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Objective Analysis of Poly-L-Lactic Acid Injection Efficacy in Different Settings

Byun, Sang-Young MD*; Seo, Koo-IL MD; Shin, Jung-Won MD*; Kwon, Soon-Hyo MD*; Park, Mi-Sook NR*; Lee, Joshua SD; Park, Kyoung-Chan MD*; Na, Jung-Im MD*; Huh, Chang-Hun MD*

doi: 10.1097/DSS.0000000000000552
Original Article
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BACKGROUND Poly-L-lactic acid (PLLA) filler is known to have continuous volume effect.

OBJECTIVE The objective of this study is to analyze objective volume effect of PLLA in different settings of injection schedule on the cheek.

METHODS A split-face, evaluator-blind randomized study in 24 volunteers was conducted. One side was injected 3 times with 4 cc dose and the other side was injected 2 times with 6 cc dose per visit. Facial volume loss scale (FVLS) and Vectra were evaluated.

RESULTS Measured average FVLS showed statistically significant improvement both in 3 and 2 times injection sides and maintained efficacy until 12 months. Vectra showed volume difference (cc) between before and after injection. In 3 times injection side, it was increased 2.12 (after 1 month) to 3.17 (after 12 months). In 2 times injection side, it was increased 2.26 (after 1 month) to 3.19 (after 12 months). Gradual volume improvement over 12 months was statistically significant in both sides. There was no statistically significant difference between 3 and 2 times injection in FVLS and Vectra. There was no severe adverse event.

CONCLUSION Poly-L-lactic acid has continuous volume effect and there was no significant difference by injection times at the same total injection volume.

*Department of Dermatology, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, Korea;

Modelo Clinic, Seoul, Korea;

College of Medicine, Emory University, Atlanta, Georgia

Address correspondence and reprint requests to: Chang-Hun Huh, MD, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-707, Korea, or e-mail: chhuh@snu.ac.kr

Handok pharmaceuticals provided support and materials (Sculptra; Dermik Laboratories, Bridgewater, NJ, Sanofi-Aventis U.) for this study.

S.-Y. Byun and K.-I Seo contributed equally to this work.

A poly-L-lactic acid (PLLA), named Sculptra (Sanofi-Aventis U, Dermik Laboratories, Bridgewater, NJ), is being used as a gradual volume restoration treatment with the added effect of collagen stimulation. It has been an approved treatment as wrinkle filler in Europe since 1999, and in 2009, the US Food and Drug Administration (FDA) approved it for volume loss treatment in the general population.1

The mechanism of action of PLLA is inducing collagen synthesis and fibroblast proliferation.2 This reaction is believed to be due to the inflammatory response caused by the presence of a foreign body compound (PLLA). However, PLLA is known to have a minimal risk of immune reactions because of its biocompatibility.3

Most fillers, such as hyaluronic acid and collagen, have a volumizing effect, solely through the persistence of the filler material, such that it induces a direct and passive response. Unlike these fillers, an injection of PLLA is continuously resorbed while also increasing collagen levels, resulting in a long-lasting volumizing effect for approximately 2 to 3 years or longer.4,54,5 However, PLLA usually requires multiple injections and takes a longer time than other fillers for its volumizing effects to take place.3

The Vectra-CR 3D camera system (Canfield Imaging System, Fairfield, NJ) is designed to accurately capture the surface of the body shape, contour, and color of parts of the body by interpreting it as a 3-dimensional anatomical structure. After consideration of its 3D applications with respect to the purpose and goal of this trial, the authors selected the Vectra system to measure objective volume differences in the selected area.6–86–86–8

The authors administered differing sets of injection schedules on either cheek of the subjects and recorded the change in volume of the immediate area using the facial volume loss scale (FLVS) and Vectra measurements over time.

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Methods

Study Design

This study is a Level I study, which is a single-center, split-face, evaluator-blind, randomized study. Approval of the hospital institutional review board (IRB) was obtained before initiation of the study. The IRB number is B-1203/147-002.

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Subjects

A total of 24 volunteers, more than 30 years, with a facial volume loss scale (FVLS) Grade of 2 or 3 were enrolled. Sample size was determined by a previously reported clinical study, which supported the PLLA's efficacy using 19 volunteers. With respect to this study, the authors concluded that at least 20 volunteers were required to obtain significant data about the efficacy of PLLA filler treatments. Twenty-four volunteers were accepted for this trial with an expectation of 15% follow-up loss.

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Exclusion Criteria

  • (1) Patients with impaired blood clotting
  • (2) Pregnant patients, breast-feeding women, or patients planning a pregnancy during the clinical trial period
  • (3) Patients with an infectious skin disease of the face
  • (4) Patients who received any treatment affecting the shape and volume of the face within the last 6 months
  • (5) Patients planning to get another dermatologic or plastic surgical procedure during the clinical trial period
  • (6) Patients involved in other clinical trial
  • (7) Patients unable to communicate or having difficulty after procedures as instructed
  • (8) Patients deemed unsuitable for this trial according to the clinician's discretion.
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Procedure

One vial of PLLA filler powder was mixed with 8 cc of injectable normal saline solution, 24 hours before the procedure, and 2 cc of 2% lidocaine was also mixed in the vial immediately before the procedure. The face of each volunteer was divided in 2 zones along the nose with each side being randomly assigned a dosage plan. On one side, the cheek was injected with PLLA filler at a volume of 4 cc per visit at Weeks 0, 4, and 8, whereas the other side was injected with a volume of 6 cc per visit at Weeks 4 and 8. The total filler dosage volumes administered by the end of the treatment were identical at 12 cc. Immediately after each injection, the practitioner gently massaged the surface of the volunteer's cheek using the finger tips of one hand while supporting the cheek from within the intraoral cavity with the fingers of the other hand.

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Evaluations

The FVLS is divided by 5 grades (Figure 1). All subjects were graded by a single investigator, and the objective volume difference was obtained using the Vectra-CR 3D camera system. Evaluations were conducted at 5 timepoints: once before the injection and also 1, 3, 6, and 12 months after the final injection. The primary evaluation of this study was performed by the observation of volume change after the PLLA injections were administered and the secondary evaluation was conducted by comparing the 2 different injection schedules.

Figure 1

Figure 1

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Vectra-CR 3D Camera

The Vectra-CR 3D camera system (Canfield Imaging System, Fairfield, NJ) is able to measure the volume difference of a selected area between 2 images. First, landmarks are assigned on the face and borders are drawn (Figure 2A). Second, the Vectra imaging software is used to calculate the volume difference of fixed space between the 2 selected images (Figure 2B). As a result, the authors can obtain volume differences of the face between 2 different points in time.

Figure 2

Figure 2

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Statistical Analyses

For statistical analyses, a paired t-test was used for evaluation of the change of FVLS and the evaluation of the FVLS and Vectra comparison between the 2 different injection schedules. A generalized linear model was used for the evaluation of the change of Vectra measurements. All data were analyzed using the SPSS software (version 20.0; SPSS Inc., Chicago, IL). A p value of < 0.05* or <0.005** was considered statistically significant.

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Results

Participants' Demographics

The mean age of the 24 volunteers was 48.1 ± 7.9 (range, 31–65 years). Four volunteers dropped out for personal reasons and 20 volunteers completed this study.

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Facial Volume Loss Scale

The FVLS measurements before the injections and at 1, 3, 6, and 12 months after the final injection were 2.25, 1.70, 1.20, 1.30, and 1.30, respectively, on the 3-dose side and 2.20, 1.65, 1.20, 1.10, and 1.25, respectively, for the 2-dose side. The FVLS showed statistically significant improvement over 3 months for the 3-dose treatment and 6 months for the 2-dose treatment after the final PLLA filler injection had been given and maintained efficacy for 12 months after the last injection (Figure 3). The FVLS grade gap was obtained by taking the grade preinjection and subtracting the grade postinjection. The differences at 1, 3, 6, and 12 months were 0.55, 1.05, 0.95, and 0.95, respectively, at the 2-dose side and 0.55, 1.00, 1.10, and 0.95, respectively, at 3-dose side. There was no statistically significant difference observed by comparing the 3-dose treatment with 2-dose treatment schedule (Figure 4).

Figure 3

Figure 3

Figure 4

Figure 4

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Vectra-CR 3D Camera

The Vectra value (cc) was obtained by taking the difference between volumes preinjection and 1, 3, 6, or 12 months postinjection. Overall, the average Vectra value continuously increased from +2.19 to +3.18 after 1 month to 12 months after the final injection (Table 1). The Vectra value was +2.12, +2.69, +2.79, and +3.17, respectively, for the 3-dose treatment and +2.26, +2.18, +2.47, and +3.19, respectively, for the 2-dose treatment. Vectra showed a statistically significant continuous volume increase over a 12-month period after the last injection (Figure 5). However, there was no statistically significant difference when comparing the Vectra measurements of 3-dose volumes with 2-dose volumes.

TABLE 1

TABLE 1

Figure 5

Figure 5

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Adverse Effects

There were no severe adverse effects except for 1 patient presenting with stinging pain in the immediate area of the injection site, which subsided after 1 week of using analgesics.

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Discussions

Poly-L-lactic acid is a filler, which has a continuous volume improvement effect compared with the effects of hyaluronic acid fillers.2 Poly-L-lactic acid induces collagen synthesis and fibroblast proliferation through an inflammatory response with a minimal risk of immune reactions.3 Injection of a cross-linked hyaluronic acid may also have a stimulatory effect in collagen synthesis because of its mechanical stretching of the dermis.9 However, its effects are insufficient to induce a direct volume increase effect and may assist in volume maintenance for only approximately 6 to 9 months after the injection of hyaluronic acid.9

The efficacy and safety of the PLLA filler have been supported by several clinical studies. Since PLLA was approved for the augmentation of soft tissue and wrinkle rectification in 1999, the first large clinical study was performed by facial lipoatrophy and wrinkles in 300 patients.10 They reported an excellent and long-lasting effect of PLLA, although they insisted clinical results and side effects depended on the physician's technique. In 2004, the US FDA approved the PLLA filler under the market name, Sculptra, limited to the HIV-positive population having lipoatrophy. Concurrently, a substantial amount of clinical data supporting the efficacy and safety of the PLLA filler was reported. Moyle and colleagues11 conducted a PLLA filler injection trial on 29 subjects with HIV-related lipoatrophy and reported successful volume improvement without serious adverse effects.12,1312,13

In 2010, Narins and colleagues14 reported the efficacy and safety of injectable poly-L-lactic acid compared with human injectable collagen (Cosmoplast) for the treatment of nasolabial fold wrinkles. This study was conducted as a large, randomized, evaluator-blind, parallel-group, multicenter study with 233 subjects. According to their findings, the injectable PLLA filler significantly improved Wrinkle Assessment Scale scores and the improvement was significantly greater than that of injectable collagen at 3 months postinjection. These results became crucial for the US FDA approval of PLLA filler injections for facial aesthetics in the general population.3

A clinical study of Narins and colleagues14 was conducted using a single regimen, which consisted of up to 4 sessions in 3-week intervals. Five cc of sterile saline was used with 1 vial of Sculptra for the treatment of nasolabial fold wrinkles.14 In this study, the authors used a total of 10 cc dilution (2 cc of lidocaine + 8 cc of sterile saline), as the cheek is a much broader area compared with the nasolabial fold. Accordingly, the authors used a lower concentration of dilutions with a larger volume of Sculptra to enable broad and even distribution during the procedure.

Aside from these clinical studies, many other studies corroborate the claims concerning the efficacy and safety of the PLLA filler.15–2215–2215–2215–2215–2215–2215–2215–22 These studies usually consisted of injecting PLLA filler a total of 2 or 3 times, administered once a month and evaluated the efficacy by the investigators' subjective score of subjects or pictures of subjects. There existed neither a consistent standard of injection times nor an objective assessment of volume improvement after PLLA injections. Thus, the authors conducted this clinical study for the purpose of comparing the most commonly used injection schedules of 2 doses versus 3 doses with the same total injection volume. Second, the authors measured the efficacy of volume improvement through Vectra analysis for the evaluation of objective volume differences, in addition to an investigator's assessment of FVLS using the subjects' pictures.

The authors observed no significant difference between the 2-dose and 3-dose injection schedules by evaluation of investigator assessment in FVLS and Vectra values. Even from 1 month to 12 months after last injection, there was little difference in volume improvement between these 2 schedules (Figure 4). Considering the fact that patients treated with a 3-dose schedule need an additional visit and are thus exposed to a higher risk of injection-related side effects than patients with a 2-dose plan, the authors recommend a 2-dose injection schedule with injections administered once a month, as an appropriate baseline to obtain a significant volume improvement with minimal side effects.

In addition, the authors demonstrated the objective volumizing effect of the PLLA filler by Vectra measurements. Overall, the average volume at 1, 3, 6, and 12 months after 12 cc of PLLA injection was increased by 2.19, 2.43, 2.63, and 3.18 cc, respectively (Table 1). Although there was a sizeable amount of variation in volume increments, there were no ineffective subjects and the authors observed continuous volume increases even in the least effective subjects. Therefore, the authors report objective gradual volume increase after PLLA injection in addition to the FVLS evaluations of subject pictures by an investigator (Figure 6).

Figure 6

Figure 6

The clinical data concerning safety after the PLLA injection have been reported extensively. Narins and colleagues14 administered PLLA filler to 116 subjects. Application-site papules or nodules were the most common side effect and usually disappeared without any treatment. Nodules are also preventable by carefully massaging the site after PLLA injections.23 Mild adverse effects, such as injection-site pain, erythema, hemorrhage, pruritus, or swelling were also reported, but there were no severe adverse effects during the 25 months of follow-up. In 2014, Duracinsky and colleagues24 reported the safety of the PLLA filler through a large observational study among HIV-positive patients. Of the 4,112 patients with a combined total of 15,665 injections sessions, there was only 1 recorded case of serious adverse effects in the form of cutaneous necrosis.

This clinical study supports the previously reported data concerning safety and adverse effects. The authors encountered only a single case of an adverse effect where the subject complained of a stinging pain at the injection site, which later disappeared after 1 week of using analgesics.

This study is limited by its small sample size.

The authors report that PLLA filler has a safe and continuous volumizing effect and maintains volume efficacy for a minimum of 12 months. Additionally, there were no statistically significant differences between 2- and 3-dose injection plans at the same total injection volume.

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References

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