Handheld microfocused ultrasound device for facial lifting: A preliminary study of ULTIGHT

Although focused ultrasound modalities have achieved positive clinical results in noninvasive skin rejuvenation, they presented various side effects and particularly severe pain during treatment. This study introduces a microfocused ultrasound (MFU) device, ULTIGHT, to overcome the severe pain issue, providing quasi‐facial lifting.


| INTRODUC TI ON
2][3][4][5][6][7] Highintensity focused ultrasound (HIFU) has been generally employed as a noninvasive high-precision surgical modality for various tumors during the past decades.This modality generates ultrasound energy with a concave piezoelectric transducer and focuses the energy onto the region of interest (ROI). 8,9The HIFU energy is converted into thermal energy with a temperature ranging from 65°C to 85°C that produces coagulative necrosis to the ROI, minimizing damage to the surrounding tissue. 8,9The HIFU frequency contributes to the penetration depth and the size of thermal coagulation point in tissue. 10[13][14] The MFU is significantly similar to HIFU but provides more accurate and relatively lower focused ultrasound energy ranging from 0.5 to 10 J with frequencies between 4 and 10 MHz and focal depths ranging from 1.5 to 4.5 mm. 10,15,16It has also been proved to generate thermal coagulation in the dermis and superficial musculoaponeurotic system (SMAS) for skin rejuvenation in terms of facial lifting and tightening 7,11,[17][18][19] that depends on the treatment site and plan, focal depth and energy, and vectoring lines. 20Additionally, it is supposed to produce discrete micro-coagulative zones at a depth between 1.5 and 4.5 mm by generating temperatures from 60°C to 70°C within a focal zone. 20,21Moreover, it induces immediate contraction of denatured collagen by micro-coagulative necrosis and then, a healing cascade of four phases (hemostasis, defensive/inflammatory, proliferative, and maturation), leading neocollagenesis and neoelastinogenesis, as well as neovascularization within the extracellular matrix with subsequent skin rejuvenation. 16,20,21The coagulative depth and volume are determined by the focusing depth and energy of MFU.A higher frequency results in less penetration depth and smaller thermal coagulation point, and vice versa. 10A higher energy density induces higher temperature rise, resulting in greater thermal coagulation interaction. 22though current MFU and HIFU modalities have often achieved positive clinical results in skin rejuvenation, they have widely known side effects such as erythema, edema, bruising, numbness, warts, skin pigmentation change, and pain during treatment. 16,23,24With the exception of the pain issue, the other side effects are generally mild and the recovery to normal condition happens naturally within a week.However, pain that ranges from mild to severe, depending on the treatment sites, is the most frequent issue associated with these modalities. 21Approximately 54% of patients have reported severe pain that may increase the treatment time owing to the limitations of energy and treatment area. 21though the mechanism of HIFU-induced pain is not clearly known, this study assumed that the level of pain may depend on the thermal interaction volume that may be determined by the energy and focal depth generated by the MFU transducer. 22This study characterized a handheld MFU device, ULTIGHT (Medicon, Seoul, Korea), to partially overcome the severe pain issue, providing quasifacial lifting and tightening efficacy.In vitro and ex vivo experiments were conducted to quantitatively evaluate the MFU thermal zones (MFUTZs) and thermal effects in tissue, respectively.Finally, clinical trials were performed to visually evaluate facial lifting performed using ULTIGHT on the lower facial region.The MFU transducer had a metal-coated surface as a matching layer to minimize the air gap of the concave piezo ceramic transducer and, therefore, improve the overall energy transmission efficiency, expecting partially the enhancement of focusability.The surface of the MFU transducer was imaged using a scanning electron microscope (SEM; S-3400 N, Hitachi) at 1000× magnification.ULTIGHT was designed to provide three different energy levels for each TC.The energies were measured using an ultrasound power meter (UPM-DT-1000PA, Ohmic).Each measurement was performed 20 times and averaged.

| In vitro evaluation of thermal zones
The 4.5 mm TC was representatively applied to a transparent acrylic plate of 4 mm thickness and produced independently 10 MFUTZs at three different energy levels.A transparent ruler was placed on top of the MFUTZs and imaged using a smartphone camera to evaluate the length of the TL and spacing of the MFUTZs.In addition, the MFUTZs at three different energy levels were imaged using a smartphone based magnifier (MAGNI) at 8× magnification and their sizes were measured using MAGNI software.ULTIGHT provided a power of 29 W for 3, 4.5, 6 mm TCs and 15 W for 2 mm TC. Figure 3 shows that the average energies at three difference energy levels for four different TCs are as follows: (a) 0.17, 0.24, and 0.32 J for 2 mm TC, (b) 0.31,0.45,and 0.59 J for 3 mm TC, (c) 0.70, 0.85, and 1.00 J for 4.5 mm TC, and (d) 1.04, 1.19, and 1.33 J for 6 mm TC.

| In vitro evaluation of thermal zone
Figure 4A shows that ULTIGHT produced 10 discrete MFUTZs at a TL of 10 mm length; additionally, the MFUTZs were evenly spaced at 1 mm distance across all three different energy levels.Figure 4B shows that the MFU transducer produced highly focused MFUTZs that had a circular shape of diameter 0.264, 0.421, and 0.453 mm at energy level one, two, and three, respectively.The precise circular shape of MFUTZs may be due to high focusability that contributes to high energy density.The temperature rise ranged from 3°C to 10°C for single MFUTZs, depending on the energy levels that may cause tissue hyperthermia for body temperature and, furthermore, thermal coagulation effect because temperature rise can be greater for multiple MFUTZs on the identical site during a treatment session.The temperature rise linearly increased as a function of the number of MFUTZs with a R 2 of 0.99 across all the energy levels.The linear regression equations were as follows at the energy levels one, two, and three, respectively: (a) y = 1.82x + 1.02, (b) y = 2.40x + 1.75, and (c) y = 2.30x + 8.26; y and x indicate the temperature rise and number of MFUTZs, respectively.As expected, the temperature rise was greater at higher energy levels for the same number of MFUTZs.

| DISCUSS ION
The MFU and HIFU are noninvasive skin rejuvenation modalities that may induce micro-coagulative collagen denaturation and subsequent biochemical synthesis, resulting in skin tightening and lifting by minimizing surrounding tissue damages.However, patients generally suffer from severe pain during treatment. 21Anesthetics such as lidocaine or epinephrine may be injected or topically applied to the treatment region for local anesthesia.However, the anesthetic may adversely affect the variations of local blood perfusion and heat absorption in tissues, resulting in unwanted irregular or non-uniform tissue coagulation.In addition, a topically applied cream or ointment may cause unwanted reaction in the dermis or subcutaneous tissue. 24The use of anesthetic may also clinically disturb the clinician's perception of patient responses, preventing corrective measures of further potential side effects. 24Therefore, using anesthetics should be carefully considered if possible although it reduces the degree of pain during a treatment session.
Various MFU modalities such as "Ulthera," "Doublo," "Ultra-Skin," and "Ultrafomer," have been previously utilized in a clinical environment. 14 In the thicker ex vivo tissue sample, the energy level three of the 4.5 mm TC resulted in a temperature rise of approximately 10°C for a MFUTZ that may contribute to tissue hyperthermia of approximately 47°C for a body temperature of 367°C.Although hyperthermia may not cause distinguishable coagulation necrosis in tissue that contributes to greater tissue contraction, it may contribute to tissue denaturation, dermal stimulation, neosynthesis of collagen, and skin tightening.The single MFUTZ of ULTIGHT may induce a temperature rise that may not be sufficient for thermal coagulation but appropriate for hyperthermia leading to radiofrequency (RF) skin tightening.A previous study demonstrated that the MFU resulted in more effective clinical skin tightening than RF, which requires extensive recovery after treatment and multiple treatment sessions, resulting in inconsistent clinical results. 7e thermal coagulation with ULTIGHT may be achieved with approximately five MFUTZs that resulted in a temperature rise of 20°C, which may result in a thermal coagulation temperature greater than 55°C against body temperature.Although ULTIGHT provided a maximum energy of 1.33 J for 29 W to minimize the pain issue, the energy can be easily increased by controlling the application time of the TC to reach the thermal coagulation temperature.For example, the maximum energy of TCs with the 1.5 s TL can be easily increased from 1.33 to 2.66 J by increasing the application time to 3 s.As a result, the coagulation effect of ULTIGHT can be easily adjusted depending on clinical requirements although higher energy may cause pain issues in clinical trials.depending on treatment sites.Other modalities utilized relatively higher energy to induce greater thermal coagulation effect, resulting in various side effects.In addition, the participants did not exhibit any facial lifting effect right after treatment but a few months later; this happened because of the greater thermal coagulation effect causing various side effects although the facial lifting effect may be greater and longer than that with ULTIGHT.

| CON CLUS IONS
ULTIGHT provided relatively lower energy and smaller even MFUTZ, which might be advantageous or disadvantageous depending on the clinical applications.Unlike other modalities with higher energy that provide greater facial lifting effect few months after treatment with various side effects, including severe pain, ULTIGHT is almost pain-free and has no side effects, providing quasi-facial lifting right after treatment.Although the thermal coagulation effect was not distinguishable in the thicker ex vivo tissue sample, the clinical results indicated that ULTIGHT induced at least a temperature of 40-47°C for a single TL that causes tissue hyperthermia and thermal coagulation effect because the temperature rise can be greater for multiple TLs; this may be achieved by overlapping TLs on the same site during treatment.The energy of ULTIGHT can be easily adjusted to induce the thermal coagulation effect for a single TL, depending on clinical requirements.This can be investigated in further studies by considering the pain issue.
Although this study presented promising potential for achieving clinical results, it is limited in scope and considered a preliminary

2 | 2 . 1 |
MATERIAL S AND ME THODS Development of treatment cartridge ULTIGHT consists of a main control body and four exchangeable treatment cartridges (TCs) of 2, 3, 4.5, and 6 mm focal depths.The TC consists of a linear piezo motor (LPM), MFU transducer, water container module, and electronic control circuit board.It employed the LPM for smooth and reproducible discrete linear translation of the MFU transducer.Unlike mechanical gearmotors, the LPM can minimize the motion artifact caused by frictional force and therefore, provide reproducible focusability of the MFU transducer.The TC was designed to provide precise control of the MFU transducer mounted on the LPM and produces 10 discrete MFUTZs with specific sizes and spacing in a treatment line (TL) of 10 mm.The MFU transducer was enclosed in a water container module to minimize acoustic impedance mismatch.
An ex vivo chicken breast sample of size 80 × 50 × 4.5 mm 3 was prepared for visual observation of MFUTZs by intentionally utilizing acoustic energy reflection on the tissue-air interface that results in higher temperature rise than expected.The 4.5 mm TC was representatively applied with 3, 6, 9, 12, and 15 TLs at the energy level one.ULTIGHT and the samples were placed in a mechanical holder (built in a laboratory) to minimize motion artifacts caused by the operator.The opposite side of the treated sample was imaged using a digital camera and visually investigated to evaluate the MFUTZ as a function of the number of TLs.Although ULTIGHT was originally designed to provide 10 MFUTZs for a TL, it was modified to produce a single MFUTZ.A thermometer (DH.The 3007, Daihan Scientific Co., Ltd.) with two thermocouple probes was employed to measure temperature rise as a function of the number of MFUTZs at the three different energy levels for the 4.5 mm TC.An ex vivo chicken breast sample of size 55 × 20 × 10 mm 3 was prepared.A 3D printed mechanical sample holder was used to place ULTIGHT orthogonal to the sample and the thermocouple probes to the depth of interest.To minimize the temperature-rise issue by tissue-thermocouple interface reflection, the thermocouple probe was placed slightly horizontally beside the focal point.The control and test temperatures of the sample were simultaneously measured every 1 s by placing two thermocouple probes at a depth of 4.5 mm with 2.2 cm distance between the probes.The temperature rise was calculated by subtracting the control temperature from the test temperature.The measurement was performed five times and averaged for each energy level.

The 4 . 25 3 | RE SULTS 3 . 1 |
Figure1Ashows the disposable TC module that includes the electronic circuit to control the MFU transducer mounted on a LPM and the water container module.Figure1Bshows ULTIGHT with a main control body and four exchangeable TCs of 7 MHz with 2, 3, 4.5, and 6 mm focal depths.

Figure
Figure2Ashows the MFU transducer with a metal-coated concave piezo ceramic surface.Figure2Bshows the surface image of

Figure
Figure 5A shows MFUTZs in an ex vivo chicken breast sample as a function of the number of TLs of 3, 6, 9, 12, and 15 at the energy level one of the 4.5 mm TC.The effect of MFUTZs was enhanced as a function of the number of TLs because larger number of TLs might result in higher temperature rise, resulting in thermal coagulation instead of the hyperthermia effect.Discrete linear MFUTZs were clearly observed up to nine TLs but started to aggregate as the number of TLs increased.The results indicated that the 4.5 mm TC might cause thermal coagulation in the depth of interest, resulting in consistent size and spacing of the thermal zone.

Figure
Figure 5B shows the temperature rise as a function of the number of MFUTZs (i.e., 1, 3, 5, 7, and 9) at the three different energy levels of the 4.5 mm TC.The average control temperature was 20°C.

Facial
lifting was visually observed for eight volunteers right after the treatment.The clinical results persisted for approximately 1-2 months with no side effects or pain during and after the treatment.Figure 6 shows three typical results of the clinical trial before F I G U R E 2 (A) Microfocused ultrasound (MFU) transducer with a smooth and even surface and (B) SEM images of MFU transducer surface at 1000× magnification.F I G U R E 3 Measured energies as a function of three different energy levels for treatment cartridges (TCs) of 2, 3, 4.5, and 6 mm focal depth.(top) and right after (bottom) the treatment on the lower facial region.The pain index of the NRS ranged from one to two, which is considerably lower than other modalities.
Unlike other modalities, ULTIGHT employs the LPM F I G U R E 4 (A) 10 MFUTZs for a TL and (B) MFUTZ diameters for energy levels one (left), two (middle), and three (right).F I G U R E 5 (A) MFUTZs in ex vivo chicken breast sample as a function of number of TLs (3,6,9,12,and 15) at energy level one of 4.5 mm treatment cartridges (TC) and (B) temperature rise as a function of the number of MFUTZs at three different energy levels.F I G U R E 6 Frontal (left) and lateral (right) views of three representative volunteers before (top) and right after (bottom) the treatment on lower facial region.for reproducible and smooth linear translation and a transducer with a metal-coated concave surface as a matching layer to improve the overall energy transmission efficiency.Therefore, ULTIGHT produces precise MFUTZs that may contribute to pain relief.ULTIGHT produced 10 discrete MFUTZs in a TL of 10 mm with even spacing of 1 mm.The in vitro MFUTZs might be visualized owing to the reabsorption of the reflected energy resulting from the greater difference of acoustic impedance on the plate-air interface boundary.ULTIGHT produced MFUTZs of a maximum diameter of 0.453 mm for the 7 MHz, 4.5 mm TC.The focusability of the MFU transducer may affect the ultrasound energy density and thus, the size and shape of MFUTZs.Therefore, it may clinically affect to the level of pain and finally, the healing and remodeling period of MFUTZs.Although ULTIGHT presented visually clear MFUTZs in the thinner ex vivo tissue sample than the expected focal depth of TC, it did not show visually distinguishable MFUTZs in the thicker ex vivo tissue sample than the expected focal depth of TC.This might be due to the relatively lower energy and micro-sized thermal zone, and lower sample temperature of 20°C which may need a temperature rise of at least 35°C to reach the thermal coagulation temperature of 55°C.The thermal coagulation effect by multiple TLs was indirectly visualized by utilizing the acoustic impedance difference in the tissueair interface boundary in which the ultrasound energy becomes two times larger than that without the interface owing to the absorption of the reflected energy. 26In fact, the ex vivo chicken breast sample presented greater coagulation effect as a function of the number of TLs.The discrete MFUTZs were clearly observed at a lower number of TLs but appeared as a larger linear coagulation zone with a greater number of TLs because of the overlapping of multiple TLs in the ROI.Based on the result of the ex vivo investigation, multiple TLs are expected to result in visually distinguishable MFUTZs in a thicker ex vivo tissue sample with body temperature if the motion artifacts during treatment are minimized to spot identical location and accumulate greater energy in the MFUTZs.Such a procedure may be clinically applied to enhance thermal effects depending on the clinicians' purpose.
The clinical trials of eight volunteers presented lower facial lifting right after treatment without pain because of the MFUTZs and relatively lower energy.The treatment session typically lasted 20 min in the case of the lower facial region without anesthetic.The clinical results indicated that ULTIGHT induced hyperthermia and a partially thermal coagulation effect owing to the overlapped TLs, study.Further investigation is needed to validate these results, including tissue histology and long-term clinical evidence of results in additional studies.AUTH O R CO NTR I B UTI O N S All authors of Y. K., H.Y., S. A., D. H., and B. J. have read and approved the final manuscript.Y. K. and H.Y. performed the experiments to evaluate the ULTIGHT and analyzed the data.S.A. performed the