Received: 13 August 2023 | Accepted: 21 August 2023

DOI: 10.1111/jocd.15985

REVIEW ARTICLE

Cryolipolysis: The future of cryolipolysis

Morgan Murphrey MD1,2 | Lilit Garibyan MD, PhD1,2

1
Wellman Center for Photomedicine,
Massachusetts General Hospital, Boston, Abstract
Massachusetts, USA
Background: Cryolipolysis has revolutionized the field of cosmetic dermatology as a
2
Department of Dermatology, Harvard
Medical School, Boston, Massachusetts,
nonsurgical procedure, utilizing controlled cooling to selectively destroy fat cells.
USA Aims and methods: This review article will focus on the future prospects of cry-

Correspondence
Lilit Garibyan, Wellman Center for
Photomedicine, Massachusetts General
Hospital, 50 Blossom Street-­Thier 2,
Boston, MA 02114, USA.
Email: lgaribyan@mgh.harvard.edu
olipolysis, considering advancements in current technology as well as innovations
that hold promise for the future. We will explore emerging trends in cryolipolysis,
considering novel applicator designs, combination therapies, an innovative injectable
treatment approach, and the evolving role of this technology in the field of cosmetic
dermatology.
Conclusion: The future holds promise for advances in cryolipolysis using both the
noninvasive topical cooling approach and the novel injectable ice-­slurry technology.

KEYWORDS
body contouring, cosmetic dermatology, cryolipolysis, fat reduction, ice slurry

1 | I NTRO D U C TI O N
Fat reduction is a goal of many cosmetic patients. While surgical fat
reduction is a common procedure, many patients are now seeking
less invasive options. In fact, more than 350 000 individuals under-
went non-­invasive fat reduction procedures in 2020 alone.1 Multiple
approaches have been explored, but in 2008, Dr. Rox Anderson
and Dr. Dieter Manstein introduced the world to “cryolysis,” a novel
2
technique for non-­invasive fat removal using controlled cooling.
Since its inception, this groundbreaking approach has been refined,
and cryolipolysis has transformed the field of non-­invasive fat re-
duction. This procedure has been performed more than 13 million
times worldwide, and is the most commonly performed non-­invasive
fat reduction procedure.3
Cryolipolysis is founded on the principle that lipid-­rich tissue,
such as fat, is more susceptible to cold injury compared to surround-
4
ing water-­rich tissue, and can therefore be selectively destroyed
with cooling. In their initial studies, Manstein et al. 2 showed that
topical controlled cooling of skin can safely and selectively reduce
subcutaneous adipose tissue in swine. This technology was adapted
and tested in humans, and has been shown to result in up to 25%
decreased subcutaneous fat volume after a single treatment.5
The currently available in-­office cryolipolysis device is equipped
with interchangeable applicators, which are applied to specific treat-
ment areas. Each applicator contains thermoelectric cooling plates
and, in most cases, vacuum suction. This combination helps freeze
the targeted tissue by holding it securely and reducing blood flow to
the treatment area. The procedure is titrated by the cooling intensity
factor (CIF), which controls the efflux of heat from the tissue. During
the procedure, patients may experience sensations like tugging,
pinching, tingling, and intense cold, but in general the procedure
is well tolerated and does not require anesthesia or pain control.3
Because the cutaneous nerves are also affected by topical cooling,
most patients report temporary loss of sensation at the treatment
site.6 This is reversible, and self-­resolves within 6–­8 weeks.7
In the United States, cryolipolysis is performed using the
CoolSculpting device (CoolSculpting; Allergan Aesthetics, an Abb-
Vie Company), which is currently US Food and Drug Administration
(FDA) cleared to treat the thighs, abdomen, flanks, upper and lower
back, upper thighs/inferior buttocks, upper arms, and submental

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2023 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.

J Cosmet Dermatol. 2023;22(Suppl. 3):37–47.  wileyonlinelibrary.com/journal/jocd | 37

 |
38
areas.8 Cryolipolysis has also been shown to improve skin texture,
and submental treatments have received FDA-­clearance for the ap-
pearance of lax tissue.9,10 Off-­label treatment areas include the chest
or breast tissue, and CoolSculpting is effective for treating patients
with pseudogynecomastia.11 The treatment has also been evaluated
for defining and enhancing the appearance of abdominal muscles,
12
often referred to as the “six pack.”
Cryolipolysis has gained significant popularity due to its numer-
ous advantages over traditional invasive fat-­reduction procedures.
This treatment provides a non-­surgical approach to body contour-
ing, avoiding the risks and recovery associated with surgery, while
delivering consistent, satisfactory results in targeted areas. A recent
2020 Delphi consensus unanimously agreed that two advantages of
cryolipolysis are that it is noninvasive and that it has minimal down-
time.13 While there are multiple modalities to approach non-­invasive
fat reduction, cryolipolysis is well tolerated and does not require an-
esthesia, causes less bruising and tenderness compared to modali-
ties like high-­intensity focused ultrasound, and demonstrates results
in fewer sessions versus modalities such as low-­level laser therapy or
acoustic wave therapy.5,14,15
The consistent results seen across multiple treatment areas
make this the preferred modality for noninvasive fat reduction. The
objective of this paper is to provide an in-­depth analysis of the future
prospects of cryolipolysis. By exploring advancements and innova-
tions in this technology, we aim to shed light on potential enhance-
ments to treatment outcomes and patient satisfaction. This article
comprehensively explores the evolving landscape of cryolipolysis,
delving into enhanced applicator designs, innovative combination
therapies, and the emergence of a novel injectable cryolipolysis
method.
2 | C LI N I C A L A DVA N C E S A N D
A PPLI C ATI O N S
Since the technology's inception in 2008, cryolipolysis has seen clini-
cal advances to streamline comfortable and effective treatments for
patients. These advances include improvements to the device ap-
plicator and treatment protocol, as well as personalized treatments
with careful patient selection. These improvements have positively
impacted patient care and have contributed to the global success of
cryolipolysis.
2.1 | Novel applicators
Cryolipolysis is performed using an applicator directly attached to
the desired treatment area, with or without vacuum suction. The
first applicator featured a flat, rectangular-­shaped cup and was in-
tended for the abdomen and flanks (Table 1, “CoolCore”). The appli-
cator used vacuum suctioning to pull in the tissue, and dual cooling
plates allowed for cooling from both sides. Although effective, in-
novative applicator designs have been developed to better adapt to
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MURPHREY and GARIBYAN
the body's contours, ensuring optimal contact and improving cooling
distribution.
The first major advancements in cryolipolysis applicators were
size and shape, allowing for more versatile treatments. For example,
the large rectangular cup was made more compact to accommodate
submental fat,16 and a flat-­counter handpiece was developed to ad-
dress “non-­pinchable” fat or longer treatment areas such as the arms
and inner thighs.17 While a conformable handpiece has been studied
and shown to be effective,18 it is not currently commercially avail-
able and may represent a future technology. Other improvements,
such as the addition of a third cooling apparatus within the hand-
piece, reduced treatment time by 40% with equivalent efficacy.19
In addition to changes in the shape and size of the applicators,
other advancements include adjusting vacuum suctioning. The de-
vice applicator contains a vacuum, which pulls the treated area into
the handpiece, securing the skin while decreasing blood flow to the
treatment site. 20 Lower vacuum skin tension is more comfortable
and preferred by patients. A recent simulation study found an in-
verse relationship between the suction angle and the cooling capac-
ity, with smaller suction angles resulting in greater cooling capacity,
as well as cooling to deeper levels of subcutaneous fat. 21 Decreasing
or maximizing suction angle can also result in increased patient com-
fort. Emerging technologies should further explore the relationship
of vacuum suction to treatment outcomes, aiming to maximize treat-
ment comfort and efficiency.
After the first generation of applicators, the “Advantage,” line
was developed, and according to the manufacturer, the newest
“Elite” range offers the most advanced applicator technology. 22 A
summary of all applicators is provided as Table 1.
2.2 | Protocol advances
Improving treatment protocols has also led to advances in cry-
olipolysis. In the recent Delphi consensus, all physicians agreed that
multiple treatments have better outcomes versus a single treatment
alone.13 Performing multiple treatments in a single session on the
flanks has been shown to be safe and effective. 23 A prospective
study evaluated the volume of fat loss after a single treatment ses-
sion to the flanks using the original first-­generation handpiece and
found that the treated areas showed ~40 mL of fat loss at 2 months
post treatment. 24 Increased volume of fat reduction can be achieved
with multiple treatments. In fact, the Delphi consensus experts
agreed that most body sites require two to four treatments, with
areas such as abdomen/flanks, back, upper arms, and male chest
requiring three to five treatments. Another study had subjects un-
dergo up to four sequential cryolipolysis sessions and found signifi-
cant improvement in body contour without an increase in adverse
side effects. 25 Importantly, when multiple sessions of heat extrac-
tion are performed, secondary sessions do not produce as significant
of results as the initial session. 26 This could be because deeper fat is
closer to vascular muscles, or because the fat cells that survived the
first cryolipolysis treatment are more resistant to cooling.
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MURPHREY and GARIBYAN 39

TA B L E 1 Summary of cryolipolysis applicators.

Name Image Vacuum Notes

First generation
CoolCore Yes Waist, flanks

CoolOriginal 6.2 Yes Underarms, inner knees,

upper back

CoolCurve + Yes Upper back (bra), waist;

Smaller version
of CoolCore,
CoolOriginal 6.2

CoolFit Yes Under arms, inner

thighs; longer
applicator

CoolMax Yes Upper and lower

abdomen; largest
device

CoolSmooth Pro No Dense fat; heats, then

cools the fat

Advantage
CoolCore Yes Abdomen
Advantage

CoolCore Yes Upper and lower

Advantage Plus abdomen; large,
“debulking”

(Continues)
 |

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40 MURPHREY and GARIBYAN

TA B L E 1 (Continued)

Name Image Vacuum Notes

CoolCurve Yes Flanks

Advantage

CoolCurve Yes Abdomen, hips, arms,

Advantage Plus chest

CoolFit Advantage Yes Inner thighs

CoolPetite No Upper arms, knees,

Advantage posterior thighs
(“banana roll”)

CoolMini Yes Submental,

submandibular

Elite
Curve 80 Yes Submental,
submandibular,
knees

Curve 120 Yes Arms, upper back (bra

fat), upper thighs
(banana roll),
abdomen

Curve 150 Yes Abdomen, flanks

 |

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MURPHREY and GARIBYAN 41

TA B L E 1 (Continued)

Name Image Vacuum Notes

Curve 240 Yes Abdomen, flanks;

largest of the Elite
applicators

Flat 125 Yes Arms, inner thighs

Flat 165 Yes Arms, inner thighs

Surface 150 No Outer thighs, abdomen,

flat device

Note: Images via https://www.cools​culpt​ingex​perts.com/cools​culpt​ing-­body-­conto​uring​-­scott ​sdale/​appli​c ator​s/ and https://www.cools​culpt​inghcp.

com/cools​culpt​ing-­elite/.

Other clinical advances in cryolipolysis include temperature and
time optimization. When performing cryolipolysis, one must con-
sider three things: the temperature of the cooling plates within the
2
applicator (°C), the rate of heat extraction from the tissue (W/cm ),
often reported as the CIF, and the actual temperature of the tar-
geted subdermal fat. Traditionally, cryolipolysis had been performed
20
with cooling plates at −10°C for 60 min. Colder temperatures (i.e.
−15°C) over shorter periods (i.e., 45 min) have been found to be ef-
27
fective and well tolerated. A recent study looked specifically at
submental fat, and tested two subsequent treatment cycles, starting
with −12°C at 45 min and 10 weeks later, −15°C at 30 min. 28 This
study reported that these shorter treatments with lower cooling-­
plate temperatures were effective and safe for patients, although
they were notably not controlled against the standard −10°C/60 min
treatment. 28 Another study of 63 flank treatments in 45 individuals
found treatment at −15°C (CIF 50.2) for 45 min resulted in 4.2 mm
fat reduction in a 25% shorter time period versus the traditional
60 min. 29 These treatments were also well tolerated by patients with
no serious adverse events.
In terms of titrating cryolipolysis treatments by CIR or rate of heat
efflux, there is variation amongst reported protocols. In the initial
swine study by Drs. Anderson and Manstein, the prototype device had
a maximum heat flux of approximately −10 W/cm2 at 0°C and −6 W/cm2
at 30°C.2 A review of nearly 1500 patients reported a range of CIFs
from 33 to 42, although did not report the rate of heat extraction.30
This same review also noted that treatment times ranged from 30 to
120 min per cycle, with a range of 1–­2 cycles per treated area.30
When considering the temperature obtained in the adipose
tissue, one study evaluated 112 patients using small and large ap-
plicators set to a CIF of 42 for 60 min to record the temperatures
in the subcutaneous adipose tissue of the abdomen. 31 They placed
a transcutaneous temperature probe 1.5 cm into the subdermal
fat. They reported cutaneous temperatures with a low of 10.7°C,
and subdermal adipose temperatures with a low of 9.5°C, both at
the 60-­min time point. At these recorded temperatures, this study
reported a noticeable and reproducible decrease in adiposity at
6 months. Future studies should work to better characterize the
necessary effective adipose tissue temperature and treatment
 |
42
duration, as well as the most efficient parameters (i.e., cooling
plate temperature, CIF, and heat efflux rate) to achieve and main-
tain fat reduction.
Additionally, post-­treatment massage has been shown to result
32
in up to 68% greater fat reduction at 2 months post-­treatment.
This was noted in a split abdomen study, where immediately after
a 60-­min session of cryolipolysis, one half of the abdomen was
treated with 2 min of manual hand massage, while the other was not.
Ultrasound measurements were used to compare fat thickness re-
duction, and the massaged side showed 68% greater fat reduction
at 2 months, and 44% greater reduction at 4 months. The authors
postulated that the manual massage may have resulted in additional
damage to adipocytes following treatment, possibly helping to fa-
cilitate reperfusion injury.32 Post-­
treatment massage also results
in a faster return to normal tissue temperatures; however, the clin-
ical impact of this expedited return to normal temperature is yet
unknown.31
2.3 | Patient considerations and personalization to
optimize treatment
Developing reliable patient selection criteria is crucial for identifying
suitable treatment candidates and accurately predicting outcomes.
Cryolipolysis is FDA-­cleared for BMI ≤46.2 kg/m2 in the submen-
tal and submandibular areas, and BMI ≤30 kg/m2 for all other body
areas.8 When considering cryolipolysis, it is important to evaluate
and express to patients that the technology is not intended to “de-
bulk” large collections of adipose tissue and is generally not effective
for obese patients. Patients who undergo cryolipolysis may be poor
candidates for more invasive procedures, such as liposuction, or can-
not tolerate anesthesia.
Cryolipolysis is most effective for stubborn, localized adipose
tissue. Some physicians find it to be particularly effective at treating
areas such as the distal thigh/knee, posterior upper thigh (“banana
roll”), and upper back/bra area, as these are more associated with
contour irregularities when liposuction is performed.33 The best
candidates have focal areas of adiposity that are easily lifted from
the musculature33; there must be adequate fat for the treatment to
18
be effective. Fibrotic areas are more difficult to treat.
Every patient has unique needs and goals when it comes to body
contouring, therefore each treatment should be personalized. One
study evaluated adjustments such as using two applicators simul-
taneously, overlapping treatment areas, and doing more than one
treatment in a single session.34 At 12 weeks, 87% of patients re-
ported satisfaction with their treatment, and there were no serious
34
adverse effects. In general, settings used are dependent on a pa-
tient's individual needs, body area treated, and appliances available
to the physician performing the procedure.34
An important aspect of patient satisfaction is a noticeable and
visible treatment result. When performing cryolipolysis, quanti-
tively demonstrating fat loss is necessary both for tangible evi-
dence of results, as well as differentiating outcomes to optimize
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MURPHREY and GARIBYAN
treatments. There are various localized adiposity evaluation tech-
niques, such as taking caliper measurements with an adipometer
or tape measurements to demonstrate quantifiable outcome mea-
sures of fat loss. 35 These local measurements can be effective in
tracking and monitoring progress. Advanced imaging techniques,
such as ultrasound, magnetic resonance imaging (MRI), and three-­
dimensional body scanning, are also emerging as valuable tools for
adipose assessment with potential for use in personalized cryo-
lipolysis. 5,24,36–­3 8 Ultrasound, which can be done in-­office, is the
best modality to assess the thickness of subcutaneous adipose
tissue, and has long been used as a tool for evaluating fat loss ob-
jectively in cryolipolysis studies. 37,39 MRI offers a more precise
and objective quantification of fat volume loss, 36 and has been
used to quantify submental fat volume reduction with other fat
loss procedures.40 One study evaluated the phase change kinetics
of adipose tissue from human pre-­abdominoplasty patients using
MRI, 38 implying that MRI may ultimately be developed into an-
other way of monitoring the progress and efficacy of cryolipolysis
applicators and devices. Finally, new techniques such as 3D body
scanning have been evaluated to successfully quantify the volume
of fat loss after cryolipolysis treatments. 24 Improving imaging and
evaluation modalities and gathering patient characteristics and
demographics may enhance our understanding of fat reduction
and allow for more accurate prediction of treatment outcomes.
2.4 | Safety considerations
Cryolipolysis is considered to be a safe procedure overall; however,
there are some special considerations when evaluating patients. If
patients are to be treated on the abdomen, they should be evalu-
ated for hernias as cryolipolysis can potentially incarcerate a hernia
via vacuum suctioning.33 The treatment is contraindicated in pa-
tients with cryoglobulinemia, paroxysmal cold hemoglobinuria, and
cold agglutinin disease.8 It should also be considered with caution
in patients with cold-­sensitive disorders, including Raynaud's phe-
nomenon and cold urticaria, or known neurologic disease, as these
conditions can potentially lead to adverse outcomes due to the cool-
ing from the treatment.8
Although the device results in adipocyte death and clearance,
extensive testing has been done to confirm that cryolipolysis does
not impact systemic lipids. This is true even when multiple proce-
dures41 are performed in 1 day and when multiple body sites42 are
treated in one session. Conversely, lab work up has also not shown
that cryolipolysis has any impact on systemic lipid levels, and does
not result in lipid level improvements.43
A recent review of the MAUDE database for non-­invasive body
sculpting from 2015 to 2021 found that the most common adverse
reaction after cryolipolysis was paradoxical adipose hyperplasia
(PAH) (n = 483, 73.2% of all MDRs).44 Legal action by a prominent
social figure who experienced this side effect has resulted in media
attention, drawing new interest to PAH.45 This was first reported in
2014, with an incidence of 0.0051%, or around 1 in 20 000.46 Since

MURPHREY and GARIBYAN
that initial report, PAH has proven to be less rare than originally sus-
pected, but still rare. Estimates increased to 1 in 10 000 treatment
cycles, and more recently manufacturers report 1 in 4000 cycles,
8
or 0.025%. A 2021 multicenter review of 2114 patients, who ul-
timately underwent 8658 cycles of cryolipolysis, reported nine pa-
tients (0.43%) developed PAH.47
Some potential risk factors for PAH have been published.
One group described their experience of 11 patients with PAH,
and noted that all patients were Hispanic, with 8 of the 11 being
men.48 They also noted that 9 of 11 cases occurred after treating
the abdomen, and 7 of 11 used the large sized applicator.48 How-
ever, the recent multicenter review of over 8658 cycles of cryolip-
olysis reported that of those who developed PAH, there was only
a slight predominance of male patients (55%), and the majority of
patients were ethnically European in origin (77.8%).47 They inter-
estingly also reported that there has been a decrease in PAH by
75% with the advent of newer units and applicator models, which
may reflect that advances in applicators have helped mitigate this
side effect; the authors did not elaborate on the suspected under-
lying mechanism.
Some have proposed shockwave therapy as a way to prevent
49
PAH and increase patient comfort during the procedure. Ulti-
mately, additional research should be done to better identify which
patients are most at risk for this feared side effect. The underlying
etiology is most likely multifactorial, due to a combination of patient
characteristics and genetic background in tandem with environmen-
tal exposures, such as diet. Future work should be taken to develop
a tool or test to determine an individual's risk for PAH, which would
be invaluable to guide patient selection and improve treatment
outcomes.
3 | FU T U R E D I R EC TI O N S : CO M B I N ATI O N
TH E R A PI E S
With the many advances in cryolipolysis, physicians can reliably and
comfortably perform non-­invasive fat reduction procedures with
high patient satisfaction. Recent advances in cryolipolysis technol-
ogy include combination therapies to augment treatment efficacy,
as well as novel treatment deliveries to treat otherwise difficult to
target areas. These modalities offer ways to enhance or improve tra-
ditional cryolipolysis, for example by decreasing treatment time or
treating other body sites or even visceral fat.
3.1 | Cryolipolysis and massage
One of the most notable combination therapies employed with
cryolipolysis is massage immediately after treatment, which is
postulated to improve results by augmenting reperfusion in-
32
jury. Typically, the treating provider manually massages the
tissue by hand post-­treatment, 32 although one study looked at
an integrated applicator that massages the tissue for 5 minutes
|
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43
post-­p rocedure. 31 The recent Delphi consensus offered a strong
recommendation for postprocedural massage,13 likely due to its
dramatic and lasting effect on treatment results, 32 as well as im-
proved post-­t reatment re-­warming and possible augmentation of
post-­reperfusion injury. 31 Future directions include using massage
technology to augment applicators, or testing massage in combi-
nation with vacuum suctioning to determine if there are superior
outcomes.
3.2 | Cryolipolysis and heat
Contrast cryolipolysis involves alternating cycles of heating and
cooling, with a handpiece that delivers 10 min of heating pre-­ and
post-­the traditional 60-­min cryolipolysis session. This technology is
based on the premise that by cooling and heating the adipose tissue,
crystals are formed more easily, and adipose tissue is more easily de-
stroyed.31 This has been tested with the Polarys® device and found
to be effective, with significant decreases in waist, skinfold, and
ultrasound measurements.31 Further studies are needed, including
head-­to-­head trials comparing cryolipolysis to contrast cryolipoly-
sis, to better understand if this is more efficacious in increasing the
volume of fat loss.
3.3 | Cryolipolysis and deoxycholic acid
A recent study evaluated sequential therapy with cryolipolysis and
deoxycholic acid for submental fullness.50 The submental area is
notably difficult to treat with non-­invasive measures. Prior stud-
ies have indicated that combination therapy likely offers the best
outcomes in this area.51 The protocol involved two sessions of cry-
olipolysis spaced 6 weeks apart, with one or two deoxycholic acid
treatments offered for patients who did not see significant improve-
ment after the cryolipolysis alone. These treatments resulted in a
2-­
grade improvement with high patient safety and satisfaction.
Additional studies should assess the ideal number and sequence of
treatments. Additional considerations should also include the timing
and sequence of the treatments, and if both treatments could be
done safely in a single treatment session.
3.4 | Cryolipolysis and radiofrequency and/or high
intensity focused electro-­magnetic technology
Other considerations include cryolipolysis with radiofrequency (RF)
or high intensity focused electro-­magnetic technology (HIFEM). One
study evaluated cryolipolysis and RF as a “sandwich method,” with
non-­contact RF 15 min before and 15 min after a single session of
cryolipolysis.52 This study evaluated patient outcomes using the
Global Aesthetic Improvement (GAI) Score, and physicians indicated
improvements in 73% (n = 18) of patients. Although the study did
not control the results by comparing with cryolipolysis alone, the
 |
44
authors endorsed the combination treatment as safe and effective. 52
Another study compared cryolipolysis alone versus cryolipolysis
with the combination of multipolar RF with pulsed electromagnetic
fields/suction. The authors also used the GAI score, and reported a
20% greater mean improvement rate and 10% higher patient satis-
53
faction rate with the combined treatment. HIFEM is another treat-
ment that has been considered in combination with cryolipolysis. A
recent feasibility study looked at these modalities alone and in com-
bination for treating the abdomen, and reported a GAI score of 1.9
54
with the combined treatment, versus 1.4 with cryolipolysis alone.
The authors also reported circumference measurements, with a
mean change of 15 mm in the combination group, versus 10 mm for
cryolipolysis alone.54
Other tools, such as high-­intensity focused ultrasound and low-­
frequency ultrasound, have independently been used to target sub-
cutaneous adipose tissue55 and may offer future opportunities for
adjunctive or sequential treatments to enhance cryolipolysis. Addi-
tionally, one could presume that physicians are likely using cryolip-
olysis in combination with other treatments in practice, although this
is difficult to assess as they may not be actively reporting or publish-
ing their experiences in the literature. Ideally, as physicians experi-
ment with combination therapies in practice, they will report their
experience or validate via controlled trials. Further efforts should be
taken to pursue this research, and to determine the optimal delivery
and combination for cryolipolysis.
4 | FU T U R E D I R EC TI O N S : N OV E L
I N J EC TA B LE M E TH O D O F C RYO LI P O LYS I S
One of the most exciting and promising advances in cryolipolysis is
cryoslurry. Cryoslurry, or ice-­slurry platform cooling technology, is
an innovative approach to traditional cooling methods. This tech-
nique involves injecting a mixture of ice particles in a biocompatible
liquid suspension, directly into target adipose tissue using a needle
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MURPHREY and GARIBYAN
and syringe (Figure 1). The cooling of the adipose tissue by the ice-­
slurry leads to selective apoptosis of adipocytes resulting in fat loss.
4.1 | Mechanism of action
While ice slurries have been used extensively in the refrigera-
tion industry, 56 this technology was only recently considered for
medical use to selectively target lipid rich tissue. The innovative
delivery is founded on the cryoslurry design, which consists of
injectable ice particles, specified by size and concentration. The
latent heat of fusion of water (334 J/g), is 80 times more than the
heat capacity of liquid water. Melting of the ice slurry particles
within the target fat tissue allows for consistent cooling and ex-
traction of a large amount of heat directly from adipocytes. This
avoids efficiency loss that is inherent in topical skin cooling, which
requires the extraction of heat from subcutaneous adipose tissue
via conduction across the skin. Injection of ice slurry into tissue is
also more time efficient, as it takes less than a minute to inject. In
addition, injection with ice-­slurry allows targeting of deeper sub-
cutaneous fat tissue.
In 2020, Garibyan et al. published the seminal paper reporting
the safety and efficacy of subcutaneous fat reduction with the
cryoslurry technology.57 This study was conducted in a swine model,
where a single injection of 30 mL of biocompatible ice-­slurry was in-
jected into the subcutaneous adipose tissue.57 The results showed
a visible reduction in fat thickness 2 months post-­treatment and ul-
trasound imaging demonstrated ~55% loss of adipose tissue layer at
the injected sites.57 The mechanism of slurry-­induced fat loss was
similar to that induced by topical cryolipolysis. Slurry injection re-
sulted in apoptosis of the fat cells, presumably through lipid crys-
tallization. A brisk immune response ensued after injection, which
was consistent with cold-­induced lobular panniculitis, and peaked at
2–­4 weeks post-­treatment. While fat loss can be detected as early
as 1-­month after treatment, peak loss was measured at 2–­3 months
F I G U R E 1 Injectable slurry for
cryolipolysis. The ice-­slurry is injected
directly into target adipose tissue using a
standard needle and syringe. The cooling
initiated in the adipose tissue leads to
adipocyte apoptosis, and subsequent
decrease in adipose volume. Slurry
particles are not shown to scale. Figure
created with BioRender.com.

MURPHREY and GARIBYAN
after treatment. The amount of fat loss closely correlates with the
57,58
ice content of the injected slurry, therefore the potential volume
of fat loss can be titrated by adjusting the slurry volume and com-
position, making this a potentially customizable treatment modality.
4.2 | Human data
The cryoslurry technology has continued to advance and is under
active investigation, but it is not currently FDA-­approved. The first
in-­human study was published in 2021, and investigated the feasibil-
ity, safety and tolerability of ice slurry injection into the subcutane-
ous fat of pre-­abdominoplasty subjects.59 The authors found that
the slurry was easily injectable into the adipose tissue using stand-
ard injection techniques, and patients tolerated the procedure well
(mean pain score 1.9/10).59 Ultrasound and tissue histology were
used to demonstrate ice slurry-­induced cryolipolysis in the injected
59
subcutaneous adipose tissue. There were no serious side effects,
with bruising and erythema being the most common side effects.
Importantly, slurry induced cryolipolysis has been shown to be se-
lective, without causing lasting damage or scarring to surrounding
57,59
tissue.
4.3 | What's new and what's next
The use of cryoslurry in cryolipolysis offers several potential ad-
vantages over the current method of topical cooling. The injectable
nature of cryoslurry dramatically improves its versatility of use com-
pared to topical cryolipolysis, as different areas and depths of fat
tissue can be targeted through a needle injection. Additionally, the
ability to adjust the composition and concentration of the slurry of-
fers endless opportunities to better customize treatments based on
patient needs. Based on the available data in swine, one can postu-
late that adjusting the volume and ice-­composition of the slurry will
allow different volumes and depths of fat to be targeted for body
sculpting.
The cryoslurry injection can be performed at any anatomical
site, targeting otherwise untreatable areas of fat tissue. The semi-­
solid consistency of the slurry allows for better conformation to the
treatment area, improved contact, and more uniform cooling distri-
bution. The high heat capacity of the ice particles within the slurry
results in more efficient cooling of the target tissue. This more effi-
cient cooling will likely lead to more significant fat reduction, which
has been seen in swine models but remains untested in humans.57
There is also evidence of new collagen formation in the areas of fat
loss,57,60,61 which has been similarly seen with topical cryolipolysis
and may indicate future use for skin tightening.
Additionally, this versatility may prove valuable beyond cos-
metic dermatology. A recent publication showed that cryoslurry can
be used to directly target visceral fat around the heart in a swine
model, which is known to play a pathologic role in cardiovascular
disease.60 The same group also showed that cryoslurry can be used
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14732165, 2023, S3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jocd.15985 by Univ of Sao Paulo - Brazil, Wiley Online Library on [26/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
45
to target pathologic fat associated with obstructive sleep apnea at
the base of the tongue in a swine model.61 These findings highlight
the many potential indications for therapeutic uses of cryoslurry
technology.
Finally, cryoslurry technology has an almost endless potential for
titration and customization. Each aspect of the slurry can be cus-
tomized, from the slurry agent to the concentration to the volume
injected. The opportunity to titrate and customize this treatment
promises to be a strong advantage, especially as medicine evolves
toward a culture of more customized care.
5 | CO N C LU S I O N S
Cryolipolysis is a non-­
invasive fat reduction technique routinely
used for body sculpting and is generally safe and well tolerated by
patients. It has advanced in the field of cosmetic dermatology as a
reliable method of fat reduction through novel applicator design
and combination therapies, but there is room for innovation and
progress to improve patient satisfaction and outcomes. The future
holds promise for further advances. The recent introduction of an
injectable method of cryolipolysis offers new possibilities and op-
portunities to harness cold induced fat reduction in novel ways.
More research is needed to continue these advances forward, and
ultimately devise the most efficient, effective and comfortable cry-
olipolysis treatments for patients.
C O N FL I C T O F I N T E R E S T S TAT E M E N T
Dr. Murphrey has no relevant conflicts of interest or disclosures.
Dr. Garibyan is an inventor on patents related to ice-­slurry technol-
ogy, which are owned by the Massachusetts General Hospital. Dr.
Garibyan holds equity in companies (Brixton Biosciences and Eye-
cool Therapeutics) founded to develop and commercialize ice-­slurry
technology for various therapeutic applications. The companies had
no involvement in this work.
DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing not applicable—­no new data generated.
E T H I C S S TAT E M E N T
Authors declare human ethics approval was not needed for this
study.
ORCID
Morgan Murphrey https://orcid.org/0000-0002-6860-6071
REFERENCES
1. Surgeons ASoP. Plastic surgery statistics report. ASPS national
clearinghouse of plastic surgery procedural statistics. https://
www.plast​icsur​gery.org/docum​e nts/News/Stati​s tics/​2020/plast​
ic-­surge​r y-­stati​stics​-­full-­repor​t-­2020.pdf Published 2020.
2. Manstein D, Laubach H, Watanabe K, Farinelli W, Zurakowski D,
Anderson RR. Selective cryolysis: a novel method of non-­invasive
fat removal. Lasers Surg Med. 2008;40(9):595-­604.
 |
46
3. Allergan. Data on file. https://www.cools​culpt​inghcp.com/#isi_
indic​ations. Published 2022.
4. Coban YK, Kurutas EB, Ciralik H. Ischemia-­reperfusion injury of
adipofascial tissue: an experimental study evaluating early his-
tologic and biochemical alterations in rats. Mediators Inflamm.
2005;2005(5):304-­3 08.
5. Krueger N, Mai SV, Luebberding S, Sadick NS. Cryolipolysis for non-
invasive body contouring: clinical efficacy and patient satisfaction.
Clin Cosmet Investig Dermatol. 2014;7:201-­205.
6. Coleman SR, Sachdeva K, Egbert BM, Preciado J, Allison J. Clinical
efficacy of noninvasive cryolipolysis and its effects on peripheral
nerves. Aesthetic Plast Surg. 2009;33(4):482-­488.
7. Garibyan L, Cornelissen L, Sipprell W, et al. Transient alterations of
cutaneous sensory nerve function by noninvasive cryolipolysis. J
Invest Dermatol. 2015;135(11):2623-­2631.
8. Allergan. CoolSculpting© patient safety information. https://www.
cools​c ulpt​i ng.com/pdfs/CSC12​5713-­v 2_Impor ​t ant_Safety_Infor​
mation.pdf. Published 2022.
9. Stevens WG. Does cryolipolysis lead to skin tightening? A first re-
port of cryodermadstringo. Aesthet Surg J. 2014;34(6):NP32-­NP34.
10. Stevens WG, Gould DJ, Pham LD, Jimenez Lozano JN.
Molecular and histological evidence detailing clinically ob-
served skin improvement following cryolipolysis. Aesthet Surg J.
2022;42(1):56-­67.
11. Hong JY, Park SJ, Kim SY, Kim BJ. Efficacy and safety of cold-­
induced noninvasive targeted fat reduction in pseudogynecomas-
tia. Ann Dermatol. 2022;34(6):412-­418.
12. Lim T, Ding SW, Chua CH, Moey HX. Enhancing the appearance
of the "six-­pack" muscles using cryolipolysis: a safe and effective
method. Plast Reconstr Surg. 2021;148(4):775-­779.
13. Altmann J, Burns AJ, Kilmer SL, et al. Global expert opinion
on cryolipolysis treatment recommendations and consider-
ations: a modified Delphi study. Aesthet Surg J Open Forum.
2022;4:ojac008.
14. Mostafa MS, Elshafey MA. Cryolipolysis versus laser lipolysis on ad-
olescent abdominal adiposity. Lasers Surg Med. 2016;48(4):365-­370.
15. Alizadeh Z, Halabchi F, Mazaheri R, Abolhasani M, Tabesh M.
Review of the mechanisms and effects of noninvasive body con-
touring devices on cellulite and subcutaneous fat. Int J Endocrinol
Metab. 2016;14(4):e36727.
16. Kilmer SL, Burns AJ, Zelickson BD. Safety and efficacy of cryolip-
olysis for non-­invasive reduction of submental fat. Lasers Surg Med.
2016;48(1):3-­13.
17. Wanitphakdeedecha R, Sathaworawong A, Manuskiatti W. The ef-
ficacy of cryolipolysis treatment on arms and inner thighs. Lasers
Med Sci. 2015;30(8):2165-­2169.
18. Stevens WG, Bachelor EP. Cryolipolysis conformable-­surface appli-
cator for nonsurgical fat reduction in lateral thighs. Aesthet Surg J.
2015;35(1):66-­71.
19. Kilmer SL. Prototype CoolCup cryolipolysis applicator with over
40% reduced treatment time demonstrates equivalent safety
and efficacy with greater patient preference. Lasers Surg Med.
2017;49(1):63-­68.
20. Jalian HR, Avram MM. Cryolipolysis: a historical perspective and
current clinical practice. Semin Cutan Med Surg. 2013;32(1):31-­3 4.
21. Yang G, Dang H, Guo N, Cui M, Xu Y. Structural design optimization
and lipolytic effect prediction of vacuum suction cryolipolysis ap-
plicator: simulation study. Lasers Surg Med. 2023;55(2):233-­246.
22. Allergan. CoolSculpting: the elite experience. https://www.cools​
culpt​inghcp.com/cools​culpt​ing-­elite/. Published 2023.
23. Bernstein EF, Bloom JD, Basilavecchio LD, Plugis JM. Non-­
invasive fat reduction of the flanks using a new cryolipolysis ap-
plicator and overlapping, two-­c ycle treatments. Lasers Surg Med.
2014;46(10):731-­735.
24. Garibyan L, Sipprell WH III, Jalian HR, Sakamoto FH, Avram M,
Anderson RR. Three-­dimensional volumetric quantification of fat
loss following cryolipolysis. Lasers Surg Med. 2014;46(2):75-­8 0.
14732165, 2023, S3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jocd.15985 by Univ of Sao Paulo - Brazil, Wiley Online Library on [26/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
MURPHREY and GARIBYAN
25. McKeown DJ, Payne J. Significant improvement in body contour
with multiple cycles of CoolSculpting: results of a prospective
study. Dermatol Ther. 2021;34(2):e14850.
26. Ingargiola MJ, Motakef S, Chung MT, Vasconez HC, Sasaki GH.
Cryolipolysis for fat reduction and body contouring: safety and
efficacy of current treatment paradigms. Plast Reconstr Surg.
2015;135(6):1581-­1590.
27. Kilmer SL, Boey G, Burns J. Safety and efficacy of colder tempera-
ture, shorter duration cryoliplysis treatments. Lasers Surg Med.
2015;47(Suppl 26):1-­78.
28. Leal Silva H, Carmona Hernandez E, Grijalva Vazquez M, Leal
Delgado S, Perez Blanco A. Noninvasive submental fat reduction
using colder cryolipolysis. J Cosmet Dermatol. 2017;16(4):460-­465.
29. Kilmer SL, Boey G, Burns J. Safety and efficacy of colder tempera-
ture, shorter duration cryolipolysis treatments. Lasers Med Sci.
2015;47(S26):1-­78.
30. Derrick CD, Shridharani SM, Broyles JM. The safety and efficacy
of cryolipolysis: a systematic review of available literature. Aesthet
Surg J. 2015;35(7):830-­836.
31. Sasaki GH, Abelev N, Tevez-­Ortiz A. Noninvasive selective cryoli-
polysis and reperfusion recovery for localized natural fat reduction
and contouring. Aesthet Surg J. 2014;34(3):420-­431.
32. Boey GE, Wasilenchuk JL. Enhanced clinical outcome with man-
ual massage following cryolipolysis treatment: a 4-­month study of
safety and efficacy. Lasers Surg Med. 2014;46(1):20-­26.
33. Few J, Saltz R, Beaty M, et al. Cryolipolysis: clinical best practices
and other nonclinical considerations. Aesthet Surg J Open Forum.
2020;2(2):ojaa010.
34. Rivers JK, Ulmer M, Vestvik B, Santos S. A customized ap-
proach for arm fat reduction using cryolipolysis. Lasers Surg Med.
2018;50:732-­737.
35. Meyer PF, Davi Costa ESJ, Santos de Vasconcellos L, de Morais CE,
Valentim da Silva RM. Cryolipolysis: patient selection and special
considerations. Clin Cosmet Investig Dermatol. 2018;11:499-­503.
36. Huber FA, Del Grande F, Rizzo S, Guglielmi G, Guggenberger R. MRI
in the assessment of adipose tissues and muscle composition: how
to use it. Quant Imaging Med Surg. 2020;10(8):1636-­1649.
37. Storchle P, Muller W, Sengeis M, Lackner S, Holasek S, Furhapter-­
Rieger A. Measurement of mean subcutaneous fat thickness: eight
standardised ultrasound sites compared to 216 randomly selected
sites. Sci Rep. 2018;8(1):16268.
38. Sajjadi AY, Manstein D, Carp SA. Measuring temperature induced
phase change kinetics in subcutaneous adipose tissues using near
infrared spectroscopy, MR imaging and spectroscopy and OCT. Sci
Rep. 2017;7(1):17786.
39. Ponga-­ Manso M. Ultrasound assessment of abdominal adipose
panniculus in patients treated with a single session of cryolipolysis
in a clinical setting. J Cosmet Dermatol. 2022;21(1):307-­315.
40. Jones DH, Carruthers J, Joseph JH, et al. REFINE-­1, a multicenter,
randomized, double-­blind, placebo-­controlled, phase 3 trial with
ATX-­101, an injectable drug for submental fat reduction. Dermatol
Surg. 2016;42(1):38-­49.
41. Klein KB, Bachelor EP, Becker EV, Bowes LE. Multiple same day
cryolipolysis treatments for the reduction of subcutaneous fat are
safe and do not affect serum lipid levels or liver function tests.
Lasers Surg Med. 2017;49(7):640-­6 44.
42. Costa A, Oliveira A, Brito A, et al. Cryolipolysis on more than one
body area increases lipid peroxidation without changing lipid profile
and inflammatory markers. Biology. 2022;11(12):1690. doi:10.3390/
biology11121690
43. Badran S, Doi SA, Iskeirjeh S, et al. Metabolic changes after non-
surgical fat removal: a dose response meta-­analysis. J Plast Reconstr
Aesthet Surg. 2023;77:68-­77.
44. Lim Y, Wulkan A, Avram M. FDA MAUDE database reported ad-
verse events on noninvasive body contouring, cellulite treatment,
and muscle stimulation from 2015 to 2021. Lasers Surg Med.
2023;55(1):146-­151.

MURPHREY and GARIBYAN
45. Swanson E. Cryolipolysis: a reconsideration of efficacy, safety,
and the risk of paradoxical adipose hyperplasia. Aesthet Surg J.
2023;43(1):NP68-­NP69.
46. Jalian HR, Avram MM, Garibyan L, Mihm MC, Anderson RR.
Paradoxical adipose hyperplasia after cryolipolysis. JAMA Dermatol.
2014;150(3):317-­319.
47. Nikolis A, Enright KM. A multicenter evaluation of paradoxical adi-
pose hyperplasia following Cryolipolysis for fat reduction and body
contouring: a review of 8658 cycles in 2114 patients. Aesthet Surg J.
2021;41(8):932-­941.
48. Kelly MR-­FJ, Kelly E, Torres C. Paradoxical adipose hyperplasia: a
report on increased incidence, clinical management, and outcomes.
Plastic Surgery The Meeting. 2017;5:53-­54.
49. Michon A. Shockwave therapy for the prevention of paradoxical
adipose hyperplasia after Cryolipolysis: myth or reality? Aesthet
Surg J. 2021;41(8):NP1137-­NP1138.
50. Jalian HR, Fitzgerald R, Bowen B, Gamio S. Submental fat reduction
using sequential treatment approach with cryolipolysis and ATX-­
101. J Cosmet Dermatol. 2022;21(6):2437-­2444.
51. Vanaman M, Fabi SG, Cox SE. Neck rejuvenation using a combi-
nation approach: our experience and a review of the literature.
Dermatol Surg. 2016;42(Suppl 2):S94-­S100.
52. Abboud S, Hachem JP. Heat shock lipolysis: radiofrequency com-
bined with cryolipolysis for the reduction of localized subcutane-
ous fat. Dermatol Res Pract. 2020;2020:4093907.
53. Few J, Gold M, Sadick N. Prospective internally controlled blind re-
viewed clinical evaluation of cryolipolysis combined with multipolar
radiofrequency and varipulse technology for enhanced subject re-
sults in circumferential fat reduction and skin laxity of the flanks. J
Drugs Dermatol. 2016;15(11):1354-­1358.
|
14732165, 2023, S3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jocd.15985 by Univ of Sao Paulo - Brazil, Wiley Online Library on [26/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
47
54. Kilmer SL, Cox SE, Zelickson BD, et al. Feasibility study of electro-
magnetic muscle stimulation and Cryolipolysis for abdominal con-
touring. Dermatol Surg. 2020;46(Suppl 1(1)):S14-­S21.
55. Ortiz AE, Avram MM. Noninvasive body contouring: cryolipolysis
and ultrasound. Semin Cutan Med Surg. 2015;34(3):129-­133.
56. Kauffeld M, Wang MJ, Goldstein V, Kasza KE. Ice slurry applica-
tions. Int J Refrig. 2010;33(8):1491-­1505.
57. Garibyan L, Moradi Tuchayi S, Javorsky E, et al. Subcutaneous
fat reduction with injected ice slurry. Plast Reconstr Surg.
2020;145(4):725e-­733e.
58. Ni P, Farinelli WA, Cheng LL, et al. Total ice content and lipid sat-
uration determine adipose tissue cryolipolysis by injection of ice-­
slurry. Lasers Surg Med. 2023;55(1):116-­125.
59. Kandula P, Javorsky E, Austen WG Jr, Kaminer MS. Injection
cryolipolysis: first-­in-­human study. Plast Reconstr Surg Glob Open.
2021;9(9):e3818.
60. Shuhaiber J, Moradi Tuchayi S, Bijari FJ, et al. Injectable ice
slurry for reducing pericardial adipose tissue. Lasers Surg Med.
2023;55:674-­679.
61. Orestes MI, Tuchayi SM, Wang Y, et al. Safety and feasibility of se-
lective tongue fat reduction with injected ice-­slurry. Laryngoscope
Investig Otolaryngol. 2022;7(5):1675-­1680.
How to cite this article: Murphrey M, Garibyan L.
Cryolipolysis: The future of cryolipolysis. J Cosmet Dermatol.
2023;22(Suppl. 3):37-47. doi:10.1111/jocd.15985