Cryolipolysis: The future of cryolipolysis

Cryolipolysis has revolutionized the field of cosmetic dermatology as a nonsurgical procedure, utilizing controlled cooling to selectively destroy fat cells.

areas. 8Cryolipolysis has also been shown to improve skin texture, and submental treatments have received FDA-clearance for the appearance of lax tissue. 9,10Off-label treatment areas include the chest or breast tissue, and CoolSculpting is effective for treating patients with pseudogynecomastia. 11The treatment has also been evaluated for defining and enhancing the appearance of abdominal muscles, often referred to as the "six pack." 12 Cryolipolysis has gained significant popularity due to its numerous advantages over traditional invasive fat-reduction procedures.
This treatment provides a non-surgical approach to body contouring, 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 downtime. 13While there are multiple modalities to approach non-invasive fat reduction, cryolipolysis is well tolerated and does not require anesthesia, causes less bruising and tenderness compared to modalities like high-intensity focused ultrasound, and demonstrates results in fewer sessions versus modalities such as low-level laser therapy or acoustic wave therapy. 5,14,15e 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 innovations in this technology, we aim to shed light on potential enhancements 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.

| CLINI C AL ADVAN CE S AND APPLI C ATI ON S
Since the technology's inception in 2008, cryolipolysis has seen clinical advances to streamline comfortable and effective treatments for patients.These advances include improvements to the device applicator 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.

| 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 intended for the abdomen and flanks (Table 1, "CoolCore").The applicator used vacuum suctioning to pull in the tissue, and dual cooling plates allowed for cooling from both sides.Although effective, innovative applicator designs have been developed to better adapt to 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 address "non-pinchable" fat or longer treatment areas such as the arms and inner thighs. 17While a conformable handpiece has been studied and shown to be effective, 18 it is not currently commercially available and may represent a future technology.Other improvements, such as the addition of a third cooling apparatus within the handpiece, reduced treatment time by 40% with equivalent efficacy. 19 addition to changes in the shape and size of the applicators, other advancements include adjusting vacuum suctioning.The device applicator contains a vacuum, which pulls the treated area into the handpiece, securing the skin while decreasing blood flow to the treatment site. 20Lower vacuum skin tension is more comfortable and preferred by patients.A recent simulation study found an inverse relationship between the suction angle and the cooling capacity, with smaller suction angles resulting in greater cooling capacity, as well as cooling to deeper levels of subcutaneous fat. 21Decreasing or maximizing suction angle can also result in increased patient comfort.Emerging technologies should further explore the relationship of vacuum suction to treatment outcomes, aiming to maximize treatment 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. 22A summary of all applicators is provided as Table 1.

| Protocol advances
Improving treatment protocols has also led to advances in cryolipolysis.In the recent Delphi consensus, all physicians agreed that multiple treatments have better outcomes versus a single treatment alone. 13Performing multiple treatments in a single session on the flanks has been shown to be safe and effective. 23A prospective study evaluated the volume of fat loss after a single treatment session 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. 24Increased 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 undergo up to four sequential cryolipolysis sessions and found significant improvement in body contour without an increase in adverse side effects. 25Importantly, when multiple sessions of heat extraction are performed, secondary sessions do not produce as significant of results as the initial session. 26This 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.
Other clinical advances in cryolipolysis include temperature and time optimization.When performing cryolipolysis, one must consider three things: the temperature of the cooling plates within the applicator (°C), the rate of heat extraction from the tissue (W/cm 2 ), often reported as the CIF, and the actual temperature of the targeted subdermal fat.Traditionally, cryolipolysis had been performed with cooling plates at −10°C for 60 min. 20Colder temperatures (i.e. −15°C) over shorter periods (i.e., 45 min) have been found to be effective and well tolerated. 27A 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. 28This study reported that these shorter treatments with lower coolingplate temperatures were effective and safe for patients, although they were notably not controlled against the standard −10°C/60 min treatment. 28Another 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. 29These 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/cm 2 at 0°C and −6 W/cm 2 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. 30is 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. 30en considering the temperature obtained in the adipose tissue, one study evaluated 112 patients using small and large applicators set to a CIF of 42 for 60 min to record the temperatures in the subcutaneous adipose tissue of the abdomen. 31

TA B L E 1 (Continued)
duration, as well as the most efficient parameters (i.e., cooling plate temperature, CIF, and heat efflux rate) to achieve and maintain fat reduction.
Additionally, post-treatment massage has been shown to result in up to 68% greater fat reduction at 2 months post-treatment. 32is 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 reduction, 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 facilitate reperfusion injury. 32Post-treatment massage also results in a faster return to normal tissue temperatures; however, the clinical impact of this expedited return to normal temperature is yet unknown. 31

| 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/m 2 in the submental and submandibular areas, and BMI ≤30 kg/m 2 for all other body areas. 8When considering cryolipolysis, it is important to evaluate and express to patients that the technology is not intended to "debulk" 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 cannot 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. 33The best candidates have focal areas of adiposity that are easily lifted from the musculature 33 ; there must be adequate fat for the treatment to be effective.Fibrotic areas are more difficult to treat. 18ery 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 simultaneously, overlapping treatment areas, and doing more than one treatment in a single session. 34At 12 weeks, 87% of patients reported satisfaction with their treatment, and there were no serious adverse effects. 34In general, settings used are dependent on a patient's individual needs, body area treated, and appliances available to the physician performing the procedure. 34 important aspect of patient satisfaction is a noticeable and visible treatment result.When performing cryolipolysis, quantitively demonstrating fat loss is necessary both for tangible evidence of results, as well as differentiating outcomes to optimize treatments.There are various localized adiposity evaluation techniques, such as taking caliper measurements with an adipometer or tape measurements to demonstrate quantifiable outcome measures of fat loss. 35These local measurements can be effective in tracking and monitoring progress.7][38] 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 objectively in cryolipolysis studies. 37,39MRI 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. 40One 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 another 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. 24Improving 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.

| 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 evaluated for hernias as cryolipolysis can potentially incarcerate a hernia via vacuum suctioning. 33The treatment is contraindicated in patients with cryoglobulinemia, paroxysmal cold hemoglobinuria, and cold agglutinin disease. 8It should also be considered with caution in patients with cold-sensitive disorders, including Raynaud's phenomenon and cold urticaria, or known neurologic disease, as these conditions can potentially lead to adverse outcomes due to the cooling from the treatment. 8though 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 procedures 41 are performed in 1 day and when multiple body sites 42 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. 43recent 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 that initial report, PAH has proven to be less rare than originally suspected, but still rare.Estimates increased to 1 in 10 000 treatment cycles, and more recently manufacturers report 1 in 4000 cycles, or 0.025%.8 A 2021 multicenter review of 2114 patients, who ultimately underwent 8658 cycles of cryolipolysis, reported nine patients (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. 48They also noted that 9 of 11 cases occurred after treating the abdomen, and 7 of 11 used the large sized applicator. 48However, the recent multicenter review of over 8658 cycles of cryolipolysis 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%). 47They interestingly 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 underlying mechanism.
Some have proposed shockwave therapy as a way to prevent PAH and increase patient comfort during the procedure. 49Ultimately, 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 environmental 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.

| FUTURE DIREC TIONS: COMB INATION THER APIE 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 technology 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 traditional cryolipolysis, for example by decreasing treatment time or treating other body sites or even visceral fat.

| 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 injury. 32Typically, 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 post-procedure. 31The 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 improved post-treatment re-warming and possible augmentation of post-reperfusion injury. 31Future directions include using massage technology to augment applicators, or testing massage in combination with vacuum suctioning to determine if there are superior outcomes.

| 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 destroyed. 31This has been tested with the Polarys® device and found to be effective, with significant decreases in waist, skinfold, and ultrasound measurements. 31Further studies are needed, including head-to-head trials comparing cryolipolysis to contrast cryolipolysis, to better understand if this is more efficacious in increasing the volume of fat loss.

| Cryolipolysis and deoxycholic acid
A recent study evaluated sequential therapy with cryolipolysis and deoxycholic acid for submental fullness. 50The submental area is notably difficult to treat with non-invasive measures.Prior studies have indicated that combination therapy likely offers the best outcomes in this area. 51The protocol involved two sessions of cryolipolysis spaced 6 weeks apart, with one or two deoxycholic acid treatments offered for patients who did not see significant improvement 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.

| 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. 52This 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 authors endorsed the combination treatment as safe and effective. 52other 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 satisfaction rate with the combined treatment. 53HIFEM is another treatment that has been considered in combination with cryolipolysis.A recent feasibility study looked at these modalities alone and in combination for treating the abdomen, and reported a GAI score of 1.9 with the combined treatment, versus 1.4 with cryolipolysis alone. 54e authors also reported circumference measurements, with a mean change of 15 mm in the combination group, versus 10 mm for cryolipolysis alone. 54her tools, such as high-intensity focused ultrasound and lowfrequency ultrasound, have independently been used to target subcutaneous adipose tissue 55 and may offer future opportunities for adjunctive or sequential treatments to enhance cryolipolysis.Additionally, one could presume that physicians are likely using cryolipolysis in combination with other treatments in practice, although this is difficult to assess as they may not be actively reporting or publishing their experiences in the literature.Ideally, as physicians experiment 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.

| FUTURE D IREC TI ON S: NOVEL INJEC TAB LE ME THOD OF CRYOLIP OLYS IS
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 technique involves injecting a mixture of ice particles in a biocompatible liquid suspension, directly into target adipose tissue using a needle and syringe (Figure 1).The cooling of the adipose tissue by the iceslurry leads to selective apoptosis of adipocytes resulting in fat loss.

| Mechanism of action
While ice slurries have been used extensively in the refrigeration industry, 56 57 This study was conducted in a swine model, where a single injection of 30 mL of biocompatible ice-slurry was injected into the subcutaneous adipose tissue. 57The results showed a visible reduction in fat thickness 2 months post-treatment and ultrasound imaging demonstrated ~55% loss of adipose tissue layer at the injected sites. 57The mechanism of slurry-induced fat loss was

| 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 feasibility, safety and tolerability of ice slurry injection into the subcutaneous fat of pre-abdominoplasty subjects. 59The authors found that the slurry was easily injectable into the adipose tissue using standard injection techniques, and patients tolerated the procedure well (mean pain score 1.9/10). 59Ultrasound and tissue histology were used to demonstrate ice slurry-induced cryolipolysis in the injected subcutaneous adipose tissue. 59There were no serious side effects, with bruising and erythema being the most common side effects.
Importantly, slurry induced cryolipolysis has been shown to be selective, without causing lasting damage or scarring to surrounding tissue. 57,59

| What's new and what's next
The use of cryoslurry in cryolipolysis offers several potential advantages over the current method of topical cooling.The injectable nature of cryoslurry dramatically improves its versatility of use compared 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 offers endless opportunities to better customize treatments based on patient needs.Based on the available data in swine, one can postulate 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 semisolid consistency of the slurry allows for better conformation to the treatment area, improved contact, and more uniform cooling distribution.The high heat capacity of the ice particles within the slurry results in more efficient cooling of the target tissue.This more efficient cooling will likely lead to more significant fat reduction, which has been seen in swine models but remains untested in humans. 57ere 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 cosmetic 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. 60The same group also showed that cryoslurry can be used to target pathologic fat associated with obstructive sleep apnea at the base of the tongue in a swine model. 61These 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 customized, 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.

| CON CLUS IONS
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 opportunities 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 cryolipolysis treatments for patients.

CO N FLI C T O F I NTE R E S T S TATE M E NT
Dr. Murphrey has no relevant conflicts of interest or disclosures.
Dr. Garibyan is an inventor on patents related to ice-slurry technology, which are owned by the Massachusetts General Hospital.Dr.
Garibyan holds equity in companies (Brixton Biosciences and Eyecool 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 TH I C S S TATEM ENT
Authors declare human ethics approval was not needed for this study.

R E FE R E N C E S
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 extraction 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 subcutaneous fat tissue.In 2020, Garibyan et al. published the seminal paper reporting the safety and efficacy of subcutaneous fat reduction with the cryoslurry technology.
similar to that induced by topical cryolipolysis.Slurry injection resulted in apoptosis of the fat cells, presumably through lipid crystallization.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.after treatment.The amount of fat loss closely correlates with the ice content of the injected slurry, 57,58 therefore the potential volume of fat loss can be titrated by adjusting the slurry volume and composition, making this a potentially customizable treatment modality.