The purpose of this chapter is to present a brief overview of the use of Poly-l-lactic acid (PLLA) to safely and effectively address changes observed with aging on the face and body. PLLA is a biocompatible, biodegradable, synthetic polymer of lactic acid that has been widely used in biomedical applications including sutures, orthopedic devices, and drug delivery systems for many years. 1 It’s ability to stimulate subclinical granulomatous inflammation resulting in extracellular collagen deposition accounts for it’s use in soft tissue augmentation.
Desired outcomes require predictability. 2 Note that biocompatibility has been defined in the bioengineering literature as “the ability of a material to elicit an appropriate host response in a specific application”. 3 Biocompatibility in the specific application of soft tissue augmentation with all collagen stimulatory products, including PLLA, is therefore contingent upon the predictability of the material (product ), the host (patient), as well as how it’s used (the methodology). Much has now been learned about how to optimize outcomes and avoid adverse events with PLLA. 4
Current commercially available forms of the product used for this purpose are Sculptra (Sinclair Pharmaceuticals), approved by the United States Federal Drug Administration (USFDA) for the treatment of human immunodeficiency virus (HIV) associated facial lipoatrophy in 2004, and Sculptra Aesthetic (Galderma Laboratories, Fort Worth, TX, USA), approved for “correction of shallow to deep nasolabial fold contour deficiencies and other facial wrinkles using a deep dermal grid pattern injection” in 2009. 5
Since that time, PLLA has been increasingly used “off label” for soft tissue augmentation both on and off the face (i.e. buttocks) as well as for improvement of skin laxity (face, décolleté, arms, abdomen).
Proper patient selection and assessment, as well as attention to technique in the preparation and injection of the material, will minimize adverse events and optimize results. Used with these guidelines in mind, PLLA provides gradual, subtle, and natural results with a lasting duration and high patient satisfaction. 4
Product Composition and Mechanism of Action
PLLA is a biocompatible, biodegradable, high molecular weight synthetic polymer of L-lactic acid. PLLA is the only resorbable filler currently on the market which is approved by the FDA to last up to 25 months (the cut off time in the initial HIV study used to gain initial FDA approval). 5
The longevity is due to the slow degradation kinetics of this high molecular weight polymer.
The currently commercially available USFDA approved products contain PLLA microparticles measuring 40 to 63 μm. This size reflects a refinement of the product following it’s initial release in Europe as NewFill in 1999, and ensures that the particles are large enough to avoid phagocytosis by dermal macrophages or passage through capillary walls, but small enough to be easily injected by needles as fine as 26 gauge. 6This change was made in response to early studies with polymethylmethacrylate (PMMA) showing phagocytosis by macrophages of particles <20 microns played a role in clinically obvious granulomatous inflammation. 7,8
The product is supplied in a glass vial containing a lyophilized powder of PLLA microparticles along with sodium carboxymethylcellulose (CMC-a suspending agent used to maintain even distribution), and mannitol (to enhance solubility). Prior to use, the product is reconstituted with 5mL sterile water for injection (SWFI) to form a suspension, which is then left to “hydrate” for at least 2 hours as per the current FDA approved label. 5
Changes to this label are currently being pursued by the manufacturer, and will be addressed below.
The prevailing theory of the mechanism of action of PLLA is that upon injection, it stimulates a subclinical inflammatory response, followed by encapsulation of the particles, and subsequent fibroblast proliferation and collagen formation. 10,11Some suggest that the product may upregulate the production of collagen by other pathways as well. 12,13,14
Once the carrier solution is reabsorbed, a slow process of biodegradation of the microspheres occurs consisting of hydration, loss of cohesion and molecular weight, solubilization, and phagocytosis of small fragments of PLLA by the host’s macrophages. PLLA is eventually degraded into lactic acid which is eliminated as CO2 and H2O through the respiratory system.6,10
Although some publications note the disappearance of the majority of the implanted PLLA within 6-9 months, 11it has been noted by others to be present as long as 28 months. 12
History and Evolution of Methodology
How to use the product to best advantage as a tissue augmentation device has evolved considerably since it’s introduction to the marketplace almost two decades ago as a ‘facial filling’ agent for HIV associated facial lipoatrophy.
The 2004 FDA approval for HIV lipoatrophy was based on early studies which used 3-4 mL SWFI with a 2hr hydration time. This was increased to 5 mL with the 2009 aesthetic approval, as newer studies with higher dilutions showed a marked decrease in the incidence of undesirable visible papules and nodules.15 This methodology has gradually evolved over the last decade of clinical practice, leading to the reconstitution most commonly used currently: 8-9 mL on face and 16 mL off face, as well as a hydration time of 24-72 hrs. In addition, subcutaneous and supraperiosteal injections are now used more commonly than the “deep dermal grid pattern” approved in 2009. 4
The above technical changes of increasing both dilution and hydration time, and of ensuring a well mixed suspension (both immediately prior to drawing up into the syringe from the vial, as well as in the syringe immediately prior to injection) are unique to PLLA. Technical issues which have been addressed with all biostimulatory products are avoidance of superficial placement leading to visible neocollagenesis as well as avoiding injection through or into hyperdynamic muscles, especially around the eyes and lips (to avoid trapping and clumping of product in the muscle). Note that the common denominator in all of the above is to minimize the presence of “clumps” of product. It may be possible that these “clumps” stimulate a slightly greater host response leading to the formation of visible papules and nodules in the patient. A recently published retrospective chart review of patients treated using the above outlined techniques at multiple sites over several years had a very low incidence of papules and nodules. 16
The product manufacturer recently carried out in vitro studies to investigate the feasibility of immediate use. Rehydration was carried out by a simple protocol of shaking vigorously following the stepwise addition of 8 mL of SWFI, followed by analysis of subsequent PLLA parameters, showing that these parameters were not significantly changed by hydration time. It should be noted however, that this study looked at the PLLA only, and not the excipients (CMC, mannitol). 17 This new reconstitution procedure with higher dilutions and no hydration time has been implemented in two large US clinical trials. Both have now been completed, with one recently published. The SCRIPT (Sculptra Contemporary Reconstitution and Injection Procedure Trial) trial compared efficacy and safety of a 5ml versus 8ml dilution with immediate use in nasolabial folds in 80 patients and demonstrates an excellent safety profile. 18 The other (and larger) of the two clinical studies is pending publication. Additionally, an investigator initiated study in Brazil, using a 12 ml dilution followed by immediate use in 26 patients also showed a favorable safety profile. 19 An updated FDA label reflective of these changes, (8 mL SWFI/1 mL lidocaine reconstitution, elimination of hydration time, as well as subdermal injections) is being pursued by the manufacturer pending final study results.
Finally, a recent publication implicating the suspending agent CMC as the cause of PLLA microclumps in the suspension of injectable PLLA deserves mention here. 20 These authors feel that the critical element in the reconstitution of injectable PLLA is the dissolution process of CMC. They note that when added to water, CMC, a type of hydrocolloid, forms clumps as partially hydrated particles collide and adhere to one another. The outer surface of the clump hydrates quickly, producing a sticky, gelatinous coating and leaving a dry interior which is then resistant to hydration. These clumps have been termed “fisheyes” because of their appearance.
In a small proof of concept study, the authors compared vials of injectable PLLA which had been reconstituted with various volumes of SWFI and hydration times. They found that in all vials, over a relatively short time (<30min), the suspension would eventually divide into 3 layers: an upper floating layer, a middle transparent layer, and a lower precipitating layer. As time or dilution increased, the upper floating layer became thinner while the lower precipitating layer became thicker. Following shaking of the vial, a microscopic exam (50x) looking at a droplet on a glass slide revealed that the upper floating layer was comprised mostly of micro-fisheyes, while the precipitating layer was essentially comprised of PLLA microparticles without micro-fisheyes. However, higher power view (200x) of the micro-fisheyes revealed that all contained PLLA micro-clumps, indicating that the entrapment of PLLA microparticles inside the dry interior of CMC micro-fisheyes is the cause of PLLA microclumps in the suspension of injectable PLLA. They also note that larger micro-fisheyes may clog injection needles, accounting for the common observation that foamy product seems to cause constant needle clogging. Due to the stickiness of their gelatinous coatings, micro-fisheyes readily adhere to the glass wall or rubber lid of the vial when agitated, and are difficult to rinse off for further hydration. Various methods, such as lengthening the reconstitution time, sonication, 21 have been used to eradicate micro-fisheyes, but cannot totally eliminate them. Because micro-fisheyes will eventually float on the suspension, discarding the floating layer before agitating and mixing the vial is the best method to prevent injection of micro-fisheyes. Further studies should be designed to investigate how to decrease formation or increase elimination of micro-fisheyes based on their properties. In addition to gains in technical insights which have improved our understanding of how to use the product to best advantage, where to use the product to best advantage in facial filling has also improved with ever evolving insights into the changes observed in the aging face.
Current thinking conceptualizes the soft tissues of the face as a concentric arrangement of five basic layers which consist of 1)skin, 2)subcutaneous fat, 3)the musculoaponeurotic layer, 4)areolar tissue, including facial ligaments and facial spaces, and 5)the periosteum and deep muscular fascia. The facial retaining ligaments pass through all layers to bind the skeleton to the superficial fascia (a composite of layers 1-3). 22
Aging leads to loss or redistribution of volume in the bony substructure and fat compartments of the face which may occur in conjunction with loss of elasticity of the skin that envelops it. The facial retaining ligaments often become more visible with aging or fat loss. These changes dictate the morphology of the face in terms of its shape, proportions, and 3D topography.23 Recognizing where these structures are changing, (or are congenitally suboptimal), as well as how that affects neighboring tissues, enhances our ability to address them with site-specific corrections in order to achieve optimal, natural-looking results. Obviously, this knowledge is in a constant state of evolution.
Current literature suggests that these changes are occurring in all tissue structures of the face, and that a change in one area may greatly influence changes in neighboring tissues, leading to a cascade of secondary events. Although a new patient may present pointing to a wrinkle, line, or fold they’ve noticed seemingly overnight, it is now becoming increasingly recognized by the medical community that these are really just downstream markers of slow progressive changes taking place in all structures of the face.
PLLA is not used directly in these wrinkles, lines, and folds, but rather in multiple areas (and tissue structures) of the face in an attempt to address the volume loss or laxity that leads to their appearance. This approach has proven capable of delivering the sort of subtle and natural looking results desired by many patients (“I don’t want to look done, I just don’t want to look tired”), and is the greatest strength of this product. Seemingly small changes in shape, proportions, balance and symmetry can sometimes have a surprisingly large effect on our perception of the face. This shift in perspective ie: looking at the face as an interlocking 3D puzzle, rather than focusing on individual lines and folds, such as nasolabial folds or marionette lines as isolated entities, is the largest part of the learning curve with all commercially available fillers, including PLLA.
Poly-L-lactic Acid: Technical Considerations
Techniques continue to evolve in order to minimize adverse events and optimize results when using stimulatory agents such as PLLA and current recommendations are outlined below. 4
The most commonly used reconstitution volumes currently are 8-9 mL on face, 12-16 mL off-face, with a hydration time of 24-72 hours. Sterile water for injection (SWFI) is recommended for dilution. Traditional reconstitution instructions are to add the SWFI slowly and avoid shaking the vial prior to a period of hydration. The hydrated vial can be stored at room temperature for 24-72hrs, or kept refrigerated for up to 3-4 weeks prior to use. Product should be warmed to room temperature prior mixing for injection.
1-2 ml of Lidocaine 1-2% with or without epinephrine may be dripped in slowly immediately prior to mixing the vial. The vial should be mixed thoroughly to ensure a homogenous suspension immediately prior to drawing up the product into syringes for injection. Immediately after mixing tiny ”champagne like” bubbles often float to the top and sidewalls of the vial as foam. Excessive foam or bubbles in the syringe will lead to a constantly clogging needle. This can be minimized by carefully drawing up product from the bottom of the vial after most of the bubbles rise to the top. Be aware, however, that the PLLA will precipitate out of suspension over time leaving a veil of white powder on the bottom of the vial or syringe. If this is noted, it should be remixed to ensure it is evenly suspended in the vial prior to drawing up the syringe, or in the syringe prior to injection in the patient.
The vial holds <10 ml. Suspensions of 8-9 ml can be drawn directly from the vial. Larger dilutions for off face injections can be done by drawing up equal parts of hydrated product and SWFI in large syringes, mixing well via a sterile connector, and then distributing to smaller syringes through the connector. A 1cc or 3cc syringe may be used for injection. Any foam can be expelled through the hub of the syringe. Priming the needle may help to avoid clogging it with tissue upon injection. Needles or cannulas may be used-a 25 gauge 1.5”or a 26 gauge 1” needle, or 22 or 25 gauge 50mm blunt-tipped cannula are the most commonly used.
Potentially newer recommendations based on the physicochemical testing and clinical trials noted above are still awaiting final determination but are as follows: 1) add 5ml SWFI and shake vigorously for minute, then 2) add an additional 3 mL SWFI and again shake vigorously for 1 minute, then 3) slowly drip in 1 mL lidocaine, swirl, and use immediately.
The volume (i.e. number of vials) of product used for any single treatment session should be determined by the surface area to be treated at that session, using approximately 0.1-0.3 mL/cm for the face, and can therefore be easily predetermined. The final volumetric correction is addressed by the number of treatment sessions. This means for instance that a very large face with mild volume loss may require 3 vials injected in only 1 session, but a small face with severe volume loss may require 1-2 vials per session over 3 or more sessions. Off face areas are most commonlytreated with 0.05-0.1 mL/cm using a 16 mL dilution, however, there is some variability described in the current literature.
This can be done with a 1-cc or 3-cc syringe and a 25-gauge (long or short) or 26-gauge (short) needle. The depth of placement varies with location. For facial rejuvenation, PLLA may be injected in a supraperiosteal location along the zygoma, maxilla (pyriform aperature) and mandible. In the temple, product is placed deeply, under the temporalis muscle. It is common practice among experienced users to place 0.3-0.5cc/depot in this area, followed by firm massage. It may be placed in the subcutaneous (sq) layer deep to the muscle in the superior aspect of the medial cheek and in the superficial subcutaneous layer inferiorly. Injections in the preauricular and lateral cheek are done subcutaneously just under the dermis as deeper injections in this area may enter the parotid gland or duct.
The injector should massage after every few injections and again at the end of treatment to ensure proper placement of the product. Follow the mantra “treat, wait, assess”. Patients should receive repeat treatment no sooner than 4 weeks after previous treatment.
Placement in or through areas of hyperdynamic muscle movement, especially around the eyes and lips (orbicularis oculi mm., depressor anguli oris mm., modiolus) should be avoided as muscle movement in these areas will clump the product leading to papules and nodules.
Product Placement/ Off Face
The product is also used in off face areas for volume augmentation and/or skin tightening. PLLA injection is a popular non-surgical approach to gluteal augmentation. 24 The number of vials and sessions needed are dependent
on the degree of laxity present and amount of augmentation requested. Combination therapy with skin tightening devices in a thin, fit patient seeking modest improvement in sagging and volume may require less product and sessions than those using monotherapy or wanting/needing substantial volume (which may require a high volume of product given over multiple sessions). The product is injected into the superolateral buttock (often referred to as the “hip dip”) using a fanning or linear threading technique, taking care to avoid redeposition of product at the apex of a fan. Injections should be beneath the dermis to avoid visible papules, but must remain superficial to muscle so as to avoid embolization of the underlying gluteal vasculature or trauma to the sciatic nerve, especially when injecting more medially. Injection into the superolateral quadrant of the buttock will help to lift while avoiding complications.
PLLA has also been used successfully in the treatment of skin laxity in the décolleté , arms, and abdomen. 25,26,27
Patients with significant laxity may require multiple sessions. Upper knees, thighs, and medial ankles have been treated with some improvement. All skin laxity is treated with superficial subcutaneous linear threading or fanning injections. Be aware that papules and nodules have been reported after treatment in the neck and dorsal hands. The product has been used successfully in combination with subcision to treat scarring, including acne scarring. Atrophic scarring has been treated with a 16cc dilution applied topically immediately following fractional erbium laser with some success as well. 28
Patient selection, expectations, and satisfaction
As we all know, setting realistic expectations is key to patient satisfaction. Proper patient selection will optimize results and decrease frustration for both the patient and the clinician. As previously noted, a predictable result following a biostimulatory product is contingent upon a predictable host response-meaning that a patient with active autoimmune disease (possibly too much response) or poor nutrition (possibly not enough response) may not be the ideal candidate for this treatment. Additionally, as this host response takes time, a patient who wants a “quick fix” for an upcoming event may be more satisfied with a product that provides immediate results.
It’s very important for the patient to recognize that their final outcome, and the amount of product and work it will take to get there, is a reflection of the quality of tissues with which they start. Very lipoatrophic faces (associated with HIV or endurance exercise) are harder to fill, and it’s harder to sustain the fill. Older faces with advanced craniofacial remodeling, fat loss, and very poor skin quality can be treated successfully, however they will need a lot of product, and multiple sessions to achieve a desirable result. Fillers of any kind may not be the most cost effective choice in a cosmetic patient who would best benefit from a face lift and fat augmentation. Conversely, fuller and younger faces “bring in their own volume” and are therefore more easily reshaped with a conservative amount of filler of any kind. This is, of course, an issue of patient selection and not product selection. Some older or thinner patients may still choose fillers, however, setting expectations allows them to make a more informed choice prior to any treatment.
Finally, multiple market studies have shown that duration of effect is very important to consumers. PLLA is the only resorbable filler currently on the market which is approved by the Federal Food and Drug Administration (FDA) to last up to 25 months (the cut off time in the study used to gain FDA approval). 5
Patients often report a subjective improvement in skin quality after facial treatment with PLLA. This, in combination with the subtle, gradual, natural appearing, and long lasting results attainable with this product have been associated with high patient satisfaction. 29,30
Adverse Events-Recognition, Avoidance, and Management
The most common adverse events (AE’s) seen with all fillers are injection-related and include swelling, bruising, erythema, and pain. Fortunately, most resolve spontaneously over a short period of time. Papules (<5mm) and nodules (>5mm) are the most common product related AE with PLLA. They result from a focal or global overabundance of product and most commonly stem from suboptimal product reconstitution or placement. Fortunately, with adherence to the guidelines presented here, most can be prevented.
Serious AE’s are fortunately very rare and are due to inflammatory or vascular events.
As mentioned above, recall that the product should be evenly suspended in the vial prior to drawing up the syringes, as well as in the syringes immediately prior to injection to avoid uneven implantation. Superficial injection into the dermis should be avoided as this can lead to visible neocollagenesis seen as lumps and bumps. Placement in or through areas of hyperdynamic muscle particularly around the eyes or lips should also be avoided as this can lead to clumping of particles trapped in muscle fibers.
Biopsy of these “lumps, bumps, and clumps” show an overabundance of product with a few foreign body giant cells (FBGC). Although the presence of these FBGC’s may lead to a histopathologic diagnosis of “granuloma” these lesions are not, in fact, true clinical granulomas, as they represent product, not proliferating cells. For the same reason, they do not respond to treatment with intralesional steroids or 5-FU.
Intralesional steroids, in fact, may make the bump even more visible by causing atrophy around it. This was a common mishap in the early days with this product that is now disappearing due to a wider understanding of the difference between the nodules and granulomas. Excision of nodules is an option, but results in a permanent scar. Reassuring the patient that this is a transient process which will resolve spontaneously over time may suffice. Hyaluronic acid filler to camouflage the nodule until it resorbs is a good option.
These are distinct from true clinical granulomas which are a systemic inflammatory response showing an overabundance of host reaction (e.g. foreign body giant cells), to a relatively small amount of product on histopathology. As this is a systemic response, true clinical granulomas occur in all treated sites simultaneously, in contrast with papules and nodules which occur in a limited area. Because true clinical granulomas represent an overabundance of proliferating foreign body giant cells they respond well to treatment with antimetabolites like 5-fluorouracil(5-FU) or anti-inflammatory agents like intralesional corticosteroids. A commonly used mixture is 0.1 cc of 40mg/cc Kenalog mixed with 0.9 cc 5-FU 50 mg/cc. This is injected directly into the granulomas using less than 1cc in one session. This can be injected once/week for 2 weeks, then every 2 weeks x 2, and then monthly until resolution. Improvement (softer, smaller lesions) is usually seen after 2-3 treatments. True clinical granulomas have been reported with all currently available commercial fillers and are fortunately rare (0.01%-0.1%). 31,32
The underlying pathophysiology remains elusive. Recall that subclinical granulomatous inflammation is an expected and desired tissue response to injected collagen stimulators and follows a predictable course in a normal host. Treatment in an area of active infection or in a patient with active autoimmune disease may not be predictable and is not recommended.
Inadvertant laceration (as well as obstruction) of the parotid duct has been described with fillers, including PLLA. Review the anatomy prior to injection to stay superficial to this duct. This may lead to extravasation of salivary fluid into the soft tissue of the cheek necessitating compression +/- antibiotic therapy. 33
Vascular complications may occur if the product is inadvertently injected into a blood vessel. This can cause local ischemia and/or skin necrosis. As the product is not dissolvable, supportive therapy such as hyperbaric oxygen can be considered. Blindness and even stroke, although extremely rare, have been described following injections of all fillers both on and off face. This is as yet incompletely understood, but is thought to involve retrograde flow of product (from the external to the internal carotid vasculature) after inadvertent intravascular injection. Knowledge of the anatomy is critical, although not failsafe, as there is individual variability in the vascular anatomy . Other precautions include slow injections with small aliquots through a constantly moving needle or cannula. Aspiration prior to injection can be used, although the reliability of this reflux maneuver is controversial. Injections should be performed slowly without using excessive pressure. Use of a pump to expedite buttock injections has been described, but the injector should be aware that risk of vascular occlusion has been associated with high injection pressure. 33
PLLA is a safe and effective treatment for cosmetic enhancement. By stimulating new collagen, PLLA can restructure the face and gradually restore volume. Optimizing outcomes and minimizing adverse events requires awareness and attention to the technical details outlined above. Careful patient selection and thoughtful facial analysis of changes in all structural tissues will enhance site-specific augmentation and maximize satisfaction.
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- Vleggaar D, Fitzgerald R, Lorenc ZP. Composition and mechanism of action of poly-l-lactic acid in soft tissue augmentation, J Drugs Dermatol. 2014;13(4 Suppl):s29-
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- Vleggaar D, Fitzgerald R, Lorenc ZP, et al. Consensus recommendations on the use of injectable poly-L-lactic acid for facial and nonfacial volumization. J Drugs Dermatol. 2014;13(4 Suppl):s44-s51.
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- Morhenn VB, Lemperle G, Gallo RL. Phagocytosis of Different Particulate Dermal Filler Substances by Human Macrophages and Skin Cells. Dermatol. Surg. 2002 Jun;28(6):484–490. doi:10.1046/j.1524-4725.2002.01273.x
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- poly(3-hydroxybutyrate) (PHB), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB/VA). J Biomed Mater Res. 1993;27(9):1135-1148.
- Goldberg D, Guana A, Volk A et al. Single-Arm Study for the Characterization of Human Tissue Response to Injectable Poly-L-Lactic Acid. Dermatol Surg. 2013;(39):915-922
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- Kim SA, Kim HS, Jung JW, Suh SI, Ryoo YW. Poly-L-Lactic Acid increases collagen gene expression and synthesis in cultured dermal fibroblast (Hs68) through the p38 MAPK pathway. Ann Dermatol. 2019;31(1):97-100
- Courderot-Masuyer C, Robin S, Tauzin H and Humbert P. Evaluation of the Behaviour of Wrinkles Fibroblasts and Normal Aged Fibroblasts in the Presence of Poly-L-Lactic Acid. J Cosm Dermatol Sci Appl. 2012;2:20-27.
- Vleggaar D, Fitzgerald R, Lorenc ZP, et al. The history behind the use of injectable poly-l-lactic acid for facial and nonfacial volumination: the positive impact of evolving methodology. J Drugs Dermatol. 2014;13(4 Suppl):s32-s34.
- Palm M, Mayoral F, Rajani A, et al. chart review presenting safety of injectable PLLA used with alternative reconstitution volume for facial treatments. J Drugs Dermatol. 2021;20(1):118-122.
- Baumann K, Alm J, Norberg M, Ejehorn M. Immediate Use After Reconstitution of a Biostimulatory Poly-L-Lactic Acid Injectable Implant. J Drugs Dermatol. 2020 Dec 1;19(12):1199-1203.
- Palm M, Weinkle S, Cho Y, LaTowsky B, Prather H. A randomized study on PLLA using higher dilution volume and immediate use following reconstitution. J Drugs Dermatol. 2021:20(7):760-766.
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- Mendelson B, Wong C. Anatomy of the Aging Face. Section I, Chap 6. Aesthetic Surgery of the Face. Elsevier; 2013
- Fitzgerald R. Addressing facial shape and proportions with injectable agents in youth and age. In:Azizzadeh B, Murphy M, Johnson C, Massry G, Fitzgerald R. Master Techniques in Facial Rejuvenation. 2nd edition. Elsevier 2018 pp15-54.
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- Cohen S, Dover J, Monheit G, Narins R, Sadick N, Werschler WP, et al. Five-Year Safety and Satisfaction Study of PMMA–Collagen in the Correction of Nasolabial Folds: Dermatol. Surg. 2015 Dec;41:S302–S313.
- Lemperle G, Gauthier-Hazan N. Foreign Body Granulomas after All Injectable Dermal Fillers: Part 2. Treatment Options: Plast. Reconstr. Surg. 2009 Jun;123(6):1864–1873.
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