Contemporary Review of Injectable Facial Fillers
the introduction of nonsurgical treatments for the relaxation of facial wrinkles and forthe restoration of lost volume. Fillers such as paraffin and silicone have been used inthe past for volume restoration, but only recently have new fillers been developed whose safety and efficacy have been supported by clinical research. The introduction of hyaluronic acid(HA) fillers in 2003 began the filler revolution and paved the way for development of biostimula-tory and permanent materials. There is an abundance of high-level evidence-based studies com-paring the HA fillers, calcium hydroxylapatite, and poly(methyl methacrylate) with collagen andother HA formulations, but there is only limited high-level data evaluating poly-L-lactic acid.
Arch Facial Plast Surg. Published online November 26, 2012. doi:10.1001/jamafacial.2013.337 developed in the new millennium. Histori- cally, silicones and paraffins were injected, with sometimes disastrous results includ- filling agents. Of the currently used der- ing granulomas and paraffinomas, often seen mal fillers, Sculptra (poly-L-lactic acid many years after treatment.1 Although col- 1980s, because of the limited longevity of results and potential for hypersensitivity, combined with the social stigma of having injections performed, these treatments were predominantly used by the “rich and fa- Aesthetics) in the early 2000s had particu- approved in 2011 (Table 1). Botulinum
lar appeal to the women of the baby boomer cal devices. For this reason, the FDA as- interested in rejuvenation procedures with ber of nonsurgical procedures performed inthe United States increased 356%, with Bo- scribe the different formulations of inject- tox taking the lead, followed by HA fillers.
able fillers. The FDA specifically defines The Aesthetic Society for Aesthetic Plastic a cosmetic injectable device as a product Surgery reported that in 2011, there were 1.2 million patients injected with HA in the impart any health benefits.3 Wrinkle fill- ers are a subcategory of medical devices,defined as injectable implants used to im- Author Affiliation: Facial Plastic Surgicenter, Johns Hopkins Medical Institutions,
Wrinkle fillers can produce either tempo- 2012 American Medical Association. All rights reserved.
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Table 1. Injectable Fillers Listed by Dates of FDA Approval
Year of FDA

Product Trade Name (Manufacturer)a
Product Description
Bovine collagen (35-mg/mL collagen cross-linked with glutaraldehyde) Restylane (Medicis Aesthetics)
Sculptra (Valeant Pharmaceuticals)
Juve´derm Ultra (Allergan)
Juve´derm Ultra Plus (Allergan)
Artefill (Suneva Medical)
Radiesse (Merz Aesthetics)
Perlane (Medicis Aesthetics)
Hydrelle (formerly Elevess) (Anika Therapeutics) Sculptra Aesthetic (Valeant Pharmaceuticals)
Juve´derm XC (Allergan)
Restylane-L (Medicis Aesthetics)
Perlane-L (Medicis Aesthetics)
Belotero (Merz Pharmaceuticals)
LaViv (Fibrocell Technologies)
Abbreviations: CaHA, calcium hydroxylapatite; FDA, US Food and Drug Administration; HA, hyaluronic acid; PLLA, poly-L-lactic acid; PMMA, poly(methyl a Products in boldface are currently available.
rary or permanent results, based on their composition.
tation of Streptococcus equi bacterium and are currently the The stringent FDA guidelines require that a new device demonstrates that it is safe and effective and equivalent Hyaluronic acid fillers differ from one another by their or noninferior to a legally marketed device. Currently, degree of cross-linking, gel consistency properties, and FDA-approved temporary fillers are collagens, HA, CaHA, concentration. Cross-linking is required to stabilize the and PLLA, while the only permanent filler with FDA ap- HA and prevent degradation when injected into the skin.
proval is PMMA. Silicone, although used for certain oph- Cross-linking transforms hylan fluid into a more cohe- thalmic conditions, is not FDA approved for any cos- sive gel. The most common cross-linking agent used is metic injection. Injectable filling agents are generally 1,4-butanediol diglycidal ether, which can be irritating approved for improvement of moderate to severe naso- or even toxic to skin. For this reason, any unlinked 1,4- labial folds (NLFs), marionette lines, or facial lipoatro- butanediol diglycidal ether must be removed during the phy; however, Restylane was recently granted FDA ap- manufacturing process. Fillers may differ by both the amount of cross-linked HA as well as the degree of cross-linking within the gel.5 HYALURONIC ACID
In addition, HAs can be classified as either monopha- sic or biphasic gels.6 Biphasic gels such as Restylane and Hyaluronic acid is a naturally occurring polysaccharide Perlane (Medicis Aesthetics) are particles of cross- found in the skin dermis, umbilical cord, synovial joint fluid, linked HA suspended in a liquid. They differ by particle hyaline cartilage, and connective tissues. Because it is bio- size: Restylane particles are roughly 250 ␮m in diam- degradable, biocompatible, and nonimmunogenic, it is an eter, and Perlane, 550 ␮m, with concentrations of 100 000 ideal filling agent. The chemical structure of HA consists particles/mL and 8000 to 10 000 particles/mL, respec- of disaccharide units of glucuronic acid and N-acetyl- tively. Monophasic gels ( Juve´derm Ultra and Juve´derm glucosamine connected by alternating ␤-1,3 and ␤-1,4 Ultra Plus [Allergan]) are cross-linked in 1 process (Hyla- bonds. Hyaluronic acids work well as fillers because of their cross technology) (Allergan), producing entirely stabi- low potential for allergic reactions, their consistency across lized smooth gel without particles. Belotero (Merz Phar- species, and their viscoelastic and hygroscopic (swelling maceuticals) is also a monophasic gel cross-linked by by the absorption of water) properties. Some early HA fill- cohesive polydensified matrix technology, which pro- ers were derived from rooster combs; however, residual duces increased elastic and viscous properties.
avian proteins caused allergic reactions in some patients.
Clinical trials for facial fillers focused on treatment of Nonanimal stabilized HAs were developed by the fermen- the NLFs. This particular anatomical area was ideal to 2012 American Medical Association. All rights reserved.
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Table 2. Wrinkle Severity Rating Scale
Score Description
No visible nasolabial fold; continuous skin line Shallow but visible fold with a slight indentation; minor facial feature; filler implant will produce a slight improvement in appearance Moderately deep folds; clear facial feature visible at normal appearance but not when stretched; excellent correction expected Very long and deep folds; prominent facial feature; less than 2-mm visible fold when stretched; significant improvement expected Extremely deep and long folds; detrimental to facial appearance; 2-4–mm V-shaped fold when stretched; unlikely to have satisfactory Table 3. The Global Aesthetic Improvement Scale
Marked improvement by not completely optimal; touch-up would slightly improve result Obvious improvement but touch-up or retreatment is indicated Appearance essentially the same as the original condition Appearance is worse than original condition study for several reasons: it is an area not well treated by over Zyplast in an RCT (n = 87) on the treatment of NLFs, most aging face surgical procedures; it has a built-in side- showing correction in 81% of subjects for up to 1 year, by-side control; and it is easy to analyze and photo- graph. Before the introduction of HA fillers, collagen in- By 2008, the clear superiority of HA products over Zy- jections were the standard treatment for the correction plast collagen became evident. For subsequent studies, of wrinkles and folds. For this reason, collagen was used Restylane became the comparator because its efficacy and as the control for early efficacy and safety studies of new safety profiles had been validated by clinical trials. Clini- cal trials focused on determining clinical differences be- The initial major US study of HA fillers was per- tween the different HA types. Treatment of glabellar lines formed by Nairns et al7 in 2003. They performed a double- with single cross-linked HA (Restylane) compared with blind, split-face, randomized controlled trial (RCT), which double cross-linked HA (Puragen, not FDA approved, compared the efficacy of Restylane (HA) with Zyplast (col- similar to Prevelle [both Mentor Corp]) was reported in lagen) (Inamed Corp) for the correction of NLFs an RCT (n = 10), which showed equal effectiveness of (n = 138). By assessing the patients using both the 5-point both products. The longevity of the double cross-linked Wrinkle Severity Rating Scale (WSRS [validated by Day HA was superior to the single cross-linked HA at 12 et al8]) (Table 2) and the Global Aesthetic Improve-
months. There were no treatment-related AEs with either ment Scale (GAIS)7 (Table 3), they found that at 6
months, approximately 60% of patients treated with HA A pilot study comparing monophasic to biphasic HA retained improvement compared with only 9% of pa- preparations was recently performed by Nast et al.13 In a tients treated with collagen. In addition, less HA prod- prospective, double-blinded RCT (n = 60) comparing cor- uct was required to produce the optimal cosmetic effect rection of the NLFs with Restylane (monophasic HA) with compared with collagen. Adverse events (AEs) were simi- Teosyal (Teoxane Laboratories) (biphasic HA, cur- lar for the 2 products. Lindqvist et al9 performed a simi- rently not FDA approved), they found that both prod- lar study in Europe, comparing Perlane with Zyplast; how- ucts showed good long-term results and were well tol- ever, the patients were followed up for 1 year. Their results erated. There was slight superiority of the mono-HA over were similar to the study by Nairns et al7 and showed that the bi-HA in terms of durability, persistence, and par- Perlane was superior to Zyplast at maintaining correc- tion of the NLFs at 6 and 9 months; however, they noted The evaluation of long-term results and effects of dif- that Perlane caused fewer local injection site reactions fering retreatment schedules was studied in an RCT (n = 75) using Restylane treatment of the NLFs, which The superiority of Juve´derm in longevity and safety differed in injection intervals to determine the optimal over collagen was studied in a multicenter RCT.10 In this retreatment schedule. They noted retreatment at either split-faced study, 439 subjects were injected on 1 NLF 4.5 or 9 months resulted in persistent nasolabial im- with 1 of 3 different preparations of Juve´derm (which dif- fered by degree of cross-linking) and with Zyplast on the In 2010, lidocaine hydrochloride was added to the HA contralateral NLF. All fillers were well tolerated; how- preparations for comfort during injection. Levy et al15 com- ever, all 3 HA products showed longer-lasting correc- pared patient comfort using lidocaine-containing HA (Ju- tion for at least 6 months compared with collagen. Lupo ve´derm Ultra 3 [Allergan]) with Restylane-Perlane. In this et al11 confirmed the superiority of Juve´derm Ultra Plus single-blind RCT (n = 126), 95% of patients preferred the 2012 American Medical Association. All rights reserved.
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lidocaine-containing HA for overall injection comfort.
fold augmentation and repair of oromaxillofacial de- Monheit et al16 compared lidocaine-containing Prevelle fects and as a radiographic soft tissue marker. Injectable Silk (Mentor Corp) with the same filler without lido- calcium hydroxylapatite (Radiesse [Merz Aesthetics], for- caine (Captique; Genzyme Corp) in 2009 and found in merly Radiance FN [Bioform Medical Inc]) was FDA ap- an RCT (n = 45) that pain was diminished by 50% using proved in 2006 as a filler for augmentation of moderate to severe NLFs. The product consists of synthetic bone Since their introduction in 2003, HA fillers have been with microspheres 25 to 45 ␮m in diameter, combined shown to have excellent effectiveness and acceptable safety in a carboxymethylcellulose carrier gel. Radiesse inject- profiles. They have been used on label to improve the able material consists of 35% CaHA microspheres sus- NLFs and lips, as well as off label to correct lines and pended in a 70% gel carrier.24 Within several weeks af- wrinkles and to volumize the aging face.17 They have been ter injection, the carrier gel is absorbed. Unlike the HAs, found to provide a longer-lasting improvement over both Radiesse induces neocollagenesis with the micro- collagen-based products as well as animal-derived HA.
spheres serving as scaffolding for the new collagen fi- Safety was reviewed from a worldwide data of 144 000 brils. This product is nonimmunogenic, and no skin test- patients treated with HA (Restylane and Perlane) in 1999 ing is required. Over time, the CaHA particles are degraded and 262 000 patients treated in 2000.18 The total AEs de- into calcium and phosphate ions and excreted by the body.
creased from 0.15% to 0.06% after the introduction of a In an RCT in 2007 (n = 117), Smith et al25 performed more purified HA raw material. The most common AE a split-face injection of the NLFs, comparing Radiesse with was hypersensivity reactions seen in 1 of every 5000 pa- human collagen (Cosmoplast; Inamed/Allergan). At 6 tients treated. Temporary events included redness, swell- months, results were graded by blinded evaluators, and ing, localized granulomas, and bacterial infections.
they found that 79% of the Radiesse-treated folds had “su- Safety has also been determined in darker-skinned pa- perior” results compared with the collagen side. In ad- tients.19 An RCT of 160 patients treated with Juve´derm dition, the amount of CaHA required for optimal cor- and Zyplast in the NLFs showed no hypersensitivity and rection was half that needed for collagen. Smith et al25 a 6-month duration of effectiveness. There were no oc- found that the clinical results of Radiesse were superior currences of keloid formation, hypertrophic scarring, hy- to collagen at 3 and 6 months and was preferred over hu- popigmentation, or hypersensitivity; however, 3 pa- man collagen by more than 96% of injectors and pa- tients developed mild hyperpigmentation.
tients. Adverse events were mild for both treatment groups The tolerability and efficacy of the newest HA, Be- and included erythema, edema, and ecchymosis.
lotero, was studied in an 18-month open-label trial. Be- Having shown clear superiority over collagen, Radiesse lotero was injected into both NLFs, and touch-ups were was then compared with the HAs. In a European study allowed for optimal correction.20 No significant AE or im- performed in 2008, Moers-Carpi et al26 enrolled 60 pa- munogenic reactions were noted, and correction was ef- tients in a 12-month, split-face RCT comparing NLFs fective for at least 48 weeks in approximately 80% of sub- treated with Radiesse and Restylane. At the 6-, 9-, and jects. Belotero was also compared with Restylane for 12-month time points, CaHA was consistently superior correction of NLFs in a 4 week, split-face RCT (n = 25) to HA in aesthetic rating using the standard WSRS and and found improved evenness of NLFs for the Belotero- GAIS tests. At 12 months, 79% of the NLFs treated with treated side compared with the Restylane-treated side at CaHA were still improved or better vs only 43% of the HA-treated folds. In a similar study, Radiesse was com- The safety and efficacy of large particle HA for facial pared with 2 HA fillers, Juve´derm 24 ( Juve´derm Ultra) contouring was evaluated by DeLorenzi et al22 in 2009 and Perlane for NLF treatment.27 In this multicenter trial, in a nonblinded, non-RCT study. Fifty-seven patients un- 205 patients randomly received either HA gel or CaHA derwent cheek or chin augmentation with Restylane SubQ injection to the NLF. At 8 months, GAIS evaluation dem- (Medicis Aesthetics) and were followed up for 12 months.
onstrated significantly more patients treated with CaHA Patients and investigators found approximately 50% aes- showed improved GAIS scores compared with either HA.
thetic improvement at 12 months with more than 90% The 2007 consensus recommendations confirmed ef- improvement at 6 months. Minimal AEs reported when ficacy of CaHA for the correction of volume loss in the the product was implanted subcutaneously or preperi- midface and lower face. As such, it serves as an excel- osteally. A similar European study compared Juve´derm lent elevator of a depressed oral commissure and re- Voluma (Allergen) with patients previously treated with stores lost volume to the marionette lines, pre-jowl sul- Restylane SubQ in the cheeks and chin. Also, in a non- cus, labiomental crease, chin, and midface.28 However, blinded, nonrandomized, and noncontrolled study, 69% because of the risk of necrosis and nodule formation, it of injectors and 61% of patients preferred Voluma in terms is contraindicated for injection into the lips and gla- bella. Sadick and colleagues29 conducted a 47-month safetyand efficacy evaluation of CaHA and reported only 7 mi- CALCIUM HYDROXYLAPATITE
nor events in 113 patients, which resolved in 30 days.
Product safety of CaHA for injection in patients with Calcium hydroxylapatite is an injectable product with darker skin types was studied in 2009 by Marmur et al.30 ideal qualities for tissue implantation including longev- In an open-label, nonrandomized, 5-center trial, 100 pa- ity; low AE profile; and nonantigenic, nonirritating, non- tients with Fitzpatrick skin types IV to VI were injected toxic, and biocompatible properties. Prior to FDA ap- subdermally with CaHA and returned at 3 and 6 months proval as a dermal filler, CaHA had FDA approval for vocal to be assessed for the presence of keloids, hypertrophic 2012 American Medical Association. All rights reserved.
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scarring, and hypopigmentation or hyperpigmentation.
trasonography, and results included significant in- There were no signs of AEs at any time during this study, creases in total cutaneous thickness with improved fa- highlighting the safety of this product.
cial aesthetics and improved quality of life.
Although Radiesse mixed with lidocaine is not com- Immediate vs delayed PLLA treatments were studied mercially available, a technique for mixing the product in a 24-week, open-label, single-center randomized study with lidocaine prior to injection was developed by Busso in 2004 by Moyle et al34 at the Chelsea and Westminster and Voigts31 in 2008 and was FDA approved in 2009.
Hospital in London, England. In this study, 30 HIV- Radiesse mixed with lidocaine, 2%, was shown to re- positive patients with facial lipoatrophy were treated with main mixed for at least 24 hours without separating or 3 PLLA injection sessions at 2-week intervals and were settling. In an RCT of NLF injection of CaHA with and observed for a total of 24 weeks. In this study, all pa- without lidocaine, subjects reported statistically signifi- tients were treated at week zero, and then subsequent cantly less pain in the fold treated with the mixture vs treatments were either immediate (weeks 2, 4, and 6) or the plain control.32 The mixing process was performed delayed (weeks 12, 14, and 16). The product was recon- using 0.2 mL of lidocaine, 2%, mixed with 1.3-mL stituted with water, and lidocaine was added, for a total Radiesse. A female-to-female Luer lock syringe was used volume of 4 to 5 mL per treatment. There were no seri- to mix the products using approximately 10 back-and- ous AEs reported, although 1 patient developed a super- ficial local cellulitis that did not require antibiotic treat-ment. Most importantly, the percentage of patients who INJECTABLE PLLA (SCULPTRA)
developed subcutaneous papules was 31%. In this study,the product was injected in the deep dermal plane.
Approved in 2004 for the correction of facial lipoatro- In a 3-year study of non-HIV patients injected with Sculp- phy in patients with human immunodeficiency virus tra for aesthetic volumization, Lowe et al35 evaluated nod- (HIV) and in 2009 for aesthetic volume replacement for ule formation in 210 patients previously treated with PLLA.
cosmetic purposes, Sculptra (Valeant Pharmaceuticals) They concluded that most nodules resolved spontane- is a collagen stimulator. Poly-L-lactic acid is a synthetic ously and were related to placement of product and rec- polymer similar to absorbable suture material. It is re- ommended not injecting around the eye or mouth. As more constituted with sterile water to create a hydrogel with experience with the product was determined by clinical a methylcellulose carrier. Poly-L-lactic acid stimulates col- practice, it was found that increasing dilution and place- lagen formation by causing a foreign body reaction ac- ment of the product in planes deeper than the dermis de- companied by dermal fibrosis. Several treatment ses- creased the incidence of subcutaneous papules. A review sions are required for optimal facial volume restoration, of the literature by Kates and Fitzgerald36 showed that the and patients must be counseled that the results are gradual.
rates of papule formation had fallen to 0% to 13% using Poly-L-lactic acid is biodegradable and does not offer per- manent correction. The longevity of the product varies In 2009, Sculptra was approved by the FDA for use but may be observed to last for several years, requiring a in volumization of the aging face. Identical to Sculptra, the cosmetic product was packaged and sold as Sculptra Poly-L-lactic acid is best injected into the superficial Aesthetic. It was approved for the correction of shallow subcutaneous or preperiosteal tissues by a fanning, cross- to deep NLFs, contour deficiencies, and other facial hatching grid or depot technique, followed by massage wrinkles and lines, which could be improved using a grid- for several days to evenly disperse the product. Early ex- pattern technique. Because there were no similar FDA- perience with the product resulted in nodule formation; approved products for facial volume restoration, Sculp- however, improvements in increasing particle size uni- tra did not need to prove equivalence to Restylane on a formity, combined with higher dilution ratios, have made split-face trial—volumization studies were only needed AEs less frequent. Multiple studies have shown that pa- tients injected with PLLA for HIV-associated lipoatro- In their comprehensive review of facial volume with phy have had prolonged improvement in dermal thick- PLLA, Fitzgerald and Vleggaar37 recommended dilution ness as well as improvement in quality of life.
of the product with 5 mL or more of sterile water and The initial pilot study on PLLA (“New-Fill” in Eu- the addition of lidocaine, 1% to 2%, to achieve a final di- rope) for HIV facial lipoatrophy was performed in the lution of 8 to 9 mL per vial. Injections were placed in VEGA study by Valantin et al33 in 2003. In this 96- the superficial subcutaneous or preperiosteal planes. Pa- week, uncontrolled, single-center, open-label study, 50 tients were instructed to massage the injected regions for HIV-infected patients who were receiving antiretroviral 5 minutes, 5 times a day for 5 days after treatment. They therapy were treated with PLLA at 2-week intervals for also recommend resuspension of the product at least 2 6 weeks. No severe treatment-related AEs were encoun- hours, preferably overnight, before use.
tered; however, 52% of patients developed palpable butnonvisible and nonbothersome subcutaneous nodules.
In addition, viral load and CD4 cell counts remained un-changed during the course of treatment. The PLLA was ArteFill (Suneva Medical) is the only FDA-approved per- reconstituted with 3- to 4-mL of sterile water. For com- manent filler used for treatment of the NLFs. Approved in fort, 1-mL lidocaine was injected locally. A total of 4 mL 2006 (originally manufactured by Artes Medical Inc), its per cheek was injected at each treatment. Patients were predecessors Artecoll and Arteplast had been used in Eu- evaluated by clinical examination, photographs, and ul- rope for the previous 10 years. The original formulations 2012 American Medical Association. All rights reserved.
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produced granulomas at an unacceptably high rate; there- lomas may be spontaneous resolution, and treatment is fore, by changing the formulation process to remove nega- often not necessary. A significant number of nodules were tive charge on the particles and refining the process to pro- reported after injection of the lips; therefore, injection duce a smooth sphere, the incidence of granuloma formation for lip augmentation is not recommended.
was resolved. Such modifications in the production ofPMMA decreased the granuloma formation from 2.5% for AUTOLOGOUS FIBROBLASTS
Arteplast to less than 0.01% for ArteFill.38 ArteFill is a polymer of microspheres suspended in a Originally known as Isolagen technology (Isolagen Inc), bovine-based collagen, 3.5%, and lidocaine, 0.3%. The tissue is harvested from patients by a postauricular punch microspheres have a diameter of 30 to 45 ␮m and are biopsy and cultured to produce a fibroblast cell line. Be- smooth and round; there are approximately 6 million mi- cause tissue is autologous, it is biocompatible and dem- crospheres per 1 mL of product. Skin testing at least 1 onstrates a low incidence of hypersensitivity reactions.
month prior to injection is required because of the bo- A pilot study (n = 10) was performed in 1999 by Wat- vine collagen content. Since 2006, PMMA has been ap- son et al43 using intradermal fibroblast injections for fa- proved by the FDA for treating the NLFs. ArteFill is stored cial rhytids and dermal depressions (3 injection ses- in the refrigerator until ready to use; it is allowed to come sions at 2-week intervals). At 6 months, they found that to room temperature before injection to ease the flow 90% of patients showed improvement of 60% to 100%, through the syringe. After injection, the initial correc- and a histologic study showed evidence of increased thick- tion is achieved by the collagen component, which is de- ness and density of the dermal collagen.
graded in 1 to 3 months. During this time, PMMA be- In 2011, The FDA approved LaViv as a dermal filler comes encapsulated with connective tissue, which results for the correction of moderate to severe NLFs. Like Iso- in volume improvement. The permanent microspheres lagen, a punch biopsy is harvested from the postauricu- are not degraded or phagocytized; the results cannot be lar area and fibroblasts are produced for injection. In a reversed. Complications of beading or lumpiness can be phase 3 clinical trial, Weiss et al44 conducted a double- seen when injected into the lips and around the eyes; blinded, randomized comparison of autologous fibro- therefore, injection is not recommended in these areas.
blasts with placebo (transport medium without living The initial FDA evaluation of ArteFill was a multi- cells). They noted that dermal injection of fibroblasts im- center, double-blinded, randomized controlled study proved wrinkles, acne scars, and other dermal defects com- (n = 251) that compared Artefill with bovine collagen pared with placebo. LaViv is still in clinical trials to de- treatment in the glabella, NLFs, radial upper lip lines, and oral commissures.39 Injections were placed by tunnel-ing technique at the deep dermal-subcutaneous junc- CONCLUSIONS
tion. Patients were evaluated using a 5-point photo-graphic Facial Fold Assessment Scale.40 At 12 months, The safety and efficacy of dermal fillers on the market significant wrinkle correction was noted for 87% of treated today are clearly delineated by the current literature. The patients. Adverse events were uncommon, and redness, development of facial filling agents is an actively evolv- swelling, and lumpiness were more common in the col- ing process. Currently available filling agents have been lagen group. A subgroup of 69 patients were contacted refined to maximize results and minimize complica- 4 to 5 years later for further assessment and were evalu- tions. As the world of facial-filling products continues ated for delayed AEs. Among these 69 patients, the total to expand, it is evident that there are multiple opportu- number of AEs was 6 of 272 wrinkles injected, for an AE nities for further research in these areas.
rate of 2.2%. Two of the 6 AEs were severe (lumpinessthat required excision for 1 patient and steroid injec- Accepted for Publication: August 31, 2012.
Published Online: November 26, 2012. doi:10.1001
Cohen et al41 reported on the 5-year safety and effi- cacy of PMMA. Patients in the original pivotal study for Correspondence: Theda C. Kontis, MD, Facial Plastic Sur-
the FDA were contacted, and blinded observers graded gicenter, Johns Hopkins Medical Institutions, 1838 Greene the NLFs on a validated 6-point assessment scale. Com- Tree Rd, Ste 370, Baltimore, MD 21208 (tckontis@aol pared with baseline, PPMA filler was noted to maintain the NLF correction over the 5 years. In addition, it was Conflict of Interest Disclosures: Dr Kontis has served
noted that the time frame between 1 and 5 years contin- on the speaker’s bureau for Allergan, Medicis, and Valeant.
ued to show improvement. Of the 145 subjects in thestudy, there were 8.3% treatment-related AEs—1.4% mod- erate and 0.7% severe. The most common treatment-related AE was lumpiness, the majority of which were 1. Kontis TC, Rivkin A. The history of injectable facial fillers. Facial Plast Surg. 2009; mild. The safety profile was reported to be consistent with other soft-tissue products including Restylane, Juve´- 2. American Society for Aesthetic Plastic Surgery. Statistics 2011. http://www .surgery.org/media/statistics. Accessed July 9, 2012.
Gelfer et al42 published the first series of complica- 3. US Food and Drug Administration. Cosmetic devices. http://www.fda.gov tions seen after ArteFill or Artecoll injections. Delayed /MedicalDevices/ProductsandMedicalProcedures/CosmeticDevices/default.htm. Accessed July 19, 2012.
granulomatous reactions were reported in 10 patients.
4. Monheit GD, Coleman KM. Hyaluronic acid fillers. Dermatol Ther. 2006;19(3):141- The authors concluded that the natural history of granu- 2012 American Medical Association. All rights reserved.
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5. Beasley KL, Weiss MA, Weiss RA. Hyaluronic acid fillers: a comprehensive review.
24. Ridenour B, Kontis TC. Injectable calcium hydroxylapatite microspheres (Radiesse).
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6. Flynn TC, Sarazin D, Bezzola A, Terrani C, Micheels P. Comparative histology of 25. Smith S, Busso M, McClaren M, Bass LS. A randomized, bilateral, prospective intradermal implantation of mono and biphasic hyaluronic acid fillers. Dermatol comparison of calcium hydroxylapatite microspheres versus human-based col- lagen for the correction of nasolabial folds. Dermatol Surg. 2007;33(suppl 2) 7. Narins RS, Brandt F, Leyden J, Lorenc ZP, Rubin M, Smith SA. A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Re- 26. Moers-Carpi MM, Tufet JO. Calcium hydroxylapatite versus nonanimal stabi- stylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg. 2003; lized hyaluronic acid for the correction of nasolabial folds: a 12-month, multi- center, prospective, randomized, controlled, split-face trial. Dermatol Surg. 2008; 8. Day DJ, Littler CM, Swift RW, Gottlieb S. The wrinkle severity rating scale: a vali- dation study. Am J Clin Dermatol. 2004;5(1):49-52.
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