Efficacy and safety of high‐intensity, high‐frequency, non‐focused ultrasound parallel beams for facial skin laxity

Ultrasound energy has been used for dermal rejuvenation to treat fine lines, wrinkles and to lift lax skin. High intensity ultrasound waves induce thermal injury in the dermis, stimulating neocollagenesis and neoelastinogenesis.


| INTRODUC TI ON
Aesthetic medicine has gathered popularity worldwide in the recent years with over than 15 million cosmetic procedures during 2020 in the United States alone, [1][2][3] with mostly minimally invasive procedures (botulinum toxin and soft tissue fillers). 2This increasing demand highlights the importance of further developing safe and efficient minimally and non-invasive aesthetic treatments.
Skin aging is driven by genetic and epigenetic factors, intrinsically and extrinsically, [4][5][6] leading to lax skin appearance due to the decrease of collagen type I and type III, and the impairment of elastic fibers functions within the dermal layer. 6,7It is a major concern in patients that are seeking for skin rejuvenation treatments.
5][6][7][8][9] Many technologies were developed based on this concept of collagen and elastin remodeling following mechanical or thermal damage in the dermis. 10,11e novel synchronous ultrasound parallel beam technology (SUPERB) 12 was previously shown to be an effective treatment for facial fine lines and wrinkles. 8 this approach, high-intensity, high-frequency, non-focused, parallel ultrasonic waves are generated by 7-transducers which propagate into the dermis layer to depths of 0.5-2 mm and create controlled thermal injury zones at the mid-dermis while preserving and avoiding damage to the epidermis and other skin layers (Figure 1).
The locally induced thermal injury is characterized by partially denatured collagen, a condition that stimulates neocollagenesis and neoelastogenesis mediated by matrix metalloproteinases (MMPs), heat shock proteins (HSPs), and other factors that subsequently lead to collagen remodeling. 11is study describes the safety and efficacy results of the high-intensity, high-frequency, non-focused ultrasound parallel beam device for the treatment of facial, submental, and neck lax skin.

| MATERIAL S AND ME THODS
In order to assess the efficacy, utility, and safety of the novel ultrasound device (SofWave Medical Ltd., Israel) for facial lax skin treatment, 15 female subjects were enrolled at one clinic in the USA.The study was reviewed and approved by an ethics committee, Advarra Institutional Review Board, conducted in accordance F I G U R E 1 Synchronous ultrasound parallel beam thermal effect.Schematic representation of the synchronous ultrasound parallel beam (SUPERB) biophysical effect during its application on human skin.The high-intensity, high-frequency ultrasound parallel beam generated by seven synchronized transducers penetrates to the mid-dermis at depths of 0.5-2 mm and consequently creates seven unique cylindrical volumetric thermal zones.The temperature varies from 60°C to 70°C along and across the thermal zone with highest value at the center, leading to partial collagen and elastin denaturation.were pregnant or planning to become pregnant; having given birth less than 3 months before treatment and/or breast feeding.
The high-intensity, high-frequency, non-focused ultrasound parallel beam device was applied on facial, submental, and neck areas in two treatment sessions followed by two follow-up visits at 3-and 6-months after last treatment.
Each treatment session included pre-and posttreatment procedures.Before treatment, subjects were asked to remove all make-up, cleanse, and dry the skin.Topical anesthesia (Benzocaine 20%/ Lidocaine 6%/Tetracaine 4%) was applied to the treatment area for 40-60 min.Furthermore, 11 subjects decided to take ketorolac, a nonsteroidal anti-inflammatory drug (NSAID) in addition to the topical anesthetic cream to reduce pain perception.The treatment areas were washed and completely dried before applying a thin layer of ultrasound gel.
The forehead, temples and cheeks areas were treated in all subjects whereas the submental and neck areas were treated only in 12 subjects.After treatment, the ultrasound gel was removed with water-soaked gauze.
Immediately after each treatment, the investigators assessed treatment immediate responses and recorded any adverse event, while subjects were asked to rank their pain level during treatment

| Treatment parameters
All 15 subjects were treated at the forehead, temple, and cheek areas, 12 received an additional treatment to their submental and neck.The mean number of pulses and standard deviation were 38 ± 10 (R: 23-62) for the forehead and temples, 79 ± 19 (R: 45-120) for the cheeks and 69 ± 13 (R: 47-97) for the submental and neck.The mean pulse energies and standard deviation were 3.7 ± 0.2 J (R: 3.2-4.0J) for the forehead and temples, 3.9 ± 0.2 J (R: 3.2-4.6J) for the cheeks and 3.9 ± 0.2 J (R: 3.2-4.0J) for the submental and neck.

| Clinical rating
According to the PGAIS results (Figures 3 and 4A), more than 80% of the subjects showed an improvement from baseline at both followup visits in all treated areas.
For the forehead and temple areas the improvement rate increased from 80% at the 3-month follow-up to 93% at 6-month follow-up.For the cheeks, submental and neck areas, 100% of subjects had improvement from baseline at the 3-month follow-up and

| Subject assessment
Subjects' assessment results (Figure 4B) revealed high overall improvement rates in all treated areas at the 3-and 6-month follow-up visits compared with baseline.For the forehead and temple areas 80% noted an improvement from baseline at 3-month following last treatment and 60% at the 6-month follow-up.For the cheeks the results were 80% and 87% whereas for the submental and neck areas the rates were 83% and 75% at the 3-and 6-month follow-up visits, respectively.
Further data analysis revealed that most subjects had an improvement in at least one of the follow-up visits.Overall, 87% (forehead and temples), 93% (cheeks), and 92% (submental and neck) of subjects reported on a noticeable improvement compared to baseline.Not even one subject assessed the results as worsening when compared to baseline.
Interestingly, more than 60% of the subjects noted at the 6-month follow-up that they would undergo additional treatments in all areas.Moreover, 83% of the subjects treated on the submental and neck regions would positively consider additional SofWave treatments.

| Safety and pain
The mean pain score and standard deviation values were 6.0 ± 1.7 during the first treatment session and 5.1 ± 1.9 during the second session with an average overall value of 5.6 for the two treatments.
Importantly, only 10% of the treatments were accompanied with a pain score of more than 7.5.

| DISCUSS ION
[15][16] A comprehensive systematic review of 122 articles analyzed the safety and efficacy of radio frequency for face and neck rejuvenation. 15Overall, the report demonstrated positive treatment effects on the appearance of patients' facial skin in most of the studies with minimal occurrence of adverse effects. 15cently, Contini et al. analyzed 16 studies and focused on the efficacy and safety aspects of the microfocused ultrasound technology for facial skin tightening. 14The study reported that 92% of treated female patients showed improvement in skin tightening and/ or in wrinkle reduction.Common adverse effects included transient erythema and oedema. 14e proven positive treatment effects of noninvasive, energy-based devices led to the development of the synchronous ultrasound parallel beam technology (SUPERB™, SofWave Medical Ltd, Israel). 12It is characterized by the generation of high-intensity, high-frequency, non-focused ultrasound parallel beams that propagate through the epidermis and target the mid-dermis at depths of 0.5-2 mm.The delivered energy increases the tissue temperature to 60°C-70°C, leading to partial collagen denaturation, coagulation, and subsequent remodeling. 8Such temperatures may cause damage to the epidermis; however, advanced built-in cooling system within the handpiece 8 protects the epidermal layer and prevents unintentional injuries, demonstrating high treatment safety standards.
In this clinical trial we report on the efficacy and safety profile of the high-intensity, high frequency ultrasound device, used for the treatment of facial lax skin.The results show high improvement and satisfaction rates among participants, importantly with long-term skin improvement effects of at least 6 months following the second sessions.The treatment appears to be tolerable and safe with only common side effects such as transient edema and erythema.All our subjects that participated in this study could return to their normal life activities with no downtime following the treatment session.This prospective study included 15 subjects, therefore, as an outlook we would suggest to increase the sample size for more precise and comprehensive statistical analysis.Moreover, the implication of advanced technological tools such as 3D skin analysis could provide us with new insights of posttreatment structural and volumetric skin changes.Such quantitative information is a reliable source for further data analysis that could support our findings.Furthermore, detecting significant trends of posttreatment volumetric changes may potentially lead to additional treatment indications.
In summary, the applied ultrasound device for the treatment of facial, submental, and neck lax skin demonstrated high safety profile and effectiveness from the clinical perspective with visible improvements backed by high satisfaction rates among our patients.The novel high-intensity, high-frequency device could be an option for patients seeking for non-invasive, safe, and effective treatment for facial skin rejuvenation.
photo consent was obtained from all subjects.Inclusion criteria were healthy non-smoker males and females, aged from 35 to 80 years, without regard to their skin type.Subjects were excluded if they had severe solar elastosis; systemic or local infections; active local skin disease that may alter wound healing process; history of smoking within the past 10 years; history of chronic drug or alcohol abuse; history of cosmetic treatments on the intended treatment area, including facial skin-tightening procedure within the past 6 months; injectable botulinum toxin or filler of any type within the past 6 months; ablative or non-ablative laser or light resurfacing/rejuvenation treatments within the past 6 months; dermabrasion or deep facial peels within the past 12 months; excessive subcutaneous fat in the cheeks area; significant scarring in treatment area; severe or cystic facial acne; usage of isotretinoin or other retinoid within the past 6 months; usage of anti-platelet or anti-coagulant drugs within the past 2 weeks; presence of a metal stent or an implant in the facial area and any physical or mental condition which might make it unsafe for the subject to participate in the study.Additionally, subjects were excluded if they using visual analog scale (10-point scale: 0 = no pain while 10 = worst possible pain).Standardized photographs were taken before and after each treatment and at both follow-up visits.Physician global aesthetic improvement scale (PGAIS) was used by investigators to grade subjects' clinical improvement from baseline to posttreatment visits.Subjects were asked to fill out an improvement questionnaire.F I G U R E 2 Subject demographics overview.(A) Ethnicity.(B) Fitzpatrick skin type I-always burns, never tans; Type II-usually burns, tans with difficulty; Type III-sometimes mild burn, gradually tans to olive; Type IV-rarely burns, tans with ease to moderate brown; Type V-very rarely burns, tans very easily.(C) Wrinkle class and degree of elastosis according to Fitzpatrick scale.Wrinkle class I-fine lines; Class II-fine to moderate depth wrinkles, moderate number of lines; Class III-fine to deep wrinkles, numerous lines with or without redundant skin folds.Degree of elastosis scores 1-3 (Mild-fine textural changes with subtly accentuated skin lines); 4-6 (Moderate-distinct popular elastosis [individual papules with yellow translucency under direct lighting] and dyschromia); 7-9 (Severe-multipapular and confluent elastosis [thickened yellow and pallid] approaching or consistent with cutis rhomboidalis).

Fitzpatrick
wrinkle and elastosis scale (3-class, 9-point) was used by investigators at baseline before treatment (Figure2C).Data analysis was performed upon completion of the study using IBM® SPSS® software.

F I G U R E 3
Facial and submental skin tightening.(A, B) Female subject 03-IMR, 53 years old, indication of nasolabial folds, before and after treatment.(C, D) Female subject 07-GDS, 59 years old, indication of submental, before and after treatment.(A, C) Baseline, (B, D) 6-month follow-up.(Courtesy of Michael H. Gold, Tennessee Clinical Research Center, Nashville, TN USA).around 92% showed an improvement at the 6-month visit.All subjects showed an improvement in all treated areas, in at least one of the two follow-up visits compared to baseline.No worsening was recorded.
67% of the subjects and slight edema in 7%, all resolved spontaneously.Mild facial peeling was observed in one subject following her first treatment which was transient and resolved without anyF I G U R E 4 Subjects' improvement rate.Portion of improved subjects at each area and visit according to the physicians (A) and subjects (B).intervention within 3 days.During the study period, no serious adverse events were observed.