- Email: [email protected]
Synthetic Fillers for Facial Rejuvenation
Sy nthe tic F iller s for Fac ial Rejuvenation Johnson C. Lee, MDa,*, Z. Paul Lorenc, MDb KEYWORDS Fillers Injectables Synthetic PLLA CaHA PMMA Silicone
KEY POINTS Calcium hydroxyapatite is a versatile semipermanent filler with a high elastic modulus for composite lifting. Poly-L-lactic acid can continue to induce local collagen formation for several months to years after injection for significant long-term results. Polymethyl methacrylate is effective for distensible atrophic acne scars. Silicone oil is a permanent filler with vitreoretinal indications, but is considered off-label use for facial injections, with potential serious complications. Synthetic fillers can provide long-lasting results through biostimulation of neocollagenesis.
According to the American Society of Plastic Surgeons’ 2014 Plastic Surgery Statistics Report, soft tissue filler procedures were the second most common minimally invasive procedures with 2.3 million procedures performed.1 This number represents a 3% increase from the previous year. Since the start of the century, soft tissue filler procedures have increased 253%, whereas cosmetic surgical procedures overall have decreased 12%. With the boom in the soft tissue filler industry, patients and physicians in the United States are encountering an increasing number of available products to choose from (Box 1). Soft tissue filler materials can be naturally (animal) sourced or synthetically produced. Mechanisms of action include volume replacement and biostimulation of autologous collagen production by native fibroblasts. Volume replacement occurs primarily through the use of hyaluronic acids, in which the hydrophilic biomaterial acts as a spacer within the tissue planes. Synthetic fillers such as calcium hydroxyapatite (CaHA), polymethyl methacrylate (PMMA),
and poly-L-lactic acid (PLLA), and silicone provide initial volume replacement but have an additional biostimulatory effect to supplement volumization. This article specifically addresses synthetic fillers in the management of facial aging.
CALCIUM HYDROXYAPATITE CaHA was first approved as an injectable implant by the US Food and Drug Administration (FDA) as a soft tissue radiographic marker in 2001 before quickly expanding its indications to include vocal fold augmentation, repair of oromaxillofacial defects, and soft tissue augmentation for stress urinary incontinence. In 2006, the FDA approved Radiesse (Merz Aesthetics, Raleigh, NC) as a CaHA filler for augmentation of moderate to severe nasolabial folds (NLFs) and human immunodeficiency virus (HIV)–associated facial lipoatrophy. Most recently, in 2015, Radiesse was approved for hand rejuvenation.2 Radiesse is considered a semipermanent filler composed of nonimmunogenic synthetic bone (CaHA) with microspheres 25 to 45 mm in diameter within a 70% carboxymethylcellulose carrier gel.
Disclosures: None of the authors have any direct financial or corporate interest in the subject matter or materials discussed in this article. a Private Practice, Enhance Medical Center, 462 North Linden Drive, Suite 333, Beverly Hills, CA 90212, USA; b Lorenc Aesthetic Plastic Surgery Center, 983 Park Avenue, New York, NY 10028, USA * Corresponding author. E-mail address: [email protected] Clin Plastic Surg 43 (2016) 497–503 http://dx.doi.org/10.1016/j.cps.2016.03.002 0094-1298/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.
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Lee & Lorenc
Box 1 Soft tissue fillers Collagen Cymetra Fascian Polymethyl methacrylate Bellafill Hyaluronic acid Restylane-L Restylane Lyft Restylane Silk Belotero Juvederm Ultra XC/Plus XC VOLUMA XC Prevelle Silk Calcium hydroxyapatite Radiesse Radiesse1 Poly-L-lactic acid Sculptra Silicone Silikon 1000 Sil-Ol 5000 Autologous cell therapy Platelet-rich plasma LaViv
Within several weeks after injection, the carrier gel is absorbed and net neutral volume replacement occurs through neocollagenesis. Because an immune response is not elicited, no skin testing is needed. The CaHA degrades into calcium and phosphate ions over time and is excreted slowly from the body, creating lasting volume for an average of 12 to 18 months.3 Radiesse has a particularly high elastic modulus (G’). G’ is the measure of the gel’s ability to resist deformation when pressure is applied. The higher the G’ of a substance, the greater its stiffness, and the less likely the substance is to deform under pressure from its surroundings. In a study by Sundaram and colleagues,4 the G’ of Radiesse was measured to be 1407 Pa compared with a range of 28 to 863 Pa in hyaluronic acid products. This property results in a greater amount of lift when injected under the skin envelope.
Because of its unique chemical composition, safety profile, and lifting properties, Radiesse has become an increasingly popular filler option. Its versatility extends to treatable facial zones, depth of injection, and delivery method. Radiesse has been used in marionette lines, the prejowl sulcus, oral commissures, and the posterior mandible.5–7 There are also reports of positive clinical results from injections in the temple and malar/submalar areas, which are considered off-label uses.8–11 Although early instructions for the use of CaHA were limited to the mid-dermis to target rhytids, practitioners have steadily expanded injection depths to the deep dermis and down to the supraperiosteal to structurally lift and contour the face12,13 (Fig. 1). This composite lift can be visualized under high-resolution ultrasonography, with which CaHA appears as hyperechoic deposits with variable degrees of posterior acoustic shadowing (Fig. 2). CaHA can be further modified by combining lidocaine in a mixing process rather than using the established protocol of preanesthetization of the treatment site before injection.14 The senior author (ZPL) recommends a 3-tiered dilution approach depending on associated areas of treatment and depth of injection (Table 1). The amount of lidocaine varies according to facial zones, whereas the volume of CaHA remains steady to facilitate ease of preparation and for consistent clinical results. Rare complications of CaHA injections include palpable nodules and vascular occlusion. Although there is no reversal agent or enzyme for CaHA, small nodules can be broken up with digital massage. Larger nodules can be treated with an injection of 5-fluorouracil and lidocaine 1:1 to reduce fibroblastic activity in these sites while breaking up the nodule. This technique is preferred to steroid injection because of potential chronic atrophic effects on overlying skin. For the exceedingly rare instances of vascular occlusion, the same protocols are advised as with other filler agents, including the use of hyaluronidase.2
POLY-L-LACTIC ACID PLLA has been in clinical use for more than 20 years as a major component of some absorbable sutures, such as Vicryl (Ethicon Inc, Somerville, NJ) and in surgical screws, pins, and staples used in maxillofacial and orthopedic procedures. It was FDA approved as an injectable implant in 2004 under the name of Sculptra (Galderma, Fort Worth, TX) for restoration or correction of the signs of facial fat loss in patients with HIV with facial lipoatrophy.15 More recently, in 2009, Sculptra Aesthetic was approved for immunocompetent
Synthetic Fillers
Fig. 1. (A) A 60-year-old woman before Radiesse injection. (B) Two weeks after Radiesse injection into the temporal, malar, and piriform areas.
patients for treating shallow to deep NLFs and other rhytids. Sculptra is composed of 150 mg of PLLA microparticles ranging from 40 to 63 mm and suspended in sodium, carboxymethylcellulose, and
nonpyrogenic mannitol.16 PLLA is a nontoxic and resorbable polymer (approximately 40–50 kDa) from the alpha-hydroxy acid family, and must be reconstituted with 3 to 5 mL of sterile water for injection at least 2 hours before use and may be stored
Fig. 2. High-resolution ultrasonography at 12 mHz reveals distinct soft tissue layers within the temporal fossa. Injection of Radiesse at the supraperiosteal level is clearly visualized with composite lifting of overlying soft tissue. Black, dermis; red, temporalis muscle; white, Radiesse; yellow, subcutaneous layer (left and right images are not shown to equal scale). RT, right.
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Table 1 Three-tiered dilution of lidocaine Tier
Injected Volumes (mL)
Areas Treated
Injection Depth
A
0.3 of lidocaine 1%; 1.5 of CaHA 0.5 of lidocaine 1%; 1.5 of CaHA 1.0 of lidocaine 1%; 1.5 of CaHA
Malar and submalar regions, temples, piriform aperture Oral commissures, prejowl sulcus Cheeks, hands
Supraperiosteal
B C
for up to 72 hours. Similar to CaHA, PLLA provides immediate volumization on injection but this effect initially fades as the carrier solution is reabsorbed.17 There is a gradual increase in dermal thickness as a foreign body response is induced and local fibroblasts encapsulate the microparticles. The PLLA is then slowly converted into lactic acid monomers that are metabolized into carbon dioxide or incorporated into glucose.18 As the initial inflammatory response wanes over 6 months, type 1 collagen deposition continues to occur for up to 2 years and results can last for several years19 (Fig. 3). Standard volumization protocols require up to 4 sessions scheduled 4 to 6 weeks apart with a deep dermal grid pattern (cross-hatch) injection, subcutaneous injection, or supraperiosteal placement of the agent. Individualization of treatment is based on the size of the area and the depth of correction involved. Although label instructions describe the use of needles for injections, blunt cannulas can be used to minimize tissue trauma. Because multiple treatments are required to achieve desirable outcomes, in order to avoid possible nodule formation it is critical to ensure that PLLA is well hydrated before the injection and is diluted to the appropriate extent.20 Patients must be informed that end point volumization is not immediate and will occur gradually over time. Some clinicians advocate 24 hours for reconstitution in an effort to ensure adequate hydration and even distribution.21–23 Other investigators recommend reconstitutions of up to 10 mL of volume and waiting 4 to 8 weeks between injections; these techniques have shown significantly decreased papule/nodule formation.24–27 In order to minimize complications, the senior author recommends adjusting both hydration time and dilution volumes according to facial zones similar to CaHA preparation28 (Table 2). Areas of injection should be gently massaged during and immediately after injection to evenly distribute the material and minimize nodule formation. The patient is further instructed to vigorously massage the treatment area for 5 minutes, 5 times per day for 5 days, using an over-the-counter petrolatum-based ointment. Persistent visible or
Postsubcutaneous-presupraperiosteal Juncture of the dermis and the subcutaneous layer
palpable nodules may be removed via intralesional injection of corticosteroids, injection of hyaluronic acid into the surrounding transition zone, or surgical excision. Similar to treatment of CaHA nodules, injection of an antimitotic such as 5-fluorouracil offers a reduced risk of skin atrophy compared with corticosteroids.28,29 Other adverse events include ecchymoses, transient soreness, and mild to moderate hematomas typical of injectable dermatologic agents.
POLYMETHYL METHACRYLATE PMMA was first used, and still most commonly used, as a biocompatible cement in neurosurgery, orthopedics, and otolaryngology.30 Bellafill (Suneva Medical, San Diego, CA) is the only FDAapproved PMMA injectable filler available in the United States. First approved as Artefill in 2007 as a dermal filler for NLFs, it recently became approved for acne scarring in 2014 for the treatment of moderate to severe, atrophic, distensible facial acne scars on the cheeks of patients more than 21 years of age. Bellafill is composed of 30-mm to 50-mm smooth, round PMMA microspheres suspended in a waterbased gel containing 3.5% bovine collagen and 0.3% lidocaine. Eighty percent of the microsphere is composed of the collagen carrier, which is absorbed 1 to 3 months after injection. The remaining nonbiodegradable PMMA microspheres act as a scaffold for neocollagenesis over an estimated period of 3 months.31 Because of the presence of bovine collagen, Bellafill requires a hypersensitivity skin injection test 4 weeks before treatment on the volar forearm. A positive skin test response includes symptoms of erythema, induration, and/or swelling appearing within the first 24 hours and lasting more than 24 hours after injection, or appearing at any time more than 24 hours after injection. An equivocal response is one with only systemic signs and symptoms of arthralgias or myalgias. Patients showing a positive skin test or 2 equivocal skin tests should not be considered candidates
Synthetic Fillers
Fig. 3. (A) A 51-year-old woman before Sculptra injection. (B) Thirteen-month follow-up after 2 Sculptra injection sessions treating the temporal, submalar, and midface zones. Each session required 2 vials at 9 mL dilution.
for treatment. Patients showing an anti–bovine collagen serum immunoglobulin G level outside the normal range at baseline should not be considered candidates for treatment.32 Patients best treated by Bellafill are those with atrophic distensible acne scarring. Similar to Sculptra, Bellafill continues to induce long-term collagen formation and is best used in broadbased scars. Therefore, conservative treatment spaced across 4-week intervals as necessary
should be planned to avoid overcorrection. The final correction of any defect should be at or below the level of normal surrounding skin.33 Bellafill is intended for injection into the deep dermis. When treating scars, using the included 26-gauge needle facilitates ease of use, in contrast with the blunt cannulas used with other fillers. When scar fibrosis is encountered, fanning the needle tip across the scar bed several times, in a subcision fashion, creates sufficient space for filler to be injected.
Table 2 Reconstitution and injection technique for injectable PLLA based on anatomic areas Area
Reconstitution Volume (mL)
Injection Technique
Malar Pyriform Mandibular angle Prejowl sulcus Temple Lower cheek
9–10
16-mm (5/8-inch), 25-gauge needle/cannula Supraperiosteal injection Posttreatment massage recommended for 5 min, 5 times/d, for 5 d after injection session
9–10
38-mm (1.5-inch), 25-gauge needle/cannula Subcutaneous injection Posttreatment massage recommended for 5 min, 5 times/d, for 5 d after injection session
501
502
Lee & Lorenc Although considered a semipermanent filler, Bellafill has been shown to be very safe. The Bellafill US Acne Scar pivotal study was a prospective, randomized, placebo-controlled, multicenter, doubleblinded clinical trial of 147 subjects older than 18 years who desired correction of moderate to severe, atrophic, distensible facial acne scarring on the cheek.34 There were no reports of hypertrophic scarring or keloid formation, granulomas, infections, or vascular occlusions. Eight percent of subjects reported mild to moderate effects, including erythema, swelling, bruising, pain, itching, lumps/ bumps, and skin discoloration related to injection, which resolved within 7 days. There was an 83% overall satisfaction rate of the treated subjects, which is consistent with 87.5% in subjects treated in the malar region.35 In a separate study by Joseph and colleagues,36,37 there was a 1.7% granuloma formation rate among 1000 patients treated with Bellafill at 5 years. In situations of overcorrection, persistent nodules, or granuloma formation, treatment may be difficult because of the permanence of the PMMA microspheres. Steroid injection to reduce inflammation or surgical excision is an option. There are anecdotal reports of off-label use of Xiaflex (Auxilium Pharmaceuticals Inc, Chesterbrook, PA), an injectable collagenase used as nonsurgical treatment of Dupytren contractures. The goal is to manually break down the fibrotic capsule formation around the PMMA microspheres, although the cost may be prohibitive.
SILICONE Unlike the other synthetic fillers composed of suspended materials, silicone is injected as a highly purified long-chain polydimethylsiloxane trimethylsiloxy terminated silicone oil. In the United States, it is FDA approved for retinal hemorrhage or retinal detachment surgery in vitreoretinal surgery (Adato Sil-Ol 5000, Bausch & Lomb, Rochester, NY; and Silikon 1000, Alcon, Fort Worth, TX). It is also available in Latin American countries from different manufacturers, although there are multiple reports of complications resulting in inconsistent formulation and impurities in the products. Facial injection techniques reported in the 1980s consist of microdroplet application with a 30-gauge needle at the dermal-subcutaneous junction.38,39 Silicone oil causes a local inflammatory response to stimulate a fibrotic reaction and capsule formation. If used off-label for facial injection, significant adverse reactions include infection, dyschromias, migration, extrusion, ulceration, granuloma formation, and vascular occlusion, which may occur years after injection and rarely resolve. Silicone is considered
permanent and difficult to treat; surgical excision is often required for removal.39
SUMMARY Proper choice of a synthetic biostimulatory agent can provide a versatile, customizable agent for enhancement of all anatomic areas. The mode of action is that of stimulating neocollagenesis using the patient’s own fibroblasts to replenish lost volume secondary to the aging process. Because of the agents’ semipermanent and permanent nature, careful consideration must be given to hydration, dilution, injection method, and postprocedural care to avoid postinjection complications.
REFERENCES 1. 2014 plastic surgery statistics. Available at: http:// www.plasticsurgery.org/Documents/news-resources/ statistics/2014-statistics/plastic-surgery-statsitics-fullreport.pdf. Accessed January 30, 2016. 2. Eviatar J, Lo C, Kirszrot J. Radiesse: advanced techniques and applications for a unique and versatile implant. Plast Reconstr Surg 2015;136(5 Suppl): 164S–70S. 3. Kontis TC. Contemporary review of injectable facial fillers. JAMA Facial Plast Surg 2013;15(1):58–64. 4. Sundaram H, Voigts B, Beer K, et al. Comparison of the rheological properties of viscosity and elasticity in two categories of soft tissue fillers: calcium hydroxylapatite and hyaluronic acid. Dermatol Surg 2010;36(Suppl 3):1859–65. 5. Alam M, Yoo SS. Technique for calcium hydroxylapatite injection for correction of nasolabial fold depressions. J Am Acad Dermatol 2007;56:285–9. 6. Hamilton DG. Calcium hydroxylapatite for augmentation of the posterior mandible angle in men. Cosmet Dermatol 2009;22:474–8. 7. 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):S122–6 [discussion: S126–7]. 8. Busso M, Karlsberg PL. Cheek augmentation and rejuvenation using injectable calcium hydroxylapatite (Radiesse). Cosmet Dermatol 2006;19:583–8. 9. Werschler WP. Treating the aging face: a multidisciplinary approach with calcium hydroxylapatite and other fillers, part 2. Cosmet Dermatol 2007;20:791–6. 10. Lizzul PF, Narurkar VA. The role of calcium hydroxylapatite (Radiesse) in nonsurgical aesthetic rejuvenation. J Drugs Dermatol 2010;9:446–50. 11. Rivkin A, Soliemanzadeh P. Nonsurgical injection rhinoplasty with calcium hydroxylapatite in a carrier gel (Radiesse): a 4-year, retrospective, clinical review. Cosmet Dermatol 2009;22:619–24.
Synthetic Fillers 12. Jasin ME. A novel alternative to conventional transcutaneous injection of calcium hydroxylapatite (Radiesse) for correction of facial deformities. J Cosmet Surg Med 2010;5:28–34. 13. Funt DK. Avoiding malar edema during midface/ cheek augmentation with dermal fillers. J Clin Aesthet Dermatol 2011;4:32–6. 14. Scheja A, Akesson A. Comparison of high frequency (20 MHz) ultrasound and palpation for the assessment of skin involvement in systemic sclerosis (scleroderma). Clin Exp Rheumatol 1997;15(3): 283–8. 15. Perry CM. Poly-L-lactic acid. Am J Clin Dermatol 2004;5(5):361–6 [discussion: 367–8]. 16. Keni SP, Sidle DM. Sculptra (injectable poly-L-lactic acid). Facial Plast Surg Clin North Am 2007;15(1): 91–7. 17. Moyle GJ, Lysakova L, Brown S, et al. A randomized open-label study of immediate versus delayed polylactic acid injections for the cosmetic management of facial lipoatrophy in persons with HIV infection. HIV Med 2004;5:82–7. 18. Brady JM, Cutright DE, Miller RA, et al. Resorption rate, route, route of elimination, and ultrastructure of the implant site of polylactic acid in the abdominal wall of the rat. J Biomed Mater Res 1973;7:155–66. 19. Vleggaar D. Facial volumetric correction with injectable poly-L-lactic acid. Dermatol Surg 2005;31(11 Pt 2):1511–8. 20. Engelhard P, Humble G, Mest D. Safety of Sculptra: a review of clinical trial data. J Cosmet Laser Ther 2005;7:201–5. 21. Butterwick K, Lowe NJ. Injectable poly-L-lactic acid for cosmetic enhancement: learning from the European experience. J Am Acad Dermatol 2009;61: 281–93. 22. Lam SM, Azizzadeh B, Graivier M. Injectable poly-Llactic acid (Sculptra): technical considerations in soft-tissue contouring. Plast Reconstr Surg 2009; 118:55S–63S. 23. Narins RS. Minimizing adverse events associated with poly-L-lactic acid injection. Dermatol Surg 2008;34(Suppl 1):S100–4. 24. Fitzgerald R, Graivier MH, Kane M, et al. Appropriate selection and application of nonsurgical facial rejuvenation agents and procedures: panel consensus recommendations. Aesthet Surg J 2010;30(Suppl):36S–45S. 25. Hirmand H. Anatomy and nonsurgical correction of the tear trough deformity. Plast Reconstr Surg 2010;125:699–708.
26. Burgess CM, Quiroga RM. Assessment of the safety and efficacy of poly-L-lactic acid for the treatment of HIV-associated facial lipoatrophy. J Am Acad Dermatol 2005;52:233–9. 27. Fitzgerald R, Vleggaar D. Using poly-L-lactic acid (PLLA) to mimic volume in multiple tissue layers. J Drugs Dermatol 2009;8(10 Suppl):s5–14. 28. Lorenc ZP. Techniques for the optimization of facial and nonfacial volumization with injectable poly-L-lactic acid. Aesthetic Plast Surg 2012;36(5):1222–9. 29. Sculptra Aesthetic [package insert] Dermik Laboratories, a business of Sanofi-Aventis U.S. SanofiAventis U.S., LLC; 2009. 30. Cohen S, Berner C, Mariono B, et al. Five-year safety and efficacy of a novel polymethyl-methacrylate aesthetic soft tissue filler for the correction of nasolabial folds. Dermatol Surg 2007;33:S222–30. 31. Lemperle G, Knapp T, Sadick N, et al. ArteFill Permanent injectable for soft tissue augmentation: I. mechanism of action and injection techniques. Aesthetic Plast Surg 2010;34:287–9. 32. Suneva. Bellafill skin test instructions for use. San Diego (CA): Suneva Medical, Inc; 2014. Available at: http:// www.bellafill.com/sites/default/files/Bellafill_Skin_Test_ IFU.pdf. 33. Hilinski J, Cohen S. Soft tissue augmentation with ArteFill. Facial Plast Surg 2009;25:114–9. 34. Karnik J, Baumann L, Bruce S, et al. A double-blind, randomized, multicenter, controlled trial of suspended polymethylmethacrylate microspheres for the correction of atrophic facial acne scars. J Am Acad Dermatol 2014;71:77–83. 35. Mills DC, Camp S, Mosser S, et al. Malar augmentation with a polymethylmethacrylate-enhanced filler: assessment of a 12-month open-label pilot study. Aesthet Surg J 2013;33(3):421–30. 36. Joseph JH, Eaton LL, Cohen SR. Current concepts in the use of Bellafill. Plast Reconstr Surg 2015; 136(5 Suppl):171S–9S. 37. Orentreich DS, Orentreich N. Injectable fluid silicone. In: Roenigk RK, Roenigk H Jr, editors. Surgery principle and practice. New York: Marcel Dekker; 1989. p. 1349–95. 38. Webster RC, Fuleihan NS, Gaunt JM, et al. Injectable silicone for small augmentations: twenty year experience in humans. Am J Cosmet Surg 1984;1: 1–10. 39. Hexsel D, de Morais MR. Management of complications of injectable silicone. Facial Plast Surg 2014; 30(6):623–7.
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KEY POINTS Calcium hydroxyapatite is a versatile semipermanent filler with a high elastic modulus for composite lifting. Poly-L-lactic acid can continue to induce local collagen formation for several months to years after injection for significant long-term results. Polymethyl methacrylate is effective for distensible atrophic acne scars. Silicone oil is a permanent filler with vitreoretinal indications, but is considered off-label use for facial injections, with potential serious complications. Synthetic fillers can provide long-lasting results through biostimulation of neocollagenesis.
According to the American Society of Plastic Surgeons’ 2014 Plastic Surgery Statistics Report, soft tissue filler procedures were the second most common minimally invasive procedures with 2.3 million procedures performed.1 This number represents a 3% increase from the previous year. Since the start of the century, soft tissue filler procedures have increased 253%, whereas cosmetic surgical procedures overall have decreased 12%. With the boom in the soft tissue filler industry, patients and physicians in the United States are encountering an increasing number of available products to choose from (Box 1). Soft tissue filler materials can be naturally (animal) sourced or synthetically produced. Mechanisms of action include volume replacement and biostimulation of autologous collagen production by native fibroblasts. Volume replacement occurs primarily through the use of hyaluronic acids, in which the hydrophilic biomaterial acts as a spacer within the tissue planes. Synthetic fillers such as calcium hydroxyapatite (CaHA), polymethyl methacrylate (PMMA),
and poly-L-lactic acid (PLLA), and silicone provide initial volume replacement but have an additional biostimulatory effect to supplement volumization. This article specifically addresses synthetic fillers in the management of facial aging.
CALCIUM HYDROXYAPATITE CaHA was first approved as an injectable implant by the US Food and Drug Administration (FDA) as a soft tissue radiographic marker in 2001 before quickly expanding its indications to include vocal fold augmentation, repair of oromaxillofacial defects, and soft tissue augmentation for stress urinary incontinence. In 2006, the FDA approved Radiesse (Merz Aesthetics, Raleigh, NC) as a CaHA filler for augmentation of moderate to severe nasolabial folds (NLFs) and human immunodeficiency virus (HIV)–associated facial lipoatrophy. Most recently, in 2015, Radiesse was approved for hand rejuvenation.2 Radiesse is considered a semipermanent filler composed of nonimmunogenic synthetic bone (CaHA) with microspheres 25 to 45 mm in diameter within a 70% carboxymethylcellulose carrier gel.
Disclosures: None of the authors have any direct financial or corporate interest in the subject matter or materials discussed in this article. a Private Practice, Enhance Medical Center, 462 North Linden Drive, Suite 333, Beverly Hills, CA 90212, USA; b Lorenc Aesthetic Plastic Surgery Center, 983 Park Avenue, New York, NY 10028, USA * Corresponding author. E-mail address: [email protected] Clin Plastic Surg 43 (2016) 497–503 http://dx.doi.org/10.1016/j.cps.2016.03.002 0094-1298/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.
plasticsurgery.theclinics.com
INTRODUCTION
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Box 1 Soft tissue fillers Collagen Cymetra Fascian Polymethyl methacrylate Bellafill Hyaluronic acid Restylane-L Restylane Lyft Restylane Silk Belotero Juvederm Ultra XC/Plus XC VOLUMA XC Prevelle Silk Calcium hydroxyapatite Radiesse Radiesse1 Poly-L-lactic acid Sculptra Silicone Silikon 1000 Sil-Ol 5000 Autologous cell therapy Platelet-rich plasma LaViv
Within several weeks after injection, the carrier gel is absorbed and net neutral volume replacement occurs through neocollagenesis. Because an immune response is not elicited, no skin testing is needed. The CaHA degrades into calcium and phosphate ions over time and is excreted slowly from the body, creating lasting volume for an average of 12 to 18 months.3 Radiesse has a particularly high elastic modulus (G’). G’ is the measure of the gel’s ability to resist deformation when pressure is applied. The higher the G’ of a substance, the greater its stiffness, and the less likely the substance is to deform under pressure from its surroundings. In a study by Sundaram and colleagues,4 the G’ of Radiesse was measured to be 1407 Pa compared with a range of 28 to 863 Pa in hyaluronic acid products. This property results in a greater amount of lift when injected under the skin envelope.
Because of its unique chemical composition, safety profile, and lifting properties, Radiesse has become an increasingly popular filler option. Its versatility extends to treatable facial zones, depth of injection, and delivery method. Radiesse has been used in marionette lines, the prejowl sulcus, oral commissures, and the posterior mandible.5–7 There are also reports of positive clinical results from injections in the temple and malar/submalar areas, which are considered off-label uses.8–11 Although early instructions for the use of CaHA were limited to the mid-dermis to target rhytids, practitioners have steadily expanded injection depths to the deep dermis and down to the supraperiosteal to structurally lift and contour the face12,13 (Fig. 1). This composite lift can be visualized under high-resolution ultrasonography, with which CaHA appears as hyperechoic deposits with variable degrees of posterior acoustic shadowing (Fig. 2). CaHA can be further modified by combining lidocaine in a mixing process rather than using the established protocol of preanesthetization of the treatment site before injection.14 The senior author (ZPL) recommends a 3-tiered dilution approach depending on associated areas of treatment and depth of injection (Table 1). The amount of lidocaine varies according to facial zones, whereas the volume of CaHA remains steady to facilitate ease of preparation and for consistent clinical results. Rare complications of CaHA injections include palpable nodules and vascular occlusion. Although there is no reversal agent or enzyme for CaHA, small nodules can be broken up with digital massage. Larger nodules can be treated with an injection of 5-fluorouracil and lidocaine 1:1 to reduce fibroblastic activity in these sites while breaking up the nodule. This technique is preferred to steroid injection because of potential chronic atrophic effects on overlying skin. For the exceedingly rare instances of vascular occlusion, the same protocols are advised as with other filler agents, including the use of hyaluronidase.2
POLY-L-LACTIC ACID PLLA has been in clinical use for more than 20 years as a major component of some absorbable sutures, such as Vicryl (Ethicon Inc, Somerville, NJ) and in surgical screws, pins, and staples used in maxillofacial and orthopedic procedures. It was FDA approved as an injectable implant in 2004 under the name of Sculptra (Galderma, Fort Worth, TX) for restoration or correction of the signs of facial fat loss in patients with HIV with facial lipoatrophy.15 More recently, in 2009, Sculptra Aesthetic was approved for immunocompetent
Synthetic Fillers
Fig. 1. (A) A 60-year-old woman before Radiesse injection. (B) Two weeks after Radiesse injection into the temporal, malar, and piriform areas.
patients for treating shallow to deep NLFs and other rhytids. Sculptra is composed of 150 mg of PLLA microparticles ranging from 40 to 63 mm and suspended in sodium, carboxymethylcellulose, and
nonpyrogenic mannitol.16 PLLA is a nontoxic and resorbable polymer (approximately 40–50 kDa) from the alpha-hydroxy acid family, and must be reconstituted with 3 to 5 mL of sterile water for injection at least 2 hours before use and may be stored
Fig. 2. High-resolution ultrasonography at 12 mHz reveals distinct soft tissue layers within the temporal fossa. Injection of Radiesse at the supraperiosteal level is clearly visualized with composite lifting of overlying soft tissue. Black, dermis; red, temporalis muscle; white, Radiesse; yellow, subcutaneous layer (left and right images are not shown to equal scale). RT, right.
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Table 1 Three-tiered dilution of lidocaine Tier
Injected Volumes (mL)
Areas Treated
Injection Depth
A
0.3 of lidocaine 1%; 1.5 of CaHA 0.5 of lidocaine 1%; 1.5 of CaHA 1.0 of lidocaine 1%; 1.5 of CaHA
Malar and submalar regions, temples, piriform aperture Oral commissures, prejowl sulcus Cheeks, hands
Supraperiosteal
B C
for up to 72 hours. Similar to CaHA, PLLA provides immediate volumization on injection but this effect initially fades as the carrier solution is reabsorbed.17 There is a gradual increase in dermal thickness as a foreign body response is induced and local fibroblasts encapsulate the microparticles. The PLLA is then slowly converted into lactic acid monomers that are metabolized into carbon dioxide or incorporated into glucose.18 As the initial inflammatory response wanes over 6 months, type 1 collagen deposition continues to occur for up to 2 years and results can last for several years19 (Fig. 3). Standard volumization protocols require up to 4 sessions scheduled 4 to 6 weeks apart with a deep dermal grid pattern (cross-hatch) injection, subcutaneous injection, or supraperiosteal placement of the agent. Individualization of treatment is based on the size of the area and the depth of correction involved. Although label instructions describe the use of needles for injections, blunt cannulas can be used to minimize tissue trauma. Because multiple treatments are required to achieve desirable outcomes, in order to avoid possible nodule formation it is critical to ensure that PLLA is well hydrated before the injection and is diluted to the appropriate extent.20 Patients must be informed that end point volumization is not immediate and will occur gradually over time. Some clinicians advocate 24 hours for reconstitution in an effort to ensure adequate hydration and even distribution.21–23 Other investigators recommend reconstitutions of up to 10 mL of volume and waiting 4 to 8 weeks between injections; these techniques have shown significantly decreased papule/nodule formation.24–27 In order to minimize complications, the senior author recommends adjusting both hydration time and dilution volumes according to facial zones similar to CaHA preparation28 (Table 2). Areas of injection should be gently massaged during and immediately after injection to evenly distribute the material and minimize nodule formation. The patient is further instructed to vigorously massage the treatment area for 5 minutes, 5 times per day for 5 days, using an over-the-counter petrolatum-based ointment. Persistent visible or
Postsubcutaneous-presupraperiosteal Juncture of the dermis and the subcutaneous layer
palpable nodules may be removed via intralesional injection of corticosteroids, injection of hyaluronic acid into the surrounding transition zone, or surgical excision. Similar to treatment of CaHA nodules, injection of an antimitotic such as 5-fluorouracil offers a reduced risk of skin atrophy compared with corticosteroids.28,29 Other adverse events include ecchymoses, transient soreness, and mild to moderate hematomas typical of injectable dermatologic agents.
POLYMETHYL METHACRYLATE PMMA was first used, and still most commonly used, as a biocompatible cement in neurosurgery, orthopedics, and otolaryngology.30 Bellafill (Suneva Medical, San Diego, CA) is the only FDAapproved PMMA injectable filler available in the United States. First approved as Artefill in 2007 as a dermal filler for NLFs, it recently became approved for acne scarring in 2014 for the treatment of moderate to severe, atrophic, distensible facial acne scars on the cheeks of patients more than 21 years of age. Bellafill is composed of 30-mm to 50-mm smooth, round PMMA microspheres suspended in a waterbased gel containing 3.5% bovine collagen and 0.3% lidocaine. Eighty percent of the microsphere is composed of the collagen carrier, which is absorbed 1 to 3 months after injection. The remaining nonbiodegradable PMMA microspheres act as a scaffold for neocollagenesis over an estimated period of 3 months.31 Because of the presence of bovine collagen, Bellafill requires a hypersensitivity skin injection test 4 weeks before treatment on the volar forearm. A positive skin test response includes symptoms of erythema, induration, and/or swelling appearing within the first 24 hours and lasting more than 24 hours after injection, or appearing at any time more than 24 hours after injection. An equivocal response is one with only systemic signs and symptoms of arthralgias or myalgias. Patients showing a positive skin test or 2 equivocal skin tests should not be considered candidates
Synthetic Fillers
Fig. 3. (A) A 51-year-old woman before Sculptra injection. (B) Thirteen-month follow-up after 2 Sculptra injection sessions treating the temporal, submalar, and midface zones. Each session required 2 vials at 9 mL dilution.
for treatment. Patients showing an anti–bovine collagen serum immunoglobulin G level outside the normal range at baseline should not be considered candidates for treatment.32 Patients best treated by Bellafill are those with atrophic distensible acne scarring. Similar to Sculptra, Bellafill continues to induce long-term collagen formation and is best used in broadbased scars. Therefore, conservative treatment spaced across 4-week intervals as necessary
should be planned to avoid overcorrection. The final correction of any defect should be at or below the level of normal surrounding skin.33 Bellafill is intended for injection into the deep dermis. When treating scars, using the included 26-gauge needle facilitates ease of use, in contrast with the blunt cannulas used with other fillers. When scar fibrosis is encountered, fanning the needle tip across the scar bed several times, in a subcision fashion, creates sufficient space for filler to be injected.
Table 2 Reconstitution and injection technique for injectable PLLA based on anatomic areas Area
Reconstitution Volume (mL)
Injection Technique
Malar Pyriform Mandibular angle Prejowl sulcus Temple Lower cheek
9–10
16-mm (5/8-inch), 25-gauge needle/cannula Supraperiosteal injection Posttreatment massage recommended for 5 min, 5 times/d, for 5 d after injection session
9–10
38-mm (1.5-inch), 25-gauge needle/cannula Subcutaneous injection Posttreatment massage recommended for 5 min, 5 times/d, for 5 d after injection session
501
502
Lee & Lorenc Although considered a semipermanent filler, Bellafill has been shown to be very safe. The Bellafill US Acne Scar pivotal study was a prospective, randomized, placebo-controlled, multicenter, doubleblinded clinical trial of 147 subjects older than 18 years who desired correction of moderate to severe, atrophic, distensible facial acne scarring on the cheek.34 There were no reports of hypertrophic scarring or keloid formation, granulomas, infections, or vascular occlusions. Eight percent of subjects reported mild to moderate effects, including erythema, swelling, bruising, pain, itching, lumps/ bumps, and skin discoloration related to injection, which resolved within 7 days. There was an 83% overall satisfaction rate of the treated subjects, which is consistent with 87.5% in subjects treated in the malar region.35 In a separate study by Joseph and colleagues,36,37 there was a 1.7% granuloma formation rate among 1000 patients treated with Bellafill at 5 years. In situations of overcorrection, persistent nodules, or granuloma formation, treatment may be difficult because of the permanence of the PMMA microspheres. Steroid injection to reduce inflammation or surgical excision is an option. There are anecdotal reports of off-label use of Xiaflex (Auxilium Pharmaceuticals Inc, Chesterbrook, PA), an injectable collagenase used as nonsurgical treatment of Dupytren contractures. The goal is to manually break down the fibrotic capsule formation around the PMMA microspheres, although the cost may be prohibitive.
SILICONE Unlike the other synthetic fillers composed of suspended materials, silicone is injected as a highly purified long-chain polydimethylsiloxane trimethylsiloxy terminated silicone oil. In the United States, it is FDA approved for retinal hemorrhage or retinal detachment surgery in vitreoretinal surgery (Adato Sil-Ol 5000, Bausch & Lomb, Rochester, NY; and Silikon 1000, Alcon, Fort Worth, TX). It is also available in Latin American countries from different manufacturers, although there are multiple reports of complications resulting in inconsistent formulation and impurities in the products. Facial injection techniques reported in the 1980s consist of microdroplet application with a 30-gauge needle at the dermal-subcutaneous junction.38,39 Silicone oil causes a local inflammatory response to stimulate a fibrotic reaction and capsule formation. If used off-label for facial injection, significant adverse reactions include infection, dyschromias, migration, extrusion, ulceration, granuloma formation, and vascular occlusion, which may occur years after injection and rarely resolve. Silicone is considered
permanent and difficult to treat; surgical excision is often required for removal.39
SUMMARY Proper choice of a synthetic biostimulatory agent can provide a versatile, customizable agent for enhancement of all anatomic areas. The mode of action is that of stimulating neocollagenesis using the patient’s own fibroblasts to replenish lost volume secondary to the aging process. Because of the agents’ semipermanent and permanent nature, careful consideration must be given to hydration, dilution, injection method, and postprocedural care to avoid postinjection complications.
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