Hypertrophic Scars and Keloids

Number: 0389

Policy

Aetna considers intralesional 5-fluorouracil, cryotherapy or corticosteroids medically necessary for treatment of keloids where medical necessity criteria for keloid removal are met.  See CPB 0031 - Cosmetic Surgery, for medically necessary indications for keloid removal.

Aetna considers the following interventions experimental and investigational for the treatment of hypertrophic scars or keloids because of insufficient evidence in the peer-reviewed literature:

  • Adipose-derived stem cell
  • Anti-vascular endothelial growth factor therapy (e.g., bevacizumab)
  • Autologous fat grafting
  • Basic fibroblast growth factor
  • Calcium antagonists
  • Combined micro-plasma radiofrequency with hypo-fractionated electron-beam radiation
  • Dermal substitutes
  • Extracorporeal shock wave therapy
  • Fractional ablative laser (for the treatment of burn scar)
  • Growth hormone-releasing peptide 6
  • Hyaluronidase
  • Hyperbaric oxygen therapy
  • Imiquimod cream
  • Intense pulsed light
  • Interferon alpha (see CPB 0404 - Interferons)
  • Interleukin-10
  • Intermittent magnetic pressure therapy
  • Intralesional bleomycin
  • Intralesional botulinum toxin type A injection
  • Intralesional fiber laser device (for the treatment of keloids)
  • Intralesional mitomycin
  • Laser-assisted administration of corticosteroid
  • Losartan ointment
  • Mesenchymal stem cells
  • Micro-needling (with Dermapen disposable tips or other devices/tools)
  • Non-ablative fractional laser
  • Photodynamic therapy
  • Radiofrequency treatment
  • Silicone products (e.g., gel, rigid shells, sheeting)
  • Topical calcipotriol
  • Topical oxandrolone
  • Topical retinoids
  • Transforming growth factor beta1

Aetna consider high-frequency ultrasound and shear wave elastography experimental and investigational for quantitative assessment of treatment efficacy in keloids because their effectiveness for this indication has not been established.

See also CPB 0062 - Burn GarmentsCPB 0244 - Wound CareCPB 0551 - Radiation Treatment for Selected Nononcologic Indications, and CPB 0559 - Pulsed Dye Laser Treatment.

Background

Keloids and hypertrophic scars develop as a result of a proliferation of dermal tissue following skin injury, and are common (keloids develop in 5 % to 15 % of wounds).

Topical silicone gel sfheeting is a soft, slightly adherent, semi-occlusive covering which is fabricated from medical grade silicone polymers.  Topical silicone gel sheeting is used to reduce the volume and increase the elasticity of hypertrophic and keloid scars, as a dressing for both donor and recipient sites in skin grafting, fand as a treatment of burn wounds.

Examples of brands of silicone gel sheeting available over-the-counter include: Sil-K, Cica-Care, ReJuveness, DuraSil and Silastic Gel Sheeting. Epi-Derm brand of silicone gel sheeting is currently available only by prescription, although the manufacturer of Epi-Derm is pursuing Food and Drug Administration (FDA) clearance for over-the-counter marketing.

Silicone has also been applied as a gel or as rigid custom-molded shell to scars, burns, and skin grafts.  Although several case series have reported improvements in the appearance (scar size, erythema, elasticity) and symptoms (pruritus, burning pain) from the application of silicone sheets, gels, or shells to hypertrophic scars and keloids, these promising results have not been confirmed by subsequent prospective randomized controlled trials (RCTs).  Prospective RCTs of silicone products in treatment of hypertrophic scars and keloids are limited, and the outcomes of these studies have not consistently demonstrated a clinically significant benefit of silicone products in treating hypertrophic scars or keloids over standard wound dressings.

In an open-label pilot study, Lacarrubba et al (2008) assessed the effectiveness and tolerability of a silicone gel in the treatment of hypertrophic scars.  A topical self-drying silicone gel containing polysiloxane and silicone dioxide was applied twice-daily in 8 hypertrophic scars.  After 6 months, all lesions showed evident clinical and/or ultrasound improvement, with a mean scar thickness reduction of 37 % (range of 20 % to 54 %).  The authors stated that although controlled trials in larger series of patients are necessary, these findings suggested that the self-drying silicone gel may represent a safe and effective treatment for hypertrophic scars.

In a prospective, single-blind, RCT, Wittenberg et al (1999) evaluated the effectiveness of the 585-nm flashlamp-pumped pulsed-dye laser and silicone gel sheeting in the treatment of hypertrophic scars in lighter-skinned and darker-skinned patients: 19 completed the laser treatments and 18 completed the silicone gel sheeting treatments.  Clinical measurements included hypertrophic scar blood flow, elasticity, and volume.  Patients' subjective complaints of pruritus, pain, and burning were also monitored.  Histological assessment of fibrosis, number of telangiectasias, and number of mast cells was performed.  Statistically significant improvements in clinical measurements and patients' subjective complaints determined treatment success.  These investigators concluded that clinical results demonstrate that the improvements in scar sections treated with silicone gel sheeting and pulsed-dye laser were no different than those in control sections.

In a discussion of treatment of keloids, Quintal (2002) concluded that “[m]ore in-depth, controlled research is needed to prove or disclaim the therapeutic effect of silicone.”  A recently published systematic review of the literature on treatment of keloid scars concluded that “[t]he effectiveness of silicone gel sheeting and other occlusive dressings in treating keloidal scars cannot be confirmed by existing studies” (Shaffer et al, 2002).

The FDA (2004) classified silicone sheeting intended for use in the management of closed hyper-proliferative (hypertrophic and keloid) scars into class I (general controls).  As a class I device, the device will be exempt from premarket notification requirements.

In a prospective, randomized, placebo-controlled, clinical trial that examined the use of silicone gel in preventing hypertrophic scar development in median sternotomy wound, Chan et al (2005) concluded that the effect of silicone gel in the prevention of hypertrophic scar development in sternotomy wounds is promising.  In a recent review on keloid pathogenesis and treatment, Al-Attar and colleagues (2006) noted that established treatment strategies for keloids include surgery, steroid, and radiation (silicone was not listed as an established treatment for keloids).

A structured assessment of the evidence of silicone gel sheeting for preventing and treating hypertrophic scars and keloids prepared for the Cochrane Collaboration reached the following conclusions (O'Brien and Pandit, 2006): “Trials evaluating silicon gel sheeting as a treatment for hypertrophic and keloid scarring are of poor quality and highly susceptible to bias.  There is weak evidence of a benefit of silicon gel sheeting as a prevention for abnormal scarring in high risk individuals but the poor quality of research means a great deal of uncertainty prevails.”

Stavrou et al (2010) stated that hypertrophic and keloid scars still are among the banes of plastic surgery.  In the treatment arsenal at the disposal of the plastic surgeon, topical silicone therapy usually is considered the first line of treatment or as an adjuvant to other treatment methods.  Yet, knowledge concerning its mechanisms of action, clinical efficacy, and possible adverse effects is rather obscure and sometimes conflicting.  The author summarized the existing literature regarding the silicone elastomer's mechanism of action on scars, the clinical trials regarding its efficacy, a description of some controversial points and contradicting evidence, and possible adverse effects of this treatment method.  Topical silicone therapy probably will continue to be the preferred first-line treatment for hypertrophic scars due to its availability, price, ease of application, lack of serious adverse effects, and relative efficacy.  Hopefully, future RCTs will help to clarify its exact clinical efficacy and appropriate treatment protocols to optimize treatment results.

In a single-center placebo-controlled double-blind trial, Stoffels et al (2010) examined the impact of silicone spray on scar formation.  These investigators reported that after 3 months of treatment the Patient Scar Assessment Scale demonstrated that patient satisfaction with the silicone application was significantly higher compared to placebo.  However, when treatment was stopped after 3 months, the topical silicone spray did not exhibit any lasting long-term impact on the objective results of scar formation.

In a review on "Prevention and management of keloid scars", Lutgendorf et al (2011) noted that "[a]lthough silicone gel sheeting is a well-accepted treatment modality, the studies to date provide level IV evidence, with a lack of controls and increased susceptibility to bias.  A recent Cochrane systematic review on the use of silicone gel sheeting for preventing and treating hypertrophic and keloid scars found that any effects were obscured by the poor quality of research".

Several clinical trials have demonstrated the effectiveness of intralesional 5-fluorouracil in the treatment of keloid scarring (Asilian et al, 2006; Nanda and Reddy, 2004; and Manuskiatti and Fitzpatrick, 2002).  Asilian and colleagues (2006) examined the effectiveness of a combination of intralesional steroid, 5-fluorouracil (5-FU), and pulsed-dye laser in the treatment of hypertrophic scars and keloids.  A total fo 69 patients were randomly assigned to treatment with intralesional triamcinolone acetonide (TA), intralesional TA plus intralesional 5-FU, and TA, 5-FU and pulse-dye laser treatment.  The investigators reported that, after 12 weeks, good to excellent improvements were reported by a blinded observer in 15 % of subjects treated with TA alone, 40 % of subjects treated with TA plus 5-FU, and 70 % of subjects treated with all 3 modalities.

Tosa et al (2009) stated that because intralesional injection of TA, a widely used for the treatment of keloid, is painful, many patients discontinue treatment.  These researchers evaluated the effects of pre-treatment with topical 60 % lidocaine tape on the pain and tolerability of intralesional TA treatment in patients with keloid.  The subjects were 42 patients with keloid who had been treated with intralesional injection of TA but had discontinued treatment owing to intolerable pain.  All patients were pre-treated with 60 % lidocaine tape placed on the keloids for more than 120 mins before intralesional injection of TA.  Patients assessed pain with a 100-mm visual analog scale (VAS) with 0 mm for "no pain" and 100 mm for "worst possible pain".  Pain was assessed with the VAS immediately after TA injection.  Finally, the patients assessed the tolerability of this treatment.  The mean VAS score during intralesional TA injection therapy without pre-treatment with lidocaine tape was 82.6 +/- 14.4 mm.  In contrast, the mean VAS score during intralesional TA injection therapy in the same patients after pre-treatment with lidocaine tape was 18.9 +/- 11.3 mm, which was significantly lower (p < 0.05), and 30 (71.4 %) of the patients tolerated this therapy well.  Pre-treatment with 60 % lidocaine tape significantly reduces the pain associated with intralesional injection of TA.  This approach increases patient comfort and should enable patients to continue the treatment.

Pai and Cummings (2011) examined if surgical excision with or without adjuvant treatment beneficial in reducing the size of the scar in patients with hypertrophic and keloid scarring of the sternotomy wound.  More than 15 papers were found using the reported search, of which 9 represented the best evidence to address this clinical issue.  The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated.  One of the studies showed no difference between surgery and adjunctive TA or colchicine.  One study showed that incomplete excision resulted in higher recurrence rates.  Post-operative radiation was found to be useful in 2 of the studies, although 1 study showed that it was not useful.  One RCT showed improvement after laser compared to no treatment; 2 other trials showed no difference between laser, silicone gel, intralesional steroid or 5-FU.  One trial showed that peri-operative systemic steroid application gave rise to no improvement but in fact worsened scar formation.  The authors concluded that small keloids can be treated radically by surgery with adjuvant therapy (radiation or corticosteroid injections) or by non-surgical therapy (corticosteroid injections, laser and anti-tumour/immunosuppressive agents, such as 5-fFU).  Large and multiple keloids are difficult to treat radically and are currently only treatable by multi-modal therapies that aim to relieve symptoms.

An UpToDate review on "Keloids" (Goldstein and Goldstein, 2012) states that "[i]ntralesional corticosteroids are first-line therapy for most keloids.  A systematic review found that up to 70 percent of patients respond to intralesional corticosteroid injection with flattening of keloids, although the recurrence rate is high in some studies (up to 50 percent at five years)".

Meshkinpour et al (2005) examined the safety and effectiveness of the ThermaCool TC radiofrequency system for treatment of hypertrophic and keloid scars and assessed treatment associated collagen changes.  Six subjects with hypertrophic and 4 with keloid scars were treated with the ThermaCool device: 1/3 of the scar received no treatment (control), 1/3 received one treatment and 1/3 received 2 treatments (4-week interval).  Scars were graded before and then 12 and 24 weeks after treatment on symptoms, pigmentation, vascularity, pliability, and height.  Biopsies were taken from 4 subjects with hypertrophic scars and evaluated with hematoxylin and eosin (H & E) staining, multi-photon microscopy, and pro-collagen I and III immunohistochemistry.  No adverse treatment effects occurred.  Clinical and H & E evaluation revealed no significant differences between control and treatment sites.  Differences in collagen morphology were detected in some subjects.  Increased collagen production (type III > type I) was observed, appeared to peak between 6 and 10 weeks post-treatment and had not returned to baseline even after 12 weeks.  The authors concluded that use of the thermage radiofrequency device on hypertrophic scars resulted in collagen fibril morphology and production changes.  ThermaCool alone did not achieve clinical hypertrophic scar or keloid improvement.  They noted that the collagen effects of this device should be studied further to optimize its therapeutic potential for all indications.

Davison et al (2006) ascertained the effectiveness of interferon alpha-2b in keloid management.  These investigators prospectively assessed the effects of interferon alpha-2b as post-excisional adjuvant therapy for keloids.  A total of 39 keloids in 34 patients were photographed, measured, and surgically excised.  The wound bed was injected twice with either interferon alpha-2b (treatment group; n = 13 keloids) or TA (control group; n = 26 keloids) at surgery and 1 week later.  The patients were followed- up in the plastic surgery clinic.  The trial protocol was terminated at mid-trial surveillance.  Among the 13 keloids that were treated with post-operative intralesional interferon alpha-2b, 7 recurred (54 % recurrence rate).  In contrast, in the 26 keloids that received TA (control group), only 4 recurred (15 % recurrence rate).  Recurrence in either group did not correlate with location of the keloid or race.  The authors concluded that interferon does not appear to be effective in the clinical management of keloids.  This finding is consistent with an earlier controlled trial which also found a lack of effectiveness of intralesional interferon alpha in the treatment of keloids (al-Khawajah, 1996).

Al-Attar et al (2006) reviewed the major concepts of keloid pathogenesis and the treatment options stemming from them.  They noted that mechanisms for keloid formation include alterations in growth factors, collagen turnover, tension alignment, and genetic and immunologic contributions.  Treatment strategies for keloids include established (e.g., surgery, steroid, radiation) and experimental (e.g., interferon, retinoid) regimens.  The authors concluded that combination therapy, using surgical excision followed by intra-dermal steroid or other adjuvant therapy, currently appears to be the most effective and safe current regimen for keloid management.

Sharma and colleagues (2007) compared the effectiveness of liquid nitrogen cryosurgery alone with liquid nitrogen cryosurgery plus intralesional TA combination in the treatment of keloids (n = 21; 60 clinically diagnosed lesions of keloids).  The statistical analysis showed synergistic action of cryosurgery and corticosteroids may offer promise in the treatment.  Karrer (2007) noted that keloids are a therapeutic challenge for dermatologists.  Although multiple therapeutic options are available, a reliably effective approach with few side effects remains elusive.  High quality research in evaluating the effectiveness of keloid therapy is also lacking.  This is in agreement with the findings of Durani and Bayat (2008) who reported that the level of evidence (LOE) of cryosurgery in the treatment of keloids is 4 (LOE-1 denotes highest quality while LOE-5 denotes lowest quality).

Berman et al (2008) evaluated the tolerability and efficacy of etanercept as compared to TA for the treatment of keloids.  A total of 20 subjects were randomly assigned to receive monthly intralesional injections of either 25 mg of etanercept or 20 mg of TA for 2 months.  Keloids were evaluated at baseline, week 4, and week 8 by subjects and investigators in a blinded fashion using physical, clinical, and cosmetic parameters.  Photographs were taken and adverse events were noted during each evaluation.  Etanercept improved 5/12 parameters including significant pruritus reduction, while TA improved 11/12 parameters at week 8, although no statistical difference was observed as compared to baseline.  There was no significant difference between the 2 treatment groups.  The authors concluded that etanercept was safe, well-tolerated, improved several keloid parameters, and reduced pruritus to a greater degree than TA therapy.  However, they noted that further studies are needed before it can be recommended for the treatment of keloids.

Berman (2010) stated that the potential of various biological agents to reduce or prevent excessive scar formation has now been evaluated in numerous in-vitro studies, experimental animal models and preliminary clinical trials, in some cases with particularly promising results.  Perhaps prominent among this group of biological agents, and, to some degree, possibly representing marketed compounds already being used "off label" to manage excessive scarring, are the tumor necrosis factor alpha antagonist, etanercept, and immune-response modifiers such as interferon-alpha2b and imiquimod.  The author noted that additional assessment of these novel agents is now justified with a view to reducing or preventing hypertrophic scars, keloid scars and the recurrence of post-excision keloid lesions.

In a meta-analysis, Anzarut et al (2009) evaluated the effectiveness of pressure garment therapy (PGT) for the prevention of abnormal scarring after burn injury.  Randomized control trials were identified from CINHAL, EMBASE, MEDLINE, CENTRAL, the "grey literature" and hand searching of the Proceedings of the American Burn Association.  Primary authors and pressure garment manufacturers were contacted to identify eligible trials.  Bibliographies from included studies and reviews were searched.  Study results were pooled to yield weighted mean differences or standardized mean difference and reported using 95 % confidence interval (CI).  The review incorporated 6 unique trials involving 316 patients.  Original data from 1 unpublished trial were included.  Overall, studies were considered to be of high methodological quality.  The meta-analysis was unable to demonstrate a difference between global assessments of PGT-treated scars and control scars [weighted mean differences (WMD): -0.46; 95 % CI: -1.07 to 0.16].  The meta-analysis for scar height showed a small, but statistically significant, decrease in height for the PGT-treated group standardized mean differences (SMD): -0.31; 95 % CI: -0.63 to 0.00.  Results of meta-analyses of secondary outcome measures of scar vascularity, pliability and colour failed to demonstrate a difference between groups.  The authors concluded that PGT does not appear to alter global scar scores.  It does appear to improve scar height, although this difference is small and of questionable clinical importance.  The beneficial effects of PGT remain unproven, while the potential morbidity and cost are not insignificant.  Given current evidence, additional research is needed to examine the effectiveness, risks and costs of PGT.

In a prospective, randomized, clinical trial, Xiao et al (2009) examined the effectiveness of intralesional botulinum toxin type A (BTX-A) injections in the treatment of hypertrophic scars.  A total of 19 patients were enrolled in this study.  At 1-month intervals, BTX-A (2.5 U per cubic centimeter of lesion) was injected in these patients for a total of 3 months.  All the patients were followed-up for at least half a year.  Therapeutic satisfaction was recorded, and the lesions were assessed for erythema, itching sensation, and pliability.  At the half-year follow-up visits, all the patients showed acceptable improvement, and the rate of therapeutic satisfaction was very high.  The erythema score, itching sensation score, and pliability score after the BTX-A injection all were significantly lower than before the BTX-A injection.  The differences all were statistically significant (p < 0.01).  The authors concluded that for the treatment of hypertrophic scars, doctors and patients both found BTX-A acceptable because of its better therapeutic results.  Its effect of eliminating or decreasing hypertrophic scars was promising.  The findings of this preliminary report need to be validated by further investigation.

In a randomized, double-blind, placebo-controlled trial using the reduction mammoplasty wound-healing model, van der Veer et al (2009) assessed the effectiveness of topical application of calcipotriol (a synthetic derivative of calcitriol or vitamin D) to healing wounds in preventing or reducing hypertrophic scar formation and investigated the biochemical properties of the epidermis associated with hypertrophic scar formation.  A total of 30 women who underwent bilateral reduction mammoplasty were included in this study.  For 3 months, scar segments were treated with either topical calcipotriol or placebo.  Three weeks, 3 months, and 12 months post-operatively, the scars were evaluated and punch biopsy samples were collected for immuno-histochemical analysis.  No significant difference in the prevalence of hypertrophic scars was observed between the placebo-treated and calcipotriol-treated scars.  Only scars with activated keratinocytes 3 weeks post-operatively became hypertrophic (p = 0.001).  The authors concluded that topical application of calcipotriol during the first 3 months of wound healing does not affect the incidence of hypertrophic scar formation.

Hayashida and Akita (2012) stated that pediatric burn wounds present unique challenges.  Second-degree burns may increase in size and depth, raising concerns about healing and long-term scarring.  Results of a clinical study in adults with second-degree burn wounds suggested that application of basic fibroblast growth factor may reduce time to second-intention healing and result in a more cosmetically acceptable scar.  These investigators evaluated the effect of this treatment on pediatric patients with deep second- degree burn wounds, 20 pediatric patients ranging in age from 8 months to 3 years (average of 1 year, 3 months [+/- 6 months]) with a total of 30 burn wounds from various causes were allocated either the growth factor (treatment, n = 15) or an impregnated gauze treatment (control, n = 15).  Wounds, which still exudative (not healed) after 21 days, were covered with a split-thickness skin graft.  All wounds were clinically assessed until healed and after 1 year.  A moisture meter was used to assess scars of wounds healing by secondary intention.  A color meter was used to evaluate grafted wounds.  Five wounds in each group required grafting.  Skin/scar color match was significantly closer to 100 % in the treatment than in the control group (p <0.01).  Wounds not requiring grafting were no longer exudative after 13.8 (+/- 2.4) and 17.5 (+/- 3.1) days in the treatment (n = 10) and control group (n = 10), respectively (p <0.01).  After 1 year, scar pigmentation, pliability, height, and vascularity were also significantly different (p <0.01) between the groups.  Hypertrophic scars developed in 0 of 10 wounds in the treatment and in 3 of 10 wounds in the control group, and effective contact coefficient, trans-epidermal water loss, water content, and scar thickness were significantly greater in control group (p <0.01).  The authors concluded that both the short- and long-term results of this treatment in pediatric burn patients are encouraging and warrant further research.

Verhaeghe et al (2013) noted that non-ablative fractional laser (NAFL) therapy is a non-invasive procedure that has been suggested as a treatment option for hypertrophic scars.  These researchers evaluated the safety and effectiveness of 1,540-nm NAFL therapy in the treatment of hypertrophic scars.  An intra-individual RCT with split lesion design and single-blinded outcome evaluations was performed.  Patients received 4 NAFL treatments at monthly intervals.  Primary end-point was a blinded on-site visual and palpable Physician Global Assessment (PhGA).  Adverse event registration and pain evaluation were used to evaluate safety.  Patient global assessment (PGA) was a secondary endpoint to additionally evaluate effectiveness.  The PhGA did not find a statistically significant difference between the treated and untreated control side of 18 patients, although there was significant difference on the PGA at 1 month (p =0 .006) and 3 months (p = 0.02) after last treatment (Wilcoxon signed rank test).  Patients experienced moderate pain during treatment and mild adverse events.  The authors concluded that in this trial, blinded PhGA could not confirm the clinical effectiveness of 1,540-nm non-ablative fractional laser in the treatment of hypertrophic scars, but the treatment is safe, and patients judged that the treated part had a better global appearance.

Waibel et al (2013) stated that hypertrophic scars and contractures are common following various types of trauma and procedures despite skilled surgical and wound care.  Following ample time for healing and scar maturation, many millions of patients are burdened with persistent symptoms and functional impairments.  Cutaneous scars can be complex and thus the approach to therapy is often multi-modal.  Intralesional corticosteroids have long been a staple in the treatment of hypertrophic and restrictive scars.  Recent advances in laser technology and applications now provide additional options for improvements in function, symptoms, and cosmesis.  Fractional ablative lasers create zones of ablation at variable depths of the skin with the subsequent induction of a wound healing and collagen remodeling response.  Recent reports suggested these ablative zones may also be used in the immediate post-operative period to enhance delivery of drugs and other substances.  These researchers presented a case series evaluating the effectiveness of a novel combination therapy that incorporates the use of an ablative fractional laser with topically applied triamcinolone acetonide suspension in the immediate post-operative period.  This was a prospective case series including 15 consecutive subjects with hypertrophic scars resulting from burns, surgery or traumatic injuries.  Subjects were treated according to typical institutional protocol with 3 to 5 treatment sessions at 2- to 3-month intervals consisting of fractional ablative laser treatment and immediate post-operative topical application of triamcinolone acetonide suspension at a concentration of 10 or 20 mg/ml.  Three blinded observers evaluated photographs taken at baseline and 6 months after the final treatment session.  Scores were assigned using a modified Manchester quartile score to evaluate enhancements in dyschromia, hypertrophy, texture, and overall improvement.  Combination same session laser therapy and immediate post-operative corticosteroid delivery resulted in average overall improvement of 2.73/3.0.  Dyschromia showed the least amount of improvement while texture showed the most improvement.  The authors concluded that combination same-session therapy with ablative fractional laser-assisted delivery of triamcinolone acetonide potentially offers an efficient, safe and effective combination therapy for challenging hypertrophic and restrictive cutaneous scars.  The main drawbacks of this study were its small sample size and the lack of a control arm.  These preliminary findings need to be validated by well-designed studies.

Jin and colleagues (2013) performed a meta-analysis to evaluate the effectiveness of various laser therapies for prevention and treatment of pathologic excessive scars.  The pooled response rate, pooled standardized mean difference of Vancouver Scar Scale scores, scar height, erythema, and pliability were reported.  A total of 28 well-designed clinical trials with 919 patients were included in the meta-analysis.  The overall response rate for laser therapy was 71 % for scar prevention, 68 % for hypertrophic scar treatment, and 72 % for keloid treatment.  The 585/595-nm pulsed-dye laser and 532-nm laser subgroups yielded the best responses among all laser systems.  The pooled estimates of hypertrophic scar studies also showed that laser therapy reduced total Vancouver Scar Scale scores, scar height, and scar erythema of hypertrophic scars.  Regression analyses of pulsed-dye laser therapy suggested that the optimal treatment interval is 5 to 6 weeks.  In addition, the therapeutic effect of pulsed-dye laser therapy is better on patients with lower Fitzpatrick skin type scores.  The authors concluded that this study presented the first meta-analysis to confirm the safety and effectiveness of laser therapy in hypertrophic scar management.  The level of evidence for laser therapy as a keloid treatment is low.  Moreover, they stated that further research is needed to determine the mechanism of action for different laser systems and to examine the effectiveness in quantifiable parameters, such as scar erythema, scar texture, degrees of symptom relief, recurrence rates, and adverse effects.

In a Cochrane review, O'Brien and Jones (2013) examined the effectiveness of silicone gel sheeting for:
  1. prevention of hypertrophic or keloid scarring in people with newly healed wounds (e.g., post-surgery);
  2. treatment of established scarring in people with existing keloid or hypertrophic scars. 
In May 2013 these investigators searched the Cochrane Wounds Group Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL for this second update.  Any randomized or quasi-RCTs, or controlled clinical trials, comparing silicone gel sheeting for prevention or treatment of hypertrophic or keloid scars with any other non-surgical treatment, no treatment or placebo were selected for analysis.  These researchers assessed all relevant trials for methodological quality.  Three review authors extracted data independently using a standardized form and cross-checked the results.  They assessed all trials meeting the selection criteria for methodological quality.  The authors included 20 trials involving 873 people, ranging in age from 1.5 to 81 years.  The trials compared adhesive silicone gel sheeting with no treatment; non silicone dressing; other silicone products; laser therapy; triamcinolone acetonide injection; topical onion extract and pressure therapy.  In the prevention studies, when compared with a no treatment option, while silicone gel sheeting reduced the incidence of hypertrophic scarring in people prone to scarring (risk ratio (RR) 0.46, 95 % CI: 0.21 to 0.98) these studies were highly susceptible to bias.  In treatment studies, silicone gel sheeting produced a statistically significant reduction in scar thickness (MD -2.00, 95 % CI: -2.14 to -1.85) and color amelioration (RR 3.49, 95 % CI: 1.97 to 6.15) but again these studies were highly susceptible to bias.  The authors concluded that there is weak evidence of a benefit of silicone gel sheeting as a prevention for abnormal scarring in high-risk individuals but the poor quality of research means a great deal of uncertainty prevails.  Moreover, they stated that trials evaluating silicone gel sheeting as a treatment for hypertrophic and keloid scarring showed improvements in scar thickness and scar color, but were of poor quality and highly susceptible to bias.

Malhotra et al (2007) evaluated the safety and effectiveness of imiquimod 5 % cream in preventing the recurrence of pre-sternal keloids after excision (3 keloids in 2 patients).  After excision with radiofrequency (RF), imiquimod 5 % cream was applied once-daily at bedtime for 8 weeks, and the defect was left to heal by secondary intention.  In all the treated keloids, the defect healed in 6 to 8 weeks, and no recurrence was seen while on imiquimod application; however, all keloids completely recurred within 4 weeks of stopping imiquimod.  Side effects were mild and acceptable in the form of burning and pain.  The authors concluded that imiquimod did exert an anti-fibrotic action but it was short-lived.

In a prospective, double-blind, placebo-controlled pilot study, Berman et al (2007) determined the tolerability and compare the effectiveness of imiquimod 5 % and vehicle cream in lowering keloid recurrence after shaving.  A total of 20 randomized, shaved keloids were administered imiquimod 5 % or vehicle cream nightly for 2 weeks, and then given 3 times a week under occlusion for 1 month.  Pain, tenderness, pruritus and keloid recurrence were evaluated at baseline, week 2, week 6 and 6 months.  Tenderness and pain were significantly (p = 0. 02 and p = 0. 02, respectively) higher at week 2 in the imiquimod group than for those treated with vehicle cream.  Pruritus did not attain statistical difference between the groups.  At 6 months, keloid recurrence rates were 37.5 % (3/8) in the imiquimod group and 75 % (3/4) in the vehicle group (p = 0.54).  The authors concluded that imiquimod was well-tolerated.  However, there was not enough statistical power to detect a significant difference in 6-month keloid recurrence rates between the imiquimod-treated group and the vehicle-treated group.

Cacao et al (2009) evaluated the effectiveness of topical imiquimod 5 % cream applied after surgical excision and primary closure of trunk keloids in the prevention of recurrence.  A total of 9 patients with a keloid lesion on the trunk were treated with surgical excision and primary closure.  Daily application of imiquimod 5 % cream for 8 weeks was initiated the night of surgery.  The patients were evaluated 2, 4, 8, 12, and 20 weeks after.  Keloid recurrence occurred in 8 patients, 7 of them 12 weeks after surgery.  These researchers lost track of 1 patient.  The authors concluded that the results of this study suggested that imiquimod 5 % cream is not effective in preventing recurrence of trunk keloids after surgical excision.  They stated that although this was a small case series, results strongly discouraged other studies using imiquimod 5 % cream in the prevention of surgically excised trunk keloids.

Viera et al (2012) stated that there is very limited evidence on the best wound management for minimizing scarring.  Multiple available therapeutic modalities have been used for the treatment of keloids; however, high-recurrence rates continue to be reported.  Currently, there are biological and anti-neoplastic agents that can potentially treat and prevent excessive scar formation.  Some of them have been used as "off-label" therapies, and others are still in the experimental phase (e.g., interferon alpha (IFN-α), imiquimod, and transforming growth factor beta1 (TGF-β1)).  The use of IFN-α2b showed 18 % recurrence rate when applied to post-surgical excised keloids.  Imiquimod 5 % can lower recurrence rate on post-shaved keloids to 37.5 % at 6-month and to 0 % at a 12-month follow-up period.  Transforming growth factor beta1 oligonucleotides have shown effective and long-lasting inhibition of TGF-β-mediated scarring in-vitro as well as in animal models.  Daily injections of neutralizing antibodies against TGF-β1 and -β2 have shown successful reductions in scarring.  The authors concluded that latest discoveries in the use of novel agents suggested therapeutic alternatives for the prevention of recurrences of hypertrophic scars and post-excision keloid lesions.

Gold et al (2014) reviewed available data on methods for preventing and treating cutaneous scarring.  Relevant scientific literature was identified through a comprehensive search of the MEDLINE database.  Additional data and published studies were submitted for consideration by members of the International Advisory Panel on Scar Management.  One of the most significant advances in scar management over the past 10 years has been the broader application of laser therapy, resulting in a shift in status from an emerging technology to the forefront of treatment.  Accumulated clinical evidence also supports a greater role for 5-FU in the treatment of hypertrophic scars and keloids, particularly in combination with intralesional corticosteroids.  The authors stated that encouraging data have been reported for newer therapies, including bleomycin, onion extract-containing preparations, imiquimod, and mitomycin C, although methodological limitations in available studies merit consideration.

An UpToDate review on “Keloids and hypertrophic scars” (Goldstein and Goldstein, 2015) states that “Imiquimod -- A few small observational studies have reported that postoperative use of imiquimod with daily or alternate day applications may reduce the rate of recurrence of keloids.  However, other studies have provided conflicting results …. Other therapies that have been used for keloids include intralesional bleomycin, mitomycin C, and topical imiquimod cream.  There is insufficient evidence to make definitive recommendations about these therapies when used alone, although they may provide benefit when used after surgical excision”.

Ledon et al (2013) provided a comprehensive review of current intralesional treatment modalities for keloids and hypertrophic scars.  These researchers performed a PubMed search for literature pertaining to intralesional treatment modalities for keloids and hypertrophic scars.  References from retrieved articles were also considered for review.  These investigators noted that many intralesional therapies for keloids and hypertrophic scars are currently available to physicians and patients.  Mechanisms of action and side effect profiles vary between these agents, and new approaches to keloids and hypertrophic scars are frequently being explored.  The authors concluded that RCTs are needed to evaluate these new and promising modalities fully.

Song (2014) noted that hypertrophic scars and keloids remain a challenge in surgery.  Although the bench to bedside conundrum remains, the science of translational research calls for an even higher level of cooperation between the scientist and the clinician for the impetus to succeed.  The clinicians alerted the possible theories in the pathogenesis of keloid formation, inter alia, the ischemia theory, mast cell theory, immune theory, TGB-β interaction, mechanical theory, and the melanocyte stimulating hormone theory.  All of the above presupposed a stimulus that would result in an uncontrolled up-regulation of collagen and extracellular matrix expression in the pathogenesis of the keloid.  This bedside to bench initiative, as in true science, realized more ponderables than possibilities.  By the same token, research into the epidermal-mesenchymal signaling, molecular biology, genomics, and stem cell research holds much promise in the bench top arena.  To assess efficacy, many scar assessment scores exist in the literature.  The clinical measurement of scar maturity can aid in determining end-points for therapeutics.  Tissue oxygen tension and color assessment of scars by standardized photography proved to be useful.  In surgery, the use of dermal substitutes holds some promise as these researchers surmised that quality scars that arise from dermal elements, molecular and enzyme behavior, and balance.  Although a systematic review showed some benefit for earlier closure and healing of wounds, no such review exists at this point in time for the use of dermal substitutes in scars.  Adipose-derived stem cell, as it pertains to scars, will hopefully realize the potential of skin regeneration rather than by repair in which the researchers were familiar with as well as the undesirable scarring as a result of healing through the inflammatory response.  The author concluded that translational research will bear the fruit of coordinating bench to bedside and vice-versa in the interest of progress into the field of regenerative healing that will benefit the patient who otherwise suffers the myriad of scar complications.

Wat and associates (2014) provided evidence-based recommendations to guide physicians in the application of intense pulsed light (IPL) devices for the treatment of dermatologic disease.  These investigators performed a literature search of the CENTRAL (1991 to May 6, 2013), EMBASE (1974 to May 6, 2013), and MEDLINE in-process and non-indexed citations and MEDLINE (1964 to present) databases.  Studies that examined the role of IPL in primary dermatologic disease were identified, and multiple independent investigators extracted and synthesized data.  Recommendations were based on the highest level of evidence available.  These researchers found Level 1 evidence for the use of IPL for the treatment of melasma, acne vulgaris, and telangiectasia; Level 2 evidence for the treatment of lentiginous disease, rosacea, capillary malformations, actinic keratoses, and sebaceous gland hyperplasia; and Level 3 or lower evidence for the treatment of poikiloderma of Civatte, venous malformations, infantile hemangioma, hypertrophic scars, superficial basal cell carcinoma, and Bowen's disease.  The authors concluded that IPL is an effective treatment modality for a growing range of dermatologic disease and in some cases may represent a treatment of choice.  It is typically well-tolerated.  Moreover, they stated that further high-quality studies are needed.

Goyal and Gold (2014) noted that keloids and hypertrophic scars remain one of the more difficult treatment concerns for clinicians.  A variety of therapies have been used in the past with moderate success.  On occasion, combination therapy has been used to treat these lesions, in an attempt to lessen the symptoms of pain and pruritus that often accompanies keloids and hypertrophic scars, as well as treating the actual lesions themselves.  These researchers introduced a novel triple combination injection process in an attempt to further reduce the signs and symptoms of these lesions.  The combination includes 5-FU, triamcinolone acetonide, and hyaluronidase.  All 3 agents supposedly work in concert to treat keloids and hypertrophic scars, and this was the first work at looking at these medicines given together, at the same time, in a series of recalcitrant keloids and hypertrophic scars.  The authors concluded that the positive results warrant further investigation and hope for those with keloids and hypertrophic scars.

Botulinum Toxin

In a systematic review, Prodromidou and colleagues (2015) examined available evidence that support the use of botulinum toxin injections for the treatment or prevention of hypertrophic scars in current clinical practice.  A systematic review searching the MEDLINE (1966 to 2014), Scopus (2004 to 2014), Popline (1974 to 2014), ClinicalTrials.gov (2008 to 2014) and Cochrane Central Register of Controlled Trials (CENTRAL) (1999 to 2014) databases together with reference lists from included studies was conducted.  A total of 10 studies (255 patients) were included.  Of these, 123 patients were injected with botulinum toxin type A, 9 patients were offered botulinum toxin type B and the remaining 123 patients represented the control groups.  Significantly improved cosmetic outcomes were observed among certain studies using the VAS (experimental group: median score 8.25 [range of 6 to 10]) versus control group: median score 6.38 [range of 2 to 9]; p < 0.001) and the Stony Brook Scar Evaluation Scale (experimental group score: 6.7 versus control group score: 4.17; p < 0.001) assessments.  However, the methodological heterogeneity of the included studies, the lack of control group in the majority of them, the use of subjective scales of measurement and the frequent use of patient self-assessment precluded unbiased results.  The authors concluded that current evidence does not support the usage of botulinum toxin; future RCTs are needed in the field to reach firm conclusions regarding its place in current clinical practice.

In a meta-analysis, Zhang and colleagues (2016) evaluated the effectiveness of therapeutic BTX-A in the prevention of maxillofacial and neck scars.  Information came from the following electronic databases: Medline, PubMed, Cochrane Library, and Embase (time was ended by August 31, 2015) to retrieve RCTs evaluating the effect of the BTX-A for hypertrophic scar on the maxillofacial or neck.  All languages were included as long as they met the inclusion criteria.  Effects of BTX-A were evaluated by comparing the width of the scar, patient satisfaction, and VAS, respectively.  Pooled WMDs, pooled odds ratios (ORs), and 95 % CI were calculated.  A total of 9 RCTs (539 patients) were included.  A statistically significant difference in scar width was identified between the BTX-A group and control group (non-BTX-A used) (WMD = -0.41, 95 % CI: -0.68 to -0.14, p = 0.003).  Statistically significant differences in patient satisfaction (OR = 25.76, 95 % CI: 2.58 to 256.67, p = 0.006) and VAS (WMD = 1.30, 95 % CI: 1.00 to 1.60, p < 0.00001) were observed between the BTX-A group and control group.  The authors concluded that the findings of this meta-analysis suggested that BTX-A is more effective and useful than non-BTX-A in eliminating hypertrophic scars from the maxillofacial area and neck; BTX-A could improve the quality of the scars and meet patients’ cosmetic requirements.  Moreover, they stated that because there were only a few studies, further clinical practice should be performed and larger databases should be consulted to better determine the effectiveness of BTX-A

This study had several drawbacks:
  1. the analysis conducted may not have taken the differences in patient ages into account; they ranged from 3 months to 70 years old,
  2. the characteristics of patients in the included studies were not homogeneous,
  3. only a few events were studied because of a lack of evidence illustrating the results, and
  4. several of the studies were found to have a high risk of performance or detection bias.

Liu and associates (2017) studied the effects of BTX-A on the treatment of hypertrophic scars (HS)  and the dose response of BTX-A.  Hypertrophic scars were harvested from the ears of 18 young adult New Zealand big-eared rabbits and treated with BTX-A or triamcinolone acetonide (TAC) in-vivo experiment.  The hypertrophic index (HI) was measured by histological examination.  Collagen fibrils were checked by sirius red straining, and the cell nucleuses of fibroblasts were checked by Ki67.  The HI of hypertrophic scars with BTX-A treatment was lower than that with phosphate-buffered saline treatment (p < 0.05).  Compared with the TAC treatment group, the effectiveness of treatment with the middle dose of BTX-A (1.0, 1.5 IU) had no significant difference, as shown by sirius red staining and immunohistochemistry Ki67.  The authors concluded that these findings showed that BTX-A effectively improved the appearance HS and inhibited the formation of collagen fibrils and fibroblasts in-vivo.  They stated that middle dose BTX-A therapy achieved similar effectiveness as TAC treatment, indicating that BTX-A might be useful for inhibiting HS and worth investigating further.

Austin and associates (2018) noted that keloids and hypertrophic scars are conditions of pathologic scarring characterized by fibroblast hyper-proliferation and excess collagen deposition.  These conditions significantly impact patients by causing psychosocial, functional, and aesthetic distress.  Current treatment modalities have limitations.  Clinical evidence indicated that botulinum toxin A (BoNT-A) may prevent and treat keloids and hypertrophic scars.  These researchers investigated cellular pathways involved in BoNT-A therapeutic modulation of keloids and hypertrophic scars.  They searched PubMed, Embase, and Web of Science for basic science articles related to botulinum toxin therapy, scarring, fibroblasts, keloids, and hypertrophic scars.  A total of 11 basic science articles involving keloids and hypertrophic scars were reviewed.  BoNT-A may reduce skin fibrosis by decreasing fibroblast proliferation, modulating the activity of transforming growth factor-beta (TGF-β), and reducing transcription and expression of pro-fibrotic cytokines in keloid-derived and hypertrophic scar-derived dermal fibroblasts.  BoNT-A may modulate collagen deposition, but there is a paucity of evidence regarding specific mechanisms of action.  The authors concluded that BoNT-A has the potential to prevent or treat pathologic scars in patients with a known personal or family history of keloids and hypertrophic scars, which may improve patient psychosocial distress and reduce clinic visits and health care costs.  Variability in keloid and hypertrophic scar response to BoNT-A may be due to inter-experiment differences in dosing, tissue donors, and assay sensitivity.

Guida and colleagues (2018) noted that recent studies have highlighted new botulinum neurotoxin (BoNT) applications in the field of dermatology.  These investigators reviewed current knowledge of BoNT use in dermatology; the literature of the past 5 years was reviewed.  These researchers described interesting protocols of BoNT treatment for hyperhidrosis (HH), hypertrophic scars and keloids, Raynaud phenomenon, facial flushing, oily skin, psoriasis, Hailey-Hailey disease, and cutaneous lesions like painful lesions and peri-orbital syringomas.  The authors concluded that several skin conditions eligible for BoNT treatment have been described.  After the wide application for HH treatment, scars as well as vascular and inflammatory skin disorders, oily skin and cutaneous lesions represent fields of application of BoNT.  Moreover, these researchers stated that further studies are needed to improve the knowledge of the connection between BoNT and the cutaneous neuro-immune system and to better define standard protocols of treatment.

Hao and co-workers (2018) stated that clinical observations indicate that botulinum toxin type A (BTXA) can inhibit the growth and improve the eventual appearance of hypertrophic scarring.  However, the molecular mechanism remains unclear.  These researchers used human keloid fibroblasts to examine the molecular mechanism of BTXA on hypertrophic scarring.  Different concentrations of BTXA (0.01, 0.1, 1, and 10 U/L) were used to treat keloid fibroblasts.  Changes in cellular morphology, viability, proliferation, cell cycle, and apoptosis were observed by immuno-fluorescence, MTT assay, and flow cytometry.  In addition, real-time quantitative polymerase chain reaction (qPCR) and Western blotting were used to explore the potential molecular mechanisms.  Keloid fibroblast viability decreased with increasing BTXA dose.  After BTXA treatment, the volume of keloid fibroblasts cells increased, but the nucleus of cells shrunk.  Long thin dendrites were formed as the concentration of BTXA increased.  Furthermore, the proliferation and S phase of keloid fibroblasts were inhibited by BTXA.  Matrix metalloproteinase (MMP)-1 and -2 RNA and protein showed high expression, but TGF-β1 and MMP-9 showed low expression than the control.  The authors concluded that BTX A may promote the healing of scars by inhibiting the proliferation of keloid fibroblasts and regulating the expression of TGF-β1, which could affect the expression of MMP-1 and MMP-2.  They stated that the findings of this study provided theoretical support for the clinical application of BTXA to control hypertrophic scarring.

Calcium Antagonists

Verhiel et al (2015) provided a comprehensive evidence-based review of current evidence on mechanism of action, effectiveness, and adverse events of calcium antagonists in treatment of hypertrophic scars and keloids.  A Cochrane Library and PubMed search was performed for the literature pertaining to treatment with calcium antagonists in pathological scars.  Articles were categorized into 2 groups:
  1. mechanism of action or effectiveness and
  2. adverse events. 
A total of 6 in-vitro studies were included in the first subgroup.  Calcium antagonists have been found to reduce extra cellular matrix production, induce procollagenase synthesis, and inhibit interleukin-6, vascular endothelial growth factor, and proliferation of fibroblasts; 8 studies with a median level of evidence of 3.5 (range of 2 to 4) were included in the second category.  A good efficacy with no major side effects was reported for calcium antagonists.  The authors concluded that important methodological shortcomings of the available literature were identified.  They stated that interesting results have been reported, but further large scale, high-quality studies are needed to optimally evaluate the effectiveness of treatment with calcium antagonists.

Wang et al (2016) evaluated the effectiveness of verapamil in preventing and treating keloid and hypertrophic scars.  Searches were conducted in Medline, EMbase and Cochrane databases from 1974 to January 2015.  The selection of articles was limited to human subjects.  A total of 5 RCTs or cluster-randomized trials or controlled clinical trials (CCTs) comparing the effectiveness of verapamil with conventional treatments were identified.  The results showed that verapamil could improve keloid and hypertrophic scars, and was not significantly different from conventional corticosteroid injections.  Few adverse effects were observed.  However, this result should be considered carefully, as most of the included studies have a high risk of bias because of issues with randomization, allocation concealment, blinding, incomplete outcomes and selective reporting.  The authors concluded that verapamil could act as an effective alternative modality in the prevention and treatment of keloid and hypertrophic scars; however, they stated that more high-quality, multiple-center, large-sample RCTs are needed to define the role of verapamil in preventing and treating keloid and hypertrophic scars.

In a double-blind RCT with a paired split-scar design, Danielsen et al (2016) compared verapamil and triamcinolone for prevention of keloid recurrence after excision.  Calcium channel blocking activity of verapamil in keloid cells was explored.  One keloid was excised per subject and each wound half randomized to receive intralesional injections of triamcinolone (10 mg/ml) or verapamil (2.5 mg/ml) at monthly intervals (4 doses).  Interim analysis was performed after 14 subjects were recruited.  Survival analysis demonstrated significantly higher keloid recurrence with verapamil compared to triamcinolone 12 months post-surgery (log-rank test, p = 0.01) and higher overall risk of recurrence with verapamil (hazard ratio [HR] 8.44, 95 % CI: 1.62 to 44.05).  The study was terminated early according to the stopping guideline (p < 0.05).  The authors concluded that verapamil is safe but not as effective as triamcinolone in preventing keloid recurrence after excision.  They stated that further study is needed to determine if clinical response to verapamil is linked to modulation of intracellular calcium.

Li and Jin (2016) stated that keloids and hypertrophic scars are the most common types of pathological scarring.  Traditionally, keloids have been considered as a result of aberrant wound healing, involving excessive fibroblast participation that is characterized by hyalinized collagen bundles.  However, the usefulness of this characterization has been questioned.  In recent years, studies have reported the appropriate use of verapamil for keloids and hypertrophic scars.  Searches were conducted on the databases Medline, Embase, Cochrane, PubMed, and China National Knowledge Infrastructure from 2006 to July 2016.  State12.0 was used for literature review, data extraction, and meta-analysis.  Treatment groups were divided into verapamil and non-verapamil group.  Non-verapamil group included steroids and intense pulsed light (IPL) therapy.  Total effective rates included cure rate and effective rate.  Cure: skin lesions were completely flattened, became soft and symptoms disappeared.  Efficacy: skin lesions subsided, patient significantly reduced symptoms.  Inefficient definition of skin was progression free or became worse.  Random-effects model was used for the meta-analysis.  A total of 6 studies that included 331 patients with keloids and hypertrophic scars were analyzed.  Analysis of the total effective rate of skin healing was performed.  The total effective rates in the 2 groups were 54.07 % (verapamil) and 53.18 % (non-verapamil), respectively.  The meta-analysis showed that there was no difference between the 2  groups.  These researchers also compared the adverse reactions between the verapamil treatment group and the steroids treatment group in 2 studies, and the result indicated that the verapamil group showed less adverse reactions.  The authors concluded that there were no differences between the application of verapamil and non-verapamil group in keloids and hypertrophic scars treatment.  These investigators stated that verapamil could act as an effective alternative modality in the prevention and treatment of keloid and hypertrophic scars; a larger number of studies are needed to confirm their conclusion.

This study had several drawbacks:
  1. articles and data were not too many according to the inclusion criteria; this probably caused publication bias,
  2. uncontrolled confounding factors and selection bias resulted in some heterogeneity in the study, and
  3. only articles published and written in English and Chinese were included this meta-analysis, which might have resulted in some degree of publication bias.

Anti-Vascular Endothelial Growth Factor Therapy (e.g., Bevacizumab)

Kwak and colleagues (2016) noted that hypertrophic scarring is a pathological condition that occurs after trauma or surgery.  Angiogenesis occurs more often with hypertrophic scarring than with normotrophic scarring.  The regulation of angiogenesis is one of the key factors in hypertrophic scar management.  Vascular endothelial growth factor (VEGF) is an essential factor in the angiogenetic response.  These researchers examined if decreasing the level of VEGF is effective for treating hypertrophic scarring.  A total of 10 8-week-old female New Zealand white rabbits were included; 4 defects were created on each ear by using a 6-mm punch.  Bevacizumab was administered in 1 ear and normal saline was administered in the other ear.  Treatment was administered starting on day 2, every 2 days, until day 14.  The levels of VEGF were measured using enzyme-linked immunosorbent assay on day 10 and histologic results were analyzed on day 40.  Bevacizumab induced-defects showed less hypertrophic scarring when compared with the control group as measured by the scar elevation index (SEI) and loose collagen arrangement.  The SEI in the experimental group was 1.89 ± 0.13, compared to 1.99 ± 0.13 in the control group (n = 30, p = 0.005).  Additionally, the VEGF level was lower (38.72 ± 11.03 pg versus 82.50 ± 21.64 pg, n = 10, p = 0.001) and fewer vessels existed (8.58 ± 0.76 versus 7.2 ± 1.20, n = 10, p = 0.007).  The authors concluded that preventing excessive angiogenesis is effective for preventing scar formation, especially with hypertrophic scarring.  Moreover, they stated that although bevacizumab reduces scar formation, it does have adverse effects.  No research on the effect of local injection or topical application of bevacizumab to scars has been published.  They stated that further research should be performed in-vivo to ensure the use of bevacizumab without adverse effects and to reveal the mechanisms underlying its effect.

Autologous Fat Grafting

Silva and colleagues (2016) noted that since the 1980s, the use of autologous fat grafting has been growing in plastic surgery.  Recently, this procedure has come to be used as a treatment for keloids and hypertrophic scars mainly due to the lack of satisfactory results with other techniques.  So far, however, it lacks more consistent scientific evidence to recommend its use.  These investigators reviewed the evidence of autologous fat grafting for the treatment of keloids and hypertrophic scars.  They performed a review in the PubMed database using the keywords "fat grafting and scar", "fat grafting and keloid scar" and "fat grafting and hypertrophic scar".  Inclusion criteria were articles written in English and published in the last 10 years, resulting in 15 studies.  These articles indicated that autologous fat grafting performed at sites with pathological scars led to a reduction of the fibrosis and pain, an increased range of movement in areas of scar contraction, an increase in their flexibility, resulting in a better quality of scars.  The authors concluded that current evidence suggested that autologous fat grafting for the treatment of keloids and hypertrophic scars is associated with a better quality of scars, leading to esthetic and functional benefits.  However, they noted that this review has limitations and these findings should be treated with reservations, since they mostly came from studies with low levels of evidence (9 of the 15 articles were classified as cases series (evidence level: IV).  They stated that new studies with the strongest level of evidence (randomized and controlled clinical trials, prospective cohort studies, and comparative studies with control groups) are needed to elucidate some of the gaps in our knowledge concerning the role of autologous fat grafting in pathological scars (e.g., the standardization of surgical indication, more prolonged post-operative monitoring assessment of late-onset results, the systematization of conduct and proof of the role of adipose-derived stem cell in the promotion of cicatricial improvement).

Pressure Therapy

Ai and colleagues (2017) stated that although pressure therapy (PT) represents the standard care for prevention and treatment of HS from burns, its practice is largely based on empirical evidence and its effectiveness remains controversial.  These researchers examined the effect of PT for HS; they performed a systematic review and meta-analysis.  Several electronic databases were screened to identify related RCTs; 12 RCTs involving 710 patients with 761 HS resulting from burn injuries were included.  Compared with non/low-PT, cases treated with PT (15 to 25 mmHg) showed significant differences in Vancouver Scar Scale score (MD = -0.58, 95 % CI: -0.78 to -0.37), thickness (SMD = -0.25, 95 % CI: -0.40 to -0.11), brightness (MD = 2.00, 95 % CI: 0.59 to 3.42), redness (MD = -0.79, 95 % CI: -1.52 to -0.07), pigmentation (MD = -0.16, 95 % CI: -0.32 to -0.00) and hardness (SMD = -0.65, 95 % CI: -1.07 to -0.23).  However, there was no difference in vascularity (MD = 0.03, 95 % CI: -0.43 to 0.48).  The authors concluded that the findings of this meta-analysis indicated that patients with HS who were managed with PT (15 to 25 mmHg) showed significant improvements.  However, due to limitations, more large and well-designed studies are needed to confirm these findings and the side-effects of the PT may also need to be evaluated.  They stated that future investigations should ensure adequate randomization, concealment of allocation, blinding of patients and outcome assessors and descriptions of withdrawals and losing.

This study had several drawbacks:
  1. the results may be influenced by the small number of included studies, the limited sample-size and inconsistent clinical outcomes of each study,
  2. due to insufficient data, the study did not consider the percentage of total body surface area (%TBSA), burn degree and burn site although the different %TBSA, burn degree and burn site may have varying efficacy,
  3. since long-term follow-up studies were rare, the study failed to analyze the prospective efficacy of PT,
  4. none of the included studies studied adverse effects and these researchers were unable to assess the safety of PT, and
  5. this analysis suffered in quality of included studies because most of the studies did not describe the allocation concealment and blinding method, which may exaggerate the treatment effects, especially in subjective outcomes.

Extracorporeal Shock Wave Therapy

Zhao and colleagues (2018) examined the effects of radial extracorporeal shock wave therapy (rESWT) on scar characteristics and TGF-β1/Smad signaling to explore a potential modality for the treatment of hypertrophic scars (HS).  The HS model was generated in rabbit ears, then rabbits were randomly divided into 3 groups: Lower (L)-ESWT [treated with rESWT with lower energy flux density (EFD) of 0.1 mJ/mm2], higher (H)-ESWT (treated with a higher EFD of 0.18 mJ/mm2) and the sham ESWT group (S-ESWT; no ESWT treatment).  Scar characteristics (wrinkles, texture, diameter, area, volume of elevation, hemoglobin and melanin) were assessed using the Antera 3D system.  The protein and mRNA expression of TGF-β1, Smad2, Smad3 and Smad7 was assessed by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-qPCR, respectively.  The Antera 3D results indicated that wrinkles and hemoglobin of the HS were significantly improved in both of the rESWT groups when compared with the S-ESWT group.  However, these changes appeared much earlier in the L-ESWT group than the H-ESWT.  Scar texture was also improved in the L-ESWT group.  However, rESWT did not influence HS diameter, area, volume of elevation or melanin levels.  rESWT had no effect on TGF-β1 or Smad7 expression in either of rESWT groups.  Although no difference was observed in Smad2 mRNA expression in the L-ESWT group, the Smad3 mRNA and protein expression significantly decreased when compared with the H-ESWT and S-ESWT groups.  By contrast, Smad2 and Smad3 mRNA expression were up-regulated in the H-ESWT group.  These results demonstrated that rESWT with 0.1 mJ/mm2 EFD improved some characteristics of the HS tissue.  Down-regulation of Smad3 expression may underlie this inhibitory effect.  The authors concluded that inhibition of the TGF-β1/Smad signal transduction pathway may be a potential therapeutic target for the management of HS.

Cui and associates (2018) noted that ESWT considerably improves the appearance and symptoms of post-burn hypertrophic scars (HTS).  However, the mechanism underlying the observed beneficial effects is not well understood.  These researchers examined the mechanism underlying changes in cellular and molecular biology that is induced by ESWT of fibroblasts derived from scar tissue (HTSFs).  They cultured primary dermal fibroblasts derived from human HTS and exposed these cells to 1,000 impulses of 0.03, 0.1, and 0.3 mJ/mm².  At 24 hours and 72 hours after treatment, real-time PCR and Western blotting were used to detect mRNA and protein expression, respectively, and cell viability and mobility were assessed.  While HTSF viability was not affected, migration was decreased by ESWT; TGF-β1 expression was reduced and alpha smooth muscle actin (α-SMA), collagen-I, fibronectin, and twist-1 were reduced significantly after ESWT.  Expression of E-cadherin was increased, while that of N-cadherin was reduced.  Expression of inhibitor of DNA binding 1 and 2 was increased.  The authors concluded that suppressed epithelial-mesenchymal transition might be responsible for the anti-scarring effect of ESWT, and has potential as a therapeutic target in the management of post-burn scars.

Growth Hormone-Releasing Peptide 6

Fernandez-Mayola and associates (2018) stated that HTS and keloids are forms of aberrant cutaneous healing with excessive extracellular matrix (ECM) deposition.  Current therapies still fall short and cause undesired effects.  These investigators evaluated the ability of growth hormone releasing peptide 6 (GHRP6) to both prevent and reverse cutaneous fibrosis and to acquire the earliest proteome data supporting GHRP6's acute impact on aesthetic wound healing.  Two independent sets of experiments addressing prevention and reversion effects were conducted on the classic HTS model in rabbits.  In the prevention approach, the wounds were assigned to topically receive GHRP6, triamcinolone acetonide (TA), or vehicle (1 % sodium carboxy methylcellulose [CMC]) from day 1 to day 30 post-wounding.  The reversion scheme was based on the infiltration of either GHRP6 or sterile saline in mature HTS for 4 consecutive weeks.  The incidence and appearance of HTS were systematically monitored.  The sub-epidermal fibrotic core area of HTS was ultrasonographically determined, and the scar elevation index was calculated on hematoxylin/eosin-stained, microscopic digitized images.  Tissue samples were collected for proteomics after 1 hour of HTS induction and treatment with either GHRP6 or vehicle.  GHRP6 prevented the onset of HTS without the untoward reactions induced by the 1st-line treatment TA; however, it failed to significantly reverse mature HTS.  The authors concluded that the findings of these preliminary proteomic study suggested that the anti-fibrotic preventing effect exerted by GHRP6 depended on different pathways involved in lipid metabolism, cytoskeleton arrangements, epidermal cells' differentiation, and ECM dynamics.  They stated that these results enlightened the potential success of GHRP6 as one of the incoming alternatives for HTS prevention.

Hyperbaric Oxygen Therapy

Ren and colleagues (2018) examined the influence of hyperbaric oxygen (HBO) on scar formation in rabbit ears.  A total of 20 New Zealand rabbits were selected to establish the hypertrophic scar model on the ears.  The rabbits were randomly divided into control group and experimental group (7d, 14d, 21d, and 28d group according to different HBO treatment days), each experimental group received HBO treatment after the operation at the same time every day for 1 hour.  After the day 29, the scars were collected.  Histo-morphological change in scars was observed by hematoxylin-eosin staining, Masson staining, and transmission electrical microscope.  The expression of bax, bcl-2, and the cell apoptosis rate was detected by immuno-histochemical method.  Both number of fibroblast and amount of collagen fibrils in experimental group were significantly reduced compared with those in control group.  In Masson staining, arrangement of collagen fibrils in experimental group was much more irregular and coarse than control groups.  HI value can be found much smaller in the experimental groups than the control (p < 0.05).  Among the 4 experimental groups, there was significant difference among 7d, 14d, and 21d groups (p < 0.05), while there was no difference between 21d and 28d groups (p > 0.05).  Expression of Bax could be detected up-regulated in experimental group (p < 0.05).  While the expression of Bcl-2 was detected significantly down-regulated in experimental group than that in control group (p < 0.05).  Compared with the 7d group, the expression of Bax and Bcl-2 had significant difference in 14d group (p < 0.05), and the expression of this 2 factors in 21d group had significant difference comparing with 14d group(p < 0.05),but there was no significant difference between 28d group and 21d group(p > 0.05).  Significant difference of cell apoptosis rate can be detected between the experimental groups and the control group (p < 0.05).  Among the 4 experimental groups, there was significant difference among 7d, 14d, and 21d groups (p < 0.05), while there was no difference between 21d and 28d groups (p > 0.05).  The authors concluded that HBO can up-regulate bax/bcl-2 value, increase the cell apoptosis rate, and inhibit the early hypertrophic scar in rabbit ears. 

Mesenchymal Stem Cell and Miscellaneous Investigational Treatments

Fan and associates (2018) noted that Cesarean delivery has already become a very common method of delivery around the world, especially in low-income countries.  Hypertrophic scars and wound infections have affected younger mothers and frustrated obstetricians for a long time.  Mesenchymal stem cells (MSCs) have strong potential for self-renewal and differentiation to multi-lineage cells.  Previous studies have demonstrated that MSCs are involved in enhancing diabetic wound healing.  Thus, this study is designed to examine the safety and efficacy of MSCs in the treatment of Cesarean section skin scars.  This trial is a prospective, randomized, double-blind, placebo-controlled, single-center trial with 3 parallel groups.  A total of 90 eligible participants will be randomly allocated to placebo, low-dose (transdermal hydrogel MSCs; 3 × 106 cells) or high-dose (transdermal hydrogel MSCs; 6 × 106 cells) groups at a 1:1:1 allocation ratio according to a randomization list, once-daily for 6 consecutive days.  Study duration will last for 6 months, comprising a 1 week run-in period and 24 weeks of follow-up.  The primary aim of this trial is to compare the difference in Vancouver Scar Scale rating among the 3 groups at 6th month.  Adverse events (AEs), including severe and slight signs or symptoms, will be documented in case report forms.  The authors concluded that this trial is the first investigation of the potential for therapeutic use of MSCs for the management of women's skin scar after Cesarean delivery.

In a review on “Recent understandings of biology, prophylaxis and treatment strategies for hypertrophic scars and keloids”, Lee and Jang (2018) listed the following as emerging therapies: botulinum toxin, fat grafting, interferons, MSCs, and transforming growth factor-beta.  The authors concluded that although encouraging results of molecular- or cytokine-targeting therapies are being continuously reported, current prophylaxis and treatment strategies still mainly focus on decreasing inflammatory processes.  They stated that further understanding of the mechanisms underlying excessive scarring is needed to develop more effective prophylaxis and treatment strategies.

Micro-Needling for the Treatment of Hypertrophic Scars and Keloids

Dogra and colleagues (2014) evaluated the safety and effectiveness of micro-needling treatment for atrophic facial acne scars.  A total of 36 patients (26 females, 10 males) with post-acne atrophic facial scars underwent 5 sittings of derma-roller under topical anesthesia at monthly intervals.  Objective evaluation of improvement was performed by recording the acne scar assessment score at baseline and thereafter at every visit.  Pre- and post-treatment photographs were compared, and improvement was graded on quartile score.  Final assessment was performed 1 month after the last sitting.  Patients were asked to grade the improvement in acne scars on VAS (0 to 10 point scale) at the end of study.  Of 36 patients, 30 completed the study.  The age group ranged from 18 to 40 years, and all patients had skin phototype IV or V.  There was a statistically significant decrease in mean acne scar assessment score from 11.73 ± 3.12 at baseline to 6.5 ± 2.71 after 5 sittings of derma-roller.  Investigators' assessment based on photographic evaluation showed 50 to 75 % improvement in majority of patients.  The results on VAS analysis showed "good response" in 22 patients and "excellent response" in 4 patients, at the end of study.  The procedure was well-tolerated by most of the patients, and chief complications noted were post-inflammatory hyperpigmentation in 5 patients and tram-trek scarring in 2 patients.  The authors concluded that micro-needling with derma-roller is a simple and cheap, means of treatment modality for acne scars re-modulation with little downtime, satisfactory results and peculiar side effects in Asian skin type.  The findings of this small (n = 36) uncontrolled study need to be validated by well-designed studies.

In a retrospective study, Chandrashekar et al (2014) assessed the safety and effectiveness of micro-needling fractional radiofrequency in the treatment of acne scars.  A total of 31 patients of skin types III to V with moderate and severe facial acne scarring received 4 sequential fractional RF treatments over a period of 6 months with an interval of 6 weeks between each session.  Goodman & Baron's acne scar grading system was used for assessment by a side by side comparison of pre-operative and post-operative photographs taken at their first visit and at the end of 3 months after the last session.  Estimation of improvement with Goodman and Baron's Global Acne Scarring System showed that by qualitative assessment of 31 patients with grade 3 and grade 4 acne scars, 80.64 % showed improvement by 2 grades and 19.35 % showed improvement by 1 grade.  Quantitative assessment showed that 58 % of the patients had moderate, 29 % had minimal, 9 % had good and 3 % showed very good improvement.  Adverse effects were limited to transient pain, erythema, edema and hyperpigmentation.  The authors concluded that micro-needling fractional RF is effective for the treatment of moderate and severe acne scars.  The findings of this small (n = 31) retrospective study need to be validated by well-designed studies.

Furthermore, UpToDate reviews on “Keloids and hypertrophic scars” (Goldstein and Goldstein, 2015), “Management of keloid and hypertrophic scars following burn injuries” (Gauglitz, 2015), and “Management of acne scars” (Saedi and Uebelhoer, 2015) do not mention micro-needling as a therapeutic option.

Ramult and colleagues (2018) noted that patients who suffer from scars or wrinkles have several therapeutic options to improve the appearance of their skin.  The available treatment modalities that provide desirable results are often overtly invasive and entail a risk of undesirable adverse effects.  Micro-needling has recently emerged as a non-ablative alternative for treating patients who are concerned with the aesthetic changes that result from injury, disease or ageing.  In a systematic review, these investigators evaluated the current evidence in the literature on micro-needling.  A systematic literature review was performed by searching the electronic databases PubMed and Google Scholar.  The reviewed articles were analyzed and compared on study design, therapeutic protocol, outcome parameters, efficacy measurement and results to evaluate the strength of the current evidence.  Micro-needling was examined in experimental settings for its effects on atrophic acne scars, skin rejuvenation, hypertrophic scars, keloids, striae distensae, androgenetic alopecia, melasma and acne vulgaris.  Several clinical trials used randomization and single-blind design to strengthen the validity of the study outcome.  Micro-needling showed noteworthy results when used on its own and when combined with topical products or RF.  When compared with other treatments, it showed similar results but was preferred due to minimal AEs and shorter down-time.  The authors concluded that this systematic review positioned micro-needling as a safe and effective therapeutic option for the treatment of scars and wrinkles.  These researchers stated that the current literature show some methodological shortcomings, and further research is needed to truly establish micro-needling as an evidence-based therapeutic option for treating scars, wrinkles and other skin conditions.

Fractional Ablative laser for the Treatment of Burn Scars

Sheridan et al (1997) stated that hypertrophic scarring is a major source of morbidity in patients with burns.  The physiologic characteristics are poorly understood, but increased neo-vascularity is typically seen in those wounds destined to become hypertrophic.  These investigators theorized that ablation of the developing neo-vasculature may favorably influence the development of the hypertrophic scar.  In a pilot study, these researchers established the practicality and safety of tunable dye laser neo-vessel ablation at 585 nm; 10 sites of evolving hypertrophic scar in 9 children were treated with a series of 450 msec 6.75 J/cm2 pulses at 585 nm.  Although all children had the expected transient post-treatment purpura, no pain, ulceration, pruritus, or worsening of the lesions was seen.  The authors concluded that this technique appeared safe and was worthy of continuing investigation.  They stated that investigations with higher fluences and multiple treatments were in progress.

Parrett and Donelan (2010) noted that hypertrophic scarring after partial-thickness burns is common, resulting in raised, erythematous, pruritic, and contracted scars.  Treatment of hypertrophic scars, especially on the face, is challenging and has high failure rates.  Excisional treatment has morbidity and can create iatrogenic deformities.  After an extensive experience over 10 years with laser therapy for the treatment of difficult scars, the pulsed dye laser (PDL) has emerged as a successful alternative to excision in patients with hypertrophic burn scars.  Multiple studies have shown its ability to decrease scar erythema and thickness while significantly decreasing pruritus and improving the cosmetic appearance of the scar.  The authors concluded that PDL should become an integral part of the management of burn scarring and would significantly decrease the need for excisional surgery.  This was a review; it did not provide clinical data to support its claim.

Hultman et al (2014) presented the largest study to-date that examined long-term impact of laser therapies, a potentially transformative technology, on scar remodeling.  These investigators conducted a prospective, before-after cohort study in burn patients with hypertrophic scars; PDL was used for pruritus and erythema; fractional CO2 laser was used for stiffness and abnormal texture.  Outcomes included Vancouver Scar Scale (VSS), which documents pigmentation, erythema, pliability, and height, as well as University of North Carolina "4P" Scar Scale (UNC4P), which rates pain, pruritus, paresthesias, and pliability.  A total of 147 burn patients (mean age of 26.9 years; total body surface area [BSA], 16.1 %) received 415 laser sessions (2.8 sessions/patient), 16 months (median) after injury, including PDL (n = 327) and CO2 laser (n = 139).  Laser treatments produced rapid, significant, and lasting improvements in hypertrophic scar.  Provider-rated VSS dropped from 10.43 [standard deviation (SD) 2.37] to 5.16 (SD 1.92), by the end of treatments, and subsequently decreased to 3.29 (SD 1.24), at a follow-up of 25 months.  Patient-reported UNC4P fell from 5.40 (SD 2.54) to 2.05 (SD 1.67), after the 1st year, and further decreased to 1.74 (SD 1.72), by the end of the study period.  The authors concluded that for the first time, ever, in a large prospective study, laser therapies have been shown to dramatically improve both the signs and symptoms of hypertrophic burn scars, as measured by objective and subjective instruments.  They stated that laser treatment of burn scars represented a disruptive innovation that could yield results not previously possible and may displace traditional methods of operative intervention.

Blome-Eberwein et al (2016) conducted a prospective study of fractional CO2 laser treatment of mature burn scars, comparing objective and subjective scar measurements evaluating at least 1 treatment and 1 control scar on the same patient pre- and post-treatments.  After institutional review board approval, burn survivors with mature blatant burn scars were invited to enter the study.  A series of 3 fractional CO2 laser treatments was performed in an office-setting, using topical anesthetic cream, at 40 to 90 mJ, 100 to 150 spots per cm.  Subjective and objective measurements of scar physiology and appearance were performed before and at least 1 month after the treatment series on both the treated and the control scar.  A total of 80 scars, 48 treatment and 32 control scars, were included in the study.  Treatment pain score averaged at 4.7/10 during and at 2.4/10 5 minutes after the treatment.  All treated scars showed improvement.  Objectively measured thickness, sensation, erythema, and pigmentation improved significantly in the treated scars (p = 0.001, 0.001, 0.004, and 0.001).  Elasticity improved, but without statistical significance; VSS assessments by an independent observer improved from 8 to 6; patient self-reported pain and pruritus remained unchanged in both groups.  The authors concluded that fractional CO2 laser treatment is a promising entity in the treatment of burn scars; these findings showed significant differences in objective measurements between the treated scars and the untreated control scars over the same time period.  In scar treatment studies, the patient/observer and VSS may not be sensitive enough to detect outcome differences.

Tao et al (2018) stated that burn scars cause cosmetic disfigurement and psychosocial distress.  These researchers presented 2 Fitzpatrick phototype (FP) III patients with burn scars successfully treated with combined PDL and non-ablative fractional lasers (NAFL).  Case 1: A 30-year old, FP III woman with a history of a 2nd-degree burn injury to the bilateral arms and legs affecting 30 % BSA presented for cosmetic treatment.  The patient received 3 treatments with 595 nm PDL (7 mm, 8 J, 6 ms), 6 with the 1,550 nm erbium:glass laser (30 mJ, 14 % density, 4 to 8 passes) and 5 with the 1,927 nm thulium laser (10 mJ, 30 % density, 4 to 8 passes).  Treated burn scars improved significantly in thickness, texture and color.  Case 2: A 33-year old, FP III man with a history of a 2nd-degree burn injury of the left neck and arm affecting 7 % BSA presented for cosmetic treatment.  The patient received 2 treatments with 595 nm PDL (5 mm, 7.5 J, 6 ms), 4 with the 1,550 nm erbium:glass laser (30 mJ, 14 % density, 4 to 8 passes) and 2 with the 1,927 nm thulium laser (10 mJ, 30 % density, 4 to 8 passes).  The burn scars became thinner, smoother and more normal in pigmentation and appearance.  These patients' burn scars were treated with a combination of PDL and NAFL (2 wavelengths).  The PDL targets scar hyper-vascularity, the 15,50 nm erbium:glass stimulates collagen re-modelling and the 1,927 nm thulium targets epidermal processes, particularly hyper-pigmentation.  They stated that this combination addressed scar thickness, texture and color with a low side effect profile and was particularly advantageous in patients at higher risk of post-procedure hyperpigmentation.  The authors concluded that their cases suggested the NAFL 1,550 nm erbium:glass/1,927 nm thulium device was effective and well-tolerated for burn scar treatment in darker skin types and could be used in combination with the 595-nm PDL and topical tacrolimus.  The thulium laser specifically addressed hyper-pigmentation, which was advantageous in patients with skin of color who were more prone to developing PIH.  Moreover, they stated that further studies are needed to optimize settings and establish treatment guidelines.

Zuccaro et al (2018) noted that treatment with laser therapy has the potential to greatly improve hypertrophic scarring in individuals who have sustained burn injuries.  More specifically, recent research has shown the success of using PDL  therapy to help reduce redness and post-burn pruritus and using ablative fractional CO2 laser therapy to improve scar texture and thickness.  This study described the authors’ early experience using laser therapy in their pediatric burn program and detailed their specific therapeutic approach when using each laser individually and in combination during the same procedure.  A retrospective before-after study of patients with hypertrophic burn scars who were treated with laser therapy at the authors’ pediatric institution was performed. A total of 125 patients were treated over a total of 289 laser sessions with more than 50 % of patients under the age of 5 years at the 1st treatment.  The majority of procedures were performed using both the PDL and CO2 lasers in combination.  Before-after VSS scores decreased from 7.37 (SD, 2.46) to 5.76 (SD, 2.29) after a single treatment.  The authors concluded that the results obtained from this study supported the use of laser therapy to improve hypertrophic burn scars in the pediatric population.  Moreover, they stated that rigorous randomized controlled trials (RCTs) are needed to confirm the effectiveness of this therapy.

Rodriguez-Menocal et al (2018) stated that hypertrophic scarring is a fibro-proliferative process that occurs following a 3rd-degree dermal burn injury, producing significant morbidity due to persistent pain, itching, cosmetic disfigurement, and loss of function due to contractures.  Ablative fractional lasers have emerged clinically as a fundamental or standard therapeutic modality for hypertrophic burn scars.  Yet the examination of their histopathological and biochemical mechanisms of tissue remodeling and comparison among different laser types has been lacking.  In addition, deficiency of a relevant animal model limits the ability to gain a better understanding of hypertrophic scar pathophysiology.  To evaluate the effect of ablative fractional lasers on hypertrophic 3rd-degree burn scars, these researchers have developed an in-vivo red Duroc porcine model; 3rd-degree burn wounds were created on the backs of animals, and burn scars were allowed to develop for 70 days before treatment.  Scars received treatment with either CO2 or erbium: yttrium aluminum garnet (YAG) ablative fractional lasers.  These investigators describe the effect of both lasers on hypertrophic third-degree burn scars in red Duroc pigs.  In this report, these researchers found that Er:YAG had improved outcomes versus fractional CO2.  Molecular changes noted in the areas of dermal remodeling indicated that matrix metalloproteinase 2, matrix metalloproteinase 9, and Decorin may play a role in this dermal remodeling and accounted for the enhanced effect of the Er:YAG laser.  They demonstrated that ablative fractional laser treatment of burn scars could lead to favorable clinical, histological, and molecular changes.  The authors concluded that the findings of this study provided support that hypertrophic 3rd-degree burn scars could be modified by fractional laser treatment.

International scar management guidelines (Monstrey, et al., 2014) included laser therapy among "Investigational treatments and those with less supporting evidence."

An UpToDate review on hypertrophic scars and keloids following burn injuries (Gauglitz, 2019) found that "laser treatment (particularly fractional ablation type), often in combination with local flap design and/or the application of intralesional agents, is increasingly being advocated and appears to show promise, though efficacy measured by objective parameters varies between studies. Patient satisfaction is nevertheless high. Further randomized controlled studies are needed." Furthermore, UpToDate reviews on “Overview of the management of the severely burned patient” (Gauglitz and Williams, 2019) and “Treatment of minor thermal burns” (Wiktor and Richards , 2019) do not mention laser / fractional ablative laser as a therapeutic option.

Intralesional Fiber Laser Device for the Treatment of Keloids

Li and colleagues (2019) presented the findings of a study conducted with a 1,470-nm diode laser using an intralesional optical fiber device for the treatment of inflamed keloid scars.  These researchers examined its efficacy as a novel alternative method to decrease keloid infection and inflammation.  Participants who underwent 1,470-nm laser treatment from February 2016 to February 2018 at the plastic and reconstructive surgery department of the Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University with keloid accompanying serious local infection and fester were included.  Subjects took curative effect evaluation before and 1 year after the treatment.  The test items included infection frequency in each year; pain (by VAS); itch (by VAS); quality of life (QOL), using QOL scale; and blood supply, using PeriCam PSI.  A total of 19 patients (mean age of 35.21 years, range of 11 to 66) with history of inflamed keloids with episodes of infection or abscess were enrolled.  Patients underwent to a 1,470-nm laser therapy for average of 1.16 times.  After treatment, infection frequency and blood supply in keloids were reduced (p < 0.001).  Pain, itching, and QOL were improved (p < 0.001).  The authors concluded that the findings of the present study showed that 1,470-nm fiber laser treatment could improve inflamed keloids fairly well by decreasing inflammation, and a relative stabilization of collagen composition.  Thus, it is an effective minimally invasive scar therapy, but further studies with more subjects and long-term follow-up are needed to confirm these preliminary findings.

Losartan Ointment for the Treatment of Hypertrophic Scars and Keloids

In a placebo-controlled, single-blind, pilot study (Hedayatyanfard and associates, 2018) on the effect of Losartan ointment on hypertrophic scars and keloid, a total of 37 adult volunteers were randomly assigned into losartan 5 % or placebo treatment groups.  The treatment was performed twice-daily for 3 months and a 6-month follow-up.  The treatment was evaluated using Vancouver scar scale (VSS) method.  A total of 30 participants were analyzed (Losartan ointment n = 20; placebo ointment n = 10; 7 placebo volunteers left the study because they thought the treatment was not effective for them).  In the Losartan group, VSS scores dropped significantly (p < 0.01) both in keloid and hypertrophic scar patients.  Vascularity and pliability were significantly reduced by Losartan treatment (p < 0.05).  The authors concluded that Losartan ointment (5 %) could alleviate hypertrophic scars and keloids.  These preliminary findings need to be validated by well-designed studies.

Topical Oxandrolone for the Treatment of Hypertrophic Scars and Keloids

Sobec and colleagues (2019) noted that wound healing is a complex process.  Despite extensive studies, hypertrophic scars and keloids still occur, and could be functionally and cosmetically problematic.  In an attempt to prevent hypertrophic scar formation, the effects of topical oxandrolone, using hyaluronic acid as a biomaterial, were studied on ear wounds in rabbits.  Deep 2nd-degree burns were inflicted on each ear in 10 New Zealand rabbits.  On the left ears, considered the control side, hyaluronic acid gel was applied, whereas on the right ears, the study side, a combination of oxandrolone and hyaluronic acid was applied.  Dressings were changed every 2 days for 2 weeks.  At week 10, biopsy specimens from the post-burn scars were harvested for histologic and immuno-histochemical examinations.  A total of 14 wounds were studied, 50 % on the control side and 50 % on the study side; 6 hypertrophic scars were encountered on the control side and only 1 scar was encountered on the study side.  In addition, an increased degree of inflammation, an increased amount of collagen and fibroblast cellularity, increased vascularization, and increased myofibroblast activity were observed on the control side.  The authors concluded that topical administration of oxandrolone using hyaluronic acid as a biomaterial led to better healing and prevented hypertrophic scar formation.  These preliminary findings need to be further investigated in human clinical trials.

Imiquimod for Prevention of Keloid Recurrence

Klotz and colleagues (2020) stated that imiquimod 5 % cream, an immune response modifier capable of inducing IFN-α, tumor-necrosis factor- alpha (TNF-α), and interleukins (ILs)1, 6, and 8. It was approved for use in the management of genital and peri-anal warts and soon embraced as a method to diminish the recurrence of keloids post-excision.  A previous meta-analysis included 4 studies.  This meta-analysis was part of a larger systematic review project on the effect of moisturizers on scars.  It was conducted following an a priori protocol and the guidance of the Joanna Briggs Institute.  Databases searched included PubMed, CINAHL, Embase, and Web of Science.  After screening and critical appraisal, subgroup meta-analysis on excision method and location of the keloid was conducted using the Miller approach for proportional meta-analysis and a random effects model.  A total of 7 studies, including 77 subjects and 82 keloids were included.  Meta-analysis revealed a recurrence rate of 39 % (95 % CI: 8.4 to 74.4 %; I2 = 87.5 %) following application of Imiquimod post-excision.  The use of primary excision or tangential excision did not alter the outcome.  For analysis based on the location of the keloid scar, earlobe keloids had a recurrence rate of 5.4 % (95 % CI:  0 to 21.7 %; I2 = 52.9 %).  For keloids excised from other areas (predominantly on the trunk) recurrence rate was higher, at 76.8 % (95 % CI: 36.1 to 100 %).  The authors concluded that for keloids, imiquimod application post-excision resulted in highly variable recurrence rates; there is very low certainty in the effect of Imiquimod; thus, it is not recommended as a therapeutic option.

Laser for Reduction of Hypertrophic Scar Formation

Behrouz-Pirnia and colleagues (2020) noted that hypertrophic scars frequently follow primary closure of surgical wounds.  Laser application at or shortly after suture may be associated with a reduction in scar formation, although the respective study results varied.  These investigators examined the efficacy of early laser applied within the first 6 months after surgery to reduce scar formation compared to no treatment.  They searched the databases Medline and CENTRAL on January 14, 2019 and included RCTs.  Primary outcome was the VSS; measure of treatment effect was the MD from baseline.  A total of 17 relevant RCTs randomized 430 scars (413 assessed) and compared laser versus no treatment; 14 studies applied a split-scar and 3 applied a simple parallel design; 3 studies with a split-scar design favored the laser group on VSS, and 1 study had indifferent findings.  Considerable heterogeneity I2 = 86 % did not justify a meta-analysis.  The remaining 13 studies did not report appropriate data.  The authors concluded that on the basis of the currently available evidence, they were uncertain whether early laser could reduce scar formation, and more high-quality research is needed for a definitive conclusion.

High-Frequency Ultrasound and Shear Wave Elastography for Quantitative Assessment of Treatment Efficacy in Keloids

In a preliminary study, Huang and colleagues (2020) examined the performance of high-frequency ultrasound (HFUS) and shear wave elastography (SWE) in the quantitative evaluation of therapeutic responses of keloids.  A total of 43 patients with 76 keloids were recruited into this study.  In keloids and symmetrical sites, the skin thickness was measured using HFUS and skin stiffness expressed as elastic moduli (Young's modulus and shear wave velocity) was measured using SWE.  The coefficient of variation values were calculated by using difference values of skin elastic moduli and skin thickness.  A significant increase of both skin stiffness and thickness appeared in pre-treated keloids compared with post-treated keloids (p < 0.001) and normal controls (p < 0.001), respectively.  Stiffness in post-treated keloids and normal skins was significantly different (p < 0.001), while the difference in thickness measurements showed no significance (p = 0.56, > 0.05).  The coefficient of variation of Young's modulus was the highest when compared between pre-treated keloids and theirs site-matched areas; pre-treated and post-treated keloids.  The authors concluded that SWE, which showed greater ability in determining the extent of keloids recovery, may provide an ideal tool to evaluate the stiffness of keloids and theirs therapeutic response.

The authors stated that this study had several drawbacks.  The number of samples in this study was still relatively small (n = 43 subjects).  Moreover, because this study was a preliminary study, keloids that received different treatments were not grouped to compare the efficacy of applied treatments.  These aspects need to be further refined in the future.  These researchers will attempt to increase sample size and further validate the role of SWE in identifying keloids, monitoring changes in keloids before and after treatment, as well as assisting clinicians to examine the curative effect of different therapeutic methods.

Combined Micro-Plasma Radiofrequency with Hypo-Fractionated Electron-Beam Radiation for the Treatment of Keloids

Zhang and colleagues (2019) stated that micro-plasma radiofrequency (MPR) technology has been demonstrated a safe and effective treatment for kinds of scars, but there is no report about the application of the MPR on keloids.  These investigators examined the use MPR technology combining with hypo-fractionated electron-beam radiation (EBR) to cure keloids.  From February 2013 to December 2016, a total of 22 Asian patients (16 male, 6 female, age 19 to 46 years, mean age of 28.14 ± 7.31 years) with keloids over 6 months were enrolled in this study.  All patients received a single MPR technology treatment by roller tip at 80-100 Watt, and then hypo-fractionated EBR of 6 MeV were performed twice, within 24 hours and 1 week after the operation with 9 Gy per time.  Improvement were determined by the VSS according to digital photographs.  The results showed that the volume of keloids reduced significantly among most patients.  Only 3 patients encountered mild-to-moderate hyper-pigmentation, and no malignance and worsening or recurrence of scars was observed.  The authors concluded that MPR technology combined with post-operative hypo-fractionated EBR therapy was an effective method for patients with multiple keloids distributed widely on the body with minimal complications, especially for patients with widely distributed keloids. Moreover, these researchers stated that further studies are needed to examine the effect of MPR technology in combination with other adjuvant therapies like irradiation and intralesional therapies.

The authors stated that this study had several drawbacks.  These investigators observed lower treatment efficacy with thick keloids, along with longer re-epithelization time, higher risk of infection and hyper-pigmentation and poor anesthetic penetration.  All of the above could decrease patients’ satisfaction.  In addition, this combination treatment was not recommended for patients who were contraindicated for radiotherapy (e.g., younger than 12 years), and on radio-sensitive locations like breasts and thyroid.  Furthermore, a study with a control-group is still needed to prove the safety and efficacy of the novel therapy and compare the therapeutic response of keloids with different thickness.

Interleukin-10 for the Treatment of Keloids

Shi and colleagues (2019) examined the therapeutic effect of interleukin-10 (IL-10) on the proliferation of keloid fibroblasts.  Keloid fibroblasts were isolated, primarily cultured, and treated with IL-10 at different concentrations.  Normal skin fibroblasts were used as normal control.  Immunofluorescent staining was performed to identify the establishment of keloid, as well as normal skin fibroblast.  Cell Counting Kit-8 (CCK-8) was used to monitor the proliferative variation, while Western blot was performed to detect the expression variation of key members involved in the TGF-β/Smad signaling pathway.  Identified by the IF staining of Vimentin, a classical biomarker of fibroblast, both primary culture of keloid and normal skin fibroblasts have been established.  Compared with control, the proliferation of keloid fibroblasts was shown to be significantly suppressed on treatment with IL-10 in a time and dose-dependent manner.  Expression of P-Smad2/3 and Smad4 were increasingly down-regulated, whereas Smad-7 was up-regulated with the increasing concentration of IL-10.  By contrast, the variation of Smad 2/3 expressions was hardly influenced.  Furthermore, the collagen Type I and collagen Type II were found to be markedly decreased after treatment with IL-10.  The authors concluded that IL-10 was shown to be able to significantly inhibit the proliferation of keloid fibroblasts, which was explicitly and strongly suggestive of its potential therapeutic effect in the management of keloid.  Furthermore, these researchers stated that these findings require a further acknowledgment using animal model in-vivo.  In addition, since the TGF-β/Smad signaling pathway was Smad-dependent and-independent, whether or not IL-10 could affect other signaling pathways remains to be further investigated.

Intermittent Magnetic Pressure Therapy for the Treatment of Keloids

Jun and colleagues (2019) stated that keloids are benign fibro-proliferative lesion, related to excessive inflammatory reactions in certain anatomical areas, including the auricles.  Their specific etiology remains unclear; nonetheless they exhibit tumor-like characteristics of significant recurrence and cause emotional distress, even with various treatment strategies.  These researchers applied intermittent magnetic pressure therapy (MPT) on ear keloids in combination with surgical excision, and presented its effectiveness.  Patients with ear keloid were treated with surgical excision followed by MPT.  The keloid tissues underwent excision and keloid marginal flaps were utilized for wound closure.  Intermittent MPT was administered 2 weeks after the surgical procedure.  The MPT consisted of a 3-hour application and 2-hour resting protocol (9 hour/day), and lasted for 6 months.  The results were analyzed 6 months after the therapeutic procedures, using the scar assessment scale.  A total of 22 ear keloids from 20 patients were finally reviewed.  Among the keloids that completed the therapeutic course, 20 ear keloids out of 22 in total (90.9 %) were successfully eradicated; 2 patients (2 keloids) exhibited slight under-correction.  Post-operative complications such as wound dehiscence or surgical site infection were not noted.  The scar assessment scale demonstrated a significant improvement in each index.  The intermittent MPT led to patient compliance, and avoided pressure-related pain and discomfort.  The authors concluded that excision followed by intermittent MPT successfully reduced the burden of fibro-proliferative keloids, and had good patient compliance.  These researchers stated that the role of intermittent MPT and resting should be studied with regard to keloid tissue re-modeling.

The authors stated that this study had several drawbacks.  The sample size was relatively small (n = 20 patients) and there was no control group.  Additionally, considering its retrospective nature and relatively short period of post-operative follow-up period (6 months), studies with longer follow-up and larger sized patient samples are needed to confirm the long-term efficacy of this management protocol.

Photodynamic Therapy for the Treatment of Keloids

Cui and colleagues (2020) noted that photodynamic therapy (PDT) has been shown to significantly inhibit fibroblast activity.  However, the effect of PDT mediated by the photo-sensitizer hematoporphyrin mono-methyl ether (HMME) on keloids is not known well.  These researchers examined the efficacy of HMME-PDT in cellular and animal models of keloids.  Keloid fibroblasts (KFbs) were isolated from human keloid specimens and the proliferation, invasion, and migration of KFbs after HMME-PDT treatment was examined in-vitro.  Apoptosis in cells was measured by flow cytometry.  Cysteinyl aspartate specific proteinase 3 (Caspase3) expression was determined by immunofluorescence staining and Western blot.  HMME-PDT inhibited KFbs proliferation, invasion, migration, increased apoptosis rate and enhanced caspase3 and cleaved caspase3 expression.  The keloid graft transplantation was performed by using nude mice.  The growth of the graft was monitored every 3rd day.  Interleukin-6 (IL-6) and TNF-α mRNA expression were detected by real-time qPCR.  It was observed that HMME-PDT attenuated graft growth and reduced vessel density in the keloid grafts.  However, HMME-PDT did not alter IL-6 and TNF-α mRNA expression in the keloid grafts.  Moreover, HMME-PDT suppressed TGF-β1 and small phenotype and Drosophila Mothers Against Decapentaplegic 3 (Smad3) expression in both KFbs and keloid grafts.  The authors concluded that the available evidence suggested that HMME-PDT inhibited the growth of the keloid graft by promoting the apoptosis of fibroblasts and reducing vessel formation of the keloid graft.  These preliminary findings need to be validated by well-designed human clinical trials.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

17110 Destruction (e.g., laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement), of benign lesions other than skin tags or cutaneous vascular proliferative lesions; up to 14 lesions [covered for keloid scar documented to be painful, ulcerated, pruritic causing a functional impairment (i.e. restricted movement)]
17111     15 or more lesions [keloid scars]
11900 Injection, intralesional; up to and including 7 lesions [corticosteroids]
11901     more than 7 lesions[corticosteroids]

CPT codes not covered for indications listed in the CPB:

Extracorporeal shock wave therapy, Growth hormone releasing peptide 6, Intense pulsed light, Intralesional fiber laser device, high-frequency ultrasound and shear wave elastography, interleukin-10, intermittent magnetic pressure therapy, hypo fractionated electron beam radiation, photodynamic therapy - no specific code
0479T Fractional ablative laser fenestration of burn and traumatic scars for functional improvement; first 100 cm2 or part thereof, or 1% of body surface area of infants and children
0480T Fractional ablative laser fenestration of burn and traumatic scars for functional improvement; each additional 100 cm2, or each additional 1% of body surface area of infants and children, or part thereof (List separately in addition to code for primary procedure)
15769 Grafting of autologous soft tissue, other, harvested by direct excision (eg, fat, dermis, fascia)
15771 Grafting of autologous fat harvested by liposuction technique to trunk, breasts, scalp, arms, and/or legs; 50 cc or less injectate
+15772     each additional 50 cc injectate, or part thereof (List separately in addition to code for primary procedure)
15773 Grafting of autologous fat harvested by liposuction technique to face, eyelids, mouth, neck, ears, orbits, genitalia, hands, and/or feet; 25 cc or less injectate
+15774     each additional 25 cc injectate, or part thereof (List separately in addition to code for primary procedure)
38232 Bone marrow harvesting for transplantation; autologous
38240 - 38241 Hematopoietic progenitor cell (HPC) transplantation
99183 Physician or other qualified health care professional attendance and supervision of hyperbaric oxygen therapy, per session

Other CPT codes related to the CPB:

11042 - 11047 Debridement; subcutaneous tissue, muscle/fascia, bone
15852 Dressing change (for other than burns) under anesthesia (other than local)

HCPCS codes covered for indications listed in the CPB:

J0702 Injection, betamethasone acetate 3 mg and betamethasone sodium phosphate 3mg
J1020 Injection, methylprednisolone acetate, 20 mg
J1030 Injection, methylprednisolone acetate, 40 mg
J1040 Injection, methylprednisolone acetate, 80 mg
J1100 Injection, dexamethasone sodium phosphate, 1 mg
J1700 Injection, hydrocortisone acetate, up to 25 mg
J1710 Injection, hydrocortisone sodium phosphate, up to 50 mg
J1720 Injection, hydrocortisone sodium succinate, up to 100 mg
J2650 Injection, prednisolone acetate, up to 1 ml
J3300 Injection, triamcinolone acetonide, preservative free, 1 mg
J3301 Injection, triamcinolone acetonide, not otherwise specified, 10 mg
J3302 Injection, triamcinolone diacetate, per 5 mg
J3303 Injection, triamcinolone hexacetonide, per 5 mg
J7638 Dexamethasone, inhalation solution, compounded product, administered through DME, unit dose form, per milligram
J9190 Fluorouracil, 500 mg

HCPCS codes not covered for indications listed in the CPB:

Dermal substitutes, Losartan ointment, Topical oxandrolone - no specific code:

A6025 Gel sheet for dermal or epidermal application, (e.g., silicone, hydrogel, other), each
C9257 Injection, bevacizumab, 0.25 mg
G0277 Hyperbaric oxygen under pressure, full body chamber, per 30 minute interval
J0585 Injection, onabotulinumtoxinA, 1 unit [Botox]
J0586 Injection, abobotulinumtoxinA, 5 units [Dysport]
J1438 Injection, etanercept, 25 mg
J3470 Injection, hyaluronidase, up to 150 units
J3471 Injection, hyaluronidase, ovine, preservative free, per 1 USP unit (up to 999 USP units)
J3472 Injection, hyaluronidase, ovine, preservative free, per 1,000 USP units
J3473 Injection, hyaluronidase, recombinant, 1 USP unit
J9035 Injection, bevacizumab, 10 mg
J9040 Injection, bleomycin sulfate, 15 units
J9212 Injection, interferon Alfacon-1, recombinant, 1 mcg
J9213 Interferon alfa-2A, recombinant, 3 million units
J9214 Interferon alfa-2B, recombinant, 1 million units
J9215 Interferon alfa-N3, (human leukocyte derived), 250,000 IU
J9280 Injection, mitomycin, 5 mg
Q5107 Injection, bevacizumab-awwb, biosimilar, (mvasi), 10 mg

ICD-10 codes covered if selection criteria are met:

L91.0 Hypertrophic scar [keloid]

The above policy is based on the following references:

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