Numerous methods have been developed to achieve minimal scarring after surgery. One effective method to make a scar finer and subdermal suturing, is widely used in plastic surgery to release tension on the wound edge. Tension on the wound is said to make the scar worse, and it sometimes becomes a cause of hypertrophic scaring and keloids. Because it takes more than six months for a scar to be fixed, taping is usually used after surgery to prevent worse scarring.
For skin closure, skin adhesives are sometimes used instead of skin sutures for their ease of use and lack of a need for removal of sutures or staples. Among skin adhesives, Dermabond AdvancedÒ (Ethicon, Inc., Somerville, New Jersey)   is used worldwide. However, the low viscosity of Dermabond AdvancedÒ may compromise its ability to keep the wound at rest to release tension on the wound. Also, because of its low viscosity, the Dermabond AdvancedÒ material has the potential to flow into the wound, which may disrupt wound adhesion.
EpinexusTM (Mitsui Chemicals, Inc., Tokyo), the skin adhesive used for this study, was developed to prevent these risks. It is constructed primarily with polymethylmethacrylate, and it is biocompatible with appropriate viscosity according to its polymerization by mixing a methylmethacrylate monomer, polymethylmethacrylate powder, and polymerization initiator immediately prior to use  . EpinexusTM is hard enough to keep the wound at rest after it becomes stiff. Therefore there were no reports using EpinexusTM in clinical use so far; we have published the results of a pilot study of EpinexusTM that showed its safety for application to the suture  . The current single-center, open-label, and parallel-group study compared the efficacy, safety, and cosmetic outcome of EpinexusTM with Dermabond AdvancedÒ in 59 subjects.
2. Materials and Methods
EpinexusTM, an acrylate skin adhesive, consists of a prefilled syringe containing polymer powder, 2 prefilled vials containing monomer liquid and polymerization initiator, respectively, a transfer needle for mixing the above 3 ingredients, and an application nozzle (Figure 1). The operators’ technique was standardized by preliminary training based on the description in the package insert and during the first study  . All of the operators had experiences more than 10 years in surgery field. The patients were randomly assigned two groups (the EpinexusTM group (EG) and the Dermabond AdvancedÒ group (DG)). The primary endpoint was cosmetic outcome at 52 weeks after treatment (Manchester Scar Scale)   , and the secondary endpoints were cosmetic outcome at 4 and 26 weeks after treatment (Manchester Scar Scale), wound closure, and usability. We evaluated 59 patients (29 cases and 30 controls). In addition, failures and adverse events were appropriately evaluated in accordance with the Japanese version of the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI) (Japan Clinical Oncology Group/Japan Society of Clinical Oncology: JCOG/JSCO v.4.0). Eligibility criteria were as follows: 1) male or female adults aged 20 or older, 2) no diseases that affect wound closure based on medical history, and no recently used or concomitant medications, 3) expecting a surgical incision of 2 - 6 cm, 4) underwent tumor removal at the Department of Breast Surgery or Plastic Surgery, 5) voluntarily agreed to participate in the
Figure 1. EpinexusTM Components.
study and submitted signed, written informed consent, and 6) agreed to visit the medical institution for the follow-up evaluation. This study was conducted in Keio University School of Medicine from 2015-2017.
2.1. Ethical Considerations
This study was conducted in compliance with the ethical principles based on the Declaration of Helsinki, the Ethical Principles for Medical Research Involving Human Subjects (6th revision, Seoul, 2008), and the Ethical Guidelines for Clinical Studies (Japan Ministry of Health, Labour and Welfare, Notification No. 415, July 31, 2008). This study was reviewed and approved by the Ethical Review Board of Keio University in advance (approval code No. 20140391). The subjects were given sufficient explanation on the informed consent form and voluntarily submitted a signed, written informed consent form at least 2 days prior to surgery. Careful consideration was paid to the protection of the privacy and personal information of the subjects.
2.2. Statistical Analysis
The Full Analysis Set (FAS) was defined as all enrolled subjects except those who did not use EpinexusTM or whose data were not available for the endpoints. The Per Protocol Set (PPS) contained subjects included in the Full Analysis Set except those in whom efficacy was difficult to evaluate or who were found to meet the exclusion criteria or deviated from the protocol after enrollment.
The FAS was used for the safety analysis. Data for the safety endpoints were accumulated from the start date to the end or discontinued date of the use of EpinexusTM. The PPS was used for the efficacy analysis. The number of subjects with or without wound dehiscence and their percentages were calculated, respectively. Cosmetic outcomes at 4 weeks ± 7 days, 24 weeks ± 14 days, and 52 weeks ± 28 days were evaluated with the Manchester Scar Scale by 2 sub-investigators. For the comprehensive evaluation of the wound, the length to the mark on the 10-cm Visual Analog Scale (VAS) was measured, and 1 cm was calculated as 1 point. The VAS score was added to the total score of the individual endpoints for the final Manchester Scar Scale result. The mean value of the scores of the 2 sub-investigators was calculated for each subject, observation time point, and endpoint, and then the mean, maximum, and minimum values were determined for each endpoint for the PPS.
To ensure the objectivity of this study, a safety and efficacy evaluation committee was established separately, in advance, to evaluate wound closure, cosmetic outcome, usability, and safety for all subjects.
Of the 63 enrolled subjects, 1 was excluded because the application site was found not to meet the inclusion criteria after enrollment. As a result, the number of subjects in both the FAS and the PPS was 62 (Figure 2).
The demographic and baseline clinical characteristics of the EpinexusTM group (EG) and the Dermabond AdvancedÒ group (DG) did not show any statistically significant differences (Table 1). These characteristics included gender, original
Table 1. Patient background.
Figure 2. Patient Disposition.
disease, height, body weight, past history, allergies, and concomitant medications. The two groups did not show any differences in physical examinations.
We observed 47 adverse events in 28 subjects (17 EG and 11 DG). None of the adverse events was severe. Among them, 8 cases (5 EG and 3 DG) were considered related to treatment (Table 2). In 4 cases (3 EG and 1 DG), erosion was observed. Two cases of non-adhesion were observed in the DG group. All cases of erosion were resolved by applying ointment to the affected sites.
With regard to the evaluation of usability, usage times for both treatment and application were significantly longer in the EG (Table 3). The ease of application was significantly better in the DG (Table 4).
With regard to cosmetic results, there were no significant differences between groups at 24 and 52 weeks (Table 5 and Table 6). However, at 4 weeks after application, the cosmetic results were significantly better in the EG (Table 7). Five cases discontinued the observations (Table 8).
Table 2. Treatment-related adverse events.
Table 3. Time needed for treatment (sec).
p < 0.0001.
Table 4. Ease of treatment.
Table 5. Cosmetic evaluation at 24 weeks.
Table 6. Cosmetic evaluation at 52 weeks.
Table 7. Cosmetic evaluation at 4 weeks.
p < 0.05.
Table 8. Discontinuations
The purpose of this study was to compare the efficacy and safety of EpinexusTM with Dermabond AdvancedÒ. We observed that the EG had a higher incidence of epidermolysis. As EpinexusTM is designed to have high viscosity and to be more adherent to the skin, these features may have contributed to the increased frequency of epidermolysis. Also, because EpinexusTM is designed to fix the wound firmly, it is harder than Dermabond AdvancedÒ. Thus, in some cases, erosion at the margin of the application site was observed. As for non-adhesion, two cases were observed in the DG. Non-adhesion may have resulted from the flow of the solution into the wound.
The usability was significantly better in the DG. EpinexusTM requires several steps before application and requires more time to set. Ease of use is an important factor in surgery; thus, EpinexusTM should be made easier to use in the future.
Interestingly, the cosmetic results at 4 weeks were significantly better in the EG than in the DG. We used the Manchester scale for the evaluation of scars; this scale is usually used for mature scars, and it contains no elements for the evaluation of acute inflammation. Thus, it is impossible to determine why the evaluators found differences between the two methods. Large differences in redness sometimes occur at 4 weeks after surgery and reflect the amount of acute inflammation. During the course of scar rearrangement, differences may be counteracted that could not be evaluated with the Manchester scar scale. Although using EpinexusTM needs attention to epidermolysis, in our study, EpinexusTM showed the same efficiency and safety as existing product (Dermabond AdvancedÒ).
NCI: National Cancer Institute.
CTCAE: Common Terminology Criteria for Adverse Events.
JCOG/JSCO: Japan Clinical Oncology Group/Japan Society of Clinical Oncology.
FAS: Full Analysis Set.
PPS: Per Protocol Set.
VAS: Visual Analog Scale.
EpinexusTM: The product name of the investigational device, a skin adhesive manufactured by Mitsui Chemicals, Inc.
Manchester Scar Scale: Each of these parameters was given a score from 1 to 4, with increasing values indicating increasing scar severity. Whether a scar was matte or shiny was also recorded, the former scoring 1 and the latter 2. An overall assessment was also made and indicated on a visual analogue scale as a vertical mark on a 10-cm line, with 0 indicating an excellent scar and 10 indicating a poor scar. This score, expressed in centimeters to one decimal place, was then added to the sum of the individual parameter scores to give an overall score for each scar. The overall score ranged from 5 to 28, with low scores representing clinically well healed scars of good cosmetic appearance and high scores representing clinically poor scars.