10 1002@lsm 23244
10 1002@lsm 23244
Background and Objectives: The use of picosecond have pulse durations between 300 and 900 picoseconds.
laser in dermatology was originally focused on optimizing Originally designed for tattoo removal, picosecond
the removal of unwanted tattoos. Subsequent advances in lasers have since shown efficacy in treating a wide
this technology have broadened its clinical indications to range of cutaneous conditions.
include treatment of benign pigmented lesions, photo- Previous seminal works have established the proposed
damage, melasma, and scar revision. In this systematic mechanism of action of picosecond laser [2–4]. Briefly, in
review, evidence‐based recommendations are developed the setting of an unfractionated beam, the ultra‐rapid
for the use of picosecond laser in dermatology. temperature changes induced by picosecond pulses gen-
Study Design/Materials and Methods: A compre- erate strong acoustic shockwaves within target chromo-
hensive search of the English language literature was phores resulting in tensile stresses that exceed the frac-
performed up to and including November 2019. Relevant ture threshold of these targets. This photomechanical or
citations were individually evaluated, synthesized, and photoacoustic effect is the primary method whereby tattoo
categorized based on the Level of Evidence. With the ad- ink particles and cellular melanosomes are shattered by
dition of the authors’ combined clinical experience, clin- picosecond laser irradiation, thus facilitating clearance by
ical recommendations were developed. macrophages and other phagocytes.
Results: After application of inclusion and exclusion cri- On the contrary, picosecond laser energy can be frac-
teria, a total of 77 unique studies were evaluated. Treat- tionated via a variety of diffractive or holographic lens
ment of benign pigmented lesions was associated with arrays. Fractionation allows for higher peak energies to
level I–IV evidence; rejuvenation was associated with be concentrated within laser microbeams, while sparing
level II evidence; melasma was associated with level II adjacent tissue. The tissue effects of fractionated pico-
evidence; scar revision was associated with level II–III second laser rely on chromophore‐assisted ionized plasma
evidence; tattoo removal was associated with level I evi- formation—a phenomenon that has been termed “laser‐
dence. induced optical breakdown” [4]. The initiating event is the
Conclusion: Picosecond laser is a safe and effective generation of a seed electron after laser irradiation of
treatment modality for an increasing range of derma- tissue. The threshold energy required to generate seed
tologic indications. Further development of this tech- electrons via multiphoton absorption without chromo-
nology is warranted. Lasers Surg. Med. © 2020 Wiley phore assistance has been estimated at 1013 W/cm2—a
Periodicals, Inc. level that is far too high to safely induce in human skin.
However, the addition of absorptive chromophore gen-
Key words: picosecond laser; photothermolysis; laser‐ erates thermal effects that exponentially lowers this
induced optical breakdown; benign pigmented lesions; threshold [5]. Multiphoton microscopy and other histo-
melasma; scar; photodamage; rejuvenation; systematic logic studies have suggested that the predominant chro-
review; photomechanical mophore in the skin that contributes to this process is
melanin, with hemoglobin also potentially playing a role
[6,7]. Immediately following laser irradiation, formalin‐
INTRODUCTION fixed histological sections reveal discrete vacuoles left
Since the advent of selective photothermolysis, the behind by the disappearance of plasma. Beyond the
importance of laser pulse duration in achieving clinical
effects within specific tissue targets has been well‐ Conflict of Interest Disclosures: All authors have completed
and submitted the ICMJE Form for Disclosure of Potential
recognized [1]. In general, lasers utilized in dermato- Conflicts of Interest and none were reported.
logic surgery can be classified as either long‐pulsed * Correspondence to: Douglas C. Wu, MD, PhD, Cosmetic Laser
lasers (with pulse durations in the microsecond to Dermatology, 9339 Genesee Avenue, Suite 300, San Diego,
CA 92121. E‐mail: dwu@clderm.com
millisecond ranges) or short‐pulsed lasers (with pulse Accepted 23 March 2020
durations in the nanosecond to picosecond ranges). Published online in Wiley Online Library
Currently available picosecond lasers in dermatology (wileyonlinelibrary.com).
DOI 10.1002/lsm.23244
boundaries of these vacuoles, no tissue damage is ob- described (Fig. 1) [12]. It is important to note that these
served. These vacuoles then fill with melanotic and other data are derived from heterogenous studies with different
cellular debris within the first 24 hours before being grading scales and classification systems utilized. For
transeliminated through the epidermis over the next example, a study that utilizes a 4‐point improvement
3–7 days [4]. A more delayed analysis of the skin reveals a scale with 0 denoting 0–25% improvement would report a
neocollagenesis and neoelastinogenesis response, which 12.5% improvement even if baseline and post‐treatment
may be due to the localized thermal effects of superheated results were identical. This variability impacts inter-
plasma and/or a photoacoustic stimulation of cell sig- pretation of these data. Therefore, a detailed breakdown
naling that propagates deeper into the dermis beyond the of all studies included in this review has been summar-
depth of acute tissue injury readily detectable on imme- ized in Data Tables 1–6 and finer scrutiny can be applied
diate histology [8–10]. A significantly higher heat sig- by the reader if so desired. Finally, practical “Bottom
nature associated with fractionated picosecond laser ir- Line” clinical summary and recommendations were pro-
radiation as compared with non‐fractionated delivery may posed taking into account the evidence‐based approach in
also contribute to tissue remodeling [11]. combination with the authors’ collective clinical experi-
In this study, we systematically review and critically ence with picosecond laser.
analyze the available literature on dermatologic applica-
tions of picosecond laser and offer recommendations to RESULTS
optimize its use in daily clinical practice.
The search strategy yielded a total of 648 citations.
Removal of duplicates resulted in 278 that remained. Of
METHODS these, a further 201 citations were excluded based on non‐
A comprehensive search of all published literature on dermatology/non‐picosecond (141), non‐English (6), non‐
the dermatologic applications of picosecond laser was human/non‐clinical (21), and review articles (35). The re-
performed up to March 2020. The following combination maining 78 citations could be classified into one of the five
search terms were utilized as “all fields” queries: categories: discrete pigmented lesions, other non‐
melasma pigmented conditions, rejuvenation, melasma,
1. Picosecond AND tattoo. scar revision, and tattoo removal. These data are sum-
2. Picosecond AND melasma. marized in Tables 1–6.
3. Picosecond AND rejuvenation.
4. Picosecond AND scar. DISCRETE PIGMENTED LESIONS
5. Picosecond AND pigment.
6. Picosecond AND argyria. Picosecond lasers with wavelengths of 532, 755, and
7. Picosecond AND dermatology. 1064 nm have been reported to be safe and effective in the
8. Picosecond AND cutaneous. treatment of a wide range of discrete pigmented lesions
9. Picosecond AND skin. including solar lentigines, freckles, verrucus epidermal
10. Picosecond AND nevus. nevus, café au lait macules (CALM), nevus of Ota, and
11. Picosecond AND (lentigo OR lentigines). Hori's macules. A total of five case reports/series; five
12. Picosecond AND (freckles OR ephelides). retrospective reviews; three prospective open‐label trials;
13. Picosecond AND (epidermis OR epidermal). and four split‐face/lesion randomized comparison trials
14. Picosecond AND (dermis OR dermal). involving a cumulative 320 subjects have documented
15. Picosecond AND trial. these findings [13–29].
Unwanted solar lentigines are common complaints
A reference manager program (Endnote X9; Clarivate among patients presenting for cosmetic dermatologic
Analytics, Philadelphia PA) was used to identify and re- treatment. Similar to the previous generation of nano-
move duplicate findings. Inclusion and exclusion criteria second lasers, picosecond lasers have demonstrated ex-
were then manually applied to the remaining citations. cellent efficacy in the removal of these lesions. When
Inclusion criteria were any primary clinical study on the utilizing short‐pulsed laser for the treatment of benign
application of picosecond laser within dermatology in- pigmented lesions, the recommended clinical endpoint is
cluding case reports, case series, retrospective reviews, whitening of the lesion with preservation of normal sur-
prospective open‐label trials, comparative clinical trials, rounding skin [90]. In fair‐skinned individuals, achieving
randomized controlled trials, and systematic reviews. this endpoint leads to safe and effective removal, typically
Exclusion criteria were non‐systematic review articles, within 1–2 treatment sessions. However, the use of
non‐human studies, non‐clinical studies, non‐English nanosecond lasers for the treatment of benign lentigines
language studies, non‐picosecond laser studies, and non‐ in skin of color has a relatively high risk of PIH, with
dermatologic studies. previous estimates ranging between 25 and 47% [91]. In
Studies were classified according to specific dermato- contrast, recent studies have suggested that the risk of
logic indications and tabulated in a chronological fashion. PIH when treating lentigines in skin of color with pico-
The Level of Evidence for each indication was then as- second lasers is lower. Guss et al. used a 375 picoseconds
sessed according to modified criteria published by the pulsed 532 nm frequency‐doubled Nd:YAG laser to treat
Oxford Center of Evidence‐Based Medicine as previously 255 discrete lentigines in six patients with type IV skin
WU ET AL. 3
Chestnut et al. [13] Nevus 3 Case series IV 755 nm All had improved None Picosure No
of Ota 750 ps response compared
3–4 mm spot with 4–10 previous
1.59–2.83 J sessions of QSR, AL,
2–3 treatments and Yag
Chan et al. [14] Ota, Hori, 13 Retro review III–IV 755 nm 25–100% resolution None Picosure No
CALM, 750 ps in all patients;
Lents, 2–4 mm treatment best for
Becker, 1.76–4.08 J Ota and CALM, less
spilus 1–7 treatment so for Beckers Lents,
and Hori
Guss et al. [15] Lents 6 Case series III–IV 532 nm 78% with 75–100% 1% worsened Picoway No
375 ps clearance
4–6 mm spot
0.5–0.8 J
1 treatment
Jerdan et al. [16] Nevus 1 Case report IV 532 nm Near‐complete None Enlighten No
of Ota 750 ps resolution; previous
6 mm spot treatments with QS
0.5 J and Pico 1064
2 treatments ineffective
Artzi et al. [17] CALM 16 Retro review II–IV 532 nm 15/16 patients had 1 patient had no Picoway No
375 ps good to excellent response to the
4‐5 mm spot response with treatment
0.8–1.6 J significant to
1–4 treatment complete resolution
Yu et al. [18] Hori 33 PRLC III–IV PSAL vs. QSAL in Efficacy PSAL PIH Picosure No
split face, vs. QSAL: vs.
randomized trial Accolade
PSAL: 3.73 vs. 2.4
2–2.5 mm spot 97% good to
A SYSTEMATIC REVIEW OF PICOSECOND LASER IN DERMATOLOGY
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
(Continued)
TABLE 1. (Continued) 6
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
70 ns
Spot size not
provided
6.92 J/cm2
1 treatment
2‐month follow‐up
Vachiramon Lenti- 30 PRLC III–IV 2 lentigines per Investigator No differences in Picoway No
et al. [24] gines in subject were evaluation detected healing time nor vs. revlite
Asians randomized to no significant adverse events
either PS 532 or difference in efficacy
QS 532:
PS 532 Subjects rated 60.7% 7.1% PIH with both
3 mm spot of PS‐treated lesions
375 ps as having excellent
0.3–0.9 J/cm2 clearance vs. 32.1%
Treat to whitening with QS, but not
QS 532 statistically
5 ns significant; subjects
were significantly
more satisfied with
PS lesions
3 mm spot
1.4–1.7 J/cm2
Treat to whitening
1 treatment
12‐week follow‐up
Wong et al. [25] Hori 3 Case series III–V 1064/532 nm with Good to excellent None Enlighten Yes
fractional clearance of lesions
microlens array
750 ps
3–5 mm spot
A SYSTEMATIC REVIEW OF PICOSECOND LASER IN DERMATOLOGY
1.8–3.0 J/cm2 at
1064 nm
0.1–0.3 J/cm2 at
532 nm
6–9 treatments at
4–12‐week
intervals over 9–12
months with a
2‐month follow‐up
evaluation
(Continued)
TABLE 1. (Continued)
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
Negishi et al. [26] Lenti- 20 Prospective III–IV 532 nm 750 ps Greater disruption 4.65% PIH rate Enlighten No
gines in OLT 0.2–0.5 J, of DEJ on H + E with
Asian 3–4 mm spot ns settings;
equivalent
melanosome
destruction on EM
but greater non‐
specific organelle
destruction with ns
Endpoint of slight 77% of lesions
whitening achieved 76–100%
93% of lesions improvement at
received 1 3‐month follow‐up
treatment, 7%
received 2
Compared ns vs. ps
effect histologically
and with EM on
one patient with
arm lentigines—ns
WU ET AL.
settings were
532 nm, 5–10 ns,
3 mm spot, 1.2 J; ps
settings were
532 nm, 750 ps,
4 mm spot, 0.5 J
Chan et al. [27] Lenti- 20 Prospective III–IV 532 nm At 12 weeks: 90% of 10.2% PIH rate that all Enlighten No
gines in OLT patients had resolved by 12 weeks;
Asian moderate to mean time to
significant resolution of 6.5 weeks
improvement as
rated by the
investigator; 75% of
patients rated
themselves as
having moderate to
significant
improvement
750 ps There was no 1 lesion
0.2–0.5 J, worsening of any hypopigmented but
7
(Continued)
TABLE 1. (Continued) 8
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
Kung et al. [29] Benign 12 OLT III–IV 1064/532 nm Good to excellent Purpura 12.9% Picoway No
pigments response for freckles
and lentigines in 1–3
treatments
450/375 ps Edema 40.3%
Lentigines: Good to excellent Erythema 80.6%
532 nm, 3 mm spot, response in CALM
0.49–0.64 J/cm2 after 3–5 treatments
CALM: 532 nm, 25%, 50%, and 25% Crusting 1.6%
3–6 mm spot, fair, good, and
0.36–0.87 J/cm2 excellent response,
Freckles: 532 nm, respectively for Pinpoint bleeding 6.5%
3 mm spot, melasma with 8–9
0.36–0.67 J/cm2 treatments
Melasma: 1064 nm, Hyperpigmentation
6 mm spot, 4.8%
0.54–1.22 J/cm2
Hori's macules: Blistering 6.5%
1064 nm, 3–4 mm
spot, 1.86–3.67 J/
WU ET AL.
Rodrigues Mino 3 Case series II 755 nm Split face comparison None Picosure No
et al. [30] 750 ps with QS Nd:YAG showed
3 mm spot picosure superior
2.8 J
1–2 treatments
DiGiorgio Argyria 1 Case report II 755 nm 80% resolution Significant Picosure No
et al. [31] 750 ps edema resolved
4 mm spot with 5 days
1.59 J
1 treatment
Moore Mino pig post‐sclero 1 Case report III 755 nm Lesions treated None Picosure No
et al. [32] 750 ps previously with QS alex,
6 mm spot yag, ruby with no change;
0.71 J picosure led to complete
2 treatments resolution
Sasaki Mino 1 Case report IV 755 nm Near complete resolution None Picosure No
et al. [33] 750 ps 1 year post‐treatment
2 mm spot
6.37 J
1 treatment
Friedman Argyria 1 Case report I 755 nm 90% resolution None Picosure No
et al. [34] 750 ps
3 mm spot
2.83 J
2 treatments
Vanaman Infraorbital dark 1 Case report IV 755 nm 90% resolution in 3 None Picosure Yes
Wilson circles 550 ps months
et al. [35] 6 mm spot
0.57 J
FLA
A SYSTEMATIC REVIEW OF PICOSECOND LASER IN DERMATOLOGY
1 treatment
Vanaman Infraorbital hyper 29 Prospective I–IV 755 nm Significant improvement None Picosure Yes
Wilson open label 750 ps after 3 treatments with Picoway
et al. [36] 6 mm spot 755, no improvement
0.71 J with 1 treatment Yag
3 treatments spaced
3 weeks apart
1064/532 nm
450/375 ps
(Continued)
TABLE 2. (Continued)
Skin
Author/date Lesion N Study type type Settings Results Complications Device Fractionated
6 mm spot
0.16–1.3 J
Two passes, one
treatment
Wu Stasis 1 Case report II 755 nm 90% clearance 1 month None Picosure No
et al. [37] 750 ps post‐final treatment
3.3 mm spot
2.34 J
3 treatments
1–2‐month intervals
Barrett Mino 1 Case report II 755 nm Near complete resolution; None Picosure No
et al. [38] 750 ps previous 5 treatments
6 mm spot with 1,064 and 532 QS
0.71 J yag ineffective
4 treatments, 1‐month
interval
Mendez Exogenous 1 Case report IV 1064/532 nm holographic Marked improvement None Picoway Yes
et al. [39] ochronosis beam splitter
6 mm spot
WU ET AL.
Skin
Author/date Lesion N Study type type Settings Results Complications Device Fractionated
post‐treatment biopsies
visualized under light
microscopy
0.71 J/cm2 Scanning electron
Single full face treatment microscopy: silver particle
—pulses not specified sizes decreased from 25 to
100+ nm to 4–15 nm;
morphological change
from intact spherules to
shattered “star‐burst”
Weiss Argyria 1 Case report II 755 nm Instant clearance of None Picosure No
et al. [42] argyria discoloration vs. QX
observed with both lasers
4.5–5.5 mm spot No clinically apparent
0.84–1.26 J/cm2 difference in efficacy
750 ps between two lasers
1064 nm
5 mm spot
2.5 J/cm2
5 ns
Tsai Drug melanonychia 1 Case report IV 1064 nm Complete resolution of None Unknown No
et al. [43] 3–4 mm spot nail pigmentation
4.8–5.0 J/cm2
750 ps
1 treatment
3‐month follow‐up
Kok Imatinib 1 Case report IV 755 nm >75% reduction of None Picosure No
et al. [44] hyperpigmentation 550 ps hyperpigmentation
3 mm spot size
2.33 J/cm2
A SYSTEMATIC REVIEW OF PICOSECOND LASER IN DERMATOLOGY
5 treatment sessions at
2‐month intervals
6‐month evaluation
Wu Lichen planus 1 Case report IV Combination treatment Significant improvement None Unknown Yes
et al. [45] pigmentosus with 0.1% tacrolimus of hyperpigmentation
ointment BID,
hydroxychoroquine
200 mg BID, and 1064 nm
picosecond Nd:YAG laser
3 laser treatment sessions
at 4‐month intervals
TABLE 3. Rejuvenation
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
Wu Chest 20 Prosp OLT I–IV 755 nm Significant improvement 1 case of urticarial Picosure Yes
et al. [46] photodamage in dyspigmentation, reaction
texture, and keratoses
6 × 6 mm spot Minimal improvement in Pain 3.7/10
rhytides
0.71 J No improvement in
750 ps erythema
2–4 passes
6,631 ± 1,915 pulses per
treatment
2–4 treatments, 3 weeks
apart
Ge Facial 10 PRLC III–IV (5 755 nm Global Photoaging Scale Treatment pain: Picosure Yes
et al. [47] photoaging skin type III, (GPS): Significant 6.0–6.9/10
5 skin improvement on
type IV) treated side
Skin type III: 6 mm spot Asian Photographic Scale 24 hours of transient
(APS): Significant erythema and edema
improvement in wrinkling,
trend toward
improvement in
pigmentation
0.71 J/cm2 60% of subjects had
WU ET AL.
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
intervals
3‐month follow‐up
Gold [54] Wrinkles 20 Prosp OLT II–IV 1064/532 nm holographic 2.1 point improvement in Pain level 3.7/10 Picoway Yes
beam splitter FWS assessment of the
perioral and periorbital
regions (P < 0.05)
1064 nm: 2.3 75% of subjects were No unexpected
mJ/microbeam, 6 mm spot, either “very satisfied” or adverse events
1,373 ± 208 pulses, 2 passes “satisfied”
532 nm: 0.58
mJ/microbeam, 6 mm spot,
1,246 ± 132 pulses, 2 passes
4 treatments at 1‐month
intervals
12‐week follow‐up
evaluation
(Continued)
15
TABLE 3. (Continued) 16
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
Yim et al. [55] Photodamage 25 PRLC III–IV Picosecond 1064 nm Investigator 5‐point scale Pain was significantly Picocare vs. Excel V Yes
Nd:YAG vs. micro pulse improvement assessment: greater on pico side
1064 nm Nd:YAG Significantly more (3.65 ± 1.70 vs.
improvement in visible 1.28 ± 1.28 out of
pores at lateral canthal 10, P < 0.05)
area in pico half (54.2% vs.
41.7%, P < 0.05)
PSYAG: Wrinkle improvement was No serious adverse
12.5% vs. 4.2% pico vs. events reported
micro, but not significant
(P = 0.125)
Microlens array 3D digital skin analysis:
both pore size and
wrinkles in the lateral
canthal areas showed
greater improvement with
pico treatment vs. micro
(16.4% vs. 0.5% P = 0.01
and 41.3% vs. 3.9%
P = 0.048, respectively)
8 mm spot Subject satisfaction was
0.6–0.8 J/cm2 equal on both sides
450 ps
1,500 total pulses
Micropulse YAG:
8 mm spot
4 J/cm2
0.3 ms
1,500 total pulses
5 treatments at 2‐week
intervals
12‐week follow‐up
evaluation after final
treatment session
A SYSTEMATIC REVIEW OF PICOSECOND LASER IN DERMATOLOGY
TABLE 4. Melasma
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
5 mm spot
1–2 passes
0.1–0.55 J
750 ps
5 treatments,
1‐week interval
1‐, 2‐, 3‐month
follow‐up
Chalermchai Melasma 30 PRLC III–IV Full face—4% 4‐week follow‐up: Mild erythema Picoway Yes
et al. [58] (prosp, split HQ; random half‐ Significant (6.7%), mild
face, rando, face—fractionated improvement in desquamation
eval blind) 1064 nm MASI with laser 6.7%), mild
6 × 6 mm treatment vs. HQ burning
1.3–1.5 mJ/beam control side sensation (3.3%)
450 ps (absolute
8–12% coverage difference 3.52
400–1,000 pulses vs 4.18)
4 Hz
Endpoint mild
erythema
(Continued)
17
18
TABLE 4. (Continued)
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
Follow‐up
evaluation
4 weeks after final
laser treatment
Lee et al. [59] Melasma 12 PRLC III–IV PSAL vs. QS YAG Pigment No unexpected Picosure vs. No
clearance was adverse events Medlite
PSAL: 4.4–5.1 mm faster and No report of
spot, 0.88–1.18 significantly rebound
J/cm2, 650 ps, better on the pigmentation
3 passes, 1,000 PSAL side in both
pulses physician and
QS YAG: patient
5 ns assessments
Pass 1: 8 mm spot,
2 J/cm2
Pass 2: 6 mm spot,
3.5 J/cm2
Pass 3: 4 mm spot,
3.2 J/cm2
Endpoint: mild
erythema with
edema but no
petechiae
4 treatments at
1‐month intervals
3‐month follow‐up
after final
treatment
Wang Melasma 26 Random- Group A1: 755 nm Significant Everyone applied Picosure Yes
et al. [60] ized single‐ diffractive lens improvement SPF50 + Q2H for
blind array noted in MASI the duration of
A SYSTEMATIC REVIEW OF PICOSECOND LASER IN DERMATOLOGY
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
analyze TCC
group as well?
2 passes, 2,500 18.2% PIH rate in
pulses, endpoint A2; 33.3%
mild erythema irritation in B
3 treatment
sessions at 4‐week
intervals
Group A2: 755 nm
diffractive lens
array
8 mm spot
0.4 J/cm2
750 ps
2 passes, 2,500
pulses, endpoint
mild erythema
5 treatment
sessions at 4‐week
intervals
19
(Continued)
20
TABLE 4. (Continued)
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
Group B: TCC
consisting of
fluocinolone
acetonide 0.01%,
hydroquinone 4%,
and tretinoin
0.05% applied
QHS for 8 weeks,
then twice weekly
for 6 weeks, then
once weekly for
6 weeks
All subjects
evaluated at
1 month following
the final
treatment for
group A2
Chen Melasma 20 OLT IV 755 nm MASI: Significant 5% PIH Picosure Yes
et al. [61] improvement
from baseline
(9.0 ± 4.8
vs. 6.5 ± 3.7)
8 mm spot VISIA: Significant
improvement in
spots and
porphyrins
0.4 J/cm2
10 Hz
2 passes,
2,000–2,500
A SYSTEMATIC REVIEW OF PICOSECOND LASER IN DERMATOLOGY
pulses
3 treatments at
4–6‐week
intervals
4‐week follow‐up
Lyons Melasma 10 PRLC vs. II–IV 9 weekly More None PiQo4 No
et al. [62] 6% HQ treatments to improvement on
randomized facial the treated side
(Continued)
WU ET AL. 21
week post‐final
performed at 1
pulse duration
evaluations
treatment
treatment
Follow‐up
variable
800 ps
ment [92].
For Nevus of Ota, there have been two case series; two
retrospective reviews; and one randomized split‐lesion
double‐blind comparison trial study involving a cumu-
lative total of 103 subjects [13,16,19,20,28]. In one retro-
spective review of 29 Chinese patients, a 750 picoseconds
pulsed 755 nm picosecond alexandrite laser achieved
N
Brauer et al. [9] Acne scar 20 Prosp OLT I–V 755 nm 24–27% scar volume Maximum 2 days Picosure Yes
reduction erythema
6 × 6 mm Also noted significant
improvement in skin
texture and
pigmentation
secondarily
0.71 J Increased collagen III
750 ps and elastic fibers
5 Hz
6 treatments, 4–8 week
intervals
Mean 3,072 pulses per
treatment
Bernstein Acne scar 31 Prosp OLT II–V 21 subjects treated with 81% showed some Maximum Picoway Yes
et al. [8] 1064 nm: improvement, 48% erythema
showed >20% duration = 4 days;
improvement, 26% majority resolved
showed >30% with 1–2 days
1.3–2.8 J improvement No post‐
6 × 6 mm spot inflammatory
4 treatments, monthly pigmentary
intervals alteration noted
450 ps
10 subjects treated with
532 nm:
1.1–1.5 mJ/microbeam
4 treatments, monthly
intervals
375 ps
Zhang Acne scar 20 Prosp OLT III–IV (chinese) 755 nm ECCA: Decreased from 3.2/10 pain Picosure Yes
et al. [63] 197.75 ± 35.26 to
142.00 ± 35.92 (28%
improvement,
P = 0.000)
6 mm spot 70% of patients showed A few days of mild
and transient
A SYSTEMATIC REVIEW OF PICOSECOND LASER IN DERMATOLOGY
>50% improvement
of PIE erythema, edema,
0.71 J/cm2 Patient reported and scabbing
improvement: 2.3 ± 1
out of 3
750 ps 50% of patients were
5 Hz “satisfied”; 30% “very
5 passes satisfied”
3 treatments at 4–6‐
week intervals
(Continued)
TABLE 5. (Continued)
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
Follow‐up evaluation: 2
months after final
treatment
Zaleski Larsen Striae alba 20 PRLC II–IV 523/1064 nm with Significant None Picoway Yes
et al. [64] holographic lens improvement in texture
and atrophy, but no
difference between
treatment halves
450 ps Striae density was not vs.
significantly improved
6 mm spot size Pain significantly Resurfx
decreased on
picosecond side
1.3 mJ/microbeam at Significantly faster
1064 nm healing time associated
0.4 mJ/microbeam at with picosecond side
532 nm
4 passes per
wavelength
1565 nm
12 mm square spot
Density: 400 dots/cm2
Energy: 40 J
WU ET AL.
1 pass
3 treatments delivered
at 3‐week intervals
6‐month follow‐up
Chayavichitsilp Acne scar 30 PRLC III–IV 1064 nm with fractional ECCA: Both treated Erythema and Discovery PICO vs. Yes
et al. [65] lens array halves had significant hyperpigmentation FineScan
improvement; ps side were the same on
–38.89% vs. Er:fiber both sides
side –33.33%; no
significant difference
8 mm Patient rated that Immediate pinpoint
improvement and bleeding was
satisfaction was the significantly
same on both sides greater on ps side
0.3–0.4 J/cm2 Significantly greater Pain was
10 Hz pore count reduction significantly
1 pass with Er:fiber (15.4% vs. greater on
1550 nm Er fiber 7.5%, P < 0.05) Er:fiber side
100–400 spots/cm2
25–30 J/cm2
2 passes
4 treatments at 4‐week
(Continued)
23
24
TABLE 5. (Continued)
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
intervals
Follow‐up at 4 and 8
weeks
Dai et al. [66] Acne scar 20 Prosp OLT III–V 1064 nm with fractional Blinded evaluator: Pain 6/10 Discovery PICO Yes
lens array mean 3/10
improvement; 85%
showed some
improvement; 45%
showed improvement of
at least 3/10
450 ps Subjects evaluation: Median healing
median 8/10 time: 4 days, range
improvement but only 1–10 days
55% “satisfied” and 45%
“very satisfied”
8 mm FASQoL: Significant No pigmentary
0.3–0.4 J/cm2 improvement in quality alteration at 1
10 Hz of life pre vs. post‐ week, 1 month, or 3
2 passes for an treatment months
estimated 10% density,
1,200–1,600 pulses
3 treatments at 4‐week
intervals
3‐month follow‐up
Koren et al. [67] Hyperpig- 16 Case series II–VI 1064 nm with Causes of None Picoway Yes
mented scars holographic lens hyperpigmented scars:
Burn injury [4], road
accident [8],
leishmaniasis [1],
surgical operation [2],
and unspecified
disease [1]
6 mm spot GAS improvement
3.31 ± 0.57 out of 4
1.7–2.5 J/cm2 Patient satisfaction
A SYSTEMATIC REVIEW OF PICOSECOND LASER IN DERMATOLOGY
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
microbeams of 200 µm
diameter
450 ps 95% of scars improved
by both investigator‐
and subject‐reported
outcomes
8 mm spot size 44% of subjects “very
satisfied”, 50%
“satisfied”, 6% “not
satisfied”
10 mJ/microbeam 3D imaging revealed
5.1 ± 2.4 point
improvement in
texture, P < 0.05
15% density delivered Reflectance confocal
over 3 passes microscopy revealed a
significant reduction in
epidermal thickness for
hypertrophic scars but
not atrophic scars
3 treatments at Also visualized “net‐
monthly intervals like” reconfiguration of
(Continued)
25
26
TABLE 5. (Continued)
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
Total pulses:
2,500–3,000
6 treatment sessions at
1‐ month interval
Final evaluation 3
months post‐final
treatment session
TABLE 6. Tattoos
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
Ross et al. [73] Black 16 PRLC, N/A 1064 nm, 35 ps, Maintaining all other None N/A N
split tattoo 1.4 mm, 0.65 J, 10 Hz parameters the same,
vs. 10 ns picosecond pulse far
more effective than
nanosecond pulse
Herd et al. [74] Ps vs. ns pig 6 Pig model N/A 795 nm 500 ps vs. Picosecond laser None Experimental N
model 752 nm 50 ns significantly has
Fluence and spot size better clearance
kept identical: 6.11,
4.24, 2.39 J and 1.25,
1.5, and 2 mm,
respectively
Izikson et al. [75] Black in pig 1 Animal N/A 758 nm 500 ps laser Picosecond‐pulsed None Prototype device N
model model used at three settings laser superior for
1.3 mm spot, 13–16 J; black ink clearance at
1.9 mm spot, 6–7.5 J; ALL settings
2.9 mm spot, 2.5–3.9 J
vs. 755 nm 30–50 ns
used at typical clinical
settings (3 mm
spot, 8 J)
Brauer et al. [76] Blue and green 12 Case series II–IV 755 nm 1–2 treatments None Picosure N
750 ps resulted in >75%
WU ET AL.
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
Bernstein All colors—black, 31 Prosp OLT I–IV 1064/532 450/350 ps After 7 treatments: Injection lido used Picoway N
et al. [80] green, red, 3–5 mm spot 92% clearance of black 13% mild hyperpigmentation
purple, 1.4–5.3 J for 1064 85% clearance of 6% mild hypopigmentation at 3
yellow, blue yellow months
0.4–2.1 J for 532 80% clearance of red
Up to 7 treatments 78% clearance of
purple
65% clearance of
green
43% clearance of blue
Bae [81] Paradoxical 2 Case series II 1064 nm Improvement of Injection lido used Cynosure study N
darkening 2.7–4.5 mm spot paradoxical darkening prototype
0.4‐1.4 J of red tattoos
Freidman Black and red 1 Case study VI Three treatments: After 1.5 months of None Picoway N
et al. [82] Treatment 1— treatment, 75%
1064 nm, 10 mm spot, clearance of black ink,
0.5 J and 532 nm, 90% clearance of
10 mm spot, 0.25 J red ink
Treatment 2—
1064 nm, 9 mm spot,
0.6 J and 532 nm,
9 mm spot, 0.3 J
Treatment 3—
1064 nm, 6 mm spot,
1.4 J and 532 nm,
9 mm spot, 0.3 J
Lee et al. [83] Black and red 6 Case series IV (Korean) 755 nm 1–5 treatments to 50% hypopigmentation at 3 Picosure N
2–3 mm spot achieve >75% months
2.68–5.25 J clearance
550–750 ps
Pinto et al. [84] Ps vs. ns, black 30 Single‐ N/A 450 ps vs. 5 ns No significant Pain significantly reduced on Picoway vs. N
blind split Exact settings not difference in clearance picosecond‐treated side Medlite C6
tattoo RCT disclosed—authors after 2 treatments
state that settings
A SYSTEMATIC REVIEW OF PICOSECOND LASER IN DERMATOLOGY
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
After 6 treatments—
66% achieved
75–100% clearance
'Lorgeau et al. [86] Ps vs. ns, all 49 Single‐ II–V Picoway: 1064 nm Picosecond device Pain slightly less with ps, not Picoway N
colors blind split 450 ps; 532 nm superior to significant Enlighten
tattoo RCT 375 ps; 2–5.5 J nanosecond device in Versapulse
Enlighten: 1064 nm clearance after 1, 2,
750 ps; 532 nm and 3 treatments for
750 ps; 2–8.4 J black ink
Versapulse: 1064/
532 nm 5 ns; 2–8.4 J
Zhang et al. [87] Ps vs. ns, black 72 Retro IV (Chinese) 755 nm 750 ps No significant None Picosure vs. N
eyeliner tattoo review 2.65 mm spot 3.75 J vs. difference noted—but Medlite C6
1064 nm 5–20 ns 3 mm wavelength is
spot 3.87 J different
32 treated with ns
Nd:YAG
40 treated with ps Alex
1–4 treatments
Eggenschwiler Qs and ps for iron 13 Retro II–IV Combination 8 of 13 patients Persistent focal Unknown N
[88] infusion tattoo review treatment with achieved complete hypopigmentation occurred in
variable combinations removal 46.2%—not stratified based on
(Continued)
29
30
TABLE 6. (Continued)
Author/date Lesion N Study type Skin type Settings Results Complications Device Fractionated
Nevus of Ota Level 1b Picosecond laser may be considered a first‐line treatment option for
Nevus of Ota and Hori's macules. Solar lentigines and freckles also tend
to respond with a high degree of safety and efficacy. Café au lait
macules may respond favorably. Other benign pigmentary conditions
may have variable response.
Hori's macules Level 1b
Solar lentigines Level 2b
Freckles Level 2b
Café au lait macules Level 3c
All other benign pigmentary Level 4
conditions
Rejuvenation Level 2a Picosecond laser is a good therapeutic option for photorejuvenation,
particularly in skin of color where laser options may be more limited.
Both unfractionated and fractionated delivery modes should be
exploited to achieve optimal results.
Melasma Level 2b Picosecond laser may be considered as an adjunctive treatment option
in combination with photoprotection, topical bleaching agents, and
possibly other laser and systemic therapies for highly motivated
patients with moderate to severe melasma who may also benefit from
the concurrent reduction of benign pigmentation and photodamage.
Acne scars Level 2b Fractionated picosecond laser should be positioned as a treatment
option for patients with mild to moderate acne scarring who desire
minimal downtime and have perhaps failed other more well‐established
treatments. Acne scar patients who are skin of color and/or who present
with concurrent pigmentary issues may also be selective candidates for
fractionated picosecond laser. Striae alba can be treated with
fractionated picosecond laser, but improvements tend to be modest.
Fractionated picosecond laser may be considered as an adjunctive
treatment modality in combination with other therapies for
hypertrophic and atrophic surgical/traumatic scars.
Striae alba Level 2b
Atrophic and hypertrophic Level 3c
surgical scars
Tattoo removal Level 1a Picosecond laser currently represents the gold standard treatment
option for the removal of unwanted tattoos of almost any color.
97% good to excellent resolution rating compared with and a small case series), and infraorbital dark circles (one
46% from the nanosecond laser; and 93% satisfied to very case report and one prospective open‐label trial). Al-
satisfied patient satisfaction rating versus 40%, re- though these reports cast an optimistic outlook on the
spectively. The picosecond laser was also associated with expanded use of picosecond lasers, further evidence is
slightly less pain and less healing time. The rate of PIH required in order to draw reliable conclusions. That being
with the picosecond laser was significantly reduced as said, it is worthwhile noting that some traditionally dif-
compared with the nanosecond counterpart, although the ficult conditions to treat, such as minocycline‐induced
absolute rates with both treatment modalities were rela- hyperpigmentation and chronic venous stasis hyper-
tively high (28% vs. 54%) [93]. pigmentation have shown promising response and the use
of picosecond laser in these settings should be considered
Other Non‐Melasma Pigmented Conditions an alternative treatment option when other modalities
The successful treatment of other non‐melasma pig- have proven unsatisfactory [30–39,41–45,94].
mented conditions has been mostly limited to single case
reports and small case series. The conditions that have Comparative Studies and Controversies
been reported to respond favorably to picosecond laser by Nevus of Ota, Hori's macules, solar lentigines in Asians,
multiple separate sources include argyria (four case re- and freckles in Chinese have been the subject of pico-
ports), minocycline hyperpigmentation (three case reports second versus nanosecond laser comparison trials
32 A SYSTEMATIC REVIEW OF PICOSECOND LASER IN DERMATOLOGY
[23,24,28,93]. Ge et al. [28] conducted a randomized, more effective than nanosecond laser in some situations,
double‐blind, split lesion clinical trial comparing a with potentially reduced risk of inducing post‐
750 picoseconds alexandrite laser with a 70 nanoseconds inflammatory hyperpigmentation. This increased safety
alexandrite laser for the treatment of Nevus of Ota. In level may be due to the reduction of non‐specific photo-
this study, 56 patients received up to six treatments that thermal damage of the melanocyte and dermal–epidermal
were delivered at 12‐week intervals with a final 3‐month junction. While dermal lesions appear to clearly respond
follow‐up evaluation. In both clinical clearance rates and better to picosecond laser versus nanosecond laser, some
subject satisfaction, the picosecond alexandrite laser of the comparative clinical data thus far remains ambig-
outperformed the nanosecond counterpart. As noted uous with regards to epidermal lesions. In the author's
above, Hori's macules also seemed to respond better to experience (DCW), the advantages of using picosecond
picosecond alexandrite laser [93]. Comparative trials be- laser for benign pigmented lesions becomes clearest at
tween picosecond and nanosecond laser for the treatment sub‐500 picoseconds domains and relies heavily on ach-
of solar lentigines and freckles have been less clear. ieving a highly sensitive and specific clinical endpoint—
Vachiramon et al. [24] compared a 532 nm Nd:YAG pico- something that is sometimes more difficult to achieve
second laser with a pulse duration of 375 picoseconds with with nanosecond devices. Optimization of these treatment
a 532 nm Nd:YAG nanosecond laser with a pulse duration settings and endpoints requires further study and addi-
of 5 nanoseconds in a split‐body clinical trial for solar tional data is required to truly define the precise risk of
lentigines. Two lentigines per subject were randomized to post‐inflammatory hyperpigmentation with picosecond
receive a single treatment with either modality and then laser stratified by skin type. Additionally, more robust
evaluated at a 12‐week follow‐up time point. Both treat- clinical comparative data with a focus on shorter pulse
ments were performed at settings that induced clinical durations and refined clinical endpoints is still needed to
whitening of the lesions. A spot size of 3 mm remained further distinguish the differences between picosecond
constant, but the nanosecond laser was used at more than and nanosecond laser for the treatment of some benign
double the fluence of the picosecond laser. Investigator pigmented lesions.
evaluation detected no significant differences in treat-
ment efficacy. Subjects rated the PS‐treated lesions as Level of Evidence
having 60.7% excellent response versus 32.1% for the NS‐
treated lesions, but this difference did not reach statistical Nevus of Ota: Level 1b
significance. Subjects reported a statistically significant Hori's macules: Level 1b
greater satisfaction level with the PS‐treated lesions. Solar lentigines: Level 2b
There were no differences in healing time or adverse Freckles: Level 2b
events, and both treatment modalities resulted in a 7.1% Café au lait macules: Level 3c
PIH rate. These data are ambiguous as subjects reported
All other benign pigmentary conditions: Level 4
a greater satisfaction level with the PS‐treated lesions,
but objective clinical evaluation detected no differences.
Interestingly, only two lesions per subject were chosen for
treatment. Treating a greater number of lesions may re- Recommendation
sult in more robust data and a clearer signal. Finally,
Yang et al. [23] reported no differences between a pico- Picosecond laser may be considered a first‐line treat-
second and nanosecond alexandrite laser for the treat- ment option for Nevus of Ota and Hori's macules. Solar
ment of Chinese freckles. Both lasers performed ex- lentigines and freckles also tend to respond with a high
cellently after a single treatment and a 2‐month follow‐up degree of safety and efficacy, although superiority over
evaluation. There were also no reported differences in side nanosecond laser is less clear. CALM may respond favor-
effects and downtime. In the author's clinical experience, ably. Other benign pigmentary conditions may have var-
simple freckles tend to respond well to a large variety of iable response.
short‐ and long‐pulsed laser and light modalities making
the sensitivity of this experimental model suboptimal to Rejuvenation
distinguish differences, if any, between picosecond and Seven prospective open‐label trials and three split‐face
nanosecond laser. comparison trials involving a cumulative 200 patients
have reported the use of picosecond laser for photo-
Bottom Line rejuvenation of the face, chest, and extremities [46–55].
Picosecond laser is currently the United States Food The first study was conducted in the setting of photo-
and Drug Administration (FDA) cleared for the treatment damaged chest and utilized a novel diffractive lens array,
of benign pigmented lesions. The accumulated evidence to which allowed for the fractionation of a picosecond alex-
date suggests that picosecond laser is a safe and effective andrite laser [46]. This array consists of approximately
treatment option for this indication across a wide spec- 120 closely packed diffractive lenses that redistribute
trum of lesions and skin types. Comparative studies uti- energy into peaks of high fluence on a background of very
lizing clinical, histological, and microscopic endpoints low fluence, thus mimicking a distribution pattern similar
further suggest that picosecond laser may be safer and to that seen with traditional fractional laser. The high
WU ET AL. 33
fluence peaks deliver 20 times greater energy as com- recovery time was reported as minimal in both cohorts
pared with the low fluence background. Wu et al. treated and consistent with previous reports using fractionated
20 patients with skin types I–IV utilizing this system. picosecond laser, the subjects treated with the 532 nm
Patients received 2–4 treatment sessions at 3‐week in- wavelength seemed to experience a slightly elevated level
tervals with a fixed 6 × 6 mm spot size, 0.71 J/cm2, of treatment pain and subsequent downtime. No sig-
750 picoseconds pulse duration, 2–4 passes for a total of nificant differences in the clinical results were detected
6,631 ± 1,915 pulses per treatment session. Both inves- between the two treatment groups.
tigator and subject‐reported outcomes were measured at 1
and 3 months after the final treatment session. These Comparative Studies and Controversies
data demonstrated significant clinical improvements in Two studies have been conducted comparing the safety,
dyspigmentation, skin texture, keratosis, and rhytids. tolerability, and efficacy of fractionated picosecond laser
Erythema remained unchanged from baseline. The ma- with 1927 nm fractionated thulium fiber laser for facial
jority of patients reported satisfaction with treatment photorejuvenation, and one study has compared fractio-
results and downtime was reported as mild. These data nated picosecond Nd:YAG versus unfractionated long‐
were confirmed in a subsequent study of similar design, pulsed Nd:YAG [52,55] [Wu et al., submitted]. In the first
which included both chest and hands [49]. Utilizing the comparative study, 20 subjects were randomized to re-
same diffractive lens array, Weiss et al. [50] treated 40 ceive either two fractionated thulium fiber laser treat-
patients with peri‐ocular and perioral rhytids. Four ments spaced 6 weeks apart or four fractionated and un-
monthly treatments were delivered at a fixed 6 × 6 mm fractionated picosecond alexandrite laser treatments
spot size, 0.71 J/cm2, 750 picoseconds pulse duration, and spaced 3 weeks apart. The results demonstrated superior
4 passes for a total of 5,000 pulses to the full face. Six clinical performance of the picosecond alexandrite laser at
patients underwent 2 mm punch biopsies of the peri‐ a 12‐week evaluation time point with an equivalent side
ocular skin at baseline, 1, 3, and 6 months post‐treatment. effect profile [52]. Several factors detracted from the ob-
The results showed significant improvement in jective comparability in this study including the uneven
Fitzpatrick–Goldman Wrinkle Scale at the 6‐month treatment numbers, the use of both fractionated and un-
follow‐up time point. Furthermore, moderate to marked fractionated picosecond laser versus purely fractionated
improvement was noted in facial dyschromia. Facial er- thulium fiber laser, relatively short follow‐up evaluation
ythema did not significantly improve. Serial histological time point, and the lack of detailed comparison of laser
analysis revealed a steady increase in both collagen and recovery time. In the second study, a randomized, split‐
elastic fibers throughout the dermis with a peak effect face, double‐blind design was utilized to compare a
seen at the 6‐month mark. Ge et al. studied 10 Chinese frequency‐doubled 1064/532 nm picosecond Nd:YAG laser
women with a split‐face, non‐randomized, evaluator‐ versus a fractionated 1927 nm thulium fiber laser [Wu
blinded clinical trial and found that treatment with the et al., submitted]. Facial halves were randomized to re-
fractionated picosecond alexandrite laser resulted in sig- ceive either one of the two treatment modalities and three
nificant improvements in wrinkling and global photo- treatments at 1‐month interval were delivered for both.
aging compared with untreated facial halves after four Statistically significant improvement in photoaging pa-
treatment sessions at 2‐week intervals [47]. This study rameters at 1, 3, and 6 months post‐treatment was de-
utilized a slightly stronger experimental design as op- tected on both sides, but no statistical difference between
posed to a simple prospective, open‐label trial and also sides was detected. In this study, subjects were asked to
utilized a lower fluence 8 mm optic for the treatment of rate their recovery period quantitatively through daily
skin types IV. Utilizing an alternative laser system, dairies measuring degrees of redness, swelling, crusting,
Berstein et al. examined the effects of a frequency‐ peeling, itch, and pain for the 14 days post‐treatment. The
doubled 1064/532 nm picosecond Nd:YAG laser on facial aggregated scores over all treatments revealed sig-
photoaging [51]. This laser system delivers fractionated nificantly less redness, swelling, peeling, crusting, and
energy via a holographic beam splitter rather than a dif- itch associated with the picosecond laser‐treated side at
fractive lens array. The 101 laser microbeams with a di- various time points. Finally, Yim et al. compared a
ameter of 150 µm are arranged in a uniform 10 × 10 grid 450 picoseconds 1064 nm fractionated Nd:YAG laser
pattern within a 6 mm spot size. Each pulse delivers ap- (PSYAG) with a 300 microseconds 1064 nm un-
proximately 5% density. In this study, 14 patients were fractionated Nd:YAG laser (LPYAG) in a split‐face trial for
treated with 1064 nm, 6 mm spot size, 450 picoseconds photorejuvenation [55]. The randomized facial halves of
pulse duration, and energy of 1.3–2.5 mJ/microbeam. Five 25 subjects received five treatments at 2‐week intervals
treatments were delivered at monthly intervals. An ad- and final evaluations were performed 12 weeks after the
ditional 10 subjects received treatment with 532 nm, final treatment session. Both lasers were used at 8 mm
6 mm spot size, 375 picoseconds pulse duration, and en- spot size and 1,500 pulses per treatment. The fluence for
ergy of 1–1.4 mJ/microbeam. This cohort received four the PSYAG was 0.6–0.8 J/cm2 compared with 4 J/cm2 with
treatments at monthly intervals. Blinded evaluators the LPYAG. Using a 5‐point scale, blinded investigators
rated 56.9% of subjects across both cohorts as having observed significantly greater improvement in visible
greater than 20% improvement. Subject satisfaction pores at the lateral canthal region with PSYAG treatment
levels were high. Interestingly, although side effects and versus LPYAG (54.2% vs. 41.7%, P < 0.05) but no
34 A SYSTEMATIC REVIEW OF PICOSECOND LASER IN DERMATOLOGY
significant difference was detected in wrinkling. However, The use of laser for the treatment of melasma has a
using 3D digital skin analysis (Antera 3D; MIRAVEX controversial history. Although previous reports with a
Ltd., Dublin) both wrinkles and pore size demonstrated variety of fractionated and non‐fractionated modalities
significantly greater improvement with PSYAG treatment have shown limited success, the risks of rapid recurrence,
versus LPYAG (16.4% vs. 0.5% P = 0.01 and 41.3% vs. rebound hyperpigmentation, and developing mottled hy-
3.9% P = 0.048, respectively). Interestingly, this study popigmentation are significant. To date, picosecond laser
reported a significantly greater pain level on the PSYAG has been used to treat melasma in one case series; one
side during treatment. A potential drawback of this study prospective open‐label trial; four prospective, randomized,
was that it compared fractionated laser (PSYAG) versus split‐face trials; and one randomized controlled trial in-
non‐fractionated laser (LPYAG). volving a cumulative total of 140 patients [56–62]. Choi
et al. [57] conducted a randomized single‐blind split‐face
Bottom Line clinical trial involving 39 patients with melasma. Facial
Fractionated picosecond laser is current U.S. FDA halves were randomly assigned to either 2% hydro-
cleared for wrinkle reduction and the evidence to date quinone control or non‐fractionated dual‐wavelength
demonstrates that it is becoming increasingly well‐ 1064/595 nm picosecond laser treatment. The treatment
established as a useful tool for general photorejuvenation. settings for the 1064 nm wavelength were 7–10 mm spot
The studies show a high level of safety associated with a size, 0.2–1.5 J/cm2, and 2–4 passes whereas the 595 nm
moderate level of efficacy. Indeed, when compared with wavelength was utilized at 5 mm spot size, 0.1–0.55 J/cm2,
traditional non‐ablative fractional laser, fractionated pi- and 1–2 passes. Both wavelengths had a pulse duration of
cosecond laser may have an improved side effect profile 750 picoseconds. Five treatment sessions were conducted
without sacrificing treatment efficacy [Wu et al. sub- at 1‐week intervals and patients were followed for
mitted]. This could be due to the unique mechanism of 3 months after their final treatment. The investigators
action of fractionated picosecond laser, which results in reported significantly better improvement in colorimeter
greater confinement of tissue injury to focal and precise assessment on the laser‐treated side versus control, but
points within the epidermis and papillary dermis [4]. the MASI score was only significantly better for the first
Further study is required to refine the optimal treatment week after treatment. No incidence of PIH or rebound was
parameters for fractionated picosecond laser in regards to reported. In a second prospective, randomized, split‐face
pulse energy, treatment density, and wavelength. Aside clinical trial, Chalermchai et al. [58] utilized a fractio-
from the ultrashort pulse durations, one unique feature of nated picosecond Nd:YAG laser at 1064 nm wavelength
currently commercially available picosecond lasers is the and 450 picoseconds pulse duration to treat facial halves
ability to deliver both non‐fractionated and fractionated versus 4% hydroquinone control. The treatment parame-
energy. For photorejuvenative purposes, and as suggested ters involved a 6 × 6 mm holographic beam splitter that
by the data from one of the comparative trials above, this delivered 1.3–1.5 mJ/microbeam for a total of 400–1,000
dual capability has the potential to be leveraged for sig- pulses for an estimated 8–12% density and an endpoint of
nificant clinical advantage by being able to optimally mild erythema. Three treatments were delivered at
target both discrete lesions as well as overall cutaneous 4‐week intervals. The primary clinical evaluation was
elastosis with a single device. Further exploration of this modified MASI score 4 weeks after the final treatment
concept is required. session. The investigators also evaluated melanin index,
global satisfaction, DLQI, and adverse effects. The results
Level of Evidence demonstrated significantly greater improvement in
Level 2a modified MASI score on the laser‐treated facial halves
versus the control, although the absolute difference was
Recommendation relatively small (3.52 ± 1.4 vs. 4.18 ± 2.0). No significant
differences were reported in melanin index and patient
Picosecond laser is a good therapeutic option for pho- satisfaction.
torejuvenation, particularly in skin of color where laser
options may be more limited due to adverse effect profile. Comparative Studies and Controversies
Both unfractionated and fractionated delivery modes Additional studies have compared modified Kligman
should be exploited to achieve optimal results. triple combination cream and nanosecond Nd:YAG
(QSYAG) against picosecond alexandrite laser (PSAL)
Melasma with or without diffractive lens array respectively [59,60].
Melasma is a benign pigmentary condition that typi- In the first comparison, Wang et al. randomized three
cally affects the face in characteristic distribution pat- groups of subjects to receive either three treatments of
terns. Risk factors associated with the development of fractionated PSAL at 4‐week intervals (Group A), five
melasma include genetic predisposition, hormonal influ- treatments of fractionated PSAL at 4‐week intervals
ences, and ultraviolet radiation exposure. There is cur- (Group A2), or triple combination cream consisting of
rently no known cure for this condition and the mainstays 0.01% fluocinonide acetonide, 4% hydroquinone, and
of treatment include topical bleaching agents and sun‐ 0.05% tretinoin applied nightly for 8 weeks, then twice
protective regimens [95]. weekly for 6 weeks, then once weekly for 6 weeks (Group
WU ET AL. 35
Subsequent prospective open‐label trials confirmed the no significant differences detected. Similarly, subject‐
above efficacy in ethnic populations using different reported improvement and satisfaction was equivalent for
metrics such as the Echelle d'Evaluation Clinique des both sides. The Canfield Visia (Canfield Imaging Systems,
Cicatrices d'acne (ECCA) scale and/or different laser Fairfield, NJ) digital imaging system was used to assess
devices [63,66]. changes in pore size. Both treatment modalities resulted
in a significant improvement, but the Er:fiber laser ach-
Other Scar Types ieved significantly more improvement as compared with
The evaluation of picosecond laser for non‐acne scars the picosecond laser. Most side effects were found to be
has been limited to case series and retrospective reviews. equivalent between the two treatment halves, but the
Reliable conclusions are therefore more difficult to arrive picosecond side was associated with significantly greater
upon. Fractionated 1064 nm picosecond Nd:YAG laser immediate pinpoint bleeding and the Er:fiber side had
showed promise for the treatment of hyperpigmented significantly greater pain. It is difficult to make strong
scars resulting from burn injury, road accident, leishma- recommendations based on a single comparative trial, but
niasis, and surgical procedure in a small case series of 16 the general equivalence between fractionated picosecond
patients [67]. Although the level of evidence is weak, there laser and traditional non‐ablative fractional laser seems
is likely an effective role for fractionated picosecond laser in keeping with other comparative trials studying dif-
for the improvement of hyperpigmented scars given its ferent indications [52] [Wu et al., submitted]. However, it
more robust track record for the treatment of hyper- is important to note that the follow‐up period of 8 weeks in
pigmentation due to other causes such as benign pig- the Chayavichitsilp et al. study above is somewhat short
mentary conditions and photodamage. Retrospective re- and a more accurate assessment of acne scar response is
views of atrophic and hypertrophic surgical scar typically seen at 3–6 months following treatment.
treatments with fractionated picosecond Nd:YAG laser
have also demonstrated benefit. Interestingly, reflectance Bottom Line
confocal microscopy of treated scars at the 6‐month time Fractionated picosecond laser is currently U.S. FDA
point post‐treatment revealed a net‐like reconfiguration cleared for the treatment of acne scars. The current evi-
of collagen fibers and a significant reduction of epidermal dence demonstrates a high level of safety and tolerability
thickness in hypertrophic scars compared to baseline associated with a moderate level of efficacy. However, ro-
[69,70]. Once again, more robust studies are required to bust and rigorous clinical trial data remains relatively
further evaluate these findings. sparse. Encouragingly, reports thus far seem to suggest
Striae alba was studied in a randomized, double‐blind, that the risk of post‐inflammatory pigmentary alteration
split‐abdomen comparison trial between 1064/532 nm is low when using fractionated picosecond laser which has
frequency‐doubled picosecond Nd:YAG laser and 1565 nm added significance due to the high prevalence of acne
erbium:glass non‐ablative fractional laser in 20 subjects scarring in skin of color. There are several unmet needs in
[64]. Three treatments were delivered at 3‐week intervals the current literature including the optimization of
and clinical evaluation was performed at 6 months post‐ treatment settings, stratification based on acne scar type,
final treatment. A modest improvement in striae texture more rigorously designed clinical trials with validated
and atrophy was reported for both treatment groups, with endpoint evaluation metrics, comparative trials, and ex-
no significant differences detected. Striae density was not ploration of potential combination strategies with other
significantly improved by either treatment modality. established therapeutic modalities.
Subjects rated their improvement between 45 and 50% on
both sides. The picosecond laser was rated as less painful Level of Evidence
in all three treatment sessions, although this difference
was only statistically significant for treatments 1 and 2. Acne scars Level 2b
Similarly, the picosecond treatment was associated with Striae alba Level 2b
faster healing time after each treatment, but the differ- Hypertrophic and atrophic surgical scars Level 3c
ence reached statistical significance only after treatment
2. Unfortunately, no histological specimens were analyzed
in this study and so no further insight could be provided.
Recommendation
Comparative Studies and Controversies Fractionated picosecond laser should be positioned as a
There has been one randomized, single‐blind, internally treatment option for patients with mild to moderate acne
controlled split‐face comparison trial between fractio- scarring who desire minimal downtime and have perhaps
nated 1064 nm picosecond Nd:YAG laser and 1550 nm failed other more well‐established treatments. Acne scar
erbium:fiber non‐ablative fractional laser [65]. The facial patients who are skin of color and/or who present with
halves of 30 subjects were randomized to receive either concurrent pigmentary issues may also be selective can-
picosecond laser or Er:fiber laser for four treatments at didates for fractionated picosecond laser. Striae alba can
4‐week intervals, with final evaluations performed 4 and be treated with fractionated picosecond laser, but im-
8 weeks later. Using the ECCA scale, blinded evaluators provements tend to be modest. Fractionated picosecond
reported roughly 30–40% improvement on both sides with laser may be considered as an adjunctive treatment
WU ET AL. 37
modality in combination with other therapies for hyper- study demonstrated no difference in clinical efficacy, but
trophic and atrophic surgical/traumatic scars. due to the increased number of variables as well as the
weaker study design, these data are difficult to interpret
Tattoo Removal with clarity.
Upon closer inspection, the Pinto et al. study had design
Tattoo removal is the oldest and most established der-
elements that call into question the investigators’ final
matologic indication for picosecond laser. It was first re-
conclusions. First, only two treatment sessions were con-
ported in the dermatologic literature at the turn of the
ducted. This short study duration raises potential prob-
century where it was utilized in a pre‐clinical and ex-
lems because it is frequently the case that the initial
perimental fashion for the removal of unwanted tattoos
tattoo treatment sessions yield the most dramatic results
[73,74]. Predicated on the theory of selective photo-
and so differences may be more difficult to detect. Addi-
thermolysis [1], the size of tattoo ink particles suggested
tionally, as tattoo treatment progresses into the later
that a picosecond pulse duration would be required to
stages, tattoo ink particle size diminishes, a fact that
optimally target and remove them [75]. To test this hy-
would theoretically increasingly favor a shorter pulse
pothesis, Ross et al. [73] compared a 35 picoseconds
duration device. It, therefore, remains an open question
versus 10 nanoseconds 1064 nm Nd:YAG laser for the re-
as to whether or not the equality of the two treatment
moval of black tattoos in 16 patients [73]. The results
modalities would have remained if the treatment sessions
clearly demonstrated the superiority of the picosecond
were continued further. Furthermore, a review of the laser
pulse. Subsequently, a 500 picoseconds 795 nm titanium
parameters used in this study reveals that the picosecond
sapphire laser was compared with a 50 nanoseconds
laser settings could have potentially been further opti-
755 nm alexandrite for black tattoo removal in a guinea
mized, and the nanosecond laser fluences were, on
pig model [74]. Once again, the picosecond pulse sig-
average, greater than double their picosecond counter-
nificantly outperformed the nanosecond pulse. Currently,
parts. One interpretation of these findings is that the
lasers with true picosecond pulse durations have been
nanosecond device requires more than double the fluence
developed at wavelengths of 532, 730, 755, 785, and
to achieve the same clinical result as the picosecond de-
1064 nm and have all been reported as effective at
vice. Previous work has demonstrated that this elevated
clearing almost every color of tattoo ink as well as para-
fluence requirement results in a demonstrable increase in
doxical darkening of tattoo [77,79–82,85,96]. A systematic
non‐specific tissue damage which may have clinical safety
review was published in 2016 analyzing the safety and
implications [26]. Alternatively, it could be argued that
efficacy of picosecond lasers for tattoo removal, and the
the picosecond laser settings could have been significantly
general consensus is that they work very well and have a
increased without affecting safety or tolerability. Either
high degree of safety and tolerability [97,98].
way, these alternative hypotheses both suggest that the
picosecond laser system has potential advantages over the
Comparative Studies and Controversies nanosecond system that could not be appropriately ex-
Although shorter pulse durations are advantageous plored and evaluated in this study design. Lorgeou et al.
from both a conceptual and scientific standpoint, there [86] performed the second split tattoo comparative clinical
remains some controversy regarding the continued role of trial using greater patient numbers, greater treatment
nanosecond pulse durations for optimal tattoo removal sessions, and including all colors and reported a statisti-
[99]. Three comparative clinical trials consisting of two cally significant picosecond advantage in black ink re-
prospective, single‐blind, randomized, split tattoo designs moval (especially those that were professionally done) but
and one retrospective review have studied nanosecond no advantage for other colors. However, the actual abso-
laser versus picosecond laser where both devices were lute clinical difference in efficacy between the two lasers
attempted to be used at optimal settings [84,86,87]. The was modest and both treatment modalities appeared safe.
first split tattoo study was conducted by Pinto et al. and It has been theorized that longer nanosecond pulses and
compared a 5 nanoseconds pulsed 1064 nm Nd:YAG laser shorter picosecond pulses are both required to optimally
versus a 450 picoseconds pulsed 1064 nm Nd:YAG laser target large and small tattoo particles respectively. In this
for the treatment of black tattoos. After two treatment scenario, the argument is that there is benefit to starting
sessions, the investigators found no statistical difference treatments at nanosecond pulses in order to target the ini-
in efficacy although the picosecond laser was significantly tial large tattoo pigments before transitioning to the pico-
less painful [84]. The second split tattoo study reported second pulses as the tattoo particles become smaller. How-
the opposite effect, with picosecond Nd:YAG lasers with ever, there seems to be little scientific or clinical evidence in
pulse durations between 450 and 750 picoseconds per- support of this hypothesis to date and, on the contrary, past
forming superiorly to their 5 nanoseconds pulsed nano- and present scientific and clinical studies have suggested
second counterpart [86]. The final study was a retro- that the need for nanosecond pulses in targeting larger
spective review of eyeliner tattoo removal that not only tattoo particles is questionable. Kato et al. conducted a
differed in comparing picosecond versus nanosecond la- retrospective review comparing combination 2 nanoseconds
sers but also different wavelengths of laser (picosecond and 750 picoseconds 1064 nm Nd:YAG laser versus 2 nano-
755 nm vs. nanosecond 1064 nm) even though the ink seconds alone 1064 nm Nd:YAG laser for removal of black
color to be removed remained a constant black [87]. This tattoo and concluded that the combination pulse was
38 A SYSTEMATIC REVIEW OF PICOSECOND LASER IN DERMATOLOGY
superior [89]. Unfortunately, no picosecond alone group was picosecond laser for tattoo removal, although greater flu-
included in the analysis, therefore, making it difficult to ences will result in greater tissue damage. Additionally, the
determine the true benefit of combining nanosecond and relationship between fluence and efficacy may be complex.
picosecond pulses. The investigators did conduct scanning For example, Izikson et al. [75] reported a decreased efficacy
electron microscopy analysis of samples treated with either of high fluence picosecond laser compared to medium and
2 nanoseconds or 750 picoseconds pulses and these data re- low fluence for the removal of iron oxide tattoo in a York-
vealed that the 750 picoseconds pulse irradiation con- shire pig model. This result could have simply been due to
sistently resulted in greater dispersion of tattoo particles spot size variation (high, 1.3 mm spot; medium, 1.9 mm
regardless of original tattoo particle size. Similarly, two‐ spot; and low, 2.9 mm spot) or the possibility that the high
photon microscopy analysis of in vivo tattoo ink irradiated fluence picosecond laser exceeded tissue plasma formation
with 5–10 nanoseconds versus 750 picoseconds laser has threshold to a greater degree resulting in the quicker and
demonstrated that the picosecond pulses fragmented tattoo more superficial formation of plasma that blocked further
particles of all sizes with higher efficiency as compared to laser penetration. It is worthwhile to note that the original
nanosecond pulses [100]. Only when the nanosecond laser work by Ross et al. utilized an experimental laser with a
fluences were elevated to greater than twice that of the pi- pulse duration of 35 picoseconds and mathematical calcu-
cosecond laser, or when the picosecond laser was deliber- lations have suggested that pulse durations of between 10
ately utilized at very low fluence was superiority demon- and 100 picoseconds may be optimal for tattoo particle tar-
strated for the nanosecond pulses [100]. Finally, Ahn et al. geting via the principles of selective photothermolysis
[101] utilized an experimental model to directly compare the [1,3,73,75]. Currently available picosecond lasers have pulse
effect on tattoo particles of a 750 picoseconds 1064 nm durations no shorter than 250 picoseconds. The future de-
Nd:YAG laser versus a 5 nanoseconds 1064 nm Nd:YAG velopment of even shorter picosecond pulsed devices has the
laser. In this study, compelling data demonstrated that (i) at potential to demonstrate the advantages of this modality in
all equivalent fluence levels, the picosecond laser achieved a a clearer fashion, shed light on whether pulse duration that
greater degree of particle fragmentation than the nano- are too short may even have a detrimental effect due to
second laser; (ii) at low fluence levels, the picosecond laser increased plasma formation, and may give rise to further
remained effective whereas the nanosecond laser was un- indications and applications.
able to induce significant particle fragmentation; (iii) re-
peated picosecond exposures continued to fragment tattoo Level of evidence
particles whereas repeated nanosecond exposures even- Level 1a
tually became ineffective at targeting the smaller fragmen-
tations; and (iv) when irradiated in sequence, picosecond Recommendation
exposure followed by picosecond exposure resulted in Picosecond laser currently represents the gold standard
greater fragmentation as compared with nanosecond‐then‐ treatment option for the removal of unwanted tattoos of
nanosecond, nanosecond‐then‐picosecond, and picosecond‐ almost any color.
then‐nanosecond. These data support the notion that
nanosecond pulses may not be necessary for the opti- CONCLUSION
mization of tattoo removal. The dermatologic applications of picosecond laser along
with their associated levels of evidence and clinical rec-
Bottom Line
ommendations are summarized in Table 7. Picosecond
Picosecond laser is a safe and effective therapeutic mo- laser is an expanding field in dermatology. A per year
dality for the removal of unwanted tattoo of almost any color analysis of Tables 1–6 reveals that the Level of Evidence
and currently represents the gold standard. The accumu- associated with each major dermatologic indication con-
lated scientific and clinical evidence to date concludes that tinues to progress as clinical trials explore increasingly
the shorter pulse duration confers a distinct advantage refined questions with increasingly rigorous experimental
when other laser parameters remain equal. The evidence designs. Future directions may include the development
also suggests that the shorter the pulse gets (within cur- of even shorter pulse durations, improvements in frac-
rently commercially available and tested devices), the tionation method and delivery, and exploration of the
greater becomes the efficacy for tattoo removal. There is no utility of pulsing other laser wavelengths in the pico-
evidence to suggest that larger tattoo particles are more second (or shorter) domain. The introduction of newer
optimally targeted by longer nanosecond pulses. Conflicting devices along with continued improvements in clinical
reports in the literature can potentially be explained by technique and experience will drive the refinement and
study design variations and variable study device opti- expansion of this technology.
mization. That being said, there still remains two practical
clinical situations in which a nanosecond laser may out-
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