Lasers in Surgery and Medicine

Comparison Between Er:YAG Laser and Bipolar

Radiofrequency Combined With Infrared Diode Laser for
the Treatment of Acne Scars: Differential Expression of
Fibrogenetic Biomolecules May Be Associated With
Differences in Efficacy Between Ablative and Non-Ablative
Laser Treatment
Seonguk Min, MD, PhD,1,2 Seon Yong Park, MD, BS,1,2 Jungyoon Moon, MD, MS,1,2 Hyuck Hoon Kwon, MD, PhD,1,2
Ji Young Yoon, MS,2 and Dae Hun Suh, MD, PhD1,2

1
Department of Dermatology, Seoul National University College of Medicine, Seoul, South Korea
2
Acne and Rosacea Research Laboratory, Seoul National University Hospital, Seoul, South Korea

Background and Objective: Fractional Er:YAG mini- INTRODUCTION

mizes the risk associated with skin ablation. Infrared
Compared with the carbon dioxide laser, Er:YAG laser
diode laser and radiofrequency have suggested compa-
provides more precise tissue ablation and less thermal
rable improvements in acne scar. We compared the
damage, therefore producing less erythema and faster
clinical efficacy of Er:YAG laser and bipolar radio-
re-epithelization [1]. With the emergence of fractional laser
frequency combined with diode laser (BRDL) for the
technology, fractional Er:YAG laser allowed for a more
treatment of acne scars. Moreover, acute molecular
controllable resurfacing and a rapid re-epithelization [2].
changes of cytokine profile associated with wound
However, ablative fractional laser still has prolonged
healing have been evaluated to suggest mechanisms of
postoperative recovery period and risk of erythema or
improvement of acne scar.
hyperpigmentation.
Study Design: Twenty-four subjects with mild-to- Infrared diode lasers, which are non-ablative laser
moderate acne scars were treated in a split-face manner maintaining epidermal integrity, are not absorbed by
with Er:YAG and BRDL, with two treatment sessions, pigments and can transfer their energy to skin effectively.
4 weeks apart. Objective and subjective assessments were Treatment with diode lasers emitting infrared light has
done at baseline, 1, 3, 7 days after each treatment and been reported to induce better wound healing through
4 weeks after last treatment. Skin biopsy specimens were promoting fibroblast stimulation and collagen forma-
obtained at baseline, 1, 3, 7, 28 days after one session of tion [3]. It has been proposed that diode lasers induced
treatment for investigation of molecular profile of acute growth factors in an animal model of wound healing [4].
skin changes by laser treatment. Furthermore, a recent study demonstrated that treatment
Results: Investigator’s Global Assessment representing with diode laser was effective in improving atrophic acne
the improvement degree shows 2.1 (50%) in fractional Er: scars [5]. Radiofrequency (RF) has been reported to induce
YAG and 1.2 (25%) in BRDL. Er:YAG induced the later and dermal collagen contraction by dermal heating and to
higher peak expression of TGFbs and collagenases, improve rhytids and photo-aged skin [6]. Bipolar RF has
whereas BRDL induced earlier and lower expression of been shown to induce profound neoelastogenesis and
TGFb and collagenases, relatively. PPARg dropped rapidly neocollagenesis, which are suggested as potential
after a peak in Er:YAG-treated side, which is associated
with tissue inhibitor of metalloproteinase (TIMP) expres-
sion. We observed higher expression of TIMP after Er:YAG
Conflict of Interest Disclosures: All authors have completed
treatment compared with BRDL by immunohistochemis- and submitted the ICMJE Form for Disclosure of Potential
try, which may be associated with the expression of Conflicts of Interest and none were reported.
upregulation of collagen fibers. Contract grant sponsor: MOTIE (Ministry of Trade, Industry
& Energy) - KIAT, Korean Government; Contract grant number:
Conclusion: The superior efficacy of Er:YAG to BRDL in N0001681.


the treatment of acne scars may be associated with higher Correspondence to: Dae Hun Suh, MD, PhD, Department of
Dermatology, Seoul National University Hospital, Seoul, South
expression of collagen which is associated with differential Korea, 101 Daehak-ro, Jongno-gu, Seoul 110–744, Korea.
expression of TGFbs, collagenases, PPARg, and TIMP. E-mail: [email protected]
Lasers Surg. Med. ß 2016 Wiley Periodicals, Inc. Accepted 8 October 2016
Published online in Wiley Online Library
(wileyonlinelibrary.com).
Key words: TGFb; collagenases; PPARg; TIMP; collagen DOI 10.1002/lsm.22607

ß 2016 Wiley Periodicals, Inc.

2 MIN ET AL.

mechanisms of clinical efficacy [7]. Based on this compre- using identical lighting conditions and camera settings
1
hensive background literature, bipolar RF combined with (EOS 600D ; Canon, Tokyo, Japan). Clinical assessment
diode laser (BRDL) is suggested to be an effective was performed by two independent dermatologists (D.H.S.
treatment for acne scars. and S.Y.P.). Random assignment codes were secured until
There have been no previous studies directly comparing all data entry was complete. Efficacy was assessed using
the efficacy between Er:YAG laser and BRDL for the the five-point Investigator’s Global Assessment (IGA:
treatment of acne scars. Therefore, the aim of this study grade 0; no improvement, 1; 0–25% improvement, 2;
was to evaluate and compare the clinical efficacy between 26–50% improvement, 3; 51–75% improvement, 4;
Er:YAG and BRDL in the treatment of atrophic acne scars. 76–100% improvement), Echelle d’evaluation clinique
To the best of our knowledge, we investigated the temporal des Cicatrices d’acne (ECCA) scores and subtype (icepick,
molecular changes produced by each treatment modality boxcar, rolling scar) analysis. ECCA grading scales are a
for the first time. semi-quantitative tool to evaluate acne scars and are used
to calculate a weighted value according to six types:
MATERIALS AND METHODS V-shaped, U-shaped atrophic, M-shaped atrophic, hyper-
Study Design and Subjects trophic inflammatory, keloid scars, and superficial elas-
tolysis [8]. The response of the skin to treatment was
A 12-week, prospective, single-blind, and comparative
evaluated using a six-point Epithelization Scale. The
(randomized split-face) clinical trial was carried out at the
degree of erythema was measured using two photometric
Department of Dermatology, Seoul National University 1
devices (Spectrophotometer CM-2002 ; Konica Minolta,
Hospital during October 2012–May 2013. Twenty-seven 1
Tokyo, Japan; Derma–spectrometer ; Cortex Technology,
subjects with Fitzpatrick skin types III–IV and mild-to-
Hadsund, Denmark). Patients’ subjective satisfaction
moderate acne scars on both sides of the face were included
score, pain degree, convenience score, and therapeutic
in the study. This study protocol was approved by the
effectiveness were surveyed from day 1 onward.
Institutional Review Board of the Seoul National Univer-
sity Hospital (No. H-1206-044-413) and conducted in
Histopathology and Immunohistochemistry
accordance with the Declaration of Helsinki. Informed
consent was obtained from all subjects prior to enrollment. Skin biopsy specimens (2 mm) were obtained before and
Subjects did not receive retinoid medication or other acne 84 days after treatment. Sections were stained with
scar treatments during the study period. The specific hematoxylin–eosin (H&E) and Masson’s Trichrome (MT).
protocol of the study was registered at clinicaltrials.gov For the investigation of molecular changes, skin tissue was
(NCT01958450). acquired at days 0, 1, 3, 7, and 28 after first Er:YAG
treatment. Samples were processed for immunohistochem-
Devices and Laser Treatment Techniques ical staining for transforming growth factor (TGF)b1,
TGFb2, TGFb3, MMP1, MMP13, PPARg, collagen 1, and
All laser procedures were conducted by a single surgeon
collagen 3 (Abcam, Cambridge, UK). The intensity of
(S.M.). For each subject, after a 30-minute treatment with
immunohistochemical staining was evaluated using an
topical anesthetic, one-half of the face was treated with a
1 image analysis program (Leica QWin version 3.5.1, Leica
fractional Er:YAG laser (Action II , Lutronic, Ilsan, Korea)
1 Microsystems, Wetzlar, Germany).
and the other half of the face with BRDL (Polaris WRA ,
Syneron Medical Inc., Yokneam, Israel). A random
Statistical Analysis
computer-generated allocation was conducted to assign
the treatment modality. The fractional Er:YAG 2940 nm The paired t-test or Wilcoxon signed-rank test were used
laser was applied at a fluence of 9–12 mJ/cm2 with a 100 to compare differences between treatments (SPSS, version
microthermal treatment zone and a 9  9 mm spot size via 12.0; SPSS Inc., Chicago, IL). Statistical significance was
short pulse mode (250 ms) in a non-overlapping manner. P < 0.05.
The BRDL delivered bipolar radiofrequency with a fluence
of 80 mJ/cm2 at 100 HZ and diode laser with a fluence of RESULTS
30 mJ/cm2. Er:YAG laser and BRDL treatments were Of the 27 subjects who were initially enrolled in the
performed in single and triple pass, respectively. The laser study, 24 subjects (mean age: 31.9) completed the study,
irradiation induced a clean, pink hue with minimal-to-no three dropped out for personal reasons. No patients were
bleeding. Volunteers were subjected to two identical lost to the study because of serious adverse effects.
sessions of treatment, with a 4 weeks interval between
treatments. Each patient was instructed to apply antibiotic Scar Improvement and Epithelization and Adverse
1
ointment (Bactroban ) about three times a day to the Er: Effects
YAG-treated side of the face, until all the crust fell off. Eight weeks after two sessions of Er:YAG or BRDL, the
grade of acne scars was improved on the Er:YAG-treated
Assessments of Clinical Outcome side of the face in 23 patients and on the BRDL-treated side
Subjects were followed-up at days 1, 3, and 7 after each in 21 patients. No patients had worse acne scar scores after
session and at 1 and 2 months after the final session. either treatment. Inter-rater agreement was evaluated
Digital photographs were taken at every follow-up visit with kappa statistics (kappa value ¼ 0.62, P < 0.001),
 COMPARISON BETWEEN ER:YAG LASER AND BDRL 3

demonstrating congruence between the two raters. The treatment. Both patterns measured by Spectrophotometer
1 1
mean IGA values showed that Er:YAG and BRDL treat- CM-2002 and Derma–spectrometer were similar
ments resulted in approximately 50% and 25% improve- (Fig. 1D). Mild adverse effects included mild pain, oozing,
ment, respectively. There was a significant difference and crust after Er:YAG laser treatment. Serious adverse
between the two treatment modalities (P ¼ 0.02). There effects were not observed.
were significant improvements of acne scar after both Er: Clinical photographs showed greater improvement of
YAG and BRDL treatments by ECCA compared with acne scars on the Er:YAG-treated side of the face
baseline (Er:YAG, P ¼ 0.014; BRDL, P ¼ 0.039), and the (Fig. 2A and B) compared with the BRDL-treated side
difference in improvement between the two modalities was (Fig. 2C and D).
significant at day 84 (Fig. 1A, P ¼ 0.029). Er:YAG was
superior to BRDL in improvement of all scar subtypes,
especially in boxcar scars (Fig. 1B). Subjective Assessments by Patients
Healing rates after treatment were evaluated with six- Immediately after treatment, and at day 1 after
point visual analogue scale (VAS). A significant difference in treatment, patients reported higher satisfaction scores
epithelization between the two modalities was present at for BRDL treatment than for Er:YAG treatment. However,
day 1 (P ¼ 0.005), as the BRDL treated side showed little or at days 7 and 84 after treatment, patients reported
no skin breach (Fig. 1C). Only slight erythema was present significantly higher satisfaction scores for Er:YAG treat-
after BRDL treatment. Photometric measurements of ment (P ¼ 0.03 and P ¼ 0.04, for days 7 and 84, respec-
erythema revealed consistently elevated redness after tively). Patient-reported pain scores indicated that BRDL
fractional Er:YAG laser treatment compared with BRDL treatment was more painful during the procedure,

Fig. 1. Acne scar improvement. (A) Significant difference in scar improvement as measured by
ECCA scores (B) The difference in improvement between the two modalities was maximized in
boxcar type scars. (C) Recovery time for complete epithelization after Er:YAG treatment took 1
week. However, BDRL did not require downtime. (D) Degree of erythema was higher in Er:YAG-
treated side than in BRDL-treated side during the whole study period. Statistical analysis was
performed using a two-tailed paired t-test;
P < 0.05 between treatment modalities; †P < 0.05 versus
baseline.
4 MIN ET AL.

Fig. 2. Clinical photographs revealed improvement in acne scars by both treatment modalities. (A,
B) Er:YAG-treated side of the face (C, D) BRDL-treated side of the face, (A, C) without any
treatment, (B, D) 4 weeks after two sessions of treatment.

whereas the pain induced by Er:YAG continued until skin slightly with time in BRDL-treated side (Fig. 4E). TIMP
breach recovered completely. Patients rated BRDL treat- expression gradually increased and reached the maximal
ment higher in convenience for all study periods, while peak at day 3 in Er:YAG-treated side. TIMP was induced
they graded Er:YAG treatment higher in scar greatly on the Er:YAG-treated side at day 1 and
improvement. maintained until day 28 (Fig. 4F, P ¼ 0.004).
Both treatment modalities resulted in increased expres-
sion of collagen 1 and collagen 3 with time. However, the
Collagen Deposition and Molecular Changes
expression level of collagen 1 and collagen 3 was higher in
Evaluated by Histology
Er:YAG-treated side with significance at day 7 compared
Both treatment modalities induced collagen deposition with BRDL treatment (Fig. 4G, collagen 1, P ¼ 0.01;
at day 84 compared with baseline. Collagen deposition was Fig. 4H, collagen 3, P ¼ 0.04).
more compact and denser in the papillary dermis after Er:
YAG treatment than after BRDL treatment (Fig. 3).
Immunohistochemistry revealed different patterns of DISCUSSION
TGFb expression between biopsies of Er:YAG-treated and The results demonstrated superior efficacy of Er:YAG for
BRDL-treated skin, with significantly higher TGFb1 the treatment of all scar types. Compared with baseline,
expression after BRDL treatment at day 1 (Fig. 4A, dermal collagen became thicker and denser at day 84 after
P ¼ 0.027). TGFb2 expression was higher in Er: both treatment modalities. However, Er:YAG treatment
YAG-treated skin than in BRDL-treated skin without showed denser and more compact collagen formation. The
significance. Significant TGFb3 expression of the Er:YAG- histologic results of this study support the clinical results
treated side was shown at day 3 compared to BRDL-treated and correspond with those of an earlier study that
skin (Fig. 4B, P ¼ 0.046). described the histologic changes after Er:YAG laser
Expression of MMP1 and MMP13 showed peak at day 1 treatment [9]. And Er:YAG induced different molecular
in BRDL-treated side, while at day 3 in Er:YAG-treated expression pattern with time compared with BRDL. As
side. The peak level was higher in Er:YAG-treated side. demonstrated previously, in the first week after treatment
MMP1 expression of Er:YAG-treatd side was higher at with Er:YAG, the effects of TGFb1, TGFb2, and TGFb3
days 3, 7, and 28 (Fig. 4C, P ¼ 0.004). BRDL treatment induced optimal wound healing [10]. TGFb isoforms
induced early increase of MMP13 expression compared similarly stimulated fibroblasts in vitro [11]. In this study,
with Er:YAG at day 1 (P ¼ 0.026). Er:YAG resulted in higher expression of TGFb may have strong association
significantly increased expression of MMP13 at day 3 with thicker and denser collagen bundle of Er:YAG-treated
compared with BRDL (Fig. 4D, P ¼ 0.026). side compared with BRDL-treated side. Moreover, early
Er:YAG treatment induced higher expression of PPARg peak and small expression of TGFb was peaked in skin
at days 1 and 3 (P ¼ 0.009). PPARg expression increased biopsies from the BRDL treatment at day 1 after
 COMPARISON BETWEEN ER:YAG LASER AND BDRL 5

Fig. 3. Histological changes after Er:YAG and BRDL treatments. Dense collagen deposition after
both treatments was observed by H&E and Masson’s Trichrome staining. Er:YAG treatment induced
more dense collagen deposition (A, B, C) Hematoxylin and Eosin staing (D, E, F) Masson’s Trichrome
(A, D) baseline (B, E) Er:YAG-treated side at day 84 (C, F) BRDL-treated side at day 84 (bar: 100 mm).

treatment, while peak expression of TGFb in skin from the important factor to the final deposition of collagen. Similar
Er:YAG treatment was at day 3. expression patterns of TGFbs, MMP1, MMP13, PPARg,
Er:YAG treatment showed higher MMP1 and MMP13 and TIMP were postulated to be involved in tissue
expression compared with BRDL. MMP1 has been remodeling in the current study. Different expression
reported to be effective in wound healing and promotion may result in difference of clinical effect of ablative Er:YAG
of keratinocyte migration [12,13]. Dang et al. reported and non-ablative BRDL treatment on acne scar. Taken
about the strong association between great increase in together with all data, clinical efficacy of Er:YAG laser for
MMP1 expression and scarless healing [14]. MMP13 has atrophic acne scar may be associated with the potentiation
been detected in physiological situation requiring rapid of fibrogenetic process via compensation for decreased
remodeling of collagenous extracellular matrix [15]. extracellular matrix induced by acne inflammation.
Ravanti et al. suggested that TGFb1 and TGFb3 induce Together with immunohistochemistry data, we investi-
upregulation of MMP13 expression leading to rapid gated transcription of TGFb1, TGFb3, collagen 1, and
turnover of collagen during fetal wound repair which PPARg from frozen tissue acquired from subjects who
associated with scarless healing [16]. In addition, treat- underwent Er:YAG treatment through semi-quantitative
ment with TGFb3 induced re-organization of collagen PCR during the study. PCR was done only with the skin
bundles in wound tissue similar to the organization of tissues obtained from Er:YAG-treated side due to ethical
collagen of normal skin in an animal study [17]. Though issue. However, PCR data is enough to validate the
exact mechanism of MMP1 and MMP13 as a scar immunohistochemistry data. The overall expression pat-
improving factor is unclear, our result shows that tern of TGFbs, collagen 1, and PPARg by PCR was similar
upregulation of MMP1 and MM13 has a role during skin to that seen by immunohistochemical staining.
remodeling period to increase clinical efficacy. By patients’ assessment, BRDL was more painful during
It has been reported that PPARg blocks the profibrotic the procedure, due to high energy level. The convenience of
action of TGFb in vivo and in vitro [18–20]. PPARg- BRDL seemed to contribute to higher satisfaction scores at
deficiency of fibroblast increased sensitivity to TGFb- days 0 and 3. Erythema, measured by photometric device,
medicated type 1 collagen production and enhanced was significantly lower on the BRDL-treated side of the face
dermal wound closure [21,22]. In the light of a role of than on the Er:YAG-treated side during the entire study
PPARg in wound healing, rapid drop of PPARg expression period. Patient-rated convenience scores were higher for
after day 3 in Er:YAG-treated side may contribute to an BRDL than for Er:YAG, and correlated with the degree of
increase in the expression of collagen fiber. And upregu- erythema throughout the study period. However, satisfac-
lation of TIMP expression in Er:YAG-treated side is also an tion scores at days 7 and 84 were dependent on improvement
6 MIN ET AL.

Fig. 4. Temporal analysis of molecular immunohistochemical staining by percent area. (A) TGFb1
(B) TGFb3 (C) MMP1 (D) MMP13 (E) PPARg (F) TIMP (G) collagen 1 (H) collagen 3. Molecular
expression showed similar patterns such as early peak at day 1 in BRDL-treated side and relatively
late peak at day 3 in Er:YAG-treated side (TGFb1, TGFb3, MMP1, MMP13, PPARg, and TIMP).


P < 0.05 between treatment modalities. Statistical analysis was performed using the Wilcoxon
signed-rank test.
 COMPARISON BETWEEN ER:YAG LASER AND BDRL 7

of scars. Subjects perceived greater scar improvement by Er: formation. J Am Coll Surg 2005;201:391–397.
YAG at day 84 than by BRDL. 11. Cordeiro MF, Bhattacharya SS, Schultz GS, Khaw PT. TGF-
beta1, -beta2, and -beta3 in vitro: Biphasic effects on Tenon’s
In conclusion, fractional Er:YAG provided greater acne fibroblast contraction, proliferation, and migration. Invest
scar improvement in all scar types. Both Er:YAG and Ophthalmol Vis Sci 2000;41:756–763.
BRDL treatments induce deposition of collagen 1 and 12. Mu X, Bellayr I, Pan H, Choi Y, Li Y. Regeneration of soft
collagen 3 associated with expression of TGFbs. TGFb tissues is promoted by MMP1 treatment after digit amputa-
tion in mice. PLoS ONE 2013;8:e59105.
associated fibrogenesis may be important factors in acne 13. Saarialho-Kere UK, Kovacs SO, Pentland AP, Olerud JE,
scar improvement by Er:YAG laser. The superior efficacy Welgus HG, Parks WC. Cell-matrix interactions modulate
of Er:YAG compared with BDRL in the treatment of acne interstitial collagenase expression by human keratinocytes
actively involved in wound healing. J Clin Invest
scars may be associated with higher expression of collagen 1993;92:2858–2866.
which is associated with differential expression of TGFbs, 14. Dang CM, Beanes SR, Lee H, Zhang X, Soo C, Ting K. Scarless
collagenases, PPARg, and TIMP. fetal wounds are associated with an increased matrix metal-
loproteinase-to-tissue-derived inhibitor of metalloproteinase
ratio. Plast Reconstr Surg 2003;111:2273–2285.
ACKNOWLEDGMENT 15. Stahle-Backdahl M, Sandstedt B, Bruce K, Lindahl A,
This study was supported by MOTIE (Ministry of Trade, Jimenez MG, Vega JA, Lopez-Otin C. Collagenase-3
(MMP-13) is expressed during human fetal ossification and
Industry & Energy) - KIAT Research Grant of 2015 funded re-expressed in postnatal bone remodeling and in rheumatoid
by the Korean government. (No. N0001681). arthritis. Lab Invest 1997;76:717–728.
16. Ravanti L, Toriseva M, Penttinen R, Crombleholme T, Foschi
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