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Light-based therapy for acne vulgaris
Yeung, Chi-keung;
Citation
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2013
http://hdl.handle.net/10722/193561
Creative Commons: Attribution 3.0 Hong Kong License
Light-based Therapy for

Acne Vulgaris
By
Dr. YEUNG Chi Keung
MBBS, MRCP (UK), FRCP (Edin), FHKCP, FHKAM
A Thesis Submitted in Fulfillment of the Requirements for the Degree of

Doctor of Medicine at the University of Hong Kong
October 2013
Abstract of thesis entitled
Light-based therapy for acne vulgaris

Submitted by
YEUNG Chi Keung
for the degree of Doctor of Medicine
at The University of Hong Kong
in October 2013
Acne is a disorder of the pilosebaceous unit often complicated by scarring. Five studies
were performed to test the hypothesis that acne is common among Chinese and that the use of
laser and light source is safe and effective for the treatment of acne and acne scars in Asians. The
self-reported prevalence of acne in Hong Kong was assessed using a questionnaire among a
randomised sample of 522 persons aged 15-25 years. The prevalence was 91.3% with a point
prevalence of 52.2%, and acne scars and pigmentation were reported by 52.6%.
The existing topical and oral anti-acne medications are limited by their efficacy, adverse
effects and patient compliance. Light can target the pilosebaceous unit and reduce the growth of
Propionibacterium acnes, for which lasers or light sources have been explored as therapeutic
options. The aim of this study was to determine whether lower fluence and shorter cooling of the
1450-nm diode laser would improve acne while minimising post-laser hyperpigmentation in
Asians. A total of 26 Chinese subjects received four treatments of three passes with this laser at a
fluence of 8 J/cm2 with dynamic cooling of 25 ms. A 40% reduction (p<0.03) in mean lesion
count was observed 6 months after treatment with a significant improvement in sebum
production and a hyperpigmentation rate of 3.8%.
A split-face, controlled study was performed to evaluate the effectiveness of intense

pulsed light (IPL) alone or in combination with short-contact 16% methyl aminolevulinate
photodynamic therapy (PDT) in 30 Chinese subjects with acne. Among the PDT-treated group,
25% withdrew due to treatment discomfort. No significant differences in the reduction of
inflammatory lesions were observed between the intervention groups and the control group. A
delayed effect with reductions in non-inflammatory lesions was observed in the PDT-treated
(38%; p=0.05) and IPL-treated (43%; p=0.01) groups 12 weeks after treatment.
Liposome was used to deliver 5-aminolevulinic acid (5-ALA) into the pilosebaceous unit
to lower the concentration of 5-ALA by 40-fold during PDT. The study aimed to investigate the
tolerability and efficacy of PDT with IPL using 0.5% liposomal 5-ALA for inflammatory acne.
A mean reduction of 65% in the inflammatory lesion count was observed after 6 months
(p=0.043) in 12 Chinese subjects. No dropout or significant side effects were observed.
The treatment of acne scars has often been complicated by Asian skin phototypes
regarding the risk of post-inflammatory hyperpigmentation. Fractionated radiofrequency induces
deep dermal heating with less epidermal disruption. The aim of this study was to examine the
efficacy and safety of combined bipolar radiofrequency and fractional diode 915 nm laser
followed by fractional radiofrequency in 24 Chinese subjects with acne scars. The mean grade
improved by 29% (p<0.001), and 52% subjects were rated as having at least a moderate global
improvement at 3 months. Subjective improvement was moderate to significant in 36.8%.
Hyperpigmentation occurred after 6.5% of the treatments.
3
In conclusion, the studies indicated that laser and light source can be used effectively and
safely for the treatment of acne and acne scars commonly found in Asians.
An abstract of 499 words
DECLARATION
I declare that this thesis represents my own work and that it has not been submitted to this
University or to any other institution for a degree, diploma or other qualifications.
Signed
YEUNG Chi Keung
October, 2013
ACKNOWLEDGMENTS
I would like to express my heart-felt thanks and warmest acknowledgments to my

supervisor, Professor Henry H. L. Chan, Department of Medicine, Queen Mary Hospital, the
University of Hong Kong, Hong Kong, for his immense support and kind supervision throughout
my studies, and his encouragement during my many years of training and mentorship. This work
would not have been possible without his immense support and help.
I would also like to acknowledge my co-investigators for their support and advice, which
were essential for the completion of the projects. They include Dr. Samantha Shek and Dr.
Nicola Chan from the Division of Dermatology, Department of Medicine, and Dr. Carol Yu from
the Department of Ophthalmology, University of Hong Kong. Miss Ida Leung and Miss Corinne
Leung, research staff of the Division, have been very helpful throughout the projects for their
technical assistance.
I would like to thank my parents, my wife Bing Ying, and my daughters Faith, Sophie
and Ava for their support throughout my career.
STATEMENT OF ORIGINALITY
I jointly designed all of the studies with Professor Henry Chan. I conducted and wrote up
the epidemiological study of acne, the studies of photodynamic therapy with intense pulsed light
using 20% methyl aminolevulinate and 0.5% liposomal aminolevulinic acid spray, and a 1450
nm diode laser in the treatment of acne and the study of fractional radiofrequency combined with
fractional infrared laser for the treatment of atrophic acne scarring in Asians. Miss Corinne
Leung and Miss Ida Leung helped with the data collection and analysis under my supervision. I
performed laser treatment on all of the patients in the therapeutic studies. Dr. Samantha Shek,
Dr. Nicola Chan and Dr. Carol Yu objectively assessed the clinical photographs of the patients
who they did not treat, before examining them for the effects of treatment and complications.
TABLE OF CONTENTS
Declaration
Acknowledgments
Statement of originality
Table of Contents
List of Figures
14
List of Tables
18
Abbreviations
20
Hypothesis, Aims and Brief Outline of the Work
22
Section A: Introduction and Epidemiology of Acne and Acne Scars

Chapter 1
General Introduction
27
Chapter 2
2.1 Clinical review of acne
2.1.1 Epidemiology
33
2.1.2 Aetiology and pathogenesis of acne
34
2.1.2.1 Sebum production
35
2.1.2.2 Microcomedones as precursor lesions of acne
38
2.1.2.3 Bacteriology of Propionibacterium acnes
38
2.1.2.4 Inflammation in acne
40
2.1.3 Clinical findings
41
2.1.4 Current treatments and limitations
43
8
2.1.4.1 General principles
43
2.1.4.2 Topical antimicrobial therapy
45
2.1.4.3 Topical retinoids
47
2.1.4.4 Miscellaneous topical agents
47
2.1.4.5 Oral antibiotics
48
2.1.4.6 Hormonal therapy
48
2.1.4.7 Systemic retinoid
49
2.2 Laser-tissue interactions and concept of selective photothermolysis
50
2.3 Mechanisms of the clinical applications of lasers and photodynamic therapy
52
2.3.1 Targeting Propionibacterium acnes
53
2.3.2 Targeting sebaceous glands
56
2.3.3 Main modalities of light treatments for acne
57
2.3.3.1 Incoherent light sources
57
2.3.3.2 Pulsed-dye laser (PDL)
59
2.3.3.3 Mid-infrared laser
60
2.3.3.4 Intense pulsed light (IPL)
63
2.3.3.5 Photodynamic therapy (PDT)
65
2.3.3.6 Photopneumatic therapy
70
Chapter 3
Acne Scars: Classification and Treatment
3.1 General introduction
73
3.2 Classification of acne scars
75
3.3 Pathophysiology of acne scarring
79
3.4 Psychological morbidity
81
3.5 Treatment options and limitations
81
3.6 Concept of fractional resurfacing for acne scars
84
Chapter 4
Epidemiological Study of Acne in Hong Kong
4.1 Introduction
89
4.2 Materials and methods
89
4.3 Results
4.3.1 Prevalence in Hong Kong
91
4.3.2 Frequency of acne
91
4.3.3 Complications of acne
92
4.3.4 Public knowledge of the aetiology and treatment options of acne
92
4.3.5 Psychological effects of acne
92
4.3.6 Health-seeking behaviour in acne patients
93
4.4 Discussion
93
Section B: Lasers and Photodynamic Therapy for Acne

Chapter 5
Treatment of Inflammatory Facial Acne with a 1450 nm Diode Laser in Type IV to V Asian
Skin Using an Optimal Combination of Laser Parameters
5.1 Introduction
100
10
5.2 Subjects and methods

5.2.1 Subjects
104
5.2.2 Laser parameters
104
5.2.3 Assessment
5.2.3.1 Clinical photographs
106
5.2.3.2 Questionnaire
107
5.2.3.3 Objective assessment of sebum production
108
5.3 Results
5.3.1 Degree of improvement
109
5.3.2 Complications
112
5.4 Discussion
118
Chapter 6
A Comparative Study of Intense Pulsed Light Alone and in Combination with Photodynamic
Therapy for the Treatment of Facial Acne in Asian Skin
6.1 Introduction
126

6.2.1 Subjects
127
6.2.2 Device parameters
128
6.2.3 Assessment
6.3 Results
129
6.2.3.2 Fluorescence photographs
129
130
11
130
6.3.2 Adverse effects
132
6.4 Discussion
139
Chapter 7
Liposome-encapsulated 0.5% 5-Aminolevulinic Acid with Intense Pulsed Light for the
Treatment of Inflammatory Facial Acne
7.1 Introduction
144

7.2.1 Subjects
146
146
7.2.3 Assessment
147
148
149
7.3 Results
149
151
7.4 Discussion
159
Section C: Treatment of Acne Scars

Chapter 8
Evaluation of Combined Fractional Radiofrequency and Fractional Laser Treatment for Acne
Scars in Asians
167
12
8.1 Introduction
167
8.1.1 Fractionated technology and concept of sublative rejuvenation
168
8.1.2 Combination of fractional bipolar radiofrequency and diode laser
170

8.2.1 Subjects
171
8.2.2 Treatment device parameters
171
8.2.3 Assessment
173
174
175
8.3.2 Complications
177
8.3 Results
8.4 Discussion
191
Section D: Concluding Remarks
197
Section E: References
201
Appendix I
226
Appendix II
241
Appendix III
243
Appendix IV
245
LIST OF PUBLICATIONS
247
13
LIST OF FIGURES
Figure 2.1. Schematic representation of the different anatomical areas of the

pilosebaceous unit
36
Figure 2.2. Left: Subject with moderate acne. Right: Fluorescence photography of
acne showing numerous orange-red punctate areas of fluorescence corresponding to
follicles and open comedones
54
Figure 2.3. Light absorption spectrum of porphyrins. The Soret Band represents the
highest peak of light absorption and thus the highest sensitiser activation. Q
Bands represent several weaker levels of absorption at longer wavelengths
55
Figure 3.1. Clinical appearance of ice-pick scars with a sharp, demarcated, V-shaped
configuration reaching into the deep dermis
76
Figure 3.2. Clinical appearance of rolling scars with broad, ill-defined, superficial depressions of
the skin
77
Figure 3.3. Clinical appearance of boxcar scars with a sharp, demarcated, U-shaped
Configuration
78
Figure 5.1. Percentage of reduction in the mean inflammatory acne lesion count after
successive treatments with a 1450 nm diode laser (*p<0.05)
113
Figure 5.2. Left: Multiple inflammatory papules and pustules on the right cheek before
treatment. Right: A marked improvement in inflammatory acne is observed one
month after four treatments with a 1450 nm diode laser
114
14
Figure 5.3. Left: Multiple inflammatory papules and pustules on the left cheek before treatment.
Right: Three months after four treatments with a 1450 nm diode laser, a
significant reduction in inflammatory acne is observed
115
Figure 5.4. Mean reduction in sebum production after successive treatments with a
1450 nm diode laser. The whiskers represent the 5th and 95th percentiles
116
Figure 5.5. Left: The right cheek before treatment. Right: Post-inflammatory
hyperpigmentation on the cheek 4 weeks after the first treatment with a 1450 nm
diode laser
117
Figure 6.1. Mean reduction in inflammatory and non-inflammatory acne lesion count
after successive treatments with a combination of methyl aminolevulinate and IPL
versus IPL alone; the whiskers represent the 5th and 95th percentiles
133
Figure 6.2. Left: Multiple inflammatory papules before treatment. Right: Twelve
weeks after four treatments with the combination of the IPL and methyl
aminolevulinate on the right side of the face, with the left side having undergone IPL
treatment only; there is marked improvement in inflammatory acne and erythema on
the side treated with methyl aminolevulinate
134
Figure 6.3. Left: Face showing punctate fluorescence of hair follicles populated with P.
acnes before treatment. Right: Reduction in the intensity of fluorescence,
especially on the left cheek and forehead, 4 weeks after the fourth treatment
with methyl aminolevulinate photodynamic therapy
135
Figure 7.1. Mean percentage reduction in the inflammatory and non-inflammatory

lesion counts after successive treatments with a combination of liposomeencapsulated ALA and IPL. The whiskers represent the 5th and 95th percentiles 156
15
Figure 7.2. Left: Pre-treatment with multiple inflammatory papules. Right:

Two months after three full-face treatments with the combination of IPL and
liposome-encapsulated ALA with improvement in inflammatory acne
157
Figure 7.3. Mean reduction in forehead sebum production after successive treatments with
liposomal ALA and IPL. The whiskers represent the standard error and the asterisks
represent a statistically significant mean reduction with a p value <0.05
Figure 8.1. Degrees of clinical improvement in acne scars after treatment
158
181
Figure 8.2. Parallel-polarised images of atrophic acne scars. Left: Photograph obtained before
treatment of multiple atrophic acne scars on the left temple. Right: A significant
improvement is seen one month after five treatments with fractional RF and
fractional laser with combined RF
183
Figure 8.3. Parallel-polarised images of multiple atrophic acne scars Left: Left cheek
before treatment. Right: An improvement in acne scars is seen 3 months after
five treatments with both devices
184
Figure 8.4. Subjective assessment of the improvement in acne scarring
185
Figure 8.5. Subjective assessment of overall patient satisfaction after the treatment
186
Figure 8.6. Subjective assessment of immediate pain level during treatment
187
Figure 8.7. Cross-polarised images showing mild post-inflammatory

hyperpigmentation before (A) and 1 month after the fifth treatment (B)
188
16
Figure 8.8. Cross-polarised images of the patient before (left) and 1 month after (right)
the second treatment, showing multiple discrete hyperpigmented macules over
the right cheek corresponding to the shape of the fractional laser with RF
device applicator
189
17
LIST OF TABLES
Table 4.1. Comparison of the prevalence of facial acne in adolescents between different
Countries
94
Table 5.1. Different combinations of laser fluence, duration of DCD, the number of passes
used to detect PIH at the 9 tested sites of the forearm
105
Table 6.1. Mean reduction in inflammatory acne lesion count at each time-point for the
IPL, photodynamic therapy and control groups
136
Table 6.2. Mean reduction in non-inflammatory acne lesion count at each time-point
for the IPL, photodynamic therapy and control groups
137
Table 6.3. Rating of percentage reduction in P. acnes florescence 4 weeks after the fourth
treatment
138
Table 7.1. Mean reduction in the inflammatory and non-inflammatory lesion counts at
each time point after treatment
153
Table 7.2. Global objective improvement in facial acne compared to the baseline at
each time point
154
Table 7.3. Subjective assessment of facial acne and overall satisfaction using a visual
analogue score (range 0-10) at each time point
Table 8.1. Acne scar scores* before and after treatment with both devices
155
179
18
Table 8.2. Skin texture, pore size and pigmentation scores* before and after treatment
with both devices. (*Rated on a scale of 1-10)
180
Table 8.3. Improvements in skin texture and pigmentary irregularity one to three months after
treatment
Table 8.4. Adverse effects and their severity per treatment session
182
190
19
ABBREVIATIONS
ALA: 5-aminolevulinic acid
CI: confidence interval
CO2: carbon dioxide
DCD: dynamic cooling device
Er:YAG: erbium:yttrium-aluminium-garnet
ICG: indocyanine green
IL: interleukin
IPL: intense pulsed light
J: Joules
J/cm2: Joules per centimetre squared
KTP: potassium titanyl phosphate
LED: light emitting diode
MAL: methyl aminolevulinate
mJ: milli-Joules
mm: millimetre
MMP : matrix metalloproteinase
20
ms: millisecond
MTZ: microscopic treatment zone
Nd:YAG: Neodymium: Yttrium-Aluminium-Garnet
nm: nanometres
PDL: pulsed-dye laser
PDT: photodynamic therapy
PIH: post-inflammatory hyperpigmentation
PpIX: protoporphyrin IX
RF: radiofrequency
TGF: transforming growth factor
TLR-2: Toll-like receptor 2
m: micrometre
UV: ultraviolet
VAS: visual analogue scale
21
Hypothesis, Aims and Brief Outline of the Work

Hypothesis
Acne is a prevalent and clinically significant condition that affects Chinese adolescents
and young adults. Acne and acne scars have a negative psychological effect that can be remedied
with effective treatments. Laser and light sources can be used effectively to treat acne and acne
scars in Asians. The adverse effects of light-based treatments for acne in Asians can be
minimised while maintaining their efficacy.
Brief outline of the work

The work described in this thesis is divided into three main sections. The first section
describes a community-based epidemiological investigation of acne in Hong Kong adolescents,
including the frequency of acne and its complications, knowledge of its causes, its psychological
effects and the pattern for its treatment. The second section describes a series of clinical
therapeutic studies that used laser and photodynamic therapy with intense pulsed light (IPL) to
treat acne in Chinese subjects. The focus was on optimising the light treatment regime to
minimise its adverse effects, particularly post-inflammatory hyperpigmentation (PIH), while
maintaining its efficacy. The final section describes the treatment of the main long-term
complication of acnenamely acne scarswith the combined fractional technologies of laser
and radiofrequency (RF) in Chinese subjects.
22
The prevalence of acne was studied in the local population of Hong Kong using a
questionnaire survey, from which the proportion of subjects with acne who suffered from
psychological disturbances and acne scars with PIH was also determined. The health-seeking
behaviour of the subjects with acne with respect to their knowledge of the therapeutic options
was studied, because these data are useful for estimating the cost to and use of health services.
The treatment of acne scars and pigmentation is often difficult and complicated by Asian skin
phototypes. The epidemiological findings suggested the need for refined educational
programmes to ensure that adolescents know what effective treatments are available and thus
reduce long-term complications. Based on the significance of the first study on the epidemiology
of acne in Hong Kong, the importance of providing effective and safe treatment for patients with
acne emerged.
Because of the limitations of existing therapeutic options for acne, I explored the
direction of light-based treatments founded on the understanding that appropriate light sources
can improve elements of the pathogenesis of acne. The response to laser and light treatments of
Asian skin often differs significantly from that of Caucasian skin because of the higher melanin
content in the epidermis and the different light-tissue interaction, which lead to an increased risk
of pigmentary alteration, blistering and subsequent scarring following light-based procedures.
The optimal use of lasers and light sources for the treatment of acne and acne scars needed to be
determined specifically for Asian skin. I studied the efficacy of a 1450 nm mid-infrared diode
laser in the treatment of inflammatory facial acne in Fitzpatrick type IV to V Asian skin. I
adopted a regime of multiple passes of laser irradiation at a low fluence of 8 J/cm2 with a
23
moderate dynamic cooling of 25 ms to minimise PIH after performing a forearm study to

determine the threshold for its induction.
The drawbacks of standard photodynamic therapy (PDT) are its significant adverse
effects, including pain, erythema, exfoliation, prolonged photosensitivity and hyperpigmentation,
which are a concern in the treatment of Asian skin. A PDT regime using light sources with lower
fluences and multiple passes and a shorter incubation with 5-aminoaluvenic acid (ALA) may
reduce these side-effects. Clinical studies using different light systems, treatment parameters and
selective vehicles for topical photosensitisers to minimise the adverse effects of PDT were an
important step. I investigated the use of IPL with or without PDT using a short topical incubation
time with the methyl ester of aminolevulinic acid for the treatment of acne in a randomised, splitface, comparative study in Asian skin. With the aim of reducing post-treatment photosensitivity
after PDT, I then investigated the clinical outcome and side-effects of PDT using short contact
time with liposome-encapsulated ALA and IPL on acne.
The limitations of the current treatment options for atrophic acne scars included a
significant risk of PIH in Asians and a long recovery period. The use of ablative fractional laser
technologies for skin resurfacing to improve scars can alleviate these limitations. A lower risk of
PIH and an efficacy comparable with that of standard laser ablation were observed using this
approach. The fractionated RF induces deep dermal heating while having less effect on the
epidermis. The effect of combining two fractional-based modalities of RF and a fractional
infrared laser on the improvement in facial acne scarring can be significant. Fractional RF
induces collagen formation in the deep layers of the skin whereas the infrared laser affects the
24
more superficial layer, thus improving the overall surface irregularities of the skin. Minimising
the epidermal disruption by using these devices may reduce the rate of PIH in Asians. I
investigated the safety and efficacy of this combined treatment on acne scars in Asians in the
final part of my work.
25
Section A: Introduction and Epidemiology of

Acne and Acne Scars
26
Chapter 1
General Introduction
Acne vulgaris is a disorder of the sebaceous glands. It is one of the most common
dermatological disorders seen in clinical practice and remains the leading reason for
consultations with dermatologists. The word may have originated from the Greek achne, which
means efflorescence, or the Greek acme, which means a summit or peak. It usually begins in
early adolescence with a peak incidence occurring around the age of 17-21 years. Acne is
considered to be a self-limiting disorder and remission often occurs spontaneously after the age
of 25 years (Cunliffe, 2001). The condition presents with a multitude of lesions comprising
comedones, papules, pustules and nodules on the face and upper trunk and can vary in severity
and extent, ranging from mild comedonal acne to a fulminant, scarring and systemic condition.
The most important consequence is lifelong acne scars on the face and upper trunk.
The prevalence of facial acne in adolescents ranges from 50 to 91% based on various
epidemiological studies (Smithard et al., 2001). The exact cause of acne remains to be elucidated
but there are a number of aetiological factors. The condition involves Propionibacterium acnes
and inflammatory responses. Circulating androgens after puberty result in increased sebum
production, and hypercornification of the epithelium occurs around the openings of the
pilosebaceous units (Charakida et al., 2004; Nestor, 2007). The blockage of the follicular
openings by the keratin plug causes comedone formation, and the blocked pilosebaceous units
attract the anaerobic bacterium, Propionibacterium acnes, which in turn induces a follicular
inflammatory response.
27
The active lesions and subsequent scar formation have substantial cosmetic and
psychological effects. The early recognition and treatment of acne are important to prevent
inflammatory lesions and subsequent long-term scarring that is associated with significant
psychological distress. The existing treatment options are unsatisfactory because the topical and
systemic anti-acne medications are limited by adverse effects, drug compliance, treatment
failure, short-lasting effects and antibiotic resistance.
Treatment generally involves combinations of oral and topical retinoids, antimicrobial

agents and oral hormonal agents. Acne management aims to alleviate symptoms, clear existing
lesions, limit disease activity to prevent the development of new lesions and scars and avoid a
negative effect on the quality of life. The conventional medical therapy comprises topical
antibiotics that are active against P. acnes. Benzyl peroxide is also used as a topical
antimicrobial agent. The use of topical retinoids is the main treatment for mild to moderate
inflammatory acne because they target the formation of comedones, which are the precursor
lesions of acne. Oral antibiotics, such as tetracyclines and macrolides, are commonly used for
moderate to severe inflammatory acnes. Oral isotretinoin is a systemic retinoid that has a drastic
effect on the pilosebaceous unit by significantly reducing sebum production and is indicated for
severe nodulocystic acne. However, the current medical treatments are limited by their shortlasting efficacy, drug compliance and their adverse effects (Nestor, 2007). Most topical anti-acne
therapies induce varying degree of irritation, dryness and occasional dermatitis. Moreover, an
increasing problem is the antibiotic resistance of P. acnes as a result of the widespread use of
topical and oral antibiotics for inflammatory acne, which can eventually lead to treatment failure
28
(Charakida et al., 2004). In addition, the long-term use of antibiotics has been reported to
increase the risk of carcinoma of the breast (Velicer et al., 2004). Compliance with daily topical
and oral treatment for weeks to months is also questionable. Hormonal therapy is restricted for
women with acne and is subject to the same risk as oral contraceptive pills. Isotretinoin is well
known to be a teratogenic agent and female patients are required to adopt stringent contraceptive
measures before they can be prescribed this drug for the treatment of severe acne. It also has a
number of common mucocutaneous side effects, such as cheilitis, dry mouth and dry eyes. There
is also controversy over the casual link with depression and suicidal attempts with the use of oral
isotretinoin (Marqueling & Zane, 2007). Hence, alternative therapeutic options remain very
desirable.
It has long been observed that exposure to sunlight improves acne in 70% of patients.
Previous studies have shown that ultraviolet (UV) light can improve acne but its use is limited by
its carcinogenic risks (Charakida et al., 2004). Lasers have become increasingly popular during
the past decade for the treatment of various dermatoses and for aesthetic purposes. A variety of
lasers and light sources are now being tested for the treatment of acne (Seaton et al., 2003;
Orringer et al., 2004). Blue light, red light, lasers and pulsed light devices (IPL) with
photodynamic therapy (PDT) have found a useful niche in the treatment of inflammatory acne
(Nouri & Ballard, 2006; Hdersdal et al., 2008). Light-based therapy has been developed to
alleviate the adverse effects caused by systemic treatments and to provide patients with a safer,
more effective and more convenient therapeutic option.
29
The targets of light-based therapies are cutaneous P. acnes and the sebaceous glands
(Bhardwaj et al., 2005; Thiboutot et al., 2009). These goals can be achieved via the photothermal
and photochemical effects of lasers/light sources on selected chromophores in the skin (Ross,
2005). Lasers in the infrared range selectively injure the sebaceous gland by heating water in the
surrounding upper dermis, provided that there is simultaneous cooling of the epidermis by a
cryogen spray (Munavalli & Weiss, 2008). Treatment with infrared lasers has been shown to
improve inflammatory acne (Paithankar et al., 2002), and also has the dual benefit of improving
acne scarring by initiating the synthesis of new collagen as a result of a heating effect on bulk
tissues (Chua et al., 2004). Infrared laser treatment is limited due to the associated procedural
pain and post-inflammatory hyperpigmentation (PIH), which is especially problematic for Asian
skin. The PIH rate was reported to be as high as 39% in a study in Singapore using the same
standard parameters as those used on Caucasian skin (Chua et al., 2004). Thus, specific
alternative treatment parameters need to be determined if this laser is to be useful for the
treatment of acne in Asian skin.
PDT is a photochemical reaction that requires the presence of a photosensitising

molecule, photoactivating wavelengths of light and tissue oxygen (Taylor & Gonzalez, 2009).
PDT has long been used for the treatment of skin cancers because of its selectivity for
precancerous and cancerous lesions and better cosmetic outcome. The process generates reactive,
free radical intermediates that damage the target tissue, namely the pilosebaceous unit in the
treatment of acne. Sebaceous glands and hair follicles selectively take up and convert topically
applied 5-aminolevulinic acid (ALA) into photosensitising protoporphyrin IX (PpIX), especially
in inflamed acne lesions. PpIX can then be activated by an appropriate light source to achieve the
30
therapeutic goal. Activating light sources, including red, blue, IPL, pulsed dye laser and lightemitting diode (LED), have been shown to be effective in PDT for acne (Mariwalla & Rohrer,
2005; Taylor & Gonzalez, 2009). New derivatives or vehicles of ALA are currently being
developed for use in PDT, with the potential benefits of higher lipophilicity, better penetration of
the stratum corneum and lesional specificity (Wiegell & Wulf, 2006).
Facial acne scars are a common long-term cosmetic concern that results from severe
acne. Atrophic scars are caused by compromised collagen production during the natural woundhealing process following an inflammatory response to acne, which results in surface
irregularities (Sriprachya-anunt et al., 2002). Different modalities, including chemical peels,
surgical excision, dermabrasion and tissue augmentation with fillers, have been used for the
treatment of atrophic scars with varying degrees of success. While laser-based ablative systems
using carbon dioxide (CO2) lasers with or without an erbium:yttrium-aluminium-garnet
(Er:YAG) laser can effectively treat facial scarring, their use may be associated with a prolonged
recovery period and cosmetic complications (induction of scarring, and hyper- or
hypopigmentation) (Tay & Kwok, 2008). Hyperpigmentation rates of up to 68% have been
reported in type IV skin following CO2 laser resurfacing.
In fractional resurfacing technology, thermally ablated microscopic arrays of the

epidermis and dermis are regularly spaced over the skin surface without injuring the surrounding
tissue, which serves as a reservoir for cells that accelerate and promote the desired effect (Jordan
et al., 2000). This technique is more efficient than non-ablative resurfacing and has a faster
recovery than complete ablative resurfacing. Ablative fractional laser devices have become
31
increasingly popular and offer the potential benefits of full-surface ablative skin resurfacing
while minimising risk and the length of recovery (Jih & Kimyaiasadi, 2008). However, their
major limitation is that they are not equally safe and effective for all skin types, especially for
Asian skin which has a higher epidermal melanin content. New fractional technology, including
RF, is now being explored to treat acne scars.
32
Chapter 2
2.1 Clinical review of acne
2.1.1 Epidemiology
Acne vulgaris is considered to be almost physiological at puberty and is one of the most
common skin diseases treated by clinicians. The prevalence of facial acne is, on average, 50-91%
in adolescence and young adulthood. The problem of acne sometimes continues into adulthood.
A significant proportion of young adults are affected by acne, and its overall prevalence in
respondents over 20 years of age in a USA survey was 73.3% (Collier et al., 2008). Women are
affected to a greater extent than men in post-adolescence. Patients with persistent acne in
adulthood have a strong family history of this ailment compared with patients who suffered from
adolescent acne (Goulden et al., 1999). Significant acne can lead to a negative psychological
effect in adolescents and young adults as a result of its effect on physical appearance. Severe
inflammatory acne may also result in persistent erythema, hyperpigmentation and permanent
scarring which occur more frequently in coloured skin, including that of Asians (Perkins et al.,
2011).
The prevalence of acne and its effect have been studied extensively in Caucasians, but
data regarding its prevalence, psychological effect and health-seeking behaviour for its treatment
in Chinese are relatively sparse. The prevalence of acne may vary between ethnic groups and
countries. In a large study of 74,589 Asian patients who attended dermatology outpatient clinics
in Singapore, acne was among the most common diagnoses observed (10.9%) (Chua-Ty et al.,
1992). A prevalence of acne of 53.5% (51.3% in males and 58.6% in females) was found in a
33
survey of 3163 adolescent students in Guangdong Province, China. The prevalence of

inflammatory acne in males and females combined was 25.8% and that of acne scarring was
7.1%. Acne vulgaris was also more prevalent in girls under and boys over 14 years of age (Wu et
al., 2007).
A community-based study in six cities in China indicated that the highest prevalence was
in the 19-year-old group (46.8%), followed by the 1519-year-old group (38.0%), then the 20
24-year-old group (36.0%) (Shen et al., 2012). Adult acne was not uncommon, with a prevalence
of 11.7% in the 30-year-old group, 30.8% of whom reported that acne had a negative effect on
their quality of life. These results suggest that the prevalence of acne in Chinese populations is
lower than that in Caucasian populations. In a cross-sectional study of 389 university entrants in
Hong Kong, the prevalence of acne was of 81.5% in late adolescents who had significant
psychological effects; 81.8% of the subjects indicated that their quality of life was impaired by
acne as measured by a validated acne disability index (Law et al., 2010). The clinical severity of
acne did not correlate strongly with the effect on quality of life (gamma = 0.445; p < 0.001). In
this study, 30.3% of subjects had used topical treatments, 3.9% had taken oral medications and
3.2% had used traditional Chinese medicine for acne.
2.1.2 Aetiology and pathogenesis of acne

The pilosebaceous unit consists of an epithelium of mature and developing sebocytes
through which the hair and sebum pass. The upper fifth of the pilosebaceous canal, the
acroinfundibulum, is similar to the adjacent epidermis and the lower four fifths of the canal are
called the infrainfundibulum (Figure 2.1). Acne is a chronic inflammatory disease of the
34
pilosebaceous unit that is associated with increased sebum production and hypercornification of
the infrainfundibulum (Charakida et al., 2004; Nestor, 2007). Blockage of the follicular openings
by the accumulation of sebum and shed keratinocytes form comedones that attract the
microaerophilic anaerobic bacterium, P. acnes, which proliferates and induces a follicular
inflammatory response with the formation of clinical inflammatory papulopustular lesions and
subsequent scarring. Understanding the pathophysiology of acne can help to improve its therapy.
Microcomedone formation is generally considered to be the precursor lesion of acne and plays a
central role in its pathogenesis.
2.1.2.1 Sebum production

Androgens have long been considered to be the driving force in the pathogenesis of acne.
The significant reduction in sebum excretion rate is clearly associated with clinical improvement.
Androgens are synthesised from cholesterol in the gonads and adrenal glands under the control
of the pituitary, and regulate sebaceous gland activities and sebum production. Elevated levels of
serum androgens are correlated with severe acne and patients with seborrhoea and acne have a
greater number of sebaceous lobules per gland. Testosterone and dihydrotestosterone are the
major androgens that interact with the androgen receptors in the sebaceous glands. Circulating
androgens are bound to the sex-hormone binding globulin, and the 1-2% of free testosterone
dictates sebaceous gland activity. Dihydrotestosterone has a 5 to 10 times greater potential to
35
Figure 2.1. Schematic representation of the different anatomical areas of the pilosebaceous unit.
36
interact with the androgen receptor in the sebaceous glands than testosterone. The type I
isoenzyme
of
5-
reductase
in
the
sebaceous
glands
converts
testosterone
into
dihydrotestosterone. Hyperfunctioning of the sebaceous glands contributes to the formation of

acne, which is caused by the end-organ hyper-response of the sebaceous glands to normal
circulating levels of androgens rather than the abnormal increase in androgen production by the
adrenals or gonads. Thus, most acne patients do not need detailed endocrine investigations if
they have no signs or symptoms of hyperandrogenism and respond well to appropriate treatment.
Cases that warrant investigation are patients who responded poorly to treatment, children with
acne aged 3-7 years, and those who have other cutaneous androgenic features, such as hirsutism
in polycystic ovarian syndrome. Investigations have been carried out on total and free
testosterone, dihydroepiandrostenedione, follicle-stimulating hormone, luteinising hormone and
prolactin. Ethinyloestradiol (0.035 mg) plus the anti-androgen cyproterone acetate (2 mg; Diane35) reduces sebum production by up to 50% and leads to the clinical improvement of acne.
Sebum secretion could be measured by its collection on a frosted glass plate, the
transparency of which is then assessed (Serup, 1991; Clarys & Barel, 1995). As sebum is
adsorbed on the roughened surface, it spreads and gives the surface a smooth appearance as a
result of less light scattering when the plate is illuminated with a beam of light. The relationship
between the amount of adsorbed lipid and light transmission can be quantitated in a non-linear
relationship. The Sebumeter (Courage & Khazaka, Koln, Germany) is one of the commercially
available instruments that is based on this principle and can be used to measure the amount of
sebum on the skin surface.
37
2.1.2.2 Microcomedones as precursor lesions of acne

Acne is a disease of the pilosebaceous follicles, for which both seborrhoea and ductal
hypercornification appear to serve as initial triggers. The hyperkeratosis of the follicular lining
with faulty desquamation that occurs in the upper portion of the follicle, namely the
infrainfundibulum, is the early structural change in acne and the subsequent development of a
plug in the follicle named the comedone precedes the inflammatory lesions, and is associated
with increased cohesiveness of the corneocytes within this lining that results in blockage of the
follicular outflow, distension of the pilosebaceous canal and microcomedone formation. The
cause of cohesiveness has not been fully elucidated. It was found that the addition of interleukin1 (IL-1) to the infrainfundibulum causes hypercornification (Yung et al., 2007). The relative
deficiency of linoleic acid in sebum, an essential fatty acid, may induce hyperkeratosis in the
affected follicles (Goldberg, 2012). Microcomedones precede any clinical evidence of
comedones and are seen as distended pilosebaceous ducts on histological examination. These
precursor lesions are followed by clinically closed comedones (whiteheads) 0.1-3.0 mm in
diameter when the entire pilosebaceous unit is distended with concentric laminae of keratinous
material. The opening of closed comedones is barely visible to the naked eye. Open comedones
(black heads), evolved from closed comedones, present clinically as black lesions as a result of
oxidation of the keratin materials in the plug when they are exposed to air.
2.1.2.3 Bacteriology of Propionibacterium acnes

The increase in lipid products, particularly triglycerides, on the skin after the onset of
puberty greatly enhances bacterial growth and, in particular, that of select bacteria that can
effectively metabolise triglycerides. P. acnes is a Gram-positive, non-motile, rod-shaped
38
coryneform dipheroid anaerobic bacterium and is one of the species of microorganisms that
colonise the skin surface as a commensal beside staphylococci, diphtheroids and the yeast,
Malassezia furfur (Noble, 1993). P. acnes is implicated in the pathogenesis of acne and resides
primarily in the anaerobic environment of the sebaceous follicles. The role of sebum in the
pathogenesis of acne is closely associated with the activity of P. acnes, which relies on
sebaceous lipids as a nutrient source and breaks down triglycerides into free fatty acid by
metabolising the glycerol fraction through an extracellular lipase. A correlation exists between
the reduction in the number of P. acnes and clinical improvement in patients treated with
antimicrobial agents, and the development of antibiotic-resistant P. acnes may lead to clinical
failures and flares of acne.
Studies have indicated that higher numbers of P. acnes were found on the skin of children
and teenagers with acne than on that of age-matched controls (Leyden et al., 1998). P. acnes is
known to produce porphyrins, particularly coproporphyrin III, which fluoresce under UV light,
and has been shown to induce pro-inflammatory cytokines, including tumour necrosis factor-,
IL-1 and IL-8, the latter of which is a potent chemotactic factor for neutrophils. P. acnes has
been shown to activate Toll-like receptor (TLR)-2, which recognises peptidoglycans from Grampositive bacteria on macrophages in the perifollicular regions, with subsequent activation of
nuclear factor-B (Kim et al., 2002) It has also been shown to activate chemotactic factors and to
release pro-inflammatory mediators, including lipases, hyaluronidase and proteases, which result
in altered infundibular keratinisation. Because acne seems to be provoked by sebum and P. acnes
is dependent on sebum for nutrition, the inhibition of sebum secretion would be expected to
improve acne by inhibiting the colonisation of P. acnes.
39
2.1.2.4 Inflammation in acne

Recent findings have indicated that the innate immune system plays multiple roles in the
pathogenesis of acne, including the destabilisation of skin barrier function, the up-regulation of
soluble factors such as chemokines, cytokines and antimicrobial peptides, and the alteration of
downstream effector pathways that are activated by P. acnes. One hypothesis is that the
increased production of sebum with a relative deficiency in specific fatty acids disrupts the
normal lipid layers and compromises the protective function of the skin barrier against
pathogens. This imbalance leads to the release of IL-1 from keratinocytes and subsequent
hyperkeratinisation (Jeremy et al., 2003). Inflammatory events mediated by the cytokine
interleukin-1 precede and may promote hyperkeratinisation (Guy & Kealey, 1998), and the upregulation of IL-1 could be initiated by the disruption of the skin barrier function that results
from increased sebum production and a relative deficiency in linoleic acid.
The inflammation in acne begins with focal infiltration of mononuclear cells, particularly
CD4+ T-lymphocytes, in early papular lesions in response to the stimulus of the up-regulation of
vascular adhesion molecules and pro-inflammatory cytokines, such as interleukin-1, from early
non-inflamed lesions (Norris & Cunliffe, 1988; Mouser et al., 2003). The chemotactic factors
from P. acnes in the pilosebaceous canal attract neutrophils that lead to structural damage and
disrupt the follicle wall (Graham et al., 2004). P. acnes is also a potent activator of the classic
and alternative complement pathways (Webster & Rawlings, 2007), and it has been shown that
the cell wall components of P. acnes activate TLR-2 in monocytes, leading to the production of
cytokines that attract lymphocytes and neutrophils (Kim et al., 2002). TLR-2 also accounts for
the presence of CD4+ lymphocytes in comedones in the early phase of acne inflammation
40
(Cunliffe, 2001). The release of the comedonal content, including sebum, bacteria and ductal
corneocytes, further attracts neutrophils and macrophages and leads to the formation of giant
cells. P. acnes also induces matrix metalloproteinase (MMP) and antimicrobial peptide
production (Shalita et al., 2011).
2.1.3 Clinical findings

Acne vulgaris presents with a multitude of morphological features, including open and
closed comedones, papules, pustules and nodules. The age at onset is early puberty (12-15 years)
with peak severity at 17-21 years. The earliest form of acne is comedones with an absence of
inflammatory response, and the most severe form is acne fulminans, which involves necrotising
acne, fever, polyarthritis, osteolytic bone lesions and elevated inflammatory markers. The
severity of acne is generally graded on the basis of the predominant type, number of lesions and
the extent of involvement. Post-inflammatory hyperpigmentation is a common consequence of
acne especially in Asian patients, and dyschromia and scarring often remain after active acne
lesions have resolved. One study reported an incidence of acne-related hyperpigmented macules
of 47% in Asians with acne (Perkins et al., 2011). The psychological component of acne should
not be underestimated, as exemplified by acn excorie in which patients frequently manipulate
their own acne lesions, leading to prolonged healing time and more extensive scarring.
Inflammatory acne and acne scarring often result in psychological distress during their
prolonged course, especially when they are localised on the face in appearance-sensitive
adolescents. The condition can cause low self-esteem, anxiety and depression. Quality-of-life
studies have shown that acne patients may encounter difficulties in coping with life and
41
experience employment problems (Bhate & Williams, 2013). A recent review of these studies by
Dunn et al. (2011) concluded that acne can negatively affect quality of life, self-esteem and
mood, and increase the risk of anxiety, depression and suicidal ideation. Between 30% and 50%
of adolescents experience psychological difficulties associated with acne, including concerns
regarding body image, embarrassment, social impairment, frustration and anger (Baldwin, 2002).
Adolescent girls are more vulnerable than boys to the negative psychological effects of acne
(Aktan et al., 2000). Previous studies have shown that acne has a greater psychological effect on
patients than asthma and epilepsy, although a correlation between the clinical severity of acne
and its effect on quality of life has not been established (Mallon et al., 1999; Thomas, 2004). It is
crucial for clinicians to detect acne patients who are at increased risk of psychological and
functional impairment or injurious behaviour.
Acne poses no diagnostic difficulty for clinicians, although other acne-like dermatoses
may occasionally mimic acne. The features of acne vulgaris that distinguish it from other forms
include typical location on the face and upper trunk, the younger age of the affected population,
polymorphic lesions and the presence of comedones. Medications that have been implicated in
the induction of monomorphic acneiform eruptions or acne include oral corticosteroids,
androgenic hormones, anabolic steroids, isoniazid, cyclosporine, anticonvulsants, halogens and
lithium. Flares of acne and acneiform eruptions are the most frequently encountered lithiuminduced adverse cutaneous effects and seem to be more prevalent in males than females (Yeung
& Chan, 2004). Lithium appears to exacerbate pre-existing acne or induce acne de novo, the
occurrence of which usually begins a few weeks after the start of lithium. Lithium-associated
acneiform eruptions are characterised by persistent, monomorphic, non-cyclical, pustules without
42
comedones or cysts, located on the limbs and trunk rather than on the face, and risk factors
include personal or family history of severe acne. Other common conditions that mimic acne are
rosacea, adenoma sebaceum in tuberous sclerosus, bacterial and fungal folliculitis, milia, perioral
dermatitis and plane warts.
Acne conglobate is an uncommon severe variant that is characterised by nodulocystic

lesions, burrowing abscesses, irregular scarring and formation of the sinus tract. The condition is
associated with hidradenitis suppurativa, which typically affects the axillae and perineum. Severe
acne can present in the form of acne fulminans with ulcerating and necrotic acne lesions, and
profound systemic disturbance including fever and polyarthralgia. Gram-negative folliculitis is a
known infective complication following prolonged courses of oral antibiotic therapy for acne.
The condition is due to excessive growth of Gram-negative enterobacteria when the commensals,
such as coagulase-negative Gram-positive cocci and aerobic diphtheroids, are suppressed by oral
antibiotic acne therapy. It presents with sudden flares of nodulopustular lesions that do not
respond to usual anti-acne treatments.
2.1.4 Current treatments and limitations

2.1.4.1 General principles
Acne is a long-term disease that is seldom rapidly controllable and prolonged courses of
treatment are therefore often necessary. The treatment strategy is based on the understanding of
the aetiological factors, namely decreased sebum production, correction of the ductal
hypercornification, and reduction of the P. acnes population and anti-inflammatory effects.
Therapies with medications remain the gold standard treatment for acne and provide adequate
43
control for most but not all patients. A number of acne therapies currently in use comprise
topical therapies such as retinoids, antibiotics, benzyl peroxide and azelaic acid, and oral
treatments such as anti-androgens, oral contraceptives, antibiotics and isotretinoin. Topical
therapy is often sufficient for mild cases, whereas the combination of topical and oral treatments
is indicated for moderate to severe inflammatory acne. However, their use is limited by their
adverse effects, slow onset of action, patient compliance and inadequate long-term efficacy
(Nestor, 2007). A recent review of systemic monotherapy indicated that approximately 68% of
treatment is effective (Larsen & Jemec, 2003). The use of topical or systemic therapy or
combinations of the two for acne management depends on the severity of the acne and the
relative proportion of inflammatory and non-inflammatory lesions. Most cases of mild to
moderate acne can be treated with topical therapy alone. Combinations of oral and topical
therapy are indicated in moderate to severe acne with significant inflammatory lesions and
tendency of scar formation, after which topical medications can be used as maintenance therapy
once the disease is under control. Most topical anti-acne therapies induce varying degrees of
irritation, dryness and occasional dermatitis.
An increasing problem is the antibiotic resistance of P. acnes as a result of the

widespread use of topical and oral antibiotics for inflammatory acne and this can lead to the
failure of treatment (Charakida et al., 2004). The combination of antibiotics and topical retinoids
or benzyl peroxide is now advocated to minimise the antibiotic resistance of P. acnes. The
compliance of patients with continual daily topical and oral treatment for weeks to months is also
questionable. Isotretinoin is a highly effective systemic treatment for severe acne, but is well
known to be a teratogenic agent and female patients taking isotretinoin are required to adopt
44
stringent contraceptive measures. It also has a number of mucocutaneous side effects such as
cheilitis, dry eyes and serum lipid abnormalities. Therefore, alternative therapeutic options that
are safe and effective remain desirable.
2.1.4.2 Topical antimicrobial therapy

Topical antibiotics remain an integral part of acne treatment, but the current general
consensus is that monotherapy with a topical antibiotic therapy should not be recommended.
Topical antibiotics currently used for acne are erythromycin and clindamycin. Dapsone 5% gel
for the topical treatment of acne has recently been introduced in North America and its short- and
long-term safety and efficacy have been demonstrated (Stotland, 2009).
Antibiotics reduce the number of P. acnes organisms in the lesions and follicular units,
which subsequently triggers inflammatory activities. Certain antibiotics also possess potent antiinflammatory properties that are limited by the induction of bacterial resistance and crossresistance, because topical or oral antibiotics are often used continuously over several months for
the treatment of acne. The emerging resistance to antibiotics of P. acnes has been the main issue
in conventional medical therapy for acne over the past 20 years. Changes in cutaneous flora have
been reported with both oral and topical antibiotic use, and the development of P. acnes
resistance results in a lack of therapeutic effect of appropriate antibiotics in some acne patients
(Eady et al., 1989). Erythromycin is the antibiotic against which P. acnes has the highest rate of
resistance (Del Rosso et al., 2008). The prevalence of tetracycline-resistant P. acnes strains has
also increased by an estimated 40% globally over three decades (Ross et al., 2003). Antibioticresistant P. acnes strains have been demonstrated on the skin of untreated contacts of acne
45
patients undergoing topical antibiotic therapy, which supports the theory of interpersonal spread.
The decreased sensitivity of P. acnes to antibiotics is correlated with chronic use, and the
bacteria start to develop resistance within 6 months after the start of treatment (Tan, 1999).
Antibiotic resistance may be demonstrated when the acne becomes aggravated despite an initial
response, when the antibiotics produce no effect after the start of treatment or when the patient
has a history of multiple antibiotic exposures. Moreover, chronic antibiotic use has been
implicated in an increased risk of breast cancer (Velicer, 2004; Velicer et al., 2006) and an
increased incidence of upper respiratory tract infections (Margolis, 2005). A 12-month
retrospective cohort study in the United Kingdom involving 118,496 subjects found a higher
likelihood of upper respiratory tract infection in those given antibiotics for more than 6 weeks.
This problem of antibiotic resistance can be partially overcome by combining topical therapy
with benzyl peroxide or retinoids (Del Rosso et al., 2008; Langner et al., 2008). This could
enhance the effectiveness of treatment by the synergistic action of treating different aetiological
factors of acne and decrease the amount of antibiotic prescribed.
Patient compliance with topical therapy is another common problem. The outcome of the
treatment depends on regular application of topical agents over a prolonged period. Both topical
antibiotics and benzyl peroxide are considered to be antimicrobial agents, while benzyl peroxide
can reduce comedone formation (Gupta et al., 2003). Benzyl peroxide is a topical disinfectant
that reduces the P. acnes population by oxidative killing. Most topical therapeutic agents are
associated with contact irritation and irritant dermatitis presenting as erythema, scaling and
stinging. The irritation can be partially relieved by the use of a moisturiser. In addition, benzyl
peroxide leads to the bleaching of clothes and contact irritation.
46
2.1.4.3 Topical retinoids

The role of topical retinoids is notably important in the treatment of acne vulgaris. They
bind to and activate the nuclear retinoid receptors after they are taken up by keratinocytes and
sebocytes. This class of drug includes vitamin A and its derivatives, and works through the
reduction of comedones and anti-inflammatory effects. Retinoids can modify cellular growth,
differentiation and immunomodulation through gene transcription. They improve acne by
altering the pathways in ductal keratinocyte proliferation, differentiation, inflammation and
sebum production. The primary mechanism is the inhibitory effect on sebaceous glands, but they
also inhibit microcomedone formation, which decreases the number of mature comedones and
inflammatory lesions, and normalises the maturation and desquamation of follicular epithelium
(Thiboutot et al., 2009). The retinoids that are mainly used topically to treat acne include
tretinoin (all-trans-retinoic acid), isotretinoin (13-cis-retinoic acid), adapalene and tazarotene.
Topical retinoids can serve as the basis of acne treatment during the early phase of therapy,
either alone or in combination with topical or oral antimicrobial therapy. Their use should be
continued as a maintenance therapy once an adequate control of the acne has been achieved. The
adverse effects of retinoids include photosensitivity, initial flares of acne, erythema, dryness and
burning discomfort. The use of topical retinoids is not recommended during pregnancy.
2.1.4.4 Miscellaneous topical agents

Azelaic acid (as a 20% cream) can be used in mild and mild to moderate acne to reduce
the formation of comedones and the P. acnes population. Salicylic acid has also been used for
decades to treat mild to moderate acne, and acts as a keratolytic and peeling agent. It also acts as
47
an antibacterial agent against P. acnes and has an anti-inflammatory effect. At high

concentrations, it can be used as a peeling agent in acne vulgaris.
2.1.4.5 Oral antibiotics

Oral antibiotics are usually indicated for patients with moderate to severe inflammatory
acne, and prolonged courses for 3-6 months are often required. The antibiotics commonly used
for acne are tetracycline, doxycycline, lymecycline, minocycline, erythromycin and
clarithromycin, and their use in combination with a topical treatment is recommended. In
addition to reducing the number of P. acnes organisms, oral antibiotics also have nonantimicrobial and anti-inflammatory effects, which include the reduction of inflammatory
cytokines, the reduction of neutrophil chemotaxis to P. acnes, the modification of
complementary pathways and the down-regulation of several matrix metalloproteinases (Sapadin
& Fleischmajer, 2006). Apart from the bacterial antibiotic resistance discussed in Section 2.1.4.2,
the other notable side effects of oral antibiotics are gastrointestinal upsets, including dyspepsia,
nausea and diarrhoea and vaginal candidiasis. Tetracycline and doxycycline are associated with
photosensitivity
and
minocycline
can
produce
dizziness,
hyperpigmentation,
lupus
erythematosus-like illness and hepatitis.
2.1.4.6 Hormonal therapy

Hormonal therapy is an option for women with acne that does not respond to
conventional treatment or has features of hormonal disturbance, and its use is considered for
moderate acne in women who require oral contraception. The options are androgen-receptor
antagonists and oral contraceptives that inhibit androgen production by the ovaries and adrenal
48
glands. The two main types are spironolactone and oestrogen + cyproterone/drospirenone.
Cyproterone acetate leads to a dose-dependent reduction in sebum excretion and comedogenesis
by blocking the effect of androgens on the sebaceous gland, while oestrogens increase the
synthesis of sex hormone-binding globulin by the liver, thereby reducing the level of circulating
testosterone by binding free testosterone. In addition, oral contraceptives inhibit the ovarian
production of androgens by suppressing ovulation. Their side-effects are nausea, weight gain, the
risk of thromboembolism and an increased risk of gynaecological cancers. Drug interactions may
also potentially occur between oral contraceptives and antibiotics. Broad-spectrum antibiotics
reduce the bacteria in the gut flora and may lead to reduced absorption of oestrogen and the
possible reduced efficacy of oral contraceptives. The effects of topical anti-androgens on
sebocytes have not been demonstrated consistently. Spironolactone is an aldosterone antagonist
and an anti-androgen that acts by both blocking androgen receptors and inhibiting androgen
synthesis. The risk of hyperkalaemia is significant mainly in patients with cardiac disease and
renal impairment.
2.1.4.7 Systemic retinoids

Oral isotretinoin is generally indicated for severe nodulocystic acne, a tendency for acne
scarring, acne that fails to response to other treatments and significant psychosocial distress from
acne. The duration of oral isotretinoin therapy is about 6-9 months with a cumulative dose of
120-150 mg/kg to achieve marked and long-lasting remission. The side effects of oral
isotretinoin are many and can be divided into mucocutaneous and systemic. Cheilitis is seen in
over 95% of patients who take the drug and dermatitis with dry skin is seen in about 30%. These
symptoms can be improved by a reduction in dose, and the use of moisturisers and topical
49
corticosteroids. The most serious side effect of isotretinoin is its teratogenicity. Stringent
contraceptive measures need to be adopted before, during and 2 months after cessation of
treatment. Other systemic side-effects are myalgia, arthralgia, headache, hair loss, phototoxicity,
raised lipid profile and hepatitis. Whether the drug leads to mood changes, depression and
suicidal ideation is still controversial.
2.2 Laser-tissue interaction and concept of selective photothermolysis

It has long been observed that exposure to sunlight improves acne in 70% of patients.
Studies have shown that UV light can improve acne but its use is limited by its carcinogenicity
and photoaging effects (Charakida et al., 2004). Lasers have become increasingly popular in the
past decade for the treatment of various dermatoses and aesthetic purposes.
Based on the theory of selective photothermolysis proposed by Anderson and Parrish

(1983), selective tissue injury can be achieved using high-energy, pulsed lasers. This theory
revolutionised the dermatological use of laser systems, which have now become an important
therapeutic option in the management of many skin conditions. The interaction of light with
skin is determined by the optical properties of the skin components and the wavelength of the
incident light. Selective tissue damage can be achieved using laser light with wavelengths that
match those of the skin chromophores (Anderson & Parrish, 1983). Laser light can produce
photothermal, photomechanical and photochemical reactions in skin. Photothermal interactions
are a result of heat generated by the laser light. If the skin is heated to a temperature below
50oC, then the consequent thermal tissue damage is reversible. At higher temperatures (50100oC), coagulation of proteins occurs, leading to irreversible thermal tissue damage. At
50
temperatures above 100oC, the vaporisation of tissue takes place. If the exposure time is
shorter than the thermal relaxation time of the target (defined as the time required for a target
to cool from the temperature that is achieved immediately after laser irradiation to half of that
temperature), then the heat will not be able to diffuse, which limits the thermal damage to the
target site. Tissue damage can also be limited to the target site using a laser with a wavelength
that is specifically absorbed by the target tissue, where it is converted to heat and results in
thermal injury. In addition to melanin, the skin chromophores that are important in laser
surgery are haemoglobin, water and exogenous pigments such as tattoos. Yellow-light lasers,
such as the pulsed-dye laser (PDL), are absorbed by haemoglobin and can be used for the
treatment of vascular lesions. The carbon dioxide and Er:YAG lasers can be used as
resurfacing devices because of their non-selective absorption by water.
In photomechanical interactions, pulsed lasers disperse the target tissue by rapid

thermal expansion and local vaporisation. Because the duration of the laser pulse is shorter
than the thermal relaxation time of the target, a temperature gradient is created between the
target and its surrounding tissue. When the temperature gradient collapses, it generates
localised shockwaves that cause the fragmentation of its targets.
Laser or light-induced photochemical interactions are known as PDT, which was

originally used for the treatment of skin cancers. It involves the use of lasers or light sources in
combination with a topical or systemic photosensitiser, such as ALA, to produce the
therapeutic effects. Solid tumours have a tendency to accumulate porphyrin derivatives, which
are red-fluorescent and can be stimulated by a red light laser to an excited state. A
51
photochemical reaction occurs with the production of free oxygen radicals, causing the
oxidation of the cell membrane, cell lysis and selective target tissue damage.
A variety of lasers and light sources are now being tested for the treatment of acne.
Ablative resurfacing lasers have been used for more than two decades to improve atrophic acne
scars. More patients are willing to pay a high price for optical therapies for acne and acne scars
when they are office-based procedures. Blue light, red light, lasers and IPL with PDT have found
a useful niche in the treatment of inflammatory acne (Nouri & Ballard, 2006; Hdersdal et al.,
2008), and were developed to provide patients with safer, more effective and more convenient
therapeutic options. The effect of light-based treatments on acne can be optimised by a good
understanding of the pathogenesis of acne and appropriate patient selection.
The approaches based on wavelengths of the light-based treatment of acne can be divided
broadly into pure photothermal (e.g., mid-infrared lasers), pure photochemical (e.g., blue light),
photosensitiser-assisted photochemical or photothermal tissue interaction (e.g., PDT) and the
combined approach. The photochemical approach entails the production of singlet oxygen by
activating light sources, which results in the death of P. acnes (PDT-mediated antibacterial
effect) while the photothermal approach entails an increase in the temperature of the
pilosebaceous units at various levels.
2.3 Mechanisms of the clinical application of lasers and photodynamic therapy

The foundation of the light-based treatment of acne is based on the understanding of its
pathophysiology. The sebaceous follicles are the site of action, and the targets of light-based
52
therapies are cutaneous P. acnes, the infrainfundibulum at 200 m below the stratum corneum
and the sebaceous gland (Bhardwaj et al., 2005; Thiboutot et al., 2009). These goals can be
achieved through the photothermal and photochemical effects of lasers/light sources on selected
chromophores in the skin (Ross, 2005). Light or laser treatment might also modulate the
inflammatory response.
2.3.1 Targeting Proprionibacterium acnes

Light destroys P. acnes by targeting endogenous porphyrins through a purely
photochemical effect. Irradiation of P. acnes colonies with blue light leads to bacterial
destruction in vitro (Charakida et al., 2004). P. acnes produces and accumulates porphyrins
(mainly PpIX and coproporphyrin III) that florescence under a Woods lamp (365 nm) or UV
photography with a follicular pattern of an orange-red glow (Figure 2.2). The absorption peak of
porphyrins occurs at 415 nm (the Soret Band) at the near-UV and blue-light spectrum and small
peaks of absorption occur at 500-700 nm (Figure 2.3). Excited porphyrin molecules then
generate singlet oxygen and free radicals (Mariwalla & Rohrer, 2005). These reactive oxygen
species can damage the lipid layers of the bacterial cell membrane and thereby reduce the levels
of P. acnes in the skin.
Although the absorption peak is highest for the blue light, this portion of the spectrum is
limited by its optical penetration depth into the skin, with rapid attenuation in the tissue, which
means it hardly reaches the sebaceous gland. The efficiency of P. acnes death with the
endogenous porphyrins is low. Red light with a longer wavelength can penetrate more deeply
into the skin but is less effective in activating porphyrins than blue light (Elman & Lebzelter,
53
Figure 2.2. Left: Subject with moderate acne. Right: Fluorescence photography of acne
showing numerous orange-red punctate areas of fluorescence corresponding to follicles and open
comedones.
54
Figure 2.3. Light absorption spectrum of porphyrins. The Soret Band represents the highest peak
of light absorption and thus the highest sensitiser activation. Q Bands represent several weaker
levels of absorption at the longer wavelengths.
Soret Band
Q Bands
IV
III
II
400
(nm)
600
55
2004), although both have been shown to possess anti-inflammatory properties (Shnitkind et al.,
2006). UV light has a better action spectrum than visible light, but it is limited by its depth of
penetration and carcinogenic potential.
The destruction of P. acnes can also be enhanced by the extrinsic use of a photosensitiser,
because the bacterium produces more porphyrins than it does normally when supplied with an
exogenous source of ALA (a prodrug that creates PpIX) (Thiboutot et al., 2009). Because PpIX
has multiple absorption peaks, different activating light sources and lasers can be used, including
red, blue, IPL and PDL (Mariwalla & Rohrer, 2005; Taylor & Gonzalez, 2009). Longer
wavelengths with a greater depth of penetration, such as red light, may be more suitable to reach
the level of the sebaceous glands within the skin.
The photo-inactivation of P. acnes depends on the concentration of porphyrins, the

wavelength of the photons, the fluence of the light sources and the temperature at which the
reaction occurs (Elman & Lebzelter, 2004). An inherent limitation in the strategy of P. acnes
eradication as a therapeutic goal is that it requires frequent treatments, because the bacteria
proliferate rapidly and quickly repopulate after being reduced by a phototoxic reaction. A
combination therapy with agents such as topical retinoids should be used to reduce the risk of
relapse (Thiboutot et al., 2009).
2.3.2 Targeting sebaceous glands

The suppression of sebaceous gland function is expected to have a longer-lasting antiacne effect than the reduction of P. acnes. This function can be damaged partially and selectively
56
by light energy, resulting in the histological reduction of glandular size and disruption of the
glandular function with decreased sebum production (Hongcharu et al., 2000). Whether the light
sources or lasers can achieve the purpose depends on the depth of penetration of the light energy,
because sebaceous glands are mainly situated in the mid-dermis below 1 mm (Ross, 2005).
Because exogenous photosensitisers are selectively absorbed and accumulated in the
pilosebaceous units, PDT can both target the sebaceous units and reduce P. acnes through
photochemical interactions.
Follicular obstruction may be altered following light treatment, which changes the level
of keratinocyte shedding and hyperkeratosis in the infra-infundibulum, and may partially explain
its efficacy in acne therapy despite the limited depth of penetration above the level of the
sebaceous gland by lasers and the fairly short application time of ALA (Munavalli & Weiss,
2008; Ross, 2005). Moreover, red light and PDL also have anti-inflammatory effects because
they influence the release of cytokines from macrophages which in turn influences the processes
of healing and wound repair (Charakida et al., 2004; Seaton et al., 2006).
2.3.3 Main modalities of light treatments for acne

2.3.3.1 Incoherent light sources
A high-intensity, narrow-band, blue light source (405-420 nm) has been developed for
the treatment of mild to moderate inflammatory acne on the face and trunk, which makes use of
the intrinsic production of coproporphyrin III and PpIX by P. acnes. Treatments often last for 15
min, twice weekly for 4 weeks. Kawada et al. (2002) reported a 64% reduction in mild to
moderate acne in 30 patients after 5 weeks of therapy. The effects are largely on inflammatory
57
lesions rather than on the formation of comedones. The findings on the reduction in the number
of comedones by visible light sources have been inconsistent. Some evidence for the superiority
of blue or blue-red light over placebo was found in three studies, with reductions in
inflammatory lesions of 4975% versus 1025% in untreated patients, with minimal side-effects
(Hamilton, 2009). The blue light source showed a clearance of acne that was comparable with
that of topical 1% clindamycin lotion in one study (Gold et al., 2005). The optimal treatment
parameters of light sources have not yet been established, but most regimes use twice weekly
treatments for 4 weeks. Adverse effects are uncommon. Overall, the combination of red-blue
light was shown to be superior to blue light alone with a 75% reduction in inflammatory lesions
after 12 weeks following 10-20 treatments (four times a week for up to 5 weeks) in one study
(Papageorgiou et al., 2000).
Blue light that covers the Soret Band is more effective in the photoactivation of
porphyrins, but it is limited by the depth of percutaneous penetration due to its short wavelength.
As a result, it clears P. acnes to a certain extent and causes damage to the acroinfundibulm,
which improves the sebum outflow. Red light (635 nm) can penetrate more deeply but is less
effective in photoactivation. Thus, the combined red and blue light seems to be more effective
than either light source alone because of their synergistic anti-inflammatory and anti-bacterial
actions (Charakida et al., 2004). Papageorgiou et al. (2000) evaluated 4-week daily treatment
with blue light and mixed blue-red light for mild to moderate acne and compared their efficacy
with that of white light and 5% benzyl peroxide cream. At 12 weeks, the mixed blue-red light
had effected the best improvement (76%) compared with blue light, white light or benzyl
peroxide alone. The advantages of the narrow-band light source are its lower cost, more uniform
58
illumination and larger areas of treatment. The efficacy of blue light is modest and variable and
results in reductions in acne lesions in the range of 30-60% compared with the baseline for
inflammatory lesion count (Bhardwaj et al., 2005; Mariwalla & Rohrer, 2005; Hdersdal et al.,
2008). However, the relapse rate is high after the discontinuation of therapy (Ross, 2005). In
addition, an increase in pigmentation can occur in coloured skin after prolonged exposure to blue
light, and it may therefore not be the ideal light source for the treatment of acne in Asians (Chan,
2005).
2.3.3.2 Pulsed-dye laser (PDL)

PDL devices emit light of 575-595 nm that is selectively absorbed by oxyhaemoglobin.
The PDL activates bacterial porphyrins and causes selective photothermolysis of the dilated
vasculature component of inflammation associated with acne (Bhardwaj et al., 2005), which may
also be mediated through the anti-inflammatory effect on the bacteria (Mouser et al., 2003). It
also helps to improve the erythema and scars that are associated with acne. A potential
mechanism of the effect of PDL on acne may be the up to 15-fold increase in transforming
growth factor (TGF)- mRNA that was observed 1 day after PDL therapy, which has both an
immunomodulating action via the inhibition of CD4+ T lymphocytes and an inhibitory effect on
keratinocyte proliferation, and hence reduces comedone formation (Seaton et al., 2006). Thus,
the follicular obstruction might be altered by a change in keratinocyte shedding and
hyperkeratosis.
Two randomised controlled studies that used the same setting of subpurpuric doses and
low fluence 585-nm PDL (1.5 or 3 J/cm2, one pass, single treatment) revealed mixed results.
59
Seaton et al. (2003) reported a statistically significant reduction in inflammatory lesion counts 12
weeks after a single treatment at low fluence (585 nm, 1.5 or 3 J/cm2, single pass) compared with
the controls, while Orringer et al. (2004) reported no statistically significant improvement in a
split-face study with a significant number of dropouts. The split-face treatment design with lightbased devices in clinical studies may offset the observed therapeutic effects. Orringer et al.
(2004) evaluated the lesion counts of 40 patients in this clinical trial with the PDL and argued
that a split-face study design was important to assess the actual improvement of acne compared
with the natural course of the disease with spontaneous flares and improvements. The efficacy of
certain therapies may be overestimated as a result of the spontaneous improvement of the
condition. Only 26 patients completed this left-right half-face comparative study, which could
not demonstrate a statistically significant improvement in acne using PDL. In contrast, a
significant reduction in inflammatory acne lesions of 53% in 27 patients treated with PDL
compared with a 9% reduction in 10 patients in the parallel placebo group was observed in a full
facial study of 31 patients (Seaton et al., 2003). The investigators commented that treating one
side of the face could influence acne on the opposite side of the face (Chu, 2004). Full facial
treatment may alter the immunological function more completely than half facial treatment.
Moreover, the rapid re-colonisation of P. acnes from the control side on the treated halves and
the subsequent inflammatory response can negate the therapeutic effects of light-based treatment
on the treated side.
2.3.3.3 Mid-infrared laser

Mid-infrared lasers were initially used for non-ablative rejuvenation of the skin and the
improvement of atrophic acne scars. The mid-infrared laser can be used to treat acne because of
60
its photothermal tissue interaction. The 1450 nm diode laser in the mid-infrared range has been
found to injure the sebaceous gland selectively by heating water in the surrounding upper dermis
at a depth of about 200500 m in the skin with simultaneous cooling of the epidermis using a
cryogen spray (Munavalli & Weiss, 2008). The 1540 nm erbium:glass laser is another infrared
device that is available for clinical use. Because the mid-infrared wavelengths are well absorbed
by water, leading to a bulk-heating effect on the dermis, and penetrate to the level of the
sebaceous glands located at about 700 m below the skin surface (Paithankar et al., 2002), they
have been shown to improve inflammatory acne by functional alteration of the sebaceous glands.
A study of acne on mens backs showed temporary thermal coagulation of the sebaceous lobule
with a significant reduction in lesion count after treatment with the 1450 nm laser using a radiant
exposure of 20.6 J/cm2, a pre-laser cryogen spray of 10 ms, an intermediate spray consisting of
three sprays of 10 ms each and a post-laser spray of 20 ms (Paithankar et al., 2002). The reports
on whether this laser treatment can effectively reduce the sebum excretion rate of the skin are
inconsistent, because the maximal heating occurs about 300-400 m below the surface (PerezMaldonado et al., 2007; Laubach et al., 2009). It appears that the 1450 nm laser also directly
heats the infundibulum, which might improve the outflow and reset the keratinisation pattern in
the follicle (Ross, 2005). Jih et al. (2006) reported a 75% reduction in mean lesion count that was
maintained at a 12-month follow-up in a 20-patient study after three treatments at fluences of 14
or 16 J/cm2.
Epidermal protection with a cooling device is essential for mid-infrared lasers,

because epidermal necrosis and blistering can develop due to the non-specific absorption of
water. Skin cooling can reduce the side-effects and enhance the clinical efficacy of lasers, and
61
involves the use of cooling agents to lower the temperature of the skin surface before, during
or after laser irradiation. Target structures can be damaged selectively while minimising the
thermal injury to the epidermis from the laser. Moreover, the tolerance of the patients can be
improved because the cooling can reduce the discomfort and swelling associated with the
treatment. Different types of skin cooling systems have been used, including the water-cooled
glass chamber, cryogen sprays, cold air and cold gels (Nelson et al., 2000). Bulk cooling
methods have been unsuccessful in improving the clinical outcome because they were nonselective and cooled not only the epidermis but also the end target, which led to a reduction in
laser-induced thermal damage. By using cryogen spray cooling, selective epidermal cooling
can be achieved (Chang & Nelson, 1999). In cryogen spray cooling, a cryogen spurt is applied
to the skin surface for tens of milliseconds, which lowers the skin surface temperature from
30oC to 0oC to 5oC.
In acne therapy that uses a laser, either the blood vessels or water component of the
dermis are the targets. Therefore, most mid-infrared range lasers are equipped with an
epidermal cooling device using a cryogen spray to achieve pulsed epidermal pre-, intra- and
post-treatment cooling, known as dynamic cooling. Dynamic pre-cooling induces epidermal
cooling before laser exposure, and provides epidermal protection during short pulses. Parallel
cooling chills the epidermis during exposure to the laser and provides protection for longer
pulses. Post-cooling chills the whole skin after exposure to the laser and further reduces pain
and swelling. However, cryogen may induce cold injury of the epidermis, leading to postinflammatory hyperpigmentation in darker skin phototypes. A 78% reduction in active acne
62
lesions was achieved 12 weeks after four treatments with an erbium:glass 1540 nm laser
(Aramis, Quantel Medical) in one study (Angel et al., 2006).
One of the limitations of the 1450 nm laser is the procedural pain and PIH which is
especially problematic for Asian skin, in whom the PIH rate has been reported to range from 7
to 39% (Hardaway et al., 2002; Tanzi et al., 2003; Chua et al., 2004). Because most cases tend
to develop after the second treatment and the total duration of cryogen spray was 60 ms, it has
been postulated that excessive cooling due to the use of sequential cryogen spurts that prolong
the overall cooling time is the main factor in the high risk of PIH in Asian patients.
Although laser absorption by epidermal melanin is low throughout the mid-infrared

range, the PIH rate has been reported to be as high as 39% in a study of acne scars in Singapore
using the same standard parameters (spot size, 6 mm; 11-12 J/cm2; dynamic cooling device
(DCD), 50 ms) as those used on Caucasian skin (Chua et al., 2004). This laser also has the dual
benefit of improving acne scarring by initiating the synthesis of new collagen as a result of the
bulk tissue heating effect in dermis (Chua et al., 2004).
2.3.3.4 Intense pulsed light (IPL)

IPL is a polychromatic non-laser light that is emitted in the spectrum of 400-1200 nm. It
emits a fixed spectrum of wavelengths rather than a fixed wavelength, which allows the
penetration of different depths and the simultaneous targeting of multiple chromophobes. The
use of a cut-off filter system to confine the emitted radiation to a certain spectrum of
wavelengths permits some degree of selectivity, although not to the same extent as laser therapy.
63
Another advantage of IPL is that different pulse widths can be set, and the appropriate
parameters that match the thermal relaxation time of the targets can be chosen. Most devices
emit in the range of 500-1200 nm, and mostly at 550-700 nm. IPL is commonly used for rosacea
and photorejuvenation, because of its known effect on erythema and inflammatory papules.
Newer-generation IPL systems (IPL2, Ellipse Flex system, Danish Dermatologic Development,
Denmark; and Starlux, Palomar, Burlington, MA, USA) offer enhanced selectivity through userspecified fluence density with wavelength and pulse width, in addition to improved filtering
technology (Ross et al., 2005). These newer IPL devices have a greater safety margin and
improved therapeutic efficacy, and have gained much popularity due to their multi-purpose
design and limited post-operative down time.
One of the mechanisms of IPL is its photothermal effect on the hyperaemic acne lesions.
The other mechanism may be photoactivation and the activation of singlet oxygen of the
endogenous porphyrins of P. acnes. The relative contribution of these two mechanisms can be
determined by the spectrum, fluences, the pulse duration and the number of pulses. A previous
study demonstrated the effectiveness of IPL-assisted ALA-PDT in acne over IPL alone
(Hdersdal et al., 2008). After three sessions of treatment with the 20% topical ALA with a 30min incubation period to the right side of the face and full facial IPL 3 weeks apart, a more
significant improvement in facial acne was observed on the ALA-treated side (Gold, 2007).
Santos et al. (2005) used a 3-hour incubation period in a comparative split-face study of topical
ALA plus IPL versus IPL alone administered twice at an interval of 2 weeks for the treatment of
acne (Gold, 2007). Six weeks after treatment, 10 out of 13 subjects (77%) had significant
64
decreases in inflammatory acne without new lesion formation on the ALA-IPL-treated half of the
face, but no improvement was observed on the IPL-treated side compared with the baseline.
2.3.3.5 Photodynamic therapy (PDT)

PDT is a photochemical reaction that requires the presence of a photosensitising
molecule, photoactivating wavelengths of light and tissue oxygen to destroy a target cell
selectively (Taylor & Gonzalez, 2009). The process generates reactive, free radical intermediates
that damage the target tissue, and was initially used in combination with a specific blue-light
source for the treatment of skin cancers and non-hyperkeratotic actinic keratosis. In addition to
acne vulgaris, other current common indications for ALA-PDT include photodamage, actinic
keratosis, sebaceous hyperplasia and hidradenitis suppurativa because ALA is preferentially
absorbed by non-melanoma skin cancer cells, sun-damaged cells and pilosebaceous units of the
skin.
For the treatment of acne, ALA is applied topically as an exogenous photosensitiser for
0.5-3 hours with or without occlusion. Sebaceous glands and hair follicles selectively take up and
convert topical ALA into photosensitising PpIX, especially in inflamed acne lesions. PpIX can
then be activated by an appropriate light source, leading to the formation of singlet oxygen
species and subsequent cellular membrane disruption and damage. Moreover, the addition of
ALA leads to a greater intracellular accumulation of coproporphyrin III. The effective dose of
photosensitiser accumulated in the sebaceous gland depends on the application time and the
vehicle used to deliver the prodrug to the targets. In general, the onset of the effect of
65
improvement on inflammatory acne is faster with exogenous ALA and light/lasers than with
light/lasers alone.
New derivatives or vehicles of ALA such as the methyl ester of aminolevulinate (MAL)
and hexyl aminolevulinate (PhotoCure ASA, Oslo, Norway) have been developed for use in
PDT, with the potential benefits of higher lipophilicity, better penetration of the stratum corneum
and lesion specificity (Wiegell & Wulf, 2006). A 54% reduction in inflammatory lesions was
shown in a split-face controlled study using MAL-PDT with red light twice at 2-week intervals
(Horfelt et al., 2006). In a comparative study of MAL and hexyl ester, a significant temporary
reduction in mean P. acnes density was found 2 days after a single application of each agent. The
hexyl ester-PDT was associated with fewer side-effects than MAL-PDT over the 14-day study
period (Yung et al., 2007).
Liposomes have been used in the delivery of drugs to the pilosebaceous units. For
hydrophobic drugs, a major fraction of the added drug is encapsulated or intercalated within the
bilayers of the liposomes (Touitou et al., 1994). If dehydration to an equilibrium stage occurs
with retention of a constant amount of water within the bilayers, the drug is continually
transferred from the lipid bilayers in liquid crystalline form into the skin. In addition, an adhesive
patch of liposomal bilayers is formed on the skin, maximising the intimacy of contact between
the drug-laden bilayers and the skin. On dehydration, the liposomal bilayers can partition and
pack into the follicular ducts that contain the lipids. The filling of the follicular openings with the
liposomal bilayers not only results in entrapped drugs being carried into the follicles, but also
allows partitioning of the free drugs into the bilayer matrix within the follicles. The use of
66
liposomes in a spray form as a delivery vehicle to encapsulate and carry ALA into the epidermis
has been studied. Liposomes can enhance the penetration of ALA, enable a 40-fold reduction in
the concentration of topical ALA (to 0.5%) used and thus drastically reduce the phototoxicity
that can occur after the procedure (Christiansen et al., 2007).
PpIX has multiple absorption peaks, and various light sources and lasers can therefore be
used. Activating light sources, including red, blue, IPL, PDL and light-emitting diode (LED),
have been shown to be effective in PDT for acne (Mariwalla & Rohrer, 2005; Taylor &
Gonzalez, 2009). Longer wavelengths with a greater depth of penetration may be more suitable
to reach the sebaceous glands within the skin. PDL seems to be the activating light source that
achieves the best result in PDT for acne (Nestor, 2007).
Hongcharu et al. (2000) used a 20% ALA cream occluded for 3 hour followed by redlight irradiation in a landmark study using ALA-PDT for inflammatory acne. Long-term
reduction of lesions on the back was demonstrated in 22 subjects. Reduced sebum excretion,
decreased follicular fluorescence and smaller sebaceous glands were observed in skin biopsies as
long as 20 weeks after multiple sessions of PDT. These observations appeared to be a result of
the effect of ALA on sebaceous glands and P. acnes. Side effects included temporary folliculitis,
erythema and hyperpigmentation. Itoh et al. (2001) reported an improvement in inflammatory
lesions after ALA-PDT in 13 patients with intractable acne using a 4-hour application of 20%
ALA and a polychromatic light source (600-700 nm), but adverse photodynamic effects were
also apparent. An increasing number of clinical trials have demonstrated the effectiveness (5060% reduction in inflammatory acne) of ALA and MAL-PDT after one to three treatments every
67
3-4 weeks on facial and back acne that improved for up to 20 weeks (Hdersdal et al., 2008;
Munavalli & Weiss, 2008; Taylor & Gonzalez, 2009). The majority of studies showed that the
benefit of PDT was greater than that of light therapy alone, but PDT tended to be more painful
than light alone (Hamilton et al., 2009).
Complete clearance of acne was achieved in all 14 patients in another study that used
monthly treatments with 595-nm PDL (7-7.5 J/cm2, 10 ms, 10-mm spot, 30/20 dynamic cooling)
and short contact ALA-PDT (45-min incubation) after a mean follow-up of 6, during which all
patients continued topical therapy (Alexiades-Armenakas, 2006). No change in sebum excretion
rates or P. acnes count has been demonstrated in previous studies, because most of the converted
PpIX is accumulated in the infundibulum and the upper dermis following short-contact therapy.
The adverse effects of PDT used as a standard regime for the treatment of other
dermatoses are significant, and may occur during or immediately after treatment, causing
significant pain, erythema, oedema and initial flare of acne, burning, hyperpigmentation,
exfoliation and prolonged photosensitivity, all of which are called photodynamic effects.
Crucially, patients need to be educated on the need to use sun protection (broad-spectrum
sunblock) for up to 48 hours after PDT (Nestor et al., 2006). Kasche et al. (2006) reported that
54% of patients treated with ALA-PDT and 14% of those treated with methyl aminolevulinatePDT had to stop irradiation prematurely because of pain; the incubation time of ALA was double
that of MAL in this study. A PDT regime with lower fluences and multiple passes can alleviate
the discomfort and pain (Taylor & Gonzalez, 2009), and a short incubation of ALA of 30-60 min
is increasingly being adopted to allow adequate penetration while reducing the length of the
68
procedure and the overall adverse phototoxic effects. Short-contact therapy has shown
comparable effectiveness with a reduction in its side effects for the treatment of photoaging and
acne (Dover, 2005; Gold, 2007). Another open, split-face study using 20% ALA for 30 min also
demonstrated an 87.7% reduction in inflamed lesions on the PDT side compared with a 68.8%
reduction on the IPL side (Rojanamatin, 2006). Consensus guidelines suggest that a 30-60 min
incubation of ALA without occlusion before photoactivation is adequate in acne therapy, but that
the short contact time only allows PpIX formation in infundibulum and upper epidermis (Nestor,
2007). To date, no study has demonstrated microscopic evidence of selective sebaceous gland
damage after short-contact ALA-PDT. Mechanisms other than a reduction in P. acnes and the
damage of sebaceous glands may account for the efficacy of the short-contact regime (Pollock et
al., 2004).
The application of indocyanine green (ICG) as a topical photosensitising agent in

combination with green-light diode laser (810 nm) has recently been described. Indocyanine
green was more selectively absorbed by the sebaceous glands and appeared to be more selective
in its action, with fewer adverse effects. Overall, selective damage of the sebaceous glands, with
no significant epidermal change, and long-term improvement in back acne up to 10 months posttreatment were reported (Lloyd & Mirkov, 2002).
PDT can be a viable option for the treatment of moderate to severe inflammatory acne in
cases of failure of or intolerance to topical or oral medications. The benefits of ALA-PDT
include its greater effectiveness, its simultaneous rejuvenating effect and a faster clinical
response after a limited number of sessions compared with the daily intake of oral medications.
69
The side effects of PDT are its phototoxic effects that result from the accumulation of porphyrins
in the epidermis and pilosebaceous unit. Erythema and hyperpigmentation that can last for days
to weeks are common adverse effects. Procedural pain is another important side effect that limits
the use of PDT. Crusting followed by exfoliation are common phototoxic side effects that occur
in the epidermis a few days after PDT, while dermal toxicity, including pustular eruption and
acute transient acne flare, occurs 2-3 days and 3-4 weeks post-treatment, respectively (Sakamoto,
2010). The adverse effects of PDT can be reduced by lowering the fluences, fractionating
treatments and increasing the selectivity of the photosensitisers.
2.3.3.6 Photopneumatic therapy

The device used for photopneumatic therapy combines suction pressure and broadband
pulsed light (400-1200 nm) for the treatment of comedonal and inflammatory acne. The
application of negative pressure to the skin surface physically evacuates trapped sebum and
necrotic cells. Moreover, the suction stretches the skin within the treatment tip, thereby reducing
the concentration of competing chromophores, such as melanin and haemoglobin, so that the
light can target P. acnes porphyrins selectively. The mechanical extrusion of comedonal contents
and thermal suppression of P. acnes have been demonstrated following treatment. Pilot studies
have shown an improvement of mild to moderate acne. The side effects were mild and limited to
transient erythema and rare purpura (Wanitphakdeedecha et al., 2009).
In another split-face study of this photopneumatic device, 20 subjects with mild to

moderate facial acne received four successive treatments at 2-week intervals on one side of the
face and the opposite side served as a control (Lee, 2012). Significant improvements in and
70
reduced numbers of acne lesions were observed on the treated sides of the faces. The side-effects
included transient erythema, purpura and exacerbation of pre-existing acne in a few patients.
71
Chapter 3
Acne Scars: Classification and Treatment
72
3.1 General introduction

Facial scarring is a common long-term complication of moderate to severe acne, and
patients with inflammatory acne should be counselled that they have a significant risk of scar
development. Every effort should be made to treat the inflammatory lesions and prevent this
long-lasting complication. Acne scars can have substantial cosmetic and psychological effects,
particularly in adolescence and young adulthood. Concerns about for PIH and scarring are one of
the main motivational factors that lead Asian patients to seek treatment for acne (Taylor et al.,
2002). The precise prevalence of acne scarring is unknown. However, one study reported the
presence of acne scars in 14% of women and 11% of men aged 25-58 years in a communitybased study (Goulden et al., 1999). Most patients presented with macular atrophic or ice-pick
scars. Other studies reported that between 30% and 95% of patients with acne developed some
form of associated scarring, and a higher incidence of scarring on the trunk was observed in men
(Kim et al., 2002).
Acne scars present with various morphology, and are generally classified into
hypertrophic and atrophic. Keloids and hypertrophic scars are resulted from excessive fibrotic
tissue formation and occur less frequently than atrophic scars on the face. Atrophic scars are
further classified into ice-pick, rolling, shallow and deep boxcar scars, and are the result of
compromised collagen production during the natural wound-healing process following an
inflammatory acne response, which leads to surface undulations (Sriprachya-anunt et al., 2002).
73
Different modalities of treatment, including chemical peeling, surgical techniques by

subcision and punch excision, dermabrasion and tissue augmentation with fillers, have been used
on atrophic scars. While laser-based ablative systems using a CO2laser with or without Er:YAG
laser for resurfacing can effectively treat facial scarring, their use may be associated with a
prolonged recovery period and cosmetic complications, including scarring and hyper- or
hypopigmentation (Jordan et al., 2000; Tay & Kwok, 2008). Hyperpigmentation rates of up to
68% have been reported in type IV skin following CO2 laser resurfacing. While non-ablative
laser is safe for the treatment of acne scars, the degree of improvement is only modest.
In fractional resurfacing, thermally ablated microscopic arrays of the epidermis and

dermis are regularly spaced over the skin surface without injuring the surrounding tissue, which
serves as a reservoir of cells that accelerate and promote the desired effect (Manstein et al.,
2004). This technique is more efficient and results in faster recovery than non-ablative
resurfacing and complete ablative resurfacing. Devices for fractional laser ablation have become
increasingly popular because they offer the potential benefits of full-surface ablative skin
resurfacing while minimising risk and recovery (Jih & Kimyaiasadi, 2008). However, their major
limitation is that they are not equally safe and effective for all skin types, especially for Asian
skin that had a higher epidermal melanin content, with regard to the risk of PIH.
Thus, the major limitation of fractional laser ablation for acne scars in Asian skin types is
the suboptimal safety and effectiveness. The use of radiofrequency (RF) devices to deliver
energy in a fractional form for treating facial scarring can achieve selective heating of the deep
dermis while protecting the overlying epidermis and initiating wound healing. The effect of
74
combining the two fractional based modalities of RF and fractional infrared laser on the
improvement of facial acne scarring can be significant. Fractional RF induces collagen formation
in the deep layers of the skin, whereas the infrared laser affects the more superficial layers and
thus the overall surface irregularities of the skin are improved. The minimisation of the
epidermal disruption by the use of these devices may reduce the rate of PIH in Asians.
3.2 Classification of acne scars

A scar is defined as the fibrous tissue that replaces normal tissue destroyed by injury or disease.
Acne scars result from abnormal wound healing after damage to the pilosebaceous unit and
surrounding tissue. Their formation is generally caused by either increased tissue formation or
loss of local tissue (Tosti et al., 2010) and they can be classified as hypertrophic and atrophic.
Differentiation between types of scar is important for the clinician to select the most appropriate
modality of treatment. In facial acne, atrophic scars are much more common than hypertrophic
scars. Ice-pick scars are deep, narrow (diameter, <2 mm), sharply delineated, depressed tracts
that taper to a point as they extend into the deep dermis or subcutaneous tissue (Figure 3.1).
Rolling scars result from the dermal tethering of the skin by abnormal fibrous adhesions that
anchor the dermis to the subcutis and are broad-based skin surface depressions with an
undulating appearance (Figure 3.2). Boxcar scars have a round or oval punched out shape with
a flat base and sharply demarcated vertical edges (Figure 3.3). Their diameter ranges from 1.5 to
4.0 mm and they are further divided into shallow (0.1-0.5 mm) and deep (0.5 mm) subtypes.
Unlike the ice-pick scars, boxcar scars do not taper to a point at the base. Hypertrophic scars and
keloids often occur on the shoulders and back in male patients with inflammatory acne.
Excessive tissue repair leads to the formation of hypertrophic scars and keloids. The
75
Figure 3.1. Clinical appearance of ice-pick scars with a sharp, demarcated, V-shaped
configuration reaching into the deep dermis.
76
Figure 3.2. Clinical appearance of rolling scars with broad, ill-defined, superficial depressions of
the skin.
77
Figure 3.3. Clinical appearance of boxcar scars with a sharp, demarcated, U-shaped
configuration.
78
distinguishing feature of keloids from hypertrophic scars is that the lesions extend beyond the
original confines of the primary tissue injury and run a prolonged continuous growth phase.
There is no consensus on the clinical grading of the severity of acne scars. A quantitative
numeric grading system according to the scar type (atrophic, macular, boxcar, hypertrophic and
keloidal), the lesion count (1-10, 11-20 and >20) and the severity (mild, moderate and severe)
has been proposed. Final scoring depends on the summation of the points assigned to each
respective category. The scale ranges from 0 to 84, reflecting the severity of acne scars
(Goodman & Baron, 2006).
3.3 Pathophysiology of acne scarring

Acne scarring is a consequence of the damage that occurs in and around the
pilosebaceous unit during inflammation. PIH is a complication of acne that is more prevalent
among Asians because of their epidermal melanin content. Erythematous or dyspigmented
macules only develop in atrophic acne scars when the epidermis and superficial dermis are
involved. When the deep dermis is affected, sharp-wall or ice-pick scars are produced, and when
more extensive dermal damage occurs, broad scars such as rolling or boxcar scars can develop
(Tosti et al., 2010). The exact mechanism of the scarring has not been fully elucidated.
Inflammatory acne lesions often lead to atrophic scarring, and the formation of acne scars of
various morphologies depends on the degree, depth and duration of inflammation and on the
extent of tissue damage (Rivera, 2008). Acne scars are the result of a suboptimal wound-healing
process that involves inflammation, granulation tissue formation with fibroplasia and new vessel
79
formation during the proliferative phase, wound contracture and tissue remodelling (Goodman &
Facd, 2000).
Under normal circumstances, the immature scar passes into the final maturation phase,
with degradation of the extracellular matrix and transformation of the immature type III collagen
of early wound into mature type I collagen. The delicate balance of synthesis and degradation of
different scar components is tightly regulated by a number of molecules, particularly epidermal
growth factor, TGF-, MMPs and basic fibroblast growth factor. Deep scars are more liable to
occur when the destruction of subcutaneous fat is involved in the inflammatory process, because
the enzymatic activity and inflammatory mediators also destroy the deeper tissue.
The exact cause of the formation of hypertrophic scars and keloid scarring has not been
fully elucidated, and it is not clear why some scars are atrophic while others are hypertrophic.
The abnormal healing response with persistent collagen production, an unbalanced production of
collagen type I relative to that of collagen type III, abnormal expression of a variety of growth
factors and dysregulation of the extracellular matrix have been implicated in the formation of
keloids, which tend to occur in families with a racial predisposition for dark skin. TGF- is
overproduced in keloids with a loss of feedback control during the production of collagen and
the extracellular matrix. Fibroblasts in keloids have a greater number of growth factor receptors
and thus an increased sensitivity to growth factor stimulation, particularly platelet-derived
growth factor and TGF- (Al-Attar et al., 2006). The use of topical agents such as retinoids to
treat acne may help to modulate the course of wound healing and prevent scar formation (Ogawa
et al., 2009).
80
3.4 Psychological morbidity

The adverse psychosocial effects of acne and scarring as its sequelae are very common
because of the high prevalence of acne, especially among adolescents. The persistent physical
complications of acne include post-inflammatory erythema, PIH and various types of scarring,
and the prolonged alteration of physical appearance of the affected areas are a source of
psychological distress (Layton, 2001). The associated effects of acne and its complication that
have been reported include poor self-esteem, anxiety, depression, suicidal ideation, social
isolation, altered perception of body image and emotional instability (Koo, 1995).
3.5 Treatment options and limitations

The treatment of scarring is a challenge to clinicians because the common long-term
consequences and outcomes of acne are variable and depend on the type and extent of the scars.
Patients who have nodulocystic acne with intense visible inflammation are more liable to
develop scarring, particularly when there is a delay in the effective treatment of the problem. In
contrast, scarring may occur early regardless of the severity of the acne (Kim et al., 2002). Thus,
the early treatment of acne is of paramount importance to reduce the risk of scarring. Retinoids
have been shown to reduce the inflammation in acne by the inhibition of leukocyte migration in
the skin, and oral isotretinoin reduces the expression of MMP-9 and MMP-13 in the sebum of
acne patients, which may prevent acne scar formation by shifting the balance of MMPs and
tissue inhibitors towards the normal (Thiboutot et al., 2009).
The different treatment options for atrophic scars include subcision, dermabrasion,
chemical peeling, ablative laser resurfacing, and non-ablative and ablative fractional laser
81
resurfacing. These options need to be discussed with individual patients with regard to their
respective risks and benefits prior to the start of any type of treatment regime. Multiple
modalities are often combined to optimise the treatment outcome. Because the apex of ice-pick
scars often extends beyond the effective depth of most resurfacing tools, a punch excision can be
performed prior to the resurfacing procedure. Tethering to the subcutis by fibrous adhesions in
the rolling scars can be released using a subcision technique. Shallow boxcar scars can be
improved by various skin resurfacing techniques, including chemical peeling and laser ablation.
Soft-tissue fillers that were initially used for facial contouring and volume augmentation can be
used to correct atrophic acne scars. Common temporary fillers include hyaluronic acid (e.g.,
Restylane, Juvederm), poly-L-lactic acid and calcium hydroxylapatite, and appear to be most
effective in boxcar scars. Dermabrasion involves the mechanical removal of the epidermis and
papillary dermis to create a newly contoured, open wound that can heal by secondary intention.
Re-epithelisation of dermabraded skin occurs by the upward migration of cells from the adnexal
structures, such as the pilosebaceous units (Tosti et al., 2010).
Carbon dioxide and Er:YAG lasers are traditional ablative devices that are used for the
improvement of atrophic acne scars. The laser skin resurfacing can be achieved through the
evaporation of water and tissue desiccation by the specific absorptive properties of water. The
ablation of the superficial skin layers and its residual thermal damage to the dermis lead to
collagen denaturation. The remodelling of the wound using neocollagenesis can improve the
textural abnormalities of the atrophic acne scarring. A case was also reported in which lowfluence Er:YAG laser resurfacing was used for inflamed cystic acne in Asian skin (Singh et al.,
2006). Traditional laser resurfacing is associated with a notable risk of complications, including
82
infection, scarring, hyperpigmentation and hypopigmentation, and should therefore be reserved

for deeper atrophic scars because of the prolonged recovery time and the high risk of adverse
effects, especially in darker phototype IV-VI skin (Nanni & Alster, 1998). Hyperpigmentation
after carbon dioxide laser resurfacing was seen in 37% of patients, with a higher rate in darker
skin phototypes. Thus, non-ablative or fractional devices may be adequate for milder and more
superficial atrophic scars. However, the use of oral isotretinoin for acne during the previous 6
months is a contraindication to laser resurfacing because of the risk of keloid formation after the
procedures.
Non-ablative laser resurfacing for acne scars focuses on remodelling the dermal
subsurface, and has the advantage of a minimal recovery time and a lower risk of adverse
effects than the use of ablative lasers. Its mechanism of action is through the selective heating
of the water in the upper dermis, subsequent collage denaturation and dermal remodelling
while the epidermis is preserved by cooling devices (Tanzi & Alster, 2004). The mid-infrared
lasers discussed in the previous chapters in the context of treating active acne can also be used
for non-ablative resurfacing of acne scars (Chua et al., 2004). The non-selective absorption of
water and the deeper penetration of the mid-infrared laser lead to a bulk tissue heating effect
with subsequent dermal remodelling and neocollagenesis; hence these lasers can be used for
acne scarring. Although the long wavelength of the mid-infrared laser is expected to be of
advantage in darker skin, the risk of PIH after the use of a 1450-nm diode laser with dynamic
cooling is significant in Asian patients. The total duration of 40-60 ms for the cryogen spray
probably contributes to the high PIH rate of 39% in Asian patients (Chua et al., 2004). In
general, the degree of improvement in acne scars after non-ablative skin rejuvenation is often
sub-optimal, and ablative resurfacing remains the preferred treatment. More recently,
83
fractional resurfacing has become a feasible alternative to ablative resurfacing for the treatment
of acne scarring.
The standard treatment for keloids and hypertrophic scars that are complications of acne
is similar to that of other excessive scarring that results from trauma and surgery, and includes
occlusion with silicone gel, intralesional corticosteroids, intralesional 5-flurouracil, PDL,
cryotherapy and surgical excision followed by radiotherapy. Corticosteroids decrease collagen
synthesis and inhibit fibroblast proliferation (Tosti et al., 2010). PDL has been shown to downregulate the expression of TGF- and up-regulate MMP-13, which results in reduced fibroblast
proliferation and collagen type III deposition (Kuo et al., 2005). This laser improves erythema
and vascularity as well as scar texture and elevation. Radiotherapy is reserved for refractory
keloids; it penetrates into the dermis and inhibits fibroblast proliferation effectively, but its
usefulness is limited by its adverse effects, which include mottled dyspigmentation, radiation
dermatitis and a low risk of carcinogenesis (Ogawa et al., 2009). A combination of the various
treatment modalities is often adopted to achieve the optimal cosmetic results.
3.6 Concept of fractional resurfacing for acne scars

Fractional photothermolysis is a technique developed by Anderson and Manstein that
only treats fractions of the skin and does not destroy the entire layer (Manstein et al., 2004).
Lasers are used to induce zones of microscopic thermal injury that comprise marked areas of
tissue denaturation of 50100 m in diameter, which are surrounded by normal viable tissue.
The adjacent viable tissue allows the rapid lateral migration of keratinocytes, leading to the
complete re-epithelialisation of the epidermis within 24 hours. Hence, skin remodelling can be
84
achieved with a minimal risk of complications and a high degree of efficacy. During each
treatment session, a variable proportion of the skin is treated, the extent of which is primarily
determined by the density settings of the device and the number of passes. Usually, about 1632% of the skin surface is targeted per treatment session. After fractional resurfacing, the stratum
corneum usually remains intact, and the risk of adverse effects associated with ablative skin
resurfacing, including infection and scarring, are therefore reduced. In addition, the depth of
collagen remodelling that is associated with the use of fractional resurfacing can be deeper than
the conventional aggressive laser resurfacing procedure (700 m compared with 300 m).
Fractional photothermolysis has the advantage of both being as efficient as traditional

ablative or laser resurfacing devices and combing a rapid recovery with the safety of nonablative lasers. The technology can generally be divided into ablative fractional and non-ablative
fractional laser resurfacing based on the extent of tissue damage. Superficial scarring may be
more amenable to treatment with a fractional non-ablative device than ice-pick and deep acne
scars. Ablative devices use a CO2 laser and therefore penetrate deeper into the scars during
resurfacing than non-ablative systems.
The 1550 nm erbium-doped fibre laser (Fraxel SR 750, Solta Medical) is the first
available system that can induce arrays of columns of thermal damage, known as microscopic
treatment zones (MTZs). The newer generation, called Fraxel Re:store, can penetrate deeper
into the dermis and avoid the use of blue dye as a tracking system in the treatment area. CO2
laser is also used for fractional resurfacing and penetrates to a deeper level than the erbium laser.
The unique feature of fractional resurfacing is its ability to induce thermal damage and
85
subsequent dermal remodelling in columns, thus leaving the adjacent tissue surrounding each
MTZ intact and facilitating subsequent healing (Manstein et al., 2004; Laubach et al., 2006).
Asian patients have higher epidermal melanin content and are more liable to develop PIH
following laser resurfacing. Non-ablative fractional laser resurfacing can be used in all skin
types, but special considerations should be given to darker skin types with regard to the risk of
PIH. The percentage of treatment areas directly affected by the laser is related to the total MTZ
density, which is determined by multiplying the MTZ density per pass by the total number of
passes. The selection of energy level is based on the desired depth of penetration, which
corresponds to the depth of the acne scars. Treatment densities and fluences can be adjusted
according to the extent of acne scarring, its anatomical location and skin tone. The energy and
the MTZ density may be limited by patient discomfort, and the additional use of an air-cooling
system may lead to greater patient tolerance (Fisher & Geronemus, 2005). Because of the
considerable degree of discomfort caused by high-energy settings, the use of topical and
parenteral anaesthetics is frequently indicated. A typical fractional laser system incorporates an
air-cooling device from Zimmer to cool the skin concomitantly and help the patients to tolerate
higher energy levels, thus facilitating the treatment of the deeper parts of acne scars. An early
study evaluated the effect of three treatments using this laser at monthly intervals on mild to
moderate atrophic acne scars in 53 patients and found that clinical improvement ranged from 51
to 75% in 90% of the subjects (Alster et al., 2007). The side effects were temporary erythema
and oedema.
86
The common side effects of non-ablative fractional photothermolysis comprise transient

erythema and mild oedema during the first few days. Transient tiny crust formation and apparent
bronzing secondary to transepidermal extrusion of concentrated melanin usually last for 1-2
weeks. Transient PIH can occur in patients with darker skin types and is related to the total MTZ
density rather than to the energy of the fractionated laser. The use of epidermal air cooling may
also decrease the incidence of post-procedural dyschromia (Chan et al., 2007). The revolutionary
advances in fractional technology have resulted in the development of new devices with different
laser and RF modalities. Other ablative fractional techniques include CO2 and Er:YAG lasers
which offer potentially greater improvement but with the drawbacks of longer recovery time and
a higher incidence of side effects.
The fractionated RF induces deep dermal heating but has less of an effect on the
epidermis. The combination device of a fractionated mid-infrared diode laser and RF energy with
a built-in contact cooler has been used to treat wrinkles and acne (Kim, 2008). A combination of
fractional bi-polar RF and a fractional diode laser plus RF energy can be used to improve acne
scars by the enhancement of collagen production in the scar indentation and by causing ablation
and resurfacing of the scar edges. I investigated the safety and efficacy of this combined
treatment on acne scars in Asians, with the aim of lowering the risk of PIH and achieving a level
of efficiency comparable with that of standard laser ablation using these devices.
87
Chapter 4
Epidemiological Study of Acne in Hong Kong
88
4.1 Introduction
Acne vulgaris is a common skin condition that presents as a chronic inflammatory
disease of the pilosebaceous units and often begins in adolescence but is not confined to this
period. In studies on the prevalence of acne in adolescents and young populations, the frequency
varied from 27.7% to nearly 91.3% (Kilkenny et al., 1998). The diagnostic criteria of acne vary
between studies and the prevalence is thought to differ between ethnic groups and countries. It
causes significant psychological morbidity including depression, anger, low self-esteem and
social impairment (Koo, 1995). Data on the population-based prevalence on acne in Hong Kong
adolescents and young adults were lacking, and information regarding the prevalence, the
psychological effect and the health-seeking behaviour was relatively scarce among Chinese.
These data are useful in estimating the costs to and use of health services. They can also be used
as a guide to determine whether there is a need to educate those who are affected and those who
provide care for them. This was the first community-based study to determine the prevalence and
severity of acne in a representative sample of adolescents and young adults in Hong Kong.
Information was also collected with respect to whether treatment had been sought for acne and
through which channels. Knowledge on and the psychological effect of acne was also assessed in
this study.

This cross-sectional study was a telephone survey using questionnaires on the prevalence
of acne in Hong Kong adolescents. The contents of the questionnaire included gender, age,
frequency of acne (including a question on whether the subjects suffered from acne at the
moment), the aetiology of acne, psychological disturbances related to acne, whether any and
89
what form of treatment had been used, and the efficacy of the treatment adopted (Appendix I).
First, telephone numbers were selected at random from the Hong Kong Residential Telephone
Directory. In the second stage, one family member aged between 15 and 25 years was further
selected for the interview after the chosen families had been successfully contacted by telephone.
Ten thousand telephone numbers were randomly selected in the first step, from which
5522 families were successfully contacted. Finally, a sample of 552 subjects in the selected age
group agreed to participate in the telephone interview and completed the questionnaire. The
response rate of this survey after the target population had been contacted was 56.3%. Data
collected from the questionnaires were entered into a computer and the Statistical Package for
Social Sciences (SPSS) was used for analysis. Prevalence estimates were expressed in terms of
prevalence rates with 95% confidence intervals (CIs).
Validation of the questionnaire

To assess the accuracy of self-reported acne during the telephone interview, I randomly
selected 22 subjects aged between 15 and 25 years from our out-patient dermatology clinic to
determine the presence of clinically active acne during consultation. The diagnostic criteria for
acne included the presence of papules, pustules, nodules and comedones. Subjects were asked
whether they thought that they had acne at the time of the assessment, before dermatological
examination by one of the authors. There was good agreement between subjects self-reports and
the clinicians diagnoses of acne (positive predictive value, 81%; negative predictive value,
100%).
90
A further 25 students aged between 15 and 25 years were also randomly selected from the
nursing school and the presence of acne scarring and pigmentation was assessed by the same
author after the self-reporting of these complications by the students. The agreement on the
judgement of scarring and pigmentation between the subjects and the clinician was satisfactory
(positive predictive value, 75%; negative predictive value, 100%), indicating that the
questionnaire was a useful tool to screen for scarring and pigmentation.
4.3 Results
In total, 552 adolescents (56.3%) aged 15-25 years (272 boys and 280 girls), from 1120
selected suitable subjects were successfully interviewed by telephone in this survey.
4.3.1 Prevalence in Hong Kong

Overall, the prevalence of self-reported facial acne in the 15-25 age group (adjusted for
the age and sex distribution of the total adolescent population in Hong Kong) was 91.3% (95%
CI, 88.9-93.7) and 52.2% (95% CI, 48.0-56.4) had acne at the time of the interview. Acne was
more common in boys (53.6%) than in girls (50.8%), but the difference was not statistically
significant. There was higher prevalence in the 15-20 age group (55.9%) than in the 21-25 age
group (43.5%; p= 0.012).
4.3.2 Frequency of acne

Frequent facial acne was reported in 14.3% of adolescents; 40.9% occasionally had acne
(less than once per week) and 36.1% seldom had acne (less than once per month). The sex and
91
age difference in the frequency of acne was negligible, although there was a trend towards more
frequent acne among the younger age group (15-20 years).
4.3.3 Complications of acne

The presence of acne scars or PIH macules on the face was considered to be a reflection
of severity of acne and its physical effect. Acne scarring and hyperpigmentation was reported in
52.6% (95% CI, 48.2-57.0), and was more commonly reported by girls than by boys (57.0% and
48.0%, respectively); the sex difference was statistically significant (p=0.05). The proportion of
subjects with acne scars and pigmentation increased from 50.3% at 15-20 years to 57.8% at 2125 years, but the difference was not statistically significant.
4.3.4 Public knowledge of the aetiology and treatment options of acne

Of the respondents, 24.4% and 20.5% knew that acne was due to increased sebum
production and blockage of the pilosebaceous units, respectively, and 7.8% were aware of the
role of a bacterium in the causation of acne. There was no significant gender difference in this
aspect of knowledge. However, up to 12.4% of the replies indicated a total lack of knowledge of
the causes of acne.
4.3.5 Psychological effect of acne

Of the respondents, 26.6% were disturbed psychologically at least to some extent (19.3%
of boys and 33.7% of girls) and 4.9% were significantly bothered by acne; 83% of the stress was
related to physical appearance. Adolescent girls were more susceptible than boys to the negative
92
psychological effects of acne (p<0.001). No significant difference was detected between younger
and older age groups.
4.3.6 Health-seeking behaviour in acne patients

Of the 504 respondents, only 2.4% of those with acne had sought advice or treatment
from their family doctors or dermatologists; 39.7% of boys and 27.0% of girls had done nothing
to improve their acne, 31% had used skin care products obtained from sources other than a
pharmacy to treat their acne and 20.2% had the habit of picking their spots; 77.5% of the
respondents had spent less than HK$100 on each course of anti-acne treatment, 17.6% had spent
between HK$100 and HK$500 on each course and 41.5% had used medications from a
pharmacy for acne, 94.7% of which were for topical use; 88.8% thought that their acne was
improved by these medications to various extents, but the recurrence of acne was noted
afterwards in 58.7%; 65.0% were not aware of the presence of highly efficacious treatments for
acne vulgaris.
4.4 Discussion
This was the first Asian community-based study to investigate the prevalence and
complications of acne among adolescents and young adults. Previous studies in Asian countries
focused on different age groups or hospital-based populations and thus did not truly reflect the
dimensions of acne prevalence (Chua-Ty et al., 1992; Goh & Akarapanth, 1994; Fung & Lo,
2000). Our study showed that the prevalence of self-reported acne was 91.3%, consistent with
other Caucasian population-based studies which reported a prevalence between 81 and 95% in
males and 79 and 82% in females (Lucky et al., 1991; Lello et al., 1995) (Table 4.1). Another
93
Table 4.1. Comparison of the prevalence of facial acne in adolescents between different countries.
Hong Kong
(present
study)
Singapore
Australia
Peru (Freyre, Glasgow/UK
Brazil
Mexico (Ruiz- Hong Kong
(Goh &
France (Daniel
(Kilkenny et Rebaza et al., (Rademaker et
(Bechelli et al., Maldonado et (Fung & Lo,
Akarapanth,
et al., 2000)
al., 1997)
1998)
al., 1989)
al. 1977)
2000)
1981)
1994)
Study population
(no.)
522
2491
2214
2014
9273
9955
10,000
1006
923
Age range (years)
15-25
10-19
12-18
12-17
0-16
6-16
0-18
8-21
11-18
Study design
Cross
sectional
Cross
sectional
Cross
sectional
Cross
sectional
Retrospective
Cross
sectional
Retrospective
Cross
sectional
Cross
sectional
Data source
Communitybased
School
student
School
student
School
student
Skin clinic
School
student
Skin clinic
Student health
centre
School
children
Prevalence (%)
91.3
81
72
Point prevalence
(%)
52.2
41.7
2.7
2.5
9.9
72
94
community-based study in Australia suggested that the prevalence of acne was lower among
Asians than Australians (Kilkenny et al., 1997). Our study investigated an older age group (1525 years), whereas the age of their study population ranged from 12 to 16 years. As suggested by
the Australian authors, young Asians may be less likely to report acne due to cultural bias
(Kilkenny et al., 1997).
The point prevalence of acne in this study was 53.6% in boys and 50.8% in girls, with a
higher prevalence noted in the younger age group (15-20 years). A previous study conducted in
Leeds, United Kingdom, also showed that 18-year-olds had the highest prevalence of clinical
acne, which then declined in both men and women (Cunliffe & Gould, 1979). This observation
may be due to the decline in serum levels of dehydroepiandrosterone sulphate that subsequently
leads to the resolution of acne in adults. In addition, pilosebaceous follicles may be more
sensitive to comedogenic stimuli during adolescence due to the lack of an effective stratum
corneum barrier (Thiboutot & Lookingbill, 1995).
A shortcoming of my study was the lack of objective assessment and its self-reporting
nature. Our results were based on the perception of the subjects themselves of the presence or
absence of acne rather than a clinical evaluation. Indeed, unlike the previous Australian study,
which indicated that moderate to severe acne was more common in males, self-reporting may
have led to a higher prevalence among girls in our study because they tend to be more conscious
of their appearance (Kilkenny et al., 1998). Nevertheless, our validation study demonstrated a
high degree of sensitivity and specificity, suggesting that the questionnaire was valid in this type
of population study.
95
In this study, 52.6% of subjects reported scarring and pigmentation due to acne, in
contrast to the 14% of women and 11% of men who had acne scarring in a survey of adults
(Goulden et al., 1999). The trend of increased scarring reported with age is consistent with the
direct relationship between the degree of scarring and the duration of the disease (Layton &
Cunliffe, 1993). An increased risk of PIH was to be expected in our study population because of
their dark Asian skin type (Fitzpatrick III/IV) (Child et al., 1999). Indeed, a previous report
indicated that there is a significantly higher degree of PIH among dark-skinned patients after
carbon dioxide laser resurfacing (Nanni & Alster, 1998). To reduce the risk of PIH, the
management regime for Asian patients must be modified. While tetracycline-type medications,
especially minocycline, are effective anti-acne agents, they may be associated with an increased
risk of hyperpigmentation, particularly in oriental skin types, due to their phototoxic properties
(Jimbow & Jimbow, 1989; Dwyer et al., 1993). This also applies to both topical and systemic
retinoid therapy. The avoidance of and protection against sunlight is therefore essential. Agents
such as erythromycin that carry a lower risk of hyperpigmentation can be used as a first-line
treatment in patients who show evidence of phototoxicity. However, there is a worldwide
increase in the resistance of P. acnes to erythromycin and clindamycin and their use should
therefore be combined with other agents that have both anti-acne and whitening properties such
as -hydroxy acid and azelaic acid (Eady et al., 1993).
Another interesting aspect demonstrated in our study was the low level of awareness in
the general public with regard to the aetiology and treatment of acne. Fewer than a quarter of the
respondents were able to indicate the correct aetiology of acne, and more than half of them did
not know that effective treatments were available. Despite the fact that a considerable proportion
96
of the adolescents were bothered psychologically by the presence of acne, the majority (33.1%)
did not take any action to improve their acne and only 2.4% had sought advice from clinicians.
The consultation rate was low, compared with a study in France where 27% of subjects received
treatment from dermatologists (Daniel et al., 2000). This might be due to differences in the
accessibility of specialist care. The dermatologist-to-patient ratio in Hong Kong is 0.83 per
100,000 of the population whereas the ratio in the United States is 3.3 per 100,000 of the
population (Chan et al., 2000; Resneck, 2001). Inadequate public awareness was also reported in
acne studies in the United Kingdom and Australia (Cunliffe & Gould, 1979; Layton & Cunliffe,
1993).
In summary, this study demonstrated that acne is very common among Hong Kong
adolescents and young adults. Further education on acne is necessary both in schools and for the
general public so that people know where to seek appropriate advice and receive early effective
treatment. Because acne scars are difficult to treat even with modern, expensive interventional
therapy, every effort should be made to reduce the complications of acne in adolescents and thus
improve their overall psychosocial well-being.
97
Section B: Lasers and Photodynamic Therapy

for Acne
98
Chapter 5
Treatment of Inflammatory Facial Acne with
a 1450 nm Diode Laser in Type IV to V Asian Skin
using an Optimal Combination of Laser Parameters
99
5.1 Introduction
In a community-based epidemiological study of Hong Kong adolescents and young
adults aged 15-25 years, the prevalence of self-reported acne vulgaris was 91.3% (Yeung et al.,
2002). The point prevalence was 52.2%, and 26.6% of the respondents were psychologically
disturbed by acne, indicating that acne and its complications are common problems. Lasers and
light sources are now being used as therapeutic options in the treatment of acne for better
compliance and sustained effectiveness. Blue light, red light, and PDT have been studied for the
treatment of acne (Hongcharu et al., 2000; Elman & Lebzelter, 2004; Pollock et al., 2004; Gold
et al., 2005). The 532 nm potassium titanyl phosphate (KTP) laser, PDL (575 nm & 595 nm),
1320 nm neodymium:yttriumaluminiumgarnet (Nd:YAG) laser, 1540 nm erbium glass laser
have also been used with variable efficacy (Baugh & Kucaba, 2005; Bhardwaj et al., 2005;
Angel et al., 2006; Deng et al., 2009; Orringer et al., 2007).
KTP 532 nm laser has been tested for treatment of acne as green light at 532 nm activates
bacterial porphyrins and has greater optical penetration depth than blue light. 35% and 21%
mean reduction of acne severity scores in 26 patients were observed at 1 week and 4 weeks after
4 sessions of the KTP 532 nm laser treatment with contact cooling in a split-face study (Baugh &
Kucaba, 2005). No side effects were reported. For PDL, conflicting results are reported as one
randomized controlled study using a sham placebo treatment reported statistically significant
efficacy on inflammatory lesions, whereas another randomized controlled spilt-face study did not
find significant differences when compared with untreated side (Orringer et al, 2004; Seaton et
al., 2003).
100
There are reports and case series of effective treatment of inflammatory acne in Asians
(Fitzpatrick skin type IV) with the low-fluence 1064 nm Nd-YAG laser alone once weekly for 10
weeks or combined with a long-pulsed 532 nm KTP laser twice weekly for 3 weeks (Ballin &
Uebelhoer, 2009; Jeon et al., 2010). An average of 55% lesion count reduction was achieved 1
week after the last treatment at low fluence with high cumulative total dose of 1064 nm laser in
this series, apart from inducing dermal collagen production and reducing scarring from acne.
1320 nm Nd:YAG laser penetrate and injure the dermis with epidermal dynamic cooling
system. A series of three laser treatments led to temporary 27% reduction of open comedones
only compared with the 12% reduction in the untreated side in a split-face study (Orringer et al.,
2007). No significant differences in inflammatory lesion count and sebum production between
the treated and control sides were observed. This infrared laser might damage the epidermis at an
energy level adequate to alter the sebaceous gland significantly. The fractional infrared laser can
induce MTZs at controllable depth in the dermis with accelerated epidermal healing (Jih &
Kimy-Aiasadi, 2008). There were statistically significant reduction in inflammatory and noninflammatory lesion counts and sebum excretion after 6 treatments at 2-week intervals with the
fractional 1320 nm Nd:YAG laser in a pilot study (Deng et al., 2009).
Similar to the 1320 nm Nd:YAG laser system, the 1540 nm erbium glass laser is another
mid-infrared range laser that targets intracellular water to a depth of 0.4 mm to 2 mm, resulting
in selective dermal heating of sebaceous units and the surrounding dermal matrix. Because
minimal absorption of energy by melanin occurs at this wavelength, safer treatment of darker or
tanned individuals would be expected. Four treatments of 1540 nm erbium:glass laser with
101
contact cooling performed at 4-week intervals in 25 patients with at least moderate facial acne
resulted in 71% mean reduction in acne lesion counts at 6-month follow-up (Angel et al., 2006).
In general, nonablative mid-infrared lasers have been found to reduce acne lesions, improve skin
oiliness and acne scars.
The infrared pulses produced by the 1450 nm laser system are absorbed by water present
in the skin tissue, and the 1450 nm wavelength heats the sebaceous gland in situ at 200-400 m
beneath the skin surface in the superficial dermis (Paithankar et al., 2002). The mechanism of
action of 1450 nm laser treatment of acne is hypothesised to be thermal injury to the sebaceous
follicles in the heated zone. The thermal alteration of sebaceous glands may lead to a reduction
in sebum secretion and thus a decrease in inflammatory acne lesions (Perez-Maldonado et al.,
2007). A dynamic cooling device (DCD) protects the epidermis of the targeted skin from thermal
injury and also reduces the pain during laser treatment. Previous clinical studies in Caucasians
have demonstrated significant reductions in the acne lesion count with the use of 1450 nm laser
(Paithankar et al., 2002; Friedman et al., 2004). Treatment-related pain was well tolerated, and
the adverse effects were limited to transient erythema and oedema at the treatment sites.
Although previous studies have demonstrated that 1450 nm diode laser is useful for the
treatment of acne, the reaction to laser of darker skin types often differs from that of Caucasian
skin types. A higher risk of hyperpigmentation after light-based therapy has been noted in Asian
skin, which is related to the richer melanin content in the epidermis (Chan, 2005). The 1450 nm
diode laser coupled with a DCD is associated with a significant risk of PIH (7-39%) in darker
skin types (Tanzi et al., 2003; Chua et al., 2004; Tanzi & Alster, 2004). It has been postulated
102
that excessive cooling due to the use of sequential cryogen spurts, which prolong the overall
cooling time, may be the main factor that leads to the high risk of PIH in Asian patients after
treatment with this laser (Chua et al., 2004; Chan, 2005). In place of the conventional singlepass, high-energy (13-14 J/cm2) protocol of 1450 nm laser treatment, a different approach using
double-pass, low-energy (8-11 J/cm2) treatment was adopted in a pilot study to minimise the pain
associated with the treatment in subjects with Fitzpatrick skin types I-III (Bernstein, 2007). Few
published studies have investigated the use of the 1450 nm diode laser with consistent laser
parameters to treat acne safely and effectively in darker skin types. The objectives of the present
study were a) to determine whether the PIH associated with the use of this laser can be
minimised by lowering the fluence and spray duration of DCD delivered in multiple passes in
patients with darker skin types of IV to V without compromising the clinical efficacy of the
treatment on facial inflammatory acne; and b) to define the optimal laser and cooling parameters
of the 1450 nm diode laser with dynamic cooling to achieve the most effective outcome while
minimising the risk of PIH, which was predetermined in a phase 1 forearm study to minimise
PIH and evaluate its safety and effectiveness for the treatment of mild to moderate acne in Asian
adolescents and adults.
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5.2 Subjects and methods

5.2.1 Subjects
A group of 26 Chinese individuals (16 men and 10 women) with Fitzpatrick skin types
IV or V and at least five active inflammatory facial acne lesions at baseline were enrolled. The
age range was 19-46 years (mean, 256 years). The study device was a 1450 nm diode laser
coupled with a DCD (Smoothbeam, Candela Corp., Wayland, MA, USA). The exclusion criteria
were a history of acne treatment with oral isotretinoin during the previous 6 months, the use of
any topical or systemic anti-acne medication 2 or 4 weeks before laser treatment, respectively, a
history of developing hypertrophic scars or keloids, and pregnancy and lactation in women.
Subjects were not allowed to use other acne treatments, including topical or oral agents, during
the treatment or the 6-month follow-up period. Written informed consent was obtained from all
subjects, and the study protocol was approved by Western Institution Review Broad (WIRB,
Inc., Olympia, WA, USA).

In a phase 1 forearm study, the optimal parameters of laser fluence, the duration of DCD
spray and the number of passes were determined to minimise PIH. The inner sides of the forearm
of the 15 recruited subjects were treated with the 1450 nm diode laser with 6-mm spot size. The
area of treatment zones and anatomical landmarks (distal ends of the ulna and radius) were
marked with a translucent paper to allow consistency for future assessment. Nine sites were
tested using the following parameters (Table 5.1).
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Table 5.1. Different combination of laser fluence, duration of DCD, the number of passes are
used to detect PIH at the 9 tested sites of the forearm.
Site
Fluence
J/cm2
DCD
Passes
(ms)
Spot size
mm
spray
21
23
25
10
21
10
23
10
25
21
23
25
105
Assessments of adverse effects were performed before treatment and then every week for
a month. A hand-held spectrophotometer (CM 503c, Minolta, Osaka, Japan) was used for the
objective assessment. Clinical digital photographs of all patients were also taken before
treatment and during each follow-up. Two independent clinicians assessed the photographs for
side-effects, particularly PIH, and scarring on the nine sites on forearm.
Based on the findings of the phase 1 study, no PIH was observed with any of the nine
combinations of parameters in all subjects. Thus, in a phase 2 study, the entire face was treated
with non-overlapping single pulses for three passes at a fluence of 8 J/cm2 every 3-4 weeks. The
DCD was set at 25 ms to cool the epidermis. Topical lidocaine 5% (Ela-Max, Ferndale
Laboratories, Ferndale, MI, USA) was applied under occlusion for at least 30 min before the
laser treatment. Subjects received a total of four full-face 1450 nm diode laser treatments with a
6-mm spot size at 3-4 weekly intervals. The entire face was treated with non-overlapping single
pulses of this laser for three passes at a fluence of 8 J/cm2, and the DCD was set at 25 ms to cool
the epidermis. Subjects with moderate to severe acne were treated with the same laser parameters
as those used for the treatment of mild acne. The subjects were instructed on post-laser care of
the treated areas, including the avoidance of and protection against sunlight.
5.2.3 Assessment
A Canfield Visia CR system was used to assess the subjects before each treatment, and 1,
3 and 6 months after the last treatment. Three standard close-up photographs (right, left and
central) were taken using a standard light, cross-polarisation, parallel polarisation and UV light.
106
The images were assessed by two blinded investigators who did not participate in the treatment
of the subjects. The evaluation of efficacy was based on close-up photographs taken before the
first treatment (baseline), before each treatment and at follow-up visits. Inflammatory lesions,
including papules, pustules, cysts and non-inflammatory acne elements, on the face were
counted. The pigmentary changes after laser were also assessed based on the images. At each
treatment and follow-up visit, the presence and severity of any adverse effects of treatment were
determined. The side effects that were evaluated at each visit included pigmentary disturbance,
erythema, oedema, burning, crusting, blistering and scarring.
An indirect measurement of fluorescence on the skin was used to assess the bacterial
porphyrin fluorescence at baseline and after treatments for three areas of the face: overall, nose
and cheeks. The emission of fluorescence has been attributed to bacterial coproporphyrin III and
PpIX (Lucchina et al., 1996). The intensity of fluorescence is related to the density of the P.
acnes population. The density of auto-fluorescent dots was rated according to the following
score: 0=none, 1=mild, 2=moderate and 3=extensive.
The subjects were also asked for their subjective assessment of the global improvement
in their facial acne, acne scarring, oiliness and pore size, compared with baseline, on a five-point
scale of 0 to 4 as follows: 0: worsening; 1: no improvement; 2: mild improvement; 3: moderate
improvement; and 4: marked improvement (Appendix II). Immediately after treatment, the
subjects were asked to rate their level of pain on the Visual Analog Scale (VAS) (McCaffery,
1999). The VAS rates pain on a scale from 0 to 10, where 0 equals no pain and 10 equals the
107
worst possible pain. A number was obtained by measuring up to the point the patient had
indicated.

A Sebumeter (SM 810, Courage and Khazaka, Cologne, Germany) was used to measure
facial sebum secretion (Youn et al., 2005). The device was a matte synthetic tape pressed on skin
using a constant force of 10 N for 30 s to measure the amount of sebum. One measurement was
taken on the forehead (1 cm above the gabella in the midline) and one on the right nasolabial fold
(1 cm lateral to ala nasi). The evaluations were made in a climate-controlled facility at a
temperature of 20-24oC and a relative humidity of 40-60%. Subjects were asked to arrive 30 min
before the evaluation time to adjust to the surrounding conditions. They were also instructed not
to wash their face at least 4 h before the evaluation.
Data were analysed to determine the reduction in the mean count of inflammatory and
non-inflammatory lesions as determined from standardised photographs by two blinded
assessors. For the purpose of statistical analysis, subjects were divided into categories of mild
(less than or equal to 15 lesions) and moderate to severe (more than 15 lesions). The efficacy of
the 1450 nm diode laser at decreased laser energy and duration of DCD spray in the treatment of
mild and moderate to severe facial acne was compared. The effects of treatment were determined
based on statistical analysis using the Wilcoxon signed rank test to compare the lesion counts
from each follow-up visit with those at baseline. Statistical significance was defined as a p-value
of less than 0.05.
108
5.3 Results
When the 1450-nm diode laser was used as a monotherapy with three passes of low
fluence at 8 J/cm2 and a correspondingly short duration of DCD spray at 25 ms, all subjects with
moderate to severe acne had a reduction in their mean inflammatory lesion count. All 26 subjects
underwent four treatments.
Subjects were equally divided into the group with mild facial acne involving 15
inflammatory lesions (n= 13; mean age, 25 years; 5 males) and the group with moderate facial
acne involving >15 inflammatory lesions (n=13; mean age, 25 years; 11 males). The mean
inflammatory lesion counts before treatment were 27.99.1 (range, 16-45; median, 27) for the
moderate to severe group and 8.82.8 (range, 5-12; median, 8) for the mild group. Five subjects
(two in the mild group and three in the moderate to severe group) did not return for the final
follow-up visit for non-medical reasons.
The percentage reduction in mean inflammatory acne lesions from baseline only reached
statistical significance in the group with moderate acne, in which the lesion count decreased from
27.99.1 to 21.25.9 (24% reduction) as early as after the first treatment (p<0.01). With
subsequent treatments, improvement was maintained with mean reductions from 26% to
20.65.8 after two treatments (p=0.01), 33% to 18.67.5 after three treatments (p<0.01) and 29%
to 19.910.8 4 weeks after the last treatment (p=0.046). There was a further reduction of 40% to
16.78.1 at the 6-month follow-up (p=0.03). Figure 5.1 shows the serial percentage change in
109
mean lesion counts by photographic assessment and Figures 5.2 and 5.3 show representative
clinical photographs of the treated subjects 1 month and 3 months post-treatment, respectively.
No notable reduction in mean inflammatory lesion counts was observed throughout the
treatment period in the group with mild acne. Mean lesion counts changed from 8.12.8 to
9.05.7 (11%) after one treatment (p=0.65). After the second, third and fourth treatments, the
mean lesion count actually increased to 11.18.2 (37%; p=0.28), 8.95.7 (10%; p=0.73) and
13.94.8 (72%; p=0.03), respectively. No significant change in acne lesion count (7.64.3) was
observed at the 6-month follow-up in this group (p=0.72).
On the assessment of non-inflammatory acne 1 month after the last treatment, a mean
clearance of 15% from 17.49.3 to 14.77.9 was observed in the group with moderate to severe
acne (p=0.033) and an increase of 31% from 8.85.5 to 11.62.1 (p=0.5) was found in the group
with mild acne. Evaluations at 3 months and 6 months post-treatment showed non-significant
decreases of 11% to 15.69.0 (p=0.26) and 21% to 13.7 5.8 (p=0.16), respectively, in the
moderate group.
Of the subjective assessments of facial acne made by all subjects, 62% perceived an
improvement in their facial acne after the first treatment, which was maintained after the second
treatment (81%), the third treatment (62%), at the 1-month follow-up (59%), at the 3-month
follow-up (68%) and at the 6-month follow-up (57%). Overall, 19-31% of the subjects graded
their acne improvement as being moderate to marked throughout the study period. Although
there was no objective improvement of acne scars or pore size as determined by the assessors
110
who compared the baseline to subsequent photographs, 58% and 52% of subjects rated at least
mild improvement in their acne scarring at the 3-month and 6-month follow-up visits,
respectively; four of 21 subjects (19%) rated a moderate improvement of their acne scars at the
6-month follow-up visit.
Sebum production measured by the Sebumeter at the nasolabial fold and forehead began
to decrease after the first treatment and improvement was maintained up to the 6-month followup visit in most subjects in both the mild and moderate groups. No statistically significant
difference in the mean Sebumeter readings was observed between the two groups, and the data
were therefore analysed altogether. A significant reduction in sebum at the nasolabial fold from
21573 g/cm2 at baseline to 17180 g/cm2 (21%) was seen after the first treatment (p=0.019)
and a further reduction to 13974 g/cm2 (35%) at 6 months post-treatment (p=0.023). Similar
significant reductions in sebum were noted at the forehead from 20751 g/cm2 at baseline to
17166 g/cm2 (17%) after the first treatment (p=0.009) and a further reduction to 14372
g/cm2 (31%) at 6 months post-treatment (p=0.006) (Figure 5.4). The findings were consistent
with the subjective improvements in skin oiliness. An increasing proportion of subjects noticed
improved oiliness after one laser treatment (62%), two treatments (73%), three treatments (77%)
and four treatments (65%), and at the 3-month (90%) and 6-month (82%) follow-ups.
Sixty-two per cent of the subjects were rated as having moderate to extensive
fluorescence on the overall face, nose and cheeks at baseline. No reduction of fluorescence
related to P. acnes using the three-point scale was observed at 1 month, 3 months or 6 months
111
after the last treatment in either the mild or moderate groups when UV photographs were
evaluated for follicular fluorescence.
5.3.2 Complications
Four episodes of post-laser temporary hyperpigmentation at treatment sites were
observed in two subjects. One subject had hyperpigmentation on the cheeks after the first, second
and fourth treatments. Another subject developed hyperpigmentation on the cheeks only after the
fourth treatment. This indicated that the rate of post-laser hyperpigmentation was very low at
3.8% for the 104 treatment sessions that used the current laser parameters in Asian skin types
(Figure 5.5).
Treatment-related pain was well tolerated and rated as mild to moderate by the majority
of subjects with a mean VAS score ranging from 3.4 to 4.5 out of 10 throughout the treatment
period. No statistically significant difference between the mild and the moderate to severe group
was found regarding the effect of density of the inflammatory lesions on the pain score. No
treatment was withheld due to pain.
112
Figure 5.1. Percentage clearance of the mean inflammatory lesion count after successive
treatments with a 1450 nm diode laser (*p<0.05).
50
Mean clearance (%)
45
40
mean
inflammatory > 15
at baseline
35
30
25
20
15
10
5
0
after 1st Tx
after 2nd Tx
after 3rd Tx
1mth after Tx
3mth after Tx
6mth after Tx
113
Figure 5.2. Left: Multiple inflammatory papules and pustules on right cheek before treatment.
Right: One month after four treatments with a 1450 nm diode laser, a marked improvement in
inflammatory acne is observed.
114
Figure 5.3. Left: Multiple inflammatory papules and pustules on left cheek before treatment.
Right: Three months after four treatments with a 1450 nm diode laser, a significant reduction in
inflammatory acne is observed.
115
Figure 5.4. Mean reduction of sebum production after successive treatments with a 1450 nm
diode laser. The whiskers represent the 5th and 95th percentiles.
120
Mean reduction of sebum production
Forehead
Naso-labial
fold
100
80
60
40
20
after 1st Tx
after 2nd Tx after 3rd Tx 1mth after Tx 3mths after

Tx
6mths after
Tx
116
Figure 5.5. Left: The right cheek before treatment. Right: Post-inflammatory hyperpigmentation
on the cheek 4 weeks after the first treatment with a 1450-nm diode laser.
117
5.4 Discussion
This study demonstrated that the 1450-nm diode laser could be a safe and effective means
to treat moderate inflammatory facial acne in skin phototypes IV and V. The multiple-pass
technique with low fluence and corresponding low DCD settings appeared to be efficacious in
skin types with a higher risk of PIH. The side-effects were minimal. Using a low fluence per
pulse but maintaining a high cumulative energy dose per treatment, improvements were apparent
in subjects with moderate acne even after the first treatment and were sustained for at least 6
months. A statistically significant decrease in inflammatory facial acne lesion counts was found
in a subgroup analysis of the more severe group that comprised subjects with a median of 27 and
maximum of 45 lesions at baseline. Our findings indicated that sustained improvement in
inflammatory acne and sebum production for up to 6 months of observation could also be
achieved using a laser fluence as low as 8 J/cm2.
The proposed mechanisms of action of the 1450 nm diode laser in the treatment of acne include
selective photocoagulation of the sebaceous glands in the upper dermis, the reduction of sebum
production and a photothermal effect on the inhibition of P. acnes growth (Paithankar et al.,
2002; Friedman et al., 2004; Perez-Maldonado et al., 2007). Unlike blue light with a pure
photochemical effect, the longer wavelengths of the 1450-nm diode laser can reach and
thermally target the sebaceous structure at a greater depth. The laser has been shown
histologically to induce thermal injury in the upper dermis (Paithankar et al., 2002). It is
hypothesised that the photocoagulation of sebaceous lobules results in a long-term alteration in
sebaceous activity with a subsequent reduction in inflammatory acne lesions, although no longterm alteration in the adnexal structure was demonstrated in a previous study (Paithankar et al.,
118
2002). One study proposed that the clinical effectiveness of the 1450 nm diode laser may be
based, at least in part, on the reduction in sebum production that results from its effects on the
sebaceous glands (Perez-Maldonado et al., 2007). Although the suppression of sebum production
by this laser should theoretically lead to a decrease in the growth of P. acnes growth, we did not
observe any reduction in florescence on the subjects, which would constitute indirect evidence of
a reduction in P. acnes, in the UV photographic study. The findings indicate that the clinical
improvement provided by the 1450 nm diode laser may result from mechanisms other than a
reduction in the growth of P. acnes; nor was the degree of suppression of sebum production
sufficient to decrease the growth of P. acnes. Other lasers for acne, such as PDL, may activate
the bacterial porphyrins and act on the vascular component of acne inflammation with
corresponding improvement of erythema. PDL is associated with less procedural pain and risk of
PIH than infrared lasers. The 1450 nm diode laser has been compared to 595 nm PDL in a splitface study (Alam et al., 2004). The 1450 nm diode laser (6 mm spot size, 1214 J/cm2 , DCD of
40 ms) produced longer remissions (up to 12 weeks) but with comparable lesion reduction as the
595 nm PDL (7 mm spot size, 89 J/cm2, 6 ms pulse duration) in a split-face trial of 25 patients
after four monthly treatments. Side effects were minimal except for mild discomfort on both
sides. The diode laser was preferred with its longer lasting results.
A drawback of the 1450 nm laser is significant pain during treatment and post-laser
hyperpigmentation in darker skin types. The significant risk of hyperpigmentation after laser
treatment is probably related to the high fluence used and the sensitivity of darker Asian skin
types to cryogen-induced injury (Chan, 2005). Decreasing the laser energy to minimise
epidermal damage may reduce the risk of PIH and treatment-related pain, but it can compromise
119
the final clinical outcomes. The use of multiple passes with lower fluences and a shorter duration
of DCD spray may maintain its therapeutic efficacy and substantially reduce the risk of PIH. The
laser fluences that effectively reduced inflammatory acne used in previous studies ranged from
10 to 14 J/cm2. As a monotherapy, the lower laser fluence used in our study resulted in modest
but significant clearance of acne at the end of four treatments (29%) and 6 months (40%) after
treatment in my study. Even at the low fluence of 8 J/cm2 used in my study, we could not totally
eliminate the complication of post-laser hyperpigmentation (3.8%) during more than 100
treatment sessions. In a study that used three treatments with a higher laser fluence of 14 J/cm2
and a duration of DCD of 40 ms in 20 patients (Jih et al., 2006), reductions in mean acne lesion
counts of 75.1% and 76.1% were achieved with a combination of topical anti-acne medications
after
three
treatments
and
at
12-month
follow-up,
respectively.
No
post-laser
hyperpigmentation was reported even at a high fluence of 16 J/cm2 in any skin type, including
skin phototypes IV-VI. In contrast, PIH was observed in 7% of 60 treatment sessions with the
1450 nm diode laser for atrophic facial scars at an average fluence of 11.8 J/cm2 and a DCD
duration of 50 ms in a series of 20 patients with skin phototypes I-V (Tanzi et al., 2003).
Hyperpigmentation has also been reported to occur in 39% of 22 Asian patients with skin
phototypes IV to V treated at fluences of 11-12 J/cm2 and a DCD duration of 50 ms for atrophic
acne scars (Chua et al., 2004). Because the exact proportions of patients with darker skin types
were not specified in these studies, the difference in their PIH rates was difficult to explain.
A number of clinical studies have indicated sustained treatment efficacy of the 1450 nm
diode laser alone or in combination with other anti-acne therapy in the treatment of acne of up to
12 months (Paithankar et al., 2002; Friedman et al., 2004; Jih et al., 2006; Uebelhoer et al.,
120
2007). Bernstein (2007) used a low-energy (8-11 J/cm2), double-pass 1450-nm laser to treat acne
in a pilot split-face study of six patients, and pain associated with the treatment was significantly
reduced compared with the single-pass high-energy (13-14 J/cm2) treatment. Acne counts were
reduced 67% on the low-energy, double-pass side 2 months after the fourth treatment. In the
study of Uebelhoer et al. (2007), an average reduction of 50% in lesion counts 3 months after
treatment was achieved using a monotherapy with double-pass versus a stacked-pulse technique
and a treatment fluence of 9.5-11 J/cm2 and a mean DCD of 29 ms.
I demonstrated that a 1450 nm diode laser using lower fluence but multiple passes and
shorter DCD cooling in Asians was effective as a monotherapy for the treatment of moderate to
severe inflammatory acne. Inflammatory acne and sebum production progressively improved up
to 6 months of observation. An objective improvement in sebum production (measured by
Sebumeter on the forehead and nasolabial folds) of 17-21% was noted as early as after the first
laser treatment and there was a further reduction up to 6 months after the last treatment of 3135%, in contrast to the 60-90% reduction of sebum production achieved after treatment with
isotretinoin. This decrease correlated well with a subjective desirable improvement in oiliness
reported by the majority of subjects. No significant difference in the baseline sebum production
or subsequent reductions after laser treatment was found between the mild group and the
moderate to severe group, although a higher degree of seborrhea was expected in subjects with
severe acne.
No clinical effect on mild acne was observed despite a significant reduction in sebum
production of facial skin. In fact, the severity of acne in the mild group increased during the
121
study up to 1 month after the last treatment. This observation might have been confounded by the
small numbers in the subgroup but it emphasises the need for further studies to determine the
optimal treatment parameters that can be recommend for acne of different degrees of severity in
darker skin types and the mechanisms of acne clearance by this laser other than suppression of
sebum production and growth of P. acnes. The findings may explain the inconsistency in
efficacy noted in previous reports on the use of laser/light sources for the treatment of acne of
various severities. Possibly, only subgroups of patients with moderate to severe inflammatory
acne respond to laser/light sources.
Non-inflammatory lesions of moderate acne were also reduced after four treatments, but
these effects appeared to be slow in onset and only began 1 month after the last treatment. This
delayed efficacy on non-inflammatory lesions reflects the changes in the sebaceous gland after
laser treatment. The reduction in sebum production leads to a decrease in comedone formation
that is revealed as non-inflammatory acne lesions. Because non-inflammatory lesions precede
inflammatory lesions, the appreciable reduction in the former at the 1-month follow-up visit
might explain the continual reduction in inflammatory lesions observed 6 months later.
A previous study showed that a mild to moderate subjective gradual improvement of

facial atrophic acne scars (15.7-20%) could be achieved with the use of a 1450 nm laser in darker
skin types (Chua et al., 2004). No significant objective improvements in acne scars were
observed at the 6-month follow-up visits after laser treatment using the parameters indicated in
our study, suggesting that higher laser energy was required to stimulate collagen remodeling to
achieve the clinical improvement of atrophic scars. Conversely, 33% and 19% of subjects
122
reported mild and moderate improvement, respectively, in their acne scars on self-assessment at
the 6-month follow-up.
A spilt-face format, with each participant acting as their own control for comparison, was
not adopted in my light-based therapeutic studies for acne. Lesion counts was compared with
baseline rather than compared with a change in lesion count on the control side. The split-face
treatment design with laser devices in clinical studies may offset the observed therapeutic effects.
It has been postulated that treating one side of the face by laser could influence acne on the
opposite side of the face by exerting a systemic effect, such that the untreated side improves too
(Chu, 2004). On the other hand, the rapid re-colonisation of P. acnes from the control side to the
treated halves and the subsequent inflammatory response may offset the therapeutic effects on
the treated side.
The adverse effects were minor with the multiple-pass technique. Previous studies have
reported that the pain experienced during treatment is often considerable despite the application
of topical anaesthetic before using the laser. Procedure-related pain was well tolerated by
subjects who were given a relatively short application of topical anaesthetic cream in our study.
The pain was reported to be mild to moderate (mean VAS score, 4.0) during laser treatment and
could not be regarded as negligible in spite of the low fluence and the short duration of DCD
spray used in our study. Most subjects experienced less pain in the subsequent sessions (mean
VAS score, 4.5 at the first treatment and 3.4 at the fourth treatment), which might be related to a
decrease in inflammatory lesions that could have contributed to the pain. The only significant
side-effect was the patchy hyperpigmentation that developed on the cheeks of two subjects with
123
skin type IV and had resolved spontaneously at subsequent follow-up visits. Transient post-laser
erythema and oedema were also observed and usually resolved within 1-2 days. No long-term
complications such as scarring and hypopigmentation were observed.
In essence, the combination of a low fluence of 8 J/cm2 and a short duration of DCD
spray appeared to be a safe and attractive alternative for the treatment of moderate inflammatory
acne with an enduring effect in Asian skin. When used as a monotherapy, modest clinical
improvement was seen in moderate to severe acne. The side effects were mainly transient
erythema and a low incidence of temporary hyperpigmentation in patients with darker skin types.
Alternative laser parameters may be used to enhance the efficacy especially for mild acne in
darker skin types. The findings of this study help to elucidate the tissue-laser interaction of this
laser at low fluences in darker skin types.
124
Chapter 6
A Comparative Study of Intense Pulsed Light Alone
and in Combination with Photodynamic Therapy for
the Treatment of Facial Acne in Asian Skin
125
6.1 Introduction
Acne vulgaris, which is a chronic inflammatory disease of the pilosebaceous units, and its
complications are common skin problems in adolescents and young populations, as reflected by
its high prevalence of 91.3% in a study of the Hong Kong population aged 15-25 years (Yeung et
al., 2002). The increased production of sebum and abnormal desquamation of the follicular
epithelium lead to the obstruction of the pilosebaceous canal and comedone formation. P. acnes
is attracted by the sebum in the pilosebaceous units, and plays an important role in mediating
follicular inflammation. Acne scarring can be a long-term consequence.
The condition is conventionally treated with anti-comedonal and antibacterial agents. The
use of both oral and topical therapies is restricted by resistance to antibiotics, limited long-term
efficacy, side-effects and patient compliance. Lasers and light sources are now being tested as
therapeutic options in the treatment of acne in terms of better compliance and sustained
effectiveness. Blue light, red light, PDL and diode lasers have been studied as treatments for
acne (Paithankar et al., 2002; Goldman & Boyce, 2003; Pollock et al., 2004; Bhardwaj et al.,
2005; Gold et al., 2005; Hong & Lee, 2005; Glaich et al., 2006). It has been hypothesised that
light destroys P. acnes by targeting the endogenous porphyrins, including coproporphyrin III and
protoporphyrin. Reactive oxygen species, which are generated by excited porphyrin molecules,
can destroy P. acnes by damaging the lipid layers in the bacterial cell wall (Elman & Lebzelter,
2004).
126
In PDT, topically applied ALA can be selectively taken up by the target sebaceous gland
and converted to PpIX, which can then be activated by the light source, leading to significant
destruction and shrinkage of the sebaceous gland (Hongcharu et al., 2000). As porphyrins have
absorption peaks in the area of 510-578 nm, their excitation spectrum within the IPL spectrum
allows the use of IPL for PDT (Elman & Lebzelter, 2004).
To date, no prospective, controlled, randomised study on the use of IPL for the treatment
of acne has been published. The reaction to IPL of Asian skin types often differs from that of
Caucasian skin types. A higher risk of hyperpigmentation after light-based therapy has been
noted in Asian skin, which is related to the higher melanin content in its epidermis (Chan et al.,
2002). The objective of the study reported here was to evaluate the clearance rate of treatment
with IPL of inflammatory and non-inflammatory acne, and its side effects in Asian skin. In
addition, we tested whether a combination of IPL and PDT with MAL increased the efficacy of
acne treatment.

6.2.1 Subjects
The study was a randomised, prospective, single-blind, split-face clinical trial. We
enrolled 30 Chinese men and women over 18 years of age who had Fitzpatrick skin types IV or
V and moderate acne with more than 10 inflammatory acne lesions. The subjects were
randomised to half-facial treatments with MAL plus IPL, IPL alone or controls in a ratio of
1:2:1. The exclusion criteria were a history of treating acne with oral isotretinoin over the
previous 6 months, the use of topical or systemic antibiotics 2 weeks before the treatment,
127
photosensitive dermatoses, and pregnancy and lactation in women. All of the subjects applied
adapalene 0.1% gel every night on the whole face until the last treatment; no other acne
treatments were allowed during the study for all three groups. Written consent was obtained from
all subjects, and the study protocol was approved by the review board of the local institution
(Institutional Review Board of the University of Hong Kong).
The mean age of the subjects was 25 years (range, 18-41 years). They were randomly
divided into one of two groups. In the first group, the subjects received treatment with IPL on
one side of the face, and the other side of the face served as a control and was treated with
topical adapalene only. The subjects in the second group received a full-facial exposure to IPL
after the topical application of 16% MAL cream (Metvix, Galderma) to one half of the face for
30 min. The treatment areas were washed with soap and alcohol scrub before applying the MAL.
The subjects washed off the MAL before the PDT. The non-MAL-treated side was used as an
IPL-treated control.
6.2.2 Device parameters

The IPL source was an Ellipse Flex system (Danish Dermatologic Development (DDD),
Hrsholm, Denmark), which emitted wavelengths of 530-750 nm via the PR applicator. The
treatment fluences ranged from 7.0 to 9.0 J/cm2, with a spot size of 10 48 mm. The filter
emitted light, which was absorbed by two of the oxyhaemoglobin absorption peaks (542 and
577nm) and further eliminated most near-infrared wavelengths. We used single passes with
double pulses of a 2.5-ms duration at a 10-ms interval and without overlapping based on
previous studies using the same applicator (Bjerring et al., 2009; de Leeuw et al., 2010). Each
128
subject received a total of four facial treatments at 3-week intervals. The device did not have a
cooling tip. A thick layer of cold transparent optical index-matching gel was applied to the skin
for contact cooling and to ensure an effective optical coupling between the applicator and the
skin. The eyes were protected with small metal eye shields. Subjects were advised to avoid
exposure to sunlight for 48 h after the treatment, and to use a regular sunblock. The side effects
that were evaluated included pigmentary disturbance, erythema, oedema, burning, stinging,
crusting, atrophy and scarring.
6.2.3 Assessment
A Canfield Visia CR system was used to assess the subjects before each treatment and 1
and 3 months after the last treatment. It consisted of a configurable head support system to
ensure proper and consistent registration of the head position. Three standard close-up
photographs (right, left and central) were taken using standard light, cross-polarisation, parallel
polarisation and UV light. The images were stored in Canfields mirror software and were
assessed by two blinded investigators who did not participate in the treatment of the subjects.
The evaluation of efficacy was based on close-up photographs taken before the first treatment
and at follow-up visits. Inflammatory lesions, including papules, pustules and cysts, and noninflammatory acne elements on each side of the face were counted.
6.2.3.2 Fluorescence photographs evaluating P. acnes

An indirect measurement of P. acnes fluorescence on the skin was used to assess the
suppression of bacterial porphyrin fluorescence by IPL or MAL-PDT. The emission of
129
fluorescence has been attributed to bacterial coproporphyrin III and PpIX (Lucchina et al., 1996).
The intensity of fluorescence is related to the P. acnes population, and the reduction in the
density of auto-fluorescent dots was rated according to the following scale: none (0%), poor (125%), fair (26-50%), good (51-75%) and excellent (76-100%).
The effects of treatment were determined based on statistical analysis using the
Wilcoxon signed rank test to compare the lesion counts from each follow-up visit with the
baseline counts. The Mann-Whitney test was used to compare the changes from the baseline
among the three groups. Statistical significance was defined as a p-value of less than 0.05.
6.3 Results
Of the 30 subjects recruited, 11 in the PDT-treated group, 23 in the IPL-treated group and
12 in the control group completed the fourth treatment. Four subjects in the PDT-treated group
(25%) dropped out after the first or second treatment because of significant stinging, burning and
erythema after the MAL-PDT. Three other subjects defaulted (one from the PDT-treated group
and two from the IPL-treated group) for non-medical reasons.

Four weeks after treatment, the assessment of inflammatory acne showed a mean
reduction in lesion counts of 53% in the PDT-treated group (p=0.17), 22% in the IPL-treated
group (p=0.24) and 72% in the control group (p=0.01). Assessment at 12 weeks post-treatment
showed decreases of 65% in the PDT group (p=0.06), 23% in the IPL group (p=0.82) and 88% in
the control group (p=0.01) (Figure 6.1 and Table 6.1). Most subjects experienced reductions in
130
inflammatory lesions on the PDT-treated side and control side at the 12th week. Only the control
group showed a statistically significant decrease in inflammatory lesions at 1 month and at 3
months. No statistically significant differences in the changes in inflammatory lesion counts
were observed between the untreated sides of both intervention groups from baseline to 12 weeks
after the last treatment. Figure 6.2 shows a subject who received MAL plus IPL treatment.
Four weeks after treatment, the assessment of non-inflammatory acne showed a mean
clearance of 52% in the PDT group (p=0.02), 15% in the IPL group (p=0.11) and 14% in the
control group (p=0.62). Evaluation at 12 weeks post-treatment showed decreases of 38% in the
PDT group (p=0.05) and 44% in the IPL group (p=0.01), and an increase of 15% (p=0.36) in the
control group. The PDT-treated group had a statistically significant reduction in noninflammatory lesions 4 weeks after the treatment, and the improvement lasted up to 12 weeks
(Table 6.2). A significant reduction in non-inflammatory lesions was also observed in both the
PDT and IPL groups compared with the control group, which experienced a 15% increase in
non-inflammatory lesions (p=0.36) 12 weeks after treatment.
A greater reduction of fluorescence related to P. acnes was found at the end of the study
in the PDT group than in the IPL and control groups when UV photographs were evaluated for
follicular fluorescence (Figure 6.3). Twenty-seven per cent of the subjects in the PDT group,
15% in the IPL group and 0% in the control group had at least a good (50%) rate of reduction at
the last observation. No statistically significant difference in the reduction of fluorescence was
noted between the three groups (Table 6.3).
131

The IPL treatment was well tolerated, but 4 of 16 subjects (25%) in the PDT-treated
group withdrew from the study after the first or second treatment with MAL because they were
unable to tolerate the side-effects. The reported adverse effects included stinging, burning,
erythema and oedema, which mostly resolved within 1-2 days. Temporary crusting and
hyperpigmentation were observed in three subjects (10%, two in the IPL group and one in the
PDT group), which subsided within 1 week after the treatment. Some subjects developed
transient acneiform flares that lasted for 1-2 weeks after the first and second treatments with
MAL-PDT. No statistically significant difference in adverse effects (pigmentation, atrophy and
scarring) was observed between the IPL-treated and PDT-treated groups.
132
Figure 6.1. Mean reduction of inflammatory and non-inflammatory acne lesion count after
successive treatments with a combination of methyl aminolevulinate and intense pulsed light
versus intense pulsed light alone; the whiskers represent the 5th and 95th percentiles.
Mean clearance of inflammatory acne

140
120
100
80
Clearance in
inflammatory
acne [MAL-PDT]%
60
40
Clearance in
inflammatory acne
[IPL](%)
20
0
-20
after 3mth
after 1- after 3rd after 2nd

mth
tx
tx
after 1st
tx
-40
-60
Mean clearance of non-inflammatory acne

100
80
60
Clearance in noninflammatory acne [MALPDT] (%)
40
Clearance in noninflammatory acne

[IPL](%)
20
0
-20
after 3mth
after 1mth
after 3rd after 2nd after 1st

tx
tx
tx
-40
133
Figure 6.2. Left: Multiple inflammatory papules before treatment. Right: Twelve weeks after
four treatments with the combination of IPL and methyl aminolevulinate on the right side of the
face, with the left side having undergone IPL treatment only; there is marked improvement in
inflammatory acne and erythema on the side treated with methyl aminolevulinate.
134
Figure 6.3. Left: Face showing punctate fluorescence of hair follicles populated with P. acnes
before treatment. Right: Reduction of intensity of fluorescence, especially on the left cheek and
forehead, 4 weeks after the fourth treatment with methyl aminolevulinate and photodynamic
therapy.
135
Table 6.1. Mean reduction in inflammatory acne lesion count at each time-point for the intense
pulsed light (IPL), photodynamic therapy (MAL-PDT) and control groups.
% +/-standard
error
After 1st tx
After 2nd
tx
After 3rd tx 4 weeks

after 4th tx
12 weeks
after 4th tx
MAL-PDT
63.5 25.8
71.5 24.2
76.7 28.9
52.7 52.5
64.5 54.8
IPL only
15.1 38.4
17.5 29.1
24.9 31.1
22.1 55.3
22.9 52.2
Control
41.4 25.3
39.9 39.3
49.2 27.4
72.4 19.9
88.0 12.5
136
Table 6.2. Mean reduction in non-inflammatory acne lesion count at each time point for the
intense pulsed light (IPL), photodynamic therapy (MAL-PDT) and control groups.
% +/-standard
error
After 1st tx
After 2nd
tx
After 3rd tx 4 weeks

after 4th tx
12 weeks
after 4th tx
MAL-PDT
21.3 30.1
37.0 29.2
44.0 32.5
51.6 26.1
38.0 53.5
IPL only
15.2 22.3
20.9 24.4
21.8 27.7
15.5 42.3
43.6 26.5
Control
7.2 24.9
-6.5 32.5
-9.8 47.1
13.8 34.0
-15.1 95.7
137
Table 6.3. Rating of percentage reduction in P. acnes florescence 4 weeks after the fourth
treatment.
Total
Worse
no. of
subjects
None
(0%)
Poor
(< 25%)
Fair
(2650%)
Good
(5175%)
Excellent
(76-100%)
MAL-PDT
11
IPL only
23
Control
12
138
6.4 Discussion
The development of a more convenient, effective and well-tolerated method of
administering light-based therapy to treat acne vulgaris is attractive. The proposed mechanisms
for ALA-PDT in acne include the suppression of P. acnes, direct injury of the sebaceous glands
and alteration of the shedding of follicular keratinocytes (Hongcharu et al., 2000; Gold &
Goldman, 2004; Pollock et al., 2004). The presence of small absorption peaks of porphyrins
within the IPL emission spectrum and the heterogeneous targets of selective light energy
absorption render IPL a potentially useful light source for PDT for the treatment of acne. Unlike
the pure photochemical effect of blue light, the multitude of longer wavelengths of IPL can reach
and thermally target multiple chromophores at different depths.
The drawback of standard PDT is the long incubation time of ALA of 3-4 hour, the long
procedure time with the original red light or blue light source, the significant pain experienced
during the irradiation and recovery time for photosensitivity and healing. The adverse effects of
PDT are probably related to the duration of ALA incubation, and a shorter contact time might
reduce recovery time and be more acceptable to patients, but the efficacy may be reduced. The
short procedure time of an average of 10 min and minimally associated pain make IPL an
attractive alternative in everyday clinical practice. A number of preliminary studies have
indicated the efficacy of PDT in the treatment of acne and photoaging after the use of topical
ALA for 30 min to 1 hour (Goldman & Boyce, 2003; Taub, 2004; Dover, 2005; Rojanamatin &
Choawawanich, 2006). In the UV photographic study, we also observed a greater reduction of
florescence in the PDT-treated than in the IPL-treated and control groups which constitutes
139
indirect evidence of the reduction of P. acnes and indicates an effect despite the relatively brief
contact with MAL.
Although previous studies have shown the effectiveness of IPL and PDT in the treatment
of acne, we could not demonstrate that PDT, which combined IPL with topical MAL, using the
studied parameters in Asians was effective for inflammatory acne of moderate severity. In this
study, progressive improvement of inflammatory acne was seen over the 12 weeks of
observation on both the control and treated sides of the face; therefore, the change was unlikely
to be due to the PDT. No appreciable improvement in inflammatory acne was noted in the IPLtreated sides. The MAL-treated group had a consistent trend of greater improvement of both
inflammatory and non-inflammatory acne lesions than the group that received IPL alone at 4 and
12 weeks after the treatment. The greatest relative improvement was observed for noninflammatory acne lesions on the MAL plus IPL-treated side. Surprisingly, a statistically
significant decrease in inflammatory lesions was observed in the control group at 4 and 12 weeks
whereas no such improvement was seen on the IPL sides. Because all of the subjects received
topical retinoids on both sides throughout the treatment period, the IPL treatment might have
counteracted their anti-inflammatory effects.
The MAL-PDT group had a statistically significant reduction in non-inflammatory acne 4

weeks after the treatment and the improvement lasted up to 12 weeks. As expected, noninflammatory lesions increased in the control group after the cessation of topical retinoid
applications at the end of light treatment in all subjects. A significant reduction in noninflammatory lesions was also observed in the IPL group only at 12 weeks after treatment. The
140
effects on non-inflammatory lesions appeared to be slow in onset, especially when the IPL was
used alone. This delayed efficacy on non-inflammatory lesions reflects the changes in the
sebaceous gland after treatment with PDT or IPL. The reduction in sebum production led to a
decrease in comedone formation that was manifested as non-inflammatory acne lesions. A
modest clearance of comedonal acne was demonstrated in a previous study when long-PDL was
used (Alexiades-Armenakas, 2006). Because non-inflammatory lesions precede inflammatory
lesions, the reduction in non-inflammatory lesions at 12 weeks might lead to a continual
reduction in inflammatory lesions beyond the 12-week period.
A 3-hour incubation period was used in a comparative split-face study of topical ALA
plus IPL versus IPL alone administered twice at 2-week intervals for the treatment of acne
(Santos et al., 2005). Thirteen of fifteen subjects completed the study, and all showed apparent
improvements on both sides of the face. Most of the subjects developed acute acneiform lesions
on the ALA-treated side after the first treatment, but these subsided after a couple of weeks. We
observed similar acneiform flare-ups in our study. At the sixth week after the second treatment in
Santoss study, 10/13 subjects (77%) had significant decreases in inflammatory acne with no
new lesion formation on the ALA-IPL-treated half of the face, but no improvement was observed
compared with the baseline on the IPL-treated side. Based on the split-face studies by our group
and Santos, IPL is not likely to be useful as a stand-alone treatment of inflammatory acne.
The results of this study were limited by the relatively small sample size and reduced
statistical power. Eleven of the sixteen subjects who were treated with MAL-PDT and twelve of
the fourteen who were treated with half-facial IPL completed our study. The drop-out rate was
141
significant and reflected the high intolerance to the application of MAL despite the relatively
short incubation time. Although MAL cream was used rather than a topical ALA solution as in
most previous studies, I do not believe that this affected the outcome. A randomised split-face
study compared the treatment effect and tolerance of ALA-PDT and MAL-PDT applied for 3
hour under occlusion using red light (Aktilite, PhotoCure ASA) (Wiegell & Wulf, 2006). There
was a 59% decrease in inflammatory lesions from baseline, with no significant differences in
response rate between the two treatments. All of the subjects experienced moderate to severe
pain during illumination, and developed erythema, pustular eruptions and epithelial exfoliation
after treatment, which were more severe and uniform in the ALA-PDT-treated area. Another
randomised, controlled split-face study of MAL-PDT using red light also showed a 54%
reduction in inflammatory lesions with significant side effects of pain and erythema (Horfelt et
al., 2006).
Robust prospective, randomised, controlled trials in the areas of light-based therapy or

PDT for acne are limited, and data on the long-term effects are still lacking. Although the
combination of short-contact ALA and IPL appears to be a safe and attractive alternative for the
treatment of inflammatory acne, I cannot support the current regime as an effective acne
treatment in Asians, based on our findings. Patient discomfort was frequent with PDT despite the
relatively short MAL incubation time in our study. The side effects were mainly transient
erythema and oedema that lasted for less than 48 hours and temporary pigmentary changes in
subjects with darker skin types. Further study is needed to investigate alternative light sources
and optimal ALA or MAL incubation times that will achieve long-lasting efficacy in Asians with
acne vulgaris.
142
Chapter 7
Liposome-encapsulated 0.5%
5-Aminolevulinic Acid with
Intense Pulsed Light for the Treatment of
Inflammatory Facial Acne
143
7.1 Introduction
An epidemiological study in Hong Kong of adolescents and young adults aged 15-25
reported a self-reported prevalence of acne of 91.3% (Yeung et al., 2002). Of the respondents in
that study, 26.6% were psychologically disturbed by their symptoms, indicating that this disorder
and its complications are common problems. Acne vulgaris is a chronic inflammatory disease of
the pilosebaceous units, in which increased sebum production and the abnormal keratinisation of
the follicular epithelium lead to comedone formation. P. acnes in the pilosebaceous units also
plays an important role in mediating the inflammatory changes. Acne scarring is the main
consequence, and it cannot be corrected completely by laser surgery despite advances in the
field.
Conventional topical and oral treatments with anticomedonal and antibacterial

medications are constrained by resistance to antibiotics, inadequate long-term efficacy, adverse
effects and poor patient compliance (Nestor, 2007). Lasers and light sources, including blue
light, red light, PDL and diode laser, are increasingly being studied as therapeutic options for the
treatment of acne with regard to improved compliance, and their safety and sustained
effectiveness (Paithankar et al., 2002; Goldman & Boyce, 2003; Pollock et al., 2004; Bhardwaj
et al., 2005; Gold et al., 2005; Glaich et al., 2006). It has been hypothesised that certain
wavelengths of light destroy P. acnes by targeting endogenous porphyrins, mainly PpIX (Elman
& Lebzelter, 2004). Reactive oxygen radicals, which are generated by excited porphyrin
molecules, destroy P. acnes by damaging the lipid layers in the cell wall.
144
In PDT with 5-ALA, topically applied 5-ALA is selectively taken up by the

pilosebaceous units and converted to PpIX, which is then activated by the light source, resulting
in significant damage and subsequent shrinkage of the sebaceous gland (Hongcharu et al., 2000).
IPL with an emission spectrum that covers the absorption peaks of PpIX at wavelengths of 407
nm and 510-578 nm can be used for PDT (Elman & Lebzelter, 2004). PDT combined with
topical 5-ALA or MAL has been shown to be beneficial in the treatment of inflammatory facial
acne, but is associated with erythema, crusting and oedema in a significant proportion of patients
(Hongcharu et al., 2000; Horfelt et al., 2006). The prolonged recovery time, especially after PDT
with a cream-based photosensitiser and red light, might be due to the inherent properties of the
cream or to the light source (Gold, 2008).
Liposomes are microscopic vesicles that comprise concentric bilayers formed from
phospholipids and thus contain both lipophilic and hydrophilic components (De Leeuw et al.,
2009). They can thus be used as a vehicle to enhance the penetration of compounds into the skin,
and have been used in dermatological preparations and now as a vehicle to deliver 5-ALA
without occlusion. In the current study, liposome-encapsulated 5-ALA was delivered via
spraying onto the epidermis. The skin fluorescence 1 hour after multiple spraying with 0.5%
liposome-encapsulated 5-ALA was comparable to that 30 min after the application of 20% 5ALA in a cream base (Bjerring et al., 2009). Similar levels of skin fluorescence enable a
reduction in the concentration of topical 5-ALA to 0.5%, although low post-treatment
photosensitivity is observed and the level of fluorescence begins to decrease 15 min after the
cessation of spraying (Christiansen et al., 2007). We hypothesised that the short duration of
145
fluorescence using this liposomal delivery system with a resultant decrease in the concentration
of ALA may result in a shorter duration of phototoxicity.
The effect of IPL on Asian skin types often differs from that on Caucasian skin types. A
higher risk of hyperpigmentation after light-based therapy has been noted in Asian skin, which is
related to the higher melanin content in the epidermis (Chan et al., 2002). The objective of the
study reported here was to evaluate the effectiveness and side effects, particularly the phototoxic
side effects, of the combination of IPL and PDT with 0.5% liposome-encapsulated 5-ALA to
treat facial inflammatory acne in Asian skin.

7.2.1 Subjects
Twelve Chinese subjects (two men and 10 women) with Fitzpatrick photo skin type IV or
V, a mean age of 24 years (range, 20-33 years) and facial acne with a mean of 7 inflammatory
and 20 non-inflammatory acne lesions were enrolled. The exclusion criteria were a history of
treating acne with oral isotretinoin during the previous 6 months, the use of topical or systemic
antibiotics 2 or 4 weeks before the treatment, respectively, photosensitive dermatoses, and
pregnancy and lactation in women. The use of other acne treatments was not allowed throughout
the study and follow-up periods. Written consent was obtained from all patients prior to
enrollment.
146

The treatment areas were washed with soap and alcohol scrub before applying the spray.
The subjects received full-face IPL treatment after 12 topical applications of 0.5% 5-ALA in a
liposomal spray (Ellipse Photo Spray, Danish Dermatologic Development (DDD), Hrsholm,
Denmark) to the face at 5-min intervals for 1 hour. The 5-ALA spray was gently massaged into
the entire face after each spraying. The Ellipse Flex IPL system (Danish Dermatologic
Development (DDD), Hrsholm, Denmark) was used, which emits wavelengths of 400-720 nm
with a spot size of 10 48 mm2. This waveband covers all of the PpIX-activating peaks (Soret
and Q bands). We treated the skin with three passes of 50-ms pulse duration without overlap and
a fluence of approximately 5.0 J/cm2. A thick layer of cold transparent optical index-matching
gel was applied to the skin for contact cooling and to ensure effective optical coupling between
the applicator and the skin. The eyes were protected with small metal eye shields. Subjects were
advised to avoid exposure to sunlight for 48 hours after the treatment and to use a sunscreen
regularly. Seven and five subjects were assigned to receive a total of three and four treatments,
respectively, at 3-week intervals.
7.2.3 Assessment
The evaluation of the efficacy of the treatment was based on close-up images captured
with a Canfield Visia CR system, which were taken before each treatment and at follow-up visits
at 1 month, 2 months and 6 months after the last treatment. Three standard close-up photographs
(right, left and central) were taken using standard light, cross polarisation and parallel
147
polarisation. All of the images were assessed by two blinded investigators who did not
participate in the treatment of the subjects and were unaware of the point in time at which the
pictures were taken.
Inflammatory lesions, including papules, pustules and cysts, and non-inflammatory acne
elements on the face were counted. Objective global improvement in facial acne, acne scarring
and pore size was graded on a five-point scale ranging from -1 to 3: -1, worsening; 0, no
improvement; 1, mild improvement; 2, moderate improvement; and 3, marked improvement.
The data were analysed to ascertain the reduction in the mean lesion counts of
inflammatory and non-inflammatory lesions as determined by the review of the standardised
photographs by two blinded assessors and the change in the objective global assessment scores
of the specified parameters. The effects of treatment were determined by statistical analysis using
the Wilcoxon signed rank test to compare the lesion counts at each follow-up visit with the
baseline counts. Statistical significance was defined as a p-value of less than 0.05.
At each treatment and follow-up visit, the adverse effects after laser treatment were
evaluated, including erythema, oedema, crusting, pigmentary disturbance, atrophy and scarring.
The severity of the side effects was graded as: none, mild, moderate or severe. Pigmentary
changes, atrophy and scarring after laser treatment were also assessed based on the images
captured by the Canfield system.
148
The subjects were also asked to rate the global improvement in their facial acne, acne
scarring, oiliness and pore size, based on a VAS from 0 to 10, at baseline and subsequent followup visits (Appendix III). Subjective improvements were defined as a decrease in VAS from the
baseline. Subjects overall satisfaction with the procedure was also scored using a VAS from 0 to
10.
The Sebumeter (SM 810; Courage and Khazaka, Cologne, Germany) was used to
measure facial sebum secretion (Youn et al., 2005). The device is a matte synthetic tape that is
pressed on the skin using a constant force of 10 N for 30 s to measure the amount of sebum. One
measurement was taken on the forehead (1 cm above the gabella at the midline) and one on the
right nasolabial fold (1 cm lateral to the ala nasi). The evaluations were carried out in a climatecontrolled facility at a temperature of 20-24oC and relative humidity of 40-60%. Subjects were
asked to arrive 30 min before the evaluation time to adjust to the conditions. They were also
instructed not to wash their face for at least 4 hours before the evaluation.
7.3 Results
The objective global assessment and the subjective evaluation indicated improvement in
facial inflammatory acne among all subjects studied after three treatments of IPL with 0.5%
liposome-encapsulated 5-ALA sprayed at 5-min intervals for 1 hour before light irradiation. No
statistically significant difference was observed in the change in the mean acne lesion count after
149
the therapy between the two groups who received three or four treatments at 3-week intervals,
and the data were therefore analysed altogether.
The mean inflammatory lesion count decreased from 7.08.0 at baseline to 3.33.2 (31%
mean reduction) 3 weeks after the second treatment (p=0.065) (Table 7.1). With subsequent
treatments, improvement was maintained, with statistically significant mean reductions of 52%
(2.92.6) at 1 month (p=0.025), 63% (1.81.5) at 2 months (p=0.008) and 65% (1.51.4) at 6
months (p=0.043) after the last treatment. However, the results at 6 months needed to be
interpreted with caution, because 6 of the 12 subjects did not complete the final assessment.
Figure 7.1 shows the serial percentage change in the mean inflammatory and non-inflammatory
lesion counts by objective assessment, and Figure 7.2 shows the improvement in the
inflammatory lesions of a subject who received liposomal ALA spraying plus IPL in three
treatment sessions 2 months after the last treatment.
For the assessment of non-inflammatory acne, the mean clearance was 23% (p=0.12) 1
month after treatment, and statistically significant clearance was only apparent 2 months after the
last treatment, with a reduction from 20.318.3 at baseline to 13.116.2 (43% mean reduction)
(p=0.003) (Table 7.1). The improvement appeared to last, with a mean decrease of 51%
(5.43.6) at 6 months after the last treatment (p=0.027), as shown in Figure 7.1. A consistent
trend of progressive reduction in both the inflammatory and non-inflammatory acne lesion
counts was observed at 2 and 6 months after three treatments. Objective global improvement in
facial acne was noted in 70% of the subjects at 1 month and in 82% at 2 months after the last
150
treatment (Table 7.2). The facial acne of 36% of the subjects was graded as moderately or
significantly improved 2 months after the last treatment.
The mean subjective acne score decreased from 6.6 at baseline to 4.5 (on a scale of 10) 1
month post-treatment, and 67% of the subjects noted improvement in their facial acne in terms of
reduction of the VAS 3 weeks after the first treatment (Table 7.3). Subjective improvement was
maintained at the 1-month (70%), 2-month (60%) and 6-month (60%) follow-up visits. The
findings of subjective improvement are consistent with those of the objective assessment of the
reduction in the number of acne lesions and global improvement. Although no objective
improvement in acne scarring was observed, as rated by assessors who compared the baseline to
the subsequent photographs, 70% and 60% of the subjects recorded a mild reduction in the VAS
for their acne scarring at the 2-month and 6-month follow-up visits, respectively. Six subjects did
not attend their final follow-up visit at 6 months because of their work schedule.
Sebum production, measured by the Sebumeter, at the forehead began to decrease after
the first treatment, but the improvement lasted for only 1 month after treatment, as shown in
Figure 7.3. There was a modest but statistically significant reduction in sebum at the forehead
from 19265 g/cm2 at baseline to 14271 g/cm2 (27%) 3 weeks after the first treatment
(p=0.005), with a further reduction to 13371 g/cm2 (30%) 3 weeks after the second treatment
(p=0.023) and 15174 g/cm2 (20%) 1 month after the third treatment (p=0.041) (Figure 7.3).
However, no statistically significant reduction in sebum was noted at the nasolabial fold at any
time-point after the treatments. The majority of subjects noticed a reduction in oiliness after one
treatment (75%) and two treatments (83%) and at the 1-month follow-up (80%). All subjects
reported an improvement in pore size at 1 and 2 months after treatment.
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The IPL treatment was well tolerated, and no subjects noted phototoxicity afterwards.
None of the subjects withdrew from the study because of side effects. The facial skin was
clinically assessed at each treatment and at each follow-up by the clinical investigator. All
subjects tolerated treatment and showed no noticeable side effects except for transient erythema
and oedema within a few hours after the procedure. No adverse effects such as scarring, atrophy,
hypopigmentation or post-PDT hyperpigmentation were observed.
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Table 7.1. Mean reduction in the inflammatory and non-inflammatory lesion counts at each time
point after treatment.
153
Table 7.2. Global objective improvement in facial acne compared to the baseline.
154
Table 7.3. Subjective assessment of facial acne and overall satisfaction using visual analogue
score (range 0-10) at each time point.
155
Figure 7.1. Mean percentage reduction in the inflammatory and non-inflammatory lesion counts
after successive treatments with a combination of liposome-encapsulated ALA and IPL. The
whiskers represent the 5th and 95th percentiles.
156
Figure 7.2. Left photo: Pre-treatment with multiple inflammatory papules. Right photo: Two
months after three full-face treatments with the combination of IPL and liposome-encapsulated
ALA with improvement in inflammatory acne.
157
Figure 7.3. Mean reduction in forehead sebum production after successive treatments with
liposomal ALA spray and IPL. The whiskers represent the standard error and the asterisks
represent a statistically significant mean reduction with a p-value <0.05.
Mean reduction in sebum production (%)

50
*
*
25
-25
-50
after 1st Tx
after 2nd Tx after 3dr Tx
1 mth after
last Tx
2 mths after
last Tx
6 mths after
last Tx
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7.4 Discussion
A convenient, efficacious and well-tolerated means of administering light-based therapy
to treat facial acne is attractive. In the present study, a treatment that combined liposomeencapsulated 5-ALA at a low concentration of 0.5% and IPL that emitted wavelengths of 400720 nm showed promising results for the improvement of facial inflammatory acne among
Asians. This treatment method abolishes the need for occlusion during the incubation of 5-ALA
and reduces the adverse effects of PDT (Bjerring et al., 2009).
Christiansen et al. (2007) found that the average skin fluorescence after 30 min of
incubation time with 20% 5-ALA cream was comparable with that after 2 hours of spraying with
liposomal 0.5% 5-ALA spray at 15-min intervals. A similar level of fluorescence was obtained
after spraying at 5-min intervals for 1 hour in a photodynamic rejuvenation study (Bjerring et al.,
2009). Fluorescence decays linearly within 15 min after spraying and returns to baseline within 8
hours (Christiansen et al., 2007). The use of liposome-encapsulated 5-ALA allows a 40-fold
reduction in the concentration of 5-ALA while inducing the same degree of skin fluorescence
without the need for occlusion.
In this pilot study, the clinical efficacy of PDT for inflammatory acne when 0.5%
liposome-encapsulated 5-ALA was sprayed at 5-min intervals for 1 hour prior to treatment was
comparable with that when 20% 5-ALA was applied under occlusion 30 min prior to treatment,
resulting in a 60-70% reduction in mean inflammatory lesion counts 1-3 months after treatment
(Hdersdal et al., 2008). In addition, the current formulation has a shorter duration of enhanced
skin fluorescence that may result in a lower level of post-treatment phototoxicity, thus sparing
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the treated patients the inconvenience of avoiding exposure to sunlight for several days after
treatment.
In this study, an improvement in mild to moderate inflammatory acne on the face was
observed over a 6-month follow-up period. Some improvement in inflammatory acne was
already noted after the second treatment, and a mean reduction of 65% in the inflammatory
lesion count was observed 6 months after the last treatment. A statistically significant reduction
in the non-inflammatory lesion count occurred at only 2 months after the last treatment, and the
improvement lasted up to 6 months. A modest clearance of comedonal acne had been
demonstrated in a previous study in which a long-PDL was used (Alexiades-Armenakas, 2006).
As non-inflammatory lesions precede inflammatory lesions, the reduction in the number of noninflammatory type at 2 months could lead to a continual reduction in the number of the
inflammatory type beyond 6 months. Moreover, the significant but temporary reduction in the
production of forehead sebum up to 1 month post-treatment might contribute to the sustained
improvement at 6 months.
In approximately 20% of subjects, facial acne had not improved at 1 month after
treatment, based on objective and subjective assessments. Bjerring et al. (2009) found large
inter-individual differences in the level of enhanced fluorescence after repeated spraying with
0.5% liposomal 5-ALA. This might be due to interpersonal variations in skin thickness.
Measures to ensure an adequate increase in fluorescence after the application of 5-ALA before
irradiation with a light source might lead to more consistent results.
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With regard to sebum production, an objective improvement was noted, with a reduction
of 20-27% on the forehead, as measured by the Sebumeter, as early as 3 weeks after the first
treatment; however, the positive effect on sebum reduction did not last for longer than 1 month
after treatment. No reduction in sebum production was observed on the nasolabial fold, which
might be due to the difficulty of applying the IPL hand-piece around the nasolabial fold and
taking Sebumeter measurements around the nose (Laubach et al., 2009).
Santos et al. (2005) used a 3-hour incubation period in a comparative split-face study of
topical ALA plus IPL versus IPL alone performed twice at 2-week intervals for the treatment of
acne. Thirteen of 15 subjects completed the study, and all showed apparent improvement on both
sides of the face. At the sixth week after the second treatment, 10/13 subjects (77%) had
significant decreases in inflammatory acne with no new lesion formation on the ALA-IPLtreated half of the face, but no improvement was observed compared with the baseline on the IPL
alone-treated side. This indicates that IPL is not likely to be useful as a stand-alone treatment
for inflammatory acne.
The proposed mechanisms of the action of ALA-PDT in acne include the suppression of
P. acnes, direct injury of the sebaceous glands and alteration of follicular keratinocyte shedding
(Hongcharu et al., 2000; Gold & Goldman, 2004; Pollock et al., 2004). The multitude of IPL
wavelengths can reach and thermally target multiple chromophores at different depths. The
coverage of absorption peaks for PpIX within the IPL emission spectrum, the heterogeneous
targets of selective light energy absorption and the large spot size render IPL a potentially useful
161
light source for PDT for the treatment of acne. We used IPL with a low fluence and long pulse
duration of 50 ms to allow a sufficient light dose to be delivered during the PDT process.
The disadvantages of standard PDT include the long incubation time of 5-ALA of 3-4
hours, the long procedure time with a red or blue light source, significant pain during irradiation
and a recovery time from photosensitivity for 48-72 hours following treatment. The adverse
effects of PDT are probably related to the use of occlusion, and the concentration and duration of
incubation of ALA. Relatively high concentrations of 5-ALA with or without occlusion are often
necessary for topical application because of the low rate of percutaneous penetration of free 5ALA. Due to the low permeability of 5-ALA through the stratum corneum, it is not possible to
the concentration of 5-ALA in standard cream or solution vehicles. A shorter contact time might
reduce recovery time and be more acceptable to patients if the efficacy of acne treatment can be
maintained. A number of clinical studies have shown the efficacy of PDT in the treatment of
acne and photoaging after a topical application of ALA from 30 min to 1 hour (Goldman &
Boyce, 2003; Taub, 2004; Dover, 2005; Rojanamatin & Choawawanich, 2006). It is possible that
5-ALA is mainly absorbed by the sebaceous glands during a short incubation of 15-30 min. In
general, the complication rate, including post-treatment phototoxicity, tends to be low when a
non-cream-based 5-ALA preparation and IPL or blue light are used in PDT for acne (Goldman &
Boyce, 2003; Gold et al., 2004, 2005; Santos et al., 2005; Gold, 2008; Oh et al., 2009).
One of the limitations of this pilot study is the lack of a comparison arm with controls
and with standard 20% 5-ALA. A spilt-face study design might not show light-based treatment
to be superior to the control side because of the possible systemic effect on the contralateral side.
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The low rate of complications and phototoxicity in our study might be attributed to the use of an
IPL device for PDT. Another limitation is the small sample size and thus the reduced statistical
power of the study. The observation at the 6-month follow-up might be undermined by the high
default rate (50%), but the high drop-out rate was due to the work schedule of the subjects and
not to the efficacy of the treatment or adverse effects. All 12 subjects who were treated with PDT
with an ALA spray tolerated the treatment well, with minimal discomfort, and completed the
treatment regime. This represents a significant improvement in the acceptance of PDT because
no subjects defaulted from the treatment sessions because of their side effects. No significant
adverse effects such as phototoxicity or dyspigmentation were reported in our study. Another
possible explanation of the findings of few complications related to phototoxicity is the
compliance of the subjects to the instruction to avoid exposure to sunlight for 48 hours after the
treatment, which may also account for the low incidence of photosensitivity in other studies that
used IPL and non-cream-based photosensitisers (Taub, 2007). PIH is of special concern in Asian
skin types. In our previous PDT study using MAL, five of the 16 subjects dropped out because of
intolerance to the application of MAL despite the relatively short incubation period of 30 min
(Yeung et al., 2007). A randomised, split-face comparative study of ALA versus MAL-PDT
using red light (Aktilite, PhotoCure ASA), in which ALA and MAL were applied for 3 hours
under occlusion, showed that all subjects experienced moderate to severe pain during
illumination (Wiegell & Wulf, 2006). Significant side effects (pain and erythema) were noted in
another randomised, controlled split-face study of MAL-PDT using red light (Horfelt et al.,
2006).
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When the concentration of topical 5-ALA was lowered from 20% to 0.5% by using
liposome-encapsulated 5-ALA in a spray form, which enhances penetration and allows a rapid
reduction in fluorescence after treatment, fewer adverse effects of ALA-PDT, especially
phototoxicity, were observed (Christiansen et al., 2007; De Leeuw et al., 2009). The increase in
surface fluorescence and the clinical improvement in acne in the current study indicated that a
sufficient amount of 5-ALA was converted by the cells into PpIX to ensure the effectiveness of
treatment. In conventional ALA-PDT using 20% 5-ALA, maximum fluorescence is found to
occur as late as 8-9 hours after the cessation of application. In contrast, the fluorescence of
liposome-encapsulated 0.5% ALA-treated areas decreased linearly starting approximately 15 min
after the last spraying and thus the susceptible period of phototoxicity after PDT due to residual
fluorescence was minimised (Christiansen et al., 2007). In addition, there was no need for
occlusion during incubation.
Prospective, randomised, controlled trials in the area of light-based therapy for acne are
few, and the data on long-term effects are lacking. Our findings indicated that the combination of
liposome-encapsulated 5-ALA and IPL is a safe and effective alternative for the treatment of
inflammatory acne among Asians. A moderately beneficial effect appeared to last for 6 months
after three sessions of treatment. Patient discomfort and photodynamic effects were minimal with
the current regime of PDT using liposome-encapsulated 5-ALA at 0.5%. Further study in a headto-head fashion is needed to confirm the effectiveness of and refine the PDT regime to determine
the optimal 5-ALA incubation time, so that the long-lasting efficacy of the treatment of acne
among Asians can be achieved with minimal procedure-related discomfort.
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Section C: Treatment of Acne Scars
165
Chapter 8
Evaluation of Combined Fractional
Radiofrequency and Fractional Laser Treatment
for Acne Scars in Asians
166
8.1 Introduction
Facial scarring with surface and colour irregularities is a common long-term cosmetic
concern resulting from acne vulgaris. In a community-based epidemiological study in Hong
Kong of adolescents and young adults, aged 15-25 years, the prevalence of self-reported acne
scars or pigmentation was 52.6%, with 26.6% of the respondents reporting psychological
disturbance due to the appearance of acne and its complications (Yeung et al., 2002). Atrophic
scars are the result of disrupted collagen production during the natural wound-healing process
following the inflammatory response that characterises acne, and the scars result in the
appearance of skin surface irregularities (Tay & Kwok, 2008). Ice-pick scars and boxcar scars
most frequently occur on the face and are sometimes associated with dyspigmentation,
particularly in Asian skin.
Different treatment modalities, including chemical peeling, surgical excision,

dermabrasion and tissue augmentation with fillers, have been used for atrophic scars with
varying degree of success (Jordan et al., 2000; Jacob et al., 2001; Goodman & Baron, 2007).
These options are limited by their efficacy and adverse effects, especially for deep acne scars in
pigmented skin types. While ablative systems that use a carbon dioxide (CO2) laser with or
without an Er:YAG laser can effectively treat deep facial scarring, their use may be associated
with a prolonged recovery period and cosmetic complications, including persistent erythema,
hyper- or hypopigmentation and even scarring (Cho & Kim, 1999; Chan et al., 2002; Sriprachyaanunt et al., 2002). Non-ablative laser devices, such as the 1450 nm diode laser, have been tested
for the treatment of acne scars with a mean objective scar improvement of 5.0-7.9% and a PIH
rate of 39%, while 60% of subjects reported significant improvements (Chua et al., 2004).
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8.1.1 Fractionated technology and concept of sublative rejuvenation

In a single-centre retrospective evaluation of 961 treatment sessions using a 1550 nm
erbium-doped fractional laser for photoaging and scars, skin phototypes III and IV had a higher
PIH incidence of 2.6% and 11.6%, respectively, than type II skin (0.26%) (Graber et al., 2008).
Chan et al. (2010a) reported statistically significant improvements in skin texture (median 6.0
versus 5.0; p<0.001) and acne scarring (median 3.0 versus 6.0; p<0.001) from baseline with a
PIH rate of 18.2% among Asian patients (types III-V) treated with three sessions of full nonablative fractional resurfacing with a 1550 nm erbium-doped laser and a mean total treatment
density of 442.5 MTZ/cm2 in an Asian series. The low complication rate of fractional
photothermolysis resulted from the microcolumns of epidermal and dermal tissue being
thermally ablated at regularly spaced intervals over the skin surface, without injury to the
surrounding tissue. The adjacent non-ablated tissue was then able to accelerate the healing effect
(Jih & Kimy-Aiasadi, 2008). This technique, in comparison with conventional non-ablative
resurfacing, increased the efficacy and resulted in a faster recovery than complete ablative
resurfacing. Ablative and non-ablative fractional laser devices, which are becoming increasingly
popular, offer the potential benefits of full-surface ablative skin resurfacing while minimising
risk and recovery time. However, the major drawback of fractional resurfacing is that it is not as
effective as traditional ablative procedures. Moreover, they may not be equally safe for all skin
types, especially for Asian skin with its relatively high epidermal melanin content in comparison
with that of fair skin. Pigmentary change is a particular concern in Asians after fractional laser
treatments (Chan et al., 2007, 2010a). Non-ablative fractional resurfacing using a 1550-nm laser
is currently considered to be a standard treatment for certain types of mild to moderate atrophic
acne scars, such as boxcar scars, and has a low incidence of adverse effects. There is still
168
controversy over whether the ablative fractional modalities for acne scars confer additional
benefits (Chan et al., 2010b; Ong & Bashir, 2012). Although the improvement is greater than
that with non-ablative fractional photothermolysis, a longer recovery time and a higher risk of
PIH are expected when using ablative photothermolysis, especially in dark-skinned patients.
A fractional bipolar RF device is now used for the treatment of wrinkles and to improve
skin texture via fractional skin ablation and coagulation. A histological study showed welldemarcated zones of ablation and coagulation and sub-necrosis up to a depth of 450 m (Hruza
et al., 2009). The controlled thermal damage in the dermis facilitates the stimulation of wound
healing through collagen remodelling. The advantage of delivering energy in a nonhomogeneous fractional form may also apply to bipolar RF devices via an array of multielectrode pins. The intact zones in between the targeted areas help to maintain skin integrity and
promote wound healing. With the use of fractional bipolar RF, the electric field produces a
pyramid-shaped thermal injury zone such that the thermal effect occurs at a depth of 0.5 mm in
the dermis instead of in the epidermis, with improvements in wrinkles and skin tightness, as
shown in one study for skin rejuvenation (Hruza et al., 2009). This sublative rejuvenation
technique involves about 5% of the epidermis compared with the 10-30% of epidermal
disruption in ablative fractional laser treatments, and most of the thermal effect is centred on the
dermis (Brightman et al., 2009). As the epidermis is disrupted to a lesser extent by this sublative
approach than the dermis, the approach aims to improve facial scars and texture, i.e., a more
uniform skin surface, with minimal recovery time and pigmentary complications.
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8.1.2 Combination of fractional bipolar radiofrequency and diode laser

The fractional 915-nm diode laser and bipolar RF coupled with surface cooling lead to
coagulation at a depth of about 1-2 mm in the deep dermis, and the device has been used to
improve wrinkles and skin texture (Sadick & Trelles, 2005). It was postulated that the fractional
laser pre-heats the target area and that the subsequent RF energy is drawn towards the heated
target deep in the dermis while the superficial part is protected by contact cooling. The use of
both devices in combination is aimed to enhance collagen synthesis in the scar indentation at
deeper layers by infrared laser, and some degree of surface ablation of the scar edges and
collagen remodelling by fractional RF (Taub & Garretson, 2011). The enhanced collagen
synthesis in deeper layers may improve the appearance of scars by elevating their deeper part,
resulting in a more uniform skin surface and improved texture, pore size and pigmentation
irregularity (Hammes et al., 2006). Combined treatment with an ablative fractional carbon
dioxide laser and a non-ablative resurfacing long-pulsed 1064 nm neodymium-doped-YAG laser,
in comparison with an ablative fractional laser alone, has been shown to yield greater
improvement in acne scars in Asian patients (Kim & Cho, 2009).
To date, the majority of clinical experience with fractional RF has been in Caucasians
(Brightman et al., 2009; Hruza et al., 2009; Peterson et al., 2011). A previous study of a similar
fractional RF technique in patients with pigmented skin showed comparable improvements in
acne scars (Ramesh et al., 2010). An increased risk of hyperpigmentation after light-based
therapy has been noted in Asian skin; the hyperpigmentation is related to the higher melanin
content in the epidermis (Chan et al., 2002). The objective of the study reported here was to
evaluate further the safety and efficacy of combined use of fractional bipolar RF and fractional
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diode laser with RF to improve atrophic facial acne scars primarily, and skin texture, pore size
and pigmentation as secondary end-points in Asians.

8.2.1 Subjects
The study was a single-centre, prospective, self-controlled clinical study. Twenty-four
male and female Chinese patients, aged over 18 years, with Fitzpatrick skin types III or IV and
moderate atrophic facial acne scars with visible skin irregularities were enrolled. Exclusion
criteria were active acne, use of topical retinoids during the previous 4 weeks, use of oral
isotretinoin during the previous 6 months, having an active electrical implant, having a
permanent implant or resurfacing procedure in the facial area, facial dermabrasion or chemical
peeling within the prior 6 months, laser, light source or RF treatment within the previous 6
months, a tendency to develop hypertrophic scars or keloids, active dermatosis in the treatment
area, immunosuppression, and pregnancy and lactation in women. The use of anti-acne
treatments and topical whitening agents was not allowed during the study period. Written
informed consent was obtained from all enrollees, and the study protocol was approved by
Western Institutional Review Board (WIRB, Inc., Olympia, WA, USA).
8.2.2 Treatment device parameters

The subjects received up to five combined RF and fractional IR laser treatments followed
by a full-face fractional RF treatment at 4-week intervals. The number of sessions was
determined according by the severity of the acne scars and the subjects response to treatment.
Topical lignocaine 5% (Ela-Max, Ferndale Laboratories, Ferndale, MI, USA) was applied to the
171
whole face under occlusion for 60 min before the interventions. The subjects were also given
oral analgesics (650 mg paracetamol and 65 mg dextropropoxyphene) 30 min before the
procedure. Intramuscular pethidine at 25-50 mg was given for additional analgesia if the pain
remained significant during the procedure despite these measures. Any hair in the treatment area
was shaved before the procedure.
A Matrix IR system (Syneron Medical Ltd., Yokneam, Israel), which emits wavelengths
of 915 nm, was used as the fractional laser plus RF source. Slight erythema and/or oedema in the
test spots were clinical end-points to determine the treatment parameters. Fluences were lowered
when a strong and persistent immediate response or excessive patient discomfort was observed.
The treatment fluences ranged from 50 to 70 J/cm2 for the infrared laser, and RF energy ranged
from 70 to 100 J/cm3. The spot size was 5 5 mm. Lower energy parameters were used over
bony areas. For treatment of the forehead, the mean laser fluence and RF energy were 65 J/cm2
and 91 J/cm3, respectively. For treatment of the cheeks, the mean laser fluence and RF energy
were 67 J/cm2 and 95 J/cm3, respectively. The device has a contact cooling tip. A thick layer of
cold transparent optical index-matching gel was applied to the skin for contact cooling and to
ensure effective optical coupling between the applicator and the skin. The eyes were protected
with small metal eye shields during the use of the laser device. Two of four anatomical areas
the forehead, temples, cheeks and perioral area were treated with 10% overlapping pulses for
two passes, one at an angle perpendicular to that of the electrodes during the first pass.
The second part of the treatment was carried out using a fractional RF device the
Matrix RF system (Syneron Medical Ltd.). The skin was patted dry with a towel, then cleaned
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with an alcohol pad and dried completely before treatment using the second device began. This
entailed a single pass of full facial treatment using a 64-pin head on a disposable applicator tip.
The spot size was 12 12 mm, and epidermal ablation coverage was 5% at a fluence of 50-62
mJ/pin. The mean RF energy applied to the forehead and cheeks was 57.6 mJ/pin and 59.1
mJ/pin, respectively. We selected programme C for deepest penetration of the dermis with
moderate ablation of skin and Mode 2 with a peak power of 75 W for optimum ablation of the
skin. A tip-shaped pattern was visible on the subjects skin after each pulse, showing that the
treated zones did not overlap. The treatment end-points were moderate but transient skin oedema
and tip-shaped erythema that usually lasted for up to a few hours and 1 day, respectively.
Moisturising cream was applied to the treatment area. The subjects were instructed to avoid
exposure to sunlight after the treatment and to use a sunscreen > SPF 30 regularly for at least 1
month.
8.2.3 Assessment
A Canfield Visia-CR System was used to assess the subjects before each treatment and
at follow-up examinations, which were scheduled for 1 and 3 months after the final treatment
because the long-term effect of acne scar improvement has often been noted to start within 3
months after the conclusion of treatment. Three standard close-up photographs (right lateral 37o,
left lateral 37o and central) were taken under standard light, cross-polarised light and parallelpolarised light. The images were stored in the Canfields Mirror software and were assessed by
two blinded investigators who did not participate in treatment of the subjects and were unaware
of the time-point at which the photographs were taken, except the baseline image for
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comparison. Treatment efficacy was evaluated on the basis of overall scar improvement assessed
by comparing close-up photographs taken before the first treatment (baseline), before each
treatment and at follow-up visits. Clinical efficacy was assessed according to a 0-10 grading
scale for the improvement of acne scars, skin texture, enlarged pores and overall pigmentation.
The degree of change was further assessed and categorised as worsening, no change, mild
improvement (1-24%), moderate improvement (25-49%), good improvement (50-74%) or
excellent improvement (75-100%).
Before each treatment and at follow-up visits, the presence and severity of any adverse
effects, including oedema, hyperpigmentation, hypopigmentation, persistent erythema and
scarring, were assessed on cross-polarised and standard photographic images. Adverse effects
were graded as absent, mild, moderate or severe. The presence of other complications, such as
blistering, erosion or infection, was also recorded.
By means of a questionnaire at each visit, the subjects were asked for their subjective
assessment of the changes in acne scarring, skin texture, pigmentary irregularity and pore size,
which they rated using a 10-point VAS (Appendix IV). Changes were then graded in relation to
baseline assessments as: worse than baseline score; 0, no improvement; 1-3, mild improvement;
4-6, moderate improvement; and 7-10, marked improvement. The subjects overall satisfaction
with the procedure was also scored as: 0, not satisfied; 1, somewhat satisfied; 2, moderately
satisfied; and 3, very satisfied. In addition, immediately after treatment with each device,
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subjects were asked to rate their immediate pain level on a scale of 0 to 4, with 0 equal to no pain
and 4 equal to maximum tolerable pain.
Clinical efficacies were determined by statistical analysis: the Wilcoxon signed-rank test
was used to compare clinical results at each follow-up visit with baseline conditions, and the
Mann-Whitney U-test was used to compare pain scores between the fractional laser and
fractional RF devices. All computations were performed with SPSS software (SPSS 15.0 from
SPSS, Inc., Chicago, IL, USA). All p-values were two-sided, and statistical significance was
defined as a p-value <0.05.
8.3 Results
Of the 24 subjects who were enrolled in this case series, 20 completed the study and were
included in the final analysis. Sixteen received five treatments, and the remaining four received
three treatments. A total of 92 treatment sessions were conducted. Three subjects (12.5%)
dropped out after the first treatment because of significant pain during the procedures. They were
mainly in the early phase of the study when the anticipation of pain was not well communicated
before the procedure and oral and/or intramuscular analgesics were not given liberally on an asrequired basis. Most subjects experienced less pain during the subsequent treatments and the
majority were satisfied after the procedures. One subject defaulted after the second treatment
because of a tight work schedule (not medical reasons).
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When the fractional 915-nm diode laser with RF and fractional RF were used, there was a
statistically significant improvement in acne scars, with a decrease in mean grade from 7.3 to 5.4
(out of 10; reduction of 26%) at 1 month after the final treatment (p<0.001) (Table 8.1). In the
assessment of acne scars 3 months after the final treatment, the improvement remained
significant, with a mean reduction in acne scar grade of 29% (p<0.001). Similarly, the
improvement in grading of skin texture, pore size and pigmentation was apparent at one month
after treatment completion and a statistically significant objective improvement in skin texture
(25% improvement), pore size (16% improvement) and pigmentary irregularity (21%
improvement) was seen 3 months after the final treatment (all p<0.001 versus baseline) (Table
8.2).
With respect to the objective overall improvement in acne scars at 1 month and 3 months
after the last treatment, 43.8% and 52.6% of subjects, respectively, showed at least moderate
(>25%) improvement (Figure 8.1). Objective assessment at follow-up visits indicated an
improvement in skin texture and pigmentary irregularity in the majority of subjects, with 52.6%
showing at least moderate improvement in skin texture at the 3-month follow-up visit (Table
8.3). In particular, none of the subjects showed an increased overall irregularity in pigmentation
at any time-point, and 68.7% of subjects had at least mild improvement 1 month after the last
treatment. Improvements in acne scars on the cheeks and temples of subjects after fractional
laser with RF plus fractional RF treatment at follow-up visits are shown in Figures 8.2 and 8.3.
In the subjective questionnaire-based assessment, most subjects reported an improvement

in acne scars and pore size at follow-up visits. The results of the subjective and objective
176
assessments were concordant, with 62.6% of subjects reporting an improvement in their acne
scars and 43.8% reporting a moderate to marked improvement at the 1-month follow-up visit. At
the time of the 3-month follow-up visit, 84.2% of the subjects reported an improvement in their
acne scars, with 36.8% of subjects grading the improvement as moderate to marked (Figure 8.4).
With respect to pore size, 50% and 26% of the subjects indicated at least a moderate subjective
improvement at 1 month and 3 months, respectively, after the final treatment; 43.8% of the
subjects reported being satisfied or very satisfied 1 month after the final treatment. The degree of
satisfaction was increased at the 3-month visit, with 63.2% of the subjects reporting being
satisfied or very satisfied with the procedure (Figure 8.5).
8.3.2 Complications
In general, treatment-related pain was considerable but 88% of the subjects completed the
course of three to five treatments with the pain-relieving measures. The mean immediate pain
score (range 0-4) during treatment was 2.7 (standard deviation, 0.92) for the fractional laser with
RF and 2.6 (standard deviation, 0.92) for fractional RF (Figure 8.6). There was no significant
difference in immediate pain between the two devices (p=0.73). Most subjects experienced less
pain during subsequent sessions, with a median score of 3 during the first treatment and 2 during
the fifth treatment. Pain during treatment was described as somewhat uncomfortable by 64.7% of
the subjects and as very uncomfortable by 33.6%. Additional intramuscular opiate analgesics
were required in 4.3% of all treatment sessions. Three of the four subjects who withdrew from
the study (12.5% of the originally enrolled subjects) withdrew after the first treatment because
they could not tolerate the associated pain.
177
All subjects experienced erythema and oedema that lasted for a few hours to 1 day after
treatment. Tiny scabs less than 1 mm in diameter often formed 1-3 days after treatment and were
shed spontaneously 1-3 days after their formation. Residual mild localised erythema that
resolved within 1 month developed in five subjects, and this adverse effect occurred in 7.6% of
all treatment sessions. As a result of the total 92 treatment sessions, six episodes of transient
post-laser hyperpigmentation at the treatment sites were observed in four subjects. The PIH rate
was 6.5% for all treatment sessions, and most such spots faded within 2 months (Figure 8.7).
Thus, the use of the two devices under the parameters we set resulted in a low PIH rate in
subjects with Asian skin types (Table 8.4). One case of discrete papules with surface erosions on
the left jaw was observed 1 week after the second treatment. In another case, local blisters
developed on both sides of the subjects jaw 1 day after the third treatment. The blisters were
treated with antibiotic ointment and healed within 1 week without scarring or pigmentary
changes. In both subjects, the epidermal injury corresponded exactly to the area treated with the
fractional laser/RF applicator (Figure 8.8).
178
Table 8.1. Acne scar scores* before and after treatment with both devices
Efficacy assessment
No.
Mean
Standard
deviation
Median
p-value
(versus baseline)
Before treatment
(baseline)
20
7.3
1.4
7.50
1 month after third

treatment
20
5.4
1.3
5.50
<0.001
1 month after fifth

treatment
16
5.4
1.6
5.75
<0.001
3 months after last

treatment
19
5.2
1.5
5.50
<0.001
*Scarring rated on a scale of 1-10
179
Table 8.2. Skin texture, pore size and pigmentation scores* before and after treatment with both
devices (*Rated on a scale of 1-10)
Efficacy
assessment for
skin texture
Before treatment
(baseline)
1 month after
third treatment
1 month after
fifth treatment
3 months after
last treatment
Efficacy
assessment for
pore size
Before treatment
(baseline)
1 month after
third treatment
1 month after
fifth treatment
3 months after
last treatment
No.
Mean
Standard
deviation
Median
p-value
(versus baseline)
20
7.3
0.9
7.25
20
5.6
1.1
5.50
<0.001
16
5.7
1.3
5.75
<0.001
19
5.5
1.3
5.50
<0.001
No.
Mean
Standard
deviation
Median
p-value
(versus baseline)
20
6.2
0.7
7.50
20
5.3
0.7
5.50
<0.001
16
5.3
0.6
5.75
<0.001
19
5.2
0.8
5.50
<0.001
p-value
(versus
baseline)
Efficacy assessment for

overall pigmentation
No.
Mean
Standard deviation
Median
Before treatment (baseline)
20
5.5
1.3
7.50
1 month after third treatment
20
4.3
1.3
5.50
<0.001
1 month after fifth treatment
16
4.5
1.4
5.75
<0.001
3 months after last treatment
19
4.3
1.3
5.50
<0.001
180
Figure 8.1. Degree of clinical improvement in acne scars after treatment
100
90
Patients (%)
80
70
55
60
45 43.8
50
42.1
36.8
40
25
30
18.8
20
12.5
10.5
10.5
10
0
No change
Slight
improvement
1mth Post Tx3
Moderate
improvement
1mth Post Tx5
Good/excellent
improvement
3mth Post Last Tx
181
Table 8.3. Improvements in skin texture and pigmentary irregularity months after
treatment
No Change
(%)
Slight
1 month after third

treatment
(%)
Moderate
(%)
Good
(%)
Excellent
(%)
45
50
1 month after fifth

treatment
6.3
50
25
18.8
3 months after fifth

treatment
5.3
42.1
36.8
15.8
Skin texture
Overall pigmentary irregularity

1 month after third
treatment
25
55
15
1 month after fifth

treatment
31.3
43.8
18.8
6.3
3 months after fifth

treatment
26.3
47.4
21.1
5.3
182
Figure 8.2. Parallel-polarised images of atrophic acne scars. Left: Photograph obtained before
treatment of multiple atrophic acne scars on the left temple. Right: A significant improvement is
seen one month after five treatments with fractional radiofrequency and fractional laser with
combined radiofrequency.
183
Figure 8.3. Parallel-polarised images of multiple atrophic acne scars Left: Left cheek before
treatment. Right: Improvement in acne scars is seen 3 months after five treatments with both
devices.
184
Figure 8.4. Subjective assessment of the improvement in acne scarring.
100
Patients (%)
90
80
70
60
47.4
50
50
37.5
40
35
31.3
26.3
30
20
18.8
15.8
10
10
0
12.5 10.5
No improvement
Mild improvement
1mth Post Tx3
Moderate
improvement
1mth Post Tx5
Marked
improvement
3mth Post Last Tx
185
Figure 8.5. Overall patient satisfaction after treatment.
Percentage of subjects (%)
100
90
80
70
60
60
43.8
50
40
25
30
18.8
20
10
0
42.1
31.6
12.5
25 21.1
15
5.3
0
Not satisfied
Slightly
satisfied
Satisfied
Very satisfied
Degree of satisfaction
1mth Post Tx3
1mth Post Tx5
3mth Post Last Tx
186
Figure 8.6. Subjective assessment of immediate pain level during treatment.
100
90
Patients (%)
80
70
60
44.6
50
35.3
40
26.1
30
23.4
15.2
13.6
20
10
32.6
8.7
0.5
0
0
Frac IR
Pain Score
Frac RF
187
Figure 8.7. Cross-polarised images showing mild post-inflammatory hyperpigmentation (A)

before and (B) 1 month after the fifth treatment.
188
Figure 8.8. Cross-polarised images of a patient before (left) and 1 month after (right) the second
treatment, showing multiple discrete hyperpigmented macules over the right cheek
corresponding to the shape of the fractional laser with the radiofrequency device applicator.
189
Table 8.4. Adverse effects and their severity per treatment session
No. (and %) of cases

Mild
Moderate
Severe
Persistent erythema
After first treatment
After second treatment
1 (1.1%)
After third treatment
1 (1.1%)
After fourth treatment
4 (4.3%)
After fifth treatment
1 (1.1%)
After first treatment
2 (2.2%)
1 (1.1%)
After second treatment
1 (1.1%)
After third treatment
After fourth treatment
After fifth treatment
2 (2.2%)
Post-inflammatory
hyperpigmentation
190
8.4. Discussion
The combined fractional 915-nm diode laser and fractional RF were shown, over 12
weeks of observation, to be safe and effective for the treatment for acne scars in Asians. Most
subjects also showed improvements in skin texture, pore size and pigmentation with a high
degree of satisfaction with the procedure. The efficacy of non-ablative fractional resurfacing
treatments has been well established for the treatment of acne scars in Asians (Lee et al., 2008;
Hu et al., 2009; Chan et al., 2010a). Three to five treatments with fractional RF can be
considered as a therapeutic alternative to the non-ablative fractional laser for acne scars in
Asians.
I hypothesised that the clinical efficacy of fractional RF is enhanced by prior treatment

with a fractional diode laser with RF. The use of a non-ablative fractional infrared laser coupled
with a bipolar RF source and contact cooling creates deep dermal heating. The longer
wavelength of the optic energy can reach a depth up to 1.5 mm and induce thermal damage in
zones at that level (Taub & Garretson, 2011). The combination of bipolar RF and infrared laser
energies acts synergistically to increase the depth of dermal penetration and dermal selectivity,
which are desirable for the treatment of atrophic acne scars. It was impossible to judge whether
there was a difference in the efficacy and side effects in a comparison of each individual
treatment modality of the current combination treatment alone because of the study design.
Early clinical studies on fractional RF involved mainly lighter-skinned patients

(Brightman et al., 2009; Hruza et al., 2009; Peterson et al., 2011). Using a prototype RF device,
Brightman et al. (2009) treated 35 patients for skin rejuvenation three times at 1-month intervals
191
with an energy of 8-20 J at 5% coverage. Notable improvements were obtained for wrinkling,
skin tightness and skin brightness with no adverse effects. Taub and Garretson (2011) similarly
treated 20 patients with acne scars with the same fractional RF device in addition to a fractional
infrared laser with RF for up to five sessions. Clinical improvements in acne scarring,
pigmentation and pore size were seen up to 12 weeks after treatment with no serious
complications. Peterson et al. (2011) reported objective improvements in acne scars, with a
72.3% decrease in acne scar scores, as well as in pigmentation and skin texture over a 90-day
observation period, but without a significant change in patient satisfaction over time.
Positive clinical outcomes of fractional RF were also demonstrated in one study

involving 30 Indian patients with skin types IV, V and VI (Ramesh et al., 2010). The VAS
improvement in acne scars ranged from 10-50% at the end of 2 months to 20-70% at the end of 6
months after a maximum of four treatments. The cosmetic result was reported to be excellent
(>60% improvement) by 13% of patients and good (35-60% improvement) by 60%. None of the
treated patients showed post-inflammatory pigmentary changes, but the authors did not specify
the treatment parameters clearly. Consistent with previous findings, I demonstrated a statistically
significant improvement in skin texture, pore size and acne scars as early as 1 month after the
third treatment. Subjective assessment revealed that only 5.3% of patients were not satisfied
overall at the final 3-month visit, with up to 88% of patients feeling satisfied or very satisfied 1
month after the final treatment despite the considerable pain reported.
One of the major concerns in treating Asians with ablative lasers is the development of
PIH. We found a low PIH rate of 6.5% for combined fractional infrared laser with RF and
192
fractional RF treatments in Asian patients with acne scars, despite the more aggressive treatment
parameters and a greater number of treatment sessions. Fractional RF creates localised zones of
thermal damage with restricted effects on the epidermis, which is associated with relatively mild
inflammation, and hence a lower incidence of PIH. Previous studies with traditional full ablative
CO2 lasers yielded a PIH rate of 21-46% in Caucasians (Jemec & Jemec, 2004). The risk of PIH
increases significantly in coloured skin, and can reach 100% in skin types IV and V, as observed
in one study (Nanni & Alster, 1998). The rate of PIH after laser treatment correlates with the
degree of inflammation and the extent of derma-epidermal junction disruption (Nanni & Alster,
1998; Chan et al., 2007). A recent study of fractional ablative CO2 laser treatment in Asians
yielded PIH rates of 55.5% and 37.5% at 1 and 3 months of follow-up, respectively (Chan et al.,
2010b). The relatively high rates of PIH were probably due to aggressive treatment parameters
for optimal clinical efficacy, leading to increased inflammation in that study. Chan et al. (2010a)
reported a PIH rate of 18.2% among Asian patients treated with three sessions of full nonablative fractional resurfacing with a 1550 nm erbium-doped fibre laser and a mean total
treatment density of 442.5 MTZ/cm2 in an Asian series. However, the risk of PIH was lowered to
6.0% when the total treatment densities were reduced to 210.5 MTZ/cm2 by decreasing the
number of passes from eight to four. This implies that the adverse effects of non-ablative
fractional resurfacing can be markedly reduced by lowering the density of resurfacing. In
retrospective study of 961 treatments by Garber et al. (2008), fractional 1550 nm erbium-doped
fibre laser treatment was associated with a relatively low complication rate of 7.6%. The side
effects observed in that studyacneiform eruptions and herpes simplex reactivationwere
temporary and did not result in permanent scarring. PIH occurred at a relatively higher frequency
in patients with darker skin phototypes with a rate of 11.6% in type IV skin.
193
The non-ablative fractional resurfacing erbium-doped laser and ablative fractional CO2
laser use either a stamping device or a rolling hand-piece with an optical tracking system to
ensure uniform delivery of treatment energy and density. However, the current fractional RF and
fractional infrared laser are stamping-mode devices that may render uniform facial treatment
more difficult than scanning-mode devices. Hence, the procedure is technically more demanding.
I observed that complications, including PIH, blistering and papule formation, tend to occur in
skin that lies in close proximity to the bone; thus, lower energy parameters should be considered
when treating these areas with the fractional infrared laser with an RF device.
Another important aspect of treatment with fractional RF is the use of adequate analgesia,
which has not been sufficiently addressed in previous studies of Caucasians (Brightman et al.,
2009; Hruza et al., 2009; Taub & Garretson, 2011). In the Hruza et al. (2009) series, topical
analgesics were applied, and the procedures were tolerated in some cases even without use of
topical anaesthesia. For both RF and laser devices, the appropriate type of analgesia depends on
the intended treatment parameters. It appears that Asian skin is more sensitive to the fractional
procedure in terms of pain threshold; adequate pain control is therefore necessary for the
treatment of acne scars, and topical anaesthetics must be used for patient comfort. Our clinical
experience also showed that fractional RF treatments in general required a similar level of
analgesia to that required by treatment with a fractional diode laser and RF energy.
This case series reported here was limited by the relatively small sample size and the
drop-out rate of 17% in the early phase of the study, mostly due to the subjects inability to
tolerate the pain engendered during the procedure. The treatments of acne scars involve
194
considerable pain, downtime and risk of adverse effects. Recruitment of subjects for randomised
controlled trials are often difficult with high drop-out rate and split-face study with visible
changes on the treated half is not acceptable by most patients. As this was a self-controlled,
single-arm study, one of the major limitations was the lack of a control arm and there was no
direct comparison of the individual devices studied and other existing treatment modalities for
acne scars such as the 1550 nm fractional laser. The relative contribution to the improvement of
acne scars of the individual devices could not be elucidated by the current study design.
Concerning the post-treatment follow-up for long-term effectiveness and side effects, our study
was limited by a relatively short follow-up of up to 3 months when the effect of a resurfacing
procedure could be more apparent at 6 months. As the degree of subject satisfaction was
increased at the 3-month follow-up visit in our study, the data at a 6-month follow-up might be
more revealing. On the other hands, the objective grading and global improvement seemed to
level off at one month post-treatment. More aggressive pain control would have been desirable
for our subjects, because relatively high energy parameters were used in our study. Nevertheless,
statistically significant moderate improvement was observed after three to five treatments with
the combined fractional devices. In addition, studies have adopted different methodologies to
assess the improvement in acne scars, which may account in part for the variation in the clinical
results obtained. Currently, there is no true consensus for the evaluation of acne scars, which is
reflected by the lack of standardisation in assessment across clinical studies and makes direct
comparisons of clinical efficacy between different devices difficult.
My results suggest that fractional RF combined with fractional laser is safe and
moderately effective for the improvement of acne scars in Asians. Further controlled studies to
195
compare the non-ablative fractional laser and radiofrequency devices are needed. The sublative
approach appears to lower the risk of PIH in Asian patients. Because its level of improvement is
comparable with the reported efficacy of non-ablative devices, its average recovery time is 1
week with slight erythema and mild crusting, and the pain level it involves is acceptable, it is a
viable alternative treatment for acne scars in Asians. The low risk of PIH and brief recovery time
of the device studied indicate that it is compatible with the current practice of using multiple
devices. Careful adjustment of energy levels for the use of a fractional laser with a RF device
over bony areas and adequate pain control are essential to reduce discomfort and the risk of
complications.
196
Section D: Concluding remarks

While topical and systemic medical therapies remain the gold standard, they have
certain limitations and light-based treatments have therefore been developed to treat acne and
atrophic acne scars, based on the effect of light on the pathogenic factors of acne, especially
the suppression of growth of P. acnes and thermal alteration of the pilosebaceous unit.
Nevertheless, the risk of PIH after laser and skin resurfacing is greater in Asians because they
have a higher epidermal melanin content than Caucasians.
My clinical studies have allowed several conclusions to be drawn. Acne and acne
scarring are exceedingly common and have a significant psychological effect in young
populations in our locality. PIH is a frequent complication that is associated with the use of
infrared diode lasers coupled with dynamic cooling in darker skin types. My study on the use
of a 1450 nm diode laser on acne indicates that a reduction in sebum production and an
improvement of inflammatory lesions can be achieved using multiple passes of lower energy
and a shorter duration of cooling while minimising the adverse effects, and, in particular,
decreasing the rate of PIH to 3.8% in Asians. Moderate to severe inflammatory acne tends to
be cleared to a greater extent than early comedonal acnes.
PDT involves the use of a photosensitising agent and a light source that achieve
selective damage of the sebaceous gland and P. acnes through the generation of oxygen free
radicals. However, the peri-procedural discomfort and prolonged phototoxic effects that it
engenders have to date limited its use for this indication. I have demonstrated that IPL alone and
in combination with a short period of contact with 16% MAL cream was not more effective than
197
the use of the topical retinoid alone in reducing inflammatory acne lesions in a randomised,
controlled, split-face study in a Chinese population. Thus, IPL is not liable to be useful as a
stand-alone treatment for inflammatory acne, and also creates considerable procedure-related
discomfort. However, IPL did produce a delayed effect of improvement of non-inflammatory
lesions. The minimisation of adverse effects and the production of an adequate photochemical
effect on the sebaceous glands are important considerations in determining the optimal
photosensitising agents. Enhanced uptake of ALA by the pilosebaceous unit through the use of a
liposomal vehicle enhanced the therapeutic efficacy of PDT for inflammatory lesions and
reduced sebum production while minimising the adverse effects, as shown in my study.
Although light-based therapies are promising for the treatment of acne, a complete cure is
still not achievable with the current technology, which resulted in a degree of objective
improvement that was moderate and was not as effective as the conventional systemic treatment
in terms of clinical efficacy, providing an average overall improvement of 40% with a reduction
in mainly inflammatory lesions for up to 6 months in my studies. Therefore, evidence of its longterm efficacy is still lacking. Selective photothermolysis to target the lipid content in the
sebaceous gland has been demonstrated in vivo using a laser with a wavelength of 1720 nm.
Highly selective and irreversible damage of the sebaceous gland may be achievable in the future.
Currently, the light-based device is most efficiently used as an adjuvant treatment to

standard medical therapy or for patients who refuse or cannot tolerate medical therapy. The cost
effectiveness of medical therapy versus light-based treatment for acne needs to be considered.
The cost of light treatment is generally high (ranged from HK$16,000 to HK$20,000) when
198
compared with conventional medical therapy such as a course of oral isotretinoin that can lead to
long-term remission in 60% of the patients (ranged from HK$10,000 to HK$14,000). The
preparation of laser procedure with the actual procedural time can be substantial. The discomfort,
downtime, and safety of light treatments have to be taken into account. Maintenance light-based
treatment may be required every six months. The most feasible approach is probably to combine
light therapy with topical medical treatment, because light therapy has a faster onset of action
while medical treatment prevents the development of new lesions.
Atrophic acne scars are a frequent consequence in patients with moderate to severe
inflammatory acne. While conventional ablative laser resurfacing using CO2 or Er:YAG lasers
can effectively improve the skin surface irregularities, fractional technology using a laser or
RF has been developed with comparable efficacy, and reduced recovery time and
complications. The concept of fractional thermolysis involves the use of lasers or RF to induce
arrays of microscopic thermal injury surrounded by normal viable tissue. The columns of intact
skin result in rapid re-epithelialisation of the epidermis within 24 hours. The main issue
regarding the use of such technology in Asians is the risk of PIH. Fractional RF results in
confined thermal injury to the skin so that the subsequent healing process can lead to new
collagen formation, with an improvement of atrophic acne scars. The pyramidal configuration
of the zone of tissue coagulation in this sublative approach is associated with less epidermal
disruption, and hence a lower risk of PIH. My study investigated the use of fractional RF
combined with a fractional diode laser for acne scars and showed that this approach can
achieve an improvement of acne scars with a high degree of patient satisfaction. Although pain
was its main limitation, the PIH rate was low when extra caution was taken when treating bony
199
areas, which makes this approach a viable alternative for the treatment of atrophic acne scars in
Asians.
In summary, light-based therapy, including mid-infrared lasers, PDT and fractional

devices, can be used effectively and safely as a therapeutic option for acne and acne scars in
Asians. Future developments will be focused on highly selective light sources and
photosensitising agents for the sebaceous units which will lead to a substantial and irreversible
reduction of the sebaceous gland function.
200
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225
Appendix I
Telephone survey on the prevalence, knowledge and management of acne in Hong Kong
adolescents and young adults
Part A: Personal information

1Are you aged between 15 and 25 years?
Yes
No Questionnaire ends here.
2How old are you?
15
16
17
18
19
20
21
22
23
24
25
Refuse to answer
3What is your gender
Male
226
Female
4What is your educational level
Never went to school or kindergarten level
Primary level
Junior secondary level (F1 to F3)
Senior secondary level (F4 to F5)
Matriculate (F6 to F7)/Institute of technology
Tertiary education (including Institute of Education/College/
Polytechnic Institute/University, etc.
Postgraduate level (including Master/Doctor)
Refuse to answer
5Are you now a student or have you been working?
Student
Unemployed/housewife
Work
Refuse to answer
6What is your monthly income
< HK$4,000
>=HK$4,000 and <HK$7,000
>=HK$7,000 and <HK$10,000
>=HK$10,000 and <HK$14,000
>=HK$14,000 and <HK$17,000
>=HK$17,000 and <HK$20,000
227
>=HK$20,000 and <HK$24,000

>=HK$24,000 and <HK$40,000
Refuse to answer/unstable income
Not applicable
Part B: Acne
1Generally, how often do you get acne ?
Often
Sometimes
Seldom
Never
2Do you have any scars or pigment remaining on the face because of acne?
Yes
No
Not applicable
3Do you have acne now?
Yes
No
Not applicable
4Do you know any of the causes of acne?
More than one answer can be chosen
Essential phenomenon in puberty
Eat too much deep fried food/inadequate fruits
228
Not enough sleep

Inheritance
Excessive sebum production
Sebum secretion blocking pores
Bacterial infection
Inadequate cleaning/poor personal hygiene
Internal body heat (concept in Chinese medicine)
Digestive problems
Hormonal imbalances
Poor air quality
Menstruation
Inadequate water intake
Sensitive skin/Skin not good
Poor wound care
Alcohol drinking/smoking
Hot weather
Make-up not adequately removed
Mental stress
I dont know/hard to say
Other reasons
5Generally, how much does your acne bother you?
Very much
Somewhat
229
A little
Not at all
5aWhich aspects mostly bother you?Only for those who are bothered by acne
Affect appearance
Itch/uncomfortable/pain
Affect interpersonal relationship
Time consuming to take care
Self-esteem
Other aspects
Refuse to answer
230
6When you have acne, how do you deal with it?

More than one answer can be chosen
Apply over-the-counter topical medications for acne
Squeeze it out by hand
Eat less deep fried food/eat more fruits
Wash face more frequently
Sleep more
Consult a general practitioner
Consult a dermatologist
Do a facial treatment
Drink herbal remedy/TCM
Use skin care products
Use oil absorbing paper
Drink more water
Reduce drinking and smoking
Wrap face with a warm towel
Relax
Use acne dressing/comedone extractor
Stop using cosmetic products/skin care products
Apply honey to face
Cover with cosmetics
Nothing, just let it be
231
Other methods
6a1Do you think over-the-counter topical medication for acne is effective?
Yes
No
6a2Do you think Squeeze it by hand is effective?
Yes
No
6a3Do you think Eat less fried food/eat more fruits is effective?
Yes
No
232
6a4Do you think Wash face more frequently is effective?

Yes
No
6a5Do you think Sleep more is effective?
Yes
No
6a6Do you think Consult a general practitioner is effective?
Yes
No
6a7Do you think Consult a dermatologist is effective?
Yes
No
6a8Do you think Do a facial treatment is effective?
Yes
No
6a9Do you think Drink herbal remedy or TCM is effective?
Yes
No
233

6a10Do you think Skin care products are effective?
Yes
No
6a11Do you think Oil absorbing paper is effective?
Yes
No
6a12Do you think Drink more water is effective?
Yes
No
234
6a13Do you think Reduced drinking and smoking is effective?

Yes
No
6a14Do you think Wrap face with a warm towel is effective?
Yes
No
6a15Do you think Relax is effective?
Yes
No
6a16Do you think Use acne dressing/comedone extractor is effective?
Yes
No
6a17Do you think Stop using cosmetic products/skin care products is effective?
Yes
No
6a18Do you think Apply honey is effective?
Yes
No
235

6a19Do you think Cover with cosmetics is effective?
Yes
No
236
7Have you tried to use medication to treat acne?

Yes
No
Not applicable* (Interviewees who have never had acne
7aAre those medications mainly topical or oral?
Topical
Oral
Not applicable* (Interviewees who never had acne or who never used medication to
treat acne)
7bHow long do those medications need to be taken for a course? (unit: day)
1
2
3
4
5
7
14
21
30
49
60
90
120
150
237
180
I dont remember/hard to say
treat acne)
238
7cHow much do these medications cost for a whole course?

<HK$100
HK$101-HK$500
HK$501-HK$1,000
HK$1,001-HK$2,000
HK$2,001-HK$5,000
HK$5,001-HK$10,000
treat acne)
7dWhat is the efficacy of these medications on your acne?
Totally clear
Less, but acceptable
Less, but still bothering
Remain the same
treat acne)
7eDid your acne relapse after the treatment?
Yes
No
treat acne)
239
8Do you know that there is a long-term cure for acne?

Yes
No
240
Appendix II
Treatment of Facial Acne with 1,450-nm Infrared Diode Laser in Asians study
Follow-up Visit Questionnaire
*After ____treatment
1. Acne
Worsening
No change
Mild
Moderate
Marked improvement
___________________________________________________________________________________
0
2. Acne Scarring
Worsening
No change
Mild
Moderate
Marked improvement
___________________________________________________________________________________
0
3. Oiliness
Worsening
No change
Mild
Moderate
Marked improvement
___________________________________________________________________________________
0
4. Pores
Worsening
No change
Mild
Moderate
Marked improvement
___________________________________________________________________________________
0
241
5. Immediate Pain Level (VAS)
No pain
Worst possible pain
Moderate
_________________________________________________________________________________
0
10
242
Appendix III
Liposomal ALA Photodynamic Therapy for Acne
1. Facial Acne
No improvement
Complete improvement
_________________________________________________________________________________
0
10
2. Acne Scarring
No improvement
_________________________________________________________________________________
0
10
3. Oiliness
No improvement
_________________________________________________________________________________
0
10
243
4. Pores
No improvement
_________________________________________________________________________________
0
10
5. Overall Satisfaction
No satisfaction
Complete satisfaction
_________________________________________________________________________________
0
10
244
Appendix IV
Combined Fractional Radiofrequency and Laser for Acne Scars
1. Acne Scarring
No improvement
_________________________________________________________________________________
0
10
2. Skin Texture
No improvement
_________________________________________________________________________________
0
10
3. Pigmentary Irregularity
No improvement
_________________________________________________________________________________
0
10
245
4. Pores
No improvement
_________________________________________________________________________________
0
10
5. Overall Satisfaction
Not satisfied
Somewhat satisfied
Moderately satisfied
Very satisfied
____________________________________________________________________________________
0
6. Immediate Pain Level (VAS)
No pain
Maximum tolerable pain
Moderate
___________________________________________________________________________________
0
246
LIST OF PUBLICATIONS
A proportion of the materials contained in the proposed thesis have been published in
international and local journals as listed below.
A community-based epidemiological study of acne vulgaris in Hong Kong adolescents.

Yeung C.K., Teo L.H., Xiang L.H., Chan H.H. 2002. Acta Derm Venereol 82(2):104-107.
A comparative study of intense pulse light alone and its combination with photodynamic
therapy for the treatment of facial acne in Asian skin.
Yeung C.K., Shek S.Y., Bjerring P., Yu C.S., Kono T., Chan H.H. 2007. Lasers Surg Med
39(1):1-6.
Treatment of inflammatory facial acne with 1,450-nm diode laser in type IV to V Asian skin
using an optimal combination of laser parameters.
Yeung C.K., Shek S.Y., Yu C.S., Kono T., Chan H.H. 2009. Dermatol Surg 35(4):593-600.
Light-based Treatment for Acne.

Yeung C.K., Chan H.H. 2009. HK J Dermatol Venereol 17(4):190-198.
Liposome-encapsulated 0.5% 5-aminolevulinic acid with intense pulsed light for the
treatment of inflammatory facial acne: A pilot study.
Yeung C.K., Shek S.Y., Yu C.S., Kono T., Chan H.H. 2011. Dermatol Surg 37(4):450-459.
Evaluation of the combined treatment with fractional laser and fractional radiofrequency for
acne scars in Asians.
Yeung C.K., Chan N.P., Shek S.Y., Chan H.H. 2012. Lasers Surg Med 44(8):622-630.
247
Peer-reviewed international conference proceedings
A comparative study of intense pulsed light alone for treatment of facial acne in Asian skin
and in combining photodynamic therapy.
Yeung CK, Shek SY, Yu CS, Kono T, Chan HH. Lasers Surg Med 2006; S18: 29.
Treatment of facial acne with 1450 nm diode laser in Asians.

Yeung CK, Shek SY, Carol YS, Chan HH. Lasers Surg Med 2007: S19: 23.
Treatment of inflammatory facial acne with 1,450-nm diode laser in type IV to V Asian skin
by optimal combination of laser parameters.
Yeung CK, Shek SY, Yu CS, Chan HH. J Invest Dermatol 2008: 128: S59.
A pilot study of intense pulsed light combined with 0.5% liposome encapsulated 5-ALA for
the treatment of facial acne in Asian.
Yeung CK, Shek SY, Yu CS, Kono T, Chan HH. Lasers Surg Med 2008; S20: 103.
Evaluation of the combined treatment with fractional laser and fractional radiofrequency for
acne scars in Asians.
Yeung CK, Chan NP, Yu CS, Chan HH. Lasers Surg Med 2011; S23: 939.
248

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Light-based therapy for acne vulgaris

Creative Commons: Attribution 3.0 Hong Kong License

Light-based Therapy for

A Thesis Submitted in Fulfillment of the Requirements for the Degree of

Abstract of thesis entitled

Light-based therapy for acne vulgaris

A split-face, controlled study was performed to evaluate the effectiveness of intense

An abstract of 499 words

I would like to express my heart-felt thanks and warmest acknowledgments to my

Hypothesis, Aims and Brief Outline of the Work

Section A: Introduction and Epidemiology of Acne and Acne Scars

2.1.2 Aetiology and pathogenesis of acne

2.1.2.1 Sebum production

2.1.2.2 Microcomedones as precursor lesions of acne

2.1.2.3 Bacteriology of Propionibacterium acnes

2.1.2.4 Inflammation in acne

2.1.3 Clinical findings

2.1.4 Current treatments and limitations

2.1.4.1 General principles

2.1.4.2 Topical antimicrobial therapy

2.1.4.3 Topical retinoids

2.1.4.4 Miscellaneous topical agents

2.1.4.5 Oral antibiotics

2.1.4.6 Hormonal therapy

2.1.4.7 Systemic retinoid

2.2 Laser-tissue interactions and concept of selective photothermolysis

2.3 Mechanisms of the clinical applications of lasers and photodynamic therapy

2.3.1 Targeting Propionibacterium acnes

2.3.2 Targeting sebaceous glands

2.3.3 Main modalities of light treatments for acne

2.3.3.1 Incoherent light sources

2.3.3.2 Pulsed-dye laser (PDL)

2.3.3.3 Mid-infrared laser

2.3.3.4 Intense pulsed light (IPL)

2.3.3.5 Photodynamic therapy (PDT)

2.3.3.6 Photopneumatic therapy

3.2 Classification of acne scars

3.3 Pathophysiology of acne scarring

3.4 Psychological morbidity

3.5 Treatment options and limitations

3.6 Concept of fractional resurfacing for acne scars

4.2 Materials and methods

4.3.2 Frequency of acne

4.3.3 Complications of acne

4.3.4 Public knowledge of the aetiology and treatment options of acne

4.3.5 Psychological effects of acne

4.3.6 Health-seeking behaviour in acne patients

Section B: Lasers and Photodynamic Therapy for Acne

5.2 Subjects and methods

5.2.2 Laser parameters

5.2.3.3 Objective assessment of sebum production

6.2 Materials and methods

6.2.2 Device parameters

6.2.3.1 Clinical photographs

6.2.3.2 Fluorescence photographs

6.3.1 Degree of improvement

6.3.2 Adverse effects

7.2 Materials and methods

7.2.2 Laser parameters

7.2.3.3 Objective assessment of sebum production

7.3.2 Adverse effects

Section C: Treatment of Acne Scars

8.1.1 Fractionated technology and concept of sublative rejuvenation