Cosmetic Technique
Understanding Injectable
Poly-L-lactic Acid
Kimberly Butterwick, MD
Injectable poly-L-lactic acid (PLLA) creates new volume by stimulating collagen production. PLLA com-
pensates for age-related changes in tissue shape, with correction enduring for up to 2 years. A defined
injection technique is necessary to maximize product efficacy, depending on the area of the face requir-
ing correction. PLLA has a good safety profile, and common device-related adverse events include the
formation of delayed, nonvisible, palpable subcutaneous papules. These can be alleviated by using a less
concentrated preparation of PLLA, correct placement of PLLA, and postprocedure massage for up to
1 month after injection.
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substantial expansion in the number of INJECTABLE PLLA
available injectable devices approved for Injectable PLLA is currently licensed in the European
use in the cosmetic market has occurred Union for correcting human immunodeficiency virus
in the past several years. Much of this (HIV)–associated facial lipoatrophy and for increasing the
expansion has been driven by growing volume of depressed facial areas, such as wrinkles, folds,
consumer demand for cosmetic products that do not and scars, and atrophic areas, such as the eyes, cheeks,
require invasive surgery.1 In addition, there is a more temples, and perioral areas. PLLA is approved by the US
diverse range of products to treat a greater variety of aes- Food and Drug Administration (FDA) for the restoration
thetic deficits. Whereas previously many “fillers” were and correction of the signs of facial lipoatrophy in people
solely intended to fill rhytides of different severities, infected with HIV. The manufacturer is seeking approval
some new agents are designed to restore volume and re- for a cosmetic indication, anticipated in 2007. Use of
create youthful facial contours. With the wide range of injectable PLLA in patients not infected with HIV is off
products available, it is important for the treating physi- label in the United States; therefore, the clinical experi-
cian to understand the benefits and limitations of each ence in healthy cosmetic patients is relatively limited.
product so that the most appropriate agent is selected PLLA is a synthetic, biocompatible, biodegradable, and
for each procedure and each patient. immunologically inert polymer derived from lactic acid.
The physical and chemical attributes of a product Although the injection of PLLA is novel, polylactides and
directly influence both injection technique and the results their derivatives have been safely used for more than
that can be obtained. In this article, the author examines 30 years in a variety of medical devices, including sutures,
the properties of injectable poly-L-lactic acid (PLLA), pins, plates, and screws for reconstructive surgery; intra-
how these properties influence injection technique, and bone and soft tissue implants; and vectors for sustained
approaches to patient treatment. release of bioactive compounds.2
Injectable PLLA is supplied as 40.8% PLLA (40- to
Dr. Butterwick is Private Practice Physician, Dermatology and 63-μm diameter microspheres), 24.5% sodium carboxy-
Cosmetic Laser Associates of La Jolla Inc, California. methylcellulose, and 34.7% nonpyrogenic mannitol and
Dr. Butterwick is an advisory board member Medicis is reconstituted to form an injectable suspension with
Pharmaceutical Corporation, a consultant and trainer for sterile water for injection (SWFI). To minimize patient
Dermik Laboratories, and a member of the Juvéderm advisory discomfort, many physicians use lidocaine in addition to
board for Allergan, Inc. SWFI before injecting the product.
388 Cosmetic Dermatology® • JUNE 2007 • VOL. 20 NO. 6
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Injectable PLLA
MODE OF OPERATION has been synthesized.8 The immediacy of results achieved
The mode of operation of many injectable products is with PMMA and CaHA can be viewed as an advantage
direct tissue augmentation by immediate volume replace- by patients who desire instant rejuvenation. However,
ment (eg, collagen and hyaluronic acid [HA]). New vol- many patients find a social advantage in returning for
ume can also be created by the carrier substance used in repeat sessions with PLLA. The progressive improvement
the product. This is true for PLLA and, to a lesser extent, in volume is unlikely to draw as much attention as a
calcium hydroxylapatite (CaHA) and polymethylmethac- more dramatic, instant transformation. Undercorrection
rylate (PMMA). However, once the product is implanted, is recommended for PLLA, with the expectation that the
it degrades (except for PMMA, which is permanent), and patient should return for a number of subsequent ses-
the duration of correction is limited by the rate at which sions spaced 4 to 6 weeks apart.8
the body responds and breaks down the material. In addition, undercorrection provides the opportunity
In contrast to tissue-augmentation products that to modify or amplify results until both patient and physi-
increase volume directly after injection, PLLA adds cian are satisfied with the augmentation achieved. Further,
volume indirectly over time (its water base is absorbed as the inability to predict how an individual will respond
after injection). An animal study further suggests that to treatment is a contributory factor to unwanted side
PLLA generates new volume by stimulating collagen effects, the cautionary “treat, wait, and assess” approach
production through a normal foreign-body reaction.3 offers some protection. This flexibility means that inject-
It is new endogenous collagen, rather than PLLA, that able PLLA is able to correct a wide range of defects, from
adds volume to depressed areas. Postinjection, PLLA is minor volume loss to substantial correction involving
gradually broken down into smaller components, which multiple sessions.5,9 The volume of other products that
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are first hydrolyzed into lactic acid monomers and then can be injected into the correct dermal plane limits the
into carbon dioxide and water.3,4 After all of the PLLA has degree of correction that can be obtained with fillers such
been absorbed, the process of neocollagenesis is thought as CaHA or PMMA after 1 treatment session.10 As the
to continue, since volume remains for many months vehicle of these products is absorbed, repeat sessions are
after the active ingredient should have been metabolized. often needed to obtain a full correction. This may be less
Indeed, PLLA correction has been reported to endure for than ideal from the perspective of the patient because vol-
up to 2 years before it starts to diminish.5,6 ume would appear to rise and fall over time, rather than
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Within this class of device, neocollagenesis is not improve gradually and less detectably. A gradual increase
unique to PLLA. For example, injectable PMMA and in volume is a feature of PLLA treatment.
CaHA also stimulate the production of collagen, which
encapsulates PMMA or CaHA microspheres, respectively.7 INJECTION TECHNIQUE
The scaffold provided by CaHA microspheres is degraded Injection technique is largely dictated by the physico-
relatively quickly over time with the subsequent loss chemical properties of a product and its predicted reac-
of correction, compared with PLLA, which provides tion in situ. It is crucial that appropriate consideration is
correction for a longer time. Conversely, PMMA is not given to the way that injection with PLLA differs from the
biodegradable and theoretically provides permanent cor- techniques used with other injectable products.
rection. However, permanency may not be ideal as the
patient ages. Areas requiring correction often change over RECONSTITUTION
time with volume and laxity. PLLA is supplied in glass vials as a lyophilized powder
that must be reconstituted with SWFI for at least 2 hours
INFLUENCE OF MODE OF OPERATION before use and preferably overnight at room temperature.
Neocollagenesis is the mechanism by which PLLA is For most patients, a dilution of 1 vial PLLA per 5 mL SWFI
thought to create volume and dictates the slightly is recommended to avoid adverse events such as nodules
unusual approach to treatment with this injectable. The and papules.10 For patients with severe HIV-associated
treating physician should treat, wait, and assess. Based lipoatrophy, a more concentrated (3 mL) suspension was
on clinical experience, a period of time (usually 4 to used years ago,11 although adverse events such as papule
6 weeks) should elapse following initial treatment and formation were more likely at this concentration.12 For
before an assessment is made of the initial correction and most patients undergoing facial correction, the author
before subsequent correction sessions. prefers diluting 1 vial with 5 mL SWFI and 1.5 mL
In contrast, it is recommended that one-to-one correc- lidocaine 1% with epinephrine. This dilution ensures at least
tion is provided with PMMA and CaHA, and the results 6 mL per vial, as some volume is lost in the mixing process.
seen a few days postprocedure will approximate the final The diluted material must be left to reconstitute for
result achieved once the carrier is absorbed and collagen at least 2 hours, but preferably longer (eg, overnight),
VOL. 20 NO. 6 • JUNE 2007 • Cosmetic Dermatology® 389
Copyright Cosmetic Dermatology 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher.
Injectable PLLA
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Available Online
Figure 2. When injecting poly-L-lactic acid using the depot technique,
the product is deposited just above the periosteum in a small bolus.
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Figure 1. The level at which poly-L-lactic acid should be injected will be visible. Should immediate or slightly delayed
when using the tunneling technique (represented by the horizontal
lines).13 Adapted with permission from: Vleggaar D, Forte R, Cosmetic blanching of the injected area occur, this is further con-
injectable devices: a review of the injection techniques, J Drugs firmation that the needle angle is incorrect. If blanching
Dermatol, 2006, 5; 951-956. is observed, the needle should be removed and the area
gently massaged.
prior to injection to facilitate full hydration. During the When the high subcutaneous plane has been reached,
reconstitution process, the product should not be shaken. the needle angle is lowered and then advanced along
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However, directly before use, the vial should be thor- this same level. Prior to depositing PLLA in the skin,
oughly agitated.10,12 a reflux maneuver should be performed to ensure that
a blood vessel has not been entered. As the needle is
INJECTING PLLA withdrawn, a thin trail of PLLA is deposited in the tis-
It is recommended that a 26-gauge needle be used for sue in a retrograde fashion, amounting to 0.1 to 0.2 mL
injection to avoid blockages and facilitate good flow of product per injection, leaving a subtle visible and
control. Depending on the area of the face requiring cor- palpable elevation of the skin. To avoid injecting the
rection, 2 techniques for the administration of PLLA are product upon withdrawal through the dermis, a brief
recognized: tunneling (threading) (Figure 1) and depot- pause should be taken before exiting.
type injections (Figure 2).13,14 The tunneling technique is Injections should be placed approximately 0.3 to
familiar to most physicians as it is one of the means by 0.6 cm apart, and following every 3 to 4 injections, the
which many products can be injected. A point of diver- site should be massaged vigorously. Subsequent injec-
gence from HA-based products is the level at which PLLA tions should be made into areas adjacent to the initial
is injected. Generally, longer-lasting products are depos- treatment area in a grid or cross-hatched pattern. Some
ited at a deeper level than are more temporary products.15 prefer a fanlike pattern, with care to avoid excess deposi-
PLLA is introduced at the junction of the dermis and sub- tion at the apex of the fan. It is important to emphasize to
cutis, with the author favoring the uppermost subcutane- patients that they must continue to massage the treatment
ous plane versus the deep dermis as described below. site daily for several days posttreatment to minimize the
The tunneling technique should be used for the mid possibility of nodule or papule formation and to ensure
and lower face. The needle should be introduced into the even distribution of the product. The “rule of 5s” is a
skin, with the beveled edge facing up at an angle of 30° to helpful mnemonic for patients: massage 5 times per day,
40°, until the deep dermal subcutaneous plane is reached for 5 minutes, for 5 days.
(Figure 1). The transition from dermis to subcutaneous When treatment of the upper face is required, the
plane is made obvious by a sudden reduction in tissue depot technique is more appropriate for the temples, tear
resistance to the passage of the needle. If the needle is trough, and malar regions. The depot technique involves
inserted at too shallow an angle, the bevel of the needle inserting the needle at an angle of approximately 45° and
390 Cosmetic Dermatology® • JUNE 2007 • VOL. 20 NO. 6
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Injectable PLLA
penetrating the dermis, subcutaneous layer, and muscle, nodules tend to be most visible in the periorbital area. Very
before depositing the product just above into the peri- conservative treatment with strict adherence to guidelines
osteum in a small bolus of approximately 0.05 mL per is advised in this area.
injection (Figure 2). To ensure that a blood vessel has not In the event of nodule formation, treatment should
been entered, a reflux maneuver should be performed be targeted at breaking down the lump. For example,
before each injection. Depressions in the temples can early, noninflammatory nodules may require subcision
be treated by injecting a bolus through the temporalis with a needle and dilution of the PLLA with sterile
muscle. The upper zygoma and especially the periorbital water or saline, or another technique to break down
regions are less forgiving of improper injection technique the lump. If the nodule is unresponsive to subcision,
with PLLA, so appropriate training and experience should injection of HA around the nodule has been recom-
be sought before attempting correction in these areas. mended to camouflage its appearance. It is recommended
According to the author, more dilute solutions of product that late-onset, active nodules receive treatment with
with 8 to 10 mL of SWFI are sometimes recommended localized anti-inflammatory therapy, systemic anti-
for these areas, although one must be cautious, as there is inflammatory therapy such as intralesional cortico-
more dispersion with a more dilute solution. steroids and 5-fluorouracil, or both. If conservative
measures fail, surgical excision may be considered.
AVOIDING ADVERSE EVENTS
Injection-site–related adverse events, such as bruis- COMMENT
ing, edema, discomfort, and pain, are to be expected PLLA can be used in most areas of the face to generate
in a proportion of patients. Rarely (,5% of patients), volume replacement. Furthermore, because of its mode of
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treatment-related adverse events such as erythema, fever, operation, PLLA can be used to provide progressive volume
induration, papules, nodules, and infection occur at the restoration. Indeed, if the appropriate training is undertaken
site of injection.10 These reactions tend to be temporary and the correct injection technique is applied, PLLA can be
and self-limiting in nature. When reconstituting the prod- used to treat a wide range of defects in any given patient.
uct, one may add lidocaine in combination with epineph- One exception to this is volume restoration of the lips
rine to ease some discomfort, prolong the duration of the because of the increased risk of adverse events in this area,
local anesthetic, and help minimize bruising. Adherence due to both the highly dynamic nature and the anatomy
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to the correct injection technique also minimizes the risk of this tissue. Very superficial lines and wrinkles, and skin
of such events occurring; however, care must be taken to requiring resurfacing, also clearly lend themselves to other
avoid intravascular injection. treatments, such as collagen, HA, or microdermabrasion.
Based on the results of 4 investigator-initiated clinical Physicians need to be mindful that PLLA is approved by the
studies of patients with HIV-associated facial lipoatrophy, FDA only for HIV-related facial lipoatrophy. Many physi-
the most common device-related adverse event associ- cians will feel more comfortable awaiting FDA approval and
ated with PLLA was the formation of delayed palpable, further clinical studies in patients not infected with HIV
nonbothersome, nonvisible subcutaneous papules at the before using the product to treat these patients.
injection site.16 Patients should be warned of the possibil- Patients should be informed of the risks and benefits
ity of nodule formation at the treatment site.9 However, of PLLA, as well as alternative products. If the physician
since the initial trials of PLLA were conducted, the injec- chooses to offer the product off label, this choice should
tion technique has been refined on the basis of accrued be openly discussed with the patient. The initial patient
experience. Three key points have emerged from adverse consultation process is critical to optimizing patient sat-
event reporting: uneven product distribution, incorrect isfaction with PLLA, since those familiar with cosmetic
placement of PLLA, and the use of an overly concentrated interventions may be disappointed if results are not
product are all thought to be major contributory factors immediate. Serial photographs help demonstrate treat-
to unsatisfactory results.11,12,17 ment progress to the patient, who can view the results
Irrespective of the area of the face to be treated, palpable in a mirror after half of the face has been injected. This
and occasionally visible papules or blanching can occur is also very helpful in establishing realistic expectations.
if PLLA is not injected at deep enough levels, so correct Furthermore, patients should be made aware of how
placement in the subcutaneous deep dermal plane is of long the correction is likely to remain. PLLA provides
paramount importance. Observance of these guidelines full correction for up to 24 months (and may not require
has been shown to dramatically reduce the incidence further treatment for 2.5 years) and is more durable than
of papules and nodule formation.11,16 Two areas are of are devices based on HA or collagen.11 Unlike permanent
special concern. The lips are prone to nodule formation products, correction will not be maintained indefinitely,
and should not be treated with this product. Additionally, but this allows for adjustments later on.
VOL. 20 NO. 6 • JUNE 2007 • Cosmetic Dermatology® 391
Copyright Cosmetic Dermatology 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher.
Injectable PLLA
Acknowledgment—Editorial support for this article was 7. Lemperle G, Morhenn V, Charrier U. Human histology and persis-
provided by Dermik Laboratories, a business of sanofi- tence of various injectable filler substances for soft tissue augmen-
tation. Aesthetic Plast Surg. 2003;27:354-366.
aventis U.S. LLC. 8. Lowe NJ, Maxwell CA, Patnaik R. Adverse reactions to dermal fill-
ers: review. J Derm Surg. 2005;31:1616-1625.
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392 Cosmetic Dermatology® • JUNE 2007 • VOL. 20 NO. 6
Copyright Cosmetic Dermatology 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher.