Dual-Plane Treatment With Highly Concentrated Hybrid Cooperative Complexes of Hyaluronans for Facial Atrophic Acne Scars

Abstract

BACKGROUND

Managing patients with acne scars remains an important challenge, as scarring negatively affects psychosocial wellbeing. Hyaluronic acid (HA) cross-linked fillers have demonstrated good efficacy and tolerability for the correction of acne scars but are limited by their reduced biological activity and low concentrations.

OBJECTIVE

This study investigated the efficacy and safety on scars of a high-concentration (4.5%) HA-based filler with hybrid cooperative complexes (HCC) of high-molecular-weight and low-molecular-weight HA.

METHODS

Participants received treatment twice; the first was provided at baseline (T0) and the second after 4 weeks (T1). Data were collected at T1 and after 4 months (T2) by photographs and instrumental evaluation of the skin.

RESULTS

The study population included 28 patients. Improvements in the mean Goodman and Baron grade were significant across time points T0 and T1 (12% improvement; p = .0002) and T0 and T2 (31% improvement; p < .0001). Instrumental evaluation of the skin surface demonstrated a 20% reduction in the average deepness of acne scars after 4 months (p < .0001). No serious adverse events were reported during the study procedure.

CONCLUSION

Highly concentrated (4.5%) HCC appears to be an effective option for the correction of facial acne scars.

Acne vulgaris is a common inflammatory chronic skin disease, which primarily affects the face but also the upper arms, trunk, and back.¹ Although more common in adolescents and young adults, with an estimated prevalence of 42% to 74%, it can also affect adults of any age.^1,2 Acne severity can vary from mild to severe,^3,4 and atrophic acne scars can be further subclassified into rolling, boxcar, or ice pick scarring.⁵ The management of acne scars remains challenging as their appearance becomes more prominent with age due to facial collagen and fat depletion.^5,6 The significant impact of acne scarring on psychosocial and emotional wellbeing are well known and have also been reported in patients with mild atrophic scarring.^7–9

Current treatments to reduce the appearance of acne scars include skin resurfacing techniques, microneedling, dermal fillers, and surgical interventions.^6,10 While some treatments have been shown to improve scar appearance and quality of life, results are often unpredictable.^6,8,10–13

Hyaluronic acid (HA)-based dermal fillers are commonly used to improve facial aesthetics with good tolerability.^14–18 Hyaluronic acid is a glycosaminoglycan with an increased ability to retain water and is also produced endogenously, reducing the chances of allergic reactions.^19,20 Hyaluronic acid formulations can be created with different polymer configurations, including crosslinked HA, high-molecular-weight HA (H-HA), and low-molecular-weight HA (L-HA), but can be limited by their reduced biological activity and low concentrations.²¹ In vitro studies have shown improved biological activity with a combination of different molecular weight HA, which reduced HA degradation and increased collagen production.^22,23 A prospective, double-blind, randomized study in patients with acne scarring also demonstrated the superiority of a formulation created with a combination of H-HA and L-HA, compared with crosslinked dermal filler.²⁴

Profhilo Structura, a new HA-based dermal filler based on hybrid cooperative complexes (HCC) of H-HA and L-HA, has been developed, which can deliver HA at higher concentrations than traditional dermal fillers treatments.²¹ This medical device avails the same NAHYCO hybrid technology that has been on the market since 2015, but it contains 45 mg/mL (4.5%) of HA, which changes the rheological properties.^21,25 Studies have reported good efficacy and safety profiles for HCC at lower concentration (3.2%) for improving age-related skin changes.^{22,23,25–27} Moreover, retrospective case series also demonstrated the efficacy of HCC at lower concentration to treat postacne scars.^24,28 However, no clinical studies have been conducted nowadays to assess the efficacy of these medical devices for the treatment of acne scars, and new evidence is required to assess the efficacy and safety of HCC at higher concentration (4.5%) in this field. The aim of this first clinical study was to evaluate the efficacy and safety of the investigated medical device for improving the appearance of facial acne scars.

Materials and Methods

Study Design

This single-center, open-label trial included volunteers with mild-to-severe acne scars, graded using the Goodman and Baron⁴ qualitative global scarring grading classification (Table 1). Patients received highly concentrated HCC twice; the first treatment was provided at baseline (T0) and the second after 4 weeks (T1). Data were collected at these time points and 3 months after the second treatment (T2). The studied medical device contains 4.5% HA for intradermal use (45 mg H-HA + 45 mg L-HA, dissolved in 2.0 mL of saline buffered sodium chloride) derived from nonanimal origin by bacterial fermentation and is delivered using a dual-plane injection technique.²⁶ First, each appropriate scar (ice pick, rolling, and boxcar scars) was marked and the injection site was outlined. Acne scar condition and tethering to the base was evaluated by a gentle pinching of the tissue around the scar. Then, each acne scar was intradermally injected with 0.02 to 0.1 mL of 4.5% HCC using a 29 G needle. Then, an entry point adjacent to each scar or scarred area was identified and the 25 G cannula was inserted into the superficial subcutaneous tissue to perform a subcision and leave a small deposit of material. A total of 0.5 to 2 mL of the product has been used depending on acne scars.²⁶ This clinical study has been registered on ClinicalTrials.gov (NCT05691049).

TABLE 1.

Goodman and Baron Global Acne Scarring Classification

Grade	Characteristics	Examples of Scars/Lesions
1: Macular	Erythematous, hyperpigmented or hypopigmented visible flat marks, irrespective of the distance	Erythematous, hyper or hypopigmented flat marks
2: Mild	Mild atrophy or hypertrophy that may not be obvious at ≥50 cm distance and can be adequately covered by makeup or the normal shadow of shaved beard hair in men	Mild rolling, small soft papules
3: Moderate	Moderate atrophic or hypertrophic scarring that is obvious at ≥50 cm distance and cannot be covered by makeup or the normal shadow of shaved beard hair in men but is still able to be flattened by manual stretching of the skin	More significant rolling, shallow boxcar, boxcar, mild-to-moderate hypertrophic or papular scars
4: Severe	Severe atrophic or hypertrophic scarring that is obvious at ≥50 cm distance and cannot be covered by makeup or the normal shadow of shaved beard hair in men but is not still able to be flattened by manual stretching of the skin	Punched-out atrophic (deep boxcar), ice pick, bridges and tunnels, gross atrophy, dystrophic scars, significant hypertrophy or keloid

Adapted from Goodman and Baron.⁴

Study Participants

Sample size has been calculated based on the incidence of adverse events (AEs) over the entire duration of the clinical study, considering a minimum of 20 patients for the enrollment. The probability that 1 or more AE did not occur in a sample of 20 patients with an anticipated incidence rate of AE of 20% was 5% (95% of power of the investigation has been planned for this evaluation). Therefore, a total of 30 volunteers with Fitzpatrick phototypes from 1 to 3 and aged older than 18 years were enrolled for the replacement of up to 25% of nonevaluable patients (dropouts). To be eligible, participants agreed to not alter their diet, physical activity, facial cosmetics, and cleansing products and to not expose their face to strong UV irradiation during the trial period. Participants agreed to refrain from using cosmetics at least 2 hours before each visit. Exclusion criteria included: HA injections, radiofrequency, and toxin treatments 6 months before the start of the trial, smoking, known allergies to components of the treatment, and pregnancy. Participants were also excluded if they had a diagnosis or were presenting with dermatitis, herpes, psoriasis, severe rosacea, scleroderma, local infections, and severe acne. Individuals with other diseases such as diabetes and cancer and those dependent on pharmacological treatments for their acne were also not eligible.

Data Collection and Assessments

Data were collected and assessed through 2 methods: (1) photographs taken with a Kodak DC 290 digital camera at each time point were used by a blinded evaluator (a specialized dermatologist) to grade acne scarring according to the Goodman and Baron global classification (Table 1), and T0 was compared with T1 and T2; (2) instrumental measurements of acne scars depth at T0 and T2 by profilometry were collected using the PRIMOS compact portable device (GFMesstechnik). PRIMOS provides a standardized and reproducible 3D quantitative measurement of the skin surface and directly compares images of the skin across time points. This analysis was performed on an area of skin 6 cm² with an average of 10 radial measurements. PRIMOS instrument is able to recreate 3D skin replicas at each considered scar, performing fringe projection analysis and performing profilometry measurement of acne scars height (deepness). Photographs were also used by the blinded evaluator to evaluate global aspects of the participants’ faces across time points according to the Goodman and Baron scoring. Local reactions induced by the injection and any systemic adverse events were also collected by the study investigators during a 6-month period. Any adverse events with a reasonable causal relationship to the studied medical device were to be reported as adverse device effects.

Statistical Analyses

Baseline characteristics were calculated using descriptive statistics (median and range). The Goodman and Baron grades and profilometry values were reported as means with standard deviations, and statistical analyses were carried out using a parametric unpaired t-test (GraphPad v10.0). The global facial clinical evaluations were reported according to improvement over time and recorded as number and percentage of participants who had significantly improved, improved, slightly improved, or had no improvement over time.

Results

Study Population

This study enrolled 30 participants with acne scars at DermIng S.r.l., Clinical Research and Bioengineering Institute in Milan, Italy. The final study population included 28 patients; 2 patients dropped out due to undisclosed personal reasons. Median age was 49 years (range 20–68), and 25 were females (89.3%). At baseline the mean Goodman and Baron grade was 2.6 ± 0.35 (range: 2–4).

Efficacy

Improvements in the mean Goodman and Baron scarring grade were significant across time points T0 and T1 (2.3 ± 0.2; 12% improvement; p = .0002) and T0 and T2 (1.8 ± 0.26; 31% improvement; p < .0001) (Figure 1A). Global clinical evaluations reported that 9 participants (32%) had significantly improved grades and 10 (36%) had improved grades (Figure 1B). Photographs of 2 participants are shown in Figure 2 and demonstrate an improvement in scarring 4 months post-treatment. Instrumental evaluation of the skin surface demonstrated a 20% reduction in the average deepness of acne scars after 4 months (p < .0001; Figure 3).

Figure 1.

Goodman and Baron global scarring grade evaluation at baseline (T0) and 1 and 4 months after the beginning of the treatment (T1 and T2, respectively). (A) Mean grades across time points, compared with baseline. (B) Clinical evaluation of global facial features evaluated 4 months after the beginning of the treatment (T2).

Figure 2.

Photographs of 2 participants at baseline and 4 months after beginning of the treatment (T2), demonstrating visible improvements in acne scarring 4 months post-treatment.

Figure 3.

Mean profilometry measurements 4 months after beginning of the treatment (T2) compared with baseline.

Safety

No unexpected or serious adverse events were reported during the study procedure and after 6 months of follow-up.

Discussion

Postacne scars are a common and ongoing challenge affecting a large proportion of the population and often cause a significant negative impact on quality of life.^2,7–9 There remains an unmet need for effective and simple treatments providing immediate and sustained improvements in the appearance of postacne scars. Dermal fillers are a popular and attractive nonsurgical choice for atrophic scarring due to their easy administration and immediate visible improvements.⁵ This study demonstrated that highly concentrated (4.5%) HCC is an effective and well-tolerated option for the treatment of postacne scars, with sustained improvements over time. There were no treatment-related adverse events reported during the study.

Hyaluronic acid formulations are characterized by their molecular weight, polymer composition, and concentration. A major challenge in the use of HA is its relatively short half-life, meaning crosslinking techniques are often required to promote HA treatment longevity.²⁰ Crosslinked HA can more often lead to greater toxicity compared with linear HA.²⁰ Crosslinked HA-based dermal fillers often demonstrate immediate results and good tolerability profiles but do not promote sustained improvements over time as they do not alter the biological and cellular function described with endogenous HA.²⁴ The studied medical device is manufactured with noncrosslinked HCC of H-HA and L-HA, which maintains the natural properties of endogenous HA but comparable longevity to crosslinked formulations.^{21–24,27,28} Hybrid cooperative complexes enables both L-HA and H-HA to be present in a single injection. L-HA has been shown to bind to receptors that stimulate fibroblasts and keratinocyte differentiation, also improving the appearance of aged skin that is known to worsen the appearance of acne scars.²⁸ H-HA has a high capacity for water retention and can interact with collagens and proteoglycans to alter dermal structure.²⁸ The longer half-life of the studied medical device and its enhanced activity may translate to fewer injections over time and improved quality of life for patients living with acne scars. These hypotheses require testing in future clinical trials.

This study had a few limitations. The study favored female participants so the results may not be representative of the entire population. This study only reported 4-month post-treatment outcomes, therefore reporting medium-term and longer-term outcomes with ongoing studied medical device treatments would provide additional insights into the effects over time. Randomized controlled trials alongside other standard treatments would also provide greater efficacy and safety insights across different postacne scarring treatments.

Conclusion

The investigated medical device is an effective and well-tolerated method to treat facial atrophic acne scars. Although further studies are needed, the benefits of this HCC HA-based formulation can be related to its higher concentration and procollagenogenic and anti-inflammatory properties.

Ethics Statement

Compliance with Ethical Standards: EC approval on Oct 2022; study code: E0622. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Conception or design of the study: A.S and G.B. Acquisition, analysis, or interpretation of data: A.S. Review of manuscript: All authors, Final approval of manuscript: All authors, Accountable for all aspects of the work: All authors.