STUDY. Skin Rejuvenation Using Intense Pulsed Light. A Randomized Controlled Split-Face Trial With Blinded Response Evaluation

STUDY Skin Rejuvenation Using Intense Pulsed Light A Randomized Controlled Split-Face Trial With Blinded Response Evaluation Lene Hedelund, MD; Eva Due, MD; Peter Bjerring, MD, DMSc; Hans Christian Wulf, MD, DMSc; Merete Haedersdal, MD, PhD, DMSc Objective: To evaluate efficacy and adverse effects of intense pulsed light rejuvenation in a homogeneous group of patients. Design: Randomized controlled split-face trial. Setting: University dermatology department. Patients: Thirty-two female volunteers with Fitzpatrick skin type I through III and class I or II rhytids. Interventions: Subjects were randomized to 3 intense pulsed light treatments at 1-month intervals or to no treatment of right or left sides of the face. Main Outcome Measures: Primary end points were skin texture and rhytids. Secondary end points were telangiectasia, irregular pigmentation, and adverse effects. Efficacy was evaluated by patient self-assessments and by blinded clinical and photographic evaluations up to 9 months after final treatment. Adverse effects were assessed clinically and by noninvasive skin reflectance measurements. Results: Skin texture was significantly improved at all clinical assessments except at the 6-month examination (P.006). The improvements peaked at 1 month after treatment, at which time 23 (82%) of 28 patients had better appearances of treated vs untreated sides. Most patients obtained mild or moderate improvements, and 16 patients (58%) self-reported mild or moderate efficacy on skin texture. Rhytids were not significantly different on treated vs untreated sides, and 19 patients (68%) reported uncertain or no efficacy on rhytids. Significant improvements of telangiectasia (P.001) and irregular pigmentation (P.03) were found at all assessments. Three patients withdrew from the study because of pain related to treatment. Conclusions: Three intense pulsed light treatments improved skin texture, telangiectasia, and irregular pigmentation but had no efficacy on rhytids. Adverse events were minimal, but included scar in 1 patient. Arch Dermatol. 2006;142:985-990 Author Affiliations: Departments of Dermatology, University of Copenhagen and Bispebjerg Hospital, Copenhagen (Drs Hedelund, Due, Wulf, and Haedersdal), and Aarhus University Hospital, Aarhus (Dr Bjerring), Denmark. NONABLATIVE SKIN REJUVEnation is used for the treatment of photodamaged skin, including skin texture, rhytids, telangiectasia, and irregular pigmentation. 1 Treatments of telangiectasia and irregular pigmentation are well established; possible improvement of skin texture and rhytids by nonablative remodeling is widely discussed. The mechanism of action is thought to be based on selective absorption of light in hemoglobin or tissue water, leading to the formation of a dermal repair zone and subsequent collagen synthesis. 2-4 Devices in the visible and midinfrared parts of the electromagnetic spectrum are used for nonablative remodeling, including intense pulsed light (IPL), potassium-titanyl-phosphate laser (532 nm), pulsed dye lasers (585 and 595 nm), Nd: YAG lasers (1064 and 1320 nm), diode lasers (532 and 1450 nm), and erbium: glass laser (1540 nm). The IPL systems emit polychromatic light in a wavelength spectrum of 500 to 1200 nm. 5 With the aid of different cutoff filters, the spectral range can be narrowed to selectively target variable structures of the skin. 5,6 Controlled split-face trials, which compare treated vs untreated control sites, have demonstrated the efficacy of visible (532- to 595-nm) and midinfrared (1064- to 1540-nm) lasers for the treatment of skin texture and rhytids. 7-11 CME course available at www.archdermatol.com The objective of this randomized controlled split-face trial was to evaluate the efficacy and adverse effects of IPL rejuvenation, with the primary end points being skin texture and rhytids. The efficacy on telangiectasia and irregular pigmentation was secondarily assessed. To our knowl- 985

edge, this study is the first randomized controlled splitface trial comparing a treated vs an untreated control site after IPL rejuvenation in a homogeneous group of patients. METHODS Thirty-two healthy female volunteers (mean age, 47 years) with Fitzpatrick skin type I through III and class I or II rhytids were treated. Inclusion criteria were nonsmokers with symmetrical skin texture, facial rhytids, irregular pigmentation, and telangiectasia on the right and left sides of the face. Exclusion criteria were pregnancy, any visible asymmetry of skin texture and facial rhytids, irregular pigmentation, and telangiectasia, any sign of infection or inflammatory skin disease, previous formation of hypertrophic scars or keloids, use of oral isotretinoin in the past 12 months, current use of aspirin or nonsteroidal anti-inflammatory drugs, exposure to UV irradiation within the past 4 weeks, and previous skin rejuvenation procedures in the facial area. The patients were recruited from the community by advertisements in local newspapers, and all gave informed consent. The study was approved by the human study committee and was conducted from January 12, 2004, to January 20, 2005. The patients were randomized to 3 IPL treatments at 1-month intervals or to no treatment of the right or left sides of the face. The randomization was carried out before treatment by patients drawing lots between 2 opaque sealed envelopes containing right or left marked cards representing the site for intervention with IPL. Twenty-nine of 32 patients received the allocated treatment, and 28 patients completed the study (2 patients allocated to treatment on the right side and 1 patient allocated to treatment on the left side withdrew from the study before finishing the treatment because of pain related to the treatment, and 1 patient allocated to treatment on the right side withdrew from the study after the final treatment because of lack of time). The IPL treatments were performed with a secondgeneration IPL system (Ellipse Flex; Danish Dermatologic Development A/S, Hørsholm, Denmark), which in contrast to the first-generation system uses dual mode filters that restrict the emitted light to a wavelength band from 530 to 750 nm, inhibiting shorter and longer wavelengths from reaching the skin surface. In addition, the pulse is more stable in the secondgeneration IPL system, with only minor pulse decay that results in a more stable spectral light distribution throughout the pulse duration. Energies varied between 7.5 and 8.5 J/cm 2 delivered at two 2.5-millisecond pulses with a 10-millisecond interpulse delay. Because longer wavelengths from 750 through 1200 nm are removed, the emitted fluence levels are significantly lower than in comparable IPL systems. Before IPL treatment, the skin was covered with a transparent gel to optimize optical coupling between the light guide and skin. Postoperative evaluations were performed at 1, 3, 6, and 9 months after the final treatment. Evaluations were performed by a blinded independent physician (E.D.) and by patient self-reports. The physician graded differences of skin texture, rhytids (periorbicular rhytids, perioral rhytids, and facial rhytids overall), telangiectasia, and irregular pigmentation on the left side vs the right side of the face by clinical on-site and photographic evaluations (using a 4-point scale, indicating no difference, mild difference, moderate difference, or marked difference). Moreover, photographs were assessed using the 9-point rhytid assessment scale by Fitzpatrick et al. 12 At the end of the study, the patient self-reported treatment efficacy (using a 6-point scale, indicating worse appearance, no efficacy, uncertain efficacy, mild efficacy, moderate efficacy, or marked efficacy) and level of satisfaction concerning rhytids, skin texture, telangiectasia, and irregular pigmentation (using a visual analog scale, ranging from 0 [unsatisfied] to 10 [maximum satisfaction]). 13 Potential adverse effects such as wounds, erythema, hypopigmentation, hyperpigmentation, and scars were evaluated clinically using a 4-point scale (indicating none, mild, moderate, or severe). Photographs were taken using a Canon digital camera (EOS D30) equipped with a lens-mounted ring flash (Canon Macro Lens EF 100 mm 1:2.8; Canon Inc, Tokyo, Japan). All photographs were taken in raw format under identical conditions and camera settings. Standardized views (en face and 45 oblique) were used, and a single laboratory processed all photographs. Objective measurements of skin pigmentation were performed by skin reflectance spectroscopy (UV-Optimize, Model 550/660 nm; Matic, Nærum, Denmark). The instrument measures pigmentation (melanin) and redness (hemoglobin) independent of each other, based on skin reflection of 555- and 660-nm wavelengths and gives the objective results on wide biological scales. Zero percent pigmentation corresponds to absolutely white skin with no melanin pigmentation at all, and 100% pigmentation corresponds to theoretically absolutely black skin without any reflection. The instrument performs 3 independent measurements and gives the mean value at the display. 14-17 Three measurements were performed on each side of the face (ie, cheek, periorbital, and perioral regions). Specific landmarks ensured that measurements were continually taken at the same skin area. Preoperative sample size calculations revealed a required sample size of 27 patients (based on a.05 significance level, 90% power, 15% uncertainty, and an expected 55% to improve on treated sides). Nonparametric statistical methods were used. The Friedman test and Wilcoxon matched pairs test were used for paired comparisons. Differences between treated vs untreated control sides were compared using a sign test (binomial test). Descriptive data are presented as median (interquartile range [IQR]). RESULTS Blinded clinical evaluations found significant improvements of skin texture at 1, 3, and 9 months after treatment (P.006) on treated vs untreated facial sides, whereas no significant differences were found at 6 months after treatment (Table 1 and Table 2). The greatest improvement was found at 1 month after treatment, when 23 patients (82%) scored better appearances of treated vs untreated sides, with 10 patients (36%), 9 patients (32%), and 4 patients (14%) having marked, moderate, and mild differences, respectively. At 3 and 9 months after treatment, the improvements declined, when 11 patients (42%) and 15 patients (56%), respectively, scored better appearances of treated vs untreated sides, with most patients having small differences. By photographic evaluations, no significant differences were found between treated vs untreated sides at any time point (Figure 1). By patient self-assessment at the end of the study, 16 patients (58%) reported mild or moderate improvements of skin texture and a corresponding median satisfaction level of 5.1 (IQR, 4.0-7.0) (Figure 2). By clinical and photographic evaluations, no significant differences were found of rhytids on treated vs untreated sides (Table 1, Table 2, and Figure 1), and the rhytid severity scores were not significantly different 986

Table 1. Blinded Clinical Evaluations of Treated vs Untreated Sides of the Face at 1, 3, 6, and 9 Months After Treatment* Treated Side Best Untreated Side Best Time After Treatment, mo No Difference Skin Texture 1 4 (1) 82 (23) 14/32/36 (4/9/10) 14 (4) 7/4/4 (2/1/1).001 3 54 (14) 42 (11) 31/12/0 (8/3/0) 4 (1) 4/0/0 (1/0/0).006 6 56 (15) 33 (9) 26/7/0 (7/2/0) 11 (3) 7/4/0 (2/1/0).15 9 41 (11) 56 (15) 37/19/0 (10/5/0) 4 (1) 4/0/0 (1/0/0).001 Periorbital Rhytids 1 0 (0) 57 (16) 7/21/29 (2/6/8) 43 (12) 7/11/25 (2/3/7).57 3 8 (2) 46 (12) 27/15/4 (7/4/1) 46 (12) 19/23/4 (5/6/1).99 6 33 (9) 37 (10) 30/7/0 (8/2/0) 30 (8) 22/7/0 (6/2/0).82 9 7 (2) 58 (15) 19/31/8 (5/8/2) 35 (9) 23/12/0 (6/3/0).31 Perioral Rhytids 1 4 (1) 57 (16) 14/11/32 (4/3/9) 39 (11) 4/21/14 (1/6/4).44 3 23 (6) 46 (12) 12/35/0 (3/9/0) 31 (8) 19/4/8 (5/1/2).50 6 48 (13) 37 (10) 26/11/0 (7/3/0) 15 (4) 7/7/0 (2/2/0).18 9 52 (13) 36 (9) 16/16/4 (4/4/1) 12 (3) 4/8/0 (1/2/0).15 Overall Rhytids 1 7 (2) 54 (15) 14/11/29 (4/3/8) 40 (11) 11/18/11 (3/5/3).56 3 42 (11) 27 (7) 8/19/0 (2/5/0) 31 (8) 19/8/4 (5/2/1).99 6 52 (14) 15 (4) 15/0/0 (4/0/0) 33 (9) 15/15/4 (4/4/1).27 9 38 (10) 19 (5) 12/0/8 (3/0/2) 42 (11) 19/19/4 (5/5/1).21 Telangiectasia 1 10 (3) 79 (22) 0/29/50 (0/8/14) 11 (3) 7/4/0 (2/1/0).001 3 4 (1) 89 (23) 12/42/35 (3/11/9) 8 (2) 0/8/0 (0/2/0).001 6 11 (3) 81 (22) 15/48/19 (4/13/5) 7 (2) 7/0/0 (2/0/0).001 9 15 (4) 85 (23) 19/48/19 (5/13/5) 0 (0) 0/0/0 (0/0/0).001 Irregular Pigmentation 1 11 (3) 71 (20) 14/32/25 (4/9/17) 18 (5) 7/0/11 (2/0/3).004 3 12 (3) 77 (20) 35/31/12 (9/8/3) 12 (3) 0/8/4 (0/2/1).001 6 22 (6) 67 (18) 19/48/0 (5/13/0) 11 (3) 4/7/0 (1/2/0).002 9 22 (6) 59 (16) 30/30/0 (8/8/0) 19 (5) 15/4/0 (4/1/0).03 *Data are given as percentages, with the exact number of patients in parentheses. Because of rounding, percentages may not all total 100. The treatment was considered ineffective if no difference was seen between the treated and untreated sides. The treatment was considered to have a positive effect when the treated side obtained a better appearance than the untreated side and, conversely, a negative effect when the untreated side obtained a better appearance than the treated side. P values less than.05 show significant differences between the percentages of patients with best appearance of treated vs untreated sides. P Value (Table 3). By patient self-assessment, 19 patients (67%) reported uncertain or no efficacy on rhytids and a corresponding median satisfaction level of 2.5 (IQR, 1.3-5.0) (Figure 2). Significant improvements of telangiectasia were found at 1 to 9 months after surgery by clinical evaluations (79%- 89% [22-23 patients], P.001) and by photographic evaluations (53%-71% [15-20 patients], P.001). By patient self-assessment, 13 patients (46%) reported moderate or marked improvements of telangiectasia and a corresponding median satisfaction level of 5.2 (IQR, 4.9-8.3). Significant improvements of irregular pigmentation were found at 1 to 9 months after treatment by clinical evaluations (59%-77% [16-20 patients], P.03) and by photographic evaluations (61%-86% [17-24 patients], P.007). By patient self-assessment, 13 patients (46%) reported moderate or marked improvements of irregular pigmentation and a corresponding median satisfaction level of 5.4 (IQR, 5.0-7.7). Adverse effects, including slight erythema and edema, were observed in all patients immediately after treatment. All patients showed photo darkening of lentigines and freckles during the first week after treatment. One patient had a crust on the chin after the first treatment, which developed into an atrophic scar. There were no reported incidences of purpura or pigmentary changes. No adverse effects were observed on untreated sides. The percentages of skin pigmentation remained constant, and no significant differences were seen between treated vs untreated sides at any time. At 1 month after treatment, the percentages were 23.5% (IQR, 20.0%-25.4%) vs 23.1% (IQR, 18.8%-25.9%) (P=.10). At 9 months after treatment, the percentages were 23.1% (IQR, 22.3%- 26.8%) vs 23.6% (IQR, 20.1%-26.8%) (P=.18). Three patients withdrew from the study because of pain related to treatment. COMMENT Although IPL rejuvenation had no efficacy on rhytids, there was long-term improvement of skin texture, telangiectasia, and irregular pigmentation. To our knowledge, the present study is the first randomized con- 987

Table 2. Blinded Photographic Evaluations of Treated vs Untreated Sides of the Face at 1, 3, 6, and 9 Months After Treatment* Treated Side Best Untreated Side Best Time After Treatment, mo No Difference Skin Texture 1 57 (16) 32 (9) 29/4/0 (8/1/0) 11 (3) 7/4/0 (2/1/0).15 3 69 (18) 23 (6) 23/0/0 (6/0/0) 8 (2) 8/0/0 (2/0/0).29 6 64 (18) 29 (8) 21/4/4 (6/1/1) 7 (2) 4/4/0 (1/1/0).11 9 63 (17) 30 (8) 26/4/0 (7/1/0) 7 (2) 7/0/0 (2/0/0).11 Periorbital Rhytids 1 18 (5) 46 (13) 18/29/0 (5/8/0) 35 (10) 14/21/0 (4/6/0).68 3 27 (7) 50 (13) 35/12/4 (9/3/1) 23 (6) 12/12/0 (3/3/0).17 6 18 (5) 39 (11) 18/21/0 (5/6/0) 43 (12) 25/18/0 (7/5/0).99 9 11 (3) 52 (14) 15/37/0 (4/10/0) 37 (10) 30/4/4 (8/1/1).54 Perioral Rhytids 1 36 (10) 39 (11) 18/14/7 (5/4/2) 25 (7) 21/4/0 (6/1/0).48 3 31 (8) 42 (11) 19/19/4 (5/5/1) 27 (7) 23/4/0 (6/1/0).48 6 32 (9) 43 (12) 18/14/11 (5/4/3) 25 (7) 21/4/0 (6/1/0).36 9 41 (11) 37 (10) 11/26/0 (3/7/0) 22 (6) 19/0/4 (5/0/1).46 Overall Rhytids 1 70 (19) 15 (4) 7/7/0 (2/2/0) 15 (4) 15/0/0 (4/0/0).99 3 73 (19) 15 (4) 8/8/0 (2/2/0) 12 (3) 4/8/0 (1/2/0).99 6 64 (18) 21 (6) 14/7/0 (4/2/0) 14 (4) 7/4/4 (2/1/1).75 9 68 (17) 16 (4) 12/4/0 (3/1/0) 16 (4) 8/4/4 (2/1/1).99 Telangiectasia 1 21 (6) 71 (20) 43/21/7 (12/6/2) 7 (2) 4/4/0 (1/1/0).001 3 27 (7) 65 (17) 46/19/0 (12/5/0) 8 (2) 4/4/0 (1/1/0).001 6 39 (11) 53 (15) 25/21/7 (7/6/2) 7 (2) 7/0/0 (2/0/0).001 9 40 (10) 60 (15) 40/12/8 (10/3/2) 0 0/0/0 (0/0/0).001 Irregular Pigmentation 1 7 (2) 81 (22) 22/44/15 (6/12/4) 11 (3) 0/7/4 (0/2/1).001 3 8 (2) 85 (22) 23/42/19 (6/11/5) 8 (2) 4/4/0 (1/1/0).001 6 21 (6) 61 (17) 29/18/14 (8/5/4) 18 (5) 11/4/4 (3/1/1).007 9 4 (1) 86 (24) 36/36/14 (10/10/4) 11 (3) 4/4/4 (1/1/1).001 *Data are given as percentages with the exact number of patients in parentheses. Because of rounding, percentages may not all total 100. P Value trolled split-face trial evaluating efficacy and adverse effects of IPL rejuvenation by comparing a treated vs an untreated control site. Three randomized controlled studies that included split-face trials previously evaluated the efficacy of IPL rejuvenation alone vs IPL treatment in combination with botulinum toxin A 18 or with topical 20% 5-aminolevulinic acid. 19,20 In all 3 studies, better results were achieved after combined treatment, although marked improvements of skin texture were demonstrated in up to 90% of patients after IPL treatments alone. In contrast to the results of our study, one study 19 reported rhytid improvement in 80% of patients treated only with IPL. Uncontrolled before-after trials support these findings. 1,21,22 Bitter 1 reported a 10% to 90% improvement of fine rhytids in 91% of patients after 4 full-face treatments with IPL, and in a study by Goldberg and Cutler 21 some improvement of rhytids was found in all patients at 6 months after 1 to 4 treatments with IPL. However, none of the previous studies evaluated an untreated control area, which stresses the importance of our study. Nonablative skin rejuvenation with lasers and IPL sources is being investigated with great interest, but no clear reproducible treatment strategies have been defined. Differences in wavelengths, treatment settings, numbers of treatments, treatment intervals, and treatment areas make it difficult to compare and draw conclusions about the efficacy of the different nonablative devices available for treatment of skin texture and rhytids. In the present study, 3 IPL treatments at 1-month intervals improved the skin texture but had no efficacy on rhytids. Treatment outcomes might have changed with the use of different treatment variables and an increased number of treatments. However, the clinical improvements of vascular and pigmented lesions are similar to previous findings in controlled trials after IPL rejuvenation. 18,23 Bjerring et al 23 reported improvements of telangiectasia and irregular pigmentation in 81.8% and 54.5% of patients, respectively, at 3 months after 2 IPL treatments using a wavelength band (530-750 nm) similar to that used in our study. In another study, 18 telangiectasia and lentigines improved markedly in 86% and 71% of patients, respectively, at 26 weeks after 5 treatments with IPL. In our study, the patients were more satisfied with the results on skin texture, telangiectasia, and irregular pigmentation than with the results on rhytids. Moreover, patient satisfaction with the results on skin texture was of the same magnitude as the satisfaction level with the 988

A B C Figure 1. A patient at 3 months after 3 intense pulsed light treatments on the left side of the face demonstrates improvement in telangiectasia and irregular pigmentation, without efficacy on skin texture and rhytids. A, Untreated right side. B, En face. C, Treated left side. % of Patients Patients Satisfaction on VAS 100 50 0 10 5 0 A B Effect Moderate Effect Skin Texture Rhytides Mild Effect Uncertain Effect Irregular Pigmentation No Effect Worse Telangiectasia Figure 2. Patient self-assessment of skin texture, rhytids, irregular pigmentation, and telangiectasia at the end of the study. A, Efficacy rated on a 6-point scale. B, Satisfaction rated using a visual analog scale (VAS). results on telangiectasia and irregular pigmentation. Clinical evaluations, which supported these patient assessments, showed no improvement on rhytids but significant improvement of skin texture at all assessments except at the 6-month examination, at which time a suntan in most patients may have masked the improvement. However, no skin texture improvement was demonstrated by Table 3. Scores on 9-Point Rhytid Assessment Scale* Time After Treatment, mo Median (25%-75% Interquartile Range) Rhytid Score Treated Side of Face Untreated Side of Face P Value Periorbital Rhytids 0 3.0 (2.0-4.5) 3.0 (2.0-4.5).82 1 3.0 (2.0-4.5) 3 (2-5).85 3 3 (2-5) 3 (2-5).62 6 3.0 (2.0-4.5) 3 (2-4).67 9 3.0 (2.0-4.5) 3 (2-5).99 Perioral Rhytids 0 3 (1-4) 2.5 (1.0-4.0).83 1 2.5 (1.5-4.0) 2.5 (1.5-4.0).33 3 3.0 (1.5-4.0) 3 (1-5).99 6 3 (1-4) 2.5 (1-4).52 9 2 (1-4) 2 (1-4).30 *Scale by Fitzpatrick et al. 12 photographic evaluations, which indicates that the improvements were too small to be visible on photographs. It is possible that information loss of small changes in depth perception caused by conversion of 3-dimensional (clinical) into 2-dimensional (photographic) methods contributes to the conflicting assessment of skin texture by clinical and photographic evaluations. Therefore, clinical evaluations are preferred to judge skin texture in clinical trials, and the use of more than 1 blinded onsite evaluator may increase the validity of the results. 24 If photographs are used, the use of parallel-polarized light might be considered for better images of skin texture. In summary, 3 IPL treatments improved skin texture, telangiectasia, and irregular pigmentation, but they had no efficacy on rhytids. Adverse events were minimal, but included scar in 1 patient. 989

Accepted for Publication: December 19, 2005. Correspondence: Lene Hedelund, MD, Department of Dermatology, University of Copenhagen and Bispebjerg Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen, Denmark (LH20@bbh.hosp.dk). Author Contributions: Study concept and design: Hedelund, Bjerring, Wulf, and Haedersdal. Acquisition of data: Hedelund and Due. Analysis and interpretation of data: Hedelund, Wulf, and Haedersdal. Drafting of the manuscript: Hedelund. Critical revision of the manuscript for important intellectual content: Due, Bjerring, Wulf, and Haedersdal. Statistical analysis: Hedelund. Administrative, technical, and material support: Bjerring, Wulf, and Haedersdal. Study supervision: Wulf and Haedersdal. Financial Disclosure: None reported. Funding/Support: This study was supported by the Aage Bang Foundation, the Gerda and Aage Haensch Foundation, the Hans and Nora Buchard Foundation, and the Danish Hospital Foundation for Medical Research (region of Copenhagen, the Faroe Islands, and Greenland). Role of the Sponsors: The study sponsors had no role in study design, data collection, data analysis, data interpretation, or writing of the article. REFERENCES 1. Bitter PH. Noninvasive rejuvenation of photodamaged skin using serial, full-face intense pulsed light treatments. Dermatol Surg. 2000;26:835-842. 2. Goldberg DJ, Samady JA. Intense pulsed light and Nd:YAG laser non-ablative treatment of facial rhytids. Lasers Surg Med. 2001;28:141-144. 3. Trelles M, Allones I, Velez M, Mordon S. Nd:YAG laser combined with IPL treatment improves clinical results in non-ablative photorejuvenation. J Cosmet Laser Ther. 2004;6:69-78. 4. Nelson JS, Majaron B, Kelly KM. What is nonablative photorejuvenation of human skin? 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