Lasers in Medical Science

https://doi.org/10.1007/s10103-021-03296-z

REVIEW ARTICLE

A systematic review of randomised controlled trials investigating

laser assisted drug delivery for the treatment of keloid
and hypertrophic scars
Kelvin Truong 1,2 & Ines Prasidha 3 & Tevi Wain 1

Received: 17 January 2021 / Accepted: 19 March 2021

# The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature 2021

Abstract
The objective of this article is to study the clinical efficacy and adverse events of laser-assisted drug delivery in the treatment of
hypertrophic and keloid scars. We searched the following databases up to 22 October 2020: the Cochrane Skin Group Specialised
Register, the Cochrane Central Register of Controlled Trials (Clinical Trials) in The Cochrane Library, MEDLINE, EMBASE,
and reference lists of articles for randomised clinical trials (RCTs) of laser-assisted drug delivery for the treatment of hypertrophic
and keloid scars. We also searched online trials registries for ongoing trials and contacted trial authors where appropriate. Our
outcomes of interest were objective clinical evaluation of scars, participant satisfaction, and adverse effects of the treatments.
Two authors independently extracted data and assessed trial quality using Cochrane Risk of Bias 2. Two authors independently
abstracted data. We included 10 RCTs involving a total of 329 participants: six trials utilised parallel-arm RCTs whilst four
employed split-scar design. Three trials had high risk of bias with the remaining seven rated as having some concerns. The
interventions and outcomes were too varied to be combined statistically. High-quality randomised controlled trials assessing
laser-assisted delivery for drugs in the context of hypertrophic and/or keloid scarring are needed. Studies with a larger number of
participants, with longer follow-up times, and standardised evaluation of outcome and adverse effects are warranted.

Keywords Laser-assisted drug delivery . Laser . Keloid . Hypertrophic scar

Introduction erythematous lesions that remain within the margins of the

Hypertrophic and keloid scars result from an imbalance of
collagen synthesis and degradation after dermal injury [1, 2].
Common causes include acne, burns, lacerations, piercings,
and surgery. Genetics play a key role in the development of
keloids scars [3, 4]. This is evidenced through the incidence of
keloids in certain ethnic groups; affecting 5–10% of Africans,
0.1–1%, of Asians, and less than 0.1% of Europeans/North
Americans [5]. Clinically, hypertrophic scars are raised
* Kelvin Truong
kelvintruong1318@gmail.com
1
Department of Dermatology, Westmead Hospital, Sydney, NSW,
Australia
2
Sydney Medical School, The University of Sydney, Sydney, NSW,
Australia
3
Department of Plastic Surgery, Westmead Hospital, Sydney, NSW,
Australia
original wound. In comparison, keloid scars extend beyond
the boundaries of original injury and may invade surrounding
skin [2].
Keloids and hypertrophic scars have psychological and
physical impact on patient lives, limiting social interaction
and an individual’s ability to work [6, 7]. It is therefore im-
portant to treat keloids and hypertrophic scars to improve
symptoms and quality of life.
Treatments include compression therapy, topical sili-
cone, intralesional injections, cryotherapy, surgical exci-
sion, and laser therapy [8]. Recurrence rates vary depend-
ing on technique used and may range from 9 to 100% [9,
10]. Multiple or combination therapies are often trialled to
help with the symptoms and appearance of hypertrophic
and keloid scars [8].
Laser therapy has been used to improve the appearance and
thickness of keloids and hypertrophic scars. Pulse dye laser
(PDL), carbon dioxide (CO2) laser, and neodymium-doped
yttrium aluminium garnet (Nd:YAG) laser have demonstrated
efficacy in reducing the appearance and symptoms [11].

Laser-assisted drug delivery (LADD) is an evolving treat-
ment modality [12]. Ablative fractional lasers create vertical
cone-shaped channels known as microablation zones (MAZ)
[12–14]. Application of topical agents to MAZ allows for
increased penetration of the stratum corneum and enhancing
bioavailability of medications [12, 15]. The combination of
ablative fractional laser treatment and topical medications is
promising for the treatment of keloids [16, 17]. A review of
the literature showed that there was a wide variation in the
quality of studies which highlighted the need for a critical
appraisal of the evidence. Guidance from a systematic review
could therefore be very helpful to evaluate the differences in
efficacy and adverse effects between laser types and ways of
treatment.
To the best of the author’s knowledge, there are no system-
atic reviews of randomised controlled trials (RCTs) for LADD
in the context of keloid and hypertrophic scars [16, 17]. The
objective of this systematic review is to evaluate the clinical
efficacy and adverse events of laser-assisted drug delivery in
the treatment of hypertrophic and keloid scars
Materials and methods
Criteria for considering studies for this review
Types of studies
All RCTs utilising laser assisted drug therapy with an inter-
vention for treating hypertrophic and/or keloid scars were
considered for this study. We will not include cross-over
studies.
Types of participants
These are individuals with hypertrophic and/or keloid scars
with no restrictions regarding age, sex, scar aetiology, or skin
type. We will not consider participants who are at risk of
developing hypertrophic or keloid scars but have not devel-
oped them (preventative treatment).
Types of interventions
Experimental Laser-assisted topical or intralesional drug ther-
apy used to treat hypertrophic and/or keloid scars. We will
consider any kind of laser device, using any fluency, course
duration, number of sessions, and follow-up time, compared
with another intervention.
Control Laser therapy, or intralesional medication, or topical
medication
Lasers Med Sci
Types of outcome measures
Primary outcomes & Clinical evaluation of hypertrophic
and/or keloid scar via a standardised
scale
& Participant evaluation of hypertrophic and/or keloid scar
via standardised scale
Secondary outcome & Incidence and severity of adverse
effects
Criteria for excluding studies for this review
Non-RCT, e.g. case control studies, case reports, cohort stud-
ies, review articles, abstracts
Search methods for identification of studies
We aimed to identify all relevant RCTs regardless of study
period, language, or publication status.
Electronic searches
We searched the following electronic databases up to 22
October 2020 (through Medline OVID):
& The Cochrane Central Register of Controlled Trials
(Clinical Trials) in The Cochrane Library using the fol-
lowing search terms: (keloid) or (hypertrophic scar) or
(laser) or (light therapy)
& MEDLINE using the strategy in Appendix 1
& EMBASE using the search strategy in Appendix 1
Ongoing trials
On 22 October 2020, we searched for ongoing trials in the
following online registries using the terms: “keloid” or “hy-
pertrophic scar” and “laser”.
& Nottingham Ongoing Skin Trials (www.nottingham.ac.
uk/ongoingskintrials)
& The Australian New Zealand Clinical Trials (www.anzctr.
org.au)
& The World Health Organization International Clinical
Trials (www.who.int/trialsearch)
& The US National Institutes of Health Ongoing Trials
(www.clinicaltrials.gov)
Lasers Med Sci
Searching other resources
We checked the references of included and excluded studies
for further trials. For missing data in the article, we sent an
email to the author to try and obtain relevant data.
We attempted to find unpublished studies by searching the
following grey literature:
& Google Scholar using the strategy in Appendix 2 up to 22
October 2020
& OpenGrey using the strategy in Appendix 3 up to 22
October 2020
Data collection and analysis
Selection of studies
Two authors independently searched for trials (KT and IP).
We checked titles and abstracts identified from the searches.
The full text of all studies of possible relevance was obtained
for independent assessment by two authors (KT and IP). The
authors independently decided which trials fulfilled the inclu-
sion criteria. Disagreements were resolved by discussion. For
the excluded trials, the reasons for exclusion were
documented.
Included full-text studies will be summarised in Table 1.
Excluded full-text studies will be summarised in Table 1. A
PRISMA flow chart diagram will be made available (Fig. 1).
Data extraction and management
Two authors (KT and IP) carried out the data extraction inde-
pendently using a standardised data extraction form.
Disagreements were resolved by discussion.
The following information was extracted:
& Study features:
Publication details
Study design
Participant characteristics
Ethnicity of patients
Details of interventions (e.g. number of laser treatment
sessions, regimen)
Number of participants randomised into each treatment
group
Funding sources
Conflict of interest
& Outcomes and results:
Outcomes assessed
Time of outcome assessment
Adverse events
Assessment of risk of bias in included studies
Two authors independently assessed the quality of the studies
included in the review according to the criteria described in
the Cochrane Handbook for Systematic Reviews of
Interventions, Cochrane Risk of Bias 2 [28]. We assessed
the domains, rating them as at low, unclear, or high risk of
bias.
We reported these assessments for each individual study in
the “Risk of bias” table located in Table 1. We tried to contact
the study author(s) to seek clarification in cases of uncertainty
over data.
Measures of treatment effect
We had planned to pool trials that evaluated similar interven-
tions using a random-effects model using Review Manager
5.4 [29].
For continuous outcomes that used similar scales, we cal-
culated mean differences (MD) and 95% confidence Intervals
(CIs). For continuous outcomes that used different scales, we
calculated standardised mean differences (SMD) and 95%
CIs.
Six trials utilised parallel arm RCT design whilst four
employed within participant design. The presented results
did not allow for an estimation of 95% CI. Therefore, we have
presented the p values, where available, that were reported in
the papers for the primary outcome measures.
Dealing with missing data
For missing or unavailable data, we contacted the study au-
thors for additional information. In case of non-response, we
reported dropout rates in Table 1 of the review and, where
possible, used intention-to-treat analysis [28].
If appropriate, we would have imputed the missing data
with replacement values. In our study of continuous out-
comes, we would have imputed the mean observed. We would
have performed sensitivity analyses excluding the participants
with missing data to assess the strength of the results [28].
Assessment of heterogeneity
Where substantial heterogeneity (I2 > 50% and p < 0.10)
existed between studies for the primary outcomes, we planned
to explore the reasons for the heterogeneity by considering the
methodological quality of the trials, the variation in treatments
(laser types, fluences, and frequencies of treatment), and the
type of participants.
 Lasers Med Sci

Table 1 Characteristics of included studies

Study Lesion Age Country Intervention(s) Control Laser setting n Follow- Outcomes
(years) of study up assessed and
method
evaluating
efficacy

Sahib et al. Hypertrophic 14–37 Iraq Fractional CO2 laser + Intralesional - 22 4 months Hypertrophy,
(2020) and keloid intralesional triamcinolone texture, and
[18] scar triamcinolone acetonide. colour
acetonide. Monthly Monthly sessions (4-point scale)
sessions for 4 for 4 months
months
Sabry et al. Hypertrophic 5–20 Egypt CO2 laser + topical Intralesional 10,600 nm with power 20* 6 months VSS, Patient
(2020) & keloid Botulinum toxin Botulinum toxin 25 W, dwell time Scar
[19] scar type A (2.5U/cm3) type A (2.5U/cm3) 1000 microseconds, Assessment
once a month for 4 once a month for 4 and spacing 800 Scale—pain,
months months micrometres for pruritus,
keloid and power 15 colour,
W, dwell time 600 thickness,
microseconds, and relief, and
spacing 800 pliability
micrometres for
hypertrophic scars.
Each session
consisted of 3
passes.
Rahman Hypertrophic 9–56 Egypt Nd:YAG laser + 4 sessions of 1064-nm-long pulsed 45 3 months VSS, Patient
et al. scar intralesional Nd:YAG at Nd:YAG laser. Spot Scar
(2020) triamcinolone 4-week intervals size of 7 mm, Assessment
[20] acetonide (1–2mg). fluence of 75 J/cm2, Scale—pain,
4 sessions at pulse duration of 20 pruritis, and
4-week intervals ms, and frequency relief
Nd:YAG laser + of 0.3 Hz s. Each
intralesional session consisted of
botulinum toxin 3 passes
type A (2.5
3
U/cm ). 4 sessions
at 4-week intervals
Khattab Keloid 18–58 Egypt Pulse dye laser Intralesional 595nm wavelength, 40 Follow-up VSS, Overall
et al. treatments at 6–8 verapamil every 3 4–15 J/cm2, 7mm at final appearance,
(2020) weeks + weeks for a spot, 1.5 ms pulse session dyschromia,
[21] Intralesional verap- maximum of 8 duration, 30 ms degree of
amil. Azithromycin sessions. spray: 20 ms delay hypertrophy
500mg daily for 3 Azithromycin and texture
days and topical 500mg daily for 3 using
fusidic acid cream days and topical modified
for a week fusidic acid cream Manchester
for a week quartile score
Sabry et al. Hypertrophic 19.8 ± Egypt Ablative fractional Ablative fractional 10,600-nm 30 1 month VSS, Patient
(2019) and keloid 14.2 CO2 + topical 5- CO2. 4 treatment wavelength. Laser Scar
[22] scar (M- fluorouracil sessions at power ranged from Assessment
ean) (50–250mg). 4 1-month intervals 15 to 20 W with Scale—pain,
treatment sessions Stack 3 or 4, dwell pruritis
at 1-month inter- time ranged from
vals 700 to 1,000 ms,
Ablative fractional and spacing ranged
CO2 + topical from 500 to 700
verapamil mm. The
hydrochloride approximate depth
(1-5mg). 4 was 1200 mm, and
treatment sessions density was 8.7%.
at 1-month inter- Energy X DOT = 36
vals mJ, and fluence was
3.27 J/cm2
Woo et al. Acne 20–70 North Long pulsed Nd:YAG Triamcinolone 0.1% Fluence of 25 to 35 13* 1 month 10-point global
(2018) keloidalis Amer- once a month for 8 cream to the scalp J/cm2, spot size of assessment
[23] nuchae ica months + twice daily 10 mm, and pulse score
Lasers Med Sci

Table 1 (continued)

Study Lesion Age Country Intervention(s) Control Laser setting n Follow- Outcomes
(years) of study up assessed and
method
evaluating
efficacy

Triamcinolone duration of 35 ms.

0.1% cream to the Smaller papules
scalp twice daily were single pulsed,
and larger lesions
were double pulsed.
Alsharnoubi Hypertrophic 2–10 Egypt Ga-As LLLT + Dimethicone + emu 905 nm, energy 15* 3 months VSS, U/S to
and scar Dimethicone + oil + beeswax + density of 12.6 measure thick-
Mohamed emu oil + beeswax almond oil. Twice J/cm2, pulsed mode ness of the
(2018) + almond oil. a week for 12 with frequency skin, Laser
[24] Twice a week for weeks 3000 Hz Doppler per-
12 weeks fusion imager
to measure
perfusion
Chen et al. Keloid 26.7 ± China Intralesional Intralesional 1,064-nm single 12-ms 62 Follow-up Patient
(2017) 7.5 diprospan and diprospan once a pulse at an energy at final self--
[25] (M- 5-flourouracil once month for 3 density of 90–100 session assessment,
ean) a month for 3 months J/cm2 with a 6-mm observer
months spot and a single assessment,
Nd:YAG + pass of spots over- erythema,
Intralesional lapping 5–10% toughness,
diprospan and pruritis
5-flourouracil once (5-point scale)
a month for 3 Measurements
month (mm)
Asilian et al. Hypertrophic 5–70 Iran Pulse dye laser + 4mg Once a week 585-nm wavelength 60 1 month Patient
(2006 ) and keloid triamcinolone + injection of 2-mgwith a pulse self--
[26] scar 45mg triamcinolone duration of 250 assessment,
5-flouruouracil. acetonide for 8 microseconds at an observer
Performed once a sessions energy density of 5 assessment,
week for 8 weeks to 7.5 J/cm2 with a erythema,
4mg triamcinolone + 5-mm spot and a pliability,
45mg single pass of spots pruritis
5-flouruouracil. overlapping (5-point scale)
Injected once a 10–20% without Measurements
week for 8 weeks. cooling for three (mm)
sessions at 1st, 4th,
and 8th weeks
Alster Hypertrophic 21-45 North Pulsed dye laser + Pulse dye laser. Two 585-nm wavelength 22* 6 weeks Clinical
(2003) scar Amer- triamcinolone treatments 6 with fluences improvement,
[27] ica acetonide injection weeks apart ranging 4.5 to 5.5 pliability,
(10–20mg). Two J/cm2 (average of symptoms
treatments 6 weeks 5.0 J/cm2) were (4-point scale)
apart applied to the length
of each scar using
nonoverlapping
10-mm collimated
spots with concom-
itant cryogenic
cooling (30 ms) and
a laser pulse dura-
tion of 1.5 ms

*Within participant studies; diprospan, 1 mL contains 2-mg betamethasone disodium phosphate and 5-mg betamethasone dipropionate; Ga-As LLLT,
gallium arsenide low level Laser therapy; Nd:YAG, neodymium-doped yttrium aluminum garnet

Fig. 1 Flowchart of study
selection
Assessment of reporting biases
For the primary outcomes, we planned to investigate publica-
tion bias, if possible, first by visual inspection of funnel plots
and then by formal testing.
Data synthesis
If we identified no substantial heterogeneity, we computed
pooled estimates of the treatment effect for each outcome
under a fixed-effect model. Otherwise, if we identified sub-
stantial heterogeneity, we performed a random-effects
analysis.
Sensitivity analysis
If there were an adequate number of studies, we would have
performed sensitivity analyses based on separation of studies
according to our assessment of the risk of bias of allocation
concealment (high, low, or unclear) and blinding of outcome
assessment (high, low, or unclear).
Lasers Med Sci
Results
Results of the search
The “Study flow diagram” summarises the results of our in-
corporated searches up to 22 October 2020 (see Fig. 1). We
identified ten potentially relevant randomised clinical trials
[18–27]. We excluded six studies [30–35].
Included studies
Design
All included studies were RCTs. Six studies employed parallel
arm randomised control trial [18, 20–22, 25, 26]. Four of these
trials were split-scar studies [19, 23, 24, 27].
Participants
Three hundred and twenty participants were included in the
ten RCTs. The age of participant ranged from 2 to 70 years
[24, 26]. Seven studies included the mean and range scar
duration [18, 19, 21, 23, 25–27].
Lasers Med Sci
Four studies investigated a mixed hypertrophic and keloid
scar population [18, 19, 22, 26]. Three studies exclusively
studied hypertrophic scars [20, 24, 27]. Two studies focused
on keloid scars [21, 25]. One study investigated acne
keloidalis nuchae [23].
All the included studies reported small numbers of partic-
ipants ranging from 13 to 62 [23, 25].
The Fitzpatrick skin type was reported in only two studies
[19, 27]. Patient ethnicities were not specified in any study.
Interventions
The following interventions were used within the included
studies (grouped by laser type):
1) Fractional carbon dioxide (CO2) and topical botulinum
toxin type A vs IL botulinum toxin type A [19]
2) Fractional CO2 and IL TAC vs IL TAC [18]
3) CO2 laser and topical 5-FU vs CO2 laser and topical
verapamil vs CO2 laser [22]
4) Long pulsed (neodymium-doped yttrium aluminium
garnet (Nd:YAG) once a month for 8 months and triam-
cinolone 0.1% cream to the scalp twice daily vs triam-
cinolone 0.1% cream to the scalp twice daily [23]
5) Nd:YAG laser and IL triamcinolone acetonide vs
Nd:YAG laser and IL BoNT-A vs Nd:YAG laser [20]
6) Nd:YAG and IL diprospan and IL 5-FU vs 5-FU and IL
diprospan vs IL diprospan [25]
7) Pulse dye Laser (PDL) and IL triamcinolone vs PDL
[27]
8) PDL laser and IL verapamil vs IL verapamil [21]
9) PDL and IL triamcinolone and 5-FU vs IL triamcinolone
and 5-FU vs IL triamcinolone [26]
10) Gallium-arsenide low light laser therapy (Ga-As LLLT)
and dimethicone and emu oil and beeswax and almond
oil vs dimethicone and emu oil and beeswax and almond
oil [24]
Methodology
Treatment protocol and length varied greatly. Trials com-
pared two or three treatments, with either laser or medi-
cation used as control. This made for difficult comparison
across studies. Moreover, one study only had two sessions
of therapy 6 weeks apart [27]. This is in contrast to 24
sessions of therapy by Alsharnoubi and Mohamed [24].
Moreover, the follow-up after final treatment varied.
Some studies evaluated scars at the end of their treatment
regimen whilst others assessed longer-term progress at 6
months [19, 21, 25].
The pre- and post-treatment of patients varied between
studies, which may have accounted for differences in adverse
events. Three studies subjected each patient to topical anaes-
thetic gel by topical lidocaine 8% for 0.5–1 h before starting
laser and intralesional steroid injection [18, 20, 22]. Sabry
et al. also used Arden healing and soothing cream twice a
day [22].
Outcome assessments
There was great heterogeneity in outcome assessment.
Although the primary outcome of interest was similar between
all studies, there were differences in the assessment methods
used. Five studies utilised the standard Vancouver Scar Scale
for the primary outcome [19–21, 23, 24]. Three studies
employed the standard Patient Scar Assessment Scale for the
participant’s assessment of improvement [19, 20, 22]. Two
studies employed similar 5-point scales in their patient self-
assessment, observer assessment, erythema, toughness,
pruritis assessments, as well as measurement of scars [25,
26]. Two studies used four point scales but for different out-
comes (hypertrophy, texture, and colour vs clinical improve-
ment, pliability, and symptoms) [18, 27]. One study used a 10-
point global assessment score [23].
Funding source
One study declared no financial disclosure [18]. One study
was supported by medical education [23]. No information
was found in the other eight articles.
Conflict of interest
Five studies declared no conflict of interest [18–21, 23]. No
information was found in the other five studies.
Excluded studies
Six studies were excluded; please see the Table 1 for the
reason for exclusion.
Risk of bias in included studies
See Fig. 2 which gives judgements about each “risk of bias”
item for each included study and Fig. 3 which gives judge-
ments about each “risk of bias” item presented as percentages
across all included studies.
The methodological quality of seven included trials was of
some concerns [18, 20, 22, 25–27]. Three trials were rated as
high risk of bias [19, 21, 23, 24].
Randomisation process
No studies included information on the randomisation pro-
cess. Only one study reported allocation concealment [24].

Fig. 2 Risk of bias summary
Deviation from intended interventions
Studies often employed single blinding [18, 20, 22–27].
Conventionally, the assessors were blinded. Although not
clearly stated by the authors, blinding participants and people
delivering interventions may have been difficult as they were
comparing combination treatment with monotherapy.
Fig. 3 Risk of bias graph
Lasers Med Sci
Missing outcome data
One study analysed 13 out of 21 participants
randomised [23]. This high lost to follow-up puts the
study at high risk of bias. One other study had an ac-
ceptable loss to follow-up [25].
Lasers Med Sci
Measurement of the outcome
Two studies did not employ blinding and therefore were con-
sidered high risk of bias, especially in the context of subjective
scoring [19, 21].
Selection of the reported result
All studies reported results according to protocol.
Effects of intervention
Due to the heterogeneity of the methodology, outcome mea-
surement, and result reporting, we were unable to present the
findings from these studies using the RevMan software.
Carbon dioxide lasers
Fractional CO2 and topical botulinum toxin type A vs
IL botulinum toxin type A [19]
Primary outcomes
Vascularity For hypertrophic scars, there was evidence to sug-
gest that improvement in combination therapy was more than
intralesional monotherapy (p = 0.017). For keloid scars, there
was evidence that vascularity improved more with
intralesional Botox compared to combination therapy (p =
0.046).
Height For hypertrophic scars, there was evidence to suggest
that improvement in combination therapy was more than
intralesional monotherapy (p = 0.019). For keloid scars, there
was no difference between treatment groups (p = 0.102).
Pliability For hypertrophic scars, there was evidence to sug-
gest that improvement in combination therapy was more than
intralesional monotherapy (p = 0.029). For keloid scars, there
was evidence to suggest that pliability improved more with
intralesional Botox than with combination therapy (p =
0.039).
Pigmentation For hypertrophic scars, there is evidence to sug-
gest that pigmentation improved with combination therapy
than with intralesional Botox (p = 0.034). Neither therapy
demonstrated improvement from baseline for keloid scars.
Total VSS For hypertrophic scars, there was strong evidence to
suggest that improvement in combination therapy was more
than intralesional monotherapy (p = 0.005). For keloid scars,
there was no difference between treatment groups (p = 0.092).
POSAS For hypertrophic scars, patients subjectively scored
better with combination therapy with a mean score of 17 ±
7.2 (SD) compared to monotherapy 25.4 ± 8.1 (p < 0.001). For
keloid scars, monotherapy had very strong evidence for im-
proving POSAS score (15.4 ± 7.8) compared to combination
therapy (24.9 ± 8.3) with a p < 0.001.
Secondary outcomes
Adverse events Sabry et al. reported minimal symptoms like
pain and pruritus which were not significantly different before
and after treatment [19].
Fractional CO2 and IL TAC vs IL TAC [18]
Primary outcome
Clinical improvement—4-point scale Hypertrophy, texture,
and colour were assessed in this study on a four-point scale
and then combined for an overall score. Combination therapy
scored 2.8 compared to monotherapy which scored 2.2.
Secondary outcomes
Adverse events Treatment was tolerable by patients, and no
adverse effects were reported except mild pain and transient
erythema in some patients immediately after treatment [18].
CO2 laser and topical 5-FU vs CO2 laser and topical
verapamil vs CO2 laser [22]
Primary outcomes
Vascularity Both combined therapy had evidence for improve-
ment in vascularity compared to monotherapy [22]. There was
no difference between combined therapies (p = 1).
Height There was evidence for a decrease in scar height for
CO2 laser and topical 5-FU compared to monotherapy (p =
0.012).
Pliability There was strong evidence for a decrease in scar
height for CO2 laser and topical 5-FU compared to monother-
apy (p = 0.001).
Pigmentation All three therapies had little to no evidence of
improvement compared to baseline. There was no evidence
for difference between the three therapies.
Total VSS Both combined therapies were superior to mono-
therapy regarding improvement of VSS score.

Patient scar assessment—pain Only CO2 laser and topical 5-
FU demonstrated evidence for decrease in pain. There was no
evidence of difference between the groups.
Patient scar assessment—pruritis All three groups demon-
strated evidence for reduction in pruritis. There was no evi-
dence of difference between the groups.
Patient scar assessment—patient satisfaction Both combined
therapies had evidence for improvement in patient satisfaction
compared to monotherapy.
Secondary outcomes
Adverse events “Topical application of 5-FU or verapamil
after laser session showed no side effects”.
Nd:YAG lasers
Long pulsed Nd:YAG once a month for 8 months and
triamcinolone 0.1% cream to the scalp twice daily vs
triamcinolone 0.1% cream to the scalp twice daily [23]
Primary outcome
10-point global assessment score The authors report “…mean
change was −3.2 (−49.2%) on the treated side and −2.2
(−32.8%) on the control side (P = .144)”. Therefore, there
was no evidence for difference.
Secondary outcomes
Adverse events The authors did not on report adverse events.
Nd:YAG laser and IL triamcinolone acetonide vs
Nd:YAG laser and IL BoNT-A vs Nd:YAG laser [20]
Primary outcomes
Vascularity Combination therapy had very strong evidence for
improvement in vascularity from baseline (p = 0.001).
Monotherapy did not improve from baseline. No comparison
between groups was made.
Height All three therapies had very strong evidence of im-
provement compared to baseline (p = 0.001). No comparison
between groups was made.
Pliability All three therapies had very strong evidence of im-
provement compared to baseline (p = 0.001). No comparison
between groups was made.
Lasers Med Sci
Pigmentation All three groups had no evidence of improve-
ment compared to baseline.
Total VSS All three therapies had very strong evidence of
improvement compared to baseline (p = 0.001). No compari-
son between groups was made.
Patient scar assessment—pain All three therapies had strong
evidence of improvement compared to baseline. No compar-
ison between groups was made.
Patient scar assessment—pruritis All three therapies had
strong evidence of improvement compared to baseline. No
comparison between groups was made.
Patient scar assessment—relief All three therapies had strong
evidence of improvement compared to baseline. No compar-
ison between groups was made.
Secondary outcomes
Adverse events Nd:YAG laser therapy was well tolerated
without any adverse effects. Slight tolerable pain was experi-
enced during intralesional injection of steroid and Botox.
Nd:YAG and IL diprospan and IL 5-FU vs 5-FU and IL
diprospan vs IL diprospan [25]
Primary outcome
Patient self-assessment (5-point scale) No mean ± SD was
provided. “Improvements were rated highest in the diprospan
+ 5-FU + Nd:YAG group and lowest in the diprospan group”.
Observer assessment (5-point scale) No mean ± SD was pro-
vided. “Improvements were rated highest in the diprospan + 5-
FU + Nd:YAG group and lowest in the diprospan group”.
Erythema (5-point scale) No mean ± SD was provided.
“Erythema score in the diprospan + 5-FU + Nd:YAG group
was significantly lower than that in the diprospan and
diprospan + 5-FU groups (p<0.05 for each)”.
Toughness (5-point scale) No mean ± SD was provided. “The
pliability score in the diprospan + 5-FU + Nd:YAG group was
significantly lower than that in the diprospan and diprospan +
5-FU groups (p<0.05 for each)”.
Pruritis (5-point scale) No mean ± SD provided. “There was a
statistically significant reduction in pruritus score in the
diprospan + 5-FU + Nd:YAG group when compared with that
in the diprospan group (p<0.05)”.
Lasers Med Sci
PDL lasers
IL verapamil and PDL laser vs IL verapamil [21]
Primary outcomes
Vascularity Combination therapy demonstrated very strong
evidence in improving vascularity compared to baseline (p <
0.001). Monotherapy did not demonstrate improvement from
baseline. No comparison between groups was made.
Height Combination therapy and monotherapy demonstrated
very strong evidence in improving height compared to base-
line (p < 0.001). No comparison between groups was made.
Pliability Combination therapy and monotherapy demonstrated
very strong evidence in improving height compared to baseline
(p < 0.001). No comparison between groups was made.
Pigmentation There was little to no evidence for decrease in
pigmentation for either therapy compared to baseline.
Secondary outcomes
Adverse events Monotherapy was associated with 2 regrowth
events and 1 depigmentation. Combination therapy experi-
enced 3 regrowth, 1 pain, 2 hyperpigmentation, 1 depigmen-
tation, and 7 purpura.
PDL and IL triamcinolone vs PDL [27]
Primary outcome
Clinical improvement (4-point scale) According to the authors
“Six weeks after the second treatment, scores were 2.42 and
2.50 for PDL alone versus PDL/steroid combination”. There
was no statistical analysis available.
Secondary outcomes
Adverse events “Side effects were limited to mild purpura
(average duration of 4.5 days), transient mild hyperpigmenta-
tion (four patients, average duration of 5 to 6 weeks), and
intraoperative pain (mild for PDL alone and moderate for
PDL/steroid combination)” [27].
PDL & IL triamcinolone and 5-FU vs IL triamcinolone
and 5-FU vs IL triamcinolone [26]
Primary outcome
Patient self-assessment (5-point scale) There was statistically
significant decrease in patient-self assessment score in the
PDL and IL triamcinolone and 5-FU group compared with
the IL triamcinolone group (p < 0.05).
Observer assessment (5-point scale) There was statistically
significant decrease in observer assessment score in the
PDL and IL triamcinolone and 5-FU group compared
with the IL triamcinolone group (p < 0.05).
Erythema (5-point scale) At the end of the study, this
measure in the PDL and IL triamcinolone and 5-FU
group was significantly lower than the IL triamcinolone
and IL triamcinolone and 5-FU groups (p < 0.05 for
both).
Pliability (5-point scale) There was no evidence for difference
in the three groups. All three groups had evidence for better
pliability than baseline
Pruritis (5-point scale) Severity of pruritus was significant-
ly decreased versus baseline in all study groups at all
follow-up visits. There was statistically significant de-
crease in pruritus score in the PDL and IL triamcino-
lone and 5-FU group compared with the IL triamcino-
lone group (p < 0.05).
Secondary outcomes
Adverse events In the TAC group, 37% of patients reported
some degree of skin atrophy and telangiectasia. Areas treated
with the PDL became purpuric, which lasted from 7 to 10
days.
GA-AS LLLT lasers
Dimethicone + emu oil + beeswax + almond oil + Ga-
As LLLT vs dimethicone + emu oil + beeswax + al-
mond oil [24]
Primary outcome
VSS—total There was very strong evidence for a decrease in
VSS score pre and post-treatment (p = 0.001). There was also
strong evidence that combination therapy with Ga-As LLLT
demonstrated a lower VSS score than the control group (p =
0.005)
Secondary outcomes
Adverse events The authors did not report adverse events.

Discussion
Summary of key findings
In this systematic review, RCTs were assessed to examine the
efficacy of laser assisted drug delivery for the treatment of
keloid and hypertrophic scars.
This review is based on ten randomised clinical trials with
329 participants. All trials evaluated two or three treatments.
The follow-up times were short for all trials and varied be-
tween 0 and 6 months after the final session of therapy. Most
trials utilised single blinding of assessors only. Four of the ten
RCTs were split-scar studies.
There is limited high quality evidence comparing laser-
assisted delivery of drugs in the context of hypertrophic and
keloid scars. Firstly, the number of included articles was very
low. Secondly, the methodology of the included studies was
poor. Three of the ten included trials had one domain which
was rated high risk of bias. Furthermore, the remaining seven
trials had some concerns. This systematic review was there-
fore limited by the studies included. Unfortunately, there was
missing information which could not be obtained from the
authors of the studies.
One of our primary outcomes was objective scar assess-
ment. We considered this end point of great importance due to
subjective nature of appearance of hypertrophic and keloid
scars. Although all the studies assessed scars, they utilised
different scales such as the Vancouver Scar Scale, 10-point
global assessment score, and clinical improvement scales.
Moreover, some studies only reported the final mean ± stan-
dard deviation without stating the difference from baseline.
This limited statistical analysis. Future studies should utilise
a standard scar assessment scale such as the Vancouver Scar
Scale with full statistical reporting.
Another one of our primary endpoints was subjective scar
assessment. This is important due to the potential psycholog-
ical impact of hypertrophic and keloid scars. Unfortunately,
not all studies investigated subjective assessment of scars.
Hopefully, future studies will utilise a standard scar assess-
ment scale such as the POSAS in their assessment.
Our secondary outcome was adverse events from laser-
assisted delivery of medications compared to control.
Although complications were reported by authors, adverse
events were not outcomes of interest in any of the included
trials. Evaluation of adverse events is warranted in future stud-
ies to enable clinicians to evaluate their use in practice.
Overall completeness and applicability of evidence
The findings of this systematic review are limited by the qual-
ities of included studies. All studies were of some concern or
high risk of bias. Moreover, there was great heterogeneity in
participants, methodology, and outcome assessment. Studies
Lasers Med Sci
with larger samples and longer follow-up times are needed to
determine potential differences in clinical outcomes and po-
tential harms.
Conclusions
Implication for further research
High-quality randomised controlled trials assessing laser-
assisted delivery for drugs in the context of hypertrophic
and/or keloid scarring are needed. Studies with a larger num-
ber of participants, with longer follow-up times, and
standardised evaluation of outcome and adverse effects are
warranted. Moreover, future studies may consider a factorial
randomised controlled trial design to gain as much informa-
tion as possible efficiently.
Supplementary Information The online version contains supplementary
material available at https://doi.org/10.1007/s10103-021-03296-z.
Availability of data and material Not applicable.
Code availability Not applicable.
Author contributions All authors contributed to the study conception and
design. Material preparation, data collection, and analysis were per-
formed by Kelvin Truong and Ines Prasidha. The first draft of the man-
uscript was written by Kelvin Truong and all authors commented on
previous versions of the manuscript. All authors read and approved the
final manuscript.
Declarations
Ethics approval Not applicable.
Consent to participate Not applicable.
Consent for publication Not applicable.
Competing interests The authors declare no competing interests
Competing interests The authors declare no competing interests
Additional declarations for articles in life science journals that report the
results of studies involving humans and/or animals Not applicable.
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