Aesthetic Plast Surg. 2009 Jul;33(4):482-8.

Clinical efficacy of noninvasive cryolipolysis and its effects on peripheral nerves.

Coleman SR, Sachdeva K, Egbert BM, Preciado J, Allison J. BACKGROUND: Cryolipolysis provides a method for noninvasive fat reduction that significantly reduces subcutaneous fat in a pig model without apparent damage to skin and surrounding structures. This study aimed to determine whether fat reduction in humans caused by cold exposure is associated

with alteration in local sensory function or nerve fibers. METHODS: In this study, 10 subjects were treated with a prototype cooling device. Fat reduction was assessed in 9 of the 10 subjects via ultrasound before treatment and at the follow-up visit. Sensory function was assessed by neurologic evaluation (n = 9), and biopsies (n = 1) were collected for nerve staining.

RESULTS: Treatment resulted in a normalized fat layer reduction of 20.4% at 2 months and 25.5% at 6 months after treatment. Transient reduction in sensation occurred in six of nine subjects assessed by neurologic evaluation. However, all sensation returned by a mean of 3.6 weeks after treatment. Biopsies showed no long-term change in nerve fiber structure. There were no lasting sensory

alterations or observations of skin damage in any of the subjects evaluated. CONCLUSION:

Noninvasive cryolipolysis results in substantial fat reduction within 2 months of treatment without damage to skin. The procedure is associated with modest reversible short-term changes in the function of peripheral sensory nerves. Dermatol Surg. 2009 Oct;35(10):1462-70. Cryolipolysis for noninvasive fat cell destruction: initial results from a pig model.

Zelickson B, Egbert BM, Preciado J, Allison J, Springer K, Rhoades RW, Manstein D. BACKGROUND: Liposuction is one of the most frequently performed cosmetic procedures in the United States, but its cost and downtime has led to the development of noninvasive approaches for adipose tissue reduction.

OBJECTIVE: To determine whether noninvasive controlled and selective destruction of fat cells (Cryolipolysis)

can selectively damage subcutaneous fat without causing damage to the overlying skin or rise in lipid levels. METHODS: Three Yucatan pigs underwent Cryolipolysis at 22 sites: 20 at cooling intensity factor (CIF) index 24.5 (-43.8 mW/cm(2)), one at CIF 24.9 (-44.7 mW/cm(2)), and one at CIF 25.4 (-45.6

mW/cm(2)). Treated areas were evaluated using photography, ultrasound, and gross and microscopic pathology. Lipids were at various times points. One additional pig underwent Cryolipolysis at various days before euthanasia. RESULTS: The treatments resulted in a significant reduction in the superficial fat layer without damage to the overlying skin. An inflammatory response triggered by cold-induced apoptosis of adipocytes preceded the reduction in the fat layer. Evaluation of lipids over a 3-month period following

treatment demonstrated that cholesterol and triglyceride values remained normal. CONCLUSIONS: Cryolipolysis is worthy of further study because it has been shown to significantly decrease subcutaneous fat and change body contour without causing damage to the overlying skin and surrounding structures or deleterious changes in blood lipids.

Lasers Surg Med. 2009 Dec;41(10):785-90.

Non-invasive cryolipolysis for subcutaneous fat reduction does not affect serum lipid

levels or liver function tests. Klein KB, Zelickson B, Riopelle JG, Okamoto E, Bachelor EP, Harry RS, Preciado JA. BACKGROUND AND OBJECTIVE: Cryolipolysis provides a method of non-invasive fat reduction that significantly reduces subcutaneous fat without injury to adjacent tissues. Preliminary animal and human data have

suggested that cryolipolysis has no effect on serum lipid profiles or liver tests. This study was intended to more fully document any effect of this procedure on lipid and liver-related blood tests. STUDY DESIGN/MATERIALS AND METHODS: Forty subjects with fat bulges on their flanks ("love handles") were treated bilaterally with a non-invasive device (Zeltiq Aesthetics, Pleasanton, CA) that precisely cools tissue to achieve a reduction in the fat layer. Serum lipid levels and liver tests were measured prior to treatment, and at 1 day

and 1, 4, 8, and 12 weeks post-treatment. RESULTS: No meaningful changes in mean values were observed for any blood lipid level or liver test at any point over the 12-week follow-up period. CONCLUSION:

Cryolipolysis, when used for reduction of subcutaneous flank fat, is not associated with changes in serum lipids or liver test results.

Lasers Surg Med. 2009 Dec;41(10):703-8. Cryolipolysis for subcutaneous fat layer reduction. Avram MM1, Harry RS. Lasers Surg Med. 2012 Jul;44(5):436.

BACKGROUND AND OBJECTIVE: Cryolipolysis is a unique non-invasive method for the selective reduction of fat cells with controlled, localized cooling. It is important, therefore, to understand the potential efficacy and safety of this new procedure for fat layer reduction. MATERIALS AND METHODS: A review of the literature associated with cryolipolysis was performed to evaluate the findings from

pre-clinical and clinical studies with respect to the mechanism of action, efficacy, and safety. RESULTS:

Cryolipolysis has demonstrated efficacy in both human and animal studies. Histology findings also confirm the selective reduction of fat in both humans and animals, with evidence of a gradual thinning of the fat layer over a period of two to four months. Importantly, cryolipolysis has not produced any significant adverse side effects in studies to date and any noted effects have been minor and temporary.

CONCLUSION: Although the mechanism of action for cryolipolysis is not yet completely understood, the efficacy and safety of this non-invasive procedure for fat layer reduction has been demonstrated in the studies available to data. Further studies will assist in identifying the mechanism and elucidate the full potential of this technology to perform safe, non-invasive fat reduction for areas of local fat accumulation.

Semin Cutan Med Surg. 2009 Dec;28(4):244-9. Cryolipolysis for reduction of excess adipose tissue. Nelson AA, Wasserman D, Avram MM.

Controlled cold exposure has long been reported to be a cause of panniculitis in cases such as

popsicle panniculitis. Cryolipolysis is a new technology that uses cold exposure, or energy extraction, to result in localized panniculitis and modulation of fat. Presently, the Zeltiq cryolipolysis device is FDA cleared for skin cooling, as well as various other indications, but not for lipolysis. There is, however, a pending premarket notification for noninvasive fat layer reduction. Initial animal and human studies have demonstrated significant reductions in the superficial fat layer thickness, ranging from 20% to 80%, following a single cryolipolysis treatment. The decrease in fat thickness occurs gradually over the first 3 months following treatment, and is

most pronounced in patients with limited, discrete fat bulges. Erythema of the skin, bruising, and temporary numbness at the treatment site are commonly observed following treatment with the device, though these effects largely resolve in approximately 1 week. To date, there have been no

reports of scarring, ulceration, or alterations in blood lipid or liver function profiles. Cryolipolysis is

a new, noninvasive treatment option that may be of benefit in the treatment of excess adipose

tissue. Aesthetic Plast Surg. 2011 Oct;35(5):901-12. Noninvasive body sculpting technologies with an emphasis on high-intensity focused ultrasound.

Jewell ML, Solish NJ, Desilets CS. BACKGROUND: Body-sculpting procedures are becoming increasingly popular in the United States. Although surgical lipoplasty remains the most common body sculpting procedure, a demand exists for noninvasive alternatives capable of reducing focal adiposity without the risks of adverse events

(AEs) associated with invasive excisional body-sculpting procedures. METHODS: This report describes the mechanism of action, efficacy, safety, and tolerability of cryolipolysis, radiofrequency ablation, low-level external laser therapy, injection lipolysis, low-intensity nonthermal ultrasound, and high-intensity focused ultrasound (HIFU), with an emphasis on thermal

HIFU. The articles cited were identified via a PubMed search, with additional article citations identified by manual searching of the reference lists of articles identified through the literature

search. RESULTS: Each of the noninvasive treatments reviewed can be administered on an outpatient basis. These treatments generally have fewer complications than lipoplasty and require little or no anesthesia or analgesia. However, HIFU is the only treatment that can produce significant results in a single treatment, and only radiofrequency, low-level laser therapy, and cryolipolysis have been approved for use in the United States. Early clinical data on HIFU support its efficacy and safety for body

sculpting. In contrast, radiofrequency, laser therapy, and injection lipolysis have been associated with significant AEs. CONCLUSIONS: The published literature suggests that noninvasive body-sculpting techniques such as radiofrequency ablation, cryolipolysis, external low-level lasers, laser ablation, nonthermal ultrasound, and HIFU may be appropriate options for nonobese patients requiring modest reduction

of adipose tissue.

Clin Plast Surg. 2011 Jul;38(3):503-20. Noninvasive body contouring with radiofrequency, ultrasound, cryolipolysis, and low-level laser therapy. Mulholland RS, Paul MD, Chalfoun C.

Noninvasive body contouring is perhaps one of the most alluring areas of esthetic surgery today. This article discusses current noninvasive body-contouring modalities, including suction massage devices, radiofrequency energy, high-frequency focused ultrasound, cryolipolysis, and low-level light laser therapy devices. It also discusses imminent technologies awaiting approval by the Food and Drug Administration, reviews the basic science and clinical effects behind each of these existing and emerging technologies, addresses patient selection and clinical applications of each

modality, and discusses the applicability and economics of providing noninvasive lipolysis services in office. Aesthetic Plast Surg. 2012 Jun;36(3):666-79.

Synergistic effects of cryolipolysis and shock waves for noninvasive body contouring.

Ferraro GA, De Francesco F, Cataldo C, Rossano F, Nicoletti G, D'Andrea F. BACKGROUND: Excess body fat, localized adiposity, and cellulite represent important social problems. To date, techniques using radiofrequencies, cavitation and noncavitation ultrasound, and carbon dioxide have been studied as treatments for noninvasive body contouring. Ice-Shock Lipolysis is a new noninvasive procedure for reducing subcutaneous fat volume and fibrous cellulite in areas that

normally would be treated by liposuction. It uses a combination of acoustic waves and cryolipolysis. Shock waves, used normally in the treatment of renal calculi and musculoskeletal disorders, are focused on the collagen structure of cellulite-afflicted skin. When used on the skin and underlying

fat, they cause a remodeling of the collagen fibers, improving the orange-peel appearance typical

of the condition. Cryolipolysis, on the other hand, is a noninvasive method used for the localized

destruction of subcutaneous adipocytes, with no effects on lipid or liver marker levels in the bloodstream. The combination of the two procedures causes the programmed death and slow resorption of destroyed adipocytes. METHODS: In this study, 50 patients with localized fat and cellulite were treated with a selective protocol for the simultaneous use of two transducers: a Freezing Probe for localized fatty tissue and a Shock

Probe for fibrous cellulite. RESULTS: The procedure significantly reduced the circumference in the treated areas, significantly diminishing fat thickness. The mean reduction in fat thickness after treatments was 3.02 cm. Circumference was reduced by a mean of 4.45 cm. Weight was unchanged during the treatment, and no adverse effects were observed. Histologic and immunohistochemical analysis confirmed a

gradual reduction of fat tissue by programmed cell death. Moreover, the reduction in fat thickness was accompanied by a significant improvement in microcirculation, and thus, the cellulite. The safety of the method also has been highlighted because it is accompanied by no significant increase in serum liver enzymes or serum lipids. CONCLUSION:

The study aimed to observe the effects of the new technique in the treatment of localized fat associated with cellulite in order to assess adipose tissue alterations, cellular apoptosis, and levels

of serum lipid or liver markers. The findings show that the action of Ice-Shock Lipolysis is a safe, effective, and well-tolerated noninvasive procedure for body contouring. In particular, the authors believe that this could be an ideal alternative to liposuction for patients who require only small or moderate amounts of adipose tissue and cellulite removal or are not suitable candidates for surgical approaches to body contouring.

Lasers Surg Med. 2012 Feb;44(2):125-30. Non-invasive cryolipolysis for body contouring in Chinese--a first commercial experience. Shek SY, Chan NP, Chan HH. Erratum in Lasers Surg Med. 2012 Jul;44(5):435. BACKGROUND:

The objective of the study is to determine the clinical efficacy and patient satisfaction of a novel cryolipolysis device (Zeltiq®) for body contouring in Chinese after a single treatment and

after 2 treatments at a commercial setting. MATERIALS AND METHODS: Two groups of patients were recruited for this procedure at their own cost. Group A, 21 subjects, received a single treatment and group B, 12 subjects, received 2 treatments, average 3 months apart using the Zeltiq Breeze System®. The thickness of fat at the treatment site was measured by

a caliper and the data were collected at baseline and 2 months post-treatment. Standardized clinical photos were also taken at baseline and follow-up visits. Subjective assessment was carried out in the form of a questionnaire. Any adverse effects were documented. Statistical analyses were performed on the data to compare the efficacy after a single treatment and after 2 treatments. RESULTS: The first group of subjects, received a single treatment, showed that there was a significant improvement (P < 0.0001). The second group of subjects showed that the improvement was

significant after 1 and 2 treatments when compared to the baseline. The extent of improvement after the second treatment however, was not as dramatic as the first treatment. CONCLUSION: Non-invasive cryolipolysis is effective for body contouring in Chinese. It is shown to have a further improvement with subsequent treatment sessions but of a lesser extent. The second treatment was

statistically significant for abdomen, though not for love handles.

Adv Ther. 2012 Mar;29(3):249-66.Epub 2012 Feb 2

Exploring channeling optimized radiofrequency energy: a review

of radiofrequencyhistory and applications in esthetic fields Belenky I, Margulis A, Elman M, Bar-Yosef U, Paun SD INTRODUCTION: Because of its high efficiency and safety, radiofrequency (RF) energy is widely used in the dermatological field for heating biological tissue in various esthetic applications, including skin

tightening, skin lifting, body contouring, and cellulite reduction. This paper reviews the literature on the use of nonablative RF energy in the esthetic field and its scientific background. The purpose of this article is to describe in detail the extensive use of medical devices based on RF technology, the development of these medical devices over the years, and recent developments and trends in RF technology. METHODS:

The authors conducted a systematic search of publications that address safety and efficacy issues, technical system specifications, and clinical techniques. Finally, the authors focused on their own clinical experiences with the use of patented Channeling Optimized RF Energy technique and mechanical massage. An in-vivo study was conducted in domestic pigs, with a thermal video camera. Twenty-seven female patients participated in a cellulite and body shaping study. The

treatments were conducted according to a three-phase protocol. An additional 16 females participated in a skin tightening case study. All of the patients underwent three treatment sessions

at 3-week intervals, each according to a protocol specific to the area being treated. RESULTS: The review of the literature on RF-based systems revealed that these systems are safe, with low risks for potential side effects, and effective for cellulite, body contouring, and skin tightening procedures. The in-vivo measurements confirmed the theory that the penetration depth of RF is an inverse function of its frequency, and using a vacuum mechanism makes an additional contribution to the RF energy penetration. The heating effect of RF was also found to increase blood circulation

and to induce collagen remodeling. The results from the cellulite and body shaping treatments showed an overall average improvement of 55% in the appearance of cellulite, with an average circumferential reduction of 3.31 cm in the buttocks, 2.94 cm in the thighs, and 2.14 cm in the abdomen. The results from the skin tightening procedure showed moderate improvement of skin appearance in 50% and significant improvement in 31%. At the follow-up visits the results were found to be sustained without any significant side effects.

CONCLUSION: Of all tissue heating techniques, RF-based technologies appear to be the most established and

clinically proven. The design and specifications of the described vacuumassisted bipolar RF device fall within the range of the specifications currently prescribed for esthetic, nonablative RF systems. Aesthetic Plast Surg. 2012 Jun;36(3):666-79.

Synergistic effects of cryolipolysis and shock waves for noninvasive bodycontouring. Ferraro GA, De Francesco F, Cataldo C, Rossano F, Nicoletti G, D'Andrea F. BACKGROUND: Excess body fat, localized adiposity, and cellulite represent important social problems. To date, techniques using radiofrequencies, cavitation and noncavitation ultrasound, and carbon dioxide have been studied as treatments for noninvasive body contouring. Ice-Shock Lipolysis is a new

noninvasive procedure for reducing subcutaneous fat volume and fibrous cellulite in areas that normally would be treated by liposuction. It uses a combination of acoustic waves and cryolipolysis. Shock waves, used normally in the treatment of renal calculi and musculoskeletal disorders, are focused on the collagen structure of cellulite-afflicted skin. When used on the skin and underlying fat, they cause a remodeling of the collagen fibers, improving the orange-peel appearance typical

of the condition. Cryolipolysis, on the other hand, is a noninvasive method used for the localized

destruction of subcutaneous adipocytes, with no effects on lipid or liver marker levels in the bloodstream. The combination of the two procedures causes the programmed death and slow resorption of destroyed adipocytes. METHODS: In this study, 50 patients with localized fat and cellulite were treated with a selective protocol for the simultaneous use of two transducers: a Freezing Probe for localized fatty tissue and a Shock Probe for fibrous cellulite.

RESULTS: The procedure significantly reduced the circumference in the treated areas, significantly diminishing fat thickness. The mean reduction in fat thickness after treatments was 3.02 cm.

Circumference was reduced by a mean of 4.45 cm. Weight was unchanged during the treatment,

and no adverse effects were observed. Histologic and immunohistochemical analysis confirmed a

gradual reduction of fat tissue by programmed cell death. Moreover, the reduction in fat thickness was accompanied by a significant improvement in microcirculation, and thus, the cellulite. The safety of the method also has been highlighted because it is accompanied by no significant increase in serum liver enzymes or serum lipids. CONCLUSION: The study aimed to observe the effects of the new technique in the treatment of localized fat

associated with cellulite in order to assess adipose tissue alterations, cellular apoptosis, and levels of serum lipid or liver markers. The findings show that the action of Ice-Shock Lipolysis is a safe, effective, and well-tolerated noninvasive procedure for body contouring. In particular, the authors believe that this could be an ideal alternative to liposuction for patients who require only small or moderate amounts of adipose tissue and cellulite removal or are not suitable candidates for surgical approaches to body contouring.

Clin Plast Surg. 2012 Oct;39(4):399-408. Tissue restructuring by energy-based surgical tools. Dobke MK, Hitchcock T, Misell L, Sasaki GH.

Energy-based noninvasive surgical tools can be used for ablative bio-stimulation (eg, collagen

production) or tissue restructuring functions (eg, tightening or lifting) and are the subject of this review. The authors present the various methods and tools for noninvasive cosmetic surgery (ultrasound, radiofrequency,cryolipolysis, and lasers) and present the clinical outcomes of each. They summarize techniques and methods and their indications, physical parameters and tissue target, and consistency.

esthet Surg J. 2013 Aug 1;33(6):835-46.Epub 2013 Jul 15. Broad overview of a clinical and commercial experience with CoolSculpting Stevens WG, Pietrzak LK, Spring MA BACKGROUND: Cryolipolysis has been shown to be a safe and effective noninvasive procedure for the reduction of

localized subcutaneous fat. OBJECTIVES:

The authors examine the safety, efficacy, and procedural growth of cryolipolysis (via the CoolSculpting device; Zeltiq, Pleasanton, California) in a single plastic surgery practice. METHODS: A retrospective chart review was conducted for 528 consecutive patients who underwent cryolipolysistreatment from January 2010 to December 2012. The number of patients,

the number of treatment cycles, the average number of cycles per patient, all treatment areas, and all procedural complications were recorded and analyzed. Overall practice growth with the device was also analyzed. RESULTS: Over the study period, 1785 anatomic sites were treated with 2729 cycles, primarily in the lower abdomen (28%, n = 490 cycles), upper abdomen (11%, n = 189), left flank (19%, n = 333), right flank (19%, n = 333), inner thigh (6%, n = 111), outer thigh (5%, n = 87), and back (6%, n =

99). The age distribution for men and women was similar (46.6 ± 12.8 years for women and 46.5 ± 12.3 years for men; overall range, 18-79 years). Only 3 cases of mild or moderate pain/neuralgia were reported and resolved in 4 or fewer days. No adverse events were reported. Procedure volume showed consistent growth, with treatment cycles increasing by 823% by 2012. CONCLUSIONS:

Based on the results in this single plastic surgery practice, cryolipolysis is a safe and effective

nonsurgical body contouring method associated with high patient satisfaction that can generate steady, significant business growth.

Australas J Dermatol. 2013 Aug;54(3):173-83.

Lasers and laser-like devices: part one. Stewart N, Lim AC, Lowe PM, Goodman G. Lasers have been used in dermatology for nearly 50 years. Through their selective targeting of skin chromophores they have become the preferred treatment for many skin conditions, including vascular malformations, photorejuvenation and acne scars. The technology and design of lasers

continue to evolve, allowing greater control of laser parameters and resulting in increased safety and efficacy for patients. Innovations have allowed the range of conditions and the skin types amenable to treatment, in both general and cosmetic dermatology, to expand over the last decade. Integrated skin cooling and laser beam fractionation, for example, have improved safety, patient tolerance and decreased downtime. Furthermore, the availability and affordability of quality device s continues to increase, allowing clinicians not only to access laser therapies more readily but also

to develop their personal experience in this field. As a result, most Australian dermatologists now have access to laser therapies, either in their own practice or within referable proximity, and practical knowledge of these technologies is increasingly required and expected by patients. Non-laser energy devices utilising intense pulsed light, plasma, radiofrequency, ultrasound andcryolipolysis contribute to the modern laser practitioners' armamentarium and will also be

discussed.

Lasers Surg Med. 2013 Apr;45(4):235-9. Operator independent focused high frequency ISM band for fat reduction: porcine model. Weiss R, Weiss M, Beasley K, Vrba J, Bernardy J. BACKGROUND: Selective fat reduction has been clearly shown for various methods and energy modalities

including cryolipolysis and high intensity focused thermal ultrasound. Mathematical modeling of focused high frequency of the EM spectrum has indicated that selective heating of fat is possible using wavelengths not previous explored. The purpose of this study was to demonstrate in the porcine model that selective heating of fat is possible with a non-contact, operator independent device. METHODS:

High frequencies of the Industrial, Scientific and Medical (ISM) RF band were utilized to reduce abdominal fat in a porcine model. Practical application of mathematical modeling allowed an auto-

feedback loop to be developed to allow operator independent adjustment of energy to maintain subcutaneous fat at 45-46°C while overlying skin remained at 40-41°C. RESULTS: Treatments of three Vietnamese pigs were performed under anesthesia in a certified veterinary facility. Gross and microscopic histologic results demonstrated a marked reduction in adipocytes of

the treated area after 4 treatments of a total of 30 minutes each, with incremental fat diminution after each treatment. A final 70% reduction of the abdominal fat layer was seen in the treated areas. Duplex ultrasound revealed a reduction of fat layer from 7.6 to 2.9 mm. Histologic

evaluation revealed that epidermis, dermis, and adnexal structures such as hair follicles were unaffected by the treatment, while adipocytes were significantly affected. CONCLUSION:

A new model of fat reduction using high frequency RF has been successfully achieved in a porcine model. This has very positive implications in the development of an operator independent, contact free device for reduction of fat in clinical practice. Dermatol Surg. 2013 Aug;39(8):1209-16.

Safety, tolerance, and patient satisfaction with noninvasive cryolipolysis. Dierickx CC, Mazer JM, Sand M, Koenig S, Arigon V. BACKGROUND: Comprehensive assessment of safety, tolerance, and patient satisfaction has not been established from noninvasive body contouring techniques, such as low-level laser therapy, ultrasound, radiofrequency, and infrared light, for reduction of subcutaneous fat.

OBJECTIVE: This multicenter study investigated the clinical outcomes of noninvasive cryolipolysis in European subjects. METHODS:

A retrospective study was performed at clinical sites in Belgium and France. Safety was assessed

according to reports of side effects. Tolerance was evaluated according to pain scores and patient

perception of treatment duration. Clinical outcomes were assessed according to patient surveys, caliper measurements, and assessment of photographs. RESULTS: The investigators treated 518 patients. No significant side effects or adverse events were reported. The procedure was well-tolerated, with 89% of respondents reporting a positive perception of treatment duration and 96% reporting minimal to tolerable discomfort. Survey results

demonstrated 73% patient satisfaction and that 82% of patients would recommend the cryolipolysis procedure to a friend. Caliper measurements demonstrated 23% reduction in fat layer thickness at 3 months. Abdomen, back, and flank treatment sites were most effective, with 86% of subjects showing improvement per investigator assessment. CONCLUSIONS: With proper patient selection, cryolipolysis is a safe, well-tolerated, and effective treatment method

for reduction of subcutaneous fat. J Cosmet Dermatol. 2013 Jun;12(2):149-52. Longitudinal evaluation of cryolipolysis efficacy: two case studies.

Bernstein EF.

Cryolipolysis treatment, or cold-induced destruction of adipocytes, provides a noninvasive option for localized subcutaneous fat reduction without damaging the overlying skin or adjacent structures. This case study examines the long-term visibility of fat layer reduction subsequent to cryolipolysis treatment, through longitudinal evaluation. Two male subjects were unilaterally treated on one flank. Baseline and post-procedure photographs (at 2 or 5 years) of the treated and contralateral untreated flanks display durable results despite natural fluctuations in body weight.

Aesthet Surg J. 2013 Aug 1;33(6):835-46. Broad overview of a clinical and commercial experience with CoolSculpting. Stevens WG, Pietrzak LK, Spring MA. BACKGROUND:

Cryolipolysis has been shown to be a safe and effective noninvasive procedure for the reduction of localized subcutaneous fat.

OBJECTIVES: The authors examine the safety, efficacy, and procedural growth of cryolipolysis (via the CoolSculpting device; Zeltiq, Pleasanton, California) in a single plastic surgery practice. METHODS: A retrospective chart review was conducted for 528 consecutive patients who

underwentcryolipolysis treatment from January 2010 to December 2012. The number of patients, the number of treatment cycles, the average number of cycles per patient, all treatment areas, and all procedural complications were recorded and analyzed. Overall practice growth with the device was also analyzed. RESULTS: Over the study period, 1785 anatomic sites were treated with 2729 cycles, primarily in the lower abdomen (28%, n = 490 cycles), upper abdomen (11%, n = 189), left flank (19%, n = 333), right

flank (19%, n = 333), inner thigh (6%, n = 111), outer thigh (5%, n = 87), and back (6%, n = 99). The age distribution for men and women was similar (46.6 ± 12.8 years for women and 46.5 ± 12.3 years for men; overall range, 18-79 years). Only 3 cases of mild or moderate pain/neuralgia were reported and resolved in 4 or fewer days. No adverse events were reported. Procedure volume showed consistent growth, with treatment cycles increasing by 823% by 2012.

CONCLUSIONS:

Based on the results in this single plastic surgery practice, cryolipolysis is a safe and effective nonsurgical body contouring method associated with high patient satisfaction that can generate steady, significant business growth.

Semin Cutan Med Surg. 2013 Mar;32(1):31-4.

Cryolipolysis: a historical perspective and current clinical practice.

Jalian HR, Avram MM. Dermatologists have long used cold-based therapeutic approaches for a variety of applications. Based on the differences in chemical composition, it is possible to selectively target certain tissues rich with lipid, while sparing the surrounding tissue predominantly containing water. With historical observations of cold-induced panniculitis suggesting the feasibility of this strategy, cryolipolysis has

emerged as a new methodology using controlled cooling to selectively target fat. Both preclinical and clinical studies have established the safety and efficacy of cryolipolysis for noninvasive body contouring. This review will focus on the evolution of cryolipolysis from initial case reports of cold-induced panniculitis, to preclinical and clinical studies, and the current clinical practice.

Dermatol Surg. 2013 Aug;39(8):1209-16. Safety, tolerance, and patient satisfaction with noninvasive cryolipolysis. Dierickx CC1, Mazer JM, Sand M, Koenig S, Arigon V. BACKGROUND:

Comprehensive assessment of safety, tolerance, and patient satisfaction has not been established from noninvasive body contouring techniques, such as low-level laser therapy,

ultrasound,radiofrequency, and infrared light, for reduction of subcutaneous fat. OBJECTIVE: This multicenter study investigated the clinical outcomes of noninvasive cryolipolysis in European subjects. METHODS: A retrospective study was performed at clinical sites in Belgium and France. Safety was assessed according to reports of side effects. Tolerance was evaluated according to pain scores and patient

perception of treatment duration. Clinical outcomes were assessed according to patient surveys, caliper measurements, and assessment of photographs. RESULTS: The investigators treated 518 patients. No significant side effects or adverse events were reported. The procedure was well-tolerated, with 89% of respondents reporting a positive perception of treatment duration and 96% reporting minimal to tolerable discomfort. Survey results

demonstrated 73% patient satisfaction and that 82% of patients would recommend the cryolipolysis procedure to a friend. Caliper measurements demonstrated 23% reduction in fat layer

thickness at 3 months. Abdomen, back, and flank treatment sites were most effective, with 86% of subjects showing improvement per investigator assessment. CONCLUSIONS: With proper patient selection, cryolipolysis is a safe, well-tolerated, and effective treatment method for reduction of subcutaneous fat.

Aesthet Surg J. 2013 Aug 1;33(6):835-46. Broad overview of a clinical and commercial experience with CoolSculpting. Stevens WG1, Pietrzak LK, Spring MA. BACKGROUND:

Cryolipolysis has been shown to be a safe and effective noninvasive procedure for the reduction of localized subcutaneous fat. OBJECTIVES: The authors examine the safety, efficacy, and procedural growth of cryolipolysis (via the CoolSculpting device; Zeltiq, Pleasanton, California) in a single plastic surgery practice.

METHODS:

A retrospective chart review was conducted for 528 consecutive patients who underwent cryolipolysis treatment from January 2010 to December 2012. The number of patients, the number of treatment cycles, the average number of cycles per patient, all treatment areas, and all procedural complications were recorded and analyzed. Overall practice growth with the device was also analyzed. RESULTS: Over the study period, 1785 anatomic sites were treated with 2729 cycles, primarily in the lower

abdomen (28%, n = 490 cycles), upper abdomen (11%, n = 189), left flank (19%, n = 333), right flank (19%, n = 333), inner thigh (6%, n = 111), outer thigh (5%, n = 87), and back (6%, n = 99). The age distribution for men and women was similar (46.6 ± 12.8 years for women and 46.5

± 12.3 years for men; overall range, 18-79 years). Only 3 cases of mild or moderate

pain/neuralgia were reported and resolved in 4 or fewer days. No adverse events were reported.

Procedure volume showed consistent growth, with treatment cycles increasing by 823% by 2012. CONCLUSIONS: Based on the results in this single plastic surgery practice, cryolipolysis is a safe and effective nonsurgical body contouring method associated with high patient satisfaction that can generate steady, significant business growth.

Lasers Surg Med. 2014 Jan;46(1):20-6. Enhanced clinical outcome with manual massage following cryolipolysistreatment: a 4-month study of safety and efficacy. Boey GE, Wasilenchuk JL.

BACKGROUND AND OBJECTIVES: Cryolipolysis procedures have been shown to safely and effectively reduce the thickness of fat in a treated region. This study was conducted to determine whether the addition of post-treatment manual massage would improve efficacy while maintaining the safety profile of the originalcryolipolysis treatment protocol.

MATERIALS AND METHODS: The study population consisted of an efficacy group (n = 10) and a safety group (n = 7). Study

subjects were treated on each side of the lower abdomen with a Cooling Intensity Factor of 42 (-72.9 mW/cm(2) ) for 60 minutes. One side of the abdomen was massaged post-treatment and the

other side served as the control. Immediately post-treatment, the massage side was treated for 1 minute using a vigorous kneading motion followed by 1 minute of circular massage using the pads

of the fingers. For the efficacy group, photos and ultrasound measurements were taken at baseline, 2 months, and 4 months post-treatment. For the safety group, histological analysis was completed at 0, 3, 8, 14, 30, 60, and 120 days post-treatment to examine the effects of massage on subcutaneous tissue over time. RESULTS: Post-treatment manual massage resulted in a consistent and discernible increase in efficacy over

the non-massaged side. At 2 months post-treatment, mean fat layer reduction was 68% greater in the massage side than in the non-massage side as measured by ultrasound. By 4 months, mean fat layer reduction was 44% greater in the massage side. Histological results showed no evidence of necrosis or fibrosis resulting from the massage. CONCLUSION:

Post-treatment manual massage is a safe and effective technique to enhance the clinical outcome from a cryolipolysis procedure.

Lasers Surg Med. 2014 Feb;46(2):75-80. Three-dimensional volumetric quantification of fat loss following cryolipolysis. Garibyan L1, Sipprell WH 3rd, Jalian HR, Sakamoto FH, Avram M, Anderson RR. Author information

BACKGROUND AND OBJECTIVES: Cryolipolysis is a noninvasive and well-tolerated treatment for reduction of localized subcutaneous fat. Although several studies demonstrate the safety and efficacy of this procedure, volumetric fat reduction from this treatment has not been quantified. This prospective study investigated the change in volume of fat after cryolipolysis treatment using three-dimensional (3D) photography. MATERIALS AND METHODS:

A prospective study of subjects treated with cryolipolysis on the flank (love handle) was performed at Massachusetts General Hospital. Volume measurements were performed with a Canfield

Scientific Vectra three-dimensional camera and software to evaluate the amount of post procedure volume change. Clinical outcomes were assessed with caliper measurements, subject surveys, and blinded physician assessment of photographs. RESULTS: Eleven subjects were enrolled in this study. Each subject underwent a single cycle of cryolipolysis

to one flank. The untreated flank served as an internal control. The follow-up time after treatment was 2 months. The mean amount of calculated absolute fat volume loss using 3D photography from baseline to 2 months follow-up visit was 56.2 ± 25.6 from the treatment site and 16.6 ± 17.6 cc from the control (P < 0.0001). A mean absolute difference of 39.6 cc between the

treated and untreated sides was calculated at 2 months post-treatment. Comparison of caliper

measurements from baseline to 2 months post-treatment demonstrated significant reduction of the

treated flank from 45.6 ± 5.8 mm at baseline to 38.6 ± 4.6 mm at 2 months post-treatment

(P < 0.001). The untreated flank did not show significant reduction with caliper measurements

demonstrating 45.3 ± 5.0 mm at baseline and 44.6 ± 5.1 mm at 2 months post-treatment (P = 0.360). No unexpected side effects or adverse events were reported. Post-treatment

satisfaction surveys demonstrated 82% of subjects were satisfied with the results. CONCLUSIONS: Cryolipolysis is a safe, well-tolerated, and effective noninvasive fat removal methodology that on average leads to 39.6 cc of fat loss of the treated flank at 2 months after a single treatment cycle.

JAMA Dermatol. 2014 Mar;150(3):317-9. Paradoxical adipose hyperplasia after cryolipolysis. Jalian HR, Avram MM2, Garibyan L2, Mihm MC3, Anderson RR2. IMPORTANCE: Cryolipolysis is the noninvasive reduction of fat with localized cutaneous cooling. Since initial

introduction, over 650,000 cryolipolysis treatment cycles have been performed worldwide. We present a previously unreported, rare adverse effect following cryolipolysis: paradoxical adipose hyperplasia.

OBSERVATIONS: A man in his 40s underwent a single cycle of cryolipolysis to his abdomen. Three months following his treatment, a gradual enlargement of the treatment area was noted. This enlargement was a large, well-demarcated subcutaneous mass, slightly tender to palpation. Imaging studies revealed

accumulation of adipose tissue with normal signal intensity within the treatment area. CONCLUSIONS AND RELEVANCE: Paradoxical adipose hyperplasia is a rare, previously unreported adverse effect of cryolipolysis with an incidence of 0.0051%. No single unifying risk factor has been identified. The phenomenon seems to be more common in male patients undergoing cryolipolysis. At this time, there is no evidence of spontaneous resolution. Further studies are needed to characterize the pathogenesis and histologic findings of this rare adverse event.

Lasers Surg Med. 2014 Feb;46(2):75-80. Three-dimensional volumetric quantification of fat loss following cryolipolysis. Garibyan L, Sipprell WH 3rd, Jalian HR, Sakamoto FH, Avram M, Anderson RR.

BACKGROUND AND OBJECTIVES: Cryolipolysis is a noninvasive and well-tolerated treatment for reduction of localized subcutaneous fat. Although several studies demonstrate the safety and efficacy of this procedure, volumetric fat reduction from this treatment has not been quantified. This prospective study investigated the change in volume of fat after cryolipolysis treatment using three-dimensional (3D) photography. MATERIALS AND METHODS: A prospective study of subjects treated with cryolipolysis on the flank (love handle) was performed

at Massachusetts General Hospital. Volume measurements were performed with a Canfield Scientific Vectra three-dimensional camera and software to evaluate the amount of post procedure volume change. Clinical outcomes were assessed with caliper measurements, subject surveys, and blinded physician assessment of photographs. RESULTS: Eleven subjects were enrolled in this study. Each subject underwent a single cycle ofcryolipolysis to one flank. The untreated flank served as an internal control. The follow-up time after treatment

was 2 months. The mean amount of calculated absolute fat volume loss using 3D photography from baseline to 2 months follow-up visit was 56.2 ± 25.6 from the treatment site and 16.6 ± 17.6 cc from the control (P < 0.0001). A mean absolute difference of 39.6 cc between the

treated and untreated sides was calculated at 2 months post-treatment. Comparison of caliper

measurements from baseline to 2 months post-treatment demonstrated significant reduction of the treated flank from 45.6 ± 5.8 mm at baseline to 38.6 ± 4.6 mm at 2 months post-treatment (P < 0.001). The untreated flank did not show significant reduction with caliper measurements demonstrating 45.3 ± 5.0 mm at baseline and 44.6 ± 5.1 mm at 2 months post-treatment

(P = 0.360). No unexpected side effects or adverse events were reported. Post-treatment

satisfaction surveys demonstrated 82% of subjects were satisfied with the results. CONCLUSIONS: Cryolipolysis is a safe, well-tolerated, and effective noninvasive fat removal methodology that on average leads to 39.6 cc of fat loss of the treated flank at 2 months after a single treatment cycle.

Aesthet Surg J. 2014 Mar;34(3):420-31.

Noninvasive selective cryolipolysis and reperfusion recovery for localized natural fat

reduction and contouring. Sasaki GH, Abelev N, Tevez-Ortiz A. BACKGROUND: Cryolipolysis is a contemporary method of reducing fat by controlled extraction of heat from adipocytes.

OBJECTIVES: The authors recorded temperature profiles during a single cryolipolysis treatment/recovery cycle (with and without massage) and report on the clinical safety and efficacy of this procedure. METHODS: In the pilot study group (PSG), the abdomens of 6 patients were treated with cryolipolysis and subdermal temperatures were recorded. In the clinical treatment group (CTG), 112 patients were

treated without temperature recordings and results were evaluated through matched comparison of standardized photographs, caliper measurements, ultrasound imaging, and global assessments. RESULTS: Thirty minutes into the cooling phase, subdermal temperatures of patients in the PSG declined precipitously from pretreatment levels and remained low until the end of treatment. During

recovery, subdermal temperatures of the only subject who received massage returned faster and to higher levels than the temperatures of subjects who did not receive massage. Patients in the

CTG who were available for follow-up measurements at 6 months (n = 85) demonstrated an average fat reduction of 21.5% by caliper measurements; 6 random patients from this group also showed an average of 19.6% fat reduction by ultrasound imaging at 6 months. Global assessments were highest for the abdomen, hip, and brassiere rolls. Minimal side effects were observed, and patients experienced no significant downtime. CONCLUSIONS: Noninvasive cryolipolysis results in a predictable and noticeable fat reduction within 6 months and

does not cause skin damage. Profiling of subdermal temperatures may provide additional insights for improving clinical effectiveness and safety. Clin Cosmet Investig Dermatol. 2014 Jun 26;7:201-5. Cryolipolysis for noninvasive body contouring: clinical efficacy and patient satisfaction.

Krueger N, Mai SV, Luebberding S, Sadick NS.

In recent years, a number of modalities have become available for the noninvasive reduction of adipose tissue, including cryolipolysis, radiofrequency, low-level laser, and high-intensity focused ultrasound. Each technology employs a different mechanism of action to cause apoptosis or necrosis of the targeted adipocytes. Among these technologies, cryolipolysis has not only been commercially available for the longest time, but has also been best researched including in vitro

and animal models and randomized controlled clinical trials in humans. The principle behind cryolipolysis exploits the premise that adipocytes are more susceptible to cooling than other skin cells. The precise application of cold temperatures triggers apoptosis of the adipocytes, which invokes an inflammatory response and leads to slow digestion by surrounding macrophages. In clinical studies, cryolipolysis was shown to reduce subcutaneous fat at the treatment site by up to 25% after one treatment. Improvements were seen in 86% of treated subjects. At 73%, the patient satisfaction rate is higher than with other technologies used for noninvasive lipolysis.

Cryolipolysis has been proven to be a very safe method for body contouring, and is accomplished with only minimal discomfort. Expected side effects are temporary erythema, bruising, and transient numbness that usually resolve within 14 days after treatment. With a prevalence of 0.1%, the most common complaint is late-onset pain, occurring 2 weeks post-procedure, which resolves without intervention. Although no procedure has been accepted as the gold standard for

noninvasive body contouring as yet, cryolipolysis is considered to be both safe and efficient with a

high patient satisfaction rate. Introduction

In 2012, it was estimated that over 10 million cosmetic procedures were performed in the USA, with total expenditures reaching 11 billion dollars. This represents a 250% increase in demand for

both surgical and minimally invasive cosmetic procedures over the last two decades. However, despite our culture’s obsession with attaining media-perpetuated standards of beauty and ideal body shapes, the number of cosmetic surgical procedures has declined by 16% since 2000, while the number of minimally invasive procedures has increased by 137% simultaneously.1These

procedures are often called “lunch time procedures” because they come with minimal down times

and can be completed in less than 2 hours. Nowadays, both men and women are looking for quick,

affordable, and safe minimally invasive fixes to maintain their youthful appearance and increase their attractiveness. These procedures are not limited to the face, and can also include treatment of body contour and shape. For decades, liposuction was the only accepted procedure for body contouring; it has now been receiving more and more competition from noninvasive approaches that involve no anesthesia, operating room time, or surgical incisions to the skin. While the results of these new technologies are less dramatic and immediate, they come without the level of risk and

side effects associated with surgical procedures. Body contouring techniques

A number of newly designed modalities have become available to the consumer recently, each employing a different mechanism of action to reduce the appearance of adipose tissue (Table 1).

One such method uses high-intensity focused ultrasound to deliver focused acoustic energy at specific depths in subcutaneous tissue, and has been cleared by the US Food and Drug Administration (FDA). The combination of a mechanical effect, that disrupts the cell membranes immediately, and a thermal mechanism, that destroys adipocytes at temperatures above 58°C, causes coagulative necrosis within a small targeted area while the surrounding tissue remains mostly unaffected.2 Studies have shown evidence of fat necrosis3 and an average reduction in

waist circumference of more than 2 cm 12 weeks after a single treatment.4

Technology Mechanism of action

Pain level

Side effects Treatments needed (n)

High-intensity focused ultrasound

Necrosis High Massive bruising and tenderness up to 2 weeks

1–2

Unipolar radiofrequency

Apoptosis Medium Redness and tenderness for 1–3 days

2–3

Low-level laser therapy

Apoptosis None None 6

Acoustic wave therapy

Apoptosis None None 8

Cryolipolysis Apoptosis Low Numbness and bruising

for up to 7 days

1–2

Table 1 Comparison of technologies for fat reduction Other players in body contouring include radiofrequency devices. While this technique also causes

thermal injury to targeted tissue layers, it does so using electrical energy. Radiofrequency devices have traditionally been used for tightening of skin laxity and rhytides, as the thermal damage that ensues results in contraction of collagen and remodeling.5 However, a clinical study by Franco et al6 shows that radiofrequency devices can be used to selectively heat subcutaneous adipose tissue and induce lethal thermal damage to adipose tissue while sparing the overlying and underlying tissues. Thermal exposures to 43°C–45°C over several minutes may result in a delayed adipocyte death response. This may have a role in decreasing overall waist circumference and fat removal as

well.7 Uniform heating of subcutaneous tissue at sustained therapeutic temperatures has been shown to trigger apoptosis of cells.8 A decrease in fat volume is supposed to be seen 3–8 weeks after treatment. Low-level laser therapy is a unique modality that is not based on thermal tissue damage. Its

efficacy is still under investigation; however, one of the proposed mechanisms of action is based on the concept of producing transient pores in adipocytes, allowing lipids to leak out.9,10 Another proposed noninvasive means of reducing localized fat accumulation is acoustic wave therapy.

Mechanical stimuli from application of these short pulsed waves are thought to activate new collagen growth, stimulate angiogenesis around fat cells, and activate lipases, resulting in tightening and improved appearance of cellulite.11 Cryolipolysis and its mechanism of action

Cryolipolysis is a completely different modality from the techniques discussed so far. The principle behind this technology exploits the premise that adipocytes are more susceptible to cooling than other skin cells.

Precise application of cold temperatures triggers the death of adipocytes that are subsequently

engulfed and digested by macrophages.12,13 No changes in subcutaneous fat are noticeable

immediately after treatment. An inflammatory process stimulated by apoptosis of adipocytes, as reflected by an influx of inflammatory cells, can be seen within 3 days after treatment and peaks at approximately 14 days thereafter as the adipocytes become surrounded by histiocytes, neutrophils, lymphocytes, and other mononuclear cells. At 14–30 days after treatment, macrophages and other phagocytes surround, envelope, and digest the lipid cells as part of the body’s natural response to injury. Four weeks after treatment, the inflammation lessens and the adipocyte volume is

decreased. Two to 3 months after treatment, the interlobular septa are distinctly thickened and the inflammatory process further decreases. By this time, the fat volume in the treated area is apparently decreased and the septae account for the majority of the tissue volume.14,15 In 2010, the FDA cleared a cryolipolytic device (CoolSculpting®; ZELTIQ Aesthetics, Inc., Pleasanton, CA, USA) for reduction of flank and abdominal fat. In April 2014, the FDA also cleared this system for the treatment of subcutaneous fat in the thighs (Figure 1).16 One part of the device

is a cup-shaped applicator with two cooling panels that is applied to the treatment area. The tissue is drawn into the handpiece under moderate vacuum and the selected temperature is modulated by thermoelectric elements and controlled by sensors that monitor the heat flux out of the tissue. Each area is treated for approximately 45 minutes and should be massaged for 2 minutes upon completion to improve the clinical outcome. The patient is then discharged home and is free to

resume normal activities immediately after treatment.17 The number of treatment cycles needed depends on the treatment area. While good results at the flanks can usually be achieved with only

one treatment, the back and the inner and outer thighs often require more than two treatments.18 Repeated treatment sessions should be spaced 8 weeks apart to allow the inflammatory process to resolve.15

Figure 1 Indications cleared by the US Food and Drug Administration (blue) and off-label indications (pink) for cryolipolysis as mentioned in peer-reviewed publications. Clinical efficacy and safety of cryolipolysis

The clinical efficacy and safety of cryolipolysis has been studied in both human and animal models.

In two separate studies, animal models demonstrated a reduction of up to 1 cm or 40% of the total fat layer thickness after a single exposure without harming the overlying skin.12,13 Manstein et al found lipid-laden mononuclear inflammatory cells and local thickening of fibrous septae at 2 weeks post-procedure, implicating apoptosis and phagocytosis as contributing factors in the mode of

action.12 Evaluation of lipids over a 3-month period following treatment showed normal cholesterol and triglyceride levels.13 Several studies in humans have shown comparable results. One study published in 2009 involving ten subjects reported a 20.4% and 25.5% reduction in the fat layer 2 months and 6 months after treatment, respectively.19 More recently, a retrospective multicenter study using patient surveys, photographic documentation, and caliper measurements, was published by Dierickx et al.20 These

investigators reported that 86% of 518 subjects showed improvement. The body sites at which

cryolipolysis was most effective were the abdomen, back, and flank. Patients completed a

satisfaction questionnaire, with 73% reporting being satisfied and 82% being prepared to

recommend cryolipolysis to a friend. The majority described minimal to tolerable discomfort during the procedure. Eighty-nine percent of respondents reported a positive perception of the treatment duration. In a report on the clinical and commercial experience with cryolipolysis in a private plastic surgery practice, only six of 528 patients were dissatisfied with the clinical outcome; four of these six patients were satisfied when treated a second time.18 A study by Garibyan et al used a three-dimensional camera to evaluate the amount of fat loss after cryolipolysis. Mean fat loss between

baseline and the 2-month follow-up visit was 56.2±25.6 cc on the treated side and 16.6±17.6 cc on the control side (P<0.0001). Two months post-treatment, the mean difference in fat loss between the treated and untreated sides was 39.6 cc.21 In an uncontrolled study by Ferraro et al, cryolipolysis was combined with acoustic waves to achieve possible synergistic effects. These authors reported significant reductions of up to 6.7 cm in circumference and up to 4.5 cm in thickness of the fat layer 12 weeks after 3–4 treatments.22 However, it should be pointed out that

body contouring studies are difficult to perform because natural variability is high and the reproducibility of many measurements is low. The long-term duration of effect of cryolipolysis has not been evaluated as yet. Only one small case study of two subjects who were treated unilaterally on one flank and followed photographically for up to 5 years post-procedure has been published. In this study, fat reduction was found to be

durable despite fluctuations in body weight.23 Although little to nothing is known about the durability of fat loss induced by selective cryolysis, there is no evidence that the fat lost after cold

exposure could regenerate. With regard to the safety profile, several publications including two systematic literature reviews have failed to identify any significant adverse events that could be attributed to cryolipolysis, including scarring, ulceration, or disfigurement. Although cold temperatures are known to induce subcutaneous panniculitis, no cases of nodule formation have been reported.12–23 Expected side effects are temporary erythema, bruising, and transient numbness that usually resolve within 14 days after treatment.13 With more than 850,000 procedures performed worldwide, only 850

adverse events have been reported. The most common complaint is late-onset pain, occurring 2 weeks post-procedure, that resolves without intervention. Paradoxical adipocyte hyperplasia, a condition where additional fat grows at the treatment site and occurs approximately 6 months postoperatively, has been reported in 33 cases.24 The pathogenesis of this phenomenon is unknown, but several hypothesized mechanisms are under discussion. Possible treatments rely on liposuction or abdominoplasty, because spontaneous resolution has not been reported as yet.

Sensory alteration was investigated by Coleman et al in nine subjects by clinical neurological examination and biopsy for nerve staining.19 Six of the nine patients had a transient reduction in

sensation, which returned to normal after a mean of 3.6 weeks. There were no neural changes on the biopsies. Potential changes in lipid levels after treatment were assessed in the two studies without any significant findings.14–25 Further, no notable changes in liver function were found in 40 patients followed for 12 weeks after cryolipolysis.25

Discussion

All nonsurgical procedures for body sculpting rest on the principle of either inducing fat cell necrosis or apoptosis in order to achieve a discernible and quantifiable result. A variety of modalities can be used to achieve this goal, including laser light, radiofrequency, acoustic waves, coldness, or chemicals. They differ from each other not only by their mechanism of action, but also

in response rate, side effects, level of discomfort/pain, and the number of treatments needed. Although no procedure has been accepted as the gold standard as yet, cryolipolysis is considered to be both safe and effective, with a high patient satisfaction rate of up to 73% after one treatment.20 This rate is comparable with that of high-intensity focused ultrasound and acoustic wave therapy (62.3% and 64%, respectively). However, these modalities are associated with either a higher rate of adverse events and pain or a high number of up to eight treatments necessary to achieve the desired effect.4–11 Studies assessing patient satisfaction and efficacy

with radiofrequency for fat reduction have not been published as yet. To the authors’ best knowledge, no studies assessing the influence of noninvasive body contouring procedures on quality of life have been reported at the time of writing. However, studies show that surgical body contouring as well as weight loss in general have a positive influence on quality of life.26,27 Cryolipolysis is safe for all skin types, with no reported pigmentary changes, and is safe for repeated application.18 The best candidates are those within their ideal weight range and those

who engage in regular exercise, eat a healthy diet, have noticeable fat bulges on the trunk, are realistic in their expectations, and are willing to maintain the results of cryolipolysis with a healthy, active lifestyle. However, there is a lack of substantial research, with current knowledge based only on uncontrolled case studies and retrospective practice reviews. No head-to-head studies

evaluating noninvasive body contouring devices have been conducted as yet. More randomized,

controlled, double-blind studies with a sufficient number of subjects and objective measurements

with high reproducibility are needed to evaluate the short-term and long-term efficacy and side effects of cryolipolysis. Further research should be directed towards identifying more ideal settings and maintenance programs. Footnotes

Disclosure The authors report no conflicts of interest in this work. References

1. The American Society for Aesthetic Plastic Surgery Plastic Surgery Statistics Report Annual Statistics. 2012. [Accessed May 17, 2014]. Available from:http://www.plasticsurgery.org/news/plastic-surgery-statistics/2012-plastic-surgery-statistics.html. 2. Fatemi A, Kane MAC. High-intensity focused ultrasound effectively reduces waist circumference by ablating adipose tissue from the abdomen and flanks: a retrospective case series. Aesthetic Plast Surg. 2010;34(5):577–582. [PubMed]

3. Shalom A, Wiser I, Brawer S, Azhari H. Safety and tolerability of a focused ultrasound device for

treatment of adipose tissue in subjects undergoing abdominoplasty: a placebo-control pilot study. Dermatol Surg. 2013;39(5):744–751. [PubMed] 4. Jewell ML, Baxter RA, Cox SE, et al. Randomized sham-controlled trial to evaluate the safety and effectiveness of a high-intensity focused ultrasound device for noninvasive body sculpting. Plast Reconstr Surg. 2011;128(1):253–262.[PubMed]

5. Zelickson BD, Kist D, Bernstein E, et al. Histological and ultrastructural evaluation of the effects of a radiofrequency-based nonablative dermal remodeling device: a pilot study. Arch Dermatol. 2004;140(2):204–209. [PubMed] 6. Franco W, Kothare A, Ronan SJ, Grekin RC, McCalmont TH. Hyperthermic injury to adipocyte cells by selective heating of subcutaneous fat with a novel radiofrequency device: feasibility studies. Lasers Surg Med. 2010;42(5):361–370.[PubMed] 7. Manuskiatti W, Wachirakaphan C, Lektrakul N, Varothai S. Circumference reduction and cellulite

treatment with a TriPollar radiofrequency device: a pilot study. J Eur Acad Dermatol Venereol. 2009;23(7):820–827. [PubMed] 8. Franco W, Kothare A, Goldberg DJ. Controlled volumetric heating of subcutaneous adipose tissue using a novel radiofrequency technology. Lasers Surg Med. 2009;41(10):745–750. [PubMed] 9. McRae E, Boris J. Independent evaluation of low-level laser therapy at 635 nm for non-invasive

body contouring of the waist, hips, and thighs. Lasers Surg Med.2013;45(1):1–7. [PubMed] 10. Avci P, Nyame TT, Gupta GK, Sadasivam M, Hamblin MR. Low-level laser therapy for fat layer

reduction: a comprehensive review. Lasers Surg Med.2013;45(6):349–357. [PMC free article] [PubMed] 11. Adatto MA, Adatto-Neilson R, Novak P, Krotz A, Haller G. Body shaping with acoustic wave therapy AWT(®)/EPAT(®): randomized, controlled study on 14 subjects. J Cosmet Laser Ther. 2011;13(6):291–296. [PubMed] 12. 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. [PubMed] 13. Zelickson B, Egbert BM, Preciado J, et al. Cryolipolysis for noninvasive fat cell destruction: initial results from a pig model. Dermatol Surg. 2009;35(10):1462–1470. [PubMed] 14. Nelson AA, Wasserman D, Avram MM. Cryolipolysis for reduction of excess adipose tissue. Semin Cutan Med Surg. 2009;28(4):244–249. [PubMed] 15. Avram MM, Harry RS. Cryolipolysis for subcutaneous fat layer reduction.Lasers Surg

Med. 2009;41(10):703–708. [PubMed] 16. US Food and Drug Administration 510(k) clearance K133212. 2014. [Accessed May 17, 2014].

Available from:http://www.accessdata.fda.gov/cdrh_docs/pdf13/K133212.pdf. 17. Jalian HR, Avram MM. Cryolipolysis: a historical perspective and current clinical practice. Semin Cutan Med Surg. 2013;32(1):31–34. [PubMed] 18. Stevens WG, Pietrzak LK, Spring MA. Broad overview of a clinical and commercial experience with CoolSculpting. Aesthetic Surg J. 2013;33(6):835–846.[PubMed]

19. 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):482–448. [PubMed] 20. Dierickx CC, Mazer JM, Sand M, Koenig S, Arigon V. Safety, tolerance, and patient satisfaction with noninvasive cryolipolysis. Dermatol Surg.2013;39(8):1209–1216. [PubMed]

21. Garibyan L, Sipprell WH, Jalian HR, Sakamoto FH, Avram M, Anderson RR. Three-dimensional

volumetric quantification of fat loss following cryolipolysis.Lasers Surg Med. 2014;46(2):75–

80. [PMC free article] [PubMed] 22. Ferraro GA, De Francesco F, Cataldo C, Rossano F, Nicoletti G, D’Andrea F. Synergistic effects of cryolipolysis and shock waves for noninvasive body contouring. Aesthetic Plast Surg. 2012;36(3):666–679. [PubMed] 23. Bernstein EF. Longitudinal evaluation of cryolipolysis efficacy: two case studies.J Cosmet Dermatol. 2013;12(2):149–152. [PubMed]

24. Jalian HR, Avram MM, Garibyan L, Mihm MC, Anderson RR. Paradoxical adipose hyperplasia after cryolipolysis. JAMA Dermatol. 2014;150(3):317–319.[PMC free article] [PubMed] 25. Klein KB, Zelickson B, Riopelle JG, et al. Non-invasive cryolipolysis for subcutaneous fat reduction does not affect serum lipid levels or liver function tests.Lasers Surg Med. 2009;41(10):785–790. [PubMed] 26. Smeets R, Noah EM, Seiferth NY, et al. Bioelectric impedance analysis and quality of life after

body-contouring procedures in plastic surgery. J Plast Reconstr Aesthet Surg. 2009;62(7):940–945. [PubMed] 27. Milder IEJ, de Hollander EL, Picavet HS, Verschuren WM, de Groot LC, Bemelmans WJ. Changes in weight and health-related quality of life. The Doetinchem Cohort Study. J Epidemiol Community Health. 2014;68(5):471–477.[PubMed]

J Cosmet Dermatol. 2014 Jun;13(2):119-24. An evaluation of the patient population for aesthetic treatments targeting abdominal subcutaneous adipose tissue. Friedmann DP, Avram MM, Cohen SR, Duncan DI, Goldman MP, Weiss ET, Young VL. A large and growing population of patients currently seeks minimally invasive therapeutic options for the aesthetic treatment of localized, central abdominal subcutaneous adipose tissue (SAT). We

sought to evaluate the ideal population for aesthetic treatment of central abdominal SAT, highlight the existing disparities between SAT in obese (body mass index [BMI] ≥ 30; BMI) and nonobese (BMI < 30) patients, and review the available FDA-cleared, minimally invasive treatment options for central abdominal adiposity. The cosmetic issue of localized, central (periumbilical) abdominal adiposity in nonobese individuals is quite distinct from abdominal bulging secondary to obesity. Given the recognized clinical and physiologic differences between obese and nonobese

counterparts, the exclusion of obese patients from clinical study by currently available FDA-cleared devices targeting abdominal fat, and the status of obesity as a chronic, systemic disease requiring

medical, surgical, and/or lifestyle-altering therapies, minimally invasive therapeutic options for aesthetic reductions in central abdominal SAT must be limited to the nonobese population. Dermatol Surg. 2014 Sep;40(9):1004-9.

Fat reduction in the inner thigh using a prototype cryolipolysis applicator. Boey GE, Wasilenchuk JL. BACKGROUND: Previous clinical studies have investigated cryolipolysis for noninvasive reduction of fat in abdomens, outer thighs, flanks, and backs. This study investigated feasibility of cryolipolysis for inner thigh treatment.

OBJECTIVE: This pilot study evaluated a cryolipolysis flat cup vacuum applicator for treatment of inner thigh fat. METHODS: A prototype vacuum applicator was used to treat n = 11 subjects in a single-side inner thigh study. Cryolipolysis treatment was delivered to the larger thigh while the contralateral thigh served

as a control. Follow-ups were conducted at 8 and 16 weeks. Equalization treatments were

subsequently delivered to the contralateral thigh. Safety was assessed by monitoring side effects and adverse events. Efficacy was evaluated by ultrasound imaging, clinical photography, and patient surveys. RESULTS: Side effects were typical and resolved spontaneously. Efficacy was demonstrated with ultrasound measurements showing 83% of subjects attained some level of fat layer reduction. Normalized mean reduction in fat layer thickness was 20%, corresponding to 3.3 mm. Patient surveys revealed

91% were satisfied and 82% felt inner thigh cryolipolysis was comfortable. Clinical photographs revealed visible reduction in inner thigh contour after treatment. CONCLUSION:

This study demonstrates feasibility of safe and efficacious cryolipolysis treatment to the inner thigh.

Skin Res Technol. 2014 Sep 15. [Epub ahead of print] Improved methods for selective cryolipolysis results in subcutaneous fat layer reduction in a porcine model. Kwon TR, Yoo KH, Oh CT, Shin DH, Choi EJ, Jung SJ, Hong H, Choi YS, Kim BJ.

BACKGROUND/AIMS: Cryolipolysis is a noninvasive method for the selective reduction of localized fat tissues. It has demonstrated efficacy in both clinical and preclinical trials; however, despite its popularity, its mechanisms of action and evaluation methods are not yet fully defined. The purpose of this study was to improved methods for cryolipolysis using a porcine model. METHODS:

The abdomens of female PWG micro-pigs were treated with a cooling device (CRYOLIPO II™ ), and we examined the treatment effects using photography, three-dimensional photography, ultrasound, gross, and microscopic pathology, and serum lipid level analyses in order to determine the mechanism of action, efficacy, and safety of CRYOLIPO II™ . RESULTS:

CRYOLIPO II™ successfully reduced abdominal fat in our porcine model. Gross and microscopic histological results confirmed the noninvasive cold-induced selective subcutaneous fat destruction,

and showed increases in pre-adipocyte differentiation and in the activation of lipid catabolism. In particular, we found that CRYOLIPO II™ may increase PPARδ (delta) levels in adipose tissue at 30-60 days post-treatment. CONCLUSION: Fat reduction by cryolipolysis was successfully achieved in our porcine model. Thus, our findings indicate that CRYOLIPO II™ may be a promising fat reduction device for body contouring and fat

reduction in humans, and that cryolipolysis exerts its effects, at least partly, by targeting the PPARδ signaling pathway. These results show that both investigative and diagnostic potentials capacity. Lasers Surg Med. 2014 Dec;46(10):731-5. Epub 2014 Nov 13.

Non-invasive fat reduction of the flanks using a new cryolipolysis applicator and overlapping, two-cycle treatments.

Bernstein EF, Bloom JD, Basilavecchio LD, Plugis JM. BACKGROUND AND OBJECTIVES: A sharply contoured cryolipolysis vacuum applicator was developed to improve fit and tissue draw in the abdomen and flanks to better accommodate a range of body types and a variety of

treatment sites. This study was carried out to evaluate the safety and efficacy of the new applicator for treatment of flank fat ("love handles"). STUDY DESIGN/MATERIALS AND METHODS: A cryolipolysis vacuum applicator with a sharply contoured cup and curved cooling plates was used to treat 20 flanks. Two treatment cycles were delivered sequentially to each flank (60-minute cycle at a Cooling Intensity Factor of 41.6). Efficacy was evaluated 12 weeks post-treatment by physicians performing blinded, independent review of clinical photographs. Safety was assessed by

the treating physician monitoring subjects for side effects and adverse events. RESULTS: Four blinded, independent physician reviewers properly identified the pre- and post-treatment photographs 94.4% of the time. Improvement was scored from 0 (none) to 10 (complete) and showed an average 4.3 point (43%) improvement. Side-effects were limited to erythema, edema,

bruising, and numbness or tingling at the treatment site, and resolved without treatment.

CONCLUSIONS: Multiple treatment cycles from a new improved-fit cryolipolysis applicator are safe and effective for reduction of flank fat bulges. A high degree of improvement was reported by blinded, physician evaluation of standardized photographs. Introduction

Cold-induced panniculitis, with subsequent atrophy is a well-known phenomenon in both children and adults [1–3]. Based upon observations of fat susceptibility to cold injury and a case report of popsicle panniculitis [4], researchers studied and developed controlled cryolipolysis; the controlled

application of cooling to non-invasively reduce subcutaneous fat. Cryolipolysis was first shown to

effectively reduce fat in a porcine model [5]. That study demonstrated fat reduction via

examination by ultrasound and histopathologic evaluation; safety data were collected in this animal model by demonstrating no skin injury and a lack of change in serum lipid levels following treatment [5]. Since then, there have been follow-up porcine [6] and human clinical studies showing safe and effective cryolipolysis in a number of treatment areas including the abdomen, flanks, and thighs [7–13]. The safety of cryolipolysis treatments has also been demonstrated in clinical studies of cryolipolysis where serum lipid levels and liver function tests were performed

[14], as well as peripheral nerve studies [15], all demonstrating no abnormalities following treatment. Cryolipolysis received U.S. Food and Drug Administration (FDA) clearance for fat reduction of the flanks in 2010, for abdominal fat reduction in 2012, and for fat reduction of the thighs in 2014. Studies have also demonstrated safety and effectiveness for treatment of undesirable fat in the back, arms, and chest [16–19]. Long-term persistence of fat reduction has been demonstrated in subjects treated to a single flank, to control for fluctuations in weight, for up

to five years following a single treatment session [20]. Since flanks are perhaps the most commonly treated of all cryolipolysis sites, this study was intended to investigate improvements to flank treatment efficacy using a new cryolipolysis handpiece. Previously, a moderately-contoured applicator (CoolCurve, eZ App 6.2, Zeltiq Aesthetics, Inc., Pleasanton, CA) was used for flank treatments. A new applicator with a sharply

contoured vacuum cup and curved cooling panels (CoolCurve+, Zeltiq Aesthetics, Inc.) was used for the current study. Design changes were intended to provide improved patient fit and tissue

draw for sharply contoured treatment sites such as flanks. This study investigates the safety and efficacy of two overlapping treatment cycles to the flanks using a sharply-contoured cryolipolysis vacuum applicator. Go to: Materials and Methods

This institutional review board (IRB)-approved clinical study investigated the safety and efficacy of treatment with two cycles per flank, administered in two separate treatment sessions utilizing a new, sharply-contoured vacuum applicator (CoolCurve+ applicator, Zeltiq Aesthetics, Inc.) in treating unwanted flank fat on 20 treatment sites in 10 subjects. Two cycles were delivered to each flank in a bilateral treatment protocol in a single office visit. Investigator measurements show the previous generation contoured applicator (CoolCurve) and the applicator evaluated in this study (CoolCurve+) treat approximately the same volume of tissue. While the cooling plate sizes are

similar, the new applicator has a curved edge to better fit a patient's contour. The geometry of the applicator cup is also different. The new applicator cup has approximately 1.6 cm longer ears

(lateral edges) and an approximately 6° increased angle to better accommodate contoured

treatment areas, such as flanks. Subjects

Twenty sites were treated in ten adult subjects. Subjects ranged from 33 to 56 years of age, averaging 42.2 years old and were all females. Subjects selected for the study had clearly visible fat on their flanks, and a body mass index (BMI) of up to 30. BMI was measured after measuring a subject's height and weight; these values were entered into an online BMI calculator (BMI Calculator, Tim O's Studios, LLC, Austin, TX). For the duration of the study, subjects were instructed to avoid implementing major diet or lifestyle changes in order to maintain their weight within 5 lbs of baseline measurement.

Cryolipolysis Treatment Cryolipolysis treatment was delivered at a Cooling Intensity Factor 41.6, corresponding to an average energy extraction rate of 72.9 mW/cm2. Two cycles were administered in sequence to each

flank, with 50% overlap. The flank fat was drawn by moderate vacuum suction between cooled plates in the applicator. At the conclusion of each 60 minute cycle, the treatment area was

vigorously massaged by hand for 5 minutes [21]; then the remaining flank fat was treated using

the same protocol. The two treatment cycles were positioned anterior to posterior with approximately 50% overlap. Thus, 4 cycles (2 per flank) were administered on the treatment day,

treating both flanks with 2 cycles each, overlapping 50%. Photographic Evaluation of Treatment Efficacy

Treatment efficacy was determined by blinded-expert analysis of clinical photographs viewed in pairs. At the baseline pre-treatment visit and 12-week follow-up visits, photographs were acquired using a standardized photography set-up using a professional digital camera with a 60 mm lens

(D300 camera, Nikon Inc., Melville, NY) with floor-standing, external, bilaterally-symmetrical strobe lighting, with 1,000 W heads and soft-boxes (Dynalite, Inc., Union, NJ) to ensure

consistency. Subjects were photographed with their feet separated at a fixed distance using a foot positioning guide and arms in a fixed, standard position. At the completion of the study, clinical photographs were reviewed by four blinded, independent physicians to choose which photographs

were pre- versus post-treatment photographs. The pre- and post-treatment photograph pairs for

each subject were randomized and presented to the blinded, independent reviewers, then the

reviewers were asked to determine which image was captured prior to treatment. The degree of improvement was quantified by three of the independent physician reviewers who graded each pair of photographs from 0 (none) to 10 (complete) removal of flank fat. For any photographs that were incorrectly identified as baseline images by a reviewer, the corresponding 0–10 improvement score was assigned a negative value. For example, an incorrectly identified baseline image that was scored an improvement score of 3 was scored as −3 in the data analysis.

Side Effects Side effects were assessed by the treating physician. All subjects were examined at the follow-up visit. Go to: Results

One subject failed to return for her follow-up visit. The subjects' weights ranged from 119.3 to 172.7 lbs. (mean 142.1 lbs.) with their BMI ranging from 21.1 to 28.1 (mean 24.3). All subjects maintained their weights within 5 lbs. of their initial baseline weights by the end of the study period

(Table1).

Treatment visit

12-week follow-up visit

Subject Weight (lb) BMI Weight (lb) Weight change (lb)

01 158.0 24.7 154.2 −3.8

02 129.8 22.3 128.9 −0.9

03 161.5 27.7 161.2 −0.3

04 148.8 28.1 147.7 −1.1

05 132.4 22.7 130.5 −1.9

06 119.3 23.3 115.3 −4.0

08 143.7 26.3 142.1 −1.6

09 127.9 21.3 130.5 2.6

10 126.6 21.1 124.5 −2.1

At the treatment visit, all subjects had BMI <29 and agreed to maintain weight over the course of the study by avoiding diet and exercise changes. At 12-week follow-up, all subjects maintained weight within 5 lbs. of baseline.

Table 1 Subject Weight and BMI Data The photographic review attempting to identify which photographs were taken before and after treatment demonstrated 94% correct identification of baseline images by four blinded, independent

physician reviewers. Two reviewers correctly identified all baseline photographs and two reviewers each scored one incorrectly, thus 34 of 36 before and after pairs were correctly identified (Table(Table2). The 0 (none) to 10 (complete) mean improvement score as rated by three blinded physician reviewers was 4.3 ± 1.4 (mean ± sem; Table 2; Figs.1 and and 2).

Independent photo review

(correct/incorrect)

Improvement score (0–10)

Subject Reviewer 1

Reviewer 2

Reviewer 3

Reviewer 4

Reviewer 2

Reviewer 3

Reviewer 4

01 C C C C 6 5 3

02 C C C C 3 4 5

03 C C C C 4 2 2

04 C C C I 3 4 −2

05 C I C C −3 5 5

06 C C C C 7 8 6

08 C C C C 7 5 6

09 C C C C 6 5 5

10 C C C C 5 4 5

Four blinded, independent physicians correctly identified 94% of baseline images; 34 of 36 correct.

Three physicians assigned improvement scores from 0 (none) to 10 (complete), resulting in a mean improvement score of 4.3 + 1.4 (mean + sem).

Table 2 Independent Photographic Review and Improvement Score Data

Figure 1 This 41 year-old female received two sequential cryolipolysis cycles to each flank. Clinical photographs show flank fat reduction between baseline (a, c) and 12 weeks

post-treatment (b, d). This subject had a weight gain of only 2.6 lbs from her initial visit

until the end of the study.

Figure 2 This 42 year-old female received two sequential cryolipolysis cycles to each flank. Clinical photographs show flank fat reduction between baseline (a, c) and 12 weeks

post-treatment (b, d). This subject lost only 0.9 lbs. from her baseline visit to her visit to her final photographic evaluation, 12 weeks later.

Side-effects were mild and were limited to erythema, edema, bruising, numbness, and tingling at the treatment site. All of the side effects resolved without intervention prior to the 12-week follow-up visit.

Discussion

This study demonstrates that the new cryolipolysis applicator with a more sharply contoured vacuum cup and curved cooling panels is both safe and effective for administering cryolipolysis treatments to the flanks. This study assessed treatment efficacy at 3 months; whereas, other clinical studies evaluated patients at 4 [21] and 6 [9] months, thus the subjects presented in this

study may attain some additional fat reduction with longer follow-up [9,21], or multiple treatment sessions as shown by Brightman and Geronemus [25]. The newly-designed applicator was developed to increase tissue draw and improve fit for curved surfaces like the flanks, and should allow treatment of patients who may otherwise not be able to be treated with the conventional applicator, due to the inability to gain sufficient suction and fit to keep the applicator in place. In addition, fit should be improved in most patients in the flank regain. Improvement after a single treatment incorporating 2 cycles per side was a score of 4.3 on

a scale of 0 (none) to 10 (complete). The mean 94% correct identification of baseline images by four blinded, independent physicians for this study was similar to the results shown by Kaminer et al [23] in a much larger study, and greater than that shown by Garibyan [22]. Garibyan et al. treated 11 subjects unilaterally on one flank and reported that blinded evaluators correctly identified the treated side in 79% of subjects [22]. Kaminer et al. showed a 92% correct identification of baseline photographs by blinded, independent reviewers that evaluated fifty

subjects treated on the flanks [23]. Areas aside from the flanks have shown similar statistically significant improvement. Mayoral et al. treated 20 subjects to their lower abdomens and demonstrated an 86% correct identification of pre-treatment images [24].

This study utilized conventional 2D photography to assess treatment efficacy, and was shown to

produce visible improvement that was statistically significant when evaluated by blinded physician

rating of digital images. Fat reduction can also be objectively quantified by methods such as ultrasound [7,8,12,13,15,17,19,21] and 3D Vectra imaging [11,25], and these methods may have more sensitivity to measure more subtle differences. In this current study, it was fortunate that the simpler, and less expensive, method of photography demonstrated statistically significant improvement. Future studies should employ multiple methods of evaluating fat reduction, to enable better comparison between different protocols. Efficacy assessment by clinical photographs may be

affected by patient weight change, but this is unlikely for the current study since the subjects had an average 1.5 lb. weight loss at follow-up, well within the 5 lb. specification from baseline. The

weight loss is likely due to increased awareness of diet and exercise while in the study, rather than fat reduction from cryolipolysis, since small volumes of fat are removed during cryolipolysis. This modest weight loss is not expected to affect the clinical efficacy as evaluated by blinded

photographic review, and likely falls within the resolution limits of daily variations in weight and scale accuracy. Cryolipolysis has also been shown to be effective in treating areas not on the abdomen as well. These different applications require the development of additional applicators to fit various body sites. Stevens et al. administered treatments to the lateral thigh in 40 subjects and showed 87% correct identification of pre-treatment photos [13]. Munavalli treated 18 male subjects for

pseudogynecomastia and that study demonstrated an 80% correct identification of baseline

photographs [19]. The significant efficacy of the sharply contoured vacuum cup applicator in the current study is consistent with other studies of cryolipolysis reported in the medical literature, as is the very low side-effect profile. Future studies incorporating a series of treatment sessions to the same area should further the amount of improvement seen in the current study. Treating even more sharply contoured areas such as extremities will require even more contoured vacuum cup applicators. Go to:

Conclusion

This study demonstrated the safety and efficacy of a new, sharply contoured vacuum cup applicator administered for a single treatment using two overlapping cycles on two flanks. Enhanced cryolipolysis clinical outcomes can be attained by selecting the appropriate applicator to maximize tissue draw for the intended treatment area and by delivering a sufficient number of

cycles to adequately address the subcutaneous fat volume. The cryolipolysis treatment protocol should be customized to the individual in order to ensure high efficacy and patient satisfaction. Go to: References

1. Collins HA, Stahlman M, Scott HW., Jr The occurrence of subcutaneous fat necrosis in an infant

following induced hypothermia used as an adjuvant in cardiac surgery. Ann Surg. 1953;138:880–885. [PMC free article] [PubMed] 2. Rotman H. Cold panniculitis in children. Adiponecrosis E frigore of Haxthausen.Arch Dermatol. 1966;94:720–721. [PubMed] 3. Solomon LM, Beerman H. Cold panniculitis. Arch Dermatol. 1963;88:897–900. [PubMed] 4. Epstein EH, Jr, Oren ME. Popsicle panniculitis. N Engl J Med. 1970;82:966–967. [PubMed]

5. 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;40:595–604. [PubMed] 6. Zelickson B, Egbert BM, Preciado J, Allison J, Springer K, Rhoades RW, Manstein D. Cryolipolysis for noninvasive fat cell destruction: initial results from a pig model. Dermatol Surg. 2009;35:1462–1470. [PubMed] 7. Dover J, Burns J, Coleman S, Fitzpatrick R, Garden J, Goldberg D, Geronemus R, Kilmer S,

Mayoral F, Weiss R, Zelickson B, Tanzi E. A prospective clinical study of noninvasive cryolipolysis for subcutaneous fat layer reduction—Interim report of available subject data. Lasers Surg Med. 2009;41(S21):43.

8. Burns AJ, Allison J, Bachelor E, Dover J, Coleman S, Fitzpatrick R, Garden J, Geronemus R, Goldberg D, Kilmer S, Kramer S, Levinson M, Tanzi E, Weiss R, Zelickson B, Mayoral F, Okamoto E, Riopelle J. Analysis of side effects of non-invasive cryolipolysis for subcutaneous fat layer reduction—Interim Report from Controlled Clinical Trials. Lasers Surg Med. 2010;42(S22):21.

9. Dover J, Kaminer M, Teahan M, Barrett L. Patient satisfaction at 2 and 6 months after a single non-invasive cryolipolysis treatment for subcutaneous fat layer reduction. Lasers Surg Med. 2011;43(S23):968. 10. Shek SY, Chan NP, Chan HH. Non-invasive cryolipolysis for body contouring in Chinese—A first commerial experience. Lasers Surg Med. 2011;44:125–130.[PubMed]

11. Garibyan L, Sipprell 3rd WH, Jalian HR, Sakamoto FH, Avram M, Anderson RR. Three-

dimensional volumetric quantification of fat loss following cryolipolysis.Lasers Surg

Med. 2014;46:75–80. [PMC free article] [PubMed] 12. Boey GE, Wasilenchuk JL. Fat reduction in the inner thigh using a prototype cryolipolysis applicator. Dermatol Surg. 2014 ; in press. [PubMed] 13. Stevens WG, Bachelor EP. Cryolipolysis conformable surface applicator for non-surgical fat reduction in lateral thighs. Aesthet Surg J. 2014 ;in press.[PubMed] 14. Klein KB, Zelickson B, Riopelle JG, Okamoto E, Bachelor EP, Harry RS, Preciado JA. Non-

invasive cryolipolysis for subcutaneous fat reduction does not affect serum lipid levels or liver function tests. Lasers Surg Med. 2009;41:785–790. [PubMed] 15. 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;33:482–488. [PubMed] 16. Stevens WG, Pietrzak LK, Spring MA. Broad overview of a clinical and commercial experience

with coolsculpting. Aesthet Surg J. 2013;33:835–846.[PubMed] 17. Sasaki GH, Abelev N, Tevez-Ortiz A. Noninvasive selective cryolipolysis and reperfusion recovery for localized natural fat reduction and contouring. Aesthet Surg J. 2014;34:420–431. [PubMed] 18. Dierickx CC, Mazer JM, Sand M, Koenig S, Arigon V. Safety, tolerance, and patient satisfaction

with noninvasive cryolipolysis. Dermatol Surg. 2013;39:1209–1216. [PubMed] 19. Munavalli G. Cryolipolysis for the treatment of male pseudogynecomastia.Lasers Surg

Med. 2013;45(S25):16. 20. Bernstein EF. Longitudinal evaluation of cryolipolysis efficacy: Two case studies. J Cosmet Dermatol. 2013;12:149–152. [PubMed] 21. Boey GE, Wasilenchuk JL. Enhanced clinical outcome with manual massage following cryolipolysis treatment: A 4-month study of safety and efficacy. Lasers Surg Med. 2014;46:20–26. [PMC free article] [PubMed] 22. Garibyan L, Sipprell 3rd WH, Jalian HR, Sakamoto FH, Avram M, Anderson RR. Three-

dimensional volumetric quantification of fat loss following cryolipolysis.Lasers Surg Med. 2014;46:75–80. [PMC free article] [PubMed] 23. Kaminer M, Weiss R, Newman J, Allison J. . Visible Cosmetic Improvement with Cryolipolysis: Photographic Evidence. Presented at the Annual Meeting of the American Society for Dermatologic Surgery, Phoenix, AZ, 2009. 24. Mayoral F, Kaminer M, Kilmer S, Weiss R, Zelickson B. Effect of multiple cryolipolysis

treatments on the abdomen. Lasers Surg Med. 2012;44(S24):15. 25. Brightman L, Geronemus R. Can second treatment enhance clinical results in cryolipolysis? Cos

Derm. 2011;24:85–88. Dermatol Surg. 2014 Dec;40 Suppl 12:S184-9.

Cryolipolysis and skin tightening. Carruthers J, Stevens WG, Carruthers A, Humphrey S. BACKGROUND: Anecdotally, there have been reports of skin tightening after cryolipolysis, but this has not been studied or reported in the literature. OBJECTIVE:

This clinical evaluation of patients treated with cryolipolysis in the thighs, abdomen, arms, and back assesses changes to skin texture, laxity, and cellulite at 2 study centers. METHODS: From the Vancouver site, a comprehensive review of cryolipolysis treatments was performed to assess treatment areas and retreatments. While reviewing data, investigators were struck by the

noticeable skin tightening shown in clinical photographs. Subsequently, a survey of Vancouver

patients was conducted to assess changes to skin texture and laxity. At the Marina del Rey site, subjects undergoing a clinical study for lateral thigh cryolipolysis were evaluated for changes to skin texture, laxity, and cellulite. RESULTS: Independent assessments by patients and investigators found consistent improvement in skin texture and laxity for treatments to the outer thighs, abdomen, arms, and back. Outer thighs also showed mild-to-moderate improvement in cellulite.

CONCLUSION:

This clinical evaluation demonstrates consistent improvement in skin texture, laxity, and cellulite

after cryolipolysis as independently assessed by patients and investigators. Prospective clinical

studies should be conducted to objectively study and quantify skin tightening after cryolipolysis. Lasers Surg Med. 2015 Feb;47(2):120-7.Epub 2015 Jan 13 Cryolipolysis for safe and effective inner thigh fat reduction Zelickson BD, Burns AJ, Kilmer SL

Abstract BACKGROUND AND OBJECTIVES: While cryolipolysis initially received FDA clearance for fat reduction in the abdomen and flanks, there was significant interest in non-surgical fat reduction for other sites, such as the inner and outer thighs. This article reports the results of an inner thigh study which contributed to FDA

clearance ofcryolipolysis for treatment of thighs. STUDY DESIGN/MATERIAL AND METHODS: A flat cup vacuum applicator (CoolFit applicator, CoolSculpting System) was used to treat 45 subjects bilaterally in the inner thighs. Single cycle treatments were delivered at Cooling Intensity Factor (CIF) 41.6 for 60 minutes followed by 2 minutes of manual massage. Follow-up visits were

conducted at 8 and 16 weeks. Efficacy was assessed by ultrasound imaging, circumference

measurements, and photographs. Safety was assessed by monitoring adverse events. Patient satisfaction was evaluated by questionnaire. RESULTS: Data is presented for n = 42 patients that completed the 16 week study follow-up and maintained their weight within 5 lbs. of baseline. Independent photo review from three blinded physicians

found 91% correct identification of baseline clinical photographs. Ultrasound data indicate fat layer reduction of 2.8 mm. Circumferential measurements indicate mean reduction of 0.9 cm. Patient

questionnaires reveal 93% were satisfied with the CoolSculpting procedure; 84% noticed visible fat reduction; 89% would recommend to a friend; and 91% were likely to have a second treatment. There were no device- or procedure-related serious adverse events.

CONCLUSION: The CoolFit flat cup vacuum applicator was found to deliver safe and effective cryolipolysistreatment to reduce inner thigh fat. Completed 16-week data from 42 subjects show 2.8 mm reduction in fat thickness and 0.9 cm reduction in circumference.

Assessment of clinical photographs found 91% correct identification of baseline images. The results of this prospective, multi-center, interventional clinical study contributed to FDA clearance

of cryolipolysis for treatment of thighs in April 2014. Lasers Surg Med. 2015 Feb;47(2):183-95 Thermal and elastic response of subcutaneous tissue with different fibrous septa architectures to RF heating: numerical study González-Suárez A, Gutierrez-Herrera E, Berjano E, Jimenez Lozano JN, Franco W

BACKGROUND AND OBJECTIVE: Radiofrequency currents are commonly used in dermatology to treat cutaneous and subcutaneous tissues by heating. The subcutaneous morphology of tissue consists of a fine, collagenous and fibrous septa network enveloping clusters of adipocyte cells. The architecture of this network, namely density and orientation of septa, varies among patients and, furthermore, it correlates with cellulitegrading. In this work we study the effect of two clinically relevant fibrous septa

architectures on the thermal and elastic response of subcutaneous tissue to the same RF treatment; in particular, we evaluate the thermal damage and thermal stress induced to an intermediate- and a high-density fibrous septa network architecture that correspond to clinical

morphologies of 2.5 and 0 cellulite grading, respectively. STUDY DESIGN/MATERIALS AND METHODS: We used the finite element method to assess the electric, thermal and elastic response of a two-

dimensional model of skin, subcutaneous tissue and muscle subjected to a relatively long, constant, low-power RF treatment. The subcutaneous tissue is constituted by an interconnected architecture of fibrous septa and fat lobules obtained by processing micro-MRI sagittal images of hypodermis. As comparison criteria for the RF treatment of the two septa architectures, we calculated the accumulated thermal damage that corresponds to 63% loss in cell viability. RESULTS: Electric currents preferentially circulated through the fibrous septa in the subcutaneous tissue.

However, the intensity of the electric field was higher within the fat because it is a poor electric

conductor. The power absorption in the fibrous septa relative to that in the fat varied with septum

orientation: it was higher in septa with vertical orientation and lower in septa with horizontal

orientation. Overall, maximum values of electric field intensity, power absorption and temperature were similar for both fibrous septa architectures. However, the high-density septa architecture (cellulite grade 0) had a more uniform and broader spatial distribution of power absorption, resulting in a larger cross-sectional area of thermal damage (≈1.5 times more). Volumetric strains (expansion and contraction) were small and similar for both network architectures. During the first seconds of RF exposure, the fibrous septa were subjected to thermal expansion regardless of

orientation. In the long term, the fibrous septa contracted due to the thermal expansion of fat. Skin and muscle were subjected to significantly higher Von Mises stresses (measure of yield) or distortion energy than the subcutaneous tissue. CONCLUSION: The distribution of electric currents within subcutaneous tissues depends on tissue morphology. The electric field is more intense in septum oriented along the skin to muscle (top to bottom)

direction, creating lines or planes of preferential heating. It follows that the more septum available for preferential heating, the larger the extent of volumetric RF-heating and thermal damage to the subcutaneous tissue. Thermal load alone, imposed by long-exposure to heating up to 50 °C, results

in small volumetric expansion and contraction in the subcutaneous tissue. The subcutaneous tissue is significantly less prone to non-reversible deformation by a thermal load than the skin and

muscle.

Plast Reconstr Surg. 2015 Jun;135(6):1581-90 Cryolipolysis for fat reduction and body contouring: safety and efficacy of current treatment paradigms Ingargiola MJ, Motakef S, Chung MT, Vasconez HC, Sasaki GH

BACKGROUND: Cryolipolysis is a nonsurgical technique for localized fat reduction. With the increased risk of complications from more invasive methods such as liposuction, cryolipolysis presents a promising method for nonsurgical body contouring. This study presents a systematic review of the available clinical data, with an emphasis on the efficacy, methods, safety, and complications of cryolipolysis. METHODS:

To identify clinical studies that assessed outcomes of cryolipolysis, a systematic review of the MEDLINE and Cochrane databases was performed with the search algorithm cryolipolysis OR cool sculpting OR fat freezing OR lipocryolysis.

RESULTS: The primary literature search returned 319 articles. After inclusion criteria were applied and additional articles were idenfied via manual review of article references, 19 studies were selected for review. Average reduction in caliper measurement ranged from 14.67 percent to 28.5 percent.

Average reduction by ultrasound ranged from 10.3 percent to 25.5 percent. No significant impact on lipid levels or liver function tests aftercryolipolysis treatments was noted in any study. Only mild, short-term side effects, such as erythema, swelling, and pain, were noted. Paradoxical adipose hyperplasia was described in one patient. CONCLUSIONS: Cryolipolysis is a promising procedure for nonsurgical fat reduction and body contouring and presents a compelling alternative to liposuction and other, more invasive methods. This procedure

appears to be safe in the short term, with a limited side effect profile, and results in significant fat reduction when used for localized adiposities. It remains unclear whether post treatment manual massage and multiple treatments in the same anatomic area enhance the efficacy of cryolipolysis. Abstract

Body contouring remains among the most common cosmetic surgical procedures performed in the

United States. Data from the American Society for Aesthetic Plastic Surgery indicate that liposuction replaced breast augmentation as the most popular surgical procedure in 2013, with 363,912 procedures performed. Its popularity has grown considerably because of advantages such as aesthetic improvements as well as numerous metabolic benefits.1,2 Despite its popularity, there remain rare but significant risks regarding liposuction, including complications from anesthesia,

infections, and even death.3 Clinical studies have reported a 21.7 percent incidence of minor complications as well as a 0.38 percent incidence of major complications.4,5 Similarly, Fischer et al. showed that the incidence of minor wound complications was 6.3 percent, and the incidence of a major morbidity was 6.8 percent within 30 days after a surgical body contouring procedure.6

Although liposuction is an effective therapeutic option for the removal of excess adipose tissue, it

remains an invasive procedure and carries the inherent risks associated with surgery. In recent

years, new modalities have been developed to address body contouring from a less-invasive perspective. These modalities primarily target the physical properties of fat that differentiate it from the overlying epidermis and dermis, thus resulting in selective destruction of fat. Devices using high-frequency ultrasound, radiofrequency energy, and laser light have the potential to improve efficiency, minimize adverse consequences, and shorten postoperative recovery time. Through thermal destruction, cavitational destruction, or creation of a temporary adipocyte cell

membrane pore, the final result is that the number of adipocytes is reduced, which, when translated over millions of fat cells, results in a measurable reduction of fat.7 Cryolipolysis is one of the most recent forms of noninvasive fat reduction to emerge. The development behind cryolipolysis stems from the clinical observation of cold-induced panniculitis.8–

10 In 1970, Epstein and Oren coined the term popsicle panniculitis after reporting the presence of a red indurated nodule followed by transient fat necrosis in the cheek of an infant who had been

sucking on a popsicle.9 Initially described in infants, cold-induced panniculitis has also been observed in adult patients. These observations led to the concept that lipid-rich tissues are more susceptible to cold injury than the surrounding water-rich tissue. With these historical observations in mind, Manstein et al. introduced a novel noninvasive method for fat reduction with freezing in 2007, termed cryolipolysis.11This technique is performed by applying an applicator to the targeted

area set at a specific cooling temperature for a preset period of time. This targets adipocytes while sparing the skin, nerves, vessels, and muscles.

Initial preclinical and clinical studies have demonstrated the efficacy of cryolipolysis for subcutaneous fat layer reduction. However, the exact mechanism of action for cryolipolysis is not yet completely understood. In addition, the techniques of cryolipolysis treatment are not uniformly applied. Studies have suggested that the addition of posttreatment manual massage may enhance the effectiveness of a single cryolipolysis treatment, and that multiple treatments may lead to further improvement.12,13 Finally, we are currently still unaware of the long-term side effects and outcomes of this treatment. The aim of the present review was to give an overview of cryolipolysis

with emphasis on the efficacy (volume reduction), methods, safety, and complications. PATIENTS AND METHODS

Search Strategy, Article Selection, and Data Extraction A systematic review of the MEDLINE and Cochrane databases was performed with the search

algorithm cryolipolysis OR cool sculpting OR fat freezing OR lipocryolysis. Two investigators independently reviewed article titles and abstracts to identify studies that assessed outcomes of cryolipolysis. Selected articles that met these inclusion criteria then underwent full article review by

the two investigators. Additional articles were then identified by manual review of the references of the articles that were initially identified via the primary search. Review papers and animal studies were eliminated. A third investigator reconciled disagreements. The Cohen Kappa coefficient was

calculated to demonstrate the level of agreement between the two initial investigators. The same two investigators performed data extraction independently, and any discrepancies were again reconciled by the third. Table Table11 lists the information extracted from each article.

Table 1. Data Extracted from Reviewed Articles

RESULTS

Search Strategy and Article Selection The primary literature search returned 319 articles (Fig. (Fig.1).1). The references of articles identified in the primary search were reviewed, yielding a total of 37 articles. Review papers and animal studies were eliminated, yielding a final number of 19 articles, including 12 prospective

studies, three retrospective studies, one study with both prospective and retrospective groups, and

three case reports. The Kappa coefficient was calculated at 0.885, indicating very good agreement between the investigators.

Fig. 1. Article search process and results, totaling 19 articles

Efficacy Common treatment areas included the abdomen, brassiere rolls, lumbar rolls, hip rolls/flanks, inner thighs, medial knee, peritrochanteric areas, arms, and ankles (Table (Table2).2). Follow-up length generally ranged from 2 to 6 months, although one study presented case reports on two patients at 2 and 5 years after treatment,14noting persistent reduction at these time points when comparing pretreatment and posttreatment photographs. Objective outcome measures included fat caliper

measurements, ultrasound measurements, and three-dimensional imaging (VECTRA M3; Canfield

Scientific, Inc., Fairfield, N.J.). Every study that evaluated clinical outcomes using these outcome measures noted a significant reduction in fat volume in treatment areas (Table (Table3).3). Although outcomes varied greatly based on treatment site and study design, average reduction in caliper measurement ranged from 14.67 percent to 28.5 percent. Average reduction by ultrasound ranged from 10.3 percent to 25.5 percent (Table (Table3).3). Three studies evaluated lipid levels and liver function tests (Table (Table33).15–17 No significant impact was noted on lipid levels or liver function tests after cryolipolysis treatments in any study.

Table 2. Reported Reduction in Caliper and Imaging Measurements after Cryolipolysis, Organized by Location

Table 3. Study Design, Demographics, Methods, Follow-Up, and Final Outcomes from Reviewed Articles

Subjective assessments included both patient satisfaction rates and investigator assessments. In all cases, high satisfaction rates were noted, as demonstrated by posttreatment patient satisfaction

surveys.13,15,16,18–20 Only one of the reviewed studies used a validated survey to assess patient satisfaction.20 A clinically apparent difference was noted by posttreatment investigator assessments.13,15,16,18,20,21Investigator assessments were based on whether or not there was an appreciable fat reduction. Blinded investigators were able to correctly differentiate between pretreatment and posttreatment images in 89 percent of cases in one study22 and 79 percent of cases in another.19 None of the studies reviewed included investigator assessments that specifically evaluated other factors, such as contour or texture.

The effect of posttreatment massage was evaluated in two studies. Sasaki et al. evaluated 5 minutes of posttreatment massage, noting an average fat reduction of 21.5 percent in treated areas by caliper measurement at 6 months.20 Another study by Boey and Wasilenchuk compared patients receiving 2 minutes of posttreatment manual massage to a control group receiving only the standard cryolipolysis treatment.12 At 2 months after treatment, average fat layer reduction was 68 percent greater on the massaged side (12.6 percent on the nonmassaged side versus 21.0 percent on the massaged side, p = 0.0007). However, at 4 months, average fat layer reduction

was only 44 percent greater on the massaged side (10.3 percent on the nonmassaged side versus

14.9 percent on the massaged side, p = 0.1).12 The effect of multiple treatments has also been evaluated. In one study, patients receiving two treatments in the peritrochanteric area yielded an average fat layer reduction of 28.5 percent, compared with 19.7 percent in patients receiving only one treatment (p = 0.046).23 The effect of multiple treatments was evaluated on love handles and abdomens of patients in another study

demonstrating different outcomes. Although a second treatment yielded a significant decrease in caliper measurements on the abdomen (p = 0.020), a statistically significant difference was not produced with a second treatment on the love handles (p = 0.084) (Table (Table33).13 Histologic outcomes were evaluated in a handful of studies. No evidence of fibrosis was noted in one study.12 Most studies demonstrate an inflammatory response at different stages after cryolipolysis, with inflammatory cell infiltrates peaking at 30 days,12 which led to adipocyte

apoptosis.15 Biopsy specimens of peripheral nerve cells showed no long-term changes in peripheral

nerves, with equal and normal numbers of epidermal nerves.21

Complications Common complications noted after cryolipolysis included erythema, bruising, swelling, sensitivity, and pain (Table (Table4).4). These side effects are generally resolved within a few weeks after treatment. No persistent ulcerations, scarring, paresthesias, hematomas, blistering, bleeding, hyperpigmentation or hypopigmentation, or infections have been described. One isolated case report described paradoxical adipose hyperplasia after cryolipolysis treatment.24

Table 4.

Complications and Complication Rates for Cryolipolysis from Reviewed Articles DISCUSSION

Recently, a surge of novel technologies involving noninvasive, energy-based techniques have been introduced to the market, signaling a potential paradigm shift in fat reduction and body contouring

practices. The major goal of these novel therapies includes volume reduction of tissue, with a possible end point of noninvasive body contouring.25 With more than 450,000 procedures performed thus far, cryolipolysis is becoming one of the most popular alternatives to liposuction for spot reduction of adipose tissue.26 Because of its ease of use and limited adverse effects, this procedure is becoming the leading technology in noninvasive techniques as well. This review sought to explore the efficacy, methods, safety, and complications of cryolipolysis in the current literature.

Although its mechanism is not fully understood, it is believed that vacuum suction with regulated heat extraction impedes blood flow and induces crystallization of the targeted adipose tissue when cryolipolysis is performed.11,27 The temperatures induced in cryolipolysis have no permanent effect on the overlying dermis and epidermis. However, this cold ischemic injury may promote cellular

injury in adipose tissue via cellular edema, reduced Na-K-ATPase activity, reduced adenosine triphosphate, elevated lactic acid levels, and mitochondrial free radical release.20 Another

mechanism proposes that the initial insult of crystallization and cold ischemic injury induced by cryolipolysis is further compounded by ischemia reperfusion injury, causing generation of reactive oxygen species, elevation of cytosolic calcium levels, and activation of apoptotic pathways.20 Ultimately, crystallization and cold ischemic injury of the targeted adipocytes induce apoptosis of these cells and a pronounced inflammatory response, resulting in their eventual removal from the treatment site within the following several weeks.7,11,25Histological studies show that within 3 months, macrophages are mostly responsible for clearing the damaged cells and

debris.26,28

With the removal of the adipocytes internally, there has been concern that cryolipolysis may cause

rising blood lipid levels and elevations in liver enzymes that may put the patient at additional risk,

particularly for cardiovascular parameters. However, multiple studies have demonstrated that cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, aspartate transaminase/alanine transaminase, total bilirubin, albumin, and glucose remained within normal limits during and after cryolipolysis.15–17 With the relatively recent emergence of cryolipolysis, many factors still need to be considered and investigated, including what type of patient would benefit most from this procedure. Ferraro et al.

suggested that patients who require only small or moderate amounts of adipose tissue and cellulite removal would benefit most from cryolipolysis treatment.15 Contraindications to cryolipolysis include cold-induced conditions such as cryoglobulinemia, cold urticaria, and paroxysmal cold hemoglobinuria.29 Cryolipolysis should not be performed in treatment areas with severe varicose veins, dermatitis, or other cutaneous lesions.23,27 Although all studies reviewed showed a fat reduction in every area examined, it is still unknown

what areas are most responsive to cryolipolysis. Various factors may play a role in the degree of fat reduction observed after cryolipolysis. The vascularity, local cytoarchitecture, and metabolic activity of the specific fat depots in question may play a role. Because of the limited size and number of studies evaluating cryolipolysis in clinical populations, it is unclear which treatment sites are most amenable to cryolipolysis. Future comparative outcome studies should be adequately

powered to determine which treatment sites are most suitable for fat reduction with this modality. Because cryolipolysis is still a relatively new procedure, treatment protocols have yet to be

optimized to maximize results. Recent studies have focused on maximizing the reduction of adipose tissue by adjusting treatment protocols. Three studies assessed the theoretical enhanced efficacy with multiple treatments in the same anatomic area and demonstrated that a second successive course of cryolipolysis treatment led to further fat reduction.13,23 It is important to note that although a subsequent treatment leads to further fat reduction, the extent of improvement was not as dramatic as the first treatment. Interestingly, one study demonstrated that a second treatment enhanced fat layer reduction in the abdomen area but not the love handles.13 One hypothesis for

the diminished effect of the second treatment may be that the fat exposed to the second heat extraction is closer to the muscle layer. The vascular supply to the muscle layer may impede the efficiency of heat extraction so that the fat closer to the muscle layer may not reach the intended optimal temperature of 4°C. Another hypothesis is that adipocytes that survived the first treatment have a higher tolerance to cold. Boey and Wasilenchuk evaluated whether the addition of a posttreatment manual massage

enhanced the efficacy of a single cryolipolysis treatment.12 Immediately after treatment, patients received a 2-minute manual massage. This consisted of 1 minute of vigorous kneading of the

treated tissue between the thumb and fingers followed by 1 minute of circular massage of the treated tissue against the patient’s body. To examine the effects of massage on subcutaneous tissue over time, histological analysis was completed through 4 months after treatment. Although the difference at 2 months after treatment was statistically significant, the difference at 4 months after treatment was not. One hypothesis for potentially improved efficacy with manual massage is

that manual massage caused an additional mechanism of damage to the targeted adipose tissue immediately after treatment, perhaps from tissue-reperfusion injury. Histological analysis revealed no evidence of necrosis or fibrosis resulting from the massage, thus showing posttreatment manual massage to be a safe and effective method to further reduce the fat layer after cryolipolysis. Sasaki et al. described cryolipolysis with 5 minutes of posttreatment integrated preset mechanical massage using the device applicator with excellent outcomes.20 A low profile of adverse effects is one of the main advantages with cryolipolysis, especially when

compared with more invasive measures. Only mild, short-term side effects, such as erythema, bruising, changes in sensation, and pain, were reported in the studies reviewed. Erythema was noted in multiple studies immediately after the treatment and subsided within a week.18–20 This is most likely because of the strength of the vacuum and the temperature at which the tissue is kept for extended durations and poses no threat to the patients. Swelling and bruising of the area were

shown to a slightly lesser extent than erythema, but are believed to be because of the same

processes. These complications also subsided shortly after.13,16,18,19Hypersensitivity and hyposensitivity were shown in studies but were never debilitating nor persisted beyond 1 month. Coleman et al. demonstrated that patients exhibiting reduction in sensation recovered normal sensation in 3.6 weeks.21 This study also showed that a nerve biopsy taken at 3 months after treatment showed no long-term changes to nerve fibers, concluding that temperature and duration of cryolipolysis have no permanent effect on nervous tissue.21 In one study, pain during the procedure was generally nonexistent to tolerable 96 percent of the time.18

Rare side effects that have been described include vasovagal reaction18 and paradoxical adipose hyperplasia.24 Jalian et al. estimated an incidence of 0.0051 percent, or approximately one in 20,000, for paradoxical adipose hyperplasia.24Affected patients exhibit fat loss after therapy and

then develop a large, demarcated, tender fat mass at the site 2 to 3 months later. The

hypothesized pathogenesis includes recruitment of stem cells and hypertrophy of existing fat cells

in the area.24 However, compared with traditional liposuction side effects, cryolipolysis poses a minor threat to patients, with a very low incidence of complications. Of note, the reviewed studies used a variety of different modalities to determine the degree of fat reduction after cryolipolysis treatments. Various studies have compared caliper, ultrasound, three-dimensional imaging, and manual tape measurements. Although no single study has compared all of these modalities, the available data suggest that these techniques correlate well with one

another.30,31Studies that used more than one of these modalities to assess outcomes after cryolipolysis also demonstrated that these measurements corresponded well.19,20 A drawback of this work is the limited number of high-quality, prospective, randomized clinical studies. Cryolipolysis was first described in 2007, and although its popularity has increased dramatically, the available literature remains limited. Tremendous variability exists in study design, machinery used, and outcome measures. Because of this lack of uniformity, comparing effect size

becomes challenging, and the value of a meta-analysis of the available data is limited. The variations in the available studies make it difficult to control for any bias present in the discussed studies. Despite these limitations, clinical data demonstrate consistent fat reduction in treated subjects, which supports the clinical utility of this technique. Go to:

CONCLUSIONS

This study presents the first systematic review of the available data on cryolipolysis. Although the body of evidence is limited because of the nascence of this procedure, cryolipolysis is a promising procedure for nonsurgical fat reduction and body contouring. While the outcomes of cryolipolysis are rather modest, this technology is well suited for patients who desire nonsurgical spot reduction at modestly sized adiposities. Cryolipolysis appeals to both men and women and is an effective means by which new patients can be drawn to the aesthetic surgery practice.32Although the

specific mechanism of cryolipolysis has not been completely elucidated, this procedure appears to be effective and safe in the short term, with a limited side effect profile. Posttreatment manual massage has the potential to improve the efficacy of cryolipolysis. Multiple treatments in the same anatomic area may lead to further fat reduction, although the efficacy of cryolipolysis appears to be attenuated with successive treatments. The efficacy of this technique in areas that have been treated previously with liposuction remains to be studied. Future studies should address which treatment sites are most amenable to cryolipolysis to enhance treatment stratification for body

contouring patients and should evaluate a potential role for cryolipolysis in skin tightening and the treatment of cellulite. Go to:

Footnotes

Disclosure: Gordon H. Sasaki, M.D., is a consultant for ZELTIQ Aesthetics, Inc. (Pleasanton,

Calif.). The other authors have no financial interest to declare in relation to any of the products or devices mentioned in this article. No funding was used for the preparation of this article.

REFERENCES

1. Berntorp E, Berntorp K, Brorson H, Frick K. Liposuction in Dercum’s disease: Impact on

haemostatic factors associated with cardiovascular disease and insulin sensitivity. J Intern Med. 1998;243:197–201. [PubMed] 2. González-Ortiz M, Robles-Cervantes JA, Cárdenas-Camarena L, Bustos-Saldaña R, Martínez-Abundis E. The effects of surgically removing subcutaneous fat on the metabolic profile and insulin sensitivity in obese women after large-volume liposuction treatment. Horm Metab Res. 2002;34:446–449. [PubMed]

3. Rao RB, Ely SF, Hoffman RS. Deaths related to liposuction. N Engl J Med.1999;340:1471–1475. [PubMed] 4. Cardenas-Camarena L. Lipoaspiration and its complications: A safe operation.Plast Reconstr Surg. 2003;112:1435–1441; discussion 1442-1433. [PubMed]

5. Thomas M, Menon H, D’Silva J. Surgical complications of lipoplasty: Management and preventive strategies. J Plast Reconstr Aesthet Surg.2010;63:1338–1343. [PubMed] 6. Fischer JP, Wes AM, Serletti JM, Kovach SJ. Complications in body contouring procedures: An

analysis of 1797 patients from the 2005 to 2010 American College of Surgeons National Surgical Quality Improvement Program databases. Plast Reconstr Surg. 2013;132:1411–1420. [PubMed] 7. Mulholland RS, Paul MD, Chalfoun C. Noninvasive body contouring with radiofrequency, ultrasound, cryolipolysis, and low-level laser therapy. Clin Plast Surg. 2011;38:503–520, vii. [PubMed] 8. Duncan WC, Freeman RG, Heaton CL. Cold panniculitis. Arch Dermatol.1966;94:722–724. [PubMed]

9. Epstein EH, Jr, Oren ME. Popsicle panniculitis. N Engl J Med. 1970;282:966–967. [PubMed]

10. Rotman H. Cold panniculitis in children: Adiponecrosis E frigore of Haxthausen. Arch

Dermatol. 1966;94:720–721. [PubMed] 11. 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;40:595–604. [PubMed] 12. Boey GE, Wasilenchuk JL. Enhanced clinical outcome with manual massage following cryolipolysis treatment: A 4-month study of safety and efficacy. Lasers Surg Med. 2014;46:20–

26. [PMC free article] [PubMed] 13. Shek SY, Chan NP, Chan HH. Non-invasive cryolipolysis for body contouring in Chinese: A first commercial experience. Lasers Surg Med. 2012;44:125–130.[PubMed] 14. Bernstein EF. Longitudinal evaluation of cryolipolysis efficacy: Two case studies. J Cosmet Dermatol. 2013;12:149–152. [PubMed] 15. Ferraro GA, De Francesco F, Cataldo C, Rossano F, Nicoletti G, D’Andrea F. Synergistic effects

of cryolipolysis and shock waves for noninvasive body contouring. Aesthetic Plast Surg. 2012;36:666–679. [PubMed] 16. Lee KR. Clinical efficacy of fat reduction on the thigh of Korean women through cryolipolysis. J Obes Weight Loss. 2013;3:1–5. 17. Riopelle JT, Kovach B. Lipid and liver function effects of the cryolipolysis procedure in a study of

male love handle reduction. Lasers Surg Med. 2009;82 18. Dierickx CC, Mazer JM, Sand M, Koenig S, Arigon V. Safety, tolerance, and patient satisfaction

with noninvasive cryolipolysis. Dermatol Surg. 2013;39:1209–1216. [PubMed] 19. 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;46:75–80. [PMC free article] [PubMed] 20. Sasaki GH, Abelev N, Tevez-Ortiz A. Noninvasive selective cryolipolysis and reperfusion recovery for localized natural fat reduction and contouring. Aesthet Surg J. 2014;34:420–431. [PubMed]

21. 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;33:482–488. [PubMed] 22. Kaminer MW, Newman J, Allison J. Visible cosmetic improvement with cryolipolysis: Photographic evidence. Paper presented at: 2009 Annual Meeting of the American Society for Dermatologic Surgery; October 1-4, 2009; Phoenix, Ariz.

23. Pinto HR, Garcia-Cruz E, Melamed GE. A study to evaluate the action of lipocryolysis. Cryo Letters. 2012;33:177–181. [PubMed]

24. Jalian HR, Avram MM, Garibyan L, Mihm MC, Anderson RR. Paradoxical adipose hyperplasia after cryolipolysis. JAMA Dermatol. 2014;150:317–319.[PMC free article] [PubMed] 25. Dobke MK, Hitchcock T, Misell L, Sasaki GH. Tissue restructuring by energy-based surgical tools. Clin Plast Surg. 2012;39:399–408. [PubMed] 26. Jalian HR, Avram MM. Cryolipolysis: A historical perspective and current clinical practice. Semin

Cutan Med Surg. 2013;32:31–34. [PubMed] 27. Pinto H, Arredondo E, Ricart-Jane D. Evaluation of adipocytic changes after a simil-lipocryolysis stimulus. Cryo Letters. 2013;34:100–105. [PubMed] 28. Preciado JA, Allison JW. The effect of cold exposure on adipocytes: Examining a novel method for the non-invasive removal of fat. Cryobiology.2008;57:327. 29. Avram MM, Harry RS. Cryolipolysis for subcutaneous fat layer reduction.Lasers Surg Med. 2009;41:703–708. [PubMed]

30. Cohen SR, Weiss ET, Brightman LA, et al. Quantitation of the results of abdominal liposuction. Aesthet Surg J. 2012;32:593–600. [PubMed] 31. Selkow NM, Pietrosimone BG, Saliba SA. Subcutaneous thigh fat assessment: A comparison of skinfold calipers and ultrasound imaging. J Athl Train.2011;46:50–54. [PMC free article] [PubMed] 32. Stevens WG, Pietrzak LK, Spring MA. Broad overview of a clinical and commercial experience

with CoolSculpting. Aesthet Surg J. 2013;33:835–846.[PubMed]

33. Brightman L, Geronemus R. Can second treatment enhance clinical results in cryolipolysis? Cosmetic Derm. 2011;24:85–88. 34. Dover J, Burns J, Coleman S, et al. A prospective clinical study of noninvasive cryolypolysis for subcutaneous fat layer reduction—Interim report of available subject data. Presented at the Annual Meeting of the American Society for Laser Medicine and Surgery; April 2009; National Harbor, Md. 35. Klein KB, Zelickson B, Riopelle JG, et al. Non-invasive cryolipolysis for subcutaneous fat reduction does not affect serum lipid levels or liver function tests.Lasers Surg Med. 2009;41:785–

790. [PubMed]

36. Rosales-Berber IA, Diliz-Perez E. Controlled cooling of subcutaneous fat for body reshaping.

Presented at the 15th World Congress of the International Confederation for Plastic, Reconstructive

and Aesthetic Surgery; 2009; New Delhi, India. 37. Dover J, Kaminer M, Teahan M, Barrett L. Patient satisfaction at 2 and 6 months after a single non-invasive cryolipolysis treatment for subcutaneous fat layer reduction. Lasers Surg Med. 2011;43:968.

Aesthet Surg J. 2015 Sep;35(7):830-836. Epub 2015 Jun 2. The Safety and Efficacy of Cryolipolysis: A Systematic Review of Available Literature Derrick CD, Shridharani SM, Broyles JM BACKGROUND: In the past decade, the practice of body contouring using cryolipolysis has increased tremendously.

While numerous anecdotal reports extol the efficacy of this product, the majority of these studies are small, retrospective case-series that lack control groups. OBJECTIVE: The authors aim to systematically review available literature to better illustrate the efficacy and safety of this new procedure.

METHODS: A systematic literature review performed using MEDLINE, Embase, PubMed, and Cochrane

databases identified all published studies evaluating cryolipolysis for body contouring. RESULTS: A total of 34 articles up to February 2015 were identified. Nineteen articles matched the selection criteria and were included in the analysis. Sixteen were evaluated in the final analysis. A total of 1445 patients had reportable data for analysis of the safety profile. Twelve patients (0.82%) reported complications with the most common being diminished sensation lasting greater than 4 weeks. An aggregate total of 295 patients had objective data for evaluation of tissue reduction. The

mean time from procedure to objective outcome evaluation was 3.83 months. The mean reduction of subcutaneous tissue was 19.55% with respect to a designated control site. CONCLUSIONS: Selective cryolipolysis appears, at short-term follow-up, to reliably decrease subcutaneous tissue deposits. Reported complications are uncommon and appear to resolve without intervention. Future studies should aim to optimize patient selection and treatment characteristics while obtaining long-

term follow-up data. LEVEL OF EVIDENCE:

4 Therapeutic. J Eur Acad Dermatol Venereol. 2015 Sep;29(9):1679-88. Epub 2015 Feb 9 Non-invasive subcutaneous fat reduction: a review

Kennedy J, Verne S, Griffith R, Falto-Aizpurua L, Nouri K The risks, financial costs and lengthy downtime associated with surgical procedures for fat reduction have led to the development of a number of non-invasive techniques. Non-invasive body contouring now represents the fastest growing area of aesthetic medicine. There are currently four leading non-invasive techniques for reducing localized subcutaneous adipose tissue: low-level laser therapy (LLLT), cryolipolysis, radio frequency (RF) and high-intensity focused ultrasound (HIFU).

To review and compare leading techniques and clinical outcomes of non-invasive subcutaneous fat reduction. The terms 'non-invasive', 'low-level laser', 'cryolipolysis', 'ultrasound' and 'radio frequency' were combined with 'lipolysis', 'fat reduction' or 'body contour' during separate searches in the PubMed database. We identified 31 studies (27 prospective clinical studies and four retrospective chart reviews) with a total of 2937 patients that had been treated with LLLT

(n = 1114), cryolipolysis (n = 706), HIFU (n = 843) or RF (n = 116) or other techniques (n = 158)

for fat reduction or body contouring. A majority of these patients experienced significant and satisfying results without any serious adverse effects. The studies investigating these devices have all varied in treatment regimen, body locations, follow-up times or outcome operationalization. Each technique differs in offered advantages and severity of adverse effects. However, multiple non-invasive devices are safe and effective for circumferential reduction in local fat tissue by 2 cm or more across the abdomen, hips and thighs. Results are consistent and reproducible for each device and none are associated with any serious or permanent adverse effects.