KELOID Keloids and hypertrophic scars represent an exuberant healing response that poses a challenge for physicians.

Patients at high risk of keloids are usually younger than 30 years and have darker skin. Sternal skin, shoulders and upper arms, earlobes, and cheeks are most susceptible to developing keloids and hypertrophic scars. High-risk trauma includes burns, ear piercing, and any factor that prolongs wound healing. Keloid formation often can be prevented if anticipated with immediate silicone elastomer sheeting, taping to reduce skin tension, or corticosteroid injections. Once established, however, keloids are difficult to treat, with a high recurrence rate regardless of therapy. Evidence supports silicone sheeting, pressure dressings, and corticosteroid injections as first-line treatments. Cryotherapy may be useful, but should be reserved for smaller lesions. Surgical removal of keloids poses a high recurrence risk unless combined with one or several of these standard therapies. Alternative postsurgical options for refractory scars include pulsed dye laser, radiation, and possibly imiquimod cream. Intralesional verapamil, fluorouracil, bleomycin, and interferon alfa-2b injections appear to be beneficial for treatment of established keloids. Despite the popularity of over-the-counter herb-based creams, the evidence for their use is mixed, and there is little evidence that vitamin E is helpful. Keloids are elevated fibrous scars that extend beyond the borders of the original wound, do not regress, and usually recur after excision. The term is coined from the Greek word cheloides, meaning crab's claw.1 Hypertrophic scars are similar, but are confined to the wound borders and usually regress over time (Table 1).1,2 Scar hypertrophy usually appears within a month of injury, whereas keloids may take three months or even years to develop.3 Both represent abnormal responses to dermal injury, with exuberant deposition of collagen developing over three basic stages: (1) inflammation (first three to 10 days); (2) proliferation (next 10 to 14 days); and (3) maturation or remodeling (two weeks to years).1 The treatments for keloids and hypertrophic scars are similar, but hypertrophic scars have a better prognosis. Risk Factors and Etiology The primary risk factor for keloids is darkly pigmented skin, which carries a 15- to 20-fold increased risk, perhaps because of melanocyte-stimulating hormone anomalies.4 Familial predisposition, with autosomal dominant and recessive genetic variants is recognized.5 Black, Hispanic, and Asian persons are far more likely to develop keloids than white persons.6,7 Hypertrophic scars, however, are less likely to be associated with skin pigmentation.

Keloids are more common in persons younger than 30 years, with risk peaking between 10 to 20 years of age, and in patients with elevated hormone levels (e.g., during puberty or pregnancy).8Sternal skin, shoulders and upper arms, earlobes, and cheeks are most susceptible to developing keloids9 (Figure 1). Certain types of trauma and delayed healing (longer than three weeks) heighten keloid incidence even more, with burns carrying the highest risk. Acne, ear piercing, chickenpox, vaccinations (particularly bacille Calmette-Gurin vaccination), biopsy procedures, and lacerations may cause abnormal scarring (Figure 2). Acne keloids are particularly common. Keloids are more than just cosmetically unacceptable; many are also pruritic and painful. They often result in severe emotional distress.

Figure 1. Cheeks are a common location for keloids, often secondary to acne. Copyright Logical Images, Inc.

Figure 2.

Mild trauma, often from shaving, can result in formation of a keloid, such as this one along the hairline.

Prevention Before any surgical procedure, patients should be asked if they have had previous problems with scarring. Discuss the potential for keloids as part of informed consent, and discourage ear piercing and other elective procedures in persons with dark skin. If ears are pierced despite this advice, pressure earrings are commercially available for reducing keloid risk. If surgery cannot be avoided in a high-risk patient, immediate silicone elastomer sheeting or corticosteroid injections should be instituted. Anything that expedites wound healing and diminishes skin tension (e.g., postsurgical taping for 12 weeks) will diminish risk.10 The cosmetic outcome of wounds closed with standard suture techniques appears to be similar to that of those closed with 2-octyl cyanoacrylate dermal adhesive (Dermabond). One small study showed that hypertrophic scars occurred in five out of 24 repairs with Dermabond versus three out of 28 repairs with traditional suture.11 Treatment Keloid and hypertrophic scar therapy is challenging and controversial (Table 2).1,79,1221 Both conditions respond to the same therapies, but hypertrophic scars are easier to treat. The large number of treatment options is a reflection of the poor quality of research on this topic, with no single proven best treatment or combination of treatments. First-line options include silicone sheeting, pressure treatment, and corticosteroid injections, but all of these require exemplary adherence and follow-up. Cryotherapy is useful, but only for smaller lesions, such as those resulting from acne. Cryotherapy may cause hypopigmentation in patients with dark skin. Surgical removal of keloids, although temporarily gratifying, is almost invariably followed (50 to 100 percent) by even more aggressive regrowth of scar tissue.8 Therefore, all surgical options

should be followed by corticosteroid injections, silicone sheeting, or these options combined with pulsed dye laser. A variety of other choices are emerging, but are less well studied. CORTICOSTEROID INJECTIONS Corticosteroid injections for prevention and treatment of keloids and hypertrophic scars are perhaps the first-line option for family physicians. Corticosteroids suppress inflammation and mitosis while increasing vasoconstriction in the scar. Triamcinolone acetonide suspension (Kenalog) 10 to 40 mg per mL (depending on the site) is injected intralesionally, which, although painful, will eventually flatten 50 to 100 percent of keloids, with a 9 to 50 percent recurrence rate.9 Lidocaine (Xylocaine) may be combined with the corticosteroid to lessen pain, whereas using adjunctive cryotherapy immediately before injection may make the procedure easier by softening the scar (based on expert opinion).22Combining cryotherapy and corticosteroid injections also improves outcomes more than either modality alone, although hypopigmentation is always a significant concern.23,24 Usually, two or three injections are given a month apart; however, therapy can continue for six months or longer.25 Newer keloids are more responsive to therapy than older, established lesions. Corticosteroid injections are more effective if combined with surgery; the sooner instituted, the greater the likelihood of success. Common adverse effects include atrophy, telangiectasias, and hypopigmentation. SILICONE SHEETING Silicone elastomer sheeting is a noninvasive and extensively studied approach to the prevention and treatment of keloids and hypertrophic scars. Silicone sheets are thought to work by increasing the temperature, hydration, and perhaps the oxygen tension of the occluded scar, causing it to soften and flatten.8 This technique should be avoided on open wounds, but can be applied as soon as the skin heals. More than 60 products have been marketed, including silicone sheets, strips, gels, sprays, and foams. Most are available over the counter, but can be expensive. To be effective, sheets must be worn over the scar for 12 to 24 hours per day for two to three months.8 The sheet and the scar should be washed daily with mild soap and water. The sheets can be reused until they start to disintegrate. Although most studies suggest silicone sheeting results in fewer scars in persons at risk, a recent Cochrane review concluded that most research in this area was of poor quality and highly susceptible to bias.26 Similar to silicone sheeting is the use of pressure dressings or garments, especially for the prevention of burn scars. However, pressure dressings (24 to 30 mm Hg) must be worn for six to 12 months, which is difficult and uncomfortable for most patients.27

COMBINATION THERAPY FOLLOWING SURGERY If neither silicone nor corticosteroids are effective over 12 months, second-line surgical treatment followed by corticosteroids and possibly silicone sheeting should be considered. The use of corticosteroid injections following keloid surgery reduces the recurrence rate to lless than 50 percent.28 Scar excision may be complete, or a minute remnant of scar may be left on the wound margin, which may reduce recurrence (based on expert opinion). Immediate wound edge corticosteroid injection after the excision is followed by weekly injections for two to five weeks and monthly injections for three to six months.9 A triple keloid therapy combining surgery, corticosteroids, and silicone sheeting has been shown to be even more effective, with only a 12.5 percent recurrence rate after 13 months.14 However, this approach was described as tedious and time intensive by the author of the study and requires a motivated patient. IMIQUIMOD Imiquimod 5% cream (Aldara), an immune response modifier that enhances healing, has also been used to help prevent keloid recurrence after surgical excision. The cream is applied on alternate nights for eight weeks after surgery. Although the trials have been small, the postsurgical recurrence rate averaged only 28 percent over a six- to nine-month follow-up period, with best results (2.9 percent recurrence) in low skin tension areas such as earlobes.12 Adverse effects include irritation and hyperpigmentation. PULSED DYE LASER Treatment of keloids with short-pulsed, 585-nm pulsed dye laser has shown limited promise, with a 57 to 83 percent improvement rate.15 It is more vascular-specific than other laser therapies and appears to be most effective if used early and in conjunction with other techniques. Laser-treated portions of keloidal median sternotomy scars showed significant improvement in erythema, pruritus, and scar height compared with untreated portions of the same scars, and these improvements persisted for at least six months.16 The principal effect of a pulsed dye laser is on scar microvasculature, reducing erythema and pruritus and improving skin texture. The effectiveness of this therapy remains controversial, however, with other studies showing insignificant reduction in scar thickness.29Disadvantages include significant expense and availability only through a specialist. OTHER THERAPIES Other therapies with limited studies include intralesional verapamil, fluorouracil, bleomycin, and interferon alfa-2b injections. Although all of these have results comparable or sometimes superior to corticosteroid injection and silicone sheeting, the optimal keloid therapy remains undefined. Combinations of therapies have proved superior to individual approaches.

Intralesional verapamil (2.5 mg per mL) in conjunction with silicone sheeting reduced keloid postsurgical recurrence by 90 percent at 18 months (54 percent of patients were keloid-free; 36 percent had partial success) compared with only 18 percent showing any improvement with silicone sheeting alone (no patients were keloid-free).17 Calcium antagonists appear to work by reducing collagen production and may be a reasonable and safe alternative to corticosteroid injection in the future. Intralesional fluorouracil (50 mg per mL, two to three times per week) appears to shrink keloids safely while avoiding the tissue atrophy and telangiectasia that may occur with repeated corticosteroid injections.30 Combining fluorouracil with corticosteroid injections and pulsed dye laser produced superior results more rapidly than corticosteroid injections alone or corticosteroids with fluorouracil.13 Good to excellent responses at 12 weeks as rated by a blinded observer were 15 percent for triamcinolone acetonide, 40 percent for triamcinolone plus fluorouracil, and 70 percent for all three modalities (all significant). Combining corticosteroids and fluorouracil diminished the adverse effects of corticosteroids. Rare skin complications of fluorouracil may include hyperpigmentation and wound ulceration. No systemic adverse effects (e.g., anemia, leucopenia, thrombocytopenia) occurred in this study. Bleomycin is another useful chemotherapeutic agent; a standard approach is bleomycin tattooing 0.1 mL (1.5 IU per mL) over two to six sessions, with a maximal dose of 6 mL.31 Results of one study showed a total regression of 84 percent.18 Multiple intralesional punctures are probably safe because it is likely that less than 5 percent of the dose ever reaches the bloodstream.18 Compared with triamcinolone injections combined with cryotherapy, bleomycin tattoo performed significantly better for keloids larger than 100 mm2 (P = .03).19 Systemically administered bleomycin is capable of causing pulmonary fibrosis (at doses greater than 400 U) and various cutaneous reactions (at doses of 200 to 300 U), including hair loss, hyperpigmentation, fibrosis, and vasospasm, any of which warrants cessation of treatment.32 Intralesional interferon alfa-2b (1.5 million IU twice daily for four days) reduced keloid size by 50 percent over nine days, proving superior to intralesional corticosteroids.31 Interferon alfa-2b was also more effective than corticosteroids for preventing keloid recurrence after excision. Injection pain and expense (about $100 per treatment) are the main concerns. A liposome-encapsulated interferon alfa-2b cream is also being investigated for scar reduction.33 Radiation, alone or (more commonly) after keloid excision, is a much more controversial option. It may pose a risk of local growth inhibition in children and possibly subsequent cancer. Commondosesrangebetween1,500to 2,000 rads over five to six sessions following surgery.28 The success rate for radiation alone is 56 percent (range of 10 to 94 percent), but this

increases to 76 percent (range of 25 to 100 percent) if administered immediately after surgery.9 Another study showed a 67 percent success rate with radiation, increasing to 75 percent if delivered within 48 hours of surgery.20 Most physicians would reserve radiation as a last resort for keloids refractory to all other approaches. OVER-THE-COUNTER TREATMENTS Many patients use topical vitamin E (alpha-tocopherol) hoping its antioxidant properties will prevent scars. However, there is little evidence that it is helpful, and some patients develop a contact dermatitis that may delay healing.34 Used early on, vitamin E may also reduce the tensile strength of the scar, and its use should be discouraged. Another over-the-counter option is onion extract topical gels (e.g., Mederma), but limited clinical trials have failed to demonstrate any clinical improvement in scar height, erythema, or pruritis.35,36Contractubex gel (not available in the United States) contains onion extract with heparin, which is thought to promote scar maturity. Although one trial compared this product favorably with corticosteroids, another showed that it was ineffective in improving scar height and itching.21,37 Moist exposed burn ointment contains multiple herbs with betasitosterol, which provides hydration and possible benefits to wound healing.38 Another plant extract product contains Centella asiatica and Bulbine frutescens (Alpha Centella cream), which may increase wound strength if used in the first six to eight weeks.39 All of these commercially available products emphasize preventive use because they are unlikely to reverse well-established keloids.

Medical Care
No single therapeutic modality is best for all keloids. The location, size, and depth of the lesion; the age of the patient; and the past response to treatment determine the type of therapy used. Prevention is key, but therapeutic treatment of hypertrophic scars and keloids includes occlusive dressings, compression therapy, intralesional corticosteroid injections, cryosurgery, excision, radiation therapy, laser therapy, interferon (IFN) therapy, 5-fluorouracil (5-FU), doxorubicin, bleomycin, verapamil, retinoic acid, imiquimod 5% cream, tamoxifen, tacrolimus, botulinum toxin, and over-the-counter treatments (eg, onion extract; combination of hydrocortisone, silicon, and vitamin E). Other promising therapies include antiangiogenic factors, including vascular endothelial growth factor (VEGF) inhibitors (eg, bevacizumab), phototherapy (photodynamic therapy [PDT], UVA-1 therapy, narrowband UVB therapy), transforming growth factor (TGF)beta3, tumor necrosis factor (TNF)-alpha inhibitors (etanercept), and recombinant human interleukin (rhIL-10), which are directed at decreasing collagen synthesis.

Prevention
Prevention is the first rule in keloid therapy. Avoid performing nonessential cosmetic surgery in patients known to form keloids; however, the risk is lower among patients who have only earlobe lesions. Close all surgical wounds with minimal tension. Incisions should not cross joint spaces. Avoid making midchest incisions, and ensure that incisions follow skin creases whenever possible.

Standard Treatments
These include occlusive dressings, compression therapy, and intralesional corticosteroid injections.

Occlusive dressings
Occlusive dressings include silicone gel sheets and dressings, nonsilicone occlusive sheets, and Cordran tape. These measures have been used with varied success. Antikeloidal effects appear to result from a combination of occlusion and hydration, rather than from an effect of the silicone. Previous studies have shown that in patients treated with silicone occlusive sheeting with pressure worn 24 h/d for up to 12 months, 34% showed excellent improvement, 37.5% showed moderate improvement, and 28% demonstrated no or slight improvement. Of patients treated with semipermeable, semiocclusive, nonsilicone-based dressings for 8 weeks, 60% experienced flattening of keloids, 71% had reduced pain, 78% had reduced tenderness, 80% had reduced pruritus, 87.5% had reduced erythema, and 90% were satisfied with the treatment. Cordran tape is a clear surgical tape that contains flurandrenolide, a steroid that is uniformly distributed on each square centimeter of the tape, and it has been shown to soften and flatten keloids over time.

Compression therapy
Compression therapy involves pressure, which has long been known to have thinning effects on skin. Reduction in the cohesiveness of collagen fibers in pressure-treated hypertrophic scars has been demonstrated by electron microscopy. Compression treatments include button compression, pressure earrings, ACE bandages, elastic adhesive bandages, compression wraps, spandex or elastane (Lycra) bandages, and support bandages. In one study, button compression (2 buttons sandwiching the earlobe applied after keloid excision) prevented recurrence during 8 months to 4 years of follow-up observation. Other pressure devices include pressure earrings and pressure-gradient garments made of lightweight porous Dacron, spandex (also known as elastane), bobbinet fabric (usually worn 1224 h/d), and zinc oxide adhesive plaster. Overall, 60% of patients treated with these devices showed 75-100% improvement.

Corticosteroids
Corticosteroids, specifically intralesional corticosteroid injections, have been the mainstay of treatment. Corticosteroids reduce excessive scarring by reducing collagen synthesis, altering glucosaminoglycan synthesis, and reducing production of inflammatory mediators and fibroblast proliferation during wound healing. The most commonly used corticosteroid is triamcinolone acetonide (TAC) in concentrations of 10-40 mg/mL administered intralesionally with a 25- to 27gauge needle at 4- to 6-week intervals. Intralesional steroid therapy as a single modality and as an adjunct to excision has been shown to be efficacious in various studies. Response rates varied from 50-100%, with recurrence rates of 9-50% in completely resolved scars. When combined with excision, postoperative intralesional TAC injections yielded a recurrence rate of 0-100%, with most studies citing a rate of less than 50%. Complications of repeated corticosteroid injections include atrophy, telangiectasia formation, and pigmentary alteration. In a recent report, a new standardized corticosteroid therapy protocol has been shown to reduce the recurrence of keloids and hypertrophic scars after excision. Intralesional TAC injection was performed after removal of the sutures and then once every 2 weeks (total of 5 treatments). In addition, patients were instructed to apply corticosteroid ointment twice daily for 6 months to the wounds after suture removal. Only 3 (14.3%) of 21 keloids and 1 (16.7%) of 6 hypertrophic scars recurred.[3]

Current and New Treatments

Current treatments for keloids and hypertrophic scars include intralesional IFN; 5-FU; doxorubicin; bleomycin; verapamil; retinoic acid; imiquimod 5% cream; tacrolimus; tamoxifen; botulinum toxin; TGF-beta3; rhIL-10; VEGF inhibitors; etanercept; mannose-6-phosphate inhibitors (M6P); onion extract; the combination of hydrocortisone, silicon, and vitamin E; PDT; intense pulsed light (IPL); UVA-1; and narrowband UVB. IFN therapy, including IFN alfa, IFN beta, and IFN gamma, has been demonstrated in in vitro studies to reduce keloidal fibroblast production of collagen types I, III, and VI mRNA. IFN alfa and IFN beta also reduce fibroblast production of glycosaminoglycans (GAGs), which form the scaffolding for the deposition of dermal collagen. IFN gamma enhances GAG production.

IFN alfa, IFN beta, and IFN gamma have been shown to increase collagenase activity. Studies have shown that IFN gamma modulates a p53 apoptotic pathway by inducing apoptosis-related genes. p53 is a protein synthesized following DNA damage. Once damage is repaired, p53 is degraded. Mutations of this protein are believed to predispose cells to hyperproliferation, possibly resulting in keloid formation. In addition, p53 is a potent suppressor of interleukin (IL) 6, a cytokine implicated in hyperproliferative and fibrotic conditions. IFN injected into the suture line of keloid excision sites may be prophylactic for reducing recurrences. Berman and Flores reported statistically significant fewer keloid recurrences in a study of 124 keloid lesions after postoperative IFN alfa-2b injection treatment (5 million U, 1 million U injected per cm of scar) into keloid excision sites (18%) versus excision alone (51.1%) and TAC treatment (58.4%).[4] Tredget et al showed a significant increase in the rate of scar improvement compared with the control period of time (P = .004) after injecting 9 patients with hypertrophic scars with 1 X 106 units of human recombinant IFN alfa-2b subcutaneously, daily for 7 days, and then 2 X 106 units administered 3 times per week for 24 weeks in total.[5] Scar assessment (P < .05) and scar volume (P < .05) also improved after 3 months of treatment. No recurrences were reported after stopping IFN therapy. Conejo-Mir et al reported that 66% of keloids (n = 20) did not recur after 3 years of follow-up after treating 30 keloids with ultrapulse carbon dioxide laser ablation followed by sublesional and perilesional injections of 3 million IU of IFN alfa-2b 3 times per week.[6] In a 2008 prospective study, Lee et al reported decreases in depth (81.6%, P = .005) and volume (86.6%, P = .002) treating 20 keloids with a combination of intralesional TAC and IFN alfa-2b compared with only a nonsignificant improvement (P = .281 and P = .245, respectively) obtained in 20 keloids treated with TAC alone.[7] Notably, however, several studies have failed to demonstrate the efficacy of IFN alfa-2b for the treatment of keloids and hypertrophic scars, including a case series of 5 patients treated by Wong et al,[8] a case series by al-Khawajah of 22 patients with keloids using lower doses of IFN alfa-2b than in prior studies,[9] and a prospective randomized clinical trial by Davison et al in which 50 patients with keloids received intraoperative intradermal injections of IFN alfa-2b at 10 million U/mL or TAC at 40 mg/mL, both receiving an extra injection 1 week later. [10] Hypertrophic scar intralesional injections of human recombinant IFN gamma at 200 mcg (6 X 106 U) per injection for 4 weeks have been reported by Pittet et al to be effective for relieving the symptoms in 6 of 7 patients and decreases in redness, swelling, firmness, and lesion area in 7 of 7 patients.[11] At week 16, the reappearance of symptoms was minimal in only 2 of 7 patients and a small increase in the lesion area occurred in 4 of 7 patients, although these lesions remained smaller than the original area.

5-Fluorouracil
5-FU, a pyrimidine analogue with antimetabolite activity, inhibits fibroblastic proliferation in tissue culture and is believed to reduce postoperative scarring by decreasing fibroblast proliferation. Its efficacy and safety have been reported when used as a monotherapy or when used in combination with other drugs (eg TAC) for the treatment of other fibrosing conditions, including infantile digital fibromatosis, knuckle pads, rheumatoid nodules, and adverse foreign body reaction and sarcoidal granulomatous complications after soft tissue filler injection. Some

data suggest that 5-FU is effective in the treatment of hypertrophic scars and is somewhat effective in small keloids. Several studies have shown the effectiveness of 5-FU. In a retrospective study of 1000 patients with hypertrophic scars and keloids over a 9-year period, the most effective regimen was found to be 0.1 mL of TAC (10 mg/mL) and 0.9 mL of 5FU (50 mg/mL) up to 3 times a week. A total of 85% of keloids showed more than 50% improvement in an open study by Kontochristopoulos et al in which 20 keloids were treated once weekly with intralesional 5-FU (50 mg/mL) for an average of 7 treatments, with a recurrence rate of 47% within 1 year of the treatment. The Ki-67 proliferative index was significantly reduced (P = .0001) after treatment.[12] Nanda and Reddy treated 28 patients with multiple keloids in a prospective, randomized, uncontrolled clinical trial with weekly intralesional injections of 5-FU at 50 mg/mL and reported almost 80% of the patients showing more than 50% improvement. Regression from the periphery and flattening occurred in all patients. In 22 of 28 patients, the symptoms completely disappeared, while the rest showed a good response. Decrease in size was reported in 70% of the patients.[13] 5-FU in combination with other therapies significantly increases the efficacy over single modalities. In a double-blind randomized study, 40 patients with keloids or hypertrophic scars received 8 weekly intralesional injections of TAC 10 mg/mL or a combination of TAC 4 mg/mL plus 5-FU 45 mg/mL. At week 12, both groups showed improvement; however, the lesions in the TAC plus 5FU group had significantly greater pliability and less erythema, height, length, and width (P < .05) than the TAC group compared with baseline (P < .05).[14] In a randomized clinical trial by Asilian et al, 69 patients with keloids and hypertrophic scars were treated with a combination of 5-FU (50 mg/mL), TAC (40 mg/mL), and a 585-nm flashlamp-pumped pulsed-dye laser (PDL) at 5-7.5 J/cm2, showing that it was more effective than the TAC and TAC plus 5-FU.[15] At week 12, a statistically significant reduction in length, height, and width was observed in all groups compared with baseline (P < .05). In a randomized clinical trial, Manuskiatti and Fitzpatrick found a statistically significant clinical improvement in keloidal and hypertrophic sternotomy scars using these 3 modalities separately and a combination of TAC and 5-FU compared with baseline. No difference was found between the 4 treatment modalities.[16] 5-FU was used to treat a patient with keloids and hypertrophic scars post facial dermabrasion. The patient received 6 intralesional injections of 5-FU with silicone sheets applied afterwards over a 3-month span. During 7 months of follow up, a significant improvement in the size, color, and texture of the scars was noticed. In addition, the pain and itching had fully resolved.[17] Sadeghinia et al compared the use of intralesional TAC 40 mg/mL at 20 mg/cm2of lesion and 5FU (50 mg/ml) tattooing in a double blind study. Forty patients were randomized into 2 groups, which received the treatment every 4 weeks for 12 weeks. At week 44, both groups showed improvement in all parameters (erythema, pruritus, height, surface, and induration), but improvement was more significant in the 5-FU group (P < .05).[18]

Doxorubicin (Adriamycin)
Doxorubicin (Adriamycin) is a commonly used chemotherapeutic agent that irreversibly inactivates prolyl 4-hydroxylase in human skin fibroblasts and has been shown to inhibit collagen alpha-chain assembly. Sasaki et al showed through sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDSPAGE) analysis that doxorubicin, at a clinically therapeutic concentration of 12.5 m, inhibits the assembly of collagen triple-helical molecules.[19] SDS-PAGE analysis of control cultures showed a large fraction of [3H]proline-labeled procollagen polypeptides in triple-helical conformation; however, after the addition of doxorubicin at 12.5 m, a very small amount of intact alpha-chains were found. These results suggest that the impaired wound healing observed in cancer patients who receive doxorubicin may result from the inhibition of prolyl 4-hydroxylase. Another mechanism of doxorubicin-induced inhibition of collagen synthesis includes the inhibition of the enzyme prolidase, which is key in the process of collagen resynthesis, cleaving imidodipeptides containing C-terminal, and making proline available for its recycling and further generation of new collagen. Muszynska et al demonstrated this process in cultured human skin fibroblasts, also suggesting that this inhibition is a posttranslational event.[20, 21] Other agents such as doxycycline, other nonsteroidal anti-inflammatory drugs (ie, acetylsalicylic acid, sodium salicylate, phenylbutazone, indomethacin), daunorubicin, gentamicin, netilmicin, anthracycline)[22] are also capable of inhibiting prolidase in cultured human skin fibroblasts. Further studies are warranted to determine if doxorubicin or any of the above-mentioned agents can be useful to treat patients with excessive scarring.

Bleomycin
Bleomycin injections cause necrosis of keratinocytes with a mixed inflammatory infiltrate. Several studies have demonstrated that bleomycin can be used effectively to treat keloids and hypertrophic scars. Bleomycin was given at a concentration of 1.5 IU/mL to 13 patients using the multiple-puncture method. Bleomycin was dripped onto the lesion, and then multiple punctures were made on the lesions using a syringe. Seven patients had complete flattening, 5 patients had highly significant flattening, and 1 patient had significant flattening. Likewise, Espana et al also reported complete flattening in 6 of 13 patients, highly significant flattening in 6 of 13 patients, and significant flattening in a single patient. Two patients presented a recurrence as a small nodule 10 and 12 months after the last infiltration.[23] In another study of 31 keloids, patients were treated with 3-5 infiltrates of bleomycin within a 1month period. Total regression occurred in 84% of the keloids, and both keloid volume and functional impairment were reduced. Bodokh and Brun reported complete flattening in 69.4% of 36 patients with keloids and hypertrophic scars.[24] Saray et al obtained complete flattening in 73.3%, highly significant flattening in 6.7%, and moderate flattening in 6.7% of lesions after the administration of jet intralesional injections of bleomycin in 15 patients.[25] In the only randomized clinical trial using the tattooing technique, with which smaller amounts of the drug are absorbed, thus minimizing systemic adverse effects, Naeini et al reported significantly better results with intralesional bleomycin compared with the control group (ie,

combination of cryotherapy and TAC) in lesions larger than 100 mm2 (P = .03).[26] Local complications, such as hyperpigmentation, were observed in 75% of the patients. Fifty patients with keloids and hypertrophic scars were treated with intralesional bleomycin. Three applications were given at 15-day intervals, and a fourth and final application was given 2 months after the third application. Complete flattening was observed in 44%, significant flattening in 22%, adequate flattening in 14%, and no flattening in 20%. Pruritus was relieved completely in 89% of patients.[27]

Verapamil
Verapamil is a calcium channel blocker that blocks the synthesis and secretion of extracellular matrix molecules (eg, collagen, GAGs, fibronectin) and increases fibrinase. In a study of 22 patients with keloids, patients were treated with surgical excision and 5 treatments of verapamil at 2.5 mg/mL (varying doses from 0.5-5 mL, depending on keloid size) over a 2-month period and were evaluated at 2-year follow-up. Two patients had keloids that decreased in size from the original lesion, 2 patients had hypertrophic scars, 4 patients had pruritus, and 1 patient had a keloid on the donor site. The case series reported an average of 6.4 in patient satisfaction on a scale from 1 to 10.[28] DAndrea et al, from a case-control comparative study, reported resolution in 54% of the patients who had their keloids treated by a combination of surgical excision, silicon sheeting, and intralesional verapamil versus 18% in the control group without intralesional verapamil.[29] The recurrence rate was 36% in the active group after 18 months of follow up. In a case series, Skaria reported complete resolution of 4 of 6 keloids and 1 of 2 hypertrophic scars at 1-year follow-up after surgical removal of the scar and further intralesional injection of verapamil at doses of 2.5 mg/mL.[30] Lawrence reported 55% cured earlobe keloids in 52% of the patients after the combination of surgical excision, intralesional verapamil, and pressure earrings after an average of 28 months of follow-up.[31] In a randomized clinical trial, Margaret Shanthi et al compared intralesional verapamil and intralesional TAC for the treatment of keloids and hypertrophic scars, reporting a reduction in vascularity, pliability, height, and width in both groups after 3 weeks of treatment. This result was maintained at 1 year after stopping the treatment. Although the rate of improvement was faster in the TAC group, overall, no difference was noted between the 2 groups.[32]

Retinoic acid
Retinoic acid decreases normal tonofilament and keratohyalin synthesis, increases the production of mucoid substances and the epidermal cell growth rate, and inhibits DNA synthesis in vitro. In a clinical trial involving 21 patients with 28 keloids and hypertrophic scars, topical retinoic acid was applied for at least 3 months twice daily and showed favorable results in 77-79% of the lesions. This includes a decrease in the size and symptoms of the scar.[33] In addition, because retinoids affect collagen metabolism, another study involving 9 females and 2 males with keloids treated with 0.05% tretinoin topically for 12 weeks showed a significant

decrease in weight (P < .04) and size (P < .01) of the keloids when comparing the status of the lesions at the beginning of the study and at week 12.[34] In vitro studies have demonstrated that retinoids can modulate collagen production and the proliferation of normal and keloidal fibroblasts. In vivo applications of 0.05% topical retinoic acid can lead to a reduction of hypertrophic scars in 50-100% of patients and of keloids in less than 20% of patients. The most common adverse effects reported have been photosensitivity, irritant contact dermatitis, and skin atrophy.

Imiquimod
Imiquimod (1-[2-methylpropyl]-1H-imidazo[4,5-c]quinolin-4-amin) belongs to the family of imidazoquinolines. Imiquimod induces TNF-alpha, IFN-alpha and IFN-gamma, IL-1, IL-4, IL-5, IL-6, IL-8, and IL-12 and alters the expression of markers for apoptosis. In one study, 13 keloids were treated with excision in combination with nightly applications of imiquimod 5% cream for 8 weeks. Ten patients with 11 keloids completed the 6-month study, and no keloids recurred after 6 months. Mild irritation was experienced with the application of imiquimod, and some patients needed a vacation period from the medication. Hyperpigmentation was experienced by more than half of the patients in the study.[35] In 2 different pilot studies, imiquimod 5% cream was applied on postshaved or totally excised earlobe keloids. It was demonstrated that the recurrence rate on postshaved keloids was 0% after 12 months of follow-up and 75% recurrence-free after 24 weeks of parallel keloid excision. Although the presence of local adverse events did not affect the treatment, a resting period was needed.[36, 37] In a different study, 15 patients with hypertrophic scars 2 months after breast surgery were treated with either petrolatum or imiquimod 5% cream. At 24 weeks, almost all the scars treated with imiquimod scored better after assessment with standardized scales. The results demonstrated that imiquimod treatment improved scar quality and color match after surgery.[38] More recently, in study by Chuangsuwanich et al, 45 patients with excised keloids were treated with imiquimod 5% cream 2 weeks after the operation, on alternate nights, for 8 weeks. [39] After a follow-up period of 6-9 months, 10 of the keloids recurred (28.6% overall recurrence rate), with adverse effects found in 13 patients (37.1%). Interestingly, the keloids localized on the pinna had the lowest recurrence rate (2.9%) compared with those at the chest wall or neck (83.3% and 14.3%, respectively).

Tacrolimus
Tacrolimus is an immunomodulator that inhibits TNF-alpha. Gli -1, an oncogene, has been found to be overexpressed in fibroblasts of keloids. Inhibition of this oncogene may restore the natural apoptosis process and decrease proliferation of the ECM protein.[40] Rapamycin, a close analogue of tacrolimus, was used in an in vitro study and was found to inhibit the gli -1 oncogene, thus giving a rationale to initiate clinical trials of topical tacrolimus and rapamycin. In an open-label pilot study, 11 patients used tacrolimus 0.1% ointment twice daily for 12 weeks on their keloids. Although the results were not statistically significant, the study showed a decrease in induration, tenderness, erythema, and pruritus for most patients.[41] Kim et al observed the resolution of a keloid in a patient during a course of topical tacrolimus for atopic dermatitis.[40]

Sirolimus
Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR), a serine/threonine kinase that regulates collagen expression. By inhibiting mTOR, sirolimus blocks the response to IL-2 and decreases ECM deposition.[42] Similar to rapamycin, sirolimus inhibits Gli -1 signal transduction. A higher concentration of VEGF and higher blood vessel density has been found in the basal layer of the epidermis of keloidal tissue in comparison to normal skin. In co-cultured keloid keratinocytes and fibroblasts exposed to sirolimus, VEGF expression has shown to be downregulated in a dose-dependent manner. Through inhibition of VEGF, sirolimus may control the expression profile of underlying dermal fibroblasts.

Tamoxifen
Tamoxifen, a synthetic nonsteroidal antiestrogen used to treat breast cancer, has been shown to inhibit proliferation of keloid fibroblasts and their collagen synthesis in monolayer cultures. Hu et al demonstrated that tamoxifen exhibits a dose-dependent and reversible inhibition of contraction of adult human dermal fibroblast in vitro.[43] Tamoxifen has also been shown to reduce TGF-alpha, and its isoform TGF-alpha1, production by keloid fibroblasts in vitro. Mikulec et al have shown that keloid fibroblasts have significantly lower TGF-alpha1 production when exposed to 16 mol/L of tamoxifen at day 2 of culture when compared with control keloid fibroblasts (P = .05).[44]

Botulinum toxin A
Botulinum toxin A (BTA) is a neurotoxin that causes a flaccid paralysis of the local musculature and reduces skin tension. This reduction in the skin tensile force during the course of wound healing may represent a novel therapeutic target for treating keloids. In an in vitro study, 64% of cultured fibroblasts were found to be in the G0-G1 phase of the cell cycle when exposed to BTA, while 35.4% were in the proliferative phases (ie, G2, M, S). In comparison, cultured fibroblasts that were not exposed to BTA had the following distribution: 36% (G0-G1) and 64% (proliferative phases).[45] The effect of BTA on the cell cycle distribution of fibroblasts may indicate that BTA can improve the eventual appearance of and inhibit the growth of hypertrophic scars and keloids. In a prospective, uncontrolled study evaluating the effects of BTA in the treatment of keloids, 12 keloids were injected intralesionally at a concentration of 35 U/mL, with the total dose varying from 70-140 U per session. Injections were given at 3-month intervals for a maximum of 9 months. At 1-year of follow up, the therapeutic outcomes were excellent (n = 3), good (n = 5), and fair (n = 4), with no patients failing therapy or showing signs of recurrence. [46] Nineteen patients with hypertrophic scars received intralesional injections of BTA (2.5 U/mL at 1-mo intervals) for 3 months. All patients showed acceptable improvement of the scars at 6 months of follow up. The erythema, pruritus, and pliability scores were significantly lower postBTA injections compared with baseline.[47] Intramuscular injections of BTA along with scar revision techniques on the face may help to reduce the development of a wider scar.[48]

Larger, randomized, controlled studies are warranted to determine the role of BTA in the treatment of keloids and hypertrophic scars.

TGF-beta and isomers

TGF-beta and its isomers have been shown to play a central role in fibrotic disorders characterized by excessive accumulation of interstitial matrix material in the lungs, kidneys, liver, and other organs. TGF-beta1 and TGF-beta2 have been shown to stimulate fibroblasts to produce collagen and have a direct and independent effect on the contraction of fibroblasts in vitro. However, TGF-beta3 may prevent scarring. A study by Shah et al demonstrated that exogenous addition of TGF-beta3 reduces fibronectin and collagen types I and III deposition in the early stages of cutaneous rat wound healing and in overall wound scarring.[49] A new antifibrotic product, avotermin (Juvista, Renovo; Manchester, United Kingdom) has been extensively studied. Avotermin is derived from human recombinant TGF-beta3. This product has shown promise in a phase I trial and 2 phase II trials completed in the United Kingdom. In these studies, wounds treated with avotermin showed a statistically significant improvement in scar appearance, with a response rate of greater than 70%. After analyzing safety data on more than 1500 human subjects, avotermin does not seem to have safety or tolerability issues for use in the prevention or reduction of scarring. In a randomized, double-blind, placebo-controlled, within-patient, phase II trial to investigate the safety and efficacy of 200 ng per 100 L per linear cm of wound margin of avotermin when administered twice following scar revision surgery, the overall analysis showed that the primary endpoint (ie, photographic evaluation by a lay panel over a period from week 6 to month 7 postsurgery using a visual analogue scale) was met (P = .038). Investigator assessment at 7 months postsurgery using a visual analogue scale also obtained statistical significance (P= .036). Approximately 75% of the 7-month scars assessed from avotermin-treated wounds were considered to have a structure more like normal skin compared with the placebo in the histopathological analysis.[50] Bush et al evaluated 71 subjects (aged 18-45 y) who received avotermin at 50 or 200 ng/100 L/linear centimeter of wound margin. Incisional wounds on the inner aspect of each upper arm were randomized to receive the following: no injection (standard wound care only), 1 intradermal injection of avotermin or placebo (immediately before surgery), or 2 injections of avotermin or placebo (immediately before surgery and 24 h later). Avotermin at 200 ng/100 L/linear centimeter, administered once or twice, achieved significant improvements in scar appearance compared with controls (P < .02 for all comparisons). The 50-ng dose, administered twice, achieved significant improvements in scar appearance versus placebo (P = .043). Treatment was well tolerated.[51] A most recent a double-blind, randomized study (ie, RN1001-0042) evaluated the efficacy and safety of 4 doses of avotermin given once. A total of 156 patients undergoing bilateral surgery to remove varicose leg veins by saphenofemoral ligation and long saphenous vein stripping were studied. Four different doses of avotermin were administered (5, 50, 200 or 500 ng per 100 L, at 100 L per linear cm of wound margin). The primary efficacy variable was lay panel Total Scar Score (ToScar) assessed between 6 weeks and 7 months. Avotermin 500 ng significantly improved groin scar appearance compared with placebo (mean lay panel ToScar difference 1649 mm; P = .036). Avotermin 500 ng per 100 L per linear cm of wound margin given once is well tolerated and significantly improves scar appearance.[52, 53, 54, 55, 51]

Surgical Care
Surgical treatments include cryotherapy, excision, laser therapy, and other light therapies.

Cryotherapy
Cryosurgical media (eg, liquid nitrogen) affects the microvasculature and causes cell damage via intracellular crystals, leading to tissue anoxia. Generally, 1, 2, or 3 freeze-thaw cycles lasting 10-30 seconds each are used for the desired effect. Treatment may need to be repeated every 20-30 days. Cryotherapy can cause pain and permanent depigmentation in selected patients. As a single modality, cryosurgery led to total resolution with no recurrences in 51-74% of patients after 30 months of follow-up observation.

Excision
Apply basic soft tissue handling techniques at primary wound repair sites. Carefully plan the closure with minimal tension, paralleling the relaxed skin tension lines. Use buried sutures, when necessary, for a layered closure and to reduce tension. Whenever feasible, apply pressure dressings and garments during the immediate postoperative period to wounds in patients in whom hypertrophic scars and keloid formation occur. Decreased recurrence rates have been reported with excision in combination with other postoperative modalities, such as radiotherapy, injected IFN, or corticosteroid therapy. Excisional surgery alone has been shown to yield a 45-100% recurrence rate and should very rarely be used as a solitary modality, although excision in combination with adjunct measures can be curative. Most studies in which excisional surgery was combined with injected steroids reported a recurrence rate of less than 50%. The authors have studied the effects of topically applied imiquimod 5% cream (Aldara) on the postexcision recurrence rates of 13 keloids excised surgically from 12 patients.[56, 35] Starting the night of surgery, imiquimod 5% cream was applied for 8 weeks. Patients were examined at weeks 4, 8, 16, and 24 for local erythema, edema, erosions, pigment alteration, and/or recurrence of the keloid. Of the 11 keloids evaluated at 24 weeks, none (0%) recurred. The rate of hyperpigmentation was 63.6%. Two cases of mild irritation and superficial erosion cleared with temporary discontinuation of imiquimod. Both patients completed the 8 weeks of topical therapy and the final 24-week assessment. At 24 weeks, the recurrence rate of excised keloids treated with postoperative imiquimod 5% cream was lower than recurrence rates previously reported in the literature.

Laser Therapy
Carbon dioxide, argon laser, and Nd:YAG laser (1064 nm)
Ablation of keloids and hypertrophic scars using a carbon dioxide laser (10,600 nm) can cut and cauterize the lesion, creating a dry surgical environment with relatively minimal tissue trauma. When used as a single modality, the carbon dioxide laser was associated with recurrence rates of 39-92%, and when the carbon dioxide laser was combined with postoperative injected steroids, it was associated with recurrence rates of 25-74%. A Korean study included 30 patients with hypertrophic scars treated with a combination of 3 different therapeutic modalities: 10600-nm ablative carbon dioxide laser (AFL), copper bromide laser (CBL), and intralesional TAC. At the end of the study, CBL achieved better outcomes for vascularity and pigmentation. AFL and AFL plus TAC were especially effective with regard to

thickness and pliability. AFL produced epidermal resurfacing due to collagen remodeling. CBL plus TAC did not aggravate vascularity and pigmentation, suggesting that CBL may compensate for the erythema resulting from TAC. In conclusion, the combination of CBL, AFL, and intralesional TAC may provide a new treatment option for hypertrophic scars.[57] Similarly to the carbon dioxide laser, the argon 488-nm laser can induce collagen shrinkage via generation of excessive localized heat. The argon laser has demonstrated recurrence rates of 45-93%. The Nd:YAG laser (1064 nm) has demonstrated recurrence rates of 53-100%.

Pulsed-dye laser (585 nm)

The 585-nm PDL provides photothermolysis, resulting in microvascular thrombosis. Beginning in the 1980s, authors noted that scars became less erythematous, more pliable, and less hypertrophic after treatment with the 585-nm PDL. The findings were later confirmed using objective measurements of erythema by reflectance spectrometry readings, scar height, and pliability measurements. Because of its efficacy, safety, and relatively low cost, the PDL remains the laser treatment of choice for hypertrophic scars. Multiple publications have continued to confirm the role of the 585-nm PDL for the treatment of keloids and hypertrophic scars. In a randomized clinical trial, Manuskiatti et al treated 10 keloidal or hypertrophic median sternotomy scars with a 585-nm flashlamp-pumped PDL at fluences of 3, 5, and 7 J/cm2, and one segment was left untreated as a control.[16] They showed consistently better results in the treatment groups over the control. A trend was obtained towards lower fluences having more rapid onset of benefits and enhanced resolution of erythema, induration, and elevation of the scar. Multiple treatment sessions achieved greater clinical improvement. Alster treated 44 bilateral, symmetric hypertrophic breast-reduction scars with a 585-nm PDL at 4.5-5.5 J/cm2 alone or in combination with intralesional TAC at 10-20 mg/mL injected immediately after the PDL irradiation.[58] All scars showed clinical improvement. The average pliability scores decreased by 50% after 2 sessions in both groups. The concomitant use of TAC reduced symptom scores by 70% compared with PDL alone (50%). In a prospective, randomized clinical trial, Nouri et al treated 11 patients with 12 postoperative scars with 585-nm PDL at 3.5 J/cm2 versus no treatment.[59] The average overall improvement scores after one treatment was superior to the control (P = .0002). Vascularity improved 54% in treated halves, compared with 8% in controls. (P = .002). A total of 38% of halves returned to normal vascularity, compared with 0% in controls. Pliability improved 64% versus 1%, respectively (P= .002). A total of 62% of halves returned to normal pliability compared with 0% in control halves. The cosmetic appearance score was significantly better for the treated halves than for the untreated controls (7.3 vs 5.2; P = .016). In contrast, Wittenberg et al found in a prospective, single-blinded, randomized, controlled study an overall reduction in blood flow (P = .001), volume (P = .02), and pruritus (P = .005) over time after a follow-up period of 4 months after treatment discontinuation, but no differences were noted among treatment and control groups treating hypertrophic scars with a 585-nm flashlamppumped PDL at 6.5-8 J/cm2 or silicone gel sheeting, or no treatment.[60]

Pulsed-dye laser (595 nm)

Two studies have demonstrated that the 585-nm PDL has more effectively cleared port-wine stains than the 595-nm PDL at the same settings. Murine studies determined that the beneficial

effect of lasers inhibiting the scar tissue growth decreased as the wavelength of the laser was increased from 585 to 600 nm. Further studies are necessary to obtain similar conclusions in human tissue. However, longer wavelength (eg, 595 nm) is an alternative vascular-specific laser for dark-skinned patients, with higher amounts of epidermal melanin, which absorbs more readily the 585-nm wavelength, causing nonspecific damage to pigmented epidermis. Currently, 595-nm PDL systems incorporate in the handpiece a cryogen-spray cooling device, which permits safe and effective treatment of hypertrophic scars by raising the threshold for epidermal damage, avoiding the resultant epidermal necrosis when the skin surface temperatures exceeds 70C immediately after PDL exposure. In a prospective randomized clinical trial, Conologue et al treated 16 patients with postoperative scars immediately after suture removal with a 595-nm cryogen-cooled PDL at 8 J/cm2 and showed significant improvement (60%) versus the untreated control (-3%) in the average sum of all clinical parameters measured.[61]Improvement was noted in vascularity (69%) versus the control (0%) (P = .53) and in pliability (67%) compared with the control (-8%) (P = .337). In order to compare the 0.45-millisecond (short) pulse width with the 40-millisecond (long) pulse width, Manuskiatti et al treated 19 patients with keloidal and hypertrophic sternotomy scars in a prospective randomized clinical trial, with a 595-nm PDL at 7 J/cm2 and a cryogen spray cooling device.[62] The short pulse width demonstrated greater overall improvement (P = .046) and scar pliability. Both pulse widths significantly reduced scar height compared with baseline; however, no differences were found between the groups. No effects were noted on scar erythema with either treatment. Both treatments were safe and effective in dark-skinned individuals. Bellew et al randomly treated 15 hypertrophic scars with a 595-nm long-pulsed PDL at 7 J/cm2 with a concomitant skin-surface cooling device or with an IPL system with a 570-nm cutoff filter and a fluence of 40-45 J/cm2 and a triple pulse, reporting a mean improvement in the long-pulsed PDL group of 80% compared with 65% in the IPL group.[63] However, no statistical difference was noted between the 2 groups. Both systems are equally effective in improving the appearance of hypertrophic surgical scars. IPL minimizes the risk of purpura. In contrast, however, Alam et al found no beneficial effect on clinical scar appearance at 6 weeks post treatment versus untreated control, after treating 20 patients with postoperative scars in a prospective, randomized, controlled trial using a 595-nm PDL at 7 J/cm2 and a 30millisecond dynamic cooling spray.[64]

Light Therapies
Photodynamic therapy
Chiu et al studied the in vitro effect of 5-aminolevulinic acid (ALA) and 635-nm diode laser irradiation on keratinocyte-fibroblast co-culture (Raft model), determining that 5 J/cm2 reduces tissue contraction and collagen synthesis and preserves fibroblast viability.[65] The authors hypothesized that ALA-PDT may be used as an adjuvant therapy postsurgical excision of keloids.

Ultraviolet A-1
UVA-1 (340-400 nm) has been reported as an effective treatment for morphea andsystemic sclerosis through induction of collagenase I (matrix metalloproteinase I) produced by fibroblasts. Asawanonda et al reported clinical improvement in one keloid in addition to the histological

reappearance of normal-looking collagen and elastic fibers, while others have not reported as good clinical results.[66] Animal models have shown a significant decrease in dermal thickness and collagen content in scars irradiated postsurgically with UVA-1 at 110 J/cm2. UVA-1 exposure to hypertropic scars in rabbits after epithelialization may lead to softening of the scar, thinning of the skin, and a decrease in collagen content. However, immediate irradiation with UVA-1 after wounding could not prevent the development of hypertrophic scarring in rabbits.[67] Two German studies have evaluated the efficacy of UVA-1 irradiation for the treatment of skin conditions with altered dermal matrix, including keloids, scleroderma, scars, granuloma annulare, and acne keloidalis nuchae. The studies are complete, but results are not yet published.[68, 69]

Narrowband UVB
Narrowband UVB in the wavelength range of 310-315 nm (peak at 312 nm) has demonstrated for more than 20 years to be less potent than broadband UVB for erythema induction, hyperplasia, edema, sunburn cell formation, and Langerhans cell depletion from the skin. Studies on human skin fibroblasts by Choi et al have demonstrated that narrowband UVB reduces type I collagen synthesis by down-regulating TGF-beta1 expression at both the mRNA and protein levels and promoting the release of MMP-1.[70] Oiso et al reported flattening of a hypertrophic scar after treating a patient with vitiligo and a Koebner phenomenon with low-dose narrowband UVB (ie, 300 mJ/cm2) once a week for 4 months.[71]

Broadband UVB
Broadband UVB (290-320 nm) at high doses (up to 320 mJ/cm2) has also been theorized to improve fibrosing skin conditions, including keloids, hypertrophic scars, scleroderma, acne keloidalis nuchae, old burn scars, and granuloma annulare, among other related conditions with altered dermal matrix, safely through collagenase-mediated removal of excess dermal collagen via activation of MMP-1 pathways in patients with increased skin pigmentation.[72] High keloid incidence is found among individuals with high melanin content in their skin. Since melanin serves as a UVB light absorber, lack of UVB light penetration may play a role in keloid etiology. Wirohadidjojo et al evaluated the effect that UVB irradiation to monolayer keloid fibroblasts has on cell proliferation, collagen deposition, and TGF-beta1 production. Keloid fibroblasts were cultures and exposed to various dosages of UVB irradiation. Collagen depositions and TGF-beta1 production were measured. UVB 100 and 150 mJ/cm2 were able to suppress keloid fibroblast viabilities and collagen accumulation significantly (P < .01). Significant suppression of TGF-beta1 production required UVB irradiation of 150 mJ/cm2 (P < .01). UVB irradiation with a minimal dosage of 150 mJ/cm2 is possible therapy for keloid prevention and treatment.[73]

Intense pulsed light

Bellew et al obtained equal effectiveness improving the appearance of hypertrophic surgical scars with IPL compared with 595-nm long-pulsed PDL.[63] IPL minimized the risk of developing postlaser purpura, frequently seen in patients treated with long-pulsed PDL. Cartier reported that IPL was effective in treating and improving inflamed hypertrophic scars in 3 patients.[74]

Other studies have suggested that IPL is effective for improving the appearance of hypertrophic scars and keloids, regardless of their origin, and in reducing the height, redness, and hardness of scars. Erol et al evaluated hypertrophic scars in 109 patients (including keloids) after treatment using an IPL (Quantum) device, administered at 2- to 4-week intervals, with patients receiving an average of 8 treatments.[75] Overall clinical improvement was seen in the appearance of scars, and reductions in height, erythema, and hardness were seen in the majority of the patients (92.5%). Improvement was excellent in 31.2% of the patients, good in 25.7%, moderate in 34%, and minimal in 9.1%. Patient satisfaction was very high.

The Efficacy of Silicone Gel for the Treatment of Hypertrophic Scars and Keloids Silicone gel contains long chain silicone polymer (polysiloxanes), silicone dioxide and volatile component. Long chain silicone polymers cross link with silicone dioxide. It spreads as an ultra thin sheet and works 24 hours per day.[ Quinn KJ. Silicone gel in the scar treatment. Burns. 1987;13:8335. Sawada Y, Sone K. Treatment of scars and keloids with a cream containing silicone oil. Br J Plast Surg. 1990;43:6836.] It has a self drying technology and itself dries within 4-5 minutes. It has been reported to be effective and produce 86% reduction in texture, 84% in color and 68% in height of scars. [Poston J. The use of the silicone gel sheeting in the management of hypertrophic and keloids scars. J Wound Care. 2000;9:102. Suetake T, Sasai S, Zhen YX, Tagami H. Effects of silicone gel sheet on the stratum corneum hydration. Br J Plast Surg. 2000;13:1579.] Silicon gel exerts several actions which may explain this benefit in scars: It increases hydration of stratum corneum and thereby facilitates regulation of fibroblast production and reduction in collagen production. It results into softer and flatter scar. It allows skin to "breathe". It protects the scarred tissue from bacterial invasion and prevents bacteria-induced excessive collagen production in the scar tissue. It modulates the expression of growth factors, fibroblast growth factor (FGF ) and tumor growth factor (TGF ). TGF stimulates fibroblasts to synthesize collagen and fibronectin. FGF normalizes the collagen synthesis in an abnormal scar and increases the level of collagenases which breaks down the excess collagen. Balance of fibrogenesis and fibrolysis is ultimately restored. Silicone gel reduces itching and discomfort associated with scars. The advantages of silicon gel include easy administration, even for sensitive skin and in children. It can be applied for any irregular skin or scar surfaces, the face, moving parts (joints and flexures) and any size of scars. A tube of 15 gram contains enough silicone gel to treat 3-4 inches (7.5-10 cm) scar twice a day for over 90 days.

BAPSCARCARE Table Analysis with direct competitors : No. Aspect 1 Varian Product BAPSCARCARE 1. Gel 20 grams 2. Extra thin silicone dressing : 5x7 cm, 10x15 cm, and 5x30 cm 3. Thick, Washable silicone dressing : a. Mamma 4x30 cm b. Mamma Anchor 4x30 cm c. Abdomen 4x40 cm d. Keyhole 10 x 18 cm e. Nipple 10 cm f. 5x20 cm g. 15x20 cm h. 10x 15 cm i. 40x40 cm j. 40x100 cm SCAR FX 1. Cream 2 oz 2. Silicon Sheet 12,5 x 7,5 cm (Washable) CICA CARE 1. Silicon Sheet 12x15 cm

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