INTRODUCTION
Scars cause significant aesthetic and psychosocial impacts on patients in the
practice of plastic surgery. Hypertrophic scars and keloids are lesions that
commonly appear after skin injury, causing aesthetic and functional damages,
which are sometimes difficult to treat. Clinical evaluation of a scar is
necessary to determine the correct treatment and effectiveness of the therapy.
Multiple objective and subjective tools were created to characterize scars,
which suggests that none of these tools is complete enough to evaluate the
clinical and psychosocial aspects of pathological scars1.
Keloids are violaceous scars of hard consistency that exceed the limits of the
initial wound and are more frequently found in individuals with genetic
predisposition, mainly those of black and oriental ethnicities, with an
incidence of 4.5–16%, as compared with an incidence of < 1% in Caucasians.
The sites of greatest involvement are the chest, back, and joints, with no
sex-specific pattern.
They are also influenced by sex hormones, which explains their higher incidence
between ages 10 and 30 years, and during pregnancy. Histological examination
revealed an increase in glycosaminoglycans and type I and III collagens, with
disorganized and irregularly dispersed fibers.
Hypertrophic scars are high, tense, reddish, do not exceed the limits of the
original lesion, and tend to regress over time. On histological examination,
they show an increase in type III collagen, with organized fibers and fibers
parallel to the epidermis. Both can cause pain and itching, and have abundant
dermal collagen due to an imbalance between its synthesis and degradation.
However, its pathophysiology has not yet been fully elucidated2.
Failures in the regulatory mechanisms of healing, which have not yet been well
established, such as the decrease in apoptosis of fibroblasts and the role of
growth factors, particularly transforming growth factor B1 (TGF-B1), have been
studied in the development of this disorder. Matrix metalloproteinase 9 (MMP9),
a family of enzymes responsible for connective tissue degradation, is known to
be less evident in keloids and hypertrophic scars than in healthy skin in
immunohistochemical tests, and measurement of MMP9 level is important for the
histological evaluation of the effectiveness of the treatment performed3-5.
Several treatments are available for these two conditions, among which the
combination of intralesional corticosteroid injections, silicone bandages, and
local pressure is referred to as standard treatment by theInternational Advisory
Panel on Scar Management consensus (IAPSM), despite its limitation. Second-line
therapy for refractory cases, in turn, includes ablative or non-ablative laser
therapy and surgical excision associated with the use of silicone gel.
Fractional laser treatments induce a healing response, increasing type III
collagen levels and remodeling the tissue6.
Tissue resurfacing using fractional photothermolysis was introduced in 2004. The
fractional technique produces columns of thermal and ablative damage, known as
microthermal treatment zones (MTZ), interspersed with areas of untreated skin, a
process that accelerates tissue recovery. In 2007, a new method to produce MTZ
using ablative carbon dioxide (CO2) was described. This method proved
effective in reaching all layers of the skin (stratum corneum, epidermis, and
dermis) through ablation and coagulation, with maximum control of tissue damage
without reducing the efficacy and with the remodeling of collagen lasting for at
least 3 months after treatment, which was confirmed by immunohistochemistry7,8.
Intracellular and extracellular water absorbs the energy of the CO2
laser at a wavelength of 10,600 nm, causing rapid heating and vaporization of
the tissue to a depth of 20 to 60 µm. The heating of the dermis causes
contraction and remodeling of the collagen with a thermal necrosis zone ranging
from 20 to 50 µm. Reepithelialization occurs after 5 to 10 days, and
erythema time depends on the energy used9.
The standard treatment for hypertrophic scars and keloids, which are frequently
encountered conditions in the routine practice of plastic surgery and
dermatology, do not always help achieve satisfactory results, and clinical
improvement is difficult to evaluate. The use of lasers was introduced as a
secondary alternative for the treatment of these conditions, and the mechanism
of the clinical and histological changes of the treated tissues is still under
study, with no consensus so far. As few studies in the literature confirm these
data and the overall improvement of a scar is difficult to objectively evaluate,
the methodologies used to confirm the results obtained after the treatment of
pathological scars with CO2 laser must be reviewed.
OBJECTIVE
This systematic literature review aimed to identify prospective experimental
before-and-after studies on the treatment of hypertrophic scars and keloids that
used fractional CO2 laser and identified clinical and histological
changes and described the methodology used for evaluating scars before and after
intervention.
METHODS
An extensive electronic review was conducted in the Latin American and Caribbean
Literature in Health Sciences (LILACS), Health Information from the National
Library of Medicine (Medline), Web of Science, and Scientific Electronic Library
Online (SciELO) electronic library databases. We searched the databases using a
combination of the following terms: “keloid/quelóide,” “hypertrophic
scar/cicatriz hipertrófica,” and “CO2 laser,” according to the PRISMA
Statement10.
Two independent researchers tracked the titles and abstracts of the articles
identified. Afterward, the full texts of the potentially relevant articles were
reviewed. The inclusion criteria were controlled or non-controlled experimental
studies, studies published between 2004 and 2017, and studies that included
patients with hypertrophic scars or keloids in which isolated treatment with
fractional CO2 laser was used, with a clearly described
methodology.
Studies in languages other than English, Spanish, and Portuguese, and outcomes
other than clinical or histological evaluation of scars before and after
treatment were excluded.
The articles were subdivided into groups according to the condition treated
(keloid and/or hypertrophic scar) and the outcome (clinical and/or
histological). The results are presented in tables according to the
outcomes.
The results of each group (mean and standard deviation, and percentage indexes)
were analyzed, and the control, pretreatment, clinical outcomes (according to
the scar evaluation scale used), and histological outcome, when applicable, were
compared.
RESULTS
Initially, 102 articles were identified in the electronic databases by evaluating
their titles and abstracts. The full texts of 28 publications were evaluated,
and 7 studies were selected for inclusion according to the established
criteria.
The studies were subdivided according to the outcome studied. Of the studies, 7
investigated the clinical changes in the treatment of hypertrophic scars, of
which 2 investigated keloids and 3 (already selected in previous selections)
reviewed histological and immunohistochemical parameters.
Clinical outcomes in hypertrophic scars
Table 1 shows the main results of
studies on changes in hypertrophic scars evaluated using clinical
measurement scales. Considering that statistically significant results have
a p value of <0.05, a statistically significant
difference was observed between the clinical scores measured before and
after treatment by El-Zawahry et al.7,
Azzam et al.3, Makboul et al.5, Lei et al.13, and Hultman et al.14. Choi et al.12
reported significant improvements in flexibility and scar height.
Table 1 - Outcome parameters of fractional CO2 laser treatment
of hypertrophic scar.
First author/year |
N |
Comparison Groups |
Platform parameters |
Outcome measures |
Clinical outcomes |
Significance between the groups |
El- Zawahry, 20157 |
11 |
Before sessions of fractional CO2
laser X After treatment
|
3 sessions, DEKA, 30w, 800-µm spacing,
800-µs dwelling time, stack 1
|
VSSa POSASb |
Hypertrophic scars showed improvement in
texture and significant decreases in Vancouver score and
POSAS.
|
p = 0.011
(VSS) p = 0.017 (POSAS observer
score) p = 0.180 (POSAS
patient score
|
Azzam, 20153 |
7 |
Half of the scar treated with fractional
CO2 laser X Half of the scar left
untreated
|
4 sessions with 6-week intervals;
DEKA; 25w; stack 3; 600-µs
dwelling time; 700-800 spacing- hypertrophic keloid:
30w; stack 4; 1000 µs; 800
spacing |
VSS |
The VSS score was significantly lower in the
treated scar halves than in the untreated scar halves.
|
p = 0.042 (after 3
months) p = 0.027 (after 6
months)
|
Makboul, 20145 |
40 |
Before sessions of fractional CO2
laser X After treatment
|
4 sessions with 1-month intervals; ATL 250
CO2 medical laser system; 25 w; time on = 1
ms; pixels per inch = 6
|
VSS |
A statistically significant difference in the
VSS score was found between before and after the fractional
CO2 laser treatment.
|
p > 0.001 (VSS)
|
Drooge, 201511 |
12 |
Half of the scar treated with fractional
CO2 laser X Half of the scar left
untreated
|
3 sessions with 8-week intervals; UltraPulse
Encore - Lumenis Inc, Santa Clara, CA - spot diameter 120
µm, 600 Hz, 30-40 mJ
|
POSAS GPAc |
GPA showed no statistically significant
difference between the treated and untreated sides of the
scar.Statistical analysis revealed no significant difference
in POSAS score between the two sides of the scar.
|
p = 0.70 (GPA at 6
months) p = 0.09 (POSAS)
|
Choi, 201312 |
10 |
Before sessions of fractional CO2
laser X After treatment
|
1-9 sessions with 4- to 8- interval;
Lutronic Corp, Korea; 40-60 mJ; 150
spots/cm2 |
VSS 5-point rating scale
|
Flexibility and scar height significantly
improved, while the improvements in vascularization and
pigmentation were negligible.
|
49.8% (change in VSS) 51%
(flexibility) 75% (height)
|
Lei, 201713 |
158 |
Before the fractional CO2 laser
sessions X After treatment
|
3 sessions with 3-month intervals; UltraPulse
Encore Lumenis, Yokneam, Israel; 150-175 mJ, 40 Hz; distance
between spots 3-5 mm
|
VSS UNCd patient
satisfaction survey
|
VSS and UNC scores showed statistically
significant differences from before to after fractional
CO2 laser treatment.
|
p < 0.0001
(VSS) p < 0.0001 (UNC)
|
Hultman, 201414 |
147 |
Before sessions of fractional CO2
laser X After treatment
|
2-6 sessions with 4- to 6-week intervals;
Lumenis UltraPulse, Santa Clara, CA
|
VSS UNC4Pe |
Fractional CO2 laser treatment
resulted in significant improvements in the scars.
|
p < 0.001
(VSS) p < 0.001 (UNC4P)
|
Table 1 - Outcome parameters of fractional CO2 laser treatment
of hypertrophic scar.
Clinical outcomes in keloids
Only two studies that compared pretreatment and posttreatment keloids were
found considering the criteria established for this review. Azzam et
al.3 reported a significant
difference in the clinical scale scores that they used, with improvement in
the treated scar halves (p = 0.006). El-Zawahry et al.7, in turn, reported no improvement in
scars, which can be seen in Table 2.
Table 2 - Outcome parameters of fractional CO2 laser treatment
of scars and keloids.
First author/year |
N |
Comparison groups |
Outcome measures |
Clinical outcomes |
Significância entre os gruposc |
El- Zawahry, 20157 |
3 |
Before sessions of fractional CO2
laser X After treatment
|
VSS scorea POSAS
scoreb |
Keloid scars showed no improvement in texture
or Vancouver or POSAS score.
|
p = 0.102
(VSS) p = 0.180 (POSAS observer
score) p = 0.018 (POSAS patient
score)
|
Azzam, 20153 |
12 |
Half of the scar treated with fractional
CO2 laser X Half of the scar left
untreated
|
VSS score |
The VSS score was significantly lower in the
treated halves than in the untreated halves.
|
p = 0.006 (after 3
months) p = 0.018 (after 3
months)
|
Table 2 - Outcome parameters of fractional CO2 laser treatment
of scars and keloids.
Histopathological outcomes
El-Zawahry et al.7 and Azzam et
al.3 reported significant
differences in the orientation and density (p = 0.001 and
p < 0.05, respectively) of collagen fibers before
and after treatment. The latter also reported an increase in the
immunohistochemical expression level of MMP9 (p < 0.05).
Makboul et al.5 reported greater
thickness of the epidermis after treatment (p < 0.001)
and decreased immunohistochemical expression of TGF-B1 (p
< 0.008). The main histopathological results are shown in Table 3.
Table 3 - Parameters of histopathological outcomes
First author/year |
N |
Comparison groups |
Outcome measures |
Histological outcomes |
Significance between the groupsd |
El-Zawahry, 21057 |
10 |
Scara
treated with CO2 X Scar left untreated
|
- Uniformity, density, and
orientation of collagen fibers in the ablation
areab |
- After 3 months: less dense and more aligned
collagen fibers in hypertrophic scars (n = 8)
|
p = 0.001
|
- Decreased thickness of hypertrophic
scars*
|
p = 0.012
|
- After 3 months: less dense and more aligned
collagen fibers in keloids (n = 2)
|
p = 0.046
|
- No difference in average keloid
thickness
|
p = 0.18
|
Azzam, 20153 |
30 |
Scarc
treated with CO2 X Scar left untreated
|
- Uniformity, density, and orientation of
collagen fibers in the ablation areab |
- After 3 months: less dense and more aligned
collagen fibers
|
p < 0.05
|
- Immunohistochemical evaluation of
MMP9c |
- Larger expressionImmunohistochemistry of
MMP9 after treatment
|
p < 0.05
|
Makboul, 20145 |
8 |
Scar treatedwith CO2 X
Scar left untreated
|
- Thickness of the epidermis-
Presence of TGF-B1
|
- Increased thickness after treatment (3
months)
|
p < 0.001
|
- Lower immunohistochemical expression (6
months)
|
p < 0.008
|
Table 3 - Parameters of histopathological outcomes
DISCUSSION
The treatment of pathological scars is considered to be unpredictable, although
it is standardized worldwide. The mechanism of keloid formation and hypertrophic
scars, which may help guide treatment, is still under study. The functions of
growth factors (TGF-B1) and degradation proteins (MMP9) are still uncertain.
Options such as the CO2 laser are important adjuvants in
treatment1.
Azzam et al.3 reported clinical
improvements in Vancouver scar scale (VSS) scores and histological findings 3
months after treatment with an ablative CO2 laser. They observed more
flexible scars and better organized and thinner collagen bundles, with
significant increases in MMP9 level after 1 month.
A study that evaluated the effect of fractional ablative CO2 in burn
scars reported decreased densities of collagen bundles and changes in the
orientation of these fibers through histopathological examination, which
clinically contributed to changes in scar texture6.
Another prospective and descriptive study conducted with a sample of 40 scars in
a population of 30 patients reported that the use of a combination of Nd:YAG of
1064 nm and fractional CO2 laser at 20 W was significantly effective
in improving the vascularization and flexibility of the treated skin, besides
reducing itching, only in hypertrophic scars. Moreover, one of the most
important effects of the laser on the scar is the generation of heat, which
culminates in an inflammatory process that increases vascular permeability, the
production of metalloproteinases, and the decomposition of collagen fibers9.
Scar clinical evaluation scales were developed to better understand treatment
results, although histopathological analysis of collagen changes and
immunohistochemical markers is important for providing scientific evidence15,16.
Although the mechanism of photothermolysis in the treatment of scars is
uncertain, the columns produced by thermal injury, characterized by localized
epidermal necrosis and denaturation of collagen, initiate a sequence of events
that results in a balance between collagenesis and collagenolysis17.
This review selected studies that compared hypertrophic scars and keloids of any
nature between before and after treatment with fractional CO2 laser,
either from a clinical or histological point of view. Some studies reported a
significant improvement in the characteristics and symptoms of scars3,5,6,12-14. Evidence of
modification of histopathological characteristics related to collagen, growth
factors, and immunohistochemical markers was also reported3,5,6.
The authors argue that fractional CO2 laser should be considered as a
promising treatment option for pathological scars. Despite the scarcity of
studies with good methodology, this treatment option has been shown to
clinically and histologically alter scar tissues, thereby modifying collagen
fibers and improving clinical signs and symptoms such as pruritus, color, and
thickness.
COLLABORATIONS
LEAS
|
Analysis and/or data interpretation, conception and design study,
conceptualization, data curation, investigation, methodology,
project administration, supervision, visualization, writing -
original draft preparation, writing - review & editing.
|
AH
|
Analysis and/or data interpretation, conception and design study,
conceptualization, final manuscript approval, project
administration, supervision.
|
MF
|
Conceptualization, final manuscript approval, project administration,
supervision, writing - review & editing.
|
IC
|
Analysis and/or data interpretation, data curation, realization of
operations and/or trials, writing - original draft preparation.
|
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1. Instituto Israelita de Ensino e Pesquisa Albert
Einstein, São Paulo, SP, Brazil
2. Pontifícia Universidade Católica do Rio Grande
do Sul, Porto Alegre, RS, Brazil.
Corresponding author: Luciana El Halal
Schuch Av. Luiz Manoel Gonzaga, nº 187/602 - Porto Alegre, RS, Brazil
Zip Code 90470-280 E-mail: luciana_schuch@yahoo.com.br /
contato@lucianahalal.com.br
Article received: April 12, 2018.
Article accepted: January 14, 2019.
Conflicts of interest: none.