Lasers in Medical Science (2020) 35:1007–1024

https://doi.org/10.1007/s10103-020-02957-9

REVIEW ARTICLE

Systematic review and meta-analysis of safety and efficacy

of high-intensity focused ultrasound (HIFU) for face
and neck rejuvenation
Azin Ayatollahi 1 & Jaleh Gholami 2 & Maryam Saberi 1 & Hamed Hosseini 1 & Alireza Firooz 1

Received: 23 October 2019 / Accepted: 2 January 2020 / Published online: 5 February 2020
# Springer-Verlag London Ltd., part of Springer Nature 2020

Abstract
High-intensity focused ultrasound (HIFU) is widely used for skin rejuvenation and tightening. The aim of this study was to
determine the safety and efficacy of HIFU for face and neck rejuvenation. A systematic search of peer reviewed articles published
before December 2017 was performed using Medline, Web of Science, and Scopus databases. Retrieved studies were screened,
and clinical trials or follow-up studies which were evaluated the effect of HIFU on rejuvenation treatments of face and neck area
were included. Risk of bias for each study was assessed and was reported. Safety and efficacy variables, which were reported
more often in papers, were included in meta-analysis. Seventeen studies involving 477 participants were included in the analysis.
Meta-analysis showed moderate improvement as scores of 2.74 (95% CI 2.06–3.43) and 2.68 (95% CI 1.92–3.45), out of 5
maximum score, for objective improvement score and subjective satisfaction score, respectively. Meta-analysis of mean pain
score, assessed by a 0–10 Likert score, was 4.2 (95% CI 4.27–5.19). Edema and erythema showed considerable heterogeneity,
and no hyperpigmentation was reported by included studies. Included studies used multiple and different outcome variables with
different scoring at various time points. Long follow-up was not reported by majority of studies. HIFU is safe procedure in short
term and has a moderate effect on rejuvenation of face and neck areas.

Keywords HIFU . Face . Neck . Rejuvenation

Introduction During this process, the fibroblast differentiation and

neocollagenesis will take place and dermal collagen remodel-
Ultrasound is an oscillating sound pressure wave with a fre- ing contributes to a decrease in overall skin laxity, skin reju-
quency greater than the upper limit of the human hearing venation, and tightening [1].
range. Ultrasound wave has mechanical, cavitation, and ther- The first aesthetic use of high intensity focused ultrasound
mal effects. By transformation of acoustic (mechanical) ener- (HIFU) or microfocused ultrasound (MFU) in dermatology
gy into thermal energy, it disrupts cellular membranes in deep was reported by White et al. in 2007 [2]. They evaluated the
dermis and the superficial musculoaponeurotic system effects of HIFU on unfixed human cadaveric specimen. After
(SMAS). The goal is to heat the superficial dermis to 60 to visualizing the SMAS layer, they targeted SMAS by using the
70 °C. It accurately focuses the heat in tissue, with minimal ultrasound imaging component of the device. They delivered
damage to surrounding structures. The wound healing cascade 202 exposure lines bilaterally in multiple facial regions by
will activate after cellular apoptosis and necrosis. varying combinations of power and exposure time (0.5–
8.0 J). Then, the tissue was excised and examined grossly
and histologically for signs of thermal injury using nitroblue
* Alireza Firooz
tetrazolium chloride viability stain. They showed that ultra-
[email protected]
sound can noninvasively target and selectively produce ther-
1
Center for Research and Training in Skin diseases and Leprosy, mal injury zones (TIZs) of reproducible location, size, and
Tehran University of Medical Sciences, Tehran, Iran geometry in the SMAS layer. So they concluded that HIFU
2
Iranian National Center for Addiction Studies, Tehran University of might have implications for aesthetic facial rejuvenation by
Medical Sciences, Tehran, Iran inducing shrinkage and tissue tightening [2].
1008 Lasers Med Sci (2020) 35:1007–1024

US Food and Drug Administration (FDA) approved HIFU risk,” “High risk,” or “Unclear risk” of bias (Appendix
treatment (Ulthera; Merz Device Innovation Center, Mesa, Table 2).
AZ) for eyebrow lifting in 2009, skin lifting and tightening
of the neck and submental laxity in 2012, and décolletage
rejuvenation in 2014 [3]. Data analysis
The aim of our study was to perform a systematic review
and meta-analysis to determine the safety and efficacy of Multiple different outcome variables were assessed in studies
HIFU for face and neck rejuvenation. and four outcome variables, which were reported more often
in papers, were included in meta-analysis: Subjective (patient)
satisfaction; Objective (physician) improvement; Subjective
Method Global Aesthetic Improvement Scale; and Objective Global
Aesthetic Improvement Scale. Safety variables including ede-
This systematic review was performed following the Preferred ma, erythema and pain at first day, and hyperpigmentation at
Reporting Items for Systematic Review and Meta-Analysis 3 months also were meta-analyzed.
(PRISMA) guideline. A comprehensive search was done for In studies with multiple arms with different protocols of
finding all articles published in peer-reviewed journals, de- HIFU, each arm considered as an individual study.
scribing the effect of ultrasonic therapy for rejuvenation of For meta-analysis, scoring of each variable was converted
face and neck in a follow-up or interventional study. to the same scale. For example, in one study [4], Subjective
Keywords such as “HIFU,” “ultrasonic therapy,” “rejuve- satisfaction was scored from 1 as not satisfied till 5 as very
nation,” “facial tightening,” “neocollagenesis,” “face lift,” and satisfied, while in another study [5], it scored from 0 as very
“neck tightening” were used for designing sensitive search satisfied till 4 as not satisfied, so mean score of subjective
strings and no limitations on the language and time of the satisfaction in this study was subtracted from 6.
study article was considered. Relevant articles in three data- Pooled mean and 95% confidence interval were estimated
bases were searched till December 2017: Ovid Medline, Web for ordinal and continuous outcome variables (Subjective sat-
of Science, and Scopus. The reference lists of included studies isfaction, Objective improvement, Subjective Global
also were added. Aesthetic Improvement Scale, Objective Global Aesthetic
After removal of duplicate references, screening on the Improvement Scale, and pain), and pooled frequency and
titles and abstracts of papers was conducted by two re- 95% CI were estimated for dichotomous variables (edema,
searchers independently. In the second step, full texts of in- erythema, and hyperpigmentation).
cluded papers were evaluated for eligibility criteria and studies Subgroup analysis was conducted based on time (for effi-
were excluded if they were not clinical trial or follow-up cacy variables) and using analgesics (for pain) to control the
study, not assessed the effect of HIFU, intervention was com- potential sources of heterogeneity. Meta-analysis was per-
bination of HIFU with other rejuvenation treatments, and/or formed using STATA version 14 and random effect models
the study was not performed on face and neck area. were used because of being more conservative in evaluation
Data were extracted for all eligible studies by two re- of heterogeneity. The overall heterogeneity across studies was
searchers independently. The data of any safety and efficacy examined using I2 statistic which describes the percentage of
outcome variables which were reported in the study were ex- variation across studies that is due to heterogeneity.
tracted and recorded in the pre-designed form. Retrieved in-
formation consisted of bibliographic information and study-
specific details including study location and year of study Results
conduction; characteristics such as age, sex, body mass index,
and skin type in participants; intervention details; place of Study characteristics
intervention; effect estimates reported in the study; and fre-
quency of adverse effects of HIFU. After data extraction was Search of databases and references of the relevant studies
completed, the results of the two researchers were compared produced 1238 results. Searching clinical trial registries added
for consistency by third investigator and any disagreements 53 additional references. After removal of duplicate records,
were discussed and resolved through consensus. 648 references remained, which 594 of them excluded be-
As the majority of included studies were uncontrolled cause they were not a trial or follow-up study of the effect of
before–after studies, risk of bias of each study were evaluated HIFU on face and neck. After screening based on title and
using 3 items out of 7 items of Cochrane Collaboration’s tool abstract, 54 records remained and full texts were obtained.
for assessing risk of bias: blinding of outcome assessment, Thirty-seven papers were excluded, from which 12 were not
incomplete outcome data, and selective reporting. For each on face and neck, one article was retrospective study, and 24
study, the judgment for any item were presented as “Low articles were not for rejuvenation therapy or intervention was
Table 1 Characteristics of studies included in systematic review

Author Year of study Study design Participants Intervention group Comparison group Place of Other interventions N N
(Year) conduct- Country characteristics intervention participants completed
(F/M)

Jones 2015-US Randomized Age Ulthera SMRF Neck Using tumescent anesthesia Ulthera: 10 Ulthera:10
(2017) trial mean ± SD: First, a 4-MHz transducer with a Neck was divided (for SMRF) + pretreatment (9/1) SMRF:7
55.05 ± 4.51 4.5-mm focal depth set to 0.90 J, into 1 to 3 60 mg IM SMRF:
Min–max: 44–62 then a 7 MHz with a 3.0-mm focal treatment sections. ketorolac tromethamine 10 (10/0)
depth set to 0.30 J. Using tumescent 30 min before
Lasers Med Sci (2020) 35:1007–1024

Total treatment lines 530, anesthesia,

each transducer 265 lines a blunt 10-cm
(+10% variance). Maximum probe was inserted
length of each line:25 mm into the subdermal
layer of the skin.,
and the probe was
slowly moved in a
fanning pattern
Saket Iran Single arm study Age UTIMS A1 – Full face – 22 (22/0) 22
(2017) mean:50 (Seoul, South Korea) and neck
Min–max: 35–62 3 transducers: 1.5 mm/10MHZ,
3 mm/7 MHz,
4.5 mm /4 MHz
spacing: 1.7 mm
(constant parameter)
The number of lines: 600–800 lines.
neck and periocular area: superficial
depth probes
brow and temple area: superficial and
deeper probes
cheek and submental skin: deepest
4-MHz 4.5-mm probe followed by
additional treatment with a
superficial probe
Werschler US Single arm study Age Ulthera – Full face 19 oral tramadol with 20 (17/3) 19
(2016) mean: 47 Transducers: first 4.0 MHz/1.5 mm, and neck acetaminophen
Min–max: 34–60 then 7.0 MHz/3 mm and one received
BMI 600 to 700 dual plane treatment lines hydrocodone with
Mean: 25.5 with vertical vectoring. acetaminophen
Min–max: Maximum length of each line of
20.9–28.5 25 mm
(spaced 2 to 3 mm apart)
Park Korea Single arm study Age Ultherasystem (Ulthera Inc., Mesa, – Full face Topical lidocaine/prilocaine 20 (18/2) 20
(2015) mean ± SD: AZ, USA) probes: 7.5 MHz and except under an occlusive
52.3 ± 13.9 focal depths of 3.0 and 4.5 mm. nose and dressing for 60 min. In
Min–max:37–75 1-cm intervals eyes three patients, a nerve
Skin type (Fitz 400 to 500 lines block of the supraorbital,
Patrick score): supratrochlear, intraorbital,
All patients skin and mental nerves.
types III and IV
1009
Table 1 (continued)
1010

Author Year of study Study design Participants Intervention group Comparison group Place of Other interventions N N
(Year) conduct- Country characteristics intervention participants completed
(F/M)

Lu (2017) Taiwan Single arm study Age Ulthera (Mesa, AZ, USA) – Face and topical 2.5% 25 (23/2) 25
mean ± SD: 4 MHz/4.5-mm (0.90 J), neck lidocaine and 2.5% prilocaine
53.3 ± 4.7 350 lines on the cheeks and neck; for 60 min and oral
Min–max: 7 MHz/3.0-mm (0.30 J), analgesics with ibuprofen
39.8–61.1 430 lines on the forehead, 800 mg before the
BMI temple area, cheeks, treatment
mean ± SD: 22 ± 2.1 and neck; and 7 MHz/3.0-mm
Min–max:18.6–26 (0.30 J), 20 lines on the
Skin type infraorbital area.
(Fitz Patrick Total 800 lines
score) No (%)
Type III: 3 (12)
Type IV: 22 (88)
Jung Korea Randomized Age Ulthera (USA) Ultra-Skin (Korea) Midface 2.5%lidocaine+ Ulthera: 20 Ulthera: 20
(2016) split-face trial mean: 59.8 Spacing: 1.5 mm Spacing: 1.0 mm 2.5%prilocaine with (18/2) Ultra-Skin:
Min–max: 40–70 (0.9 J energy) (1.3 J energy) occlusion for 1 h Ultra-Skin: 20
Skin type (Fitz Transducers: 4.4 MHz/4.5 mm. Transducers: 20 (18/2)
Patrick score) No The thermal coagulative zone was4.0 MHz/4.5 mm.
(%) set at 17 The thermal
Type III: 15 (75) The ratio of exposure lines was five.
coagulative zone
Type IV: 5 (25) was set at 21 zones
The ratio of exposure
lines was four
Buamann US Nonrandomized Age Ulthera (USA), B: Ulthera, Neck and – A: 34 (32/2) A: 32
(2016) trial mean: 55.32 Submental and submandibular areas: Submental and lower B: 5 (5/0) B: 5
Min–max: 39–62 two transducers (4 MHz/4.5 mm submandibular face C: 25 (24/1) C: 24
BMI and 7 MHz/3 mm) areas: two
Mean:25.58 Lower neck: one transducer transducers
Min–max:18.5–36.4 (7 MHz/3 mm) (4 MHz/4.5 mm
Skin type (Fitz Treatment lines:246–296 and
Patrick score 7 MHz/3 mm),
(No (%) lower neck: two
Type I: 10 (15.6) transducers
Type II: 31 (48.4) (4 MHz/4.5 mm
Type III: 22 (34.4) and
Type V: 1 (1.6) 7 MHz/3 mm).
The platysmal
muscle above the
jaw line: two
transducers
(4 MHz/4.5 mm
and 7 MHz/
3 mm). Treatment
lines: 426–526
Lasers Med Sci (2020) 35:1007–1024
Table 1 (continued)

Author Year of study Study design Participants Intervention group Comparison group Place of Other interventions N N
(Year) conduct- Country characteristics intervention participants completed
(F/M)

C: Ulthera,
Submental and
submandibular
areas: two
transducers
Lasers Med Sci (2020) 35:1007–1024

(4 MHz, /4.5 mm
and
7 MHz/3 mm).
Lower neck: two
transducers
(4 MHz/ 4.5 mm
and
7 MHz/3 mm).
Treatment lines:
346–446
Suh Korea Single arm study Age DoubloTM, HIRONIC Co., Korea) – Full face topical anesthetic cream 11 (10/1) 11
(2015) Mean: 46 Forehead, temples,and malar area: 40 min before treatment
Min–max: 7 MHz/3.0-mm (forehead,
35–64 0.25–0.3 J; malar, 0.35 J;
temple,0.35 J).
Cheeks and submentum:
4 MHz/4.5-mm (1.0 to 1.2 J) and
7 MHz/3.0-mm (0.35 to 0.45 J).
Spacing: 1.5–2.0 mm.
Total lines: 400 lines
Pak March 2011–May 2012- Single arm study Age Ulthera (USA) – Lower EMLA cream for 60 min 7 (7/0) 7
(2014) Korea mean: 42.7 Lower eyelid: 1.5 mm (0.2 J) eyelid
Min–max: and3 mm (0.45 J) probe.
20–62 Total treatment lines: 30
length of the treatment lines:14 mm,
12–13 thermal coagulation points
were created in each treatment
line.
Oni July 2010–August 2010 Single arm study Age Ulthera – lower half Oral diazepam 103 (87/16) 93
(2014) - US mean:49.2 Transducers:4–4.5 (deeper) and 7–3 of Face and
Min–max: (superficial) and neck hydrocodone/-
35–60 Total lines: 295multiple exposure acetaminophen at least
BMI Line length(maximum): 25 mm 30 min and Intramuscular
Mean: 25.6 medication
Min–max: (ketorolactromethamine)
18.7–36.5 was given 60 min before
Skin type treatment
(Fitz Patrick
score) No (%)
Type I: 12 (8.3)
1011
Table 1 (continued)
1012

Author Year of study Study design Participants Intervention group Comparison group Place of Other interventions N N
(Year) conduct- Country characteristics intervention participants completed
(F/M)

Type II: 66 (64.1)

Type III: 15 (14.6)
Type IV: 5 (4.8)
Type V: 3 (2.9)
Type VI: 2 (1.9)
Fabi 2011- US Single arm study Age Ulthera (USA) – face and topical 23%lidocaine/7% 48 (48/0) 45
(2014) mean:58.5 Transducers:4-MHz/4.5-mm and upper tetracaine (10% of
Min–max: 7-MHz/3.0-mm neck cases) + oral diazepam
31–85 Treatment lines:370–420 (5–10 mg) (15% of cases),
BMI +IM inj. Meperidine +
mean:22.1 hydroxyzine (majority of
Min–max: cases)
17.9–30.8
Skin type
(Fitz Patrick
score) No (%)
Type I: 1 (2.1)
Type II: 24 (50)
Type III: 17 (35.4)
Type IV: 6 (12.5)
Suh Korea Single arm study Age Ulthera (USA). – Infraorbital Topical anesthetic cream for 15 (13/2) 15
(2012) mean:50 Transducer: 7.0 MHz/3.0 mm 60 min
Min–max: Spacing: 3.0–5.0 mm.
27–69 Energy per ultrasound pulse: 0.25 to
Skin type 0.35 J.
(Fitz Patrick
score): All
patients skin
Types III–V
Alam US Single arm study Age Ulthera (USA) Transducers: 4 MHz, – Full face Topical (7%/7% 36 (34/2) 35
(2010) Median: 44 /4.5-mm (0.75–1.2 J); and neck lidocaine-tetracaine)
Min–max: 7 MHz/4.5-mm (0.75–1.05 J); 45 min before the
32–62 and 7 MHz/3.0-mm (0.4–0.63 J). procedure
Maximum treatment line length:
25-mm The pulse duration for
each individual exposure: 25 to 40
milliseconds.
Lee Korea Single arm study Age Ulthera (USA) – Face and Topical lidocaine 9% 45 to 12 (12/0) 10
(2012) mean:59 Transducers: 4-MHz/4.5-mm neck 60 min before procedure
Min–max: (1.2 J0 and 7 MHz/3.0-mm
55–71 (0.63 J).
Treatment lines: 238
Suh Korea Single arm study Age Ulthera(USA) – Full face Topical anesthetic cream 22 (20/2) 22
(2011) mean: 48.5 Forehead (0.3–0.35 J), temples 60 min before procedure
Min–max: (0.35 J) and the malar area
Lasers Med Sci (2020) 35:1007–1024
Table 1 (continued)

Author Year of study Study design Participants Intervention group Comparison group Place of Other interventions N N
(Year) conduct- Country characteristics intervention participants completed
(F/M)

38–73 (0.35 J): 7.5-MHz/3.0-mm, the

cheeks and submentum:
4.4 MHz/4.5 mm (1.0 J) and
7.5 MHz / 3.0-mm (0.45 J).
Spacing: 1.5 to 2.0 mm.
Lasers Med Sci (2020) 35:1007–1024

Treatment lines: forehead (30),

each temple (10), each cheek (70),
and submentum(90)
Harris 2011- US Single arm study Age Ultera The lower face and – Face and –
(2015) mean: 53 submental:4.4 MHz/4.5 mm and neck
Min–max: 7 MHz/3 mm
32–64 Treatment lines:370
BMI Maximumlength:25 mm
Mean: 27.5 microcoagulation zones spaced: 2 to
Min–max 3 mm
20.9–37.9
Skin type
(Fitz Patrick
score) No (%)
Type III: 9 (17%)
Type IV: 25 (48%)
Type V: 15 (29%)
Type VI: 3 (6%)
Sasaki May 2014–January Randomized Age 1a:DS4 MHz-4.5 mm 30 lines/DS7 1: bDS4 Marionette – 1a: 10 (8/2) 1a: 10
(2017) 2016- US split-face trial mean:53.3 MHz-3.0 mm 30 lines MHz-4.5 mm 45 fold 2a: 10 (8/2) 2a: 10
(2 pilot Min–max: 2a:DS4 MHz-4.5 mm 30 lines/DS7 lines/DS7 1b: 10 (8/2) 1b: 10
studies) 36–72 MHz-3.0 mm 30 lines MHz-3.0 mm 45 2b: 10 (8/2) 2b: 10
lines
2b: DS4
MHz-4.5 mm 30
lines/DS7
MHz-3.0 mm 30
lines/DS10
MHz-1.5 mm 30
lines
1013
1014 Lasers Med Sci (2020) 35:1007–1024

Fig. 1 Study flow diagram Records idenfied through database searching

Addional arcles idenfied through
(Ovid Medline = 273, Web of science =371
reference list (N=101)
Scopus=440, Clinical trial registries=53)

Iden tification
Records retrieved
N= 1238

Screening
duplicate records
removed
(N=590)
Records screened
N= 648

Records excluded
Eligib ility

(n =594)
Full-text arcles assessed for
eligibility
(n =54)
Full-text arcles excluded
not on face and neck: 12 not trial: 1
not for rejuvenaon therapy or HIFU
combined with other procedures: 24
(n = 37)
Includ ed

Studies included in quantave

synthesis (meta-analysis)
(n = 17)

HIFU combined with other procedures. Finally, the data of 17 2.82 (95% CI 1.78–3.86) at 3 months, 2.28 (95% CI 0.77–
studies were extracted and analyzed. Further description of 3.80) at 6 months, and 2.82 (95% CI 1.10–4.55) at 12 months.
search and screening process is shown at the study flow dia- The meta-analysis showed heterogeneity of 0% between four
gram (Fig. 1). included studies and overall satisfaction of 2.68 (95% CI
Seventeen studies were included involving 477 participants. 1.92–3.45) (Fig. 2).
The number of participants included in individual studies The objective improvement score assessed by physician
ranged from 5 to 52. Ninety-two percent of all participants were judgment scored from 1 (worse) to 5 (very much improved).
women and it ranged 80–100% in individual studies. Only two studies had provided data on objective score and
Participants’ BMI and Fitzpatrick skin types were reported in pooling this outcome showed overall improvement as 2.74
6 and 8 studies, respectively. One of the studies was RCT, one (95% CI 2.06–3.43) (Fig. 3).
was non-randomized trial, 2 were randomized split-face trial, Pooled average of any improvement in objective or physi-
and the other 13 were single arm follow-up studies. Eight stud- cian global aesthetic improvement scale (PGAIS) score was
ies were conducted in the USA, seven studies were conducted 0.95 (95% CI 0.89–1), 0.83 (95% CI 0.64–1), and 0.89 (95%
in Korea, and two of them were conducted in Iran and Taiwan. CI 0.75–1) 2, 3, and 6 months after HIFU therapy respectively.
Minimum and maximum follow-up times in included studies Seven studies were included in this analysis and showed 0.88
were 2–12 months. The characteristics of these studies, as well (95% CI 0.80–0.96) overall improvement and considerable
as the assessment of risk of bias, are shown in Table 1 heterogeneity (I2 = 84.66%).
and Table 2 of appendix. Meta-analysis of subjective global aesthetic improvement
scale (SGAIS) revealed that 83% of patients (95% CI 0.76–
0.91) report improvement after HIFU therapy. It was 0.86
Efficacy of HIFU (95% CI 0.70–1), 0.80 (95% CI 0.69–0.92), and 0.85 (95%

Subjective (patient) satisfaction, Objective (physician) im- CI 0.73–0.96) after 2, 3, and 6 months respectively.
provement, Subjective Global Aesthetic Improvement Scale
(SGAIS), and Physician Global Aesthetic Improvement Scale
(PGAIS) were analyzed in order to evaluate the efficacy. Safety of HIFU
Meta-analysis of the subjective or patient satisfaction score
as a five-point Likert scale, ranging from 1 (not satisfied) to 5 For safety profile, edema, erythema, pain in the first
(extremely satisfied), showed moderate overall satisfaction day, and hyperpigmentation 3 months after HIFU
Lasers Med Sci (2020) 35:1007–1024 1015

Subjective (Patient)Satisfaction
Year of %
Author publication ES (95% CI) Weight

3 months
Park 2015 3.800 (2.173, 5.427) 22.27
Park 2014 2.150 (0.798, 3.502) 32.22
Subtotal (I-squared = 57.2%, p = 0.126) 2.824 (1.784, 3.864) 54.48

6 months
Jones 2017 2.100 (-1.585, 5.785) 4.34
Sasaki 2017 2.000 (-1.920, 5.920) 3.83
Sasaki 2017 2.000 (-1.920, 5.920) 3.83
Sasaki 2017 2.000 (-0.940, 4.940) 6.82
Sasaki 2017 3.000 (0.060, 5.940) 6.82
Subtotal (I-squared = 0.0%, p = 0.989) 2.283 (0.767, 3.799) 25.64

12 months
Sasaki 2017 3.000 (-0.528, 6.528) 4.73
Sasaki 2017 3.000 (-0.920, 6.920) 3.83
Sasaki 2017 2.000 (-2.116, 6.116) 3.48
Sasaki 2017 3.000 (0.256, 5.744) 7.83
Subtotal (I-squared = 0.0%, p = 0.980) 2.825 (1.103, 4.547) 19.87

Heterogeneity between groups: p = 0.833

Overall (I-squared = 0.0%, p = 0.976) 2.686 (1.918, 3.453) 100.00

0 2 4 6 8

Fig. 2 Forest plot of the effect of HIFU on Subjective satisfaction score 3, 6, and 12 months after intervention

therapy were reported more frequently among different 100% [3, 7] with a considerable heterogeneity (I2 =
studies. The meta-analysis of 7 articles, which reported 99.38%), and pooled estimate for prevalence of erythe-
edema, showed that 0.45 (95% CI 0.05–0.84) of pa- ma at the first day was 0.48 (95% CI 0.8–0.88).
tients had edema at the first day. Edema reported in Meta-analysis of the pain score as a 10-point Likert
included studies varied from 3.8% [6] to 100% of par- scale, ranging from 0 (no pain) to 10 (worst possible
ticipants [3, 7] and I2 statistic for heterogeneity was as pain), showed low to moderate pain with the pooled
high as 99.2%. average 3.9 (95% CI 2.80–5.01) with using analgesics
The similar pattern was found for erythema, different and 5.09 (95% CI 3.45–6.72) without suing analgesics.
included studies reported erythema from 1.9% [6] to The meta-analysis showed zero heterogeneity between

objective (physician)improvement
Year of %
Author publication ES (95% CI) Weight

3 months
Pak 2014 4.350 (1.292, 7.408) 4.98
Subtotal (I-squared = .%, p = .) 4.350 (1.292, 7.408) 4.98

6 months
Sasaki 2017 3.000 (0.256, 5.744) 6.18
Sasaki 2017 3.000 (0.844, 5.156) 10.02
Sasaki 2017 4.000 (2.432, 5.568) 18.94
Sasaki 2017 3.000 (1.628, 4.372) 24.74
Subtotal (I-squared = 0.0%, p = 0.785) 3.316 (2.434, 4.198) 59.88

12 months
Sasaki 2017 3.000 (0.256, 5.744) 6.18
Sasaki 2017 3.000 (0.648, 5.352) 8.42
Sasaki 2017 3.000 (0.648, 5.352) 8.42
Sasaki 2017 3.000 (1.040, 4.960) 12.12
Subtotal (I-squared = 0.0%, p = 1.000) 3.000 (1.849, 4.151) 35.14

Heterogeneity between groups: p = 0.705

Overall (I-squared = 0.0%, p = 0.987) 3.257 (2.574, 3.939) 100.00

0 2 4 6 8

Fig. 3 Forest plot of the effect of HIFU on Objective (physician) improvement score 3, 6, and 12 months after intervention
1016 Lasers Med Sci (2020) 35:1007–1024

included studies, overall and in subgroups, and overall with the use of higher amounts of energy and treatment planes
pain score of 4.27 (95% CI 3.36–5.19). after 180 and 360 days [9].
No post-inflammatory hyperpigmentation was reported af- Baumann eta al. compared the efficacy of two focal depths
ter 3 months in any of 5 included studies . of HIFU treatment with a single focal depth of treatment on
neck and lower face. They concluded that applying treatment
with MFU-V at two focal depths may provide improved aes-
Discussion thetic results in some subjects compared to single focal depth
treatment [14].
This systematic review aimed to assess the available evidence Among 17 evaluated studies, 15 of them used
for use of HIFU for face and neck rejuvenation. We used Ulthera (USA) device and 2 of them used Korean de-
rigorous methods for search strategy, data extraction, and out- vices: UTIMS A1 (Seoul, South Korea) [13] and
come assessment. We had no limitation on the language of the DOUBLO (Hironic co, South Korea) [18], which do
literature and time of the study, so the risk of publication bias not have US FDA approval.
was low. Jung et al. compared the efficacy and safety of two HIFU
We included 17 papers, only 1 of them was a randomized, devices (Ulthera vs Ultra-Skin) for facial skin tightening. The
controlled trial [8], and 2 randomized, split-face studies were two devices had similar efficacy in quantitative assessment by
reported in 1 paper [9]. The majority of studies [6, 7, 10–16] clinician. But there were some differences in patient satisfac-
treated both face and neck. Two studies treated just the tion and degree of pain [19].
periorbital area [5, 17]. A total of 477 patients with a mean In conclusion, all included studies showed some degree of
age of 51.73 years were treated. Overall, 83% of subjects improvement and patient satisfaction. One study compared 2
reported at least minimum degree of improvement. The im- different HIFU devices and did not revealed any significant
provement percentage was variable from 66 to 100% in dif- difference between their efficacies [18]. The comparison of
ferent studies and different time points. The physician global different energy and focal depths and treatment planes showed
aesthetic improvement scale showed 88% of patients had any more efficacy with the higher energy, more treatment planes,
degree of improvement. The heterogeneity among different and more focal depths.
studies was high. In all of these studies, the HIFU treatment was pro-
The result of this meta-analysis revealed the low risk of vided free of charge to the patients. Considering the
immediate side effects such as edema and erythema. But we relatively high cost of HIFU treatment, in future studies,
cannot judge about its long-term side effects due to lack of it is required to know if the patients are satisfied
studies with long term follow-up periods (maximum follow- enough to receive the treatment for a fee.
up was 12 months). Although the results of these studies are promising, the
The mean score of pain was 4.3 (95% CI 3.35–5.19) in a 0– majority of them have limitations in design or report such as
10 scale. Among the included articles, 4 of them did not use small size, lack of suitable control group and randomization,
any anesthesia before the procedures [6, 9, 13, 14]. So HIFU is and long term follow-up.
well tolerated, and the pain is tolerable for most cases. So larger, randomized, controlled studies with long follow-
Jones et al. compared the efficacy of subsurface up are required to assess the safety and efficacy of HIFU in
monopolar radiofrequency (SMRF) with microfocused rejuvenation of face and neck.
ultrasound for neck tightening and rejuvenation. They
revealed that both SMRF and MFU-V significantly de-
creased the investigator-assessed neck laxity as early as Funding information This study was supported by research grant number
90 days after treatment, and there was no significant 36562-34-03-96 from Undersecretary of Research, Tehran University of
difference between them. After 180 days, SMRF showed Medical Sciences.
a lower laxity grade. Subject-assessed measures of firm-
ness, texture, and laxity/sagging skin showed improve-
ment with both interventions, although MFU-V made Compliance with ethical standards
changes earlier than SMRF. Subject satisfaction at the
Conflict of interest The authors declare that they have no conflict of
end of study was identical between the 2 groups [8]. interest.
Sasaki et al. reported the results of two randomized split
face pilot studies in their published paper. They measured Ethics This study was approved by Ethics Committee of
tissue displacement at the marionette folds after single treat- Undersecretary of Research, Tehran University of Medical
ments of 2 different treatment densities or number of lines and Sciences IR.TUMS.VCR.REC.1396.4144.
2 vs 3 planes of treatment. Their studies demonstrated more
tissue displacements, elasticity measurement, and pain scores,
Lasers Med Sci (2020) 35:1007–1024 1017

Appendix 1

Table 2 Main findings of included studies and assessment of risk of bias

Author Outcome variables Risk of bias (high risk/low risk/unclear)

(year) Measurement Measurement score Findings Blinding of Incomplete Selective
Time-points outcome outcome reporting
assessment data
Jones Safety: Safety: Safety: Low risk Low risk Unclear
(2017) Pain (day 0) Pain: 0 (no pain)–10 (severe pain) Pain: 2.55 (± 7.36) risk
Edema, (day 30) Edema: 0 (being normal)–4 Edema: 4/10
Erythema (day 0) (extremely visible and dense) Erythema: 1/10
Contour irregularity Erythema: 0 (being normal)–4 Contour irregularity: 2/10
(days 30, 90) (extremely visible and dense) Bruising: 0/10
Bruising Contour irregularity: 0 (being
(days 30, 90, 180) normal)–4 (extremely visible
and dense)
Bruising: 0 (being normal) to 4
(extremely visible and dense)
Efficacy: Efficacy: Efficacy:
Neck laxity Neck laxity: 0 (none)–4 (extreme) Neck laxity:
(days 30, 90, 180) Subject satisfaction: 0 day 0: 2.8 (± 0.63)
Subject satisfaction (being not satisfied) to (extremely day 30: 2.4 (± 1.07)
(day 180) satisfied) day 90: 5 (± 0.53)
day 180:1.4 (0.7)
Subject satisfaction: 2.1 (± 1.88)
Saket Safety: Safety: Safety: High risk Low risk Unclear
(2017) Pain (during treatment), Pain: 0 (no pain) - 5 (severe pain) Pain: 17/22 (1–2), risk
mild to moderate Mild to moderate erythema (occurred 1/22 (2–3), 4 (3–4)
erythema or not occurred) Mild to moderate erythema:19/22
(first few hours), Edema (yes, no) Edema: 15/22
Edema (days 2–3), Numbness (yes, no) Numbness 12/22
Numbness (days 7–10), Transient post-inflammatory pigmen- Transient post-inflammatory pigmen-
Transient tation (yes, no) tation 0/22
post-inflammatory Mild to moderate tenderness: (yes, no) Mild to moderate tenderness: most of
pigmentation the patients
(month 3)
Mild to moderate
tenderness (week 1–2)
Efficacy: Efficacy: Efficacy:
Improvement by Improvement by doctor’s opinion: Improvement by doctor’s opinion:
doctor’s opinion 10% (no efficacy) to 100% (maximum 7/22 (50–58), 11/22 (58–66), 3/22
(3 m) efficacy) (66–74), 1 (74–82)
Improvement by Improvement by patients’ opinion Improvement by patients’ opinion:
patients’ opinion (3 m) 6/22 (40–50), 8/22 (50–60), 6/22
(3 m) 10% (no efficacy) to 100% (maximum (60–70), 1/22 (80–90)
efficacy)
Werschler Safety: Safety: Safety: Low risk Low risk Low risk
(2016) Pain (during treatment), Pain: 0 (no pain) to 10 Pain: 4.0 for 4.0 Mhz/4.5 mm, 3.2 for
Swelling (30 min after (severe pain) 7.0 Mhz/3.0 mm, and 5.5 for the
exposure and during Swelling: (yes, no), 7.0 Mhz/4.5 mm.
study), Edema: (yes, no) Swelling: 1/20 after treatment
Edema (30 min after Erythema: (yes, no) Edema: -
exposure and during Erythema: -
study),
Erythema (30 min after
exposure and during
study)
Efficacy: Efficacy: Efficacy:
Physician global Physician global Aesthetic Physician global Aesthetic
Aesthetic Improvement Scale—PGAIS (0: Improvement Scale—PGAIS:
Improvement Scale— very much improved. − 5: worse) Day 90: 20/20
PGAIS: Subject global Aesthetic Improvement Day 180: 19/19
(days 90, 180, 365) Scale—SGAIS: (0: very much Day 365: 18/19
Subject global Aesthetic improved. − 5: worse) Subject global Aesthetic
Improvement Scale— Patient satisfaction: 5 Improvement Scale—SGAIS:
SGAIS: (very satisfied) to 0 Day 90: 18/20
(days 90, 180, 365) (very dissatisfied) Day 180: 18/19
1018 Lasers Med Sci (2020) 35:1007–1024

Table 2 (continued)
Patient satisfaction Patient satisfaction Day 365: 18/19
(days 90,180, 365) (recommend or not recommend) Patient Satisfaction
Patient recommendation: Skin lifting and tightening in lower Day 90: 19/20
Skin lifting and face and Eyebrow: lower face Day 180: 19/19
tightening in lower measurement Day 365: 18/19
face and eyebrow (≥ 1 mm lift) Patient Satisfaction:
(mm) Eyebrow lift (≥ 0.5 mm) submental Day 90: 19/20
(days 90, 180, 365) area ≥ 20 m Day 180: 19/19
Day 365: 18/19
Not included due to lots of details
Park Safety: Safety: Safety: Low risk Low risk Unclear
(2015) Erythema and swelling Erythema and swelling (yes, no) Erythema and swelling: risk
(months 0, 6, 12) Purpura and bruising (yes, no) Month 0: 6/20
Purpura and bruising Neuralgia (yes, no) Month 6: 0/20
(months 0, 6, 12) Nerve palsy (yes, no) Month 12: 0/15
Neuralgia (months 6, 12) Severe edema (yes, no) Purpura and bruising
Nerve palsy Blistering (yes, no) Month 0: 2/20
(months 6, 12) Atrophy (yes, no) Month 6: 0/20
Severe edema Month 12: 0/15
(months 6, 12) Neuralgia:
Blistering (months 6, 12) Month 6: 0/20
Atrophy (months 6, 12) Month 12: 0/15
Nerve palsy:
Month 6: 0/20
Month 12: 0/15
Severe edema:
Month 6: 0/20
Month 12: 0/15
Blistering:
Month 6: 0/20
Month 12: 0/15
Atrophy: (0/20, 0/15)
Month 6: 0/20
Month 12: 0/15
Efficacy: Efficacy: Efficacy:
PGAIS PGAIS (0, none; 4, severe) PGAIS (overall):
(overall, supraorbital, SGAIS (overall, supraorbital, Day 0: 2.37 (± 0.68)
zygomatic, zygomatic, infraorbital, perioral, Month 3: 1.47 (± 0.51)
infraorbital, perioral, cheek, preauricular, jawline) Month 6: 1.47 (± 0.51)
cheek, preauricular, SGAIS (overall):
jawline Month 3: 3.80 (± 0.83)
(day 0, month 3, 6)) Month 6: 3.65 (± 0.81)
SGAIS (overall,
supraorbital,
zygomatic,
infraorbital, perioral,
cheek, preauricular,
jawline (months 3, 6))
Lu (2017) Safety: (day 0–day 180) Safety: Safety: Low risk Low risk Unclear
Pain Pain (0 no pain, 10 severe pain), Pain: 4.1 ± 62.0 with 4.5-mm risk
Soreness/tenderness, Soreness/tenderness: (yes, no) transducer and 2.7 6 ± 1.6 with
Bruising/raised area of Bruising/raised area of 3 mm
Edema/erythema, edema/erythema: (yes, no) Soreness/tenderness: 3/25
Burns Burns: (yes, no) Bruising/raised area of
Contact dermatitis due to Contact dermatitis due to topical Edema/erythema:20/25
topical anesthesia, anesthesia: (yes, no) Burns: 1/25
Paresthesia, Paresthesia: (yes, no) Contact dermatitis due to topical
Numbness, Numbness: (yes, no) anesthesia: 1/25
Tingling Tingling: (yes, no) Paresthesia: 0/25
Numbness: 0/25
Tingling: 0/25
Efficacy: Efficacy: Efficacy:
PGAIS (days 90, 180) PGAIS (1,very much improved PGAIS (any improvement): 21
SGAIS (days 90, 180) −5,worse) (84%), 22 (88%) on days 90 and
Wrinkles score: SGAIS (1,very much improved 180.
(days 0, 90, 180) −5,worse) SGAIS: 21 (84%), 20 (80%) on days
Texture score: Wrinkles score 90 and 180.
(days 0, 90, 180) Texture score Wrinkles score: − 4.72*
Lasers Med Sci (2020) 35:1007–1024 1019

Table 2 (continued)
Pores score: Pores score, Texture score: 196.96
(days 0, 90, 180) Brow height: (mm) Pores score: 9.82
Brow height: Mid-cheek angle Brow height: − 0.12
(days 0, 90, 180) Submental lift (mm2) Mid-cheek angle (abandoned)
Mid-cheek angle: Submental lift: − 0.12
(days 0, 90, 180) *Change from baseline to day 180
Submental lift
(days 0, 90, 180)
Jung Safety: Safety: Safety: Low risk Low risk Unclear
(2016) Pain (day 0) Pain (0 no pain, 10 severe pain) Group Ulthera: risk
Erythema (during Erythema: NR Pain:0/20
2 month) Edema: NR Erythema:0/20
Edema (during 2 month) Purpura: NR Edema:0/20
Purpura (during Scarring: NR Purpura:0/20
2 month) Hyperpigmentation: NR Scarring:0/20
Scarring Hypopigmentation: NR Hyperpigmentation:0/20
Hyperpigmentation Hypopigmentation:0/20
(during 2 month) Group ultra-skin:
Hypopigmentation Pain:0/20
(during 2 month) Erythema:0/20
Edema:0/20
Purpura:0/20
Scarring:0/20
Hyperpigmentation:0/20
Hypopigmentation:0/20
Efficacy: Efficacy: Efficacy:
Facial tightening and Facial tightening and skin laxity Group ulthera:
skin laxity Patient satisfaction: Facial tightening and skin laxity:1.23
Patient satisfaction (much improvement = 3, moderate Patient satisfaction: 16/20
(month 2) improvement = 2, mild a/x (horizontal line from the upper
a/x line (month 2) improvement = 1, no change = 0, margin of the philtrum to the
b/x line (month 2) worse = − 1) lateral borderline of the
a/x line: horizontal line from the upper face/horizontal line between the
margin of the philtrum to the lateral lateral canthus of both eyes): 14/20
borderline of the face/horizontal b/x (horizontal line from the lower
line between the lateral canthus of margin of the philtrum to the
both eyes) lateral borderline of the face/ hori-
b/x line: horizontal line from the lower zontal line between the lateral
margin of the philtrum to the lateral canthus of both eyes): 13/20
borderline of the face/ horizontal Group Ulthera:
line between the lateral canthus of Facial tightening and skin laxity: 1.22
both eyes) Patient satisfaction: 15/20
a/x (horizontal line from the upper
margin of the philtrum to the
lateral borderline of the face/ hori-
zontal line between the lateral
canthus of both eyes):13/20
b/x (horizontal line from the lower
margin of the philtrum to the
lateral borderline of the
face/horizontal line between the
lateral canthus of both eyes): 12/20
Buamann Safety: Safety: Safety: Low risk High risk Low risk
(2016) Pain (submental, Pain (0 no pain, 10 severe pain) Pain (submental, submandibular,
submandibular, lower Any sign of adverse reaction lower neck, lower face) (during
neck, lower face) (yes, no) procedure): 4 (± 1.7); 4.2 (± 1.8);
(during procedure) 5.1 (± 2.1); 0 (± 0)
Any sign of adverse Any sign of adverse reaction: 17
reaction reported, only 2 related to
(after 30 min) treatment (numbness and
prolonged pain)
Efficacy: Efficacy: Efficacy:
Overall lifting and Overall lifting and tightening of the Overall lifting and tightening of the
tightening of the jowls jowls and/or neck laxity (improved/ jowls and/or neck laxity
and/or neck laxity no change/improved, but incorrect PGAIS
(90 days) pre- vs post-treatment image se- (groups A, B. C respectively)
PGAIS lected) Day 60: 63.9%, 74.2%, 56.0%
(days 60, 90, 180) Day 90: 87.7%, 78.1%, 87.5%
1020 Lasers Med Sci (2020) 35:1007–1024

Table 2 (continued)
SGAIS PGAIS (1: very much improved to 5: Day 180: 66.7%, 42.0%, 95.8%
(days 60, 90, 180) worse) SGAIS (group A, C respectively)
Patient Satisfaction SGAIS (1: very much improved to 5: Day 60: 66.0%, 75%
(days 60, 90, 180) worse) Day 90: 66.0%, 75.0%
L’Oreal Photographic Patient Satisfaction (0: very satisfied Day 180: 55.0%, 70.2%
Scale scores to 5: very dissatisfied) Patient Satisfaction:
(horizontal neck folds,
L’Oreal Photographic Scale scores (groups A, B. C)
neck sagging, texture, (Horizontal neck folds, neck Day 90: 20/31,2/5, 18/24
ptosis) sagging, texture, ptosis): Day 180: 13/32,2/5, 18/24
(0, 60, 90, 180 days) horizontal neck folds (grades 0–6); L’Oreal Photographic Scale scores:
neck sagging (grades 0–7); texture Not included due to lots of details
(female grades 0–5; male grades
0–7); ptosis (female grades 0–5;
male grades 0–7)
Suh Safety: (during 8 weeks) Safety: (during 8 weeks) Safety: (during 8 weeks) Low risk Low risk Unclear
(2015) Pain (0 day), Pain (0 no pain, 10 severe pain) Pain (average score of 3) risk
Erythema, Erythema (yes/no) Erythema
Edema, Edema (yes/no) (mild persisted for 2–3 days)
Purpura, Purpura (yes/no) Edema: -
Hypopigmentation, Hypopigmentation (yes/no) Purpura: -
Scarring, Scarring (yes/no) Hypopigmentation: -
Prolonged numbness Prolonged numbness (yes/no) Scarring: -
Prolonged numbness: -
Efficacy: Efficacy: Efficacy:
Objective satisfaction Objective satisfaction: Objective satisfaction:
(8 weeks) (1; no improvement to 5; excellent (2/11 mild, 2/11 moderate, 4/11
Subjective satisfaction imp, > 75%) good, and 3/11 excellent improve-
(8 weeks) Subjective satisfaction: ment)
(1; no improvement to 5; excellent Subjective satisfaction:
imp, > 75%) (2/11 mild, 3/11 moderate, 3/11
good, and 3/11 excellent improve-
ment)
Pak Safety: Safety: Safety: Low risk Low risk Unclear
(2014) Pain (0 day) Pain (0 no pain, 10 severe pain) Pain: 4.57 (± 0.51) risk
Any allergic reactions Any allergic reactions (graded 1–3 Any allergic reactions
(12 weeks) based on CTCAE V.4.0) (no adverse reaction reported)
Efficacy: (change over Efficacy: Efficacy:
12 weeks) Distance A: (the line between the most Distance A (mean change)
Distance A (changes in inferior point of the supraorbital Right eye: 0.51 (± 0.23)
lower eyelid) rim and the most superior point of Left eye: 0.54 (± 0.17)
Distance B (changes in infraorbital rim by CT scan—mm) Distance B
lower eyelid) Distance B: (distance B was measured Right eye: 0.55 (± 0.28)
Skin tightening: from the baseline to the most Left eye: 0.65 (± 0.40)
(12 weeks) protruding point of the skin by CT Skin tightening (eyes)
Objective satisfaction scan—mm) Right eye: 6.31 (± 4.94)
scores Skin tightening (eyes): (mm2) Left eye: 4.78 (± 3.51)
Patient satisfaction Objective satisfaction scores: Objective satisfaction scores:
(12 weeks) (0: no involvement; 1: mild; 2: Researcher 1: 3.45 (± 1.69)
moderate; 3: marked, and 4: severe) Researcher 2: 3.25 (± 1.43)
Patient satisfaction: Patient satisfaction: 3.58 (± 0.69)
(0: no involvement; 1: mild; 2:
moderate; 3: marked, and 4: severe)
Oni Safety: Safety: Safety: Low risk Low risk Unclear
(2014) Pain (during treatment), Pain (0 no pain, 10 severe pain) Pain (cheek 5.68, submental 6.09, risk
Wheals (cheek, neck) Wheals: (yes/no) submandibular 6.53),
(0 day), Ulceration: (yes/no) Wheals (cheek, neck): 3/103
Ulceration (day 90) Scarring: (yes/no) Ulceration: -
Scarring (day 90) Burns: (yes/no) Scarring: -
Burns (day 90) Hypopigmentation: (yes/no) Burns: -
Hypopigmentation Hyperpigmentation: (yes/no) Hypopigmentation: -
(day 90) Hyperpigmentation: -
Hyperpigmentation
(day 90)
Efficacy: Efficacy: Efficacy:
Patient satisfaction: Patient satisfaction: (yes/no) Patient satisfaction: 61/93
(day 90) Skin laxity: (yes/no) Skin laxity:
Skin laxity (day 90) Improved:54/93
no change:16/93
Lasers Med Sci (2020) 35:1007–1024 1021

Table 2 (continued)
Getting worse: 23/93
Fabi Safety: (day 90 or 180) Safety: Safety: (day 90, 180) Low risk High risk High risk
(2014) Scars Scars: (yes/no) Scars: 0/16, 0/45
Burns Burns, (yes/no) Burns: 0/16, 0/45
Hyperpigmentation Hyperpigmentation: (yes/no) Hyperpigmentation: 0/16, 0/45
Hypopigmentation Hypopigmentation: (yes/no) Hypopigmentation: 0/16, 0/45
Efficacy: (day 90 or 180) Efficacy: Efficacy:
Overall improvement in Overall improvement in skin laxity Overall improvement in skin laxity
skin laxity (1, slight to 4, Excellent) PGAIS
PGAIS PGAIS: (1, very much improved to 5, (any improvement—day 180):
SGAIS, worse) 35/45
Subject noticed SGAIS (1, very much improved to 5, SGAIS
improvement worse) (any improvement—day 180):
Patient satisfaction Subject noticed improvement 35/45
Patient satisfaction: (1, very satisfied Subject noticed improvement:
to 5, very dissatisfied) (day 180): 38/45
Patient satisfaction (satisfied and very
satisfied—day 180): 27/45
Suh Safety: Safety: Safety: Low risk Low risk Unclear
(2012) Pain (day 0) Pain (0: no pain, 10: severe pain) Pain: 1.93 ± 1.44 risk
Erythema (day 0) Erythema (yes/no) Erythema: 2/15
Purpura (day 0) Purpura, (yes/no) Purpura: 1/15
Edema (day 0) Edema (yes/no) Edema: 1/15
Hyperpigmentation Hyperpigmentation (yes/no) Hyperpigmentation: 0/15, 0/15
(day 0, 180) Hypopigmentation (yes/no) Hypopigmentation: 0/15, 0/15
Hypopigmentation Scarring (yes/no) Scarring: 0/15, 0/15
(day 0, 180)
Scarring (day 0, 180)
Efficacy: (day 180) Efficacy: Efficacy:
Objective improvement Objective improvement Objective improvement: (2.2 ± 0.46 |
(tightening of (0: worse; unchanged: 2; improved:11; much
infraorbital laxity), 1: no change; 2: improved; improved:2)
Subjective improvement 3: much improved) Subjective improvement: (2.2 ± 0.41 |
(tightening of Subjective improvement improved:12; much improved:3)
infraorbital laxity) (0: worse; Patient satisfaction
Patient satisfaction 1: no change; 2: improved; Histopathologic analysis: increased
Histopathologic analysis 3: much improved) collagen and elastic fiber
Patient satisfaction (2 patients)
Histopathologic analysis
Alam Safety: Safety: Safety: Low risk Low risk Unclear
(2010) Pain (day 0) Pain: (0: no pain, 10: severe pain) Pain: risk
Erythema (day 0) Erythema: 0 to 4 3–4: 31/36
Ulceration/erosion (0 = absent; 1 = trace; > 7: 5/36
(day 2, 7, 30, and 90) 2 = slight;3 = moderate; Erythema:
Hypopigmentation 4 = prominent) 1–2: 34/36
(day 2, 7, 30, and 90) Ulceration/erosion: 0 to 4 (0 = absent; 3: 3/36
Hyperpigmentation 1 = trace; 2 = slight;3 = moderate; Ulceration/erosion: 0/35
(2 days, 7 days, 1, 4 = prominent) Hypopigmentation: 0/35
3 m) Hypopigmentation: 0 to 4 (0 = absent; Hyperpigmentation: 0/35
1 = trace; 2 = slight;3 = moderate;
4 = prominent)
Hyperpigmentation: 0 to 4
(0 = absent; 1 = trace;
2 = slight;3 = moderate;
4 = prominent)
Paresthesia: 0 to 4
(0 = absent; 1 = trace;
2 = slight;3 = moderate;
4 = prominent)
Efficacy: Efficacy: Efficacy:
(day 90) (day 90) Improvement in eyebrow-lift: 30/35
Improvement in Improvement in eyebrow-lift (clini- Eyebrow height: 1.7
eyebrow-lift, eyebrow cally) Patient satisfaction
height Eyebrow height (mm)
Patient satisfaction Patient satisfaction
1022 Lasers Med Sci (2020) 35:1007–1024

Table 2 (continued)
Lee Safety: Safety: Safety: Low risk High risk Unclear
(2012) (immediately after Pain: (0: no pain, 10: severe pain) Pain: 3.9 ± 1.66 risk
treatment, 3 m) Erythema: (yes/no) Erythema: 10/10 immediately, 0/10
Pain Edema: (yes/no) at day 90
Erythema Other adverse events Edema: 10/10, 0/10 at day 90
Edema Other adverse events: 0/10
Other adverse events
Efficacy (day 90) Efficacy (day 90) Efficacy:
Physician assessment Physician assessment: Physician assessment:
Patient assessment (skin laxity mild improvement: (no improvement: 2/10; mild
improvement of superficial improvement: 2/10; moderate
laxity; moderate improvement: improvement: 4/10; significant
focal improvement of structural improvement: 2/10)
laxity with or without Patient assessment: (no
improvement of superficial improvement: 1/10; mild: 2/10;
laxity; significant improvement: moderate: 5/10; significant:
overall improvement of 2/10)
structural laxity with or without
improvement of superficial
laxity)
Patient assessment:
(worse, none, mild, moderate,
and good)
Suh Safety: Safety: Safety: Low risk Low risk Unclear
(2011) Pain (0 day) Pain: NR Severe pain:0/22 risk
Numbness (0 day) Numbness: NR Numbness: 4/22
Erythema (3 days) Erythema: NR Mild erythema: 22/22
Swelling (3 days) Swelling: NR Swelling: 22/220
Whitish wheals or Whitish wheals or Striations: NR Whitish wheals or striations: 2/22
striations
(after treatment)
Efficacy: Efficacy: Efficacy:
Subjective score of Subjective score of nasolabial fold Subjective score of nasolabial fold
nasolabial fold and and jaw line improvement: improvement: mean = 1.77
jaw line 2 (Much improvement), Subjective score jaw line
improvement (2 m), 1 (improvement), improvement: mean = 1.72
Objective score of 0 (no change), and − 1 (worse) Objective score of nasolabial fold
nasolabial fold and Objective score of nasolabial fold and jaw line improvement:
jaw line and jawline improvement: 1 mean = 1.91
improvement (2 m) (improved), 0 (no change), Histologic dermal thickness
Histologic dermal and − 1 (worse) (0 day): mean = 1.32 (SD =
thickness (0 day, Histologic dermal thickness: 0.18)
2 m) millimeter Histologic dermal thickness (2 m):
Area fraction of Area fraction of collagen: percent mean = 1.63 (SD = 0.31)
collagen (papillary Area fraction of collagen -papillary
dermis, reticular dermis (0 day): mean = 54.4
dermis) (0 day, 2 m) (SD = 10.9)
Area fraction of collagen -papillary
dermis (2 m): mean = 556 (SD =
0.8.2)
Area fraction of collagen -reticular
dermis (0 day): mean = 527
(SD = 7.8)
Area fraction of collagen -reticular
dermis (2 m): mean = 65.2
(SD = 7.9)
Harris Safety: Safety: Safety: NA High risk Low risk
(2015) Erythema (0 day) Erythema: NR Erythema:1/52
Edema (0 day) Edema: NR Edema: 2/52
Hypopigmentation Hypopigmentation: NR Hypopigmentation: 0/52
(90, 180 days) Hyperpigmentation: NR Hyperpigmentation: 0/52
Hyperpigmentation Ulceration: NR Ulceration: 0/52
(90, 180 days) Scarring: NR Scarring: 0/52
Burns: NR Burns: 0/52
Lasers Med Sci (2020) 35:1007–1024 1023

Table 2 (continued)
Ulceration Neurologic: NR Neurologic: 0/52
(90, 180 days) Neurologic adverse events: NR Neurologic adverse events: 0/52
Scarring (90, 180 days)
Burns (90, 180 days)
Neurologic adverse
events (90,
180 days)
Efficacy: Efficacy: Efficacy:
Global Aesthetic Global Aesthetic Improvement Global Aesthetic Improvement
Improvement Scale Scale Patient Satisfaction Scale: NR
(90, 180 days) Patient satisfaction: NR
Patient satisfaction
(90, 180 days)
Sasaki Safety: Safety: Safety: Low risk Low risk Unclear
(2017) Pain (day 0) Pain: Pain (groups 1a, 1b, 2a, 2b risk
Dyschromia (0 = no pain; 2.5 = mild pain; respectively): 4 ± 1.2, 5.5 ± 1.7,
(days 180, 360) 5 = moderate pain; 7.5 = intense 6 ± 1.9, 8.3 ± 3
Scarring (days 180, pain; 10 = intolerable Day: 180, 360
360) Pain) Dyschromia:0/40
Ulceration Dyschromia: NR Scarring:0/40
(days 180, 360) Scarring: NR Ulceration: 0/40
Blistering Ulceration: NR Blistering: 0/40
(days 180, 360) Blistering: NR Permanent paresis/paralysis: 0/40
Permanent paresis/ Permanent paresis/paralysis: NR Prolonged sensory dysesthesias:
paralysis, (days 180, Prolonged sensory dysesthesias: 0/40
360) NR
Prolonged sensory
dysesthesias
(days 180, 360)
Efficacy: Efficacy: Efficacy:
(days 180, 360) SGAIS: Day 180
SGAIS 1 = very much improved; SGAIS: (group 1a, 1b, 2a, 2b
IGAIS 2 = much; improved; respectively): 3 ± 2, 3 ± 2, 3 ±
Elasticity analysis 3 = improved; 1.5, 2 ± 1.5
tissue displacement 4 = no change; IGAIS: (groups 1a, 1b, 2a, 2b
5 = worse respectively): 3 ± 1.4, 3 ± 1.1, 4
IGAIS: ± 0.8, 3 ± 0.7
1 = very much improved; Percent elasticity changes:
2 = much; improved; 1a: 11.1% ± 7.7%
3 = improved; 1b: 18.4% ± 16.5%
4 = no change; 2a: 33.6% ± 15.7% 2b: 44.0% ±
5 = worse 28.9%
percent elasticity changes: Day: 360
MPa units SGAIS: (group 1a, 1b, 2a, 2b
respectively): 2 ± 1.8, 2 ± 2, 3 ±
2.1, 2 ± 1.4
IGAIS: (group 1a, 1b, 2a, 2b
respectively): 3 ± 1.4, 3 ± 1.2, 3
± 1.2, 3 ± 1
Percent elasticity changes:
1a: 25.3% ± 14.0%
1b: 27.5% ± 8.8%
2a: 36.5% ± 17.2%; 2b: 54.6% ±
22.1%
1024 Lasers Med Sci (2020) 35:1007–1024

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