Cryolipolysis: A promising nonsurgical technique for localized fat reduction

Cryolipolysis, also known as fat freezing, is a nonsurgical technique specialized for localized fat reduction. Utilizing targeted cold exposure to adipose tissue, cryolipolysis devices induce cellular apoptosis in adipocytes while sparing surrounding tissues, resulting in the selective disruption of fat cells and subsequent removal of damaged cells by macrophages. A reduction of the fat layer produces a noninvasive cosmetic benefit that provides an accessible alternative to liposuction. Objective and subjective measurements have demonstrated significant reduction in fat volume and high patient satisfaction rates. Cryolipolysis has been proven to be safe with minimal adverse effects. However, further research is needed to fully understand the mechanism of cryolipolysis and its efficacy in different treatment areas. This paper aims to provide a comprehensive overview of cryolipolysis, including its mechanism of action, indications, contraindications, adverse effects, results and outcomes, safety profile, and areas requiring further research.


| INTRODUC TI ON
Body contouring has become increasingly popular in the field of dermatologic surgery, as it offers a noninvasive alternative to major surgeries such as liposuction.The American Society for Dermatologic Surgery reports that in the year 2019, 25% of all 1 000 000 body contouring procedures were cryolipolysis procedures. 1 Cryolipolysis, also known as fat freezing, is a nonsurgical technique for localized fat reduction. 2The first report of cold sensitivity in adipose tissue was in 1902 by Hovhsinger, who observed and described nodules under the chin of children that he believed to be an "acute freezing reaction." 3Following this observation, Haxuthausen published a case series of four children with a similar phenomenon of nodules that were worsened by cold weather and named it "adiponecrosis e frigore." 3 In 1970, Epstein and Oren founded the term "popsicle panniculitis" based on the presence of a red indurated nodule followed by fat necrosis in an infant's cheek who had been sucking on a popsicle. 3yolipolysis was thus developed in 2007 using this idea of cold-induced panniculitis, in which lipid-rich tissues are more susceptible to cold injury than surrounding water-rich tissue. 4For this reason, cryolipolysis primarily targets the physical properties of fat that differentiate from the overlying epidermis and dermis, resulting in the selective disruption of fat cells that spares its surrounding tissues. 4Since 2007, there have been several devices utilizing cryolipolysis for body contouring purposes in cosmetic dermatology, including CoolSculpting®, CoolContour, Zeltiq, and CoolTech.

| ME THODS
Our primary phase of literature review consisted of a PubMed search seeking all published literature around cryolipolysis.We employed a review approach that examined over 20 papers with the key search terms of "cryolipolysis," "fat-freezing," "cosmetic dermatology," "body contouring," "adverse effects," "adipocyte apoptosis," "Coolsculpting®," and "localized fat reduction."The next phase of our literature review involved compiling the papers that defined our key terms and extracting information from each to present a consolidated review of different aspects of cryolipolysis.We wanted to understand the proposed mechanisms behind cryolipolysis and its effectiveness in achieving body contouring noninvasively, while also exploring its safety profile.We also explored papers that discussed the effect of cryolipolysis on skin tightening and collagen remodeling.We finally reviewed the indications, contraindications, and adverse effects of cryolipolysis to provide a comprehensive literature review.

| Mechanism of action
One of the earliest cases of cold panniculitis was discussed by Duncan et al. in a case study regarding a very young boy who developed indurated nodules in his cheeks after sucking on a popsicle for an extended amount of time. 4,5Intrigued, researchers took a 4 mm punch biopsy after applying ice to the patient's buttock and thigh, and identified a infiltration of histocytes most intensely present at the dermal-subdermal junction. 5This reaction intensified at 48 and 72 h after removal of the ice. 5At this point, researchers noticed that some of the adipose tissues had burst, lipid aggregated, and a more intense histocyte reaction presented. 5To the researcher's surprise, this reaction subsided completely 2 weeks following the boy's exposure.Duncan hypothesized that the boy had a sensitivity to cold, that he later grew out of once he surpassed 18 months of age. 5 This understanding of cold panniculitis laid the foundation for the development of cryolipolysis and localized fat reduction. 6yolipolysis utilizes external thermal devices to lower the temperature of the skin and underlying adipose tissue to achieve selective tissue apoptosis. 7The temperature of the device typically ranges from −3 to 6°C, which is cold enough to induce cellular changes, but not cold enough to cause permanent damage to the skin. 7pending on the device used, an applicator is applied to a localized area of adipose tissue and set at a specific cooling temperature for a preset period of time.The skin transitions from its body temperature to a supercooled, unfrozen state across the dermal layer for the duration of the treatment.The exposure to cold temperatures induces crystallization of lipids in the adipose layer, triggering an apoptotic cascade that ultimately results in the gradual resorption of these damaged cells. 7,8ere have been several proposed mechanisms attempting to explain the cellular processes leading up to adipocyte apoptosis. 9e hypothesis suggests that the cold-ischemic injury inflicted upon the adipose tissue during cryolipolysis triggers a cascade a positive impact on skin elasticity and tightening.Further investigation of this mechanism is needed to provide a better understanding of its potential in achieving optimal cosmetic outcomes for patients.By combining the benefits of fat reduction and skin tightening, cryolipolysis has the potential to offer a comprehensive nonsurgical solution for body contouring.
adverse effect, cool sculpting, cosmetic dermatology, cryolipolysis of cellular damage, characterized by cellular edema, diminished Na-K-ATPase activity, reduced adenosine triphosphate levels, heightened lactic acid concentrations, and the release of mitochondrial free radicals. 10Another proposed mechanism suggests that the cold-ischemic injury induced by cryolipolysis is further compounded by ischemia reperfusion injury, leading to the generation of reactive oxygen species, an elevation in cytosolic calcium levels, and an increased activation of apoptosis. 10Ultimately, the adipose layer experiences an inflammatory response as a result of the cold injury, causing the adipocytes in the treated area to undergo apoptosis. 10This allows for targeted destruction of the adipocytes while sparing surrounding tissues including the skin, nerves, vessels, and muscles. 11Over the course of the following months, these damaged cells are engulfed and eliminated by macrophages, contributing to the gradual reduction of fat in the treated area. 10

| Indications
Cryolipolysis devices have been specifically designed for the targeted reduction of adipose tissue in localized areas. 12While several devices exist, one of the most renowned and widely used cryolipolysis devices is the CoolSculpting® system.CoolSculpting® is FDA cleared to treat the submental area, under the jawline, the upper arms, lumbar rolls, brassiere rolls, flank area, abdomen, thighs and under the buttocks. 12Ferraro et al. explains that cryolipolysis procedures cater to a diverse patient demographic, encompassing both men and women. 13This treatment option is particularly suitable for individuals who only require small to moderate amounts of adipose tissue and cellulite removal. 13Moreover, cryolipolysis appeals to those individuals who are seeking body contouring but wish to avoid a lengthy recovery period associated with invasive procedures.Furthermore, cryolipolysis is an attractive solution for individuals who have concerns about potential adverse reactions to anesthesia.It provides a safe and effective method for targeting stubborn pockets of unwanted fat without the need for general anesthesia. 13is aspect makes it an ideal choice for those who are new to the realm of aesthetic surgery and are seeking a less intimidating approach to body contouring.

| Contraindications
While cryolipolysis has become increasingly accessible to a wide range of patients, it is important to acknowledge that cryolipolysis is not a suitable option for all patients.There are certain medical conditions and circumstances that may contraindicate the use of fatfreezing procedures.Patients with a history of cold-induced conditions, such as cryoglobulinemia, cold urticaria, and paroxysmal cold hemoglobinuria, may not be suitable candidates for cryolipolysis. 14ese conditions involve abnormal reactions to cold temperatures, and subjecting the body to cryolipolysis may exacerbate their symptoms.
In addition, cryolipolysis should not be performed on treatment areas affected by severe varicose veins, dermatitis, or other cutaneous lesions. 12These conditions can compromise the integrity of the skin and increase the risk of complications during cryolipolysis.Furthermore, patients who exhibit poor blood circulation in the specific area to be treated may also be contraindicated for cryolipolysis. 12Conditions such as Raynaud's disease, pernio, or chilblains can impair blood flow and compromise the body's ability to respond to the cold temperatures involved in cryolipolysis. 12In such cases, alternative treatment options should be explored to ensure the safety and effectiveness of the procedure.
While cryolipolysis has gained popularity as a noninvasive fat reduction procedure, it is important to recognize that it may not be suitable for everyone.Health care professionals play a crucial role in assessing each patient's individual circumstances and medical history to ensure the appropriateness and safety of cryolipolysis as a treatment option.

| Adverse effects
Since being FDA cleared in 2010, cryolipolysis has gained significant traction as a noninvasive procedure, lauded for its favorable safety profile and promising outcomes.While cryolipolysis is generally considered safe, it is crucial to acknowledge that complications can arise, although infrequently. 15These complications encompass a range of adverse effects, including rather mild symptoms including bruising, swelling, redness, pain or discomfort, and skin discoloration which often resolve spontaneously without intervention, to much more serious ones. 15ld burns, previously considered an unlikely risk of cryolipolysis, have been reported. 12,14,16case series presented by Barry et al. discussed eight female patients and two male patients between the years 2012 and 2020 who experienced cold burns on various body parts, including the abdomen, limbs, neck, flank, and buttocks. 16These burns ranged from superficial partial thickness to full thickness, necessitating inpatient management and even skin grafts for two patients. 16Although rare, severe frostbite has also been reported as an adverse effect of cryolipolysis. 14One case study presented a 61-year-old woman who developed full-thickness frostbite on her abdomen after undergoing cryolipolysis at a nonmedical facility. 13,14The patient experienced significant pain following treatment, and was required to be hospitalized for 2 days. 13,14It is crucial to emphasize that the device used in this case was not FDAapproved, underscoring the importance of seeking treatment from reputable and regulated establishments.
Another potential adverse effect of cryolipolysis is the development of a hernia. 17A hernia occurs when an organ or tissue bulges through a weak area in the abdomen or abdominal wall lining.Cryolipolysis treatments in or around preexisting hernias or structurally weak regions, such as surgical scars or the separation between stomach muscles (commonly observed after pregnancy), can exacerbate hernia formation. 17Patients with a history of hernias are contraindicated for cryolipolysis to mitigate this risk altogether.
One of the most concerning and common adverse effects of cryolipolysis is paradoxical adipose hyperplasia (PAH). 11PAH is characterized by the counterintuitive growth of fatty tissues in the treated area, rather than their reduction. 11This condition typically develops two to five months after cryolipolysis and may necessitate surgical intervention for removal. 11Jalian et.al presented a 41 years old male who underwent a single cycle of cryolipolysis and developed a large mass on his abdomen 1-2 months following his treatment. 11,18This patient had more pronounced adipose tissue at the lateral edges of the handpiece, and reported the lesion being firm but not hard, and non tender. 11,18Another patient who presented as a 56 years old female with no significant medical history underwent one cycle of cryolipolysis and developed a similar mass on her abdomen. 11,18Upon surgically removing the mass with an abdominoplasty and sending the specimen to pathology, Jalian et al. reports areas with disorganized adipocytes in various shapes and sizes. 11,18lian et al. also notes that there was an increase in vascularity within the adipose layer of the treated area, but spared the epidermis and dermis, indicating a localized fat reduction mechanism that is specific to adipose tissue. 11,18e underlying mechanism behind PAH remains elusive; however, some have hypothesized that this phenomenon could happen due to hypertrophy of preexisting adipocytes, recruitment of resident circulation, and/or stem cell populations, changes in the expression of receptors or soluble factors associated with adipocyte mechanism, reduction in sympathetic innervation, and hypoxic injury. 11,18Researchers have also identified certain trends in patient populations prone to experiencing PAH, including a higher incidence among men, Hispanic demographics, treatment of the abdominal region, and the use of larger handpieces. 11Additionally, there may be a genetic component, as evidenced by a study involving twins who underwent cryolipolysis at different facilities and both developed PAH. 11,18ports of serious long-term adverse effects stemming from cryolipolysis treatments continue to emerge.Other adverse effects include cold panniculitis, transient loss of sensation, 19 fat necrosis, clots, systemic inflammation, fat embolism, and lipoma. 6,12While cryolipolysis has been deemed to have a low-risk safety profile, it is essential to be aware of the potential adverse effects associated with this procedure.Health care professionals and patients must weigh the potential risks and benefits before undergoing cryolipolysis treatment, and it is imperative to continue reporting complications to enhance our understanding and make informed decisions.

| RE SULTS AND OUTCOME S
Following cryolipolysis, patients may not immediately notice visible changes in their treated area.While some patients may notice a visible change as early as three weeks after treatment, the most significant benefits are usually observed between three to six months post-treatment. 20This gradual process allows the body to naturally eliminate the damaged fat cells and reshape the treated area.The extent of adipose reduction achieved through cryolipolysis can vary from patient to patient.Factors such as individual goals, treatment area, and amount of unwanted fat to be treated all play a role in determining the overall outcome.On average, patients can expect a reduction of fat ranging from 10% to 25% per treatment. 21asuring the outcomes of cryolipolysis treatments is another variable factor among published studies.Researchers employ both objective and subjective measurements to quantify the effectiveness of cryolipolysis treatments. 21,22Objective measurements include fat caliper measurements, ultrasound imaging, 2D and 3D imaging, and histology, 4,21 while subjective measurements include subject satisfaction surveys and investigator assessments. 2rly preclinical trials first demonstrated the efficacy of cryolipolysis in reducing localized adiposity through subjective and objective measurements. 2One of the earliest studies showed improvement of the flank, or "love handle," region following cryolipolysis in 32 subjects. 2Of those 32 subjects, 10 subjects underwent ultrasonography which demonstrated an average reduction of fatlayer thickness of 22.4% at 4 months posttreatment. 2 A more subjective measure confirmed these findings by demonstrating an 82% accuracy rate among three blinded physician investigators who were tasked with differentiating between pretreatment and posttreatment sites treated with cryolipolysis. 2,23These evidence-based improvements displayed the efficacy of cryolipolysis in fat reduction, which lead to its FDA clearance for the treatment of flanks in 2010, followed by clearance for the abdomen in 2012. 3bsequent to FDA clearance, several clinical studies were conducted and published that further substantiate the efficacy of cryolipolysis.In one study, subjects treated with two sessions of cryolipolysis in the petrochanteric area displayed an average reduction in caliper measurement ranging from 14.67% to 28.5%. 22This was further supported by ultrasound measurements that showed fat reduction ranging from 10.3% to 25.5%. 22Another study focused on the submental region and involved 14 participants (12 women, 2 men). 21Three-dimensional imaging demonstrated a mean fat reduction of 2.3 mm after two cryolipolysis treatments lasting 45 min each. 21more recent study evaluated 30 female participants after one treatment of Coolsculpting, using ultrasound assessment to measure fat layer thickness and contour. 24They demonstrated that 6 months after their treatment, the mean abdominal fat layer thickness reduction was 46.6%, and measured mean contour was significantly reduced from 84.3, 99.2, 90.6, and 97.1 cm to 81.0, 93.6, 85.8, and 92.2 cm in the infracostal, supraumbilical, umbilical, and ischiopubic regions, respectively. 24The researchers also looked at their ultrasound data more qualitatively and highlighted the fact that there was an appearance of numerous bands of ordered and structured collagen fibers, indicating a potential skin remodeling and/or tightening result of cryolipolysis. 24Overall, these clinical studies provide compelling evidence that cryolipolysis leads to reductions in subcutaneous fat while preserving the surrounding tissues.

| Skin tightening
Although cryolipolysis treatments have proven to be effective in reducing overall fat, there have also been numerous reports highlighting the enhanced skin appearance in the treated area. 20,21,25 a study of bilateral submental cryolipolysis, 14 participants were treated with the CoolSculpting CoolMini® applicator for two treatments at 6 weeks apart, each lasting 60 min each. 21Researchers utilized several different measurements to quantify fat reduction in the treated area including participant satisfaction surveys, caliper measurement, 2D photographic evaluation, and 3D image evaluation. 21ile 3D image analysis showed a statistically significant average fat layer reduction of 4.8 cm 3 , the 3D image analysis also allowed researchers to assess the skin surface area reduction of the treated area as well. 21The image analysis demonstrated a mean surface area reduction of 1.29 cm 2 of 47.09 cm 2 , or an overall 2.7% reduction, which they hypothesized to be a result of skin tightening as an outcome of cryolipolysis. 21itially, Stevens hypothesized that the clinical observation of improved skin laxity and quality was due to dermal thickening following treatment, rather than due to skin tightening itself. 20Researchers reasoned that thickening of the dermis potentially caused by stimulated collagen production, new elastin formation, fibrosis and tissue compaction would result in an improvement in thin, crepey skin. 20evens investigated this mechanism further by measuring key biomarkers located in the skin after one treatment of Coolsculpting® to the abdomen for 35 min at about −11°C, followed by a 2 min massage of the treated area. 20Using a sample size of 7 subjects, a sample was collected from both the treated side of the abdomen and the untreated side of each subject, which were then analyzed using RNA-sequencing, RNA in-situ hybridization (RNA-ISH), immunohistochemistry (IHC), and heat map imaging. 20Researchers found that gene expression in the treated area displayed an upregulation of specific collagen mRNAs COL1A1, COL1A2, and COL3A1 after 3, 10, and 24 days in comparison to the untreated area. 20These collagen mRNAs are primarily responsible for skin stiffness and strength. 20This finding is further supported by their RNA-ISH analysis of COL1A1, which demonstrated increased COL1A1 expression throughout the dermal layer following cryolipolysis treatment. 20C analysis was also used to quantify transforming growth factor beta (TGF-β), heat shock protein 47 (HSP47), Procollagen Type I, and Tropoelastin.TGF-β, a key player in stimulating fibroblast proliferation, wound healing and remodeling, and collagen production, displayed a 2.91-fold increase in cryolipolysis treated tissue compared to the untreated tissue. 20HSP47, specifically responsible for collagen folding, assembly and transport, showed a 1.54-fold increase in treated tissue. 20Procollagen Type I, which interacts transiently with HSP47 to properly fold and form collagen, displayed a 3.62-fold increase, and lastly, tropoelastin, the soluble precursor to the elastin molecule, displayed a 1.57-fold increase in treated tissue compared to the control. 20is molecular and immunohistochemical analysis following cryolipolysis treatment represents a pioneering study that provides evidence supporting the occurrence of at least some degree of dermal remodeling following cryolipolysis.Stevens suggests that due to the significant induction of molecular markers for Type I collagen found in the dermis after cryolipolysis, TGF-β-fibroblast mediated neocollagenesis could play a role in the improvement of skin quality following cryolipolysis. 20This proposed mechanism sheds light on future treatment alternatives for conditions such as cellulite, which require a more comprehensive aesthetic approach to simultaneously enhance skin quality and reduce fat deposition.

| Sequential treatments
Multiple cryolipolysis treatments may lead to further improvement in fat reduction than a single treatment would alone.In one case study, a 32-year-old male underwent two treatments of CoolSculpting® on the flank, with 2 months in between treatments. 26The subject's initial circumferential measurement was 97 cm at baseline. 26Two months following his first treatment, this measurement was measured at 96.4 cm, and then 94.6 cm 5 months after the second treatment.Overall, this subject had a 2.4 cm reduction following two treatments of cryolipolysis. 26Following this observation, a larger study conducted on the pertrochanteric area showed that patients who received two treatments of cryolipolysis experienced a 28.5% fat reduction, compared to 19.7% in those who received only one treatment. 27However, it is important to note that some studies have shown that the reduction of fat in the second treatment is not as dramatic as the first one. 27ese findings suggest that multiple cryolipolysis treatments can indeed lead to further improvement in fat reduction compared to a single treatment.The case study of the 32-year-old male who underwent two treatments on the flank demonstrated a gradual reduction in circumferential measurement over time.This indicates a potential continued reduction in fat volume following each treatment.While the mechanism remains unclear, the discrepancy has been proposed to be due to either higher cold tolerance in surviving adipocytes from the first treatment or the failure of remaining fat to reach the optimal temperature of 4°C due to its proximity to the vasculature of the muscle layer. 27Further studies are needed to better understand the mechanisms behind the enhanced fat reduction observed with multiple cryolipolysis treatments.

| CON CLUS ION
As minimally invasive body contouring procedures become more accessible to the public, the demand for safe and effective devices will continue to rise.Experts predict a 14.02% annual growth