Synthetic Fi l lers for FacialRejuvenation

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 compositelifting.

� Poly-L-lactic acid can continue to induce local collagen formation for several months to years afterinjection 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 forfacial injections, with potential serious complications.

� Synthetic fillers can provide long-lasting results through biostimulation of neocollagenesis.

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INTRODUCTION

According to the American Society of Plastic Sur-geons’ 2014 Plastic Surgery Statistics Report, softtissue filler procedures were the second mostcommon minimally invasive procedures with 2.3million procedures performed.1 This number rep-resents a 3% increase from the previous year.Since the start of the century, soft tissue filler pro-cedures have increased 253%, whereas cosmeticsurgical procedures overall have decreased 12%.

With the boom in the soft tissue filler industry,patients and physicians in the United States areencountering an increasing number of availableproducts to choose from (Box 1). Soft tissue fillermaterials can be naturally (animal) sourced or syn-thetically produced. Mechanisms of action includevolume replacement and biostimulation of autolo-gous collagen production by native fibroblasts.Volume replacement occurs primarily through theuse of hyaluronic acids, in which the hydrophilicbiomaterial acts as a spacer within the tissueplanes. Synthetic fillers such as calcium hydroxy-apatite (CaHA), polymethyl methacrylate (PMMA),

Disclosures: None of the authors have any direct financiarials discussed in this article.a Private Practice, Enhance Medical Center, 462 North Lb Lorenc Aesthetic Plastic Surgery Center, 983 Park Aven* Corresponding author.E-mail address: JCLMD@enhancemedicalcenter.com

Clin Plastic Surg 43 (2016) 497–503http://dx.doi.org/10.1016/j.cps.2016.03.0020094-1298/16/$ – see front matter � 2016 Elsevier Inc. All

and poly-L-lactic acid (PLLA), and silicone provideinitial volume replacement but have an additionalbiostimulatory effect to supplement volumization.This article specifically addresses synthetic fillersin the management of facial aging.

CALCIUM HYDROXYAPATITE

CaHAwas first approved as an injectable implant bytheUSFood andDrug Administration (FDA) as a softtissue radiographic marker in 2001 before quicklyexpanding its indications to include vocal foldaugmentation, repair of oromaxillofacial defects,andsoft tissueaugmentation forstressurinary incon-tinence. In 2006, the FDA approved Radiesse (MerzAesthetics, Raleigh,NC) as aCaHA filler for augmen-tation of moderate to severe nasolabial folds (NLFs)and human immunodeficiency virus (HIV)–associ-ated facial lipoatrophy. Most recently, in 2015, Rad-iesse was approved for hand rejuvenation.2

Radiesse is considered a semipermanent fillercomposed of nonimmunogenic synthetic bone(CaHA) with microspheres 25 to 45 mm in diameterwithin a 70% carboxymethylcellulose carrier gel.

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eclinics.

Box 1Soft 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

Lee & Lorenc498

Within several weeks after injection, the carrier gelis absorbed and net neutral volume replacementoccurs through neocollagenesis. Because an im-mune response is not elicited, no skin testing isneeded. The CaHA degrades into calcium andphosphate ions over time and is excreted slowlyfrom the body, creating lasting volume for anaverage of 12 to 18 months.3

Radiesse has a particularly high elastic modulus(G’). G’ is the measure of the gel’s ability to resistdeformation when pressure is applied. The higherthe G’ of a substance, the greater its stiffness, andthe less likely the substance is to deform underpressure from its surroundings. In a study by Sun-daram and colleagues,4 the G’ of Radiesse wasmeasured to be 1407 Pa compared with a rangeof 28 to 863 Pa in hyaluronic acid products. Thisproperty results in a greater amount of lift wheninjected under the skin envelope.

Because of its unique chemical composition,safety profile, and lifting properties, Radiesse hasbecome an increasingly popular filler option. Itsversatility extends to treatable facial zones, depthof injection, and delivery method. Radiesse hasbeen used in marionette lines, the prejowl sulcus,oral commissures, and the posterior mandible.5–7

There are also reports of positive clinical resultsfrom injections in the temple and malar/submalarareas, which are considered off-label uses.8–11

Although early instructions for the use of CaHAwere limited to the mid-dermis to target rhytids,practitioners have steadily expanded injectiondepths to the deep dermis and down to thesupraperiosteal to structurally lift and contour theface12,13 (Fig. 1). This composite lift can be visual-ized under high-resolution ultrasonography, withwhich CaHA appears as hyperechoic depositswith variable degrees of posterior acoustic shad-owing (Fig. 2).CaHA can be further modified by combining lido-

caine in a mixing process rather than using theestablished protocol of preanesthetization of thetreatment site before injection.14 The senior author(ZPL) recommends a 3-tiered dilution approachdepending on associated areas of treatment anddepthof injection (Table 1). Theamount of lidocainevaries according to facial zones, whereas the vol-ume of CaHA remains steady to facilitate ease ofpreparation and for consistent clinical results.Rare complications of CaHA injections include

palpable nodules and vascular occlusion. Althoughthere is no reversal agent or enzyme for CaHA,small nodules can be broken up with digital mas-sage. Larger nodules can be treated with an injec-tion of 5-fluorouracil and lidocaine 1:1 to reducefibroblastic activity in these sites while breakingup the nodule. This technique is preferred to steroidinjection because of potential chronic atrophiceffects on overlying skin. For the exceedingly rareinstances of vascular occlusion, the same proto-cols 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 20years as a major component of some absorbablesutures, such as Vicryl (Ethicon Inc, Somerville,NJ) and in surgical screws, pins, and staplesused in maxillofacial and orthopedic procedures.It was FDA approved as an injectable implant in2004 under the name of Sculptra (Galderma, FortWorth, TX) for restoration or correction of the signsof facial fat loss in patients with HIV with faciallipoatrophy.15 More recently, in 2009, SculptraAesthetic was approved for immunocompetent

Fig. 1. (A) A 60-year-old woman before Radiesse injection. (B) Two weeks after Radiesse injection into the tem-poral, malar, and piriform areas.

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patients for treating shallow to deep NLFs andother rhytids.

Sculptra is composed of 150 mg of PLLAmicroparticles ranging from 40 to 63 mm and sus-pended in sodium, carboxymethylcellulose, and

Fig. 2. High-resolution ultrasonography at 12 mHz revealInjection of Radiesse at the supraperiosteal level is clearlysue. Black, dermis; red, temporalis muscle; white, Radiessenot shown to equal scale). RT, right.

nonpyrogenic mannitol.16 PLLA is a nontoxic andresorbable polymer (approximately 40–50 kDa)from the alpha-hydroxy acid family, and must bereconstitutedwith3 to5mLof sterilewater for injec-tion at least 2 hours before use and may be stored

s distinct soft tissue layers within the temporal fossa.visualized with composite lifting of overlying soft tis-; yellow, subcutaneous layer (left and right images are

Table 1Three-tiered dilution of lidocaine

Tier Injected Volumes (mL) Areas Treated Injection Depth

A 0.3 of lidocaine 1%;1.5 of CaHA

Malar and submalar regions,temples, piriform aperture

Supraperiosteal

B 0.5 of lidocaine 1%;1.5 of CaHA

Oral commissures, prejowlsulcus

Postsubcutaneous-presupraperiosteal

C 1.0 of lidocaine 1%;1.5 of CaHA

Cheeks, hands Juncture of the dermis and thesubcutaneous layer

Lee & Lorenc500

for up to 72 hours. Similar to CaHA, PLLA providesimmediate volumization on injection but this effectinitially fades as thecarrier solution is reabsorbed.17

There is a gradual increase in dermal thickness as aforeign body response is induced and local fibro-blasts encapsulate the microparticles. The PLLAis then slowly converted into lactic acid monomersthat are metabolized into carbon dioxide or incor-porated into glucose.18 As the initial inflammatoryresponse wanes over 6 months, type 1 collagendeposition continues to occur for up to 2 yearsand results can last for several years19 (Fig. 3).Standard volumization protocols require up to 4

sessions scheduled 4 to 6 weeks apart with a deepdermal grid pattern (cross-hatch) injection, subcu-taneous injection, or supraperiosteal placement ofthe agent. Individualization of treatment is basedon the size of the area and the depth of correctioninvolved. Although label instructions describe theuse of needles for injections, blunt cannulas canbeusedtominimize tissue trauma.Becausemultipletreatments are required to achieve desirable out-comes, in order to avoid possible nodule formationit is critical to ensure that PLLA is well hydratedbefore the injection and is diluted to the appropriateextent.20 Patients must be informed that end pointvolumization is not immediate and will occur gradu-ally over time.Somecliniciansadvocate24hours forreconstitution in an effort to ensure adequate hydra-tion and even distribution.21–23 Other investigatorsrecommend reconstitutions of up to 10 mL of vol-ume and waiting 4 to 8 weeks between injections;these techniques have shown significantlydecreased papule/nodule formation.24–27 In ordertominimize complications, the senior author recom-mends adjusting both hydration time and dilutionvolumes according to facial zones similar to CaHApreparation28 (Table 2).Areas of injection should be gently massaged

during and immediately after injection to evenlydistribute the material and minimize nodule forma-tion. The patient is further instructed to vigorouslymassage the treatment area for 5 minutes, 5 timesper day for 5 days, using an over-the-counterpetrolatum-based ointment. Persistent visible or

palpable nodules may be removed via intralesionalinjection of corticosteroids, injection of hyaluronicacid into the surrounding transition zone, or surgi-cal excision. Similar to treatment of CaHA nodules,injection of an antimitotic such as 5-fluorouracil of-fers a reduced risk of skin atrophy compared withcorticosteroids.28,29 Other adverse events includeecchymoses, transient soreness, andmild to mod-erate hematomas typical of injectable dermato-logic agents.

POLYMETHYL METHACRYLATE

PMMA was first used, and still most commonlyused, as a biocompatible cement in neurosurgery,orthopedics, and otolaryngology.30 Bellafill(Suneva Medical, San Diego, CA) is the only FDA-approved PMMA injectable filler available inthe United States. First approved as Artefill in2007 as a dermal filler for NLFs, it recently becameapproved for acne scarring in 2014 for the treat-ment of moderate to severe, atrophic, distensiblefacial acne scars on the cheeks of patients morethan 21 years of age.Bellafill is composed of 30-mm to 50-mm smooth,

round PMMA microspheres suspended in a water-based gel containing 3.5% bovine collagen and0.3% lidocaine. Eighty percent of the microsphereis composed of the collagen carrier, which isabsorbed 1 to 3 months after injection. The remain-ing nonbiodegradablePMMAmicrospheres act asascaffold for neocollagenesis over an estimatedperiod of 3 months.31

Because of the presence of bovine collagen,Bellafill requires a hypersensitivity skin injectiontest 4 weeks before treatment on the volar fore-arm. A positive skin test response includes symp-toms of erythema, induration, and/or swellingappearing within the first 24 hours and lastingmore than 24 hours after injection, or appearingat any time more than 24 hours after injection.An equivocal response is one with only systemicsigns and symptoms of arthralgias or myalgias.Patients showing a positive skin test or 2 equivocalskin tests should not be considered candidates

Fig. 3. (A) A 51-year-old woman before Sculptra injection. (B) Thirteen-month follow-up after 2 Sculptra injectionsessions treating the temporal, submalar, and midface zones. Each session required 2 vials at 9 mL dilution.

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for treatment. Patients showing an anti–bovinecollagen serum immunoglobulin G level outsidethe normal range at baseline should not be consid-ered candidates for treatment.32

Patients best treated by Bellafill are thosewith atrophic distensible acne scarring. Similar toSculptra, Bellafill continues to induce long-termcollagen formation and is best used in broad-based scars. Therefore, conservative treatmentspaced across 4-week intervals as necessary

Table 2Reconstitution and injection technique for injectable

Area Reconstitution Volume (mL)

MalarPyriformMandibular anglePrejowl sulcusTemple

9–10

Lower cheek 9–10

should be planned to avoid overcorrection. Thefinal correction of any defect should be at or belowthe level of normal surrounding skin.33 Bellafill isintended for injection into the deep dermis. Whentreating scars, using the included 26-gauge needlefacilitates ease of use, in contrast with the bluntcannulas used with other fillers. When scar fibrosisis encountered, fanning the needle tip across thescar bed several times, in a subcision fashion, cre-ates sufficient space for filler to be injected.

PLLA based on anatomic areas

Injection Technique

16-mm (5/8-inch), 25-gauge needle/cannulaSupraperiosteal injectionPosttreatment massage recommended for

5 min, 5 times/d, for 5 d after injection session

38-mm (1.5-inch), 25-gauge needle/cannulaSubcutaneous injectionPosttreatment massage recommended for

5 min, 5 times/d, for 5 d after injection session

Lee & Lorenc502

Although considered a semipermanent filler,Bellafill has beenshown tobe very safe. TheBellafillUSAcne Scar pivotal studywas a prospective, ran-domized, placebo-controlled, multicenter, double-blinded clinical trial of 147 subjects older than 18years who desired correction of moderate to se-vere, atrophic, distensible facial acne scarring onthe cheek.34 There were no reports of hypertrophicscarring or keloid formation, granulomas, infec-tions, or vascular occlusions. Eight percent of sub-jects reported mild to moderate effects, includingerythema, 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 treatedin themalar region.35 In a separate study by Josephand colleagues,36,37 there was a 1.7% granulomaformation rate among 1000 patients treated withBellafill at 5 years.In situations of overcorrection, persistent nod-

ules, or granuloma formation, treatment may bedifficult because of the permanence of thePMMA microspheres. Steroid injection to reduceinflammation or surgical excision is an option.There are anecdotal reports of off-label use of Xia-flex (Auxilium Pharmaceuticals Inc, Chesterbrook,PA), an injectable collagenase used as nonsurgicaltreatment of Dupytren contractures. The goal is tomanually break down the fibrotic capsule forma-tion around the PMMA microspheres, althoughthe cost may be prohibitive.

SILICONE

Unlike the other synthetic fillers composed of sus-pended materials, silicone is injected as a highlypurified long-chain polydimethylsiloxane trimethyl-siloxy terminated silicone oil. In the United States,it is FDA approved for retinal hemorrhage or retinaldetachment surgery in vitreoretinal surgery (AdatoSil-Ol 5000, Bausch & Lomb, Rochester, NY; andSilikon 1000, Alcon, Fort Worth, TX). It is also avail-able in Latin American countries from differentmanufacturers, although there are multiple reportsof complications resulting in inconsistent formula-tion and impurities in the products. Facial injectiontechniques reported in the 1980s consist of micro-droplet application with a 30-gauge needle at thedermal-subcutaneous junction.38,39 Silicone oilcauses a local inflammatory response to stimulatea fibrotic reaction and capsule formation. If usedoff-label for facial injection, significant adverse re-actions include infection, dyschromias, migration,extrusion, ulceration, granuloma formation, andvascular occlusion, which may occur years afterinjection and rarely resolve. Silicone is considered

permanent and difficult to treat; surgical excision isoften required for removal.39

SUMMARY

Proper choice of a synthetic biostimulatory agentcan provide a versatile, customizable agent forenhancement of all anatomic areas. The mode ofaction is that of stimulating neocollagenesis usingthe patient’s own fibroblasts to replenish lost vol-ume secondary to the aging process. Because ofthe agents’ semipermanent and permanent nature,careful consideration must be given to hydration,dilution, injection method, and postproceduralcare to avoid postinjection complications.

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