Prospective Clinical Trial Demonstrating the Efficacy of Hyaluronic Acid Filler for the Improvement of Atrophic Facial Scars up to 2 years

Abstract

BACKGROUND

Hyaluronic acid (HA) filler longevity has been studied for wrinkles. However, its long-term use for treating atrophic facial scars has not yet been analyzed in long-term prospective studies.

OBJECTIVE

Analyze the safety and duration of a HA filler for the use in atrophic scars.

MATERIALS AND METHODS

Fifteen subjects received VYC-17.5L in atrophic scars on 1 randomized cheek and saline on the other, with 1 optional touch-up treatment and crossover after the short-term trial. Grading for this long-term extension was done on Day 720, using the Global Aesthetic Improvement Scale (GAIS) and the Quantitative Global Scarring Grading System.

RESULTS

On Day 720, a live blind evaluator rated the VYC-17.5L assigned side as having significant reduction in scar severity (−7.2 [t(22) = −6.01, p = .00009]) and number of scars (−8.8 [t(22) = −6.25, p = .00006]) as compared with baseline. There was no significant difference in the results from Day 120 to Day 720. Ninety-two percent (11/12) of subjects reported improvement (GAIS), were satisfied with the treatment, thought it looked natural, and had fewer side effects than expected. There were no persistent or late-onset side effects.

CONCLUSION

VYC-17.5L improved rolling atrophic facial scars, and the results were sustained throughout the 2-year trial without side effects.

There are many causes of facial atrophic scars including acne, varicella, skin cancer surgery, and trauma. The most common cause is acne, with many adolescents and a minority of adults experiencing this condition and some developing subsequent scarring. Atrophic scarring is one of the most difficult conditions to treat and can cause significant psychological distress. Treatment options include polymethylmethacrylate (PMMA)¹ or hyaluronic acid (HA)^2–10 filler, fibroblast growth factor,¹¹ platelet-rich plasma (PRP),^12,13 fat grafting,¹⁴ saline,^8,15 chemical peels,^16,17 ablative or nonablative laser treatments,^18–29 microneedling,^17,30 microneedling with radiofrequency or PRP,^21,31,32 fractional microplasma radiofrequency,^31,33 punch techniques,³⁴ botox,³⁵ dermabrasion,³⁶ and subcision.^37–39 However, many of these treatments have side effects, limited efficacy, and prolonged downtime.

There is a lack of data to educate physicians and patients on which treatment is best for atrophic scars. In fact, a Cochrane Systematic Review⁴⁰ and a recent update⁴¹ on atrophic acne scarring concluded that while there was evidence that filler might be effective, the authors recommended long-term placebo-controlled trials to verify if any treatments “produce meaningful benefits over the long term.”⁴⁰

There are many HA fillers approved by the Federal Drug Administration (FDA), that vary in their particle size, cross-linking, concentration, hardness, and cohesivity which allow for many differing indications. Polymethylmethacrylate (PMMA) is currently the only FDA-approved filler in the United States for this condition¹; however, permanent fillers such as this one may carry an increased risk of permanent complications. While HA filler is reversible and therefore may have a lower risk of permanent complications, many question the use of HA filler for long-term treatment despite recent evidence suggesting that HA filler likely persists longer than originally thought^42,43 and may be a safer, long-lasting alternative.

Recently a small, short-term, randomized placebo-controlled clinical trial showed significant improvements with HA filler as compared with saline with minimal transient side effects.⁸ Since there were no long-term clinical trials in the United States utilizing HA filler for atrophic scarring, a longer extension of that study was completed. To this end, the data from the first long-term prospective clinical trial in the United States, utilizing a HA filler (Juvéderm Vollure XC) to treat atrophic facial scars up to 720 days, is reported in this study.

Materials & Methods

A study was performed in a single private practice in Boynton Beach, Florida, in accordance with good clinical practice and the ethical guidelines and principles of the 1975 Declaration of Helsinki. The FDA granted an Investigational Device Exemption approval on June 17, 2020. Sterling Investigational Review Board approved the study on August 10, 2020.

Patient Selection

To enroll, subjects were required to be in good general health, aged 22 years and older, and obtain a score of 4 to 55 on the Quantitative Global Scarring Grading System (QGSGS).⁴⁴ Subjects were excluded for the following: neuromodulators in the past 6 months, HA filler in past year or surgery or permanent fillers at any time in the treatment area, allergy to lidocaine or HA, nursing, or pregnant. In addition, they were excluded if they used the following drugs during the 2 weeks before the trial or needed to use them during the trial: diuretics, antihistamines, chemotherapy, anticoagulants, immunosuppressive or immunomodulatory agents, and anti-inflammatory drugs.

Study Design

The investigator and research coordinator enrolled, consented, randomized, and assigned 15 subjects (30 cheeks) using a computer-generated sequence to randomly sort the subjects into 2 groups: (1) left side with up to 1 mL of VYC-17.5L and right side with saline and (2) right side with up to 1 ML of VYC-17.5L and saline on the left.

On Day 30, if deemed appropriate by the primary investigator, up to 1 mL could be used for a second touch-up treatment with the same group assignment. On Day 120, the saline side received a crossover treatment with up to 2cc of VYC-17.5L. The evaluator was blind during the entire study, while the subjects remained blind until Day 120. Grading was done live by a blind evaluator, standardized photographs were taken, and the subject with the longest follow-up was analyzed for volumetric changes by Canfield. Subjects completed both daily diaries and questionnaires on Day 120 for the short-term trial and on Day 720 for the long-term extension presented in this study.

Treatment

An anesthetic cream was placed on the treatment area for 30 minutes and wiped off with 70% isopropyl alcohol. A single board-certified dermatologist performed the injections in the treatment area on the cheeks. The copacked 30-gauge needle was utilized to inject parallel in the dermis for broad scars (∼0.005 mL per thread) and perpendicularly superficially in the dermis (∼0.002 mL, 50 injections per 0.1 ML of product). Superficial dermal blebs were then smoothed with a rolling Q-tip with a final goal of 100% correction. The investigator determined the total amount injected based on the depth, width, and number of scars treated. Long-term follow-up visits occurred on Day 360, 540, and 720.

Study End Points

The primary long-term end point was the difference on the QGSGS from baseline to Day 720, which was scored in 12 of 15 subjects (2 subjects were lost to follow-up and, 1 subject was deemed ineligible to continue due to exclusion criteria) on the side that received active treatment on Day 0. Additional secondary end points included (1) the number of atrophic scars, (2) the Global Aesthetic Improvement Scale (GAIS), (3) the change in the QGSGS and number of atrophic rolling scars from 90 days after their last treatment as compared with Day 720, and (4) the number and type of side effects.

Safety Assessments

At all visits, the primary investigator and evaluator examined subjects for side effects. Subjects also reported side effects both at every visit and in daily diaries for 30 days after the treatment.

Statistical Analysis

A Student t-test with a 2-tailed hypothesis was used with confidence intervals when reporting the difference on the QGSGS and the number of scars. A descriptive summary of both categorical outcomes (side effects, sex, and skin type of the subjects) and continuous measures (age and baseline QGSGS scores) reported with the mean, minimum and maximum, are presented. The sample size was determined by a pilot study with 5 patients. In this study, the authors tested 12 hypotheses, with an expected rate of false discovery of 0.05. The Benjamini–Hochberg procedure was used to correct p Values (see Individual p values were placed in ascending order, with an ordinal rank assigned starting with smallest p value (rank = 1). Each p value's critical value was calculated using the formula (i/m)Q, where i = each p value's rank, m = total number of tests, and Q = the false discovery rate. The largest p value smaller than its corresponding critical value was identified, and all smaller p values (lower ordinal rankings) are considered significant.

Results

Demographics

The subjects' ages averaged 42.1 years with a range from 26 to 59 years. There were 11 women and 4 men and a minimum of 2 of each with Fitzpatrick Skin Type. The mean baseline number of atrophic scars was 13 on both the left and right with a minimum of 4 and maximum of 21, according to the blind evaluator.

Product Amount

All 15 subjects had 2 treatments, 30 days apart. The average amount of VYC-17.5L injected was 0.66 and 0.61 cc on the first and second treatment, respectively. The subjects' opposite sides were the control until Day 120, at which point the control side was eligible to receive up to 2 cc of VYC-17.5L.

Primary Long-Term End Point

According to the blind evaluator doing a live assessment, there was a significant mean reduction of 7.2, 95% CI [4.9–9.4] on the QGSGS from baseline to Day 720 [t(22) = −6.01, p = .00009]), and the same followed for the investigator, with a reduction of 7.8, 95% CI [5.9–9.8] [t(22) = −7.62, p = .00001]) as presented in Table 1.

TABLE 1.

Atrophic Scar Data From Live Evaluation

	Baseline	Day 120	Day 720
Mean investigator QGSGS score	9.7	2.6	1.8
Mean blind evaluator QGSGS score	9.6	3.3	2.4
Investigator # scars	9.7	3.6	3.3
Blind evaluator # scars	12	4.1	3.2

QGSGS, Quantitative Global Scarring Grading System.

Secondary Long-Term End Points

According to both the blind evaluator and the investigator, there was a significant mean reduction from baseline to day 720 in the number of scars, −8.8, 95% CI [6.2–11.6] and −6.4, 95% CI [3.6–9.3], respectively, [t(22) = −6.25, p = .00006]) [t(22) = −4.22, p = .00143]) as presented in Table 1. In addition, Table 1 presents that both the number and QGSGS score from Day 120 to 720 does not significantly change. Finally, 92% (11/12) of subjects who completed the 2-year trial reported improvement on the GAIS were satisfied with the treatment, thought it looked natural, and experienced fewer side effects than expected.

Safety

All side effects reported within the first 30 days by the investigator, evaluator, or subject resolved. There were no reports by the evaluator, investigator, or subject of delayed onset side effects such as the Tyndall effect or late-onset granulomas, infections, or allergies.

Volumetric Photo-analysis

Canfield Primos system was used to analyze the subject with the longest primary end point on Day 810. This subject showed no improvement in the atrophic scars on the saline side at Day 120, but an improvement of 76.3% 2 years after 1 crossover treatment with VYC-17.5L. On the active treatment side, there was an average reduction in atrophic scars of 87.8% on Day 120 (90 days after 2 injections of VYC-17.5L), which maintained to Day 810 (Figure 1A–C and Table 2) without any additional treatments.

Figure 1.

(A–C) Canfield Primos 3D photo-analysis of 46-year-old man with atrophic scarring (A) before treatment and (B) 90 days after treatment with VYC-17.5L, and (C) over 2 years after treatment.

TABLE 2.

Atrophic Scar Photo-Analysis Data (Figure 1A–C)

Scar No.	Baseline	Day 120	Day 810
1	29.11 mm3	3.29 mm3	2.7 mm3
2	2.88 mm3	0.00 mm3	0.00 mm3
3	2.92 mm3	1.10 mm3	0.88 mm3
4	2.17 mm3	0.00 mm3	0.12 mm3
5	1.02 mm3	0.27 mm3	0.23 mm3
Total	38.1 mm3	4.66 mm3 (−87.8%)	3.93 mm3 (−89.7%)

Discussion

Atrophic facial scarring occurs often, is extremely difficult to treat, and can create substantial psychological distress. While there are a variety of treatment options, the long downtime, suboptimal outcomes, risk of side-effects, and requirement for a series of procedures make many first-line options, such as laser resurfacing, subcision, microneedling, and surgery more costly and riskier than HA filler. Unfortunately, there is a lack of either prospective or randomized placebo-controlled trials in this important field of dermatology. In addition, there are only a few useful comparative studies, as most combine multiple treatment modalities together to obtain satisfactory results, which makes it difficult to analyze each modality on its own.^27,45,46

Currently, the only FDA-approved filler with an indication for atrophic facial scars is PMMA, which requires a skin test due to its bovine collagen. In a trial where success was rated as a 2-point improvement on a 4-point scale, 64% and 33% of subjects receiving PMMA and saline, respectively, achieved this improvement. A major concern and limitation of PMMA is the creation of a permanent visible bump, especially since superficial placement is often required for optimal projections and correction. On the other hand, HA's reversibility lends to a better risk profile when placed high in the dermis.

The current leading cosmetic dermal filler is HA, since it is safer (low allergenicity and ability to be reversed) and efficacious. Previous studies on atrophic scars showed that HA treatments had high satisfaction rates with mild transient side effects such as bruising, erythema, and pain.^2–5,7,8 One article published a technique utilizing retrograde vertical injections of HA bringing the product into the superficial dermis with over 70% resolution.⁴ The article also noted the importance of the creation of superficial blebs in the dermis that are massaged out,⁴ something that should not be done with PMMA. Overall, most patients (11/12) in this study rated themselves as improved with less side effects than expected, highlighting that this should be considered as a first-line treatment for rolling atrophic scars due to its ease of use for both practitioners and patients, as well as its efficacy and side effect profile.

While most HA fillers have an indication for 12 months, recent studies have shown HA fillers to last many years, in fact over 10 years in several publications,^43,47 especially in certain areas. The misperception that HA fillers are only a short-term solution comes from their use with rhytids, where the area continues to undergo the same motion that caused the original rhytid. This movement likely pushes the filler away before it is completely metabolized. Since the inflammation or trauma that caused the atrophic scar is not repeated, HA fillers last much longer for this indication. In fact, the subject with the longest recorded end point (810 days) was chosen for further computer analysis and had no loss of improvement using 3D volumetric data analysis (Figure 1A–C and Table 2). Similarly, most subjects appeared to improve over the 2 years as presented in Table 1. As HA fillers degrade into smaller particles, there is more surface area to bind water. While this can lead to an unwanted side effect of filler swelling for large boluses of filler, the water around the microdroplets used for atrophic scars likely leads to continual improvement. Finally, VYC-17.5L was chosen for this indication because it is the VYCROSS technology (Allergan Inc., Irvine, CA), creates a high degree of cross-linking which could be more resistant to degradation leading to increased longevity.⁴⁸

When assessing a scar, it is necessary to analyze the epidermis and the distensibility. Atrophic scars are commonly described as ice pick, boxcar, or rolling with rolling scars being most amenable to filler treatment. Rolling scars with sloping edges and a fully intact distensible dermis are most likely to resolve completely, while those with vertical irregular edges and/or white scarring (full thickness) will yield a minimal and often unsatisfactory response. Therefore, it is vital to manage expectations based on examination of each scar. The “Dimple Sign” is often a useful test for distensibility and can be done by putting lateral inward pressure on both sides of the scar. If a depression (dimple) is produced from underlying attachments (positive dimple sign), then it will not respond to HA filler alone. For these scars, other treatments (excision and laser) may be needed. However, if the dimple sign is negative and the atrophic scar levels out and becomes even with the surrounding skin, then it is an appropriate candidate for HA filler treatment.

While rolling distensible atrophic scars are the best candidates for HA filler treatment, boxcar scars can often be transformed into rolling scars by using a resurfacing laser, deep chemical peel, or dermabrasion to smooth out the epidermal surface irregularities and edges of the scar before injecting HA filler. However, in several studies, HA filler has been destroyed by deep fractional lasers and radiofrequency.^49,50 Therefore, due to the superficial placement of HA filler for atrophic scars which leaves it vulnerable to destruction by energy-based devices, it is recommended to use the devices first before filler placement.

Analyzing atrophic scars in photographs is difficult, especially since direct light is used in most photograph systems and decreases the appearance of scars while tangential lighting can exaggerate the depth through shadows. Therefore, a live evaluator was utilized for grading the QGSGS, but a photo-analysis system (Canfield Primos) was also used to create height mapping in 1 subject, as shown in Figure 1. This height and width data could then be used to objectively measure the 3-D volume improvement in each scar. This volumetric data would be ideal to utilize on all subjects as a primary end point in future studies since often the number of scars do not decrease but the depth of those scars do. Utilizing artificial intelligence for photo-analysis creates more objective outcome measures and will likely be used in all future trials for most indications. The limitations of this study were its regional single-center study design with a small sample size.

Conclusion

There are numerous treatments for atrophic scars, but no long-term prospective trials examining efficacy and longevity. Injection of VYC-17.5L with a needle into the dermis achieved significant improvements in atrophic scarring without any significant side effects, and the improvement obtained on Day 120 was maintained to Day 720 with no significant loss of efficacy. Based on this pilot study, VYC-17.5L was efficacious in reducing atrophic rolling facial scars for up to 2 years without any long-term side effects.