantly improved in the silicone and eucalyptol combination group. The average number of missed cream applications per week was significantly lower in the combination group compared with the silicone-only group (1.8±1.0 vs. 4.2±1.5; P=0.001). The mean difference was 2.4 missed applications per week (95% CI, 1.49–3.31).
Discussion
Silicone-based therapies remain the cornerstone of conservative scar management and are widely used for prevention and treatment of hypertrophic scars [15]. However, patient discomfort associated with prolonged occlusion frequently discourages long-term adherence. This study was conducted to overcome the inherent limitations of conventional silicone-based scar therapies, particularly discomfort caused by occlusion-related heat sensation and pruritus. By incorporating eucalyptol, a TRPM8 agonist, into a silicone-based topical ointment, we aimed to maintain the anti-scarring properties of silicone while improving patient comfort and treatment adherence [6].
Eucalyptol (1,8-cineole) is a naturally occurring bicyclic monoterpene ether found in a variety of aromatic plants, particularly the species of Eucalyptus. This substance has been widely investigated to exert anti-inflammatory, antimicrobial, and analgesic effects [16,17]. Eucalyptol activates TRPM8 receptors, which are ion channel receptors located on sensory nerve endings which respond to cool temperatures and other specific agonists such as eucalyptol or menthol. Such agonists open the ion channels to an intracellular Ca2+ and Na+ influx, triggering action potentials that send cooling sensation signals to the brain. These agonists can achieve this effect without excessively lowering skin temperature [8]. Eucalyptol also inhibits transient receptor potential ankyrin 1, which results in an analgesic effect [18]. TRPM8 activation may contribute to modulation of neural pathways associated with pruritus signaling, including gastrin-releasing peptide receptor-related pathways [10,19]. Through these mechanisms, eucalyptol can provide a cooling sensation and has the potential to inhibit pain and pruritus, thereby improving subjective symptoms commonly observed in hypertrophic scars [4,20].
Table 1
Demographic characteristics and scar outcomes after 3 months of treatment
The results of this pilot study demonstrated that adding eucalyptol to conventionally proven silicone therapy maintained the hydration-maintaining and fibroblast-regulating effects of silicone, while simultaneously providing clinically meaningful cooling sensation and preventing pruritus [6]. It should be noted that the silicone-only ointment also demonstrated favorable scar outcomes, which is consistent with the well-established moisturizing and occlusive effects of silicone-based scar therapies. Therefore, the observed improvement in patient comfort and treatment adherence in the eucalyptol-containing group should be interpreted as an adjunctive benefit rather than a replacement for the established anti-scarring effects of silicone.
Although no significant difference in total VSS score was observed between the groups, the addition of eucalyptol was associated with significantly reduced pruritus and improved treatment adherence. These findings suggest that symptom control may contribute to sustained use of silicone-based scar therapy. Because long-term adherence is essential for the effectiveness of conservative scar management, improving patient comfort may represent a clinically meaningful benefit even when scar severity scores remain comparable.
The authors acknowledge that this pilot study has several limitations. First, the sample size was relatively small, and objective quantitative measurements such as transepidermal water loss or ultrasound-based scar thickness analysis were not performed. Therefore, the absence of statistically significant differences in VSS scores should not be interpreted as evidence of equivalence between treatments. Furthermore, baseline VSS measurements were not obtained prior to treatment initiation. Long-term efficacy beyond 3 months was not evaluated because many patients experienced difficulty maintaining regular follow-up beyond 4 months. Compliance was also subjectively self-reported, allowing for the possibility of recall bias. The inclusion criteria allowed enrollment of healthy subjects only, and therefore real-world data encompassing perception of individuals who have systemic comorbidities was not evaluated. In addition, inter-rater reliability statistics for VSS assessment were not calculated, which may limit interpretation of the consistency of scar evaluation.
Nevertheless, the present formulation demonstrated potential as a symptom-oriented adjunctive therapy for improving comfort and adherence during scar management. The addition of eucalyptol to silicone-based creams may alleviate pruritus-related discomfort, thereby enhancing compliance with topical scar treatment. Future large-scale studies with longer follow-up periods are warranted to validate long-term efficacy and safety.
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