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State-of-the-art treatment modalities for cellulite a comprehensive review
A COMPREHENSIVE REVIEW
SACHIN M. SHRIDHARANI, MD, FACS, Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University – St. Louis, School of Medicine, St. Louis, MO; LUXURGERY, New York, NY; JOSHUA KOHAN, BA, The Larner College of Medicine at the University of Vermont, Burlington, Vermont
email: sms@luxurgery.com
KEYWORDS Cellulite, subcision, acoustic subcision, focal fibrous septa release, collagenase
Sachin M. Shridharani, MD, FACS, and Joshua Kohan, BA, evaluate the evidence for three subcision treatments aimed at reducing the appearance of cellulite
ABSTRACT Background: Cellulite is a multifactorial condition characterised by a dimpled, ‘orange peel’ appearance of the skin. While the aetiology of cellulite has not yet been entirely elucidated, subcision treatments targeting fibrous septae have demonstrated efficacy and continue to be the mainstay of treatment. Objectives: To evaluate the evidence for three novel subcision treatments: controlled focal subcision, acoustic subcision, and enzymatic subcision, and provide physicians and practitioners with an overview of studies examining these therapeutic options. Methods: For enzymatic subcision, peer-reviewed articles containing data on the efficacy of cellulite treatments from in vivo human studies were considered. In total, seven articles written in English were analysed for the following information: therapeutic intervention utilised, presence of a control group, randomisation, blinding, sample size, description of statistical methods, results, and level of evidence and statistical power. However, of the seven articles, three randomised control trials (RCTs) were suitable for review. Clinical data on controlled focal subcision and acoustic subcision were obtained directly from the manufacturers. Conclusion: The advent of new subcision-based treatments is an exciting development for the treatment of cellulite. The studies reviewed suggest that these new treatments are safe and efficacious. Of the three approaches, enzymatic subcision has robustly designed RCTs that demonstrate efficacy. The clinical data for acoustic and controlled focal subcision modalities remains limited and warrants further investigation through future research.
CELLULITE IS A MULTIFACTORIAL condition characterised by a dimpled, ‘orange peel’ appearance of the skin and is associated with histologic changes in the dermis, adipose tissue, and fibrous septae1. The aetiology of cellulite has not yet been fully elucidated; however, the efficacy of treatment strategies targeting fibrous septae suggests that these structures play a significant role in its development1 .
Estimates suggest that cellulite affects approximately 80–90% of post-pubertal women of all races2. No direct associations with morbidity or mortality have been identified, leading to the consideration of cellulite as a secondary gender-related characteristic of females rather than a disease process or pathological state. However, aesthetic concerns remain closely related to physical and psychological well-being3. Idealised, retouched photos on social media alter the human perception and standards of beauty while simultaneously underestimating the true incidence of cellulite in the public consciousness2–3. In regions of the world where there is more frequent body exposure, up to 80% of individuals have reported feeling pressure to seek cellulite treatment4. These treatments have targeted some combination of adipose tissue, dermis, and fibrous septae, with varying degrees of success1 .
This review will evaluate the evidence for three novel subcision treatments aimed at reducing the appearance of cellulite by targeting fibrous septae. These treatments are controlled focal subcision (Avéli™, Revelle Aesthetics, Inc.; Mountain View, CA), acoustic subcision (rapid acoustic pulse device, Resonic™, Soliton, Inc.; Houston, TX), and collagenase-based enzymatic subcision
(collagenase clostridium histolyticum-aaes, QWO®, Endo Aesthetics‚ LLC, Malvern, PA). The objective of this review is to provide practitioners with an overview of the literature examining these therapeutic modalities and further the understanding of cellulite and the available treatment options available to plastic surgeons and dermatologists.
Materials and methods
In June 2022, we performed a comprehensive search review via PubMed and ScienceDirect databases using various combinations of the following search terms, ‘Collagenase’, ‘Cellulite’, ‘Collagenase Clostridium Histolyticum’, ‘fibrosclerotic panniculopathy’, ‘gynoid lipodystrophy’, and ‘adiposis edematosa’. Only original articles in English with data on the efficacy of this treatment from in vivo human studies were considered. The review team assessed each article and its references. Conference papers and abstracts were excluded as per PRISMA guidelines. Three randomised control trials were included in the final review of collagenase clostridium histolyticum-aae literature. In addition, two published articles on the controlled focal subcision device and one article on the rapid acoustic pulse device were obtained from their respective manufacturers; however, no published RCTs are yet available on these treatment modalities. Collectively, a total of 6 articles were reviewed using the following variables: therapeutic intervention, presence of a control group, randomisation, blinding, sample size, description of statistical methods, results, level of evidence, and statistical power.
Treatment modalities
Subcision-based treatments
Subcision is a surgical technique first described in 1995 in which subcutaneous fibrous septal bands tethered to the reticular dermis are divided5. The resulting redistribution of mechanical tension and adipose tissue contributes to a smoother appearance of the skin. Subcision techniques include manual6, vacuum-assisted7, and laser-assisted8 . However, these have been noted to have limitations, including operator dependence, bruising, hyperpigmentation, and the persistence of postprocedural pain9. In the subsequent section, we will address three novel approaches designed to minimise these adverse effects.
Novel subcision-based treatments
Controlled focal fibrous septa release device
Controlled focal fibrous septa release is a minimally invasive method designed for in-office use. The device is a single-use instrument for the manual release of fibrous septa. Cellulite depressions are marked with the patient in a relaxed, standing position. For the procedure, the patient is placed in the prone position and local anaesthesia is applied to the marked areas. The device is inserted into the subcutaneous adipose tissue and advanced to the marked areas. A light shining perpendicularly to the plane of the skin allows the operator to correctly locate the distal end of the device. Once at a marked area, the operator can deploy a blunt hook to engage the target septa. If correctly engaged, the depression will be reproduced, and the septa can then be divided using a sharpened link stored in the device shaft. The steps are repeated until the operator is unable to reproduce the depression and can proceed to the next appropriate marked location. This technique is designed to allow multiple depressions to be accurately and comprehensively treated through a small entry point, minimising the risk of pain, scarring and adverse events.
An open-label, multi-centre study evaluated female patients (n=20) aged 21–55 with moderate-to-severe cellulite on the buttocks and thighs that underwent controlled focal fibrous septa release. Baseline and interval images post-procedure were reviewed by an independent, blinded assessor against a modified Cellulite Severity Scale (CSS) score. Efficacy was measured by the primary endpoint of a ≥1 point reduction in CSS. 95% (n=18) of patients achieved the primary endpoint at day 180 post-procedure, with a mean improvement of 2.6. In unblinded scoring of baseline and day 180 follow-up images, 100% (n=19) of patients were rated as ‘much improved’ or ‘very much improved’ against the Global Aesthetic Improvement Scale (GAIS). 85% of patients reported satisfaction with the outcome, with low pain scores post-procedure day 7. No serious or unexpected adverse events were recorded.
Video analysis of the procedures demonstrated that a mean of 8.4 cuts were performed per depression. The investigators concluded that in contrast to the idea of a single fibrous strand for each depression, the septa structure is three-dimensional and complex, with webbing and branching structures observed in the video analysis.
In an earlier feasibility study, female patients (n=10) aged 21–55 with moderate-to-severe cellulite underwent the same procedure unilaterally on the buttocks and thighs11. The primary feasibility endpoint was the number of subjects achieving a GAIS score improvement of ≥1
point 90 days post-procedure and a secondary endpoint was reached if more than 50% of subjects had a noticeable improvement in GAIS scores at day 90. The researchers reported that at day 90, most regional treatment areas (84.6%) demonstrated an improvement of ≥1 point in GAIS scores, while 90% of subjects achieved an improvement of ≥2 points.
These studies suggest that controlled focal septa release is safe, efficacious, and acceptable to patients. However, it is important to note that both studies have several design limitations, including the lack of a control group, single blinding, small study population (total n=30), limited follow-up, and were not powered for assessment of statistical significance. Both studies were sponsored by the device manufacturer.
Larger, independently-funded, double-blinded studies with longer follow-up periods are required to provide statistically significant information on the efficacy of this treatment modality. The implementation of standardised baseline and endpoint measures would assist further, enabling direct comparison of results across future studies.
Acoustic therapies for cellulite
Acoustic wave therapy (AWT) has an established range of clinical applications and is widely utilised as a treatment for renal calculi and a range of musculoskeletal conditions12. The use of AWT as a treatment approach for cellulite is also well-documented in the literature. AWT has been demonstrated in small-scale studies to statistically improve neocollagenesis, microcirculation, and lymphatic drainage13. Several studies have sought to ascertain the efficacy of AWT using endpoint measures, such as biophysical measurements and photographs. In these studies, several potential mechanisms and targets have been proposed, such as remodelling of collagen14, stimulation of metabolic activity in subcutaneous fat tissues15, dermal strengthening16 or improved microcirculation13, and lymphatic drainage17. These mechanisms have been hypothesised to be secondary to the activation of C nerve fibres in the skin by shock waves with the subsequent release of substance P18 .
Generally, study results examining AWT as a treatment for cellulite have been inconsistent; however, three randomised control trials13,17,19 demonstrated a significant improvement in the appearance of cellulite. It is important to mention while these studies were designed to evaluate the effects of AWT on cellulite, none examined the effects on fibrous septa. One study did, however, hypothesise that the therapeutic benefits could have been in part due to the mechanical disruption of fat components, fibrous septae or both19 .
Rapid acoustic pulse device
Acoustic subcision is a non-invasive approach to cellulite treatment utilising a rapid acoustic pulse device. The device is designed to use rapid acoustic pulses to noninvasively disrupt fibrous septae leading to tissue release that results in the improvement of cellulite appearance.
Like the previously mentioned acoustic devices, the manufacturers also hypothesise that effects on the dermal extracellular matrix promote neocollagenesis leading to an improved appearance by reducing skin laxity.
The rapid acoustic pulse device comprises three components — a console, handpiece, and disposable cartridge. The console houses the power supply and transmits high voltage to electrodes housed in the cartridge. The cartridge can be removed and replaced when the electrodes wear out. The console also contains a system for circulating saline to cool the cartridge. For treatment, target areas are identified on the buttocks or thighs and the patient is positioned on a bed in a prone or lateral decubitus position. An acoustic coupling hydrogel pad and hydrogel are applied to the marked treatment areas before 1-minute doses of acoustic therapy are administered. No local anaesthesia is required for this procedure.
In an open-label, multi-centre trial, female patients (n=56) aged 18–50 with moderate-to-severe cellulite on a six-point CSS, as determined by investigators, were enrolled to receive a single office-based acoustic subcision treatment using the rapid acoustic pulse device20. A total of 9–15 treatment areas were identified and 1–2 minute-long doses of 50Hz were administered to each area. Baseline and 12-week photographs were taken under standardised conditions and analysed by three blinded, independent reviewers. The primary efficacy endpoint was a reduction of a simplified CSS score of ≥1. Secondary efficacy endpoints were the correct identification of >60% of post-treatment photographs by reviewers, an average improvement of cellulite appearance in GAIS scoring, and an average improvement of skin laxity in GAIS and skin Laxity Scale (LS). The baseline CSS score was 3.41 (±0.89) and investigators reported that a statistically significant mean CSS reduction of 1.01 ±0.5 (p<0.0001) was noted by reviewers at 12 weeks compared to baseline images. At 12 weeks, 90.9% of the treated cellulite sites were noted as appearing ‘improved’, ‘much improved’, or ‘very much
improved’ using a GAIS score for cellulite appearance. A mean LS reduction of 0.57 from baseline was noted in treatment sites — a 27.9% reduction from the baseline score. The difference between the baseline and 12-week LS was statistically significant (p<0.0001). Reviewers rated 67.3% of the treated sites as appearing ‘improved’, ‘much improved’ or ‘very much improved’ using GAIS; however, no further statistical analysis was provided with this score. 98.2% (n=55) of patients found the procedure tolerable and average pain scores during treatment were 2.4 on a 1–10 scale. The highest pain during the procedure was recorded as six. The patients largely found the procedure comfortable (76.8%) and felt their cellulite appearance had improved (92.9%). All adverse effects (AEs) were mild and selfresolving and no serious or unexpected AEs were noted.
This study, sponsored by the device manufacturer, suggests that acoustic subcision is effective, tolerable, and safe. It is worth noting that no data was provided on the percentage of patients that achieved the efficacy endpoints. Instead, data on individual treatment sites was given. While site treatment effects are important, global appearance is a more pertinent outcome for patients undergoing these procedures and the inclusion of patient-reported providers’ clinical support system (PR-PCSS) could provide valuable insight. Other limitations of the study design include single blinding, the lack of a control group, the potential for recruitment bias, a non-representative cohort of patients (92.9% of patients were white) limiting the generalizability of these findings and a short followup period of 12 weeks.
Robustly designed, independent, randomised control trials are required to obtain evidence of efficacy in white and non-white patients, with longer follow-up periods. Furthermore, as previous studies of AWT modalities did not examine the effects on fibrous septa, focused analysis on their utility for acoustic subcision would enable more direct comparison with the other novel treatment modalities available for cellulite.
Enzymatic subcision
Collagenase clostridium histolyticum-aaes (CCH) is composed of two injectable, purified bacterial collagenases, AUX-I and AUX-II (clostridial class I and II collagenases, respectively), that act locally to break down Types I and III collagen21–23 .
CCH has previously been investigated as a nonsurgical treatment for the release of Dupuytren’s contracture, a fixed flexion deformity in the digito-palmar fascia caused by excessive collagen deposition24 .
In cellulite treatment, injection of CCH into target areas has been associated with localised enzymatic degradation of mature collagen-rich septae, reorganisation of adipose tissue and neocollagenesis in human and porcine histological studies25 .
CCH was approved by the US FDA in 2020 for the treatment of moderate-to-severe cellulite in the buttocks of adult women. As a treatment for thigh cellulite, it remains investigational.
Two identically designed, phase-3, randomised, double-blind, placebo-controlled, multi-centre studies (23) (RELEASE-1 and RELEASE-2) involving female patients (n=843) aged 18-78 with moderate-to-severe cellulite on both buttocks on the Clinician Reported Photonumeric Cellulite Severity Scale (CR-PCSS) were analysed. Participants were randomised to receive up to three treatments of CCH 0.84mg or placebo in both buttocks, and one buttock was randomly assigned as the target buttock to assess the primary efficacy endpoint. Standardised digital photographs for evaluation of cellulite severity were taken at screening, on each of the three treatment days (days 1, 22, and 43), and 28 days post-treatment (day 71). The primary efficacy endpoint was the percentage of women with composite improvement from baseline ≥2 levels in both CR-PCSS and PR-PCSS scores at day 71. Safety assessments included monitoring of adverse events, vital signs, clinical laboratory parameters, and immunogenicity testing. In a pooled analysis, women treated with CCH were 5.5 times as likely as placebotreated women to be a ≥2-level composite responder (6.6% vs 1.2%) and 4.7 times as likely (9.9% vs 2.1%) in either buttock at day 71 (p<0.001). CCH group patients were 2.7 times as likely to be ≥1-level composite responders in the target buttock vs placebo group (39.4% vs 14.6%) and 2.6 times as likely as the placebo group (48.1% vs 18.6%) in either buttock (p<0.001). In subgroup analyses, higher response rates were observed in those of lower age and with a BMI <32 kg/m2 .
These findings confirmed those of an earlier phase 2, randomised, double-blind, placebo-controlled RCT(26) of 375 women aged 18–60 with moderate-to-severe cellulite (CR-PCSS). Participants were randomised to receive up to three treatments of CCH 0.84 mg or placebo injections in one buttock or thigh. As with the RELEASE trials, the primary efficacy endpoint was the percentage of ≥2-point improvement in CR-PCSS and PR-PCSS scores at day 71. In the treatment group, 10.6% of participants achieved the primary efficacy endpoint compared to 1.6 in the placebo group (p<.001). 44.6% of participants in the CCH group achieved the secondary endpoint of ≥1-level composite response (p<.001).
Across these RCTs, CCH was generally safe and welltolerated and discontinuations due to AEs were approximately 4%. In Sadick et al.,26 82% of the CCH group
III collagen.
experienced AEs such as injection site bruising (75%), pain (59%), and nodules (14%). In RELEASE-1 and 2, 88% of women in the CCH treatment group experienced one or more AEs, the majority of which were related to injectionsite bruising (84%), pain (48%) or injection-site nodule (33%). 93% of the AEs were mild or moderate and reduced in incidence, intensity, and duration of AEs at subsequent treatment sessions. No safety signals were identified in pooled or subgroup analysis.
These robustly designed RCTs provide strong evidence for the efficacy and safety of CCH as a treatment for cellulite. However, some limitations have been identified. The study by Sadick et al.26 is limited by its homogeneous patient population. All three RCTs used subjective endpoints and included only patients with moderate-to-severe cellulite; therefore, no conclusions on the efficacy of CCH on mild cellulite can be made. Funding for all three RCTs was obtained by Endo Aesthetics. Future studies should aim to include objective measures to quantitatively assess changes in skin quality.
Discussion
This review evaluated the existing scientific evidence regarding the efficacy of three novel subcision-based cellulite treatments. For the controlled focal fibrous septa release and rapid acoustic pulse device technologies, the existing level of evidence from the studies provided on their efficacy is low (level 4). No detailed statistical analysis is possible from the data provided on these treatments and a comprehensive assessment of efficacy is challenging in studies that did not include doubleblinding, randomisation, and comparison with placebo in their design. The use of intra-patient designs (assessment of treatment areas rather than patient response) can contribute to increasing the data points for analysis; however, it must be noted that as cellulite causes emotional distress and negatively affects the quality of life, it could be argued that these outcome measures do not reflect the holistic impact on patients4. The studies of CCH reviewed are large, robustly designed, doubleblinded, multi-centre RCTs.
In all the studies reviewed, women with mild cellulite severity were excluded, presumably to detect larger posttreatment improvements; however, it is important to note that this is unlikely to be representative of the heterogeneity in pre-procedure cellulite severity in women seeking this treatment. Further studies should aim to include participants with mild cellulite to give a comprehensive range of information on the efficacy of these treatments. Additionally, only RELEASE-1 and 2 included patients with a diverse range of Fitzpatrick skin types.
The lack of universally accepted and standardised measures of cellulite severity and biophysical measurement techniques also poses a challenge for the comparison of quantitative effects across studies of cellulite treatments. The implementation of such measures would augment the scientific rationale guiding patients as well as practitioners.
Conclusion
The advent of new subcision-based treatments is an exciting development for the treatment of cellulite. The studies reviewed suggest that the new treatments are both safe and efficacious. Of the three modalities discussed, the enzymatic subcision intervention has robustly designed RCTs that demonstrate efficacy. The level of evidence for acoustic and controlled focal subcision is of lower quality. More independently-funded, large, multi-centre RCTs with high-quality trial design and robust statistical analysis are recommended to support conclusive recommendations about their efficacy.
Declaration of interest None
Key points
Cellulite is a multifactorial condition characterised by a dimpled, ‘orange peel’ appearance of the skin
Three novel subcision treatments remain pivotal in the treatment of cellulite: controlled focal subcision, acoustic subcision, and enzymatic subcision
Subcision is a surgical technique in which subcutaneous fibrous septal bands tethered to the reticular dermis are divided
Of the three approaches described, enzymatic subcision has robustly designed RCTs that demonstrate efficacy
The clinical data for acoustic and controlled focal subcision modalities remains limited and warrants further investigation through future research
References
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