From 2005 to 2010, the cosmetic interventions market

ABSTRACT To order reprints or e-prints of JAM articles please contact editor@jaesthmed.org July 2015 6 Volume 1 Issue 1 Copyright 2015 Over recent years there has been increasing use of dermal fillers to improve facial appearance. A variety of non-autologous fillers are available including hyaluronic acid, calcium hydroxylapatite, and poly-l-lactic acid based products. Despite there being over 140 dermal fillers available in the UK, the evidence-base for dermal fillers is limited, with fewer than 30 randomised controlled studies published associated with less than 15 individual brands. The strongest evidence is for the treatment of nasolabial folds, with data more limited for other areas of the face. The lack of placebo-controlled data, variability in study methodology and lack of objective outcome measures, complicate the comparison of the individual fillers. More research is required, particularly in the longer-term, in order to effectively evaluate the effectiveness of dermal fillers. Keywords: Aesthetic; cosmetic; nasolabial folds; marionette lines; glabellar lines; lip augmentation, dermal filler Date received: 1 November 2014; accepted 2 December 2014 Original Article Dermal Fillers for Facial Rejuvenation: A Review of Clinical Evidence MSc(Lond) Mbbs(Lond) Mrcs(Lond) Mfpm LLM MBA Managing Director, The Jandhyala Institute, Banbury, Uk Consultant Pharmaceutical Physician, Medical Director, Latralis Ltd President of United Kingdom Society for the Study of Aesthetic Medicine (UKSSAM) J Aesth Med. 2015;1(1):6 13. Introduction in the 201 -Journal UK over tripled, from 720m to 2.3bn, of and is Aesthetic non-permanent fillers. Medicine. From 2005 to 2010, the cosmetic interventions market predicted to rise to 3.6bn in 2015. 1 This growth was predominately driven by the increasing popularity of non-surgical procedures, 1 including the use of injectable dermal fillers. Currently, there are estimated to be between 140 and 190 dermal filler products available in the UK (including CE marked and non-ce marked products). 2,3 The most common indications for dermal fillers include reduction of facial lines (e.g. nasolabial folds, periorbital lines, forehead lines, glabella lines, and perioral lines) and lip, cheek and chin enhancement. 2,4,5,6 Dermal fillers are produced from a range of sources and can be broadly classified as being autologous (i.e. using the patient s own tissue; e.g. autologous fat transplant, autologous fibroblast transplant) or non-autologous (i.e. xenografts, allogenic sources, synthetic materials). 2,5 Variation in the materials that comprise dermal fillers contributes to significant differences in their respective properties. Non-autologous fillers can be further classified as non-permanent or temporary (typically lasting 6 to 9 months), semi-permanent (typically lasting 1 2 years), or permanent (lasting multiple years). 2 Temporary, non-autologous dermal fillers include bovine and porcine collagen, human collagen, and hyaluronic acid. Calcium hydroxylapatite, poly-l-lactic acid, and polycaprolactone are all considered semi-permanent fillers, whilst permanent fillers include polymethylmethacrylate, polyacrylamide hydrogel, and silicone. 2,5,6 The majority of aesthetic facial procedures carried out in the UK involve non-autologous, Over the last few years there has been the withdrawal of several of the leading collagen brands from the market, including Zyderm, Zyplast, Cosmoderm, Cosmoplast, and Evolence. Commercial, rather than safety reasons, are purported as being behind the discontinuations, 7 commensurate with rises in the use of predominantly hyaluronic acid-based dermal fillers. 8 The events surrounding Poly Implant Prothèse (PIP) silicone breast implants have, however, raised issues regarding the safety and regulation of cosmetic interventions, 2 and there have been specific appeals for more stringent regulation of dermal fillers. 2 At present, manufacturers are not required to notify the Medicines and Healthcare products Regulatory Agency (MHRA) that they are bringing dermal fillers to market in the UK and there are no restrictions on who can purchase or administer these products. 2 In the US, all dermal fillers are regulated by the Food and Drug Administration (FDA) as medical devices under a more restrictive system of regulation than in the EU (Table 1). 2,9 In comparison to the UK, only 11 different dermal fillers have been approved by the FDA for cosmetic indications. 6 In a report published by the Department of Health (DoH) in April 2013, 2 dermal fillers were considered a crisis waiting to happen and a new regulatory framework for cosmetic interventions was proposed covering high quality care, an informed and empowered public, and accessible resolution and redress. In light of this increased scrutiny, the aim of this article is to

7 Table 1. Regulation of high-risk devices in the US and EU (adapted from 9 ) Standard for approval Evidence required US - Safety - Effectiveness: proof of actual benefit to patients - Valid clinical trials: generally randomised and controlled EU - Safety - Technical performance, no benefit to patients - Limited data, dermal fillers can be studied in only 10 20 patients with a six month follow-up Approval granted by - Central regulatory authority: FDA - Notified bodies: private, for profit organisations chosen and hired by the manufacturer. Approval by any notified body authorises marketing throughout EU Transparency of approval decisions Post-approval reporting requirements and transparency - Approved and their evidentiary basis disclosed to public - Side effects and recalls must be reported to FDA and are publicly disclosed on its website - Neither approvals nor evidentiary basis disclosed to public - Reported side effects and recalls are not publically disclosed review the best available evidence for dermal filler use in facial rejuvenation. Methods 201 -. In order to assess the evidence-base for dermal fillers in facial rejuvenation, a literature search was performed in Medline (1980-August 2013). The review focussed on non-autologous fillers due to their widespread use in cosmetic procedures in the UK. Search terms included generic and brand names, with results restricted to clinical studies, reports accredited to the FDA, and guidance documents concerning dermal fillers or aesthetic medicine. The evidence was graded using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. 10 The available evidence supporting dermal fillers in other facial areas was generally poor. Limited level-2 evidence was found for hyaluronic acid fillers in the glabella, 48,49 cheeks, 50 and for the lips and perioral area. 51,52 In addition, there were nonrandomised studies (level-3) undertaken which investigated use of hyaluronic acid in the periorbital area 53,54 and chin. 55 For the semi-permanent fillers, only calcium hydroxylapatite had evidence outside the nasolabial folds, with level-4 evidence (case-series, case-control studies, or historically controlled studies 10 ) covering a number of areas (glabella, periorbital, nose, lips/perioral). 56,57 Limited evidence was also found for the permanent fillers, polymethylmethacrylate in the glabella and lips/perioral areas (one level-2/3 study 44 ), polyacrylamide in the lips/perioral area (one level-3 study 46 ), and silicone in the glabella, cheeks, lips, and chin (one level-4 study 58 ). Evidence for non-autologous dermal fillers in facial rejuvenation The vast majority of the available evidence for the use of dermal fillers in facial rejuvenation assessed their efficacy for the treatment of nasolabial folds (Table 2). Hyaluronic acid fillers, in particular, have demonstrated effectiveness in the treatment of nasolabial folds, with 27 randomised studies 11,12,13,14,15,16,17, 18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38 identified (level-2 evidence 10 ). There was also reasonable level-2 evidence for the effectiveness of calcium hydroxylapatite in the treatment of nasolabial folds, with five studies identified. 35,36,39,40,41,42 For the other fillers reviewed, only one randomised study each for poly-l-lactic acid, polycaprolactone, and polymethylmethacrylate could be found in nasolabial folds, 43,44,45 whilst there was limited level-3 evidence (non-randomised, controlled cohort/ follow-up study 10 ) for polyacrylamide hydrogel in this treatment area. 46,47 When considering individual brands, unsurprisingly, the majority of the evidence comes from those approved by the FDA (Table 3). In total, level-2 evidence from randomised studies was found for only 13 distinct brands of non-autologous dermal fillers currently available, although there were four additional studies identified which did not state the specific brand under investigation (three for hyaluronic acid 30,33,48 and one for calcium hydroxylapatite 42 ). Of the brands, Restylane/Perlane (hyaluronic acid) and Radiesse (calcium hydroxylapatite) had the most evidence. The breadth of evidence for Restylane is reflected in the fact that it is the only dermal filler specifically approved for lip augmentation by the FDA (FDA approval has typically been granted for moderate-severe nasolabial folds and unspecified other wrinkles). 6 Supplementary evidence is available for Aquamid (polyacrylamide hydrogel) and Sculptra (poly-l-lactic acid) in that they have been approved by the FDA for use in the treatment of lipoatrophy secondary to HIV. 6

8 201 -. Table 2. Best available evidence from clinical studies for non-autologous dermal fillers in cosmetic facial rejuvenation Evidence-level* (number of studies published at that level) Forehead Glabella Periorbital Nose Cheeks Nasolabial folds Lips/perioral Pre-jowl sulcus Chin Filler Non-permanent L2 (n 2) 51,52 None L3 (n 1) 55 11,12,13 14,15, Hyaluronic acid None L2 (n 2) 48,49 L3 (n 2) 53,54 None L2 (n 1) 50 L2 (n 27) 16,17,18,19,20,21,22,23,24, 25,26,27,28,29,30,31,32, 33,34,35,36,37,38 Semi-permanent Calcium hydroxylapatite None L4 (n 1) 56 L4 (n 1) 56 L4 (n 1) 56 None L2 (n 5) 35,36,39,40,42 L4 (n 1) 56,57 None None Poly-l-lactic acid None None None None None L2 (n 1) 45 None None None Polycaprolactone None None None None None L2 (n 1) 43 None None None Permanent Polymethylmethacrylate None L2/3 (n 1) 44 None None None L2 (n 1) 44 L2/3 (n 1) 44 None None Polyacrylamide hydrogel None None None None None L3 (n 2) 46,47 L3 (n 1) 46 None None Silicone None L4 (n 1) 58 None None L4 (n 1) 58 None L4 (n 1) 58 None L4 (n 1) 58 *Level 1: systematic reviews of randomised trials or n-of-1 trials; Level 2: randomised trial or observational study with dramatic effect; Level 3: non-randomised controlled cohort/follow-up study; Level 4: Case-series, case-control studies, or historically controlled studies 10 including crows feet, tear troughs etc.; including marionette lines, melomental folds etc.; 85% of patients were treated for nasolabial folds, 65 so evidence level downgraded

9 Table 3. Best available evidence for selected brands of non-autologous dermal fillers in facial rejuvenation Filler FDA approved? Evidence level* (number of studies) Facial area(s) Hyaluronic acid (non-permanent) Restylane (R)/Perlane (P) Yes R: L2 (n 8); L3 (n 3) P: L2 (n 8); L3 (n 1); L4 (n 1) R: Nasolabial folds 11,13,15,16,17,18,21,27 (L2); glabellar 49 (L2); lips/perioral 59,66 (L3); cheeks and chin 55 (L3) P: Nasolabial folds 13,19,20,28,29,30,35 (L2); lips/perioral (L2; 51 L3 59 ); cheeks 67 (L4) Juvéderm Yes L2 (n 8) Nasolabial folds 12,22,23,24,25,27,35 (L2); lips/perioral 52 (L2) Belotero Balance Yes L2 (n 3); L3 (n 1) Nasolabial folds 21,27,37 (L2); multiple sites 68 (L3) Elevess Yes L2 (n 2) Nasolabial folds 14,26 (L2) Prevelle Yes L2 (n 1) Nasolabial folds 32 (L2) Emervel Deep No L2 (n 2) Nasolabial folds 28,29 (L2) Dermal gel extra No L2 (n 1) Nasolabial folds 31 (L2) Puragen No L2 (n 1) Nasolabial folds 34 (L2) Wipeline No L2 (n 1) Wrinkles (unspecified) 38 (L2) 201 -. sites, including glabella, nose, lips, and periorbital 56,71 (L4) E Classic/E Lips/E Deep/E Volume No L3 (n 3) Lips/perioral 69 (L3); cheeks 70 (L3); periorbital 54 (L3) Calcium hydroxylapatite (semi-permanent) Radiesse Yes L2 (n 4); L4 (n 3) Nasolabial folds 35,36,39,40,41 (L2); lips/perioral 57 (L4); multiple Poly-L-lactic acid (semi-permanent) Sculptra aesthetic Yes L2 (n 1) Nasolabial folds 45 (L2) Polycaprolactone (semi-permanent) Ellansé No L2 (n 1) Nasolabial folds 43 (L2) Polymethylmethacrylate (permanent) Artefill Yes L2 (n 2) Nasolabial folds 44,61 (L2); glabella, lips/perioral 44,61 (L2/3 ) Polyacrylamide hydrogel (permanent) Aquamid No L3 (n 2) Nasolabial folds 46,47 (L3); lips 46 (L3) Silicone (permanent) Silikon (contains hyaluronic acid) No L4 (n 1) Glabella, cheeks, lips, and chin (L4) 58 *Level 1: systematic reviews of randomised trials or n-of-1 trials; Level 2: randomised trial or observational study with dramatic effect; Level 3: non-randomised controlled cohort/follow-up study; Level 4: Case-series, case-control studies, or historically controlled studies; 10 individual formulations of the same brand (e.g. with or without lignocaine or thicker and thinner versions) have been grouped together; 85% of patients were treated for nasolabial folds, 65 so evidence level downgraded; approved by the FDA for other indications

10 Figure 1. Schematic of level-2 evidence for dermal fillers in facial rejuvenation. Level-2: randomised trial or observational study with dramatic effect 10. The 37 randomised studies (level-2) identified varied considerably in terms of design, patient numbers (ranging from 10 to 400 patients), and duration (from 1 month to 2 years) (Figure 1). Just over half (15/27; 56%) of the studies investigating hyaluronic acid fillers had 6 months follow-up, with only Infection 201 -Journal of Aesthetic oo e.g. activation of HSV Medicine. oo acute or chronic three studies 18,24,25 lasting more than 1 year. The vast majority of these studies (34; 92%) used semi-quantitative scales to assess effectiveness. This would typically be using a 5-point, Wrinkle Severity Rating Scale (WSRS), scored by the investigator, sometimes with blinding, sometimes with the patient also making an assessment. The Global Aesthetic Improvement Scale (GAIS) and patient rated satisfaction were common secondary endpoints. The three studies using objective measures of effectiveness all investigated hyaluronic acid, in the treatment of nasolabial folds, 21 cheeks, 50 and lips. 51 Improvements in the depth and evenness of nasolabial folds was evaluated by the Phase-shift Rapid In-vivo Measurement of Skin (PRIMOS) system. 21 Whilst elasticity and dermal thickness of the cheeks were measured by cutometry and 20 MHz echography. 50 Volume changes in the lips were assessed by mathematically derived facial volume changes using 3D stereophotogrammetry. 51 Table 4. Serious complications associated with dermal fillers (adapted from 2,59 ) Granuloma formation oo oo lumps and nodules in the skin can be chronic and may be related to progressive destruction and deformity Ulcer formation Vascular occlusion oo can result in ulceration, tissue necrosis and scarring Tissue necrosis oo can results in loss of the affected tissues Safety All dermal fillers have the potential to cause injection site reactions, erythema, oedema/swelling, bruising, pain/tenderness, hypersensitivity, overcorrection, anaphylaxis, and pruritus. 2,59,60 The majority of these complications, however, can resolve on their own within a few weeks. 40,60 There are also a number of more serious complications associated with the use of dermal fillers some of which can occur years after initial treatment (Table 4). 2,59,61 The dermal filler chosen (type and whether Allergic reaction oo Local or systemic Prolonged swelling, bruising Nerve damage Blindness oo rare but has been associated with a range of filler injections used in the periorbital area

11 includes lignocaine), the technique of the administrator, the equipment used, and the area of the face treated can all affect the rate of adverse events. 62,63 Importantly, due to the lack of formal reporting channels, data on the rates of adverse events for dermal fillers are poor. 2 Discussion Whilst there are between 140 and 190 dermal filler products available in the UK, 2,3 the vast majority of the published, level-2 clinical evidence was found to be limited to less than 15 individual brands (i.e. 10% of total available). Of the fillers, most evidence was for hyaluronic acid-based products, reflective of the larger number of brands available. Importantly, the evidence for one brand of filler should not be generalised to others of the same type and it should be the responsibility of the manufacturer to demonstrate their particular brand of filler is both safe and effective. The overwhelming focus of most of the studies was the treatment of nasolabial folds, with very limited evidence available for other facial areas. Some practitioners are now choosing to treat nasolabial folds with a cheek augmentation in the first instance. This review has highlighted the lack of evidence for these products in the cheek area and furthermore, this new 201 -Journal of Aesthetic Disclosures Medicine. All Rights conflicts Reserved of interest to declare. approach to the management of nasolabial folds, it can be argued, has rendered obsolete studies carried out in this area where the product has been directly injected into them. This further stresses the importance of generating evidence on both the efficacy and safety of products administered with up-todate techniques. The relative lack of published evidence is most likely attributable to the fact that dermal fillers are classified as medical devices with less stringent requirements for approval than prescription only medicines. As would be expected, most published data relate to FDA-approved products and it appears advisable that practitioners preferentially use these more rigorously tested fillers. The comparative benefits with other non-surgical cosmetic procedures, such as Botox, also require discussion with the patient. Due to the lack of placebo controlled data, the effect of the mechanical trauma of injection of a volume of fluid into the dermis on overall appearance of the skin cannot be separated from that resulting from the dermal filler. Under normal circumstances with a medicinal product, unless ethical concerns preclude this, an intervention is usually compared to placebo in order to demonstrate its efficacy. These studies have not been conducted with dermal fillers, therefore, it could be argued that their true efficacy has not been evaluated correctly. A further limitation is the lack of objective outcome measures in the studies. The vast majority of studies rely on semi-objective or subjective measures, such as WSRS, GAIS, or satisfaction; these are highly observer dependent. Inter- as well as intraobserver errors have been noted with some rating scales. 64 More research using objective measures are recommended in order to neutralise this bias. Despite the aforementioned caveats, there is evidence that the products included within the review increased skin thickness and improved appearance. The results from a relatively small number of well-designed clinical trials indicate that dermal fillers appear efficacious and well tolerated within the short-term. Longer-term efficacy and safety data for their use are currently limited, which is important for informed consent purposes and also has financial implications for the patient, since the vast majority of procedures are undertaken privately. Long-term follow-up data are required in order to gain a greater understanding of the effectiveness of dermal fillers, although it may be difficult to obtain these data because patients are likely to undergo subsequent cosmetic interventions. Grant Support No external funding sources supported this work. The author received no remuneration for the article and has no References 1. Cosmetic Surgery, Market Intelligence, Mintel, 2010. 2. Department of Health. Review of the Regulation of Cosmetic Interventions. Final Report. April 2013. Available at: https://www.gov.uk/government/ uploads/system/uploads/attachment_data/file/192028/review_of_the_ Regulation_of_Cosmetic_Interventions.pdf [accessed July 2013]. 3. Mercer NSG. Dermal fillers are medical devices in the UK. BMJ 2009;339:b2923. 4. United States of America. Food and Drug Administration. Dermal filler devices. Executive summary 2008. Available at: http://www.fda.gov/ohrms/ dockets/ac/08/briefing/2008 4391b1-01%20-%20FDA%20Executive%20 Summary%20Dermal%20Fillers.pdf [Accessed May 2013]. 5. Dastoor SF, Misch CE, and Hom-Lay Wang, DDS. Dermal fillers for soft tissue augmentation. J Oral Implantol 2007;33:4. 6. United States of America. Food and Drug Administration. Approved wrinkle fillers. Available at: www.fda.gov/medicaldevices/productsandmedicalprocedures/ CosmeticDevices/WrinkleFillers/ucm227749 [Accessed September 2013]. 7. Dermatology Times. Dermatologists prepare for departure of collagen from U.S. market. Available at: http://dermatologytimes.modernmedicine. com/dermatology-times/news/modernmedicine/modern-medicine-featurearticles/dermatologists-prepare-depart [accessed July 2013]. 8. The American Society for Aesthetic Plastic Surgery. Cosmetic Surgery National Data Bank Statistics 2012. Available at: http://www.surgery.org/ sites/default/files/asaps-2012-stats.pdf [accessed July 2013]. 9. United States of America. Food and Drug Administration. Unsafe and Ineffective Devices Approved in the EU that were Not Approved in the US. May 2012. 10. OCEBM Levels of Evidence Working Group. The Oxford 2011 Levels of Evidence. Oxford Centre for Evidence-Based Medicine. Available at: www.cebm.net/index.aspx?o 5653 [accessed August 2013].

12 11. Narins RS, Brandt F, Leyden J et al. A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg 2003;29:588 595. 12. Baumann LS, Shamban AT, Lupo MP, et al. Comparison of smooth-gel hyaluronic acid dermal fillers with cross-linked bovine collagen: a multicenter, double-masked, randomized, within-subject study. Dermatol Surg 2007;33: S128 S135. 13. United States of America. Food and Drug administration. Perlane. Summary of safety and effectiveness data. Available at: www.accessdata.fda.gov/ cdrh_docs/pdf4/p040024s006b.pdf?utm_campaign Google2&utm_ source fdasearch&utm_medium website&utm_term Perlane%20 summary&utm_content 2 [Accessed May 2013]. 14. United States of America. Food and Drug Administration. Cosmetic tissue augmentation product (CTA). Summary of safety and effectiveness data. Available at: www.accessdata.fda.gov/cdrh_docs/pdf5/p050033b. pdf?utm_campaign Google2&utm_source fdasearch&utm_ medium website&utm_term CTA%20dermal%20filler&utm_content 1 [Accessed May 2013]. 15. Rao J, Chi GC, and Goldman MP. Clinical comparison between two hyaluronic acid-derived fillers in the treatment of nasolabial folds: Hylaform versus Restylane. Dermatol Surg 2005;31:1587 1590. 16. Narins RS, Brandt FS, Lorenc P, et al. A randomized, multicenter study of the safety and efficacy of dermicol-p35 and non-animal-stabilized hyaluronic acid gel for the correction of nasolabial folds. Dermatol Surg 2007;33:213 221. 17. Narins RS, Brandt FS, Lorenc ZP, et al. Twelve-month persistency of a novel ribose-cross-linked collagen dermal filler. Dermatol Surg 2008;34 Suppl 1: S31 39. 18. Narins RS, Dayan SH, Brandt FS, et al. Persistence and improvement of nasolabial fold correction with nonanimal-stabilized hyaluronic acid 100,000 gel particles/ml filler on two retreatment schedules: results up to 18 months on two retreatment schedules. Dermatol Surg 2008;34 Suppl 1:S2 8. 19. Carruthers A, Carey W, De Lorenzi C, et al. Randomized, double-blind comparison of the efficacy of two hyaluronic acid derivatives, restylane perlane and hylaform, in the treatment of nasolabial folds. Dermatol Surg 2005;31:1591 1598. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. Lindqvist C, Tveten S, Bondevik BE, et al. A randomized, evaluator- 41. blind, multicenter comparison of the efficacy and tolerability of Perlane versus 201 -Journal Zyplast in the correction of nasolabial folds. Plast Reconstr Surg Aesthetic Surg J 2010;30:235 238. Medicine. 2005;115(1):282 289. 42. Prager W & Steinkraus V. A prospective, rater-blind, randomised comparison of the effectiveness and tolerability of Belotero Basic versus Restylane for correction of nasolabial folds. Eur J Dermatol 2010;20:748 752. 36(3):309 315. Weinkle SH, Bank DE, Boyd CM, et al. A multi-center, double-blind, randomized controlled study of the safety and effectiveness of Juvéderm injectable gel with and without lidocaine. J Cosmet Dermatol 2009;8(3):205 210. Levy PM, De Boulle K, Raspaldo H. Comparison of injection comfort of a new category of cohesive hyaluronic acid filler with preincorporated lidocaine and a hyaluronic acid filler alone. Dermatol Surg 2009;35 Suppl 1:332 336. Pinsky MA, Thomas JA, Murphy DK. Juvéderm injectable gel: a multicenter, double-blind, randomized study of safety and effectiveness. Aesthet Surg J 2008;28(1):17 23. Lupo MP, Smith SR, Thomas JA, et al. Effectiveness of Juvéderm Ultra Plus dermal filler in the treatment of severe nasolabial folds. Plast Reconstr Surg 2008;121(1):289 297. Dover JS, Rubin MG, Bhatia AC. Review of the efficacy, durability, and safety data of two nonanimal stabilized hyaluronic acid fillers from a prospective, randomized, comparative, multicenter study. Dermatol Surg 2009;35 Suppl 1: 322 230. Prager W, Wissmueller E, Havermann I, et al. A prospective, split-face, randomized, comparative study of safety and 12-month longevity of three formulations of hyaluronic acid dermal filler for treatment of nasolabial folds. Dermatol Surg 2012;38(7):1143 1150. Ascher B, Bayerl C, Brun P, et al. Efficacy and safety of a new hyaluronic acid dermal filler in the treatment of severe nasolabial lines - 6-month interim results of a randomized, evaluator-blinded, intra-individual comparison study. J Cosmet Dermatol 2011;10(2):94 98. Rzany B, Bayerl C, Bodokh I, et al. Efficacy and safety of a new hyaluronic acid dermal filler in the treatment of moderate nasolabial folds: 6-month interim results of a randomized, evaluator-blinded, intra-individual comparison study. J Cosmet Laser Ther 2011;13(3):107 112. Nast A, Reytan N, Hartmann V, et al. Efficacy and durability of two hyaluronic acid-based fillers in the correction of nasolabial folds: results of a prospective, randomized, double-blind, actively controlled clinical pilot study. Dermatol Surg 2011;37(6):768 775. 31. Monheit GD, Baumann LS, Gold MH. Novel hyaluronic acid dermal filler: dermal gel extra physical properties and clinical outcomes. Dermatol Surg 2010;36 Suppl 3:1833 1841. 32. Monheit GD, Campbell RM, Neugent H. Reduced pain with use of proprietary hyaluronic acid with lidocaine for correction of nasolabial folds: a patient-blinded, prospective, randomized controlled trial. Dermatol Surg 2010;36(1):94 101. 33. Taylor SC, Burgess CM, Callender VD. Safety of nonanimal stabilized hyaluronic acid dermal fillers in patients with skin of color: a randomized, evaluator-blinded comparative trial. Dermatol Surg 2009;35 Suppl 2:1653 1660. 34. Onesti M, Toscani M, Curinga G. Assessment of a new hyaluronic acid filler. double-blind, randomized, comparative study between Puragen and Captique in the treatment of nasolabial folds. In Vivo 2009;23(3):479 486. 35. Moers-Carpi M, Vogt S, Santos BM, et al. A multicenter, randomized trial comparing calcium hydroxylapatite to two hyaluronic acids for treatment of nasolabial folds. Dermatol Surg 2007;33 Suppl 2:S144 151. 36. Moers-Carpi MM, Tufet JO. Calcium hydroxylapatite versus nonanimal stabilized hyaluronic acid for the correction of nasolabial folds: a 12-month, multicenter, prospective, randomized, controlled, split-face trial. Dermatol Surg. 2008;34(2):210 215. 37. United States of America. Food and Drug Administration. Belotero Balance. Summary of safety and effectiveness data. Available at: http://www. accessdata.fda.gov/cdrh_docs/pdf9/p090016b.pdf [accessed August 2013]. 38. Dessy LA, Trignano E, Scuderi N. Randomized prospective study on the efficacy of a new revitalizing filler composed of hyaluronic acid (Wipeline). G Ital Dermatol Venereol 2008;143(2):161 165. 39. Fakhre GP, Perdikis G, Shaddix KK, et al. An evaluation of calcium hydroxylapatite (Radiesse) for cosmetic nasolabial fold correction: a metaanalysis and patient centric outcomes study. Ann Plast Surg 2009;63:486 489. 40. Smith S, Busso M, McClaren M, et al. A randomized, bilateral, prospective comparison of calcium hydroxylapatite microspheres versus human-based collagen for the correction of nasolabial folds. Dermatol Surg 2007;33: 112 121. Bass LS, Smith S, Busso M, et al. Calcium hydroxylapatite (Radiesse) for 43. 44. 45. 46. 47. 48. 49. 50. 51. treatment of nasolabial folds: long term safety and efficacy results. Aesthet Marmur E, Green L, Busso M. Controlled, randomized study of pain levels in subjects treated with calcium hydroxylapatite premixed with lidocaine for correction of nasolabial folds. Dermatol Surg. 2010 Mar; Moers-Carpi MM, Sherwood S. Polycaprolactone for the correction of nasolabial folds: a 24-month, prospective, randomized, controlled clinical trial. Dermatol Surg 2013;39(3 Pt 1):457 463. Cohen SR, Holmes RE. Artecoll: a long-lasting injectable wrinkle filler material: Report of a controlled, randomized, multicenter clinical trial of 251 subjects. Plast Reconstr Surg 2004;114(4):964 976. United States of America. Food and Drug Administration. Sculptra Aesthetic. Summary of safety and effectiveness data. Available at: http://www. accessdata.fda.gov/cdrh_docs/pdf3/p030050s002b.pdf [Accessed August 2013]. Pallua N, Wolter TP. A 5-year assessment of safety and aesthetic results after facial soft-tissue augmentation with polyacrylamide hydrogel (Aquamid): a prospective multicenter study of 251 patients. Plast Reconstr Surg 2010;125(6): 1797 1804. Wolters M, Lampe H. Prospective multicenter study for evaluation of safety, efficacy, and esthetic results of cross-linked polyacrylamide hydrogel in 81 patients. Dermatol Surg 2009;35 Suppl 1:338 343. Kono T, Kinney BM, Groff WF, et al. Randomized, evaluator-blind, split-face comparison study of single cross-linked versus double crosslinked hyaluronic acid in the treatment of glabellar lines. Dermatol Surg 2008;34:25 30. Carruthers J, Carruthers A. A prospective, randomized, parallel group study analysing the effect of BTX-A (Botox) and nonanimal sourced hyaluronic acid (NASHA, Restylane) in combination compared with NASHA (Restylane) alone in severe glabellar rhytides in adult female subjects: treatment of severe glabellar rhytides with a hyaluronic acid derivative compared with the derivative and BTX-A. Dermatol Surg 2003;29:802 809. Baspeyras M, Rouvrais C, Liégard L, et al. Clinical and biometrological efficacy of a hyaluronic acid-based mesotherapy product: a randomised controlled study. Arch Dermatol Res. 2013 May 29. [Epub ahead of print]. Downie J, Mao Z, Rachel Lo TW et al. A double-blind, clinical evaluation of facial augmentation treatments: a comparison of PRI 1, PRI 2, Zyplast and Perlane. J Plast Reconstr Aesthet Surg 2009;62:1636 1643.

13 52. Carruthers A, Carruthers J, Monheit G, et al. Multicenter, randomized, parallel-group study of the safety and effectiveness of onabotulinumtoxina and hyaluronic acid dermal fillers (24-mg/mL smooth, cohesive gel) alone and in combination for lower face rejuvenation. Dermatol Surg 2010;36: 2121 2134. 53. Rzany B, Cartier H, Kestemont P. Full-face rejuvenation using a range of hyaluronic acid fillers: efficacy, safety, and patient satisfaction over 6 months. Dermatol Surg 2012;38(7 Pt 2):1153 1161. 54. Rzany B, Cartier H, Kestermont P. Correction of tear troughs and periorbital lines with a range of customized hyaluronic acid fillers. J Drugs Dermatol 2012;11(1 Suppl):s27 34. 55. DeLorenzi C, Weinberg M, Solish N, et al. The long-term efficacy and safety of a subcutaneously injected large-particle stabilized hyaluronic acid-based gel of nonanimal origin in esthetic facial contouring. Dermatol Surg 2009;35 Suppl 1:313 321. 56. Jacovella PF, Peiretti CB, Cunille D. Long-lasting results with hydroxylapatite (Radiesse) facial filler. Plast Reconstr Surg 2006;118(3 Suppl):15S 21S. 57. Roy D, Sadick N, Mangat D. Clinical trial of a novel filler material for soft tissue augmentation of the face containing synthetic calcium hydroxylapatite microspheres. Dermatol Surg 2006;32(9):1134 1139. 58. Fulton J, Caperton C. The optimal filler: immediate and long-term results with emulsified silicone (1,000 centistokes) with cross-linked hyaluronic acid. J Drugs Dermatol 2012;11(11):1336 1341. 59. Bray D, Hopkins C, Roberts DN. A review of dermal fillers in facial plastic surgery. Curr Opin Otolaryngol Head Neck Surg 2010;18:295 302. 60. Brandt F, Bassichis B, Bassichis M, et al. Safety and effectiveness of small and large gel-particle hyaluronic acid in the correction of perioral wrinkles. J Drugs Dermatol 2011;10(9):982 987. 61. Cohen SR, Berner CF, Busso M. ArteFill: a long-lasting injectable wrinkle filler material summary of the U.S. Food and Drug Administration trials and a progress report on 4- to 5-year outcomes. Plast Reconstr Surg 2006; 118(3 Suppl):64S 76S. 62. Glogau RG, Kane MA. Effect of injection techniques on the rate of local adverse events in patients implanted with nonanimal hyaluronic acid gel dermal fillers. Dermatol Surg 2008;34 Suppl 1:S105 109. 63. 64. Conkling N, Bishawi M, Phillips BT, et al. Subjective rating of cosmetic treatment with botulinum toxin type A: do existing measures demonstrate interobserver validity? Ann Plast Surg 2012;69:350 355. 65. United States of America. Food and Drug Administration. Artefill. Summary of safety and effectiveness data. Available at: www.accessdata.fda.gov/ cdrh_docs/pdf2/p020012b.pdf [Accessed May 2013]. 66. Solish N & Swift A. An open-label, pilot study to assess the effectiveness and safety of hyaluronic acid gel in the restoration of soft tissue fullness of the lips. J Drugs Dermatol 2011;10:145 149. 67. Taub AF. Cheek augmentation improves feelings of facial attractiveness. J Drugs Dermatol 2012;11(9):1077 1080. 68. Pavicic T. Efficacy and tolerability of a new monophasic, double-crosslinked hyaluronic acid filler for correction of deep lines and wrinkles. J Drugs Dermatol. 2011;10(2):134 139. 69. Cartier H, Trevidic P, Rzany B. Perioral rejuvenation with a range of customized hyaluronic acid fillers: efficacy and safety over six months with a specific focus on the lips. J Drugs Dermatol 2012;11(1 Suppl):s17 26. 70. Kestemont P, Cartier H, Trevidic P, et al. Sustained efficacy and high patient satisfaction after cheek enhancement with a new hyaluronic acid dermal filler. J Drugs Dermatol 2012;11:9 16. 71. Sadick NS, Katz BE, Roy D. A multicenter, 47-month study of safety and efficacy of calcium hydroxylapatite for soft tissue augmentation of nasolabial folds and other areas of the face. Dermatol Surg 2007;33 Suppl 2:S122 126. AUTHOR CORRESPONDENCE MSc(Lond) MBBS(Lond) MRCS(Lond) MFPM LLM MBA Address:...The Jandhyala Institute, 13 Horse Fair, Banbury, OXON, OX16 0AN E-mail:...rjandhyala@latralis.com Telephone:...01295 273849 Lam SM, Azizzadeh B, Graivier M. Injectable poly-l-lactic acid (Sculptra): technical considerations in soft-tissue contouring. Plast Reconstr Surg Fax:...01295 273849 2006;118(3 201 -Journal Suppl):55S 63S. of Aesthetic Medicine.