A systematic review evaluating the influence of incisional Negative Pressure Wound Therapy on scarring

Abstract Pathological scars can result in functional impairment, disfigurement, a psychological burden, itch, and even chronic pain. We conducted a systematic review to investigate the influence of incisional Negative Pressure Wound Therapy (iNPWT) on scarring. PubMed, EMBASE and CINAHL were searched for preclinical and clinical comparative studies that investigated the influence of iNPWT on scarring‐related outcomes. Individual studies were assessed using the OHAT Risk of Bias Rating Tool for Human and Animal studies. The body of evidence was rated using OHAT methodology. Six preclinical studies and nine clinical studies (377 patients) were identified. Preclinical studies suggested that iNPWT reduced lateral tension on incisions, increased wound strength, and reduced scar width upon histological assessment. Two clinical studies reported improved patient‐reported scar satisfaction as measured with the PSAS (1 year after surgery), POSAS, and a VAS (both 42, 90, and 180 days after surgery). Five clinical studies reported improved observer‐reported scar satisfaction as measured with the VSS, SBSES, OSAS, MSS, VAS, and POSAS (7, 15, 30, 42, 90, 180, and 365 days after surgery). Three clinical studies did not detect significant differences at any point in time (POSAS, VAS, and NRS). Because of imprecision concerns, a moderate level of evidence was identified using OHAT methodology. Preclinical as well as clinical evidence indicates a beneficial influence of iNPWT on scarring. Moderate level evidence indicates that iNPWT decreases scar width and improves patient and observer‐reported scar satisfaction.

the US alone, 170 000 scar revisions are performed each year. 9 Incisional Negative Pressure Wound Therapy (iNPWT) is an increasingly applied treatment of surgical incisions, that has been shown to prevent postoperative wound complications such as surgical site infection and wound dehiscence. 10,11 Although it has been suggested that iNPWT may result in improved scar quality, 12 the effect of iNPWT on scar formation still remains unclear. The aim of this paper is to systematically review preclinical and clinical studies that have investigated the influence of iNPWT on scar-related outcomes. We hypothesize that iNPWT improves scar quality and reduces the formation of pathological scars.

| MATERIALS AND METHODS
This systematic review and meta-analysis was performed in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 13  Preclinical and clinical studies that investigated the influence of iNPWT on scar-related outcomes were included. Outcomes of scar scales and quantitative measurements of wound/scar properties were regarded as relevant scar-related outcomes. As excessive lateral tension around incisions increases the likelihood of pathological scar formation, 14 we also included studies that performed finite element analyses in order to predict the influence of iNPWT on lateral incisional tension. Articles in languages other than English, German, and French were excluded, as were duplicates, congress abstracts, and articles without original data. References from included articles were also assessed for potential inclusion.
Two reviewers (P.R.Z. and F.W.T.) critically appraised each study using the Office of Health Assessment and Translation (OHAT) Risk of Bias Tool for Human and Animal Studies. We chose this tool because it allows for assessment of both animal as well as human clinical studies through a single framework. Discrepancies were resolved through discussion to reach a final risk of bias rating for each item, as guided by the instructions provided in the OHAT Handbook. 15 Based on the design of an individual study, a number of items were rated to be at "definitely high," "probably high," "probably low," or "definitely low" risk of bias.
When studies did not report the necessary information "NR" (not reported) was recorded. One reviewer (P.R.Z.) extracted data in predefined evidence tables, that were checked subsequently by a second reviewer (F.W.T.). Disagreements were resolved through discussion until reach of consensus. Data collection included study characteristics and study outcomes such as results of finite element analyses, biomechanical tests, quantitative scar measurements, and patient and observer-reported scar satisfaction assessments. We graded our confidence in the body of evidence using OHAT methodology, 15 an adaptation of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group guidelines.

| Statistical analysis
The extracted data was summarized in tables. A meta-analysis was planned in case studies reported the same outcome. Reported values represent means from individual studies unless reported otherwise.
Standard errors from individual studies are abbreviated as "SE," whereas standard deviations are abbreviated as "SD." 3 | RESULTS

| Systematic review
The search strategy resulted in 6094 records. After removal of duplicates (n = 2108), 3986 records were screened by two independent reviewers (P.R.Z. and B.T.T.), and 3810 records were excluded based on title and abstract. A total of 176 full text articles was assessed for eligibility, after which 15 articles were included. An overview of the systematic review process is presented in Figure 1.

| Preclinical studies: Finite element analyses
Two studies aimed to assess the effects of iNPWT on mechanical stress applied to incisional tissue by use of computer models, that is, finite element analyses (FEAs). 12,20 Wilkes et al used two FEA models with −125 mmHg of subatmospheric pressure; one concerning an incision with a subcutaneous void, and another model that incorporated fascial separation. 12 In the first model, lateral tension at the skin level was reduced from 2.2 to 2.5 kPa, to 0.9 to  Table 1.

| Clinical studies: Quantitative scar measurements
Nagata et al measured the scar width of 13 incisions of women undergoing tissue expansion for breast reconstruction, where they randomized half of the incisional wound to iNWPT, and the other half to film dressing treatment. All patients received a minimum of 42 days of treatment (average 58.5, range 42-81 days). Scar width was measured by using photographic image analysis after 6 months, and demonstrated a decreased scar width to be associated with iNPWT (2.92 vs 4.75 mm, P = .0015). 21 Although the paper did not provide numeric values, scars treated with iNPWT were also reported to be softer as measured with a scanning acoustic microscope (a technique used to measure tissue elasticity). 21 Tanaydin et al measured scar viscoelasticity, skin water content, and transepidermal water loss on POD 42, 90, 180, and 365 of 32 women undergoing bilateral breast reduction mammoplasty. Through randomization, each side received either iNPWT or fixation strips. They reported that skin viscoelasticity, transepidermal water loss, and hydration measurements did not show significant improvement with iNPWT (the paper only provided graphs, numeric values were not provided). 23

| Clinical studies: Patient-reported scar evaluation
Four clinical studies (142 patients) assessed patient-reported scar satisfaction. 22,23,27,28 These studies included two RCTs 22,23 and two prospective comparative studies. 27,28 In the observational study by itchiness, color, stiffness, thickness, irregularity, or total score), nor did they detect a difference in VAS-measured scar appearance (6.9, SD 2.5 vs 7.1, SD 2.1, P = .795). 28   Explanation Initial rating: As the exposure was experimentally controlled, occurred prior to the development of the outcome, and the outcome was assessed on the individual level with appropriate comparisons, the body of evidence received a high initial rating.

Risk of bias:
As the body of evidence also included randomized studies with blinded outcome assessment, we did not downgrade because of risk of bias. Unexplained inconsistency: Although not all studies indicated a significant benefit of iNPWT on scar formation, we consider it unclear whether this is the result of the limited sample sizes, a lack of an effect, or other causes, and therefore did not downgrade because of unexplained inconsistency. Directness and applicability: All studies their methodology was also aimed at addressing scar-related outcomes, we did not downgrade because of indirectness. Imprecision: We considered all studies to have limited sample sizes (all less than 100 participants). In order to detect subtle differences in scar formation at 1 year postoperatively, we presume large sample sizes to be required. As a result, we downgraded because of imprecision concerns.
Publication bias: Although a considerable amount of studies reported they had received industry support, we did not detect evident signs of publication bias. Magnitude: Because of the limited amount of evidence we did not upgrade because of effect magnitude. Dose-response relationship: The included studies did not present data to evidently suggest the presence of a dose-response relationship.
Residual confounding: Some studies excluded patients that developed wound complications. This could be considered residual confounding. Yet, because of the limited amount of identified evidence, we did not upgrade because of residual confounding.
Study consistency: The body of evidence exhibits incongruences between studies, with some clinical studies reporting improvements, while other studies report an absence of any effect of iNPWT. We therefore did not consider an upgrade to be justified.

| Safety and iNPWT-related adverse events
No adverse reactions related to iNPWT were reported by any of the included studies.

| Level of evidence
Because the exposure (iNPWT) was experimentally controlled, occurred prior to the development of the outcome, and the outcome was assessed on the individual level, the body of evidence received an initial "high confidence" rating. Because most studies had small sample sizes, we downgraded the level of evidence because of imprecision concerns. Ultimately, we identified a "moderate" level of evidence. An overview of the rating process according to the OHAT approach is presented in Table 3.
Preclinical studies indicated that iNPWT reduced incisional tension, 12,20 increased the amount of force needed to disrupt incisions, [16][17][18] and decreased scar/granulation tissue width as judged by photographic assessment 19 and blinded histological specimen measurement. 17,18 Nevertheless, all preclinical evaluations were performed within 40 days after surgery; long-term outcomes would be more appropriate but less feasible in experimental settings.
Clinical scar width measurements 6 months after surgery indicated a reduced scar width after more than 6 weeks of iNPWT (13 patients In addition, postoperative wound complications such as wound dehiscence, surgical site infection, or skin necrosis are also notorious causes of pathological scar formation. 32 As several metaanalyses indicate that iNPWT reduces the incidence of these postoperative wound complications, 10,33 there is a substantial amount of indirect evidence to suggest a beneficial effect of iNPWT on scar quality in general. This systematic review has several limitations. One finding of our systematic review is that differences between groups seem to become increasingly difficult to detect with time, as many small studies could not detect an effect after 1 year of surgery, whereas the effect remained intact in the larger study. 26 Yet, most studies had limited sample sizes and length of follow-up, and scar-related outcomes were a secondary outcome in most of the identfied studies. We did not identify any study that performed an a priori sample size calcution for a scar formation-related outcome. A considerable number of studies reported they had received industry funding (9 of 15 studies). 12,[16][17][18][19][20]23,25,28 When considering the patient-specific nature of scar formation, another methodological limitation of the present literature is the limited evidence available from intra-patient controlled studies (only two small studies were identified). 20,22 Quantitative clinical scar measurements were only available for a limited amount of patients. A meaningful meta-analysis could not be performed because of methodological heterogeneity. Because of the scarcity of reports that provided outcomes for specific scar scale domains, a meaningful analysis of distinct domains (such as pain, itch, or scar appearance) was also precluded.
Although a beneficial effect of iNPWT on scar quality seems to be present, the evidence is of moderate level because it suffers from imprecision due to insufficient number of patients. Moreover, only one study addresses cost-effectiveness of iNPWT. Although Abatangelo et al report that iNPWT reduces the total costs for management of local wound complications ($750 vs $1066), their study has a limited sample size of only 11 patients. Ideally, an adequately powered intra-patient controlled RCT with adequate length of followup and cost-effectiveness analysis should be performed in order to confirm or refute the results of this systematic review.
The evidence summarized in this review suggests that iNPWT seems to reduce pathological scar formation and improve scar quality.
Incisional NPWT also seems to reduce the risk of other postoperative wound complications, 10