Combination of Microfocused Ultrasound with Visualization and Dilute Calcium Hydroxylapatite Filler for Moderate to Severe Knee Skin Laxity

J Clin Aesthet Dermatol. 2023;16(2):14–18.

by Margit Juhász, MD, MSc*; Katerina L. Yale, MD*; Akshitha Thatiparthi, BS;
Arash Babadjouni, BS; and Natasha Atanaskova Mesinkovska, MD, PhD

Drs. Juhász and Dr. Yale share co-first authorship of this article. Drs. Juhász, Yale, and Mesinkovska are with the Department of Dermatology at the University of California Irvine in Irvine, California. Ms. Thatiparthi is with Western University of Health Sciences and the College of Osteopathic Medicine of the Pacific in Pomona, California. Mr. Babadjouni is with Midwestern University and the Arizona College of Osteopathic Medicine in Glendale, Arizona.

ABSTRACT: Background. Microfocused ultrasound with visualization (MFU-V) and calcium hydroxylapatite (CaHA) filler are modalities for improving skin laxity. Their use in combination on body sites other than the face is expanding.

Objective. To investigate the effectiveness and safety of combination MFU-V and dilute CaHA (dCaHA) for lower anterior thigh and knee laxity over 12 and 24 weeks.

Methods. Twenty women (40-71 years) with moderate to severe laxity of the anterior thigh and knee were enrolled in this split-body trial. Subjects received dual-depth (3.0mm, 1.5mm) or triple-depth MFU-V (4.5mm, 3.0mm, 1.5mm) to the inferior anterior thigh (127-381 lines) along with dCaHA (1:1 normal saline) injection (0.5-3mL). Clinical effectiveness was monitored using photography, qualitative clinician and subject assessments, and quantitative analysis of skin topography by three-dimensional imaging and dermal thickness by optical coherence tomography.

Results. At 12 and 24 weeks, the treated thigh and knee experienced significant improvement in qualitative clinician scales (p<0.01), with subjective improvement on photography and subject-reported assessments; no significant changes were noted by quantitative measures. Adverse events were reported in 68 percent of patients, including mild bruising (n=12) and swelling (n=10).

Conclusion. Combining MFU-V and dCaHA is safe and results in clinical improvement of anterior thigh and knee laxity.

Keywords. Skin laxity, intense focused ultrasound, microfocused ultrasound, calcium hydroxylapatite

As the population ages, therapies targeting skin laxity are becoming more popular. Invasive surgeries provide impressive results, however they are accompanied by prolonged downtime and unwanted adverse events (AEs). Non-invasive procedures, such as ultrasound, radiofrequency, microneedling, and laser resurfacing can also provide targeted laxity improvement with little to no downtime and minimal AEs.

Microfocused ultrasound with visualization (MFU-V), currently available in the United States as Ultherapy® (Merz Aesthetics, Raleigh, NC, USA; Ulthera, Inc. Mesa, AZ, USA), has been used with success to treat skin laxity of the face, neck, and décolletage, as well as off-label treatment of the arms, buttocks, thighs, and legs.1–8 MFU delivers low energy pulses to the deep reticular dermis and subdermis producing thermal injury zones in the musculoaponeurotic systemic, while sparing the surrounding tissue. By heating the dermis to 60 to 70oC and causing thermal tissue coagulation, the wound healing cascade is activated, neocollagenesis occurs, with subsequent improvement in skin properties such as distensibility, elasticity, and viscoelasticity. Histologic analysis of skin after treatment with MFU shows an increase in dermal collagen between fat layers, a thickened epidermis and an increase in straight elastic fibers.1,2

The use of dilute calcium hydroxylapatite (dCaHA) has also expanded outside of the Food and Drug Administration (FDA)-approved indications to the treatment of skin laxity of the neck, décolletage and other body sites including the knee.9–12 Given the tightening effect of MFU-V and the three-dimensional (3D) volume restoration which may be achieved with filler, combination therapy is an area of special interest. With demand for greater clinical results using non-invasive methods, combining MFU-V and intradermal filler for skin laxity of the buttocks and thighs demonstrated significant improvement in cellulite severity, and histologically appreciable neocollagenesis.2,13–15

In this study, we used a combination of MFU-V and dCaHA for knee rejuvenation and correction of anterior thigh skin laxity. Rebuilding dermal collagen should result in improvement of laxity based on clinician and subject assessment, as well as improved skin tone and texture to be captured with novel non-invasive imaging modalities. Using a split-knee study design we hypothesize the combination of MFU-V and dCaHA will result in significant improvement of thigh and knee skin laxity. 


This pilot, open-label, prospective, split-body study was approved by the University of California, Irvine Institutional Review Board (2018-4856). Funding and study product for this study were provided by Merz North America, Inc.. The primary endpoint of this study was assessment of changes in knee skin laxity at 12 weeks, and the respective secondary endpoint was at 24 weeks.

Twenty women with moderate-to-severe skin laxity (Grades 2 to 3) of the anterior thigh and knee as determined by the Merz Skin Laxity at Rest Assessment Scale for Anterior Thighs and Knees (Merz Scale) were enrolled (Figure 1). Sixteen exclusion criteria included trauma or procedures on the legs within the past three months, pregnancy, or very severe knee skin laxity. The first 10 subjects (Group A) received dual-depth MFU-V (Ultherapy®; 7MHz, 3.0mm and 10MHz, 1.5mm) to a randomly assigned leg, while the remaining subjects (Group B) received triple-depth treatment (4 mHz, 4.5mm, 7MHz, 3.0mm and 10MHz, 1.5mm) if the 4.5mm aponeurotic band was visualized (n=8), otherwise they were also treated with dual-depth therapy. MFU-V was followed by intradermal injection of 1:1 dCaHA (Radiesse®, Merz Aesthetics, Raleigh, NC, USA) and bacteriostatic normal saline. Subjects were followed at 6, 12 and 24 weeks for evaluation. If necessary, subjects received further dCaHA injection at Weeks 6 and 12 for optimal volume correction (Figure 2).

Clinical improvement at all evaluation points was qualitatively monitored by two individual investigators throughout the study using 1) digital photography, 2) Merz Scale, and 3) investigator and patient-directed Global Assessment of Improvement Scales (PGA and SGA, respectively, ranging 1 to 7, with one being “much improved” and 7 being “much worse”). Subjects also completed a numeric rating scale (NRS) satisfaction questionnaire and a likelihood of referral to a friend or colleague NRS questionnaire (each ranging 0-10) at Weeks 6, 12, and 24. In addition, quantitative assessment of improvement was completed using optical coherence tomography (OCT; Beckman Laser Institute, Irvine, CA)-measured tissue attenuation coefficient as a surrogate for dermal thickness at baseline, Week 12 and Week 24. The 3D-imaging (Cherry Imaging, Cherry Imaging Ltd., Yokneam, Israel) of the treated knee with computer-based analysis of changes in skin roughness index and rhytide depth was completed for a subset of 10 subjects at baseline and Week 12. Statistical analyses were completed using paired t-tests with significance set at p<0.01.


Patient characteristics. Twenty women (19 Caucasian, 1 Black; age: 40-71 years) were enrolled and randomly selected to have the right (n=10) or left (n=10) inferior anterior thigh and knee treated. A total of 80 percent (n=16) of subjects completed the 24-week study. One subject was lost to follow up after baseline visit, while three were lost to follow up after 12 weeks. Nine subjects (56%) who completed the study opted for treatment of the previously untreated leg at the end of the study period.

Treatment parameters. Of the subjects receiving dual-depth MFU-V (n=12), an average of 173 lines (range: 160–210) of 3mm depth and 59 lines (range: 40–70) of 1.5mm depth were used; for subjects receiving triple-depth MFU-V (n = 8), an average of 108 lines (range: 71–160) of 4.5mm depth, 100 lines (range: 32–161) of 3mm depth, and 45 lines (range: 24–60) of 1.5mm depth were given. All subjects received a total average of 240 lines (range: 127–381) of MFU-V treatment at baseline. An average of 2.2mL (range: 0.5–3.0 mL) of dCaHA was injected at baseline. Two subjects received an additional average of 2.2mL of dCaHA (range: 1.3–3mL) at Week 6.

Qualitative assessments. At baseline there was no significant difference between the Merz Scale grades of the treated and untreated knees (2.7+/-0.6 versus 2.6+/-0.5, respectively). At 12 and 24 weeks the Merz Scale grades for the treated knee significantly improved to 1.9+/-0.7 (p=0.001063) and 2.0+/-0.8 (p=0.004423) from baseline, respectively; no significant changes from baseline were noted for the untreated knee using the Merz Scale at either time point (2.3 +/-0.7 and 2.3+/-0.7, respectively) (Figure 3 and 4). When analyzing dual- and triple-depth MFU-V treatment groups individually, there was no significant difference from baseline to Week 12 or 24 for either group.

Investigators noted a mild improvement in overall skin laxity appearance at Week 6 of the treated knee, while subjects reported a mild to moderate improvement. At Week 12, both investigators and subjects reported a mild to moderate improvement; and at Week 24 both noted a mild improvement in the treated knee. At Week 12, subjects averaged a 6.6 out of 10 score on the satisfaction scale and a 6.1 out of 10 score on the likelihood to recommend the treatment to a friend. Similarly, at Week 24 subjects averaged a 6.1 score on the satisfaction scale and a 5.8 score on the referral scale (Table 1).

Quantitative assessments. OCT analysis of dermal thickness showed an average baseline attenuation coefficient of 1.98+/-0.36 for the treated knee and 2.00+/-0.40 for the untreated knee. At Weeks 12 and 24 the treated knee was noted to have an average coefficient of 2.04+/-0.38 (p=0.36) and 1.86+/-0.30 (p=0.75), respectively, that was not significantly improved from baseline. Similarly, the untreated knee demonstrated no significant improvement from baseline (Table 1).

3D-imaging analysis of the treated knee showed baseline average wrinkle depth of 0.21+/-0.04mm and skin roughness index of 0.66+/-0.24. At Week 12, average wrinkle depth improved to 0.20+/-0.05mm (p=0.36); similarly, average skin roughness index improved to 0.60+/-0.29 (p=0.25), however neither reported improvement was significant.

Adverse events. At Week 6, 68 percent of patients reported an AE within the first month of treatment. All post-procedure AEs were of mild intensity; these were bruising (63%), swelling (52%), temporary palpable nodules (37%), erythema (32%), skin sensitivity (26%), local pain/discomfort (21%), and local numbness (5%). At Weeks 12 and 24, no AEs were reported.


This study demonstrates that combining MFU-V and dCaHA is safe and modestly effective for the treatment of thigh and knee skin laxity by qualitative assessments. Merz Scale assessment showed statistically significant improvement in the treated knee at both the primary (Week 12) and secondary (Week 24) endpoints. Furthermore, subjects and clinicians reported overall mild improvement and satisfaction with the treatment at each evaluation point. However, only 45 percent of subjects elected to have the second knee treated at the end of the study, and on average subjects were only mildly likely to refer a friend for the procedure. Upon quantitative assessment, no significant changes in collagen thickness, wrinkle depth, or skin roughness were observed after the treatment. Overall, the procedure was well-tolerated with minor, but frequent, AEs reported. Temporary pain, swelling, erythema, and bruising are well-known AEs associated with both MFU-V and CaHA injection. There was no further risk or increased severity of AEs when treatments were combined.

The use of MFU-V in combination with other rejuvenation modalities has become a popular area of clinical experimentation and research. A retrospective analysis combining MFU-V with ablative fractional carbon dioxide (CO2) lasers for treatment of skin aging of the face and neck reported significant improvement in outcome when using combination therapy compared to either therapy alone.17 

Our results corroborate existing data in the literature using MFU-V and dCaHA combined treatment to other areas of the body.2,13–15 When MFU-V was used alone in the buttocks area, 89.5 percent of patients demonstrated clinical and subjective improvement based on Physician and Subject Global Aesthetic Improvement scales.18 MFU-V has also been used for “lifting” skin over joint areas such as the knees and elbows. One study noted a 56 percent patient-reported improvement in elbow laxity and 86 percent improvement in knee laxity. No significant side effects were reported in either area of treatment.3,7,8 Choi et al19 used MFU-V on the arms, abdomen, thigh, calf with a significant clinical improvement in all areas by blinded investigator evaluation at four weeks. Post-treatment measurements with a cutometer also showed significant improvement in skin elasticity. The use of two transducers sequentially (4.0MHz, 4.5mm depth and 7.0MHz, 3.0mm depth) over arms, thighs and knees showed improvement in clinical scores compared to a single pass treatment, however results were insignificant.19 Contraindications to MFU-V treatment include open wounds or infection at the site of treatment (including severe acne) and metallic implants in the area (including pacemakers and defibrillators). Although it is possible to perform MFU-V over keloids and dermal fillers, one must do so with caution.1

One study in the literature discussed the use of hyper-dCaHA for the treatment of knee skin laxity. Utilizing a 1:4 dilution of dCaHA to saline injected with a fanning technique to cover the area of interest (up to 6mL), significant improvement in skin laxity and cellulite was reported after three months, with a 100-percent satisfaction rate. AEs were noted to be erythema, bruising, and swelling and resolved in 2 to 3 weeks post-procedure.9

Further studies on the use of multiple non-invasive skin rejuvenation techniques are needed to determine safe and effective combination protocols.

Limitations of this study include its small sample size thus limiting statistical comparison of dual to triple depth MFU-V treatment. Furthermore, the quantitative assessments utilized in this study, OCT and 3D-imaging, remain explorative in the analysis of changes in collagen thickness and skin topography.


Combination therapy with MFU-V and dCaHA is a safe and modestly effective treatment option for the clinical improvement of anterior thigh and knee skin laxity. Newer quantitative analysis methods, such as OCT and 3D-imaging, did not reveal significant changes in dermal thickness or skin topography. With the rise of non-invasive skin rejuvenation techniques for treatment of skin laxity in the body areas beyond the face and neck, further studies are needed to determine safe and beneficial treatment options.


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