Review of Fractional Photothermolysis: Treatment Indications and Efficacy

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1 REVIEW ARTICLE Review of Fractional Photothermolysis: Treatment Indications and Efficacy EMILY P. TIERNEY, MD, DAVID J. KOUBA, MD, PHD, y AND C. WILLIAM HANKE, MD, MPH BACKGROUND Fractional photothermolysis (FP) is one of the most significant milestones in laser technology and resurfacing. METHODS Review of the Medline English literature and recent international conferences regarding FP technology, applications, and indications. RESULTS Successful conditions treated with nonablative FP reported in the literature include acne ; dyschromia and fine wrinkling of photoaging on the face, chest, neck, and hands; melasma; poikiloderma of Civatte; nevus of Ota; scars; minocycline hyperpigmentation; telangiectatic matting; residual hemangioma; granuloma annulare; colloid milium; and disseminated superficial actinic porokeratosis. An advance in 2007 was the introduction of ablative FP (AFP), which results in significantly greater improvement in skin laxity and textural abnormalities. Most recently, AFP has demonstrated significantly greater improvement than nonablative FP in reducing acne and skin redundancy and laxity associated with photoaging. CONCLUSIONS Through the induction of microthermal zones of injury, FP technology stimulates a robust and rapid wound healing response resulting in improvement in a diversity of aesthetic, inflammatory, and preneoplastic skin disorders. Further investigation into the technology and diverse array of cutaneous conditions that can benefit from FP is highly needed. The authors have indicated no significant interest with commercial supporters. Background Manstein and colleagues 1 introduced fractional photothermolysis (FP) in 2004 with their original prototype FP device. The device emitted light in a pixilated fashion to the skin, producing an array of microthermal zones (MTZs) and creating small columns of thermal injury to the skin. 1 This concept of fractional emission of light into microscopic zones of injury contrasts with ablative skin resurfacing, in which a confluent, uniform patch of epidermal or dermal injury is induced. 1 Manstein and colleagues first reported the results of treating forearm skin and periorbital rhytides with their prototype FP device, with resulting improvement in skin texture and wrinkle appearance, which correlated with unique histologic changes. Manstein and colleagues noted with their prototype FP device a significant improvement in periorbital rhytides 3 months after treatment. Of 30 patients treated with FP, 34% showed moderate or better improvement of wrinkles, and 47% demonstrated moderate or better improvement in skin texture. 1 After treatment with MTZs with a diameter of 100 mm, epidermal and dermal disruption occurred in a fractionated pattern, consistent with the grid pattern of light applied. 1 It was noted that thermal damage induced by the MTZs occurred to a depth of 300 to 400 mm into the dermis. 1,2 In spite of the depth of injury (mid-dermis), re-epithelialization occurred rapidlyfwithin 1 day after treatment. Laser and Skin Surgery Center of Indiana, Carmel, Indiana; and y Department of Dermatology, Division of Mohs Micrographic Surgery, The Henry Ford Health System, Detroit, Michigan & 2009 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: Dermatol Surg 2009;35: DOI: /j x 1445

2 REVIEW OF FRACTIONAL PHOTOTHERMOLYSIS At 3 months, significant clinical improvement was observed in fine periorbital rhytides, correlating with histologic changes of enhanced undulating rete ridges and increased mucin deposition within the superficial dermis. 1,2 Scientific Conception of FP The scientific concept underlying FP involves the application of microscopic beams of pixilated light, which induce small, focal zones of tissue injury. Because the pixilated zones of treatment spare surrounding normal tissue, re-epithelialization occurs at a significantly faster pace. The tissue injury created with FP stimulates the process of collagen remodeling and deposition and promotes elastic tissue formation. These molecular changes are postulated to be responsible for the clinical improvements seen with FP. 1 With FP, laser parameters can be customized to produce differing three-dimensional columns of injury with varying shapes and depths. 1,2 Manstein and colleagues performed histologic analysis using cell viability staining (as measured using lactate dehydrogenase (LDH)); immediately after treatment, epidermal and dermal cell necrosis were present in a MTZ 100 mm in diameter, and extending to a depth of 400 mm. 1 After 3 months, there was no evidence of the MTZ detected using LDH staining in the dermis or epidermis. Repair of the epidermal defect occurred rapidlyfwithin the first 24 hoursfthrough keratinocyte migration and extrusion of damaged epidermal components at the border of the column of thermal damage. Additionally, shortly after treatment, in the most inferior aspect of MTZs, morphologic changes were observed, consistent with conversion from a stationary cuboidal cell to a migratory spindle cell. This change in cellular phenotype is postulated to account for the rapid wound healing after FP, with migratory spindle cells mediating the rapid post-treatment migration and re-epithelialization. Although there was visible necrosis of the epidermis and dermis in the MTZ, the stratum corneum remained histologically intact; thus, resurfacing with the prototype FP device was termed nonablative. 1 Hantash and colleagues 3 further validated the hypothesis of Laubach and colleagues, 2 which postulated that the columns of cellular debris in the epidermis and dermis are eliminated by extrusion through a damaged dermal epidermal junction. Hantash and colleagues demonstrated, using anti-human elastin antibody, the phenomenon of transepidermal elimination of dermal epidermal debris through the MTZs of injury. Furthermore, they observed the subsequent stimulation of reepithelialization and repair by FP, which adjacent columns of intact tissue mediated. Hantash and colleagues 3,4 validated with histologic studies and immunohistochemistry where degenerated dermal material is incorporated into the columns of microscopic epidermal necrotic debris (MENDs) and is shuttled up the epidermis and, ultimately, exfoliated through the stratum corneum. FP is the first nonablative laser technology to result in the extrusion of damaged dermal material through a perforated dermal epidermal junction. 1 4 Given the novel mechanism of injury and repair through extrusion of dermal and epidermal zones of injury, Hantash and colleagues speculated that FP may provide a unique therapeutic option for a number of diverse clinical indications of epidermal and dermal biology, including pigmentary disorders such as melasma 5 7 and photoaging, 8 17 as well as depositional diseases such as colloid milium, 18 mucinosis, 3 and amyloidosis. 3 The effects of FP on epidermal pigment are of interest because few of the currently available nonablative laser treatments in the infrared spectrum have significant effects on epidermal pigmented lesions. In contrast, traditional ablative laser resurfacing completely removes the pigmented layer, which can result in permanent hypopigmentation. In the initial report by Manstein, 1 there were several darkskinned patients who demonstrated little or no significant pigmentary change after FP at low or medium MTZ densities per treatment. Histology revealed that there is a localized, well-controlled 1446 DERMATOLOGIC SURGERY

3 TIERNEY ET AL melanin release and transport mechanism using MENDs as the vehicle for pigmentary redistribution. Furthermore, unwanted localized accumulations of pigment (i.e., solar lentigines) appear to be effectively removed in a precise and gradual manner, as originally described by Manstein and colleagues. 1 Further recent investigation regarding this aspect of FP has lead to novel concepts for treatment of conditions characterized by pigment abnormalities, such as melasma, 5 7 nevus of Ota, 19 minocycline-induced hyperpigmentation, 20 and hyper- or hypopigmented scars Nonablative FP has been used for a broad spectrum of skin conditions, beyond the initial studies demonstrating improvement in periorbital rhytides and forearm skin. 1 Indications for nonablative FP reported in the literature include mild to moderate acne ; dyschromia; fine wrinkling and texture changes associated with photoaging on the face, chest, neck, and hands; 8 17 poikiloderma of Civatte (PC); 24 acne ; melasma; 5 7 nevus of Ota; 19 minocycline-induced hyperpigmentation; 20 hyper- and hypopigmented scars; residual hemangiomas; 33 telangiectatic matting; 34 granuloma annulare; 35 colloid milium; 18 and disseminated superficial actinic porokeratosis. 36 Most recently, in 2007, Hantash and colleagues described the first use of a novel ablative carbon dioxide (CO 2 ) fractional resurfacing device that similarly produces an array of MTZs of a customizable density and depth but results in a confluent array of ablation and coagulation that extends through the stratum corneum, epidermis, and dermis. 4 In the initial in vivo studies demonstrating the histologic and clinical effects of this prototype ablative fractionated CO 2 device, Hantash and colleagues confirmed with immunohistochemistry that persistent collagen remodeling occurred for at least 3 months after treatment. With the greater degree of injury with fractionated CO 2, the authors predicted a greater and prolonged effect on induction of new collagen and remodeling of dermal collagen. 4 Several early reports in the literature have evaluated the clinical efficacy of fractionated ablative CO 2 (10,600 nm) and erbium-doped yttrium aluminum garnet (Er:YAG) (2,940 nm) and have confirmed the initial hypothesis of Hantash and colleagues 4 that this mode of resurfacing produces improvements in the skin signs of photoaging (improvement moderate to severe rhytides, dyschromia and skin mottling, and other texture abnormalities) analogous to that only previously achievable with traditional ablative resurfacing. Specifically, several recent reports have confirmed the efficacy of ablative FP (AFP) in the treatment of moderate to severe acne and moderate to severe photoaging (deep rhytides, dyschromia, and texture abnormalities). In addition, several recent split-face studies have confirmed that the degree of improvement with ablative fractionated resurfacing significantly surpasses that of the original prototype nonablative fractionated devices, with only slightly longer downtimes and similar low side effect profiles. 8 Herein, we present a review of the recent developments and novel applications reported in the literature for FP. In addition, we report a comparison of the indications and efficacy of nonablative and ablative fractional resurfacing. Current Indications for FP Nonablative FP for Photoaging Manstein and colleagues reported significant improvements in periorbital rhytides and skin texture after treatment initial treatments with their prototype FP device (Table 1). They found a linear pattern of shrinkage along the triangular-shaped sides of tattoos of treated skin, suggesting that thermal injury induced by FP resulted in wound contraction and tissue shrinkage. Initially, at 1 week, there was statistically significant shrinkage, followed by an apparent relaxation after 1 month, with retightening at 3 months. A similar sequence of skin shrinkage and tightening has also been reported with ablative laser resurfacing. 1 35:10:OCTOBER

4 REVIEW OF FRACTIONAL PHOTOTHERMOLYSIS TABLE 1. Fractional Photothermolysis (FP) for Photoaging Indication Author FP Laser Used/Parameters Results Nonablative fractional photothermolysis Photoaging Manstein et al. 1 Original prototype Settings: fluence 6 12 mj, final MTZ density 2,500/cm 2 Photoaging of the face and neck Photoaging of the hands Photoaging of the face and nonfacial surfaces Photoaging, melasma, rhytides Photoaging of the face Percentage of patients with moderate to significant improvement in rhytides and skin texture: at 1 month, 54%; at 3 months, 34% with improvement in rhytides and 47% with improvement in texture Geronemus 9 Fraxel SR, Reliant Technologies, Inc. Improvement in vertical lines of the upper lip Improvements in facial textural and pigmentary abnormalities Jih et al. 10 Fraxel SR, Reliant Technologies, Inc. Settings: 8 9 mj fluence, 2,500 MTZ/cm 2 total density At 1 and 3 months: 51 75% mean improvement in pigmentation, 25 50% improvement in roughness and wrinkling Wanner et al. 11 Fraxel SR, Reliant Technologies, Inc. Mean clinical improvement at 3 months: face, 2.23; and non-facial skin, 1.85 (po.001). Mean improvement at 6 months: face, 2.10; nonfacial skin 1.81 (po.001) Mean improvement at 9 months: face, 1.96; nonfacial skin, 1.70 (po.001) Rahman et al. 12 Mezzana et al. 13 Fraxel SR, Reliant Technologies, Inc. For photoaging, melasma, and off-face resurfacing: Mild rhytides: 5 10% coverage, 6mJ Moderate rhytides: 10 22% coverage, 8 10 mj or 19 24% coverage, 8 12 mj Severe rhytides: 19 27% coverage, mj Fraxel SR, Reliant Technologies, Inc. plus IPL versus FP alone Ablative fractional photothermolysis Photoaging: Periocular rhytides Weiss et al. 8 Fractional CO 2 laser (Active Fx, Lumenis) versus nonablative fractional erbium (Fraxel SR, Reliant Technologies, Inc.). For CO 2 side, Active Fx spot size of 1.3 mm and fluence of 80 mj. For erbium side, final density of 1,000 MTZs/cm 2 Photoaging of the face Lapidoth et al. 14 Ablative fractionated Er:YAG laser (2,940 nm) (Pixel, Alma Lasers) 2 4 stacked passes were performed for a penetration of 20 mm (evaporative) 30 mm (thermal) (1st pass), mm (2nd pass), mm (3rd pass), mm and (4th pass; and a microzone diameter of 150 mm Qualitative improvement reported in photoaging, melasma, and rhytides Greater improvement in pigmentation and telangiectasias with FP 1 IPL than with FP alone For fractionated CO 2, median improvement 75% For nonablative erbium, median improvement 25% At 2 months after treatment, 75% of patients rated the improvement as excellent, and 25% of the patients rated the improvement as good 1448 DERMATOLOGIC SURGERY

5 TIERNEY ET AL TABLE 1. Continued Indication Author FP Laser Used/Parameters Results Photoaging of the face Photoaging of the face Photoaging of the face Photoaging: Severe lower eyelid rhytides Lomeo et al. 15 Ross et al. 16 Foster et al. 17 Munavalli et al. 37 Half of the face was treated with the microfractional Er:YAG (Demablate, MCL 30) versus half treated with a microfractional CO 2 laser (Mixto Sx, Slim Evolution, Lasering, Modena, Italy). Settings: Density 17% (Er:YAG) and 20% (CO 2 ) 2,940-nm microfractional Er:YAG laser compared with a standard ablative Er:YAG laser in the treatment of facial rhytides and dyspigmentation. Settings: density of microbeams/cm 2 Dual-wavelength (1,320/1,440 nm) fractionated device Fractionated CO 2 technology (Clinipro Antiaging SD, Barcelona, Spain). Settings: fluence of mj, with varying densities (depending on wrinkle severity) Greater improvement in skin texture and color ( 1 15%) on the side treated with fractionated CO 2 laser than Er:YAG Microfractional Er:YAG significantly greater improvement in wrinkle reduction than with standard Er:YAG Equivalent healing times Significant improvement in periocular rhytides and generalized skin laxity in the nasolabial folds Clinically significant reduction in rhytides observed in all 10 patients MTZ = microthermal zones; IPL = intense pulsed light; Er;YAG = erbium-doped yttrium aluminum garnet; CO 2 = carbon dioxide. Since the initial studies performed with the prototype FP device by Manstein and colleagues, 1 a number of investigators have confirmed improvements in photoaging with ablative and nonablative fractional photothermolysis. In 2006, Geronemus reported improvement in fine to moderate rhytides with FP, with lesser efficacy for deeper wrinkle lines. Geronemus reported improvement in the vertical lines of the upper lip but without the same degree of efficacy as that achieved with ablative laser resurfacing techniques. 9 However, anecdotally, many patients accepted the decreased success in exchange for the significant advantages of FP of decreased postoperative down time and significantly lower risk of pigmentary change. In addition to facial textural and pigmentary abnormality improvements after FP, Geronemus cited advantages of the technology in allowing safe treatment of photoaging and associated dyschromia off the face, neck, chest, back, and extremities, where ablative laser treatment can lead to permanent or hypopigmentation. 9 Jih and colleagues 10 reported the first results of a pilot study in 10 patients treated with FP for photoaging of the hands with a 1,550-nm fractionated erbium fiber laser (Fraxel SR, Reliant Technologies, Inc., Mountain View, CA). Improvement in skin pigmentation, roughness, and wrinkling was noted that correlated with histology demonstrating greater density of dermal collagen. Patients experienced transient erythema and edema after treatment, without or adverse effects. This was the first pilot study confirming the safety and efficacy of fractional resurfacing for correcting the pigmentary and textural aspects of photoaging of the dorsal hands. 10 Wanner and colleagues 11 reported a study on the comparative efficacy of a nonablative 1,550-nm FP laser (Fraxel SR, Reliant Technologies, Inc.) in the treatment of facial and nonfacial photodamaged skin. Improvement of 51% to 75% in photodamage at the 9-month follow-up was achieved in a signifi- 35:10:OCTOBER

6 REVIEW OF FRACTIONAL PHOTOTHERMOLYSIS cantly greater proportion of patients treated on the face (73%) than on nonfacial skin (55%) (po.001). Side effects were limited to transient erythema and edema in the majority of patients. No prolonged pigmentary changes or were observed. Rahman and colleagues 12 published a review of currently recommended treatment protocols and settings for photoaging using a nonablative FP device. The surface area treated can be calculated by analyzing the combined effect of the energy level and density of treatment. For example, both a lowenergy, high-density (10 mj, 2,000 MTZ/cm 2 ) treatment and a high-energy, low-density (20 mj, 1,000 MTZ/cm 2 ) treatment have 20% surface area coverage. Rahman and colleagues recommended lower surface area coverage and lower energy levels (5 10% coverage, 6 mj) for off-face resurfacing, with greater surface area coverage and higher energy for moderate facial rhytides (19 24% coverage, 8 12 mj) and severe facial rhytides (19 27% coverage, mj). Mezzana and Valeriani 13 published a study presenting the results of a hybrid approach of treating photoaging with FP in combination with intense pulsed light (IPL), with the goal of achieving additional improvement in background photoaged skin. After treatment of 29 patients with FP followed by IPL, greater improvement of background dyschromia and telangiectasia were seen than with FP alone. The authors postulated that FP resulted in stimulation of dermal collagen remodeling and improvement in rhytides and surface texture, whereas IPL mediated improvements in surface pigmentation and telangiectasias. Ablative Fractionated Resurfacing for Photoaging Hantash and colleagues demonstrated the first report of a prototype device of a novel AFP (fractionated CO 2 laser) device in human skin in vivo in 2007 (Table 2). The results indicated a similar column of thermal coagulation as with the nonablative FP device of Manstein and colleagues, with the critical distinction of a confluent column of ablation and thermal injury that extended from the dermis and epidermis through the stratum corneum. Using human in vivo forearm skin, Hantash and colleagues demonstrated that, with AFP, a controlled MTZ of injury could be induced with stimulation of the wound healing response by adjacent intact skin. With AFP, immunohistochemical studies indicated a prolonged wound remodeling response for at least 3 months after treatment. With this prolonged stimulation of wound repair induced by AFP, Hantash and colleagues theorized that greater clinical improvements in skin texture and wrinkling could be achieved with AFP than with FP. 4 Significantly greater degrees of improvement in the cutaneous signs of photoaging have been demonstrated in preliminary studies with fractionated CO 2 laser technology than with the original generation of nonablative FP devices. Weiss and colleagues reported a comparative split-face trial with half treated with fractionated CO 2 laser and the contralateral half treated with a 1,550-nm nonablative fractional erbium laser. 8 Significantly greater improvement in periocular rhytides (75% improvement) was observed in 10 patients treated with the fractionated CO 2 laser than the 1,550-nm erbium laser (25% improvement) on blinded photographic analysis. Lapidoth and colleagues 14 reported on the efficacy of an ablative fractionated Er:YAG laser (2,940 nm) to improve the appearance of photoaging. Twentyeight patients were treated for mild to moderate actinic damage. Two months after treatment, patients rated the improvement as excellent in 75% of cases (n = 21) and good in the remaining 25% of cases (n = 7). Upon follow-up 6 to 9 months after treatment, all patients reported persistence of the results obtained in the initial follow-up. Lomeo and colleagues 15 reported the results of a split-face comparative trial of microfractional Er:YAG and microfractional CO 2 laser resurfacing in 10 patients. Half of the face was treated with the 1450 DERMATOLOGIC SURGERY

7 TIERNEY ET AL microfractional Er:YAG (Dermablate, MCL 30, Ascelpion, Jena, Germany) with the contralateral half treated with a microfractional CO 2 laser (Mixto Sx, Slim Evolution, Lasering, Modena, Italy). There was significantly greater improvement in skin texture and color ( 1 15%) on the side treated with the microfractional CO 2 laser than on the side treated with the microfractional Er:YAG laser. The Er:YAGtreated side had a shorter average downtime after treatment (3.4 vs 4.5 days) as a result of shorter duration of crusting. Patient satisfaction was slightly greater for CO 2 laser resurfacing in spite of prolonged downtime after treatment (3.8/5 vs 3.4/5). Ross and colleagues 16 published the results of a study comparing the efficacy of a 2,940-nm microfractional Er:YAG laser with that of a standard ablative Er:YAG laser in the treatment of facial rhytides and dyspigmentation. Improvement in moderate to severe periorbital and perioral rhytides after one treatment with a microfractional Er:YAG laser was approximately 50% from baseline (baseline grades 5 9, Fitzpatrick wrinkle scale). On comparative analysis, traditional Er:YAG laser resurfacing demonstrated wound healing times equivalent to those of microfractional Er:YAG, although preliminary data demonstrated that areas treated with microfractional CO 2 demonstrated significantly greater improvement in wrinkle reduction. 16 Foster and colleagues 17 recently reported the results of a dual wavelength device with benefits of treating skin laxity and facial wrinkles. By using two wavelengths (1,320 and 1,440 nm), light is emitted sequentially through a specialized lens, which allows high-intensity treatment zones more superficially, with deeper heating of lower intensity. After one to three treatments with this combination wavelength fractionated device, significantly greater improvement in periocular rhytides and generalized skin laxity in the nasolabial folds was noted than with a single-wavelength 1,320-nm device. Munavalli and colleagues 37 studied patients with severe lower eyelid rhytides treated with fractionated CO 2 technology (Clinipro Antiaging SD, Barcelona, Spain). After treatment of 10 female patients with severe lower eyelid periocular rhytides, complete reepithelization was observed 5 to 7 days after treatment, and clinically significant reduction in rhytides was observed in all patients, as established according to photography and patient satisfaction rating. Poikiloderma of Civatte In addition to improvement of photoaging with FP, significant improvement has also been noted in a case report for the treatment of PC (Table 1). Although several other laser treatment modalities, including argon lasers, potassium titanyl phosphate lasers, pulsed dye lasers (PDLs), and IPL devices, have been used to treat this condition, clinical experience has demonstrated that complete clearing is difficult to achieve. Moreover, depending on the laser modality used, adverse effects such as, post-treatment pigmentary variation, post-treatment purpura, mottled appearance, crusting, and erythema have been reported. Behroozan and colleagues 24 reported the first case report of treatment of a patient with PC using FP. Analogous to improvements in fine wrinkles and epidermal dyschromia, the MTZs of thermal injury induced with FP resulted in rapid healing and clinical improvement in pigmentary and texture variation associated with PC. Behroozan and colleagues hypothesized that, in PC, the 1,550-nm wavelength of FP (with water as the chromophore) specifically targets dermal vasculature by the induced MTZs of injury in the dermis. Support for the this comes from a report by Laubach and colleagues 2 that recently reported the histologic finding of dermal vascular damage in patients undergoing resurfacing FP. Nonablative FP for Acne Scarring In 2006, Geronemus 9 reported initially on the treatment of acne with nonablative FP (Table 2). Efficacy of treatment of patients with diverse morphology of scars was noted, ranging from 35:10:OCTOBER

8 REVIEW OF FRACTIONAL PHOTOTHERMOLYSIS TABLE 2. Fractional Photothermolysis (FP) for Acne Scarring Indication Author FP Laser Used/Parameters Results Nonablative fractional photothermolysis Acne Acne Acne (atrophic type) Acne Acne (atrophic type) Geronemus Fraxel SR, Reliant Technologies, Inc. Mean clinical improvement in acne : 25 50% et al. 9 Mean improvement in scar volume, assessed using high-resolution topographic imaging: 22 66% Weiss 1,540-nm nonablative fractionated 1,540-nm laser et al. 25 Settings: density of 100 microbeams/pulse for 3 5 passes (Lux 1,540, Palomar, Burlington, MA) Long-term follow-up series of 500 patients: Alster Fraxel SR, Reliant Technologies, Inc. Mean clinical improvement: et al. 26 Physician evaluation: 50 75% median improvement Patient evaluation: 85% of patients rated their skin as improved 51 75% in 90% of patients after three monthly laser treatments Lee et al. 27 Fraxel SR, Reliant Technologies, Inc. Patients self-assessed improvement: excellent in 8 patients (30%), significant in 16 patients (59%), and moderate in 3 patients (11%) Glaich Fraxel SR, Reliant Technologies, Inc. et al. 28 Settings: 6 18 mj fluence; 1,250 2,000 MTZs/cm 2 total density Ablative fractional photothermolysis Acne Acne Acne Ortiz et al. 29 Fraxel re:pair, fractionated CO 2 laser (ablative fractional photothermolysis), Reliant Technologies, Inc. Settings: mj fluence, 600 1,200 MTZ/cm 2 total treatment density Chapas Fraxel re:pair, Settings: mj fluence per pulse, 200 et al. 30 1,200 MTZ/cm 2 total treatment density, depending on treatment location and scar morphology Lloyd Affirm fractionated device comparing the dual wavelength et al. 31 1,320-/1,440-nm setting with the 1,320-nm setting. Settings: 14-mm spot size was used with 1,320 nm at 10 J/cm 2 ; 1,320/1,440 nm had the same parameters with the addition of 1,440 nm at 2 J/cm 2 Physician clinical assessments: moderate to marked improvement in atrophic acne in all patients 3 months after treatment, 87% of subjects sustained significant improvement in the appearance of acne After 2 3 treatments, patients had 26 50% improvement in texture, atrophy, and overall improvement Topographic analysis of depths of scar: % (66.8% mean improvement) Significantly greater improvement in acne was noted with the multiplex dual (1,320/1,440 nm) wavelength than with the 1,320-nm single-wavelength setting Acne (focal atrophic scars) Kim et al. 32 Ultrapulse nonfractionated ablative CO 2 laser used only over acne scars Significant clinical improvement in all 35 patients treated Minimal adverse effects and significantly less erythema, edema, and crusting than with standard mode of CO 2 laser resurfacing MTZ = microthermal zones; CO 2 = carbon dioxide DERMATOLOGIC SURGERY

9 TIERNEY ET AL ice-pick to box-car and rolling scars, with a series of five FP treatments at 1- to 3-week intervals. Mean clinical improvement ranged from 25% to 50% assessed using digital photography and from 22% to 66% assessed using high-resolution typographic imaging. Adverse side effects such as hyperpigmentation, hypopigmentation, induced textural abnormalities, and were not observed. Weiss and colleagues 25 reported the results of the largest series of patients (N = 500) treated for acne with the 1,540-nm FP laser with 100 microbeams/cm 2 (Lux 1,540, Palomar, Burlington, MA). ResultsofFPin500patientstreatedwithFPforacne, as assessed according to blinded physician photographic analysis, indicated a median improvement of 50% to 75%. Patient rating correlated with physician assessment, with 85% of patients rating their skin as improved. Side effects were minimal and included mild post-treatment erythema that resolved within 24 hours after treatment. Pain was also reported as minimal (mean of 2.75 out of 10). Alster and colleagues 26 reported on the results of a cohort of 53 patients with atrophic acne scars treated with a series of FP treatments (Fraxel SR, Reliant Technologies, Inc.). After a series of three monthly treatments, clinical improvement ranged from 51% to 95% in 90% of patients; side effects included transient erythema and edema in most patients, but no dyspigmentation, ulceration, or was observed. FP has become an increasingly popular treatment modality to treat acne in individuals of darker skin types (Fitzpatrick skin types III VI), in whom previous nonablative and laser treatments and surgical treatment modalities carry the risk of permanent postinflammatory hyperpigmentation. Lee and colleagues 27 performed a study with nonablative FP in which 27 Korean patients (type IV V skin) with moderate to severe facial acne received three to five treatment sessions. Patients self-assessed degrees of improvement were excellent improvement in 30%, significant improvement in 59%, and moderate improvement in 11%. Adverse events were limited to transient pain, erythema, and edema, with no incidence of postinflammatory hyper- or hypopigmentation. Glaich and colleagues 28 reported two cases of treatment of marked atrophic acne and postinflammatory erythema with FP. Marked improvement was noted in the postinflammatory erythema after one treatment session. Significant improvement in the atrophic and ice-pick acne scars were noted 3 months after a series of five FP treatments. Analogous to improvement noted in PC, Glaich and colleagues speculated that the 1,550-nm wavelength used in FP targets tissue water and thus may lead to thermally induced destruction of dermal blood vessels, resulting in improvement of erythema. AFP for Acne Scarring Ortiz and colleagues 29 presented the first results of a pilot study with the fractionated CO 2 laser (Fraxel re:pair, Reliant Technologies, Inc.) for the treatment of acne (Table 2). Fifteen subjects underwent up to three treatments. Patients with a diversity of skin types (I V) were treated with no complications of short- or long-term hyperpigmentation reported; 87% of subjects sustained significant improvement in the appearance of acne at 3-month follow-up visits. All subjects reported transient erythema that resolved within the first 2 weeks after treatment. In a larger case series, Chapas and colleagues 30 demonstrated that AFP technology with the fractionated CO 2 laser (Fraxel re:pair, Reliant Technologies Inc.) significantly improved moderate to severe acne. With AFP, improvements of 26% to 50% in texture, atrophy, and overall improvement were noted in all patients. In addition, no adverse events, including immediate or delayed hypo- and hyperpigmentation, were observed after AFP treatment. Lloyd and Tanghetti 31 reported the results of a comparison of the Affirm fractionated device 35:10:OCTOBER

10 REVIEW OF FRACTIONAL PHOTOTHERMOLYSIS (Cynosure, Westford, MA), comparing the dualwavelength 1,320-/1,440-nm setting with the 1,320- nm setting alone in the treatment of acne scars. After a series of five treatments at 3-week intervals, significantly greater improvement was noted with the multiplex dual wavelength (1,320-/1,440-nm) than with the single-wavelength setting. Histologic analysis also demonstrated that thermal damage occurred in the dermis 24 hours after the treatment, and new collagen was found in the dermis 3 months after the treatment. Kim 32 published a study using a standard CO 2 laser for the treatment of atrophic acne scars, with treatment focused exclusively on the scars themselves, mimicking the approach of the fractionated devices with the advantage of significantly less downtime than with standard CO 2 resurfacing and less cost associated with purchasing a fractionated CO 2 device. They reported significant clinical improvement in all 35 patients treated, with minimal adverse effects and significantly less erythema, edema, and crusting than with standard CO 2 laser resurfacing. FP for Melasma In 2005, Rokhsar and Fitzpatrick 5 provided one of the initial reports on the efficacy of FP for the treatment of melasma (Table 3). Ten female patients (Fitzpatrick skin types III to V) who were unresponsive to previous treatment modalities were treated at 1- to 2-week intervals with FP. After four to six treatment sessions, the physician evaluation confirmed that 60% of patients achieved 75% to 100% clearance, with only 30% of patients demonstrating less than 25% improvement. In terms of side-effect profile, one of the 10 patients exhibited mild transient postinflammatory hyperpigmentation (which resolved within 3 months of treatment), and no patients exhibited hypopigmentation. Goldberg and colleagues 6 reported the results of treatment of 10 patients with melasma (skin types III IV) with a nonablative FP device (Fraxel SR 750). Patients received a total of four treatments at 2-week intervals. This study was the first to present characteristic histologic changes after FP treatment of melasma. Histologically, Goldberg and colleagues reported that post-treatment specimens demonstrated a relative decrease in melanocytes from pretreatment according to light microscopy. Posttreatment electron microscopy also revealed fewer melanocytes and less melanin in the surrounding keratinocytes than in pretreatment specimens. In addition, improvements in melasma were less extensive in patients with progressively darker skin types; six patients with skin type III were determined TABLE 3. Fractional Photothermolysis (FP) for Melasma Indication Author FP Laser Used/Parameters Results Melasma Melasma Rokhsar et al. 5 Goldberg et al. 6 Fraxel SR laser, Reliant Technologies, Inc. Settings: 6 12 mj fluence, 2,000 3,500 MTZ/cm 2 total density Fraxel SR, Reliant Technologies, Inc. Settings: 6 10 mj fluence, 2,000 2,500 MTZ/cm 2 total density Melasma Naito et al. 7 Fraxel SR, Reliant Technologies, Inc. After completion of 4 6 treatment sessions, physician evaluation: 60% of patients achieved % clearance of melasma, 30% of patients had o25% clearance On post-treatment biopsy specimens, a relative decrease in melanocytes on light and electron microscopy was observed. Decrease in melanocytes correlated with observed clinical improvement Mean improvement of 35% after treatment MTZ = microthermal zones DERMATOLOGIC SURGERY

11 TIERNEY ET AL to have good improvement, whereas four patients with skin type IV had only fair improvement. The current theory whereby FP results in decreased pigmentation was demonstrated in the initial prototype studies by Manstein and colleagues. After FP treatment, melanin concentration, observed clinically as minute brown crusts seen at 3 days post-treatment, within the microthermal columns of injury was found to be significantly higher than in the surrounding tissue. 1,2 Subsequently, epidermal melanin and keratinocyte debris as well as dermal contents, such as elastotic material, are eliminated through the newly formed channels in the skin (MTZs) induced by FP. These observations have lead to a theory of a melanin shuttle after FP, whereby MTZ creation and tissue destruction results in elimination of melanocytes and keratinocytes containing melanin granules. This melanin shuttle formation results in significant improvement in epidermal and dermal pigmentation associated with conditions such as melasma and dyschromia of photoaging. 1,2 However, several more recent reports have suggested limitations of efficacy of FP for melasma, especially in patients with darker skin types, with modest efficacy and high recurrence rates after treatment. Naito 7 reported the results of six female patients of Chinese descent (Fitzpatrick skin types III IV) who were treated with three to four treatment sessions of nonablative FP at approximately 4-week intervals. Although all patients experienced at least 20% overall improvement in the appearance of their melasma, mean improvement noted 2 months after completion of treatment was only 35%. FP for Other Forms of Cutaneous Pigmentation Minocycline-Induced Hyperpigmentation: Izikson and Anderson 20 recently published a novel finding whereby minocycline-induced hyperpigmentation was markedly improved with the use of nonablative FP (Table 4). Pigment deposition after minocycline use is a well-documented side effect of therapy that has been reported to occur in 3% to 14% of patients treated with prolonged courses of the drug. The pigmentation is attributed to iron complexed with minocycline. 20 There are three forms of minocycline hyperpigmentation: type 1, blue black pigmentation within scars; type 2, blue gray pigmentation in TABLE 4. Fractional Photothermolysis (FP) for Other Pigmentary Disorders Indication Author FP Laser Used/Parameters Results Minocycline induced facial hyperpigmentation Nevus of Ota Izikson and Anderson et al. 20 Kouba et al. 19 Fraxel SR, Reliant Technologies, Inc. Settings: Initially, 4 15 mj fluence, 125 MTZ/cm 2 density applied with 8 10 passes; 6 months later, 20 mj fluence, 5.11 kj total energy; 4 months later, 20 mj fluence, 4.78 kj total energy; 2 months later, 60 mj fluence, 5.48 kj total energy A fractionated 1,440-nm neodymium-doped yttrium aluminum garnet laser (Affirm, Cynosure Inc., Westford, MA) Settings: 300 mm penetration depth, 3.5 J/cm 2 fluence and then 4.0 J/cm 2 fluence. For each treatment, only 1 pass was made, with an overlap of 20% between pulses Two months after completion of a series of 4 FP treatments, near-complete resolution of blue pigmentation on the face was observed After 1 treatment, 10% improvement was noted After 2 treatments, the lesion completely resolved 4 months later; there was no evidence of recurrence or postinflammatory hyperpigmentation MTZ = microthermal zones. 35:10:OCTOBER

12 REVIEW OF FRACTIONAL PHOTOTHERMOLYSIS previously normal skin, especially that of the shins; and type 3, brownish discoloration in sun-exposed sites. In types 1 and 2, the pigment is positive for Perls and Fontana Mason, and in type 3, there is only Fontana Mason staining, and no deposition of iron is observed. 20 Izikson and Anderson reported the case of a 66-year-old woman with a 2-year history of minocycline use for rosacea with resulting bluish pigmentation of cheeks and upper lip treated with FP using a 1,550-nm FP laser (Fraxel, Reliant Technologies, Inc.) over four treatment sessions. 20 There was gradual improvement of blue dyspigmentation approximately 1 month after each treatment session. Remarkably, 2 months after the last treatment, nearcomplete resolution of blue pigmentation on the face was observed. The authors postulated that the mechanism of improvement was probably analogous to improvement of deeper pigmentation in photoaging and melasma, with gradual clearance of drug-induced dermal pigment and deposition and remodeling of healthy new dermal collagen, accounting for the progressive decrease in blue pigmentation observed clinically. Nevus of Ota: Kouba and colleagues 19 published a case report detailing treatment of a nevus of Ota treated successfully with FP. The patient had failed prior attempts at treatment with a standard Q-switched laser, as well as recurrent pigmentation and after a prior surgical excision of the area. A fractionated 1,440-nm neodymium-doped (Nd):YAG laser (Affirm, Cynosure Inc.) was used, with the end point of immediate, confluent erythema of the entire treatment area. The interval between treatments was 4 weeks. Although there was only approximately 10% improvement after the first treatment, the nevus of Ota completely resolved within 6 weeks of the second treatment, and 4 months later, there was still no evidence of recurrence or postinflammatory hyperpigmentation. It was proposed that the likely mechanism of action of FP on nevus of Ota was an ablative phenomenon whereby the superficial dermal pigment was destroyed with the coagulated tissue. 19 It is likely that two treatments were required to achieve the response because only a portion of the target area was treated during each session. FP avoided the postinflammatory hyperpigmentation and that are sometimes observed when Q-switched lasers are used to treat nevus of Ota in adults, especially in those of Fitzpatrick skin types III and higher. The authors concluded that, because the 1,440-nm Nd:YAG FP laser has been shown to be safe for use on individuals with darker skin types, FP may become the mainstay of treatment for adult or long-standing cases involving this type of lesion. 19 Surgical Scars Whereas nonablative laser resurfacing has traditionally been unsuccessful at effecting improvements in hypopigmented and atrophic scars, FP has shown early promise in case reports and early pilot studies in both of these scar types (Table 5). In a case report, Behroozan and colleagues 21 noted 75% overall improvement in a surgical scar on the chin after a single treatment with the 1,550-nm Fraxel SR. In 2007, Glaich and colleagues 22 established the efficacy of the 1,550-nm Fraxel SR in hypopigmented facial scars, whereby after two to four treatments, 51% to 75% improvement in hypopigmentation was observed in six of seven patients. Additional improvements were also noted in this study in the overall texture of the skin of the scar and surrounding area treated with FP. In a study performed by Tierney and colleagues 23 comparing the efficacy of FP for the cosmetic improvement of surgical scars with that of the PDL, greater improvements were noted with FP than with PDL. Fifteen scars were treated on half of the scar with 1,550-nm fractionated erbium laser (Fraxel SR, Reliant Technologies, Inc.) and on the contralateral half with the 595-nm V-Beam PDL (Candela Corporation Inc., Wayland, MA). After a series of four treatments, greater improvements were noted in the portion of surgical scars treated with FP than the V-Beam PDL in overall cosmetic outcome (Fraxel SR, mean improvement 75.6%, vs PDL 53.9%; po.001). Analogous to the results of Behroozan and 1456 DERMATOLOGIC SURGERY

13 TIERNEY ET AL TABLE 5. Fractional Photothermolysis (FP) for Scars/Striae Distensae Indication Author FP Laser Used/Parameters Results Hypopigmented surgical scars Hypopigmented surgical scars Surgical scars after Mohs surgery Behroozan et al. 21 Glaich et al. 22 Tierney et al. 23 Fraxel SR, Reliant Technologies, Inc. Fraxel SR, Reliant Technologies, Inc. Settings: ranged from 7 to 20 mj fluence and 1,000 2,500 MTZ/ cm 2 total density Fraxel SR, Reliant Technologies, Inc. versus V-Beam PDL, Candela Corporation Settings: Fraxel SR, 70 mj fluence, coverage 23%, 16 passes, kj total energy delivered per session. PDL 7.5 J/cm 2 fluence, 0.45 ms pulse duration delivered with cryogen cooling of 20 ms and 20 ms at a spot size of 10 3mm Striae distensae Kim et al. 38 Fraxel SR (1,550 nm), Reliant Technologies, Inc. 75% improvement in scar appearance and texture 51 75% improvement in hypopigmentation was observed in 6 of 7 patients. Additional improvements were also noted in the overall texture of the scar Overall cosmetic outcome: FP 75.6% versus PDL 53.9%, po.001 Pigmentary variation: FP 64.2% versus PDL 45.8%, po.05 Scar thickness: FP 86.8% versus PDL 45.8%, po.001 Scar texture: FP 73.2% versus PDL 52.5%, po.001. A total of 5 hypopigmented scars improved after FP (65.0%) with no improvement after PDL (0%) (po.001) 8 weeks after treatment, substantial improvement in the appearance of striae distensae was noted MTZ = microthermal zones; PDL = pulsed dye laser. colleagues, 21 four scars with significant hypopigmentation had improvements in pigmentation after treatment with FP (mean improvement 65.0%), with no improvement or worsening after treatment with PDL (mean improvement 0%) (po.001). 23 Striae Distensae: Kim and colleagues 38 reported the first case series of FP treatment of striae distensae, in which improvement in overall appearance, patient satisfaction, erythema index, melanin index, and skin elasticity were noted. Six Asian women with chronic striae distensae on both buttocks were treated with a 1,550-nm FP laser. After one treatment with FP, substantial improvements in the appearance of striae distensae were noted 8 weeks after treatment. The erythema and melanin indices of striae distensae approached those of normal skin at the 4-week follow-up visit, although skin elasticity was found to be only partially normalized after FP. On histologic examination, a significant increase in epidermal thickness and new collagen and elastic fiber deposition were noted. Although one treatment with FP demonstrated promising clinical and histologic improvement, additional larger-scale studies investigating the clinical improvement and sideeffect profile of striae distensae treated with FP are warranted. Thermal Burns: Waibel and Beer 39 provided a case report of efficacy of FP for burn scars with postulated mechanisms of the unique efficacy of this technology resulting from the greater depth of penetration and stimulation of wound-healing properties. Although more extensive studies are needed to validate this approach, FP represents a novel, promising therapeutic option for localized and extensive in burn patients. FP for Vascular Disorders Telangiectatic Matting: Glaich and colleagues 34 provided the first case report of improvement in telangiectatic matting after treatment with FP (Table 6). Significant improvement was noted in a case report of matted telangiectasias on the thigh 35:10:OCTOBER

14 REVIEW OF FRACTIONAL PHOTOTHERMOLYSIS TABLE 6. Fractional Photothermolysis (FP) for Vascular Disorders Indication Author FP Laser Used/Parameters Results Telangiectatic matting Residual hemangioma Glaich et al. 34 Blankenship et al. 33 Fraxel SR (1,550 nm), Reliant Technologies, Inc. Fraxel SR (1,550 nm), Reliant Technologies, Inc. Settings: 2.4 kj total energy delivered after 8 10 successive laser passes Physician evaluation after a series of treatments: marked improvement in the clinical appearance of matted telangiectasias Marked clinical improvement of the skin areas apparent 1 and 6 months after treatment treated with five sessions of FP at monthly intervals with the 1,550-nm Fraxel SR. Side effects were limited to mild pain during the treatment and mild post-treatment erythema and edema. Analogous to reports by Glaich and colleagues 22 and Behroozan and colleagues 21 of improvement in background erythema associated with acne and poikiloderma of Civatte, 24 specific damage to dermal vasculature in FP is theorized to result in improvement in telangiectatic matting with FP. Residual Hemangioma: Blankenship and Alster 33 reported a case of a residual hemangioma in the wrinkled and hypertrophic skin in the glabellar and right temple areas of the face treated with FP (Fraxel SR, Reliant Technologies, Inc.). The patient had an infantile hemangioma covering 80% of the surface area of the right half of her face that had undergone significant spontaneous resolution during the first 10 years of life. She underwent PDL treatment for residual superficial telangiectasias and CO 2 laser resurfacing to improve areas of residual skin thickness and textural abnormality at 13 years of age. After the first FP treatment, she reported rapid healing of the areas, with full resolution of erythema and swelling and no discernible peeling within 4 to 5 days after treatment. One month thereafter, another FP treatment was applied to the areas without complications. Marked clinical improvement of the skin areas was apparent 1 month after the treatment and was maintained at 6-month follow-up. Particularly remarkable improvements were noted in normalization of skin texture markings and residual tissue bulk at the site of the infantile hemangioma. FP for Deposition, Inflammatory and Premalignant Disorders Granuloma Annulare: Karsai and colleagues 35 recently demonstrated a unique application of FP in the treatment of disseminated granuloma annulare (GA) with FP using a 1,440-nm Nd:YAG laser (Table 7). After two treatment sessions administered at 3-week intervals, four sample GA lesions on the patient s left upper arm were completely cleared. Karsai and colleagues reported that, since these initial treatments, the patient had subsequently undergone three treatment sessions of the other GA lesions on both arms, neck, chest, and abdomen, with complete clearance and persistent resolution after 8 months of follow-up. On histology, the authors identified similar changes of FP wounding and repair as those observed in studies of FP for photoaging and. Thus, wound healing stimulated by FP may act to resolve the granulomatous inflammation analogous to FP-induced stimulation of wound healing in photoaging,, and pigmentary disorders. Similar improvements in GA have been observed after treatment with other destructive modalities, including local injections, trauma, biopsies, and cryotherapy. 40,41 Disseminated Superficial Actinic Porokeratosis: Chrastil and colleagues 36 reported a series of two cases of refractory disseminated superficial actinic porokeratosis (DSAP) on the lower and upper extremities treated with FP. After a series of FP treatments, improvement in the individual DSAP lesions and in texture abnormalities and associated pruritus were noted DERMATOLOGIC SURGERY