DERMATOLOGIC SURGERY

A randomized study of the efficacy and safety of

injectable poly-L-lactic acid versus human-based
collagen implant in the treatment of nasolabial fold
wrinkles
Rhoda S. Narins, MD,a Leslie Baumann, MD,b Fredric S. Brandt, MD,c Steven Fagien, MD,d Scott Glazer, MD,e
Nicholas J. Lowe, MD, FRCP,f,g Gary D. Monheit, MD,h Marta I. Rendon, MD,i Rod J. Rohrich, MD,j and
Wm. Philip Werschler, MDk,l
New York, New York; Miami, Coral Gables, and Boca Raton, Florida; Buffalo Grove, Illinois; Los Angeles
and Santa Monica, California; Birmingham, Alabama; Dallas, Texas; and
Seattle and Spokane, Washington

Background: Injectable poly-L-lactic acid (PLLA) is a synthetic, biodegradable, biocompatible polymer device.

Objective: We sought to compare the efficacy and safety of injectable PLLA with human-derived collagen
in treating nasolabial fold wrinkles.

Methods: In this randomized, evaluator-blinded, parallel-group, multicenter study, subjects received

injectable PLLA (n = 116) or collagen (n = 117) injections (1-4 visits, 3-week intervals). Wrinkle Assessment
Scale scores were calculated at screening; posttreatment week 3; months 3, 6, 9, and 13 (injectable PLLA or
collagen groups); and months 19 and 25 (injectable PLLA group). Safety data were obtained from subject
interviews and case report forms.

Results: Injectable PLLA significantly improved mean Wrinkle Assessment Scale scores (all time points,
P \ .001). Improvements (up to 25 months after last treatment) were significantly greater (P \ .001) than
with collagen for posttreatment months 3 to 13.

Limitations: Mostly white women and subjects with Fitzpatrick skin types II and III were included.

Conclusion: Injectable PLLA provides well-tolerated, effective, and long-lasting (up to 25 months)
nasolabial fold wrinkle correction. ( J Am Acad Dermatol 2010;62:448-62.)

Key words: aesthetic; dermal filler; injectable device; injectable poly-L-lactic acid; soft-tissue augmentation.

From the Department of Dermatology, New York University
School of Medicinea; Division of Cosmetic Dermatology,
University of Miamib; private practice, Coral Gables, Floridac;
private practice, Boca Raton, Floridad; private practice,
Buffalo Grove, Illinoise; Department of Dermatology, Univer-
sity of California-Los Angeles School of Medicinef; Clinical
Research Specialists, Inc, Santa Monicag; Departments of
Dermatology and Ophthalmology, University of Alabama at
Birminghamh; Dermatology and Aesthetic Center, Inc, Boca
Ratoni; University of Texas Southwestern Medical Center,
Dallasj; Medicine/Dermatology, University of Washington
School of Medicine, Seattlek; and Premier Clinical Research,
Spokane.l
Sponsored by Dermik Laboratories, a business of sanofi-aventis
U.S. LLC. Editorial support for this article was also provided by
Dermik Laboratories, a business of sanofi-aventis U.S. LLC, and
by the editorial staff at Medicus International and Embryon.
Disclosure: Drs Narins, Baumann, Fagien, Glazer, and Monheit were
consultants for Dermik Laboratories, a business of sanofi-aventis
U.S. LLC, during the time of the study. Dr Brandt receives grant
support from Dermik Laboratories, a business of sanofi-aventis
U.S. LLC. Dr Lowe was a consultant for and received grant
support from Dermik Laboratories, a business of sanofi-aventis
U.S. LLC, during the time of the study. Dr Rendon is a consultant
for and receives grant support from Dermik Laboratories, a
business of sanofi-aventis U.S. LLC. In addition, Dr Rendon is an
advisory board member for and receives grant support from
BioForm Medical Inc. Dr Werschler was a consultant, investiga-
tor, advisory board member, and speaker for Dermik Laborato-
ries, a business of sanofi-aventis U.S. LLC, during the time of the
study. Dr Rohrich has no conflicts of interest to declare.
Clinical trial registry: NCT00444210 (comparative study);
NCT00444353 (long-term follow-up).
Reprint requests: Rhoda S. Narins, MD, Dermatology Surgery and
Laser Center, 222 Westchester Ave, White Plains, NY 10604.
0190-9622/$36.00
ª 2009 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2009.07.040

448
J AM ACAD DERMATOL Narins et al 449
VOLUME 62, NUMBER 3

According to the American Society of Plastic The purpose of this randomized, controlled clin-
Surgeons, the use of soft-tissue fillers, including ical study was to evaluate the efficacy and safety of
calcium hydroxylapatite, collagen, fat, and hyalur- injectable PLLA and to compare it with a commer-
onic acid, for soft-tissue augmentation increased cially available human-derived collagen for the cor-
133% from the year 2000 to 2007.1 The increase in rection of mild to severe nasolabial fold wrinkles
the popularity of soft-tissue fillers is understandable, (NLFW) in immunocompetent subjects. The active
particularly because they are noninvasive and are comparator used in this study, highly purified human
effective for restoring lost collagen (CosmoPlast,
volume and for correcting Allergan-Inamed, Irvine, CA),
contour deficiencies to the CAPSULE SUMMARY is chemically cross-linked us-
aging face. However, the du- ing glutaraldehyde and
d To our knowledge, this study is the first
ration of effect of these fillers suspended in phosphate-
randomized, comparative clinical study
is limited: a few months for buffered physiologic saline
to demonstrate the efficacy, safety, and
autologous fat transfer and containing 0.3% lidocaine. It
tolerability of injectable poly-L-lactic acid
collagen (human or bovine is approved in both the
for the treatment of nasolabial fold
derived), and approximately European Union and the
wrinkles in a healthy, immunocompetent
12 months for hyaluronic United States for the correc-
population.
acid preparations and tion of soft-tissue contour
calcium hydroxylapatite.2-5 d
This study establishes the extended deficiencies, such as wrin-
Therefore, it is desirable to duration of effect (25 months) of kles and acne scars.24 It has
identify injectable materials injectable poly-L-lactic acid for the been found to be immuno-
for soft-tissue augmentation treatment of nasolabial fold wrinkles. logically inert, and subjects
that have a duration of effect d
The results of this randomized, do not require a skin test
that extends beyond what is comparative study support the use of a before treatment.25 The
currently available. One such novel injectable dermal filler for soft- safety and efficacy of colla-
category of injectable agents tissue augmentation. gen products have largely
consists of poly-L-lactic acid been inferred from the safety
(PLLA), which has a demon- and efficacy record of
strated use for medical devices.6 bovine-derived collagen.
PLLA is a synthetic, biodegradable, biocompatible, The primary objective of this study was to evalu-
and immunologically inert polymer device derived ate the degree of correction attainable, using the
from the alpha-hydroxy-acid family, and it has a long mean change from baseline in Wrinkle Assessment
history of safe use in numerous therapeutic applica- Scale (WAS) scores, with injectable PLLA compared
tions.7-16 Polylactides are used as resorbable suture with human-based collagen in the treatment of
materials in ophthalmologic, neurologic, and thoraco- NLFW at month 13 after the last injection of study
abdominal surgery; are widely used as support mate- treatment. Secondary objectives in the comparative
rials in maxillofacial surgery, periodontology, and 13-month study included global investigator and
stomatology; and are used as carriers for the prolonged subject evaluations of treatment, subject treatment
delivery of several therapeutic agents.7,10,11,17-19 More satisfaction scores, time to peak correction, and
recently, PLLA has become the focus of attention by treatment success rate. This article reports the mean
aesthetic dermatologists and plastic surgeons. change from baseline in WAS scores. The results of
Injectable PLLA is marketed under the trade name the global investigator and subject evaluations of
Sculptra (Dermik Laboratories, a business of sanofi- treatment, and subject treatment satisfaction scores
aventis U.S. LLC, Bridgewater, NJ) and consists of a will be presented in subsequent reports. The primary
lyophilized preparation composed of PLLA micro- safety objective was the overall incidence of adverse
particles, sodium carboxymethylcellulose, and non- events (AEs) reported during the 13-month follow-
pyrogenic mannitol.20,21 Injectable PLLA is approved up period, regardless of severity, onset, duration, or
in the United States for use in immune competent relationship to study treatment. After the compara-
people as a single regimen for the correction of tive treatment phase, subjects receiving injectable
shallow to deep nasolabial fold contour deficiencies PLLA were followed up for an additional 12 months
and other facial wrinkles in which deep dermal grid (the long-term surveillance phase) to collect safety
pattern injection technique is appropriate.22 and efficacy data. In the long-term surveillance
Injectable PLLA is also approved for the restoration phase, only subjects treated with injectable PLLA
and/or correction of the signs of facial fat loss were scheduled to return for follow-up visits at
(lipoatrophy) in people with HIV.23 months 19 and 25 after their final study treatment.
450 Narins et al
Abbreviations used:
AE: adverse event
CRF: case report form
NLFW: nasolabial fold wrinkles
PLLA: poly-L-lactic acid
WAS: Wrinkle Assessment Scale
METHODS
Study design
This was a randomized, evaluator-blinded,
parallel-group, multicenter clinical trial with screen-
ing, treatment, and posttreatment follow-up phases.
At visit 1, subjects were screened for nasolabial fold
severity (only subjects with a grade of $ 2 and # 4
on the photonumeric WAS were to be enrolled in
the study), and eligible subjects gave their written,
informed consent to participate in the study. The
treatment phase consisted of one to a maximum of 4
visits at 3-week intervals. Subjects were randomized
to treatment with either injectable PLLA or human
collagen at the first treatment visit (visit 2). Because
a skin hypersensitivity test is not required before
use, human collagen was chosen as the comparator
for this study. At each treatment visit, subjects
received injections of the randomized study material
into the left and right NLFW. Subjects underwent
treatment sessions until optimal correction (score of
0-1 on the WAS for both nasolabial folds) had been
achieved.
The follow-up phase consisted of visits at week 3
and months 3, 6, 9, and 13 after the last comparative
study treatment injection session, and visits at
months 19 and 25 for the long-term surveillance
phase of the injectable PLLA group only.
Standardized photographs were taken at screening
and at all treatment and follow-up phase visits.
Efficacy evaluations were made from these photo-
graphs using a validated, standardized, photonu-
meric scale26 by an independent, blinded committee
of 3 evaluators. The safety and tolerability of the
study products were assessed from AE data collected
at each visit (up to 13 months after the last study
treatment for the human-collagen group, and up to
25 months after the last study treatment for the
injectable PLLA group). Only device-related AEs
were collected on the case report form (CRF) for
the subjects treated with injectable PLLA during the
long-term surveillance phase (months 19 and 25
follow-up visits). The study was conducted in accor-
dance with good clinical practice, conforming to the
ethical principles of the Declaration of Helsinki. In
addition, the clinical study protocol, informed con-
sent documents, and all other appropriate study-
J AM ACAD DERMATOL
MARCH 2010
related documents were reviewed and approved by
a duly constituted institutional review board.
Study population
A total of 240 subjects were planned to be enrolled
in the study (120 per treatment group), with 24
subjects at each of the 10 sites. Assuming that fewer
than 20% of subjects would discontinue during the
follow-up period, this sample size was predicted to
provide greater than 99% power to detect a 1.0-U
difference between treatment arms in improvement
in WAS score at month 13, assuming SD of 0.9.
Subjects seeking treatment for dermal contour de-
formities of the nasolabial fold area were recruited
from the investigators’ outpatient populations.
Subjects were required to be 18 to 75 years of age,
of any race or sex, and female subjects were required
to have been postmenopausal for at least 1 year or to
have had a hysterectomy/tubal ligation. Women of
childbearing age were required to agree to use an
approved method of birth control throughout the
study. Women who were pregnant, planning to
become pregnant in the next 13 months, or nursing
were excluded from the study.
To proceed to the treatment phase, subjects were
required to have a grade of $ 2 and # 4 on the
photonumeric WAS of both the left and right naso-
labial folds at the first visit, as assessed by the treating
investigator and confirmed by a blinded indepen-
dent screening evaluator. Subjects were excluded if
they had a personal history of allergic/anaphylactic
reactions, a known history of keloids or bleeding
disorders, or an active inflammatory process in the
nasolabial area. Subjects who developed any clini-
cally important disease within 3 months of study
initiation, as judged by the investigator, were also
excluded from the study. To eliminate the possibility
of additional cosmetic treatments confounding the
results, subjects who had undergone recent treat-
ments or who planned to undertake such treatments
during the course of the study were also excluded
from the study. These treatments included botuli-
num toxin type A below the level of the zygomatic
arch within 6 months of visit 1, nonpermanent
cosmetic filler-type products (eg, bovine collagen)
in the facial area within 1 year of visit 1, and
permanent cosmetic filler-type products (eg, sili-
cone) in the facial area at any time before or during
the comparative study. Deep dermal resurfacing
procedures and superficial dermal resurfacing pro-
cedures in the facial area were exclusionary if they
had been undertaken within 6 months and 6 weeks
of visit 1, respectively. The following medications
were also grounds for exclusion: prescription facial
J AM ACAD DERMATOL
VOLUME 62, NUMBER 3
wrinkle therapies or topical steroids within 4 weeks
of visit 1 and during the study, immunosuppressive
medications within 6 months of visit 1 and during the
study, antiplatelet therapy within 72 hours before
treatment, and anticoagulant therapy 2 weeks before
or during treatment. However, for the long-term
surveillance phase there were no prohibited con-
comitant treatments or procedures. These concom-
itant treatments or procedures were to be captured in
the CRF.
Method of administration
To maintain single-blind conditions, subjects
were blindfolded during the treatment sessions and
were not informed of what treatment had been
administered. Injectable PLLA was supplied as vials
of lyophilized powder and reconstituted with 5 mL of
sterile water for injection. After the addition of sterile
water for injection under aseptic conditions, the vial
was left to stand for at least 2 hours and then it was
gently agitated immediately before injection to ob-
tain a uniform suspension. Treatment with injectable
PLLA consisted of one to a maximum of 4 treatment
sessions at 3-week intervals until optimal cosmetic
correction was achieved. Each treatment session
consisted of multiple deep dermal injections of
approximately 0.1 to 0.2 mL into the left and right
nasolabial folds (up to a maximum of 2.5 mL/side, or
5 mL total/treatment session) using a 26-gauge sterile
needle. This injection method for injectable PLLA is
similar to that reported by Woerle et al.27
Human-based collagen was supplied as individ-
ual sterile treatment syringes packaged with 30-
gauge needles. The treatment consisted of one to 4
treatment sessions at 3-week intervals, until an
optimal cosmetic correction was achieved. Each
treatment session consisted of multiple mid-dermal
to deep dermal injections into the left and right
nasolabial folds, according to the package insert.
Study treatment injections (injectable PLLA or hu-
man collagen) were stopped when both nasolabial
folds reached a WAS grade of 0 to 1. In the case
where one nasolabial fold reached optimal correc-
tion (WAS grade of 0-1) before the opposite side,
then no further injections were made to the side at
full correction. Injections were continued in the side
requiring additional treatment until full correction
was attained (up to 4 treatment sessions). Correction
was limited to no more than 100% of the baseline
defect.
Efficacy assessments
Efficacy assessments were based on the evalua-
tion of standardized photographs of each subject’s
nasolabial folds using the validated WAS. A
Narins et al 451
stereotaxic positioning device was used to keep the
subject’s head in a fixed position in relation to
camera distance, flash, and lighting. During the
treatment phase, subjects were photographed before
any administration of study treatment. Photographs
were taken of the nasolabial folds during screening
and at all treatment and follow-up visits. After the last
subject completed the 13-month follow-up visit, all
standardized photographs of the left and right naso-
labial folds were collated and randomized according
to a prespecified procedure. This efficacy assessment
methodology also was applied for the follow-up
visits in months 19 and 25 for the subjects in the
injectable PLLA group. Randomization was per-
formed at the level of subject, treatment, and time
point to mask the evaluator completely. Eligible
subjects were randomized into one of two treatment
groups (injectable PLLA or human collagen), strati-
fied by age (\55 or $ 55 years).
Physician and subject blinding
Because of the differences in physical character-
istics for the two products, it was not possible to
double blind the trial. Therefore, the treating physi-
cian and other clinical site personnel were aware of
the treatment (unblinded). A nonbiased evaluation
of treatment efficacy was accomplished by using an
independent committee of 3 physicians, who did not
participate in the administration of the study treat-
ments, to conduct blinded evaluations of the stan-
dardized photographs. The evaluating physicians
were board-certified dermatologists and plastic sur-
geons. There was no interaction between the treating
physicians and the evaluation committee. The sub-
jects were asked to guess their treatment assignment
at each study visit to assess the effectiveness of
blinding techniques.
Photographic assessment of NLFW
Comparative 13-month follow-up phase. After
the last subject had completed the 13-month follow-
up visit, all standardized photographs of the left and
right nasolabial folds were batched and randomized
according to a prespecified procedure. Each photo-
graph was separately graded in a blinded manner by 3
independent evaluators. Evaluators independently
classified the severity of both the left and right
nasolabial folds (separately) by comparing the sub-
ject’s photograph with the pictures on a 6-point,
photonumeric scale to assess WAS,26 with a score
of 0 = no wrinkles; 1 = just perceptible wrinkle;
2 = shallow wrinkle; 3 = moderately deep wrinkle; 4 =
deep wrinkle, well-defined edges; 5 = very deep
wrinkle, redundant fold.
452 Narins et al
Fig 1. Subject disposition diagram.
The average of the left and right grades was
calculated for each subject by each evaluator and
the median grade of 3 average grades from each
evaluator was used in the analysis of treatment effect.
Wrinkle assessments were based on a snapshot at a
specific time point and were not based on a com-
parison with the pretreatment photographs. The
WAS score was used as an initial screening tool at
visit 1 to qualify subjects for entry into the study
(subjects were required to have a score of either $ 2
or # 4 for both nasolabial folds at entry) and during
the treatment phase to determine if further treat-
ments were needed. To assess the effectiveness of
the blinding procedure, evaluators were also asked
to guess the treatment assignment for each photo-
graph. Subject and physician evaluations were then
compared with the actual treatment given and the
degree of concordance was evaluated. The intraclass
correlation coefficient was used to measure inter-
evaluator reliability to assess the amount of agree-
ment between the rating physicians. The intraclass
correlation coefficient was calculated using an anal-
ysis of variance with factors for subject and physi-
cian, and a P value was reported from the analysis of
variance to indicate whether there was significant
agreement among the evaluators.
J AM ACAD DERMATOL
MARCH 2010
Long-term surveillance phase
Similar to the comparative follow-up phase,
all standardized left and right nasolabial fold
photographs taken at the month-19 and -25 visits
(injectable PLLA group only) were batched and
randomized according to a prespecified procedure
after the last subject had completed the long-term
surveillance phase. The same grading process, WAS
scoring, and board-certified plastic surgeons/derma-
tologists were used in the evaluation of these pho-
tographs as had been used in the comparative phase.
Safety assessments
At screening, the subject’s medical history and
prior or concomitant medications and treatments
were assessed, and a physical examination was
performed. Blood and urine specimens were also
obtained to assess general health and eligibility.
During all subsequent visits, subjects were inter-
viewed regarding treatment success, AEs, and med-
ication use. AEs occurring during the observation
period were recorded on a CRF.
Subjects assessed the severity (mild, moderate,
or severe) and duration (\1 hour, 1-24 hours, 2-7
days, 8-14 days, and $ 15 days) of injection- and
procedure-related AEs. Any injection-site pain,
J AM ACAD DERMATOL Narins et al 453
VOLUME 62, NUMBER 3

Table I. Summary of demographics and baseline Statistical analyses

characteristics (intent-to-treat population) All efficacy analyses were performed on the
Injectable PLLA,
intent-to-treat population, defined as all subjects
Injectable Human long-term who were randomized, received study treatment,
PLLA collagen surveillance and had baseline evaluations. Safety analyses were
(n = 116) (n = 117) (n = 106)
Characteristic n (%) n (%) n (%)
performed on the all-treated population, defined as
all subjects who received at least one study treat-
Sex
ment. Statistical tests were 2-sided with a significance
Male 3 (2.6) 10 (8.5)* 3 (2.8)
Female 113 (97.4) 107 (91.5) 103 (97.2) level of .05, unless stated otherwise. Tests for signif-
Age, y icance, both within- and between-treatment changes
Mean (SD) 51.2 (7.8) 51.6 (8.4) 51.5 (7.9) from baseline, were performed. The primary efficacy
Age group, y variable was analyzed using an analysis of covari-
\55 77 (66.4) 75 (64.1) 70 (66.0) ance model with covariates/factors consisting of
$ 55 39 (33.6) 42 (35.9) 36 (34.0) treatment and center, baseline wrinkle severity
Weight, lb grade, and age group (\55 and $ 55 years). The
Mean (SD) 148.3 (30.0) 143.8 (28.1) 149.3 (30.9) interaction between treatment and center was tested
Height, in at the 0.10 level and, if significant, was to be explored
Mean (SD) 64.5 (2.8) 64.6 (2.9) 64.4 (2.9)
further. Baseline characteristics were summarized by
Body mass
treatment group and displayed by descriptive statis-
index, kg/m2
Mean (SD) 25.1 (4.9) 24.2 (4.3) 25.3 (5.0) tics, frequencies, and percentages where appropri-
Race ate. Continuous variables were analyzed with
White 96 (82.8) 89 (76.1) 86 (81.1) between-group, 1-way analysis of variance.
Black 1 (0.9) 5 (4.3) 1 (0.9) Discrete variables were analyzed with Cochran-
Asian 0 (0) 1 (0.9) 0 (0) Mantel-Haenszel tests.
Hispanic 19 (16.4) 21 (17.9) 19 (17.9)
Other 0 (0) 1 (0.9) 0 (0) RESULTS
Fitzpatrick skin Subjects
typey A total of 234 subjects were randomized into the
I 11 (9.5) 5 (4.3) 10 (9.4)
study between July 19, 2004 (first subject treated),
II 39 (33.6) 43 (36.8) 34 (32.1)
and December 13, 2004 (last subject treated) (Fig 1).
III 44 (37.9) 48 (41.0) 41 (38.7)
IV 16 (13.8) 15 (12.8) 16 (15.1) The final subject completed the month-13 follow-up
V 5 (4.3) 4 (3.4) 4 (3.8) visit on January 10, 2006. In all, 233 subjects (116 in
VI 1 (0.9) 2 (1.7) 1 (0.9) the injectable PLLA group and 117 in the collagen
group) comprised the intent-to-treat population
PLLA, Poly-L-lactic acid. (one subject withdrew consent before receiving
*P \ .05 injectable PLLA vs collagen groups. treatment). A total of 16 subjects (6.9%) discontinued
y
Fitzpatrick skin phototypes range from type I (fair skinned) to
type VI (dark skinned).
the study. One of the 16, in the collagen-treatment
group, discontinued because of an AE that was not
bleeding from site(s), localized redness, bruising, related to the study treatment. Five in each of the
swelling, tenderness, itching, and other injection- treatment groups withdrew consent and a further 5,
related events were noted. All AEs (injection related all in the injectable PLLA group, were lost to follow-
and product related) that lasted for $ 15 days were up. Of the 106 subjects completing 13 months of
recorded on the CRF and coded according to body follow-up in the injectable PLLA group and continu-
system (Medical Dictionary for Regulatory Activities ing into the long-term surveillance phase, 11 (10.4%)
[MedDRA] term). Nonconventional AEs reported for discontinued before month 25: one because of an AE
the treatment area, such as lumps and bumps, which (a rash on the forehead, cheek, nose, and chin)
did not directly map into MedDRA, were coded as considered unrelated to treatment by the investiga-
application-site nodules or application-site papules, tor; 8 subjects were lost to follow-up; and two
depending on the largest size reported. Events subjects elected to withdraw from the study (with-
smaller than 5 mm in diameter were classified as drew consent).
papules and events 5 mm or larger in diameter were Demographic and baseline characteristics were
classified as nodules. During the long-term surveil- similar between treatment groups (Table I). The
lance phase of this study, only product-related AEs majority of subjects were female (220 of 233
were recorded on the CRFs and summarized in the [94.4%]), white (185 of 233 [79.4%]), with
clinical database. Fitzpatrick skin type II to III (174 of 233 [74.7%]),
454 Narins et al J AM ACAD DERMATOL
MARCH 2010

Table II. Change from baseline in Wrinkle Assessment Scale score (intent-to-treat population)
Change from baseline
Visit/wrinkle Difference in 95% Confidence
assessment score* Injectable PLLA (n = 116) Human collagen (n = 117) mean changey intervalz P value§
Wk 3 (e0.17, 0.14) .848
Mean (SE) 0.66 (0.059) 0.69 (0.062) 0.03
LS mean (SE)z 0.65 (0.057) 0.64 (0.057) 0.01
P value§ \.001 \.001
Mo 3 ( 0.89, 0.63) \.001
Mean (SE) 0.70 (0.054) 0.04 (0.056) 0.74
LS mean (SE)z 0.65 (0.050) 0.11 (0.048) 0.76
P value§ \.001 .482
Mo 6 ( 1.02, 0.75) \.001
Mean (SE) 0.73 (0.056) 0.11 (0.047) 0.84
LS mean (SE)z 0.72 (0.049) 0.17 (0.049) 0.89
P value§ \.001 .023
Mo 9 ( 1.01, 0.74) \.001
Mean (SE) 0.74 (0.058) 0.07 (0.048) 0.82
LS mean (SE)z 0.75 (0.050) 0.13 (0.050) 0.87
P value§ \.001 .132
Mo 13 ( 1.12, 0.84) \.001
Mean (SE) 0.85 (0.059) 0.09 (0.055) 0.94
LS mean (SE)z 0.83 (0.053) 0.15 (0.052) 0.98
P value§ \.001 .112
Mo 19 Not applicable
Mean (SE) 0.77 (0.065)
P value§ \.001
Mo 25 Not applicable
Mean (SE) 0.72 (0.066)
P value§ \.001

LS, Least squares; PLLA, poly-L-lactic acid.

*Based on median of 3 evaluators’ scores, where each score is average of left and right nasolabial folds Wrinkle Assessment Scale scores.
y
Difference in mean change is difference in raw mean change (or LS mean change) from baseline values between treatments.
z
Based on treatment comparison using analysis of covariance model with main effects for treatment and site and covariates for baseline
median wrinkle score and age group.
§
Within-treatment comparison obtained from paired t test.

and a mean age of 51.4 years. A significant difference
was observed between groups with respect to the
numbers of male subjects enrolled: 3 subjects in the
injectable PLLA group compared with 10 in the
collagen group (P \.05). No differences were noted
between groups in any other demographic parame-
ter or were revealed by physical examination at the
screening stage. In addition, no differences in de-
mographic or baseline characteristics were noted
between the subjects in the injectable PLLA group of
the 13-month comparative phase and those continu-
ing in the long-term surveillance phase.
Number of treatment sessions
Subjects were scheduled to receive study injec-
tions every 3 weeks (63 days) during the treatment
phase. Subjects received study treatment until opti-
mal correction was achieved (defined as a grade of 0-
1 on the WAS) with a maximum of 4 treatment
sessions during a 9-week period (63 days). The
mean number of treatment sessions required per
subject was 3.2 in the injectable PLLA group com-
pared with 2.6 in the collagen group. The mean (SD)
volume of injectable PLLA used per session for both
nasolabial folds was as follows: session 1: 4.1
(1.1) mL; session 2: 3.5 (1.2) mL; session 3: 3.3 (1.2)
mL; session 4: 3.5 (1.1) mL. For human collagen, the
mean (SD) volume used per session was: session
1: 3.1 (1.1) mL; session 2: 2.1 (1.1) mL; session 3: 1.9
(1.1) mL; session 4: 1.7 (1.0) mL.
Wrinkle assessment score at the month-13
follow-up
The injectable PLLA group achieved significantly
greater improvement in the mean change from
baseline in the WAS score versus the collagen
group at 13-month follow-up time point (P \
.001). The difference in the least squares mean
J AM ACAD DERMATOL
VOLUME 62, NUMBER 3
Fig 2. Improvement in Wrinkle Assessment Scale (WAS)
score, as shown by mean (standard error [SE]) change from
baseline by visit. Scale of figure has been reversed to show
positive improvement, correlating with decreasing WAS
values from baseline. Week 3 (W3) is first follow-up time
point after final treatment session. Subjects received
between one and 4 treatments every 3 weeks until opti-
mum correction. M, Month. *P \ .001 vs baseline; yP \
.001 vs human collagen; zonly subjects treated with
injectable poly-L-lactic acid (PLLA) (n = 106) were in-
cluded in long-term surveillance phase.
change from baseline values between treatments
was 0.98 WAS U at the 13-month follow-up. The
least squares mean (SE) change from baseline in
WAS score was 0.83 (0.053) in the injectable PLLA
group, compared with 0.15 (0.052) in the collagen
group at the month-13 time point (Table II). It is
important to note that stratification by age group
did not result in any differences. Further, injectable
PLLA-treated subjects demonstrated a significantly
greater mean (SE) overall time to peak correction
of NLFW of 192.7 (12.6) days, compared with 106.6
(10.5) days in the collagen group (P \ .001). (The
treatment phase was included in the time to peak
value).
Efficacy during the entire study period,
including long-term surveillance
Consistent and significant reductions from base-
line in mean WAS scores were observed with the
injectable PLLA group, beginning at week 3 (first
follow-up time point after final treatment session)
and continuing through to month 25 (P \.001 at all
time points) (Table II and Fig 2). Significant reduc-
tions from baseline were also observed with the
collagen group at the week-3 follow-up time point (P
\ .001), but no significant difference from baseline
was observed at months 3, 6, 9, or 13 (Fig 2). A
comparison between groups in the change from
baseline in mean WAS scores resulted in statistically
significant differences in NLFW improvement in
Narins et al 455
favor of injectable PLLA at months 3, 6, 9, and 13
(P \ .001) (Table II). Fig 3 shows photographs of
subjects with mild, moderate, or severe NLFW both
before and after (months 13 and 25) treatment with
injectable PLLA.
In the injectable PLLA group, a total of 5 subjects
reported procedures or medication use in the naso-
labial fold area during the long-term surveillance
period (which was not prohibited by the study
protocol during this phase). To ensure that these
treatments did not affect the long-term surveillance
results, the WAS data were reanalyzed excluding the
results from these 5 subjects. After excluding the
results from the 5 subjects, the mean (SE) change
over baseline in WAS score was 0.77 (0.065) for
month 19 and 0.72 (0.066) for month 25, both of
which were significant changes from baseline
(P \.001).
Safety profile at the 13-month follow-up
The majority of AEs observed in this study were
mild to moderate in intensity and self-limiting. There
were only 3 serious AEs reported in the comparative
13-month study. All 3 serious AEs occurred in the
collagen group (interstitial lung disease, throat squa-
mous cell carcinoma, and chest pain) and none were
considered to be related to the study treatment.
A higher rate of overall product-related AEs
(35.9% [42/117] vs 20.7% [24/116]) and product-
related general disorders and administrative condi-
tions (34.2% [40/117] vs 20.7% [24/116]) were
observed in the collagen group compared with
the injectable PLLA group during the comparative
follow-up phase (through month 13) (Table III).
This was primarily because of the greater incidence
of product-related injection-site erythema reported
with the collagen group (26.5% [31/117]) compared
with the injectable PLLA group (2.6% [3/116]). A
higher rate of product-related injection-site pruritus
was observed in the collagen group compared with
the injectable PLLA group (7.7% [9/117] vs 0.9%
[1/116]). Product-related application-site papules
were reported more frequently by the investigators
in the injectable PLLA group (8.6% [10/116]) com-
pared with the collagen group (3.4% [4/117]).
Product-related application-site nodule incidences
were comparable between treatment groups (col-
lagen, 6.0% [7/117] vs injectable PLLA, 6.9%
[8/116]).
Overall, a higher incidence of AEs was recorded
on the CRFs for the collagen group (63.2% [74/117])
compared with the injectable PLLA group (53.4%
[62/116]) (ie, injection-site AEs lasting $ 15 days or
noneinjection-site AEs) (Table IV). There was a
higher rate of injection-site erythema reported for
456 Narins et al J AM ACAD DERMATOL
MARCH 2010

Fig 3. Left and right nasolabial folds of subjects before (left) and 13 and 25 months after
(middle and right, respectively) treatment with injectable poly-L-lactic acid: mild (36-year-old
woman) (A), moderate (44-year-old woman) (B), and severe (57-year-old woman) (C).

collagen (32.5% [38/117]) compared with injectable
PLLA (3.4% [4/116]). In addition, higher rates (differ-
ence of [3%) of the following AEs were observed
with collagen than with injectable PLLA: injection-
site pruritus (10.3% [12/117] vs 0.9% [1/116]),
injection-site hemorrhage (5.1% [6/117] vs 1.7%
[2/116]), and application-site dryness (4.3% [5/117]
vs 0.9% [1/116]). Conversely, rates of overall appli-
cation-site papules (\5 mm in diameter) were
reported more frequently in the injectable PLLA
group (8.6% [10/116]) than in the collagen group
(3.4% [4/117]). Rates of overall application-site nod-
ules ( $ 5 mm in diameter) were similar between
collagen and injectable PLLA treatment groups (9.4%
[11/117] vs 8.6% [10/116]).
There were 5 subjects in the injectable PLLA
group and one subject in the collagen group
reporting papules lasting $ 31 days. Rates of nod-
ules with duration $ 31 days were comparable
between groups (6 subjects in the collagen group
and 7 subjects in the injectable PLLA group). No
granulomas were reported for any of the groups.
Safety profile during the long-term
surveillance phase and the entire study period
During the long-term surveillance phase, only
product-related AEs were collected, and these results
are shown in Table III. Three subjects reported 5
product-related AEs during this phase (month 13-
25), for an overall incidence rate of 2.8% (3/106).
One subject (0.9%) reported an application-site
nodule (one event), one subject (0.9%) reported
application-site pain (two events), and two subjects
(1.9%) reported application-site papules (two
events) (Table III). Uses of any concomitant proce-
dures or other medication were not reported by
these 3 subjects during the long-term phase of the
study.
Most nodule and papule events were mild or
moderate in intensity and resolved without treat-
ment. Only one nodule/papule event, from the
comparative 13-month study, received an intrale-
sional injection of corticosteroid and subsequently
resolved. No nodule or papule event required exci-
sion or any other procedures. No granulomas were
J AM ACAD DERMATOL Narins et al 457
VOLUME 62, NUMBER 3

Fig 3. (Continued)
458 Narins et al J AM ACAD DERMATOL
MARCH 2010

Table III. Incidence of product-related treatment-emergent adverse events (all-treated population)

Injectable PLLA Human collagen Injectable PLLA Long-term
Comparative phase (n = 116) Comparative phase (n = 117) surveillance (n = 106)
Adverse event Subjects* n (%) Events n Subjects* n (%) Events n Subjects* n (%) Events n
Any adverse 24 (20.7) 32 42 (35.9) 88 3 (2.8) 5
events overall
General disorders and 24 (20.7) 32 40 (34.2) 82 3 (2.8) 5
administrative
conditions overall
Application-site dryness 0 (0) 0 2 (1.7) 3 0 (0) 0
Application-site nodule 8 (6.9) 9 7 (6.0) 7 1 (0.9) 1
Application-site papule 10 (8.6) 10 4 (3.4) 5 2 (1.9) 2
Injection-site burning 0 (0) 0 1 (0.9) 1 0 (0) 0
Injection-site 0 (0) 0 2 (1.7) 2 0 (0) 0
discoloration
Injection-site eczema 0 (0) 0 1 (0.9) 1 0 (0) 0
Injection-site erythema 3 (2.6) 3 31 (26.5) 35 0 (0) 0
Injection-site hemorrhage 1 (0.9) 1 3 (2.6) 3 0 (0) 0
Injection-site induration 0 (0) 0 1 (0.9) 2 0 (0) 0
Injection-site irritation 0 (0) 0 1 (0.9) 1 0 (0) 0
Injection-site pain 6 (5.2) 7 4 (3.4) 7 1 (0.9) 2
Injection-site pruritus 1 (0.9) 1 9 (7.7) 9 0 (0) 0
Injection-site swelling 1 (0.9) 1 3 (2.6) 4 0 (0) 0
Swelling 0 (0) 0 2 (1.7) 2 0 (0) 0
Immune system 0 (0) 0 1 (0.9) 1 0 (0) 0
disorders overall
Urticaria 0 (0) 0 1 (0.9) 1 0 (0) 0
Skin and subcutaneous 0 (0) 0 5 (4.3) 5 0 (0) 0
tissue disorders overall
Acne 0 (0) 0 1 (0.9) 1 0 (0) 0
Oily skin 0 (0) 0 1 (0.9) 1 0 (0) 0
Skin tightness 0 (0) 0 2 (1.7) 2 0 (0) 0
Skin wrinkling 0 (0) 0 1 (0.9) 1 0 (0) 0

PLLA, Poly-L-lactic acid.

*Subjects experiencing multiple episodes of a given adverse event were counted once within each Medical Dictionary for Regulatory
Activities term and within each system organ class.

reported during the entire 25-month duration of the
follow-up period.
DISCUSSION
Treatment with injectable PLLA resulted in
consistent, progressive, and highly significant im-
provements from baseline in WAS score assessments
(P \.001), beginning 3 weeks after the last treatment
and continuing through to the month-13 follow-up.
The mean degree of correction achieved with inject-
able PLLA at 13 months ( 0.85 WAS U) was greater
than that obtained with collagen at any time point.
Indeed, better results were obtained with injectable
PLLA at all time points beyond week 3 (P \ .001).
The difference between groups in least squares
mean change from baseline at month 13 (of 0.98
WAS U) was also considered to be a clinically
relevant difference because the WAS validation
confirmed that integer increments are reliably differ-
entiated by observers. Importantly, the duration of
treatment effect with injectable PLLA was essentially
maintained during long-term surveillance of up to 25
months posttreatment ( 0.77 and 0.72 WAS U at
months 19 and 25, respectively).
The results from this analysis also demonstrate
that injectable PLLA treatment is associated with
gradual correction of NLFW, with a time to peak
correction of 192.7 days. These results are consistent
with those of a previous study by Valantin et al,15
which described increases in total cutaneous thick-
ness for up to 2 years after injection of PLLA in
patients with HIV-related facial lipoatrophy. The
study by Valantin et al15 also showed that the effect
of injectable PLLA treatment continued to increase
for up to 48 weeks after treatment.15 Although the
statistically significant increases in cutaneous
J AM ACAD DERMATOL Narins et al 459
VOLUME 62, NUMBER 3

Table IV. Adverse events from physician case given 3 weeks prior were assessed before adminis-
report forms experienced by $ 2% of subjects* tration of further study treatment. It should be noted,
(all-treated population, through month 13) however, that since the beginning of this study in July
Injectable PLLA Human collagen
2004, and based on their clinical experience with
Adverse events (n = 116) n (%) (n = 117) n (%) injectable PLLA, several clinicians have recommend-
No. of subjects with $ 1 62 (53.4) 74 (63.2) ed using slightly longer time periods of 4 to 6 weeks
adverse event between treatments as opposed to 3 weeks as was
Acne 3 (2.6) 4 (3.4) done in this study.20,31-33 The rationale for extending
Application-site dryness 1 (0.9) 5 (4.3) the treatment intervals to 4 to 6 weeks includes
Application-site noduley 10 (8.6) 11 (9.4) providing for the adequate assessment of the full
Application-site papulez 10 (8.6) 4 (3.4) volumetric response to the previous treatments and
Headache 5 (4.3) 4 (3.4) to minimize the potential for the occurrence of
Hypertension 3 (2.6) 0 (0) nodules and papules.20,31,34
Influenza 1 (0.9) 5 (4.3)
A higher incidence rate of overall product-related
Injection-site dermatitis 3 (2.6) 1 (0.9)
AEs (35.9% [42/117] vs 20.7% [24/116]) was observed
Injection-site erythema 4 (3.4) 38 (32.5)
Injection-site hemorrhage 2 (1.7) 6 (5.1) in the collagen group compared with the injectable
Injection-site pain 11 (9.5) 12 (10.3) PLLA group. The reason for these differences was the
Injection-site pruritus 1 (0.9) 12 (10.3) higher rates of injection-site erythema and pruritus
Injection-site swelling 1 (0.9) 4 (3.4) noted with human collagen. Although there have
Nasopharyngitis 7 (6.0) 9 (7.7) been reports of erythematous reactions for human-
Pain 3 (2.6) 2 (1.7) based collagen, the rate of persistent erythema
Sinusitis 1 (0.9) 6 (5.1) reported here (32.5%) is higher than the 1.5%
reported in a recent literature report.35 However, in
PLLA, Poly-L-lactic acid.
*Excluding injection-related events lasting \15 days.
a study comparing the efficacy and safety of hyalur-
y
Application-site nodule refers to lesions $ 5 mm, typically onic acid with bovine collagen (subjects were
palpable, asymptomatic, and nonvisible. prescreened for bovine collagen sensitivity), 24.6%
z
Application-site papule refers to lesions \5 mm, typically of the subjects treated with the bovine collagen
palpable, asymptomatic, and nonvisible. reported erythema (redness) and 5.6% reported
pruritus.36 The reason for this higher incidence of
erythematous reactions and pruritus observed in the
thickness from baseline were maintained for up to 96 current study may be the number of human collagen
weeks in this study (2 years), at week 96 the injections used compared with the number typically
improvements appeared to be trending back toward used in clinical practice. In the current study, up to 4
baseline levels.15 This gradual onset of effect with injections of human collagen were used to maintain
injectable PLLA treatment may be attributed to the the study design and the blinded nature of the study
hypothesized mode of operation, which has been as compared with a single injection in clinical prac-
suggested in preclinical and human histologic stud- tice. The overall AE profiles of the two products were
ies to involve a foreign body response that leads to similar, although the human-collagen group had a
the development of collagen.8,28 However, random- higher incidence of AEs (63.2% [74/117]) compared
ized, controlled studies are needed to fully under- with the injectable PLLA group (53.4% [62/116]).
stand the mechanisms by which injectable PLLA Product-related application-site nodule and pap-
exerts its effect. ule events associated with injectable PLLA were 6.9%
In this study of an immunocompetent population, and 8.6%, respectively, in the 13-month comparative
collagen treatment demonstrated, as expected, a phase. In the long-term phase of the study (months
significant improvement over baseline in WAS score 19 and 25) with injectable PLLA, 5 product-related
only at week-3 follow-up after last treatment AEs were reported in 3 subjects; two subcutaneous
(P \ .001). The results of this clinical trial are papules (1.9%), one nodule (0.9%), and two
consistent with what has been reported in the liter- injection-site pain (0.9%). Most nodule and papule
ature,29,30 indicating that injectable PLLA can provide events were mild or moderate in intensity, resolved
longer-term correction of NLFW than currently avail- spontaneously, and were reported as nonvisible by
able soft-tissue fillers. the treating investigators.
This study was designed such that subjects were The rates of nodule and papule events in this
scheduled to visit the study site every 3 weeks (63 study are consistent with the current literature on
days) during the treatment phase. At each visit during injectable PLLA. It is worth noting that the rates of
the treatment phase, the effects of the treatment nodule and papule events have decreased as the
460 Narins et al
reconstitution volumes for injectable PLLA have
increased.15,27,33,37-44 In studies where the reconsti-
tution volume for injectable PLLA totaled less than
5 mL, the incidence of nodules and papule events
ranged from 13% to 44%.15,37-41 Studies using recon-
stitution volumes of injectable PLLA of $ 5 mL have
reported nodule/papule incidence rates of 8% or
less.27,33,42,43 In a 3-year follow-up study in patients
with facial lipoatrophy with and without HIV, Levy
et al44 reported an overall rate of subcutaneous
papule formation in 11% (7 of 65) of patients.
The variance in the reported incidence of nodule
or papule formation after collagen treatment, how-
ever, is not as clear. This is largely because different
clinical studies have used either bovine-, human-, or
porcine-derived collagen. In a recent study the
incidence of nodules and papules was 2.0% and
1.3%, respectively, in patients treated with porcine
collagen.45 The incidence of nodules and papules in
studies using bovine-derived collagen ranges from
3.5% in a study by Narins et al36 to 78% to 84%
reported by Baumann et al.46 Finally, Smith et al47
reported an incidence of nodules by 2.6% of patients
treated with human collagen.
In this study, only one AE that was a papule did
not resolve spontaneously and had to be treated
with a single intralesional corticosteroid injection.
Furthermore, there were no reports of granuloma
during either the comparative 13-month phase of the
study or during the long-term phase (months 19 and
25 follow-up period). Refinements in injection tech-
nique from earlier studies in patients with HIV-
related facial lipoatrophy (avoiding overcorrection,
superficial placement, and implementing postinjec-
tion massage) have been noted to contribute to the
relatively low rates of papules by other investigators
as well.27,42,48,49
From the safety point of view, this trial was
specifically designed to assess and compare the types
and incidence of AEs between injectable PLLA and
human collagen. Short-term injection siteerelated
reactions were common in both treatment groups (as
observed with all dermal fillers). Injectable PLLA was
associated with significantly higher rates of injection-
site pain, localized bruising, and localized swelling,
whereas subjects in the collagen group reported
higher rates of injection siteerelated localized itching
and persistent injection-site erythema. Physicians
had the option to apply a topical or local anesthetic
to the area before injection.23
The results of this study show that injectable PLLA
is safe and efficacious for the treatment of NLFW and
has a duration of effect that is maintained for up to 25
months. The results also demonstrate that the onset
of effect of injectable PLLA is gradual, resulting in a
J AM ACAD DERMATOL
MARCH 2010
need for up to 4 treatment sessions for optimal
correction. The duration of effect of injectable PLLA
as reported in the current study is longer than for
calcium hydroxylapatite (approximately 12 months),
the hyaluronic acids (up to 12 months depending on
formulation), and collagens (up to 6 months depend-
ing on formulation).2-5,50,51
Recent European studies show that a high level of
satisfaction with injectable PLLA has been reported
by patients and indicate that treatment resulted in a
natural-looking appearance. Using patient satisfac-
tion as an assessment of efficacy, a retrospective
analysis reported that more than 95% of 2131 patients
remained satisfied with the results for at least 2 years
after treatment with injectable PLLA.52 The majority
of subjects in the analysis were women (89.2%)
aged 22 to 83 years (average age=50.1 years)
seeking cosmetic augmentation. Treatment areas
included the nasolabial and malar regions.52 In a
questionnaire-based study, Lowe et al53 reported
similarly high rates of satisfaction where 72% (116 of
161) of patients responded that they would plan
future injections with injectable PLLA if needed. In a
series of case studies, Vleggaar20 showed that a
natural effect of facial volumetric augmentation
was obtained with injectable PLLA as demonstrated
by the maintenance of dynamic facial expressions
without visible or palpable evidence of localized
textural alterations. The cases included 3 women,
aged 47 to 63 years, who were treated with injectable
PLLA for nasolabial folds and aging-related facial
volume loss. For each of the subjects, the effect of
injectable PLLA was achieved with a series of injec-
tions over time allowing for a gradual improve-
ment.20 Thus, these reports show that gradual and
natural-looking results likely lead to high patient
satisfaction with treatment for facial volume deficits.
A limitation of this study may be that most of the
tested population were white or Hispanic women
and subjects with Fitzpatrick skin types II through IV.
Although this population may be indicative of the
typical patient who may elect to receive injectable
PLLA for soft-tissue augmentation, it might have
been advantageous to include other subject groups
to illustrate the differences in magnitude of improve-
ment in the NLFW from baseline among patients
from different ethnic backgrounds or with different
skin types.
CONCLUSION
In conclusion, injectable PLLA was demonstrated
to be a safe and effective treatment for NLFW. In the
13-month comparative phase with human collagen,
injectable PLLA treatment resulted in consistent and
significant improvements over baseline for the
J AM ACAD DERMATOL
VOLUME 62, NUMBER 3
efficacy variable (WAS scores) beginning 3 weeks
after last treatment and continuing through 13
months of follow-up (P \ .001). The safety profile
for the injectable PLLA treatment group was similar
to that for the human-collagen treatment group, with
a higher incidence of overall AEs observed for the
human-collagen treatment. Commonly occurring
short-term injection siteerelated reactions were
reported in both treatment groups. Product-related
nodule and papule events in the injectable PLLA
treatment group were 6.9% and 8.6%, respectively.
The results from the long-term surveillance phase
(injectable PLLA group only), which included the
month-19 and -25 follow-up posttreatment visits,
demonstrated that injectable PLLA continued to be a
well-tolerated and effective treatment for NLFW.
During the long-term surveillance phase, product-
related AEs were infrequent, with 3 of the 106
subjects who entered the long-term surveillance
phase reporting a total of 5 events. There were no
reports of granulomas during the entire 25-month
study period. Finally, during the 25-month posttreat-
ment long-term surveillance phase, the injectable
PLLA group continued to demonstrate significant
improvements over baseline WAS scores (P \.001).
Therefore, the results of this study demonstrate that
injectable PLLA is safe and effective for the cosmetic
correction of NLFW in an immunocompetent popu-
lation, and that the improvement is gradual and long-
lasting, maintained for up to 25 months after last
treatment. The efficacy of injectable PLLA will pro-
vide subjects and physicians with a new treatment
option for the correction of NLFW.
We would like to thank George Vamvakias from
sanofi-aventis for overseeing this clinical study; Spencer
Brown, MD, from the University of Texas Southwestern
Medical Center, and Paul Yamauchi, MD, PhD, from
Clinical Research Specialists for assisting with this trial;
and Missy McKean-Matthews from Prosoft Software, Inc,
for providing statistical support. The authors gratefully
acknowledge Marci Mikesell, PhD, who assisted in the
preparation of a revised draft of this article based on
author-provided comments. Drs Brown, Yamauchi, and
Mikesell have no relationships to disclose.
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