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Dermal Fillers

Leslie Baumann, MDMarianna Blyumin, MDSogol Saghari, MD

HISTORY

In 1893, by transplanting fat from thearms into facial defects, Neuber becamethe first physician to practice soft tissueaugmentation.1 In the middle of the 20thcentury, soft tissue augmentation couldbest be characterized by the use of sili-cone. Although popular in the 1940s and1950s, silicone use was associated withthe development of foreign body granulo-mas, which ultimately prompted the ban-ning of silicone in 1992 until a new formof the substance (intended for ophthalmo-logic use) was approved by the UnitedStates Food and Drug Administration(FDA) in the late 1990s. In the meantime,though, the field of soft tissue augmenta-tion had come into its own, in the 1970s,with the introduction by StanfordUniversity researchers of animal-derivedcollagen implants.2 By the 1980s, the use of collagen injections for wrinkles had entered the mainstream. WhileAmericans were enjoying the benefits ofbovine collagen fillers (i.e., Zyderm andZyplast), other countries began to experi-ment with dermal HA fillers such asHylaform and later Restylane in the midto late 1990s. The beginning of the 21stcentury ushered in the introduction ofnewer nonbovine collagen fillers,CosmoDerm and CosmoPlast, and HAfillers, such as Captique and Juvéderm, aswell as other synthetic fillers, Sculptra,Radiesse, and Artefill into the UnitedStates market. With different forms of softtissue augmentation agents currentlyavailable in the United States and others inthe pipeline, selecting the appropriatefiller is challenging for physicians andpatients alike. In order to achieve optimalcosmetically-pleasing results, it is incum-bent upon dermatologists to obtainthorough comprehension of the charac-teristics of available fillers, their indica-tions, contraindications, benefits anddrawbacks, and ways to resolve potentialcomplications. In this chapter, we willreview the basics behind the art andscience of the broad array of dermal fillerson the market in the United States. Thiswill be preceded by a brief discussion ofregulatory issues and the patient evalua-tion and consultation.

REGULATION

In the US, dermal fillers are regulated asmedical devices. In order to obtain FDAapproval, the company applying for

approval for a dermal filler must satisfythe intense safety and efficacy criteriaincluding nonteratogenicity, nonmigra-tion, noncarcinogenesis, biocompatibil-ity, and optimal purity, as well as repro-ducible and durable efficacy in correctingskin defects. Unfortunately, some physi-cians and physician extenders choose touse dermal filling substances that havenot yet received FDA approval for anyindication. This is not advisable for sev-eral reasons including the fact that it isillegal and that the safety of these prod-ucts has not been established. With themultitude of safe, efficacious, anddurable fillers on the market, there is noneed or justifiable reason to use unap-proved dermal fillers in the US.

PATIENT EVALUATION

AND CONSULTATION

When embarking on soft tissue augmen-tation, proper preparations are essential.An initial consultation should includedistant and close evaluation of thepatient’s facial structure and discussionof the cosmetic treatment options. Thepatient’s history is taken to assess con-traindications including allergy to fillercomponents, herpes facialis, pregnancy/lactation, keloid predisposition, andautoimmune diseases. In addition, use ofmedications that inhibit clotting such asaspirin and ibuprofen should be exam-ined. The ideal cosmetic outcome isachieved through a combination of vari-ous cosmetic procedures in order toattain an even tone, smooth texture, andadequate facial volume and shape. Thediscussion of the sequence and descrip-tion of each proposed procedure, alterna-tives, risks and benefits, financial cost,and recovery period prepares the patientfor realistic expectations and informeddecision-making. After the treatmentprocedures are selected and informedconsent is signed and witnessed, thepatient should undergo pretreatmentphotography for the purpose of docu-mentation; posttreatment photographyis scheduled immediately after and onthe follow-up visits. For novice patients,it is better to start the soft tissue inter-vention with the temporary and pre-dictable fillers (e.g., collagen and HA),and then gradually advance with morelasting fillers (e.g., Sculptra and Radiesse)based on their comfort level and desire.

The best approach to minimizing theside effects of soft tissue augmentation

The dermal filler market is rapidlygrowing worldwide. According to theAmerican Academy of Aesthetic PlasticSurgeons, 1,448,716 people receivedhyaluronic acid (HA) injections by plas-tic surgeons in 2007 (Table 23-1). Theactual number is likely much higherwhen factoring in procedures performedby dermatologists and other aestheti-cally oriented physicians and physicianextenders. Although collagen products(Zyplast and Zyderm) were the first der-mal fillers to become widely available,collagen fillers have largely beenreplaced by HA fillers.

The ultimate goal of dermal fillers isto smooth out wrinkles and folds, evenout scars, volumize furrows and sunkenvalleys, contour unevenness and laxity,and sculpt skin into a 360-degree, reju-venated look. Over the last quarter cen-tury, several kinds of products suitablefor soft tissue augmentation havebecome available, with intense industryresearch yielding more and more filleroptions with increasing regularity.Different regulatory mechanisms usu-ally leave the US a few months or yearsbehind other developed countries inmaking the latest products available topatients.

TABLE 23-1

Soft Tissue Augmentation Procedures

Performed in 2007 by Members of the

Academy of Aesthetic Plastic Surgeons

PROCEDURES NUMBER

PERFORMED

IN 2007

Fat injections 44,547

Calcium hydroxylapatite 119,397

(Radiesse/Radiance)

Collagen 63,769

Hyaluronic acid 1,448,716

Sculptra (not yet 34,972

FDA approved)

Polymethyl methacrylate 12,075

(Artecoll, Artefill)

Data obtained from www.surgery.org.

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is, first, to prevent them. To reducebruising, patients should avoid anticoag-ulant medications or supplements (e.g.,aspirin, vitamin E, etc.) for 10 days priorand several days after the procedure (seeChapter 21). The utility of Arnica mon-tana oral tablets or topical gel or post-procedure oral bromelain supplementsto decrease ecchymoses is anecdotal butthese are often used in the primaryauthor’s practice. The pain associatedwith injection can be diminished withtopical (e.g., lidocaine cream, ice),regional (e.g., infraorbital, dental nerveblock), or intraprocedural anesthesia(e.g., fillers that contain lidocaine).Patients prone to regional herpes out-breaks should obtain antiviral prophy-laxis with systemic medications (e.g.,valcyclovir 1 g twice daily for 3 days,starting a day before the procedure). Theprocedure should be conducted in aclean, safe, well-lit, and soothing envi-ronment that is prepared to address anypotential complications. Vasovagalresponses are not uncommon; therefore,orange juice should be available in theevent that the patient feels dizzy orfaint. Topical steroids may be needed incase of a contact allergy to lidocainecream. Most importantly, nitropasteshould be immediately available in casea purple duskiness is seen on injection,warning of a possible arterial occlusion.Some physicians suggest keepinghyaluronidase on hand in case an arterialocclusion occurs with HA.3

TYPES OF FILLERS

Dermal fillers can be classified based onvarious criteria: depth of implantation(superficial upper and middermis, deepdermis, and subcutaneous levels);longevity of correction (temporary,semipermanent, and permanent); aller-genicity (whether preprocedure allergictesting is required); composition of theagent (xenografts, allografts, or autolo-gous, semi/fully synthetic); and stimula-tory behavior (capacity to drive physio-logic processes of endogenous tissueproliferation) versus replacement fillers(space-replacing effect). Safety and effi-cacy studies of the available fillers arerequired by the FDA; however, studieslooking at the durability of the filler arenot required and, therefore, subject todisagreement and frequent citing ofanecdotal evidence. The lasting effect ofthe filler is dependent on the composi-tion, amount used, depth injected, andcarrier of the agent. Our discussion offillers will proceed by dividing them

according to composition: collagenfillers will be discussed first, followed byHA fillers, and then other agents.

TEMPORARY FILLERS

Injectable fillers such as collagen and HAare biodegradable and last from 4 to 9 months. These fillers commonly servean important role as the initial step fornew patients interested in soft tissueaugmentation. Because of their transienteffect, the potential patient dissatisfac-tion and side effects are also short-lived.Therefore, temporary fillers shouldalways be the first line of therapy, sav-ing the longer-lasting fillers for futurepatient visits.

Collagen

The major structural component of thedermis, collagen is the most abundantprotein in the human organism as wellas the skin, in particular, and confersstrength and support to the skin.Collagen is also one of the strongest nat-ural proteins, imparting durability andresilience to the skin, and comprising70% of dry skin mass4 (see Chapter 2).What is known as “collagen” is actuallya meshwork of scaffolding-like structurescomposed of a complex family of over18 types, 11 of which are found in thedermis. Type I collagen (80%–85%) andtype III collagen (10%–15%) are the pri-mary collagen constituents in the dermalmatrix of adult human skin. Dermalfibroblasts produce a precursor form ofcollagen, � procollagens, which in turnproduce both collagen types I and III,each of which is composed of three col-lagen chains.

Skin fragility and wrinkles resultfrom the loss of collagen, which occurswith aging as well as solar exposureand other insults. UV light, free radi-cals, and other factors cause the bodyto produce collagenase, an enzyme thatbreaks down collagen. The injection ofvarious forms of collagen into the skinhelps it regain a youthful appearance,but such results are temporary. The

range of collagen products has in-creased in recent years as manufactur-ers have worked to extend the durationof product effects.

BOVINE COLLAGEN

Overview With a record of safety andefficacy spanning over two decades,bovine collagen was the traditional der-mal filler agent used to ameliorate unde-sirable signs of cutaneous facial aging.5

In 1977, Zyderm I was introduced as thefirst injectable bovine collagen implant;it was approved by the FDA in 1981 forfine lines and shallow acne scars.Zyderm II and Zyplast were introducedand approved, respectively, in 1983 formoderate lines and deeper acne scarsand 1985 for deep dermal folds andlines. Although these products were thestandard for years to which newerimplants were compared, because ofbetter safety profiles, human-derivedcollagen and HA products have becomemore widely used. Zyderm I is 96%type I collagen and 4% type III collagenderived from the bovine skin of USenclosed cattle herds. Zyderm I and IIdiffer only by collagen concentration.Zyderm I contains 35 mg/cc, whileZyderm II contains 65 mg/cc. The differ-ence in concentration is significant inso-far as it renders Zyderm II thicker andstiffer than Zyderm I. Like Zyderm I,Zyplast contains 35 mg/cc of collagen,but this collagen is cross-linked withglutaraldehyde, which makes it lastlonger via resistance to degradation(Table 23-2). Consequently, Zyplast ismore viscous and less immunogenicthan Zyderm.6

Zyderm and Zyplast are white sub-stances prepackaged in 0.5-, 1-, and 2-mLsyringes and injected with a 30-gauge0.5-inch needle. The product should bestored in the refrigerator ideally at 4�C.While Zyderm I is properly injected intosuperficial dermis at 20- to 30-degreeangles with the expectation of tempo-rary skin blanching, Zyderm II can be injected slightly deeper at 35- to 45-degree angles with less anticipatedblanching and minimal overcorrection.

TABLE 23-2

Collagen Concentration Comparison

COLLAGEN FROM BIOENGINEERED

COLLAGEN FROM COW HIDE SKIN CONCENTRATION

Zyderm I CosmoDerm I 35 mg collagen/cc

Zyderm II CosmoDerm II 65 mg collagen/cc

Zyplast CosmoPlast 35 mg collagen/cc cross-linked

with glutaraldehyde

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Since Zyderm is diluted with phosphate-buffered sterile saline, which is rapidlyreabsorbed in skin, to achieve the opti-mal effect, overcorrecting implantationis necessary. Zyplast is implanted intoeven deeper dermis at 45- to 90-degreeangles with minimal delayed blanchingand without overcorrection.

Benefits Bovine-derived collagen dermalfilling agents effectively reduce wrinklesand scars. Zyplast is appropriate forshaping the vermilion border of the lipsand treating moderate and deep wrin-kles, such as nasolabial folds andatrophic scars. Zyderm I is well suitedfor treating superficial rhytides (e.g.,horizontal forehead wrinkles, crow’sfeet, fine perioral wrinkles, and scars) orfor use over Zyplast in deeper wrinkles.The higher concentration of collagen inZyderm II renders this product moreappropriate for acne scar revision (seeChapter 26), but Zyplast lasts longerbecause it is cross-linked. Collagenaseultimately succeeds in degrading theseproducts, returning the skin to itsappearance prior to injection. Zyplast isthe most commonly used bovine colla-gen product and lasts approximately 4 months, just slightly longer thanZyderm I and II. Bovine collagen can besafely reinjected 3 to 4 times per year ifneeded. Zyderm and Zyplast are theleast expensive dermal fillers on themarket and typically engender lessbruising than products that contain HA.All the bovine collagen products contain0.3% lidocaine to reduce the pain asso-ciated with the procedure.

Drawbacks Two skin tests, 6 and 2 weeksbefore the scheduled treatment, arerequired before the use of bovine colla-gen agents to reduce the risk of inducinghypersensitive or allergic reactions. Suchresponses can occur as early as 6 hoursafter the test, but are more likely toemerge 48 hours or 4 weeks after the test.A positive skin test disqualifies a patientfor treatment with bovine collagen.

Approximately 3% of the general pop-ulation is thought to be sensitive tobovine collagen.7 Although a patient isunlikely to react to bovine collagenimplants after two negative skin tests, therisk is never completely eliminated. Therisk of hypersensitive reaction is 1.3% to6.2% after one negative test8,9 and 0.5%after two negative tests (Fig. 23-1).Patients should be advised that shouldsuch a reaction occur, it can be expectedto spontaneously resolve within 4 to 24 months.8,9 Allergic reactions alsoarise, albeit rarely, following multiple

treatments. Topical, intralesional, or abrief course of systemic corticosteroidscan be effective to treat these reactions.Oral cyclosporine10 (Figs. 23-2 and 23-3)and topical tacrolimus11 have also report-edly been used for the successful treat-ment of recalcitrant hypersensitive reac-tions to bovine collagen. Patients withlidocaine hypersensitivity are contraindi-cated for obtaining these injectionsbecause the fillers contain lidocaine.

Nonhypersensitive reactions tobovine collagen fillers can also infre-quently occur (e.g., abscesses, bacterial

infections, beading, cyst and granulomaformation, ecchymoses, and local necro-sis). Several previously discussed pre-ventative steps can be taken to reducethe likelihood of such outcomes.Because of its viscosity, Zyplast shouldnot be injected into the glabellar region,as there have been reports of localnecrosis and retinal artery occlusionleading to visual loss.12 However,Zyderm I or II can be injected into theglabellar area very slowly and withextreme caution. Vascular occlusion orcompression manifests as prominent

� FIGURE 23-1 Collagen hypersensitivity reaction in a patient treated by another physician after only

one skin test.

� FIGURE 23-2 Collagen hypersensitivity reaction prior to treatment with cyclosporine. Note the indi-

cated lesions in the forehead and glabellar area.


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immediate blanching and pain. Warmcompresses, topical nitroglycerin, andmeticulous wound care are necessarytreatments. Prior to 1990, beads andcysts were reported at the injection sitein 0.04% of patients treated withZyderm or Zyplast, most likely causedby injections that were too superficial.12

Injections should be made only into thedermis to avoid such reactions.13

Abscesses should be treated with inci-sion and drainage and a combination ofantibiotics and corticosteroids to reducesecondary scarring. More than a decadeago, there was some speculation thatautoimmune diseases, namely, poly-myositis and dermatomyositis, might beinduced by the injection of bovine colla-gen,14 but studies have demonstratedthat antibodies to bovine collagen donot cross-react with human collagen.15,16

Therefore, the FDA has agreed that it isunlikely that bovine collagen causesconnective tissue disease in humans.9,17

Further, a study by Hanke et al. showed that the incident rate ofpolymyositis/dermatomyositis in patientsreceiving bovine collagen was not higherthan the control-matched population.18

However, the authors recommendavoiding the use of bovine collagen-containing fillers in patients with a his-tory of autoimmune disease. Anothermajor downside to using bovine colla-gen is the minimal durability of about 3 to 4 months.

BIOENGINEERED HUMAN COLLAGEN

Overview Over the last 10 years, severalcompanies, motivated by the drawbacks

of bovine-derived collagen, have devel-oped human-derived soft tissue fillers.Unlike earlier cadaver-derived collagen(i.e., Cymetra) and, more recently, autol-ogous collagen (i.e., Isolagen), bioengi-neered human collagen is pregeneratedto ensure ease of accessibility. The man-ufacturing process begins with the har-vesting of dermal fibroblasts from bio-engineered human skin and placementinto a three-dimensional mesh. Thefibroblasts are then cultured in a bioreac-tor that simulates the conditions of thehuman body. Then, the fibroblastssynthesize collagen and extracellularmatrix proteins. The derived collagen ispurified to enhance safety. Human-

bioengineered collagen implants includeCosmoDerm I, CosmoDerm II, andCosmoPlast (Allergan Corporation,Irvine, CA), which contain humancollagen types I and III, and wereapproved by the FDA in March 2003.CosmoDerm I is composed of 35 mg/cchuman-bioengineered collagen distrib-uted in a phosphate-based saline solu-tion and 0.3% lidocaine. CosmoDerm IIcontains twice the collagen concentra-tion of CosmoDerm I. CosmoPlastcontains the same ingredients as Cosmo-Derm I, but is cross-linked by glutaralde-hyde, yielding a product more resistantto degradation, thus lasting longer, andmore appropriate for use in treatingdeeper furrows. While CosmoDerm isindicated for superficial wrinkles andshallow scars, CosmoPlast, whichexhibits a stiff consistency (even more sothan products containing HA), is wellsuited to treating the vermilion border ofthe lips (Fig. 23-4), as well as raising thecorners of the mouth. In addition, it is agood choice to correct deformities of thebridge of the nose or to raise the nasal tip(Fig. 23-5). CosmoPlast is typically usedin combination, usually with an HAagent, to treat medium and deep wrin-kles, with the collagen product injectedfirst to create a volume-filling base andthe HA filler injected more superficiallyinto the same location.

Similar to bovine collagens, Cosmo-Derm and CosmoPlast are white sub-stances prepackaged in 1-mL syringesand injected via 30-gauge 0.5-inch nee-dles. Although some anecdotal reportsindicate better rheology of human colla-gen fillers, their technique of injection,cosmetic outcome, and durability are

A B

� FIGURE 23-4 A. Before CosmoPlast to vermilion border. B. Immediately after CosmoPlast.

� FIGURE 23-3 Collagen hypersensitivity reaction after 11 days of treatment with cyclosporine 5

mg/kg/d. The lesions flattened and had decreased redness. Only hyperpigmentation remained and

resolved after a week.


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comparable to bovine collagen fillers.Furthermore, like bovine collagen,CosmoDerm and CosmoPlast must bekept refrigerated when stored. Forhuman-derived collagen devices, onaverage, one syringe is used for patientsin their twenties, two syringes forpatients in their thirties, three syringesfor patients in their forties, and asneeded for older patients in order to cor-rect age-related lines and folds.

Benefits Given the absence of allergyrisk associated with these agents, noskin testing is required. This allows forpatients to be treated in their initial visitto the physician. The cosmetic effects ofCosmoDerm and CosmoPlast are imme-diate, lasting about 3 months for the for-mer and about 4 months for the latter,19

and are typically associated with lessbruising than the effects of proceduresusing agents containing HA. Also similarto the bovine-derived fillers, Cosmo-Derm and CosmoPlast contain lidocaineto mitigate the pain of injection andlower the risk of edema and ecchymosesby inhibiting the activation ofeosinophils.20 CosmoPlast can create thebeautiful “Snow White line” and“Cupid’s bow” shape of the lip bordersas well as upturn the tip of the nose tocreate a poised appearance. AlthoughHA fillers are favored because they lastlonger and are softer, CosmoDerm I canbe used to plump the body of the lip.CosmoDerm I can be layered overCosmoPlast for the purpose of idealcontouring of deep lines, such asnasolabial folds and marionette lines. Inaddition, to treat medium and deepwrinkles, HA fillers can be superim-posed on top of CosmoPlast or injectedin the same plane as CosmoPlast.Although fillers should be used rarelyand with great caution in the glabellarrhytides because of the potential risk of

tissue necrosis, CosmoDerm I can beused with great care in this region. Atthe time of publication of this text, therewere no HA fillers geared for superficialplacement, although Prevelle, Juvéderm,and Restylane may have superficialfillers soon. Therefore, CosmoDerm I,although it lasts only about 3 months, isthe filler of choice for periorbital wrin-kles and smoker’s lines above the top lip.CosmoDerm II is most often used foracne scars.

Drawbacks Bioengineered human-derived collagen is expensive to pro-duce, rendering these agents somewhatcostly. Further, the cosmetic effects fromthese products do not last, on average,any longer than the bovine-derivedproducts. The duration is thought to bearound 4 months. However, these prod-ucts are associated with less bruising,erythema, and pain than other fillingagents and, consequently, remain desir-able options for those who cannotafford to have downtime. Excluding thereduction in immunogenic potential,human collagen fillers have similar sideeffect profiles to bovine collagen fillers.Likewise, patients with lidocaine aller-gies should avoid these agents.

CADAVERIC COLLAGEN

Overview Approved by the FDA in 2000 for soft tissue augmentation,Cymetra® (LifeCell Corp., Palo Alto, CA)is a micronized collagen derived fromprocessed human cadaver skin. A similarproduct, Fascian (Fascia Biosystems,Beverly Hills, CA), is obtained fromcadaver fascia, and has a heavier consis-tency. Cymetra is packaged as a 330-mgwhite powder in a 5-cc syringe, stored atroom temperature and reconstitutedwith 1 mL of 1% lidocaine to create athick paste.6 Tunneling and threadinginjection methods are accomplished

through a 26-gauge syringe into a subcu-taneous plane, avoiding overcorrection.

Benefits This acellular and purified fillernegates a potential sensitivity reactionand pretesting is, therefore, unnecessary.The cadaver collagen has somewhatlonger durability versus other collagenproducts, lasting from 3 to 9 months,although durability is controversial.6

Cymetra is indicated for use in deeprhytides (i.e., nasolabial folds), depressedscars, and volumizing of the lips.Reconstitution with lidocaine yieldsreduction in intraprocedural pain.

Drawbacks Based on the composition ofthe product, Cymetra is contraindicatedin patients with gentamicin allergies.The product is very viscous, whichmakes it difficult to operate, generatingmore local tissue discomfort and traumaas well as leading to longer recoverytime for patients. Fascian is an eventhicker and stiffer product, which trans-lates to more side effects and difficultyin administration. The implantation ofcadaver products into superficial andmobile wrinkles can induce migrationand, therefore, is discouraged. Themajor issues with employing theseagents are the cumbersome preparationsand deficit of adequate clinical trialsdemonstrating their long-term efficacyand safety.

Hyaluronic Acid

In the last few years, HA filler sub-stances have become the new gold stan-dard, far outpacing in usage the othersoft tissue augmentation agents.21 HA,or hyaluronan, is a nonsulfated gly-cosaminoglycan (GAG) that occurs nat-urally in the skin and other tissues(specifically, connective, epithelial, andneural tissues) as space-occupiers of the

CA B

� FIGURE 23-5 A. This patient has a dropped nasal tip. Options to raise the tip include a dermal filler or a botulinum toxin. B. CosmoPlast or Restylane is

placed just below the cartilage of the central nose as shown with the white arrow. C. After CosmoPlast or Restylane is injected, the tip of the nose rises immedi-

ately. Note that it is now parallel to the ground rather than curling down.


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extracellular matrix. HA is also ubiqui-tous across animal species, which makesit nonimmunogenic. This polysaccha-ride has the capacity to bind water up to1000 times its mass. The biologic behav-ior of HA is predictable; it creates lubri-cation and volume with an aqueous andpliable framework that suspends andadheres to collagen, elastin, and cells.With age, the concentration of HA inskin decreases, translating to more lax,sallow, and dull skin. The viscoelasticqualities of HA serve to plump up theskin, yielding a more youthful appear-ance. Naturally-occurring, unmodified,or uncross-linked HA has a half-life ofabout 24 hours. For this reason, HA iscross-linked when formulated into adermal filler product. Higher concentra-tions and moderate cross-linking of theHA in a product impart greaterlongevity. There exists a certain thresh-old where beyond that value additionalcross-linking can cause biocompatibilityissues. In effect, cross-linking has to bein the right balance to maintain durationand biocompatibility of the HA filler.HA is readily metabolized by the liverinto by-products, water, and carbondioxide. In the skin, HA is broken downby hyaluronidase, mechanical degrada-tion caused by facial movement, and byfree radicals. Supplementation with oralantioxidants theoretically will increasethe duration of HA fillers, but this hasnot been proven (see Chapter 34).

There are two main categories of HAfillers: animal derived (e.g., Hylaform)and bacteria derived (e.g., Restylane,Captique, Juvéderm, etc). Medicis, thecompany that sells Restylane, trade-marked the name “nonanimal derivedsynthetic hyaluronic acid (NASHA)” toshow that their products, Restylane andPerlane, are not animal based. Becauseof the expense of animal-derived prod-ucts, the vast majority of HA productsare bacterial derived. At the time thischapter was written, no HA products onthe market contained lidocaine and,therefore, were more painful than fillersthat contain lidocaine. However, lido-caine-containing injectables, such asPrevelle Silk, have recently entered themarket. Because of their nonallergenicnature and manufacturing, HA fillers donot require prior testing and can bestored at room temperature. Theiradvantages over collagen products arelonger duration (6–12 months), betterpliability, and less immunogenic andallergic side effects. On the whole, sideeffects of various HA fillers are similar,mild, and rare; these include bruising(Fig. 23-6), temporary swelling, lumps,

acneiform eruptions, and, rarely, acutehypersensitivity.22 In addition, arterialocclusion, thought to be due to swellingof the HA implant, causing vascularcompromise, can rarely occur. (Fig. 23-7).

A major advantage of HA fillers is thatif skin nodules do arise, these reactionscan be easily dissolved with intralesionalhyaluronidase (Fig. 23-8). The disadvan-tages of the currently available HA fillersare increased pain on injection and post-procedure edema, erythema, and ecchy-moses as compared to CosmoPlastinjections.

CONSIDERATIONS IN CHOOSING AN HA

FILLER HA fillers do not require skin

testing and the risk of allergy with allproducts that are FDA approved is mini-mal. Cost, availability, duration of cor-rection, and size of the required needlefor injection all play a role in productselection and manufacturers all strive tocreate an affordable, long-lasting productthat can be injected with a 30-gauge orsmaller needle. However, there areother, less obvious, scientific considera-tions to be taken into account whenchoosing a filler (Table 23-3). The stiff-ness or G� (G prime) of a product is oneof the most important considerations.G� is a measurement of gel hardness. Itis obtained when a gel is placed on aplate. A second plate is placed over the

� FIGURE 23-7 This patient developed redness, blisters, and lumps after receiving an HA injection.

The most likely cause was vascular compromise due to swelling of the implant. All cultures were nega-

tive, other treated sites were normal and the lesions resolved without scarring.

� FIGURE 23-6 This is a common site at which bruises occur after a dermal filler is injected.


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gel and a lateral force is applied. Themeasurement of resistance to deforma-tion is known as the elastic modulus orthe G� (Fig. 23-9). Together with thecohesivity of the product, G� valuescould be used to determine the appro-priate placement of an HA dermal filler.For example, more robust products(higher G� values and higher cohesivi-ties) such as Juvéderm Ultra Plus andPerlane, in the primary author’s opinion,should be used in deeper lines, such asnasolabial folds and marionette lines, aswell as to lift the lateral brow, to correctthe nasal bridge, to give the ear lobeyouthful volume, to evert the nipples,and to raise the nasal tip. More fluidproducts such as Juvéderm Ultra andRestylane are better suited to be usedover large areas such as the cheekbones

and cheeks. Low G� products such asHylaform and Juvéderm Ultra are neces-sary in areas that require a softer agent,such as the body of the lip or the teartrough. As new products reach the mar-ket, knowing the G� will help practition-ers match fillers with indications.

The concentration of HA in a product isimportant to consider as well (Table 23-4).Many authorities believe that the higherthe concentration of HA, the stiffer theproduct and the longer its duration. Thisis true in general when comparing prod-ucts within a brand, for example, whencomparing Juvéderm 18 to Juvéderm 24.However, this does not hold true acrossbrands because not all of the HA in thedermal fillers is cross-linked. Many HAfillers contain uncross-linked HA andlightly cross-linked chains and frag-ments. The uncross-linked HA, frag-ments of HA, and lightly cross-linkedHA are included in the overall concen-tration measurement but only remain inthe skin for a limited time and shouldminimally contribute to the longevity ofthe filler. The uncross-linked HA doeshelp decrease extrusion force and make

injection easier, which is the mainreason it is included. Therefore, the factthat Restylane contains 20 mg of HA/ccand Juvéderm contains 24 mg of HA/ccdoes not give a physician enough infor-mation to decide which filler will havelonger duration. It is actually the amountof modified HA that plays the primaryrole in duration.

The type of modification (cross-link-ing) and the cross-linking agent used isalso important. Cross-linking can bebest visualized by imagining a ladder(Fig. 23-10). Each side of the ladder is anHA chain. The rungs of the ladder arethe cross-links. When the “rungs” of theladder attach to both sides of the ladder,the agent is considered completely mod-ified. However, the cross-linking agentused may incompletely cross-link thechains of HA, leaving the sides of therungs unattached and resulting inincomplete modification. Such a prod-uct might not be as durable as a com-pletely modified product. In addition,there are two types of rungs in the HAladder. One is called an ether linkage andthe other is called an ester linkage. Etherlinkages are formed by 1,4-butanedioldiglycidyl ether (BDDE, the cross-linkingagent in Restylane and Juvéderm) anddivinyl sulfone (DVS, the agent used inPrevelle Silk, Captique, and Hylaform).The cross-linking agent used in PrevelleDura, 1,2,7,8 diepoxyoctane (DEO),forms both ether and ester linkages(known as “double cross-linking”). It is

TABLE 23-3

Factors to Consider When Choosing a

Hyaluronic Acid Filler

Concentration of HA

Cost

Cross-linking

Degree of cross-linking

Quantity of HA cross-linked versus

uncross-linked

Type of cross-linking technology used

Duration of correction

G� (elastic modulus)

Hydration level of product in the syringe

Presence of lidocaine

Required needle size for injection

Sizing technology

Syringe

Design of syringe

Size

Complete crosslink

HA chain

HA chain

Incomplete crosslink

� FIGURE 23-10 Cross-links that occur dur-

ing the cross-linking process may be complete or

incomplete.� FIGURE 23-8 Visible lumps of Hylaform in the upper lip.

Applied force

Moving Plate

Fixed Plate

Gel

� FIGURE 23-9 Measurement of G�. A force is applied laterally on the top plate. The more the gel

resists the movement, the harder the gel, the higher the G�.


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unknown at this time what advantages,if any, ether linkages impart to a dermalfiller.

The hydration status of the filler onceit is packaged in the syringe also affectsfiller performance. HA is well known tobind up to 1000 times its weight inwater. The amount of water bound tothe HA prior to its packaging in thesyringe determines how much morewater the filler can absorb once it isinjected into the skin. In other words,fillers that are completely hydrated in the syringe will bind less water oninjection and the volume will expandless upon injection as compared to fillersthat are not completely hydrated in thesyringe. Fillers that are not completelyhydrated in the syringe will swell some-what within 24 hours after correction;therefore, it is prudent to slightly under-correct with these substances. In addi-tion, patients can be told that they will “look even better” 24 hours after the injection. Restylane and Juvédermare not completely hydrated in the syringewhile Captique and Hylaform are closeto being fully hydrated (Table 23-5).

Another process that may affect theperformance of the filler is referred to as“sizing technology.” This term is usedby Allergan to differentiate Juvédermfrom the other HA fillers. When an HAfiller is cross-linked, the chains of modi-fied sugars form a gel. In the process ofmanufacturing Restylane, RestylaneFine Line, Restylane Lip, Restylane

Touch, Perlane, and Restylane Sub-Q,this gel is extruded through a screen.This produces various sizes of the gelthat are considered “sized.” The largepieces become Perlane or Restylane Sub-Q, while the small pieces are mar-keted as Restylane Fine Line orRestylane Lip. The medium-sized piecesare Restylane. The larger pieces yieldproducts that are best used in the mid tolower dermis while the small piecessuch as Restylane Fine Line can be usedmore superficially. The Juvéderm familyof products is not sized. In other words,Juvéderm is not pushed through a screenand broken into sized pieces and, there-fore, it consists of randomly sized andshaped pieces.23 It is unknown at thistime what role sizing technology plays,if any, in the performance of a filler.

There are many factors that must beunderstood in order to make the mostsuitable choice of HA filler. There are nopeer-reviewed publications that reviewthe above mentioned properties so it isdifficult at this point to know howimportant these various characteristicsare in choosing a filler. More data needto be collected to properly ascertain if,for example, sizing technology makes adifference or if ester bonds last longerthan ether bonds. These distinctionswill become clearer and more importantas more HA fillers are introduced ontothe market and more data are collected.A discussion of the individual HAbrands follows.

HYLAFORM (NO LONGER ON THE MARKET)

Overview Although Hylaform is nolonger on the market, it will be dis-cussed because it was the first producton the market that used the DVS cross-linking system. The knowledge gleanedfrom this revolutionary agent has led tomany spin-off products using similartechnology such as Captique andPrevelle. Hylaform is an animal-basedHA product derived from roostercombs. It is produced by cross-linkingthe hydroxyl groups of HA with DVS toyield a gel-like substance that is sized by

extruding the gel through a sieve in theproduction process discussed above.24

The smallest pieces of the gel are pack-aged as Hylaform Fine Line, which isindicated for superficial wrinkles, buthas never been approved for the US mar-ket. Hylaform, composed of medium-sized (average size 400 �m) particles, isindicated for injection into the midder-mis for medium facial wrinkles and finelines. Hylaform Plus is composed oflarger particles (average size 700 �m)and is used for deeper furrows. In 2004,the FDA approved two products in thisfamily, Hylaform and Hylaform Plus(Allergan, Irvine, CA), the latter ofwhich remains on the US market. Themoderate density of cross-linking ren-ders the Hylaform fillers biocompatible,soft, and pliable. The G� of this filler islow compared to other HA products on the market; therefore, this is thesoftest HA filler currently on the mar-ket. This softness makes it an idealfiller for use in the lips. The Hylaformproducts contain 5.5 mg/mL of cross-linked HA.

Benefits Hylaform has a low G�, whichmeans that it is not very stiff and has avery natural feel in the skin. It is soft andmalleable making it ideal for use in thebody of the lip, smoker’s lines, and theperiorbital tear-trough as well as in largeareas such as the cheekbones and jowls.Hylaform is very easy to inject with alow extrusion force through a 30-gaugeneedle. The side effects of Hylaform arerare, mild, and temporary.

Drawbacks Side effects, which are rareand relatively mild, typically includebruising, erythema, induration, andpruritus.25 The contraindications forHylaform products are similar to thosefor most fillers (e.g., autoimmune andinflammatory disorders, allergic back-ground, history of anaphylactic reac-tions, immunosuppressant therapy, andpregnancy or breastfeeding). In addition,patients allergic to products of avianorigin (e.g., eggs) cannot use theseagents.25,26 Hylaform is close to beingfully saturated with water in thesyringe;27 therefore, there is no volumeexpansion of the filler after injection.Additionally, the injection of Hylaform,as with other fillers that do not containan anesthetic, could be painful. How-ever, the softness of Hylaform renders itless painful than other HA fillers toinject. The use of topical anestheticsreduces the pain on injection. The cos-metic effects of Hylaform and HylaformPlus are believed to last only about 3 to 4

TABLE 23-4

Hyaluronic Acid Fillers: Cross-Linking Agents and Concentration of HA

PRODUCT CROSS-LINKING AGENT CONCENTRATION (mg/mL)

Captique DVS 4.5–6.5

Hylaform DVS 4.5–6.5

Juvéderm Ultra and Ultra Plus BDDE 24

Prevelle Dura DEO 20

Prevelle Silk DVS 4.5–6.5

Restylane and Perlane BDDE 20

TABLE 23-5

Hyaluronic Acid Filler Hydration in the

Syringe

ALMOST COMPLETELY NOT COMPLETELY

HYDRATED IN HYDRATED IN

THE SYRINGEa

THE SYRINGEb

Captique Restylane

Hylaform Juvéderm

Prevelle Silk Prevelle Dura

aNo need to undercorrect.bSlightly undercorrect.


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months, most likely because of theircross-linking properties and lower con-centration of HA than the newer HAfillers (e.g., Restylane and Juvéderm).

CAPTIQUE (NO LONGER ON THE MARKET)

Overview Captique (Allergan, Irving,CA) differs from Hylaform only insofaras the former is derived from bacterialfermentation rather than rooster combs;otherwise, it is also composed of 5.5 mg/mL of HA. In 2004, it wasapproved by the FDA for moderate tosevere wrinkles. The bacterial origin ofCaptique renders it slightly stiffer thanHylaform, but not as firm as Restylane.Captique is packaged as a clear gel in a0.75-mL syringe and injected dermallywith a 30-gauge needle via the serialpuncture method. Like Hylaform,Captique is no longer available.

Benefits This product is suitable fortreating similar periorbital and perioralwrinkles as Hylaform as well as enhanc-ing lip fullness and shallow scars. Notesting or refrigeration is required andthe agent can be injected in the initialphysician’s visit. As an HA filler, it has alow side effect profile because of itsimmunogenic inertness and low likeli-hood of allergic reactions. The equilib-rium hydration of Captique is also com-parable to Hylaform, meaning that it isfully hydrated with water in the syringe.In the primary author’s experience,patients complained of less stinging afterinjection with Captique as comparedwith Juvéderm.

Drawbacks The longevity of Captique isquestionable but believed to be about 4to 6 months. Few duration studies wereperformed, however. It has a high extru-sion force when injected through a 30-gauge needle, which renders injectionmore difficult than that for Hylaform orRestylane. Captique does not containlidocaine, thus it is similar to other HAfillers in the capacity to cause moderatepain, bruising, edema, and redness oninjection. Captique has been taken offthe market because its parent company,Allergan, is focusing on promotingJuvéderm.

RESTYLANE

Overview Restylane (Medicis, Scottsdale,AZ) was the first nonanimal HA prod-uct approved in the US. It is a NASHAgel formulated through fermentation,with sugar present, in bacterial culturesof equine streptococci. Restylane has ahigher concentration of HA comparedto Hylaform and Captique and the

highest G´ of the fillers currently on themarket, denoting that it is a slightlystiffer product. It is the most popular ofthe HA fillers in the US because of itssafety profile, brand recognition, andease of injection. Restylane is com-posed of approximately 100,000 parti-cles/mL (approximately 250 �m onaverage)28 and contains 20 mg/mL ofHA. Restylane is indicated for midder-mal wrinkle reduction and was the firstHA filler approved in the US in 2003.29

Perlane, another product in theRestylane family, was more recentlyapproved by the FDA for significantlydeeper folds and furrows. Restylane ismade of medium-sized particles of HAgel, while Perlane is composed of largerHA gel particles (approximately 1000�m),28 but with the same HA concen-tration. The Restylane family of prod-ucts also includes Restylane Fine Line,Restylane Touch, Restylane Lip, andRestylane Sub-Q, which are not cur-rently approved for use in the US.These products have the same formu-lation as Restylane and differ only intheir particle size. Restylane andPerlane are packaged as transparentgels, with a shelf life of 18 months, andstored at room temperature. Restylaneis enclosed in 0.4- and 1-mL syringeswhile Perlane is packaged in a 0.7-mLsyringe; both are injected via a 27-gauge needle. Restylane is implantedusing linear threading anterograde orretrograde techniques. It is importantto avoid injecting at withdrawal of theneedle, which can result in superficialinjection, creating blue-colored nod-ules. A fanning threading techniquecan also be employed with Restylaneat the nasolabial fold or lip commis-sures.

Benefits The stiffness of Restylane ren-ders it well suited for moderate to deepwrinkles and it is this quality amongother factors that is thought to impartgreater longevity in human tissue ascompared to Hylaform and Captique.The cosmetic effects of Restylane arethought to last over 6 months; Perlanedelivers a durability of 6 to 9 months.Product stiffness makes Restylane andPerlane more suitable for moderate anddeep wrinkles than for use in the bodyof the lips or the tear trough. Restylaneis ideal to fill nasolabial and marionettelines, chin and jowl depressions, nasaldeformities, and for nasal tip-lift as wellas acne scars and other defects.

Drawbacks Bruising is associated withall HA fillers. However, the stiffness is

a downside if the product is used by apoorly skilled physician, with bumpsand blue blebs possibly arising fromimproper injection technique. Injectioninto the tear trough may result in visi-ble blebs. Slower injection of any HAfiller will limit the risk of inflammation.Restylane can be used in the vermilionborder to augment the shape of the lip.In the primary author’s opinion,Restylane and Perlane are a poor choicefor the body of the lips. However, out-side the US, Restylane Lip is availableand is a better choice for use in thisarea. As with other fillers that do notcontain an anesthetic, the injection ofRestylane can be painful. The use oftopical anesthetics and/or dental nerveblocks is recommended to reduce thepain on injection. Restylane tends tosting less after injection when com-pared to Juvéderm. It is unknown whythis occurs as they are both the samepH of approximately 7.0.

JUVÉDERMTM

Overview Juvéderm (Allergan, Irvine,CA), is manufactured by a bacterial fer-mentation process similar to that usedfor other stabilized bacterial-based HAfillers and was approved by the FDA inlate 2006. There are many products inthe Juvéderm line (Juvéderm 18,Juvéderm 24, Juvéderm 24 HV,Juvéderm 30, and Juvéderm 30 HV), butonly Juvéderm 24 HV (also known asJuvéderm Ultra) and Juvéderm 30 HV(also known as Juvéderm Ultra Plus) arecurrently approved by the FDA andsold in the US. All the products in theline vary by the amount of HA concen-tration, the amount of cross-linking,and the regularity of the cross-linking.Both Juvéderm Ultra and Ultra Plusconsist of 24 mg/cc of HA, butJuvéderm Ultra Plus has a higher degreeof cross-linking than Juvéderm Ultra,which makes Ultra Plus more suitablefor the deepest facial grooves and fur-rows. Unlike Restylane, which consistsof stiff and a fairly narrow range ofparticle sizes, Juvéderm is a smoothconsistency gel composed of a broadrange of particles of various sizes andshapes30 (referred to as “Hyalacrosstechnology”).

Juvéderm products are packaged as aclear gel in 0.8-mL syringes. They arestored at room temperature. JuvédermUltra is injected into the middermis viaa 30-gauge needle while JuvédermUltra Plus is implanted deeper via a 27-gauge needle.27 The needles must betightly attached to the Luer-locksyringe to prevent detachment during


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injections. Various techniques of injec-tion can be used with Juvéderm,including serial puncture and tunnel-ing.

Benefits Juvéderm Ultra and Ultra Plusare in the medium range of stiffness;therefore, they can be used in any wrin-kles, moderate or deep, and to correctscars. Juvéderm Ultra is easily placed inthe vermilion border or the body of thelips. The high concentration of HA inJuvéderm Ultra and Ultra Plus and thehigh degree of cross-linking results inlonger-lasting aesthetic effects as com-pared to products such as Hylaform. Asother HA products, these agents havean overall low, mild, and transientadverse-event profile. Juvéderm is notcompletely hydrated in the syringe,27 soit will slightly expand after injection asit absorbs more water. This is importantto remember when injecting the bodyof the lips, which should be slightlyundercorrected to allow for the expan-sion. Similar to Restylane, the longevityof Juvéderm Ultra is about 6 to 9months and Ultra Plus may last up to 12months.

Drawbacks All HA products can causeerythema, swelling, and bruising afterimplantation (see Chapter 21). Pain dur-ing injection caused by lack of anes-thetic can be alleviated with the use oftopical or regional anesthesia. Juvédermcan be placed with care in the teartrough area, but the proximity to theeye is unnerving with the risk of theneedle popping off, so injections shouldbe very slow with only moderate extru-sion force. The needle is more likely topop off when the syringe is almostempty; therefore, the tear trough areashould be injected with a new syringeand the last part of the syringe can besaved for less dangerous areas such asthe nasolabial folds. As with all fillers,the skill and experience of the physicianis crucial for optimal outcome. IfJuvéderm is injected too superficially, itcan create a bluish hue. Caution shouldbe taken in overinjecting the vermilionborder and creating an unnatural “duck-bill” appearance. In addition, superficialplacement of Juvéderm in the teartrough defects can result in blue nod-ules. Blue nodules and unwanted bulgescan be corrected with the use ofhyaluronidase.

PREVELLE SILK

Overview Prevelle Silk is sold by theMentor Corp. (Santa Barbara, CA). Thisbacterial-derived product is similar to

the Captique formulation with moder-ate softness illustrated by its G´ in themiddle of the spectrum. This product issofter than Restylane and is similar insoftness to Juvéderm. Prevelle Silk has ahigher degree of cross-linking densitythan Hylaform and therefore is slightlystiffer than Hylaform. The gel contains5.5 mg/mL of cross-linked HA with anaverage particle size of 300 �m. Prevelleis suitable for treating shallow to moder-ate wrinkles, lips, and scars. Thelongevity of the product is unknown butreported to be about 4 months. PrevelleSilk contains 0.3% lidocaine. It wasapproved in the United States in 2008.This product is suitable for use in the lipssince it generates less pain during injec-tions. Side effects, which are rare and rel-atively mild, include redness, swelling,and pruritus.

Benefits This product is softer thanother products on the market sinceHylaform and Captique were discontin-ued. It can be used in any moderate todeep facial wrinkles, the body of the lip,and periorbital areas. Prevelle Silk is the first lidocaine-containing HA in theUnited States.

Drawbacks Longevity of the correctionis not known but thought to be 4-6months.

PREVELLE DURA

Overview Prevelle Dura (Mentor Corp.)is another bacterial-derived fillerapproved for the US market in 2008. It iscomposed of 220-μm HA particles cross-linked with DEO. As mentioned previ-ously, DEO cross-linking results in bothether bonds and ester bonds, known asdouble cross-linking. These ester bondsmay confer better stability and longerduration but this has not yet beenproven.31 Prevelle Dura is touted forsuitability in any dermal layer to correctmiddermal and deep rhytides. The G�(stiffness) of this product is 900 Da,which renders it slightly stiffer thanRestylane.

Benefits Preliminary studies demon-strate the safety of this product;31 how-ever, more trials need to be performed toestablish its strengths and weaknesses.Based on double cross-linking technol-ogy, the company claims that this devicemay last longer than previous HA fillers;however, this has not been proven. Therole of the double cross-linking technol-ogy in terms of duration of the filler hasnot been ascertained.

Drawbacks Prevelle Dura is slightlymore viscous and, therefore, requiresmore pressure on injection.

Hyaluronidase

Hyaluronidase is a soluble enzyme thathydrolyzes HA, other GAGs, and otherconnective tissue components in the skinand vitreous humor of the eye.32 It hasbeen approved by the FDA, as Vitraseand Amphadase, for enhancement ofinjectable drug absorption and resorp-tion of radiopaque agents. However,effective off-label uses include woundcare and postsurgical flap care amongother uses.

Several reports have indicated theusefulness of hyaluronidase to dissolveHA filler overcorrection for symmetriccontouring, as well as to manage impend-ing tissue necrosis because of HA skininjections.33–35 Specifically, Hirsch et al.published two cases of imminent tissuenecrosis caused by intra-arterial injectionof HA and surrounding tissue compres-sion of vital vessel, which resolved withemployment of hyaluronidase. Afterusing other appropriate techniques tomanage impending tissue necrosisincluding systemic aspirin, Nitro BIDunder occlusion, and hot compresses withmassage without significant response, theauthors injected 30 units of hyaluronidaseinto deep dermal tissue and subcutis usinga serial puncture method along thedistribution of affected arteries, which ledto the resolution of symptoms within aday.32,33 Although early reports have rec-ommended the utility of hyaluronidaseonly within 16 minutes of the criticalevent, Hirsch et al. reported successfulresponses after several days.32 Further-more, the effectiveness of hyaluronidasefor bluish (Tyndall) manifestations andasymmetric lumpiness from HA overcor-rection has also been reported at variousconcentrations.34–36

Because of the described benefits ofhyaluronidase for the treatment of com-plications of the popular HA fillers, ithas been recommended as a necessaryagent to keep in an aesthetic physician’soffice.37 Hyaluronidase is a clear liquidthat is stored in the refrigerator andreconstituted with 1 mL of normal salineto generate 150 units. Very rare adverseacute and delayed-type hypersensitivityreactions to hyaluronidase have beenreported, so it may be prudent toperform a skin test prior to the use ofthis agent. Injection of hyaluronidaseinto patients with an allergy tohymenoptera stings and thimerosal iscontraindicated.33,38


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Semipermanent Fillers

Fat, Radiesse, and Sculptra are consid-ered semitransitory because they arepartly biostimulatory and partiallybiodegradable; this balance allows themto last approximately 1 to 3 years.39 Theadverse events associated with semiper-manent fillers include rare granulomaformations. The aesthetic effects ofthese fillers are best preserved withannual touch-up sessions.

AUTOLOGOUS FAT

Overview Originating in the 1890s,transplantation of fat from a patient’sexcess adipose areas to other skindefects is the oldest soft tissue augmen-tation method.1 Fat injection filling hasgained recognition for several reasons.Naturally, the patient’s own cells areunlikely to cause sensitivity or inflam-mation and are therefore consideredsupremely biocompatible. Furthermore,the technique of fat implantation hasundergone remarkable polishing overmany years, especially with the adventof harvesting subcutis through liposuc-tion. The procedure is a multistepprocess, whereby the fat cells areobtained from the buttock, thigh, andabdominal regions, then segregated,stored (refrigerated up to 18 months),and injected back into the patient’s sub-cutis on the face, hands, and any otherareas requiring volume enhancement.As anticipated, this process is more inva-sive, time-consuming, both for the clini-cian to prepare and perform as well asthe patient to recover from, as well asmore costly. In effect, the optimal effi-cacy with minimal adverse effects ismainly achieved in the hands of a quali-fied dermasurgeon. Approximately 0.1cc aliquots of fat are inserted into sub-cutis through a 17- to 18-gauge needlevia a tunneling technique, without over-correction.40 Postprocedure massage isrecommended for proper shaping ofcontours.

Benefits Because of its autologous char-acter, lipotransfer is unlikely to causesensitivity and reactivity of the tissue,minimizing potential long-term sideeffects and obviating prior testing.Nasolabial folds, sunken cheeks, teartroughs, marionette lines, scars, and lipsare the most appropriate areas of cor-rection with fat. Furthermore, fat trans-fer provides a reported duration ofabout 12 months; although the concreteduration is controversial.41 Because theinjectable material used is the patient’sown tissue, its use decreases the

amount of money spent on the actualfiller. The procedure also has an attrac-tive double-gain, where two cosmeticareas can be simultaneously addressed,lipoexcess and lipodystrophy. Stemcells have been isolated from fat cells. Itis believed that the stem cells found infat lead to increased skin rejuvenation(see Chapter 3). When performed by askilled physician, the results of lipo-transfer are remarkable.42

Drawbacks Fat injections require pro-phylactic local or regional anesthesia.Because of the fact that the procedure ismore surgically invasive, more complexpreparations and settings are requiredwith longer and more frequent officevisits. Although the harvesting portioncan cause a longer recovery time and anincreased risk of side effects (e.g., infec-tion, scarring), the actual injection has asimilar adverse event profile to the otherfillers (e.g., edema, redness, bruising,and discomfort lasting a few days).34

Another variable to consider whenselecting candidates for this procedure isto ensure that the patient has a sufficientgraft supply. In some patients, the fatinjections last several years and in otherpatients the injections last merelymonths. Many tricks are employed totry and increase longevity, but at thistime there are no guarantees.32

RADIESSE

Overview Radiesse (BioForm Medical,San Mateo, CA) was approved by theFDA in 2006 for the correction of mod-erate to severe folds and wrinkles alongwith HIV-associated lipoatrophy. It iscomposed of 30% calcium hydroxylap-atite (CaHA) microspheres (25–45 μm)suspended in an aqueous gel carrier(1.3% sodium carboxymethyl cellulose,6.4% glycerin, and 36.6% sterile water).As the gel carrier of this filler dissipatesin several months, the microspheresstimulate cutaneous cells to generatefocal foreign body reaction and neocol-lagenesis.32,33 This leads to envelopmentof the microspheres by fibrin, collagen,and fibroblasts, and slows the degrada-tion by macrophages and metabolisminto calcium and phosphate ions.Because of a similar mineral constitutionas human bones, and no foreign anti-genic properties, CaHA is particularlybiocompatible. It is critical for patientsto be aware that Radiesse is a radio-opaque material that can be visualizedand misinterpreted on facial radi-ographs, but importantly, it does notradiographically mask surroundingtissues.

Radiesse is a white material packagedin a 1-mL syringe and injected via a 25-to 27-gauge and 11/4-inch needle intothe deep dermis or subcutis withoutovercorrection.33 The product should bestored at room temperature. A reason-able injection method for Radiesse istunneling or crisscross threading tech-niques.32 A placement of Radiesse in thesupraperiosteal plane yields better con-trol and ability to contour skin with thisstiffer filler.43

Benefits Since Radiesse is immunologi-cally inert, it does not require skin test-ing. With more than 20 years of use asimplantable devices for otolaryngologyand orthopedic specialties, CaHA pos-sesses an excellent safety record. Theaverage duration of Radiesse is 9 to 18 months. The proper locations ofinjection include the nasolabial folds,marionette lines, prejowl sulcus, andcheek depressions. Unlike Sculptra,where time is necessary to build up newcollagen, Radiesse offers the advantageof immediate wrinkle ablation.Interestingly, although Radiesse inducesforeign body reaction, it is not known tocause granuloma formation.36 In its gelform, the device is also quite pliable,permitting timely manipulation andappropriate modification. In addition, itcan be combined with other fillers, suchas Sculptra, HA, and collagen.

Drawbacks The main drawback ofRadiesse is that it is not reversible likeHAs. Radiesse also does not contain ananesthetic and because of its high vis-cosity, requires administration through ahigh-bore needle. However, Radiessecan be combined with lidocaine in thesyringe to decrease pain on injection.Hence, the use of topical or regionalanesthesia is recommended. Minimalside effects such as ecchymoses, edema,and erythema appear soon afterRadiesse injection and are transitory.Rare nodules have also been associatedwith Radiesse and can be managed withintralesional steroids or excision. Similarto Sculptra, an implantation of Radiessein the superficial and mobile wrinkles(e.g., lips and periorbital area) and thebody of the lips is discouraged becauseof the palpable and visible whitepapules that can develop (also known as“popcorn lips”). Radiesse should not beperformed in the nose of a patient antic-ipating rhinoplasty. Several facial plasticsurgeons have given anecdotal reports inlectures suggesting that this complicatesrhinoplasty surgery. An HA or collagenfiller would be a more appropriate


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choice in preoperative rhinoplastypatients.

SCULPTRA

Overview. Sculptra is a synthetic,biodegradable, biocompatible, immuno-logically inert peptide polymer (alsoknown as NewFill).44–46 Sculptra(Dermik Laboratories, Sanofi-Aventis,Bridgewater, NJ) is composed of poly-L-lactic acid (PLLA) microspheres, sodiumcarboxymethylcellulose, and nonpyro-genic mannitol and is manufacturedfrom powdered, absorbable suturematerial (e.g., Vycryl). This agent is not atrue dermal filler because it does not fillthe dermis the way collagen and HA dobut, rather, it promotes the productionof new and organized collagen in thedermis. Many physicians refer to it as a“dermal stimulator.” Sculptra is thoughtto foster neocollagenesis by stimulatingfibroblasts and gradually restoring facialvolume.47–49 However, Sculptra is even-tually cleared from the skin via phago-cytic digestion. In the US, Sculptra wasapproved by the FDA in 2004 for thetreatment of HIV-associated facial lipoa-trophy, but it has been used off-label forcosmesis, and Dermik is currentlyapplying for approval for its use in facialrejuvenation. NewFill has been used inEurope and Asia for many years. Whenit was first introduced, NewFill wasdiluted with a lower amount of salineand many granules and nodules werereported. This led to new recommenda-tions to dilute one bottle with 5 to 10 ccof sterile water and massage after appli-cation. With the new recommendations,adverse events have been minimal.

Freeze-dried Sculptra powder isstored at room temperature and recon-stituted approximately 2 to 4 hours priorto injection. The package label statesthat the product should be used within72 hours. In our practice, we preferusing Sculptra that has been reconsti-tuted for at least 2 days because thesolution is easy to work with and resultsin less needle clogging. Sculptra is recon-stituted and kept in the refrigerator for 2days to 2 weeks. Although the packagelabel recommends that the formulationbe reconstituted with 5 cc of sterilewater, many physicians reconstitutewith 4 mL of sterile water and 1 mL of2% lidocaine with epinephrine. Thelidocaine decreases pain while the epi-nephrine reduces bruising. Strong agita-tion of the filed syringes is recom-mended directly before injection tohomogenize the white suspension.(Sculptra tends to settle in the bottom ofthe syringe.) By means of tunneling and

threading techniques, a 25- or 26-gaugeneedle is utilized to implant Sculptrainto overlapping deep dermal and sub-cutaneous layers of the skin.

The mechanism of action and propertechnique of injecting Sculptra requirepractitioners to restore volume to aselected treatment plane rather than aspecific wrinkle.50 Indeed, injectingSculptra is more similar to fat injectionprocedures than collagen or HA injec-tions, because it serves to sculpt theprominent hollows and deep groovesassociated with loss of deep soft tissue.In addition, specialized training to useSculptra is required prior to injections.Small and exact aliquots of Sculptra areinjected in the correct tissue plane with-out overcorrection. In general, 2 to 3 ccof the product are used for patients intheir thirties, 4 cc for patients in theirforties, and 5 cc or more for olderpatients. The cost is approximately $230per syringe.

Once Sculptra is injected, there is atransient period lasting about 1 hour dur-ing which the patient can see a slighteffect because of the volume of fluidinjected. Once this resolves, results arenot seen until about 4 weeks after treat-ment when results may begin to appear.Injections are performed on a monthlybasis until desired results have beenobtained. The number of injection ses-sions required varies greatly from personto person and it is difficult to predict thetotal number of sessions needed. Injectionsare performed 3 to 6 weeks apart.Anecdotal reports state that premeno-pausal women and postmenopausalwomen on hormone replacement therapy(HRT) require fewer sessions than post-menopausal women not on HRT.Postmenopausal women not on HRTmay require up to eight sessions. Mentend to correct more quickly thanwomen for unknown reasons. After theprocedure, the patient’s skin is strenu-ously massaged with topical arnica (forits anticoagulant properties) for about 5 minutes to reduce bruising, pain, andnodule formation. Patients should be toldto massage the treated area for 5 minutesevery night for five nights.

Sculptra treatments can be combinedwith other fillers for instant gratifica-tion. In this case, Sculptra is injectedfirst, the massage with arnica is per-formed, and then the HA or collagenfiller is applied in the treatment area.Sculptra is often used in the cheeks andcheekbone area while an HA filler isused in the nasolabial folds, marionettelines, and the lips. Alternatively, a courseof three to four Sculptra treatments is

used and then an HA filler is used afterSculptra at the last visit. Sculptra shouldalways be used first, then massaged,before the HA is injected so that thelidocaine and epinephrine in theSculptra will reduce the pain and bruis-ing of the HA injection, and the massag-ing will not affect the placement of theHA filler.

Benefits Sculptra does not require priorskin testing. It is ideal for treating vol-ume loss in the cheeks, nasolabial folds,and the malar area. Once the desiredresult is achieved, results last about 18 to 24 months.42,44,51,52 The correction isvery natural looking. Having been usedsuccessfully in various medical devicesfor more than 30 years, PLLA has anestablished safety record.53 Moreover,new product guidelines and injectiontechniques (e.g., using a more diluteproduct, avoiding overcorrection, notinjecting too superficially, and postinjec-tion massage) have reduced the inci-dence of side effects (i.e., formation ofgranulomas and nodules) as comparedto when the product was originallypackaged as NewFill.54

Drawbacks Sculptra injection results arenot immediate and multiple courses arerequired to achieve the optimal cosmeticeffect, with the number of treatmentsdepending on volume of the defectbeing treated.45 Preinjection reconstitu-tion can contribute to scheduling limita-tions because it must be made at least 2hours in advance. Injecting suspensioncan be slightly difficult because of recur-rent clogging of the needles, which leadsto frequent needle changes. Adverseevents are rare, but PLLA can causepostinjection site pain, bruising, andswelling, as compared to other products,partly because of the larger needle used.Adding lidocaine to the diluent miti-gates injection pain. Ecchymoses can bereduced by mixing epinephrine into thePLLA suspension and taking bromelainsupplements (500 mg twice daily) afterinjection (see Chapter 21). Hyperkineticareas (e.g., crow’s feet and the corner ofthe mouth) and regions with thin skin(e.g., around the eyes, smoker’s linesabove the lips) should not be treatedwith Sculptra because of irregularpapules that can emerge. Most lumpsthat do arise are from superficial admin-istration of Sculptra and are not visible,although they are palpable by thepatient. Reassuring patients that theselumps are transient in nature is impor-tant. Nodule and hematoma formationare the other rare adverse effects that


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have been reported, but are less likely ifthe new injection guidelines are fol-lowed.55,56 Sculptra injection techniqueis very different than that of HA fillersand the learning curve is higher. In addi-tion, there is lack of reversibility as withHA fillers. Specialized training is requiredby the manufacturers of Sculptra beforethey will sell the product to a physician.

Permanent Fillers

Although the current momentum in thecosmetic market is toward the less inva-sive procedures, which are safer, perma-nent fillers are very popular outside theUS because of the lower cost. Many ofthese products are used by unskilledpractitioners and lead to disfiguringresults. If practitioners are to use a per-manent filler, they should be skilled inthe technique and certain of thepatient’s expectations. In the primaryauthor’s opinion, it is best to use a tem-porary filler first, to make sure that apatient is pleased, before proceeding to apermanent or semipermanent option.Newer fillers (e.g., Artefill) as well asolder fillers (e.g., silicone) are being usedfor this purpose. These nonbiodegrad-able fillers stay enclosed by the skin foran indeterminate and lasting period oftime. However, these fillers are not to beused for and by the lighthearted. Theyare associated with rare, significant sideeffects such as granulomas, migration,and asymmetry and are best implantedinto a patient experienced with priorsoft tissue augmentations and by a profi-cient physician. Remember, as with any-thing enduring, if one is not pleasedwith the results, one has to live withlong-term consequences.

ARTEFILL

Overview In October 2006, the FDAapproved the novel permanent fillerArtefill (Artes Medical, Inc., San Diego,CA) for the correction of nasolabialfolds.57 Artefill is constituted with 20%homogenous polymethylmethacrylate(PMMA) suspended in equilibrium withpartly denatured 3.5% bovine collagen(from enclosed US cattle herds) and0.3% lidocaine. As opposed to the origi-nal European product, Artecoll, whichcontained different size microspheres ofPMMA that potentially contributed to ahigher risk of granulomas, Artefill iscomposed of uniform size PMMAmicrospheres (30–50 �m) that are lesslikely to result in the formation of gran-ulomas. Small size, uniformity, andsmoothness are refined characteristics ofArtefill that promote biocompatibility

and resistance to phagocytic degrada-tion and migration as well as ensureencapsulation by patients’ collagen lead-ing to lasting nonimmunogenic results.

Artefill is packaged in a kit of three0.8-mL and two 0.4-mL syringes that areinjected through a 26-gauge needle intosubdermal and subcutaneous space via atunneling technique without overcorrec-tion.33 After injection, gentle massage isrecommended to evenly distributematerial in the skin and prevent clump-ing. Artefill must be stored via refrigera-tion (2�C–10�C) and warmed before use.In order to achieve optimal correction ofrhytides, two to three treatment ses-sions, a few months apart, are sug-gested.51 Like Sculptra, specific injectiontraining for Artefill is required.

Benefits Artefill offers the dual action ofimmediate wrinkle correction from col-lagen (lasting about 1–3 months) andpermanent deep-fold ablation fromPMMA (lasting for more than 5 years).51

The long-term efficacy is believed to bebecause of the stimulatory influence ofPMMA on the surrounding skin, causingfibroblast and collagen proliferationaround the material starting at 1month.33 Although approved only fornasolabial folds, PMMA has also beensuccessfully used in other deeper defects(e.g., the cheek and malar regions).Lidocaine content eliminates the neces-sity for alternative anesthesia and allevi-ates intrainjection discomfort. As com-pared to the standard of bovinecollagen, PMMA filler has been foundto be superior in efficacy with a compa-rable safety profile.51 Widely used inimplantable medical devices for morethan 50 years, PMMA has a long safetyrecord.32

Drawbacks Artefill contains bovine colla-gen; therefore, skin testing prior to injec-tions is strongly advised to reduce the incidence of hypersensitivity. Thismeans that patients cannot be treated onthe initial office visit. Furthermore,because of Artefill’s higher viscosity,more administration pressure is requiredby the clinician, and the product is moredifficult to inject than collagen and HAfillers. Although the majority of sideeffects caused by Artefill are mild andtransient (e.g., swelling, redness, hyper-sensitivity, and temporary lumpiness,which is amenable to massage), raremoderate-to-severe effects have beenreported (e.g., granuloma and inflamednodule formation, manageable withintralesional steroids or excision).51

Because of the reported lumpiness with

this product, it is currently discouragedfor lip augmentation or any superficialwrinkle correction. Having to injectthrough a larger bore needle may induce more posttreatment edema andecchymoses, which require slightlylonger downtime. The disadvantage ofimplanting permanent fillers such asArtefill is the inability to foretell thelong-term appearance of the patient;since the skin changes with age, the nat-ural look may be altered. Time will tellthe exact risk-to-benefit ratio of thisfiller.

SILICONE

Overview Silicone is composed ofdimethylsiloxane chains linked by oxy-gen with varied viscosity based on thelength of the polymer. Used in patientssince the 1940s, the liquid form of thisproduct is one of the oldest soft tissueaugmentation materials.58 The use of thisinjectable filler is fraught with contro-versy because the initial unpurified prod-uct was associated with long-term disfig-uring side effects, including migrationand granuloma formation. It was illegalto perform silicone injections in the US insome states until recently. However,because of the purification of liquid sili-cone and honing of the injection tech-nique, this soft tissue filler has returnedand is very popular in Brazil. At the turnof the 21st century, the FDA approvedtwo forms of medical-grade silicone oils: ADATO (or Sil-ol 5000, Bausch &Lomb Surgical, Inc., San Dimas, CA) with5000 centistoke (cs) viscosity and Silikon1000 (Alcon Laboratories, Inc., FortWorth, TX) with 1000 cs viscosity. Theseare both indicated for the ophthalmo-logic uses of retinal temponade anddetachment.32,33 Although neither ofthese products have been approved bythe FDA as skin injectables, they are usedoff-label. Furthermore, there are ongoingstudies in the US assessing the safety andefficacy of SilSkin (a 1000 cs, highlypurified polydimethylsiloxane, OFAS-Therapeutic Silicone Technologies, Inc.,New York, NY) for the correction ofnasolabial folds and HIV-associatedlipoatrophy. Pilot studies in patients withHIV-lipoatrophy have revealed satisfac-tory results with minimal side effects.59

Similar to PMMA and PLLA, siliconeoil biostimulates the surrounding skin toslowly generate a focal fibro-granuloma-tous reaction that leads to a permanentvolumizing. Zappi et al. analyzed themicroscopic biologic behavior of liquidsilicone and concluded that it was aneffective, durable (up to 23 years), andimmunologically compatible filler.60


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Silikon 1000 is the preferred injectablefiller over ADATO because of its lowerviscosity and therefore easier injectabil-ity. It is stored at room temperature andpackaged as clear oil. The proficiency inthe injection technique is the crucial vari-able in achieving successful soft tissueaugmentation with silicone. The favoredtechnique is a serial puncture of micro-droplets and subdermal implantation of0.01 to 0.02 mL silicone aliquots at 2- to4-mm intervals using a glass syringe witha 30-mL needle.32,52 The key is not toovercorrect. Instead, patients shouldanticipate steady changes with multipletreatment sessions, 1 to 2 months apart,in order to achieve the most natural andsafe outcome in several months.

Benefits Since it is immunologicallyinert, no prior skin testing is required.Practitioners with experience in usingSilikon have reported its value in cor-recting wrinkles and scars, augmentinglips, and panfacial contouring of deeperfolds and valleys.61 Its low cost andlongevity are obvious benefits.

Drawbacks As with any temporary filler,potential long-term consequencesshould be broached when discussingthis treatment option with patients.Most side effects associated with med-ical-grade silicone injectables are mini-mal and include anticipated temporarypain, edema, bruising, and redness.53

The pain is likely because of the absenceof anesthetic as part of the product for-mulation, so appropriate preprocedureanesthesia should be provided. However,it is important to keep in mind that rarereports of appropriately-injected, puri-fied silicone causing significant nodules,granulomas, cellulitis, and ulcerationalso exist.53 The skill of the physician iscrucial as this is a permanent filler. Theprimary author has seen myriadunhappy patients who have lumps andasymmetry after treatment by otherphysicians (Figs. 23-11 and 23-12). Inaddition, many patients who are treatedby nonphysicians are treated withimpure silicone. This results in disfigur-ing edema and long-term complications.In our clinic, we have tried to treat com-plications of silicone injections by non-physicians with injectable steroids,tacrolimus, cyclosporine, and Aldarawith minimal and short-term improve-ment. Surgical excision has remainedthe only effective long-term treatment.

POLYTETRAFLUOROETHYLENE

Overview. Approved by the FDA in the1990s for the purpose of soft tissue aug-

mentation, several forms of expandedpolytetrafluoroethylene (PTFE) are cur-rently on the market: Gore-Tex strings orstrands (Gore Advanced TechnologiesWorldwide, Newark, DE); Soft-Form andUltraSoft tubes (Tissue Technologies,Inc., San Francisco, CA); and newer dual-porous, soft, varied-shape Advanta

(Atrium Medical Corporation, Hudson,NH).62,63 PTFE is a synthetic materialused in medical devices since the 1970swith a good safety record. These arespongy products that provide significantvolume enhancement and stimulate localtissue fibrosis and integration, whichrelays permanence and stability. PTFE is

� FIGURE 23-11 Patient who had an unknown substance injected by an aesthetician in a hotel room

in Miami. Analysis of biopsy material showed silicone. No treatments have been effective long-term in this

patient.

� FIGURE 23-12 Patient who had silicone injections to the lips. She is unhappy with the large size of

her lips.


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biocompatible with rare instances ofinflammatory reactions.

The extended PTFE subdermal implantsrequire a more invasive procedure via sur-gical implantation, which translates tohigher procedural risks and the necessityfor a more specialized setting and training.Because of these complex features andgenerally lower physician satisfaction, theuse of these devices by cosmetic derma-tologists is not popular.57

Benefits PTFE fillers have been shown toimpart an enduring correction of thenasolabial folds, marionette lines, malarand mandibular deficits, and enhance-ment of the lips.56 Additionally, theseproducts do not require prior testingbecause of immunologic inertness.Although the implants are consideredpermanent, if patients are dissatisfiedwith their image alterations, the productscan be removed in bulk within 3 months.

Drawbacks The side effects of bleeding,bruising, redness, postoperative pain,scarring, palpability, and secondaryinfection occur more frequently withPTFE fillers as compared to HA fillersand the recovery time is longer.64 Theseproducts have high displacement andextrusion rates and an unnaturally stiffappearance.58 In addition, they canshrink with time leading to an asymmet-ric correction.

Fillers on the Horizon

As noninvasive cosmetic interventionshave become more prominent, the man-ufacturing market has responded bydeveloping newer products. In fact,there are so many products to consider,it has become ever more challenging forregulatory organizations, physicians,and patients to discern their differences.While some clinicians opt to jump onthe bandwagon and use novel fillingagents by interpreting newer as better,others await satisfactory clinical evi-dence before integrating these fillers intotheir practices. It is crucial to appreciatethe fact that the products once pro-claimed innovative have either stood thetest of time, with manufacturers reapingthe rewards, or they have been super-seded. This section provides an overviewof the up and coming soft tissue aug-mentation devices.

EVOLENCE

Overview Evolence (Colbar LifeScienceLtd., Herzliya, Israel) is cross-linkedporcine-derived collagen (30 mg/mLconcentration). Because of the greater

biologic similarity between pig andhuman skin versus bovine and humanskin, this filler has potentially lowerimmunogenicity than bovine collagenfillers, with no preprocedure sensitivitytesting required.65 It is currently onlyapproved in Europe and Israel as twoproducts, Evolence and EvolenceBreeze (finer version), for soft tissueaugmentation.

Evolence is injected through a 25- to27-gauge 1.25- to 1.5-inch needle intomid-depth dermal space using tunnelingand cross-hatching techniques, whileEvolence Breeze is injected in 0.1-mLaliquots via a 31-gauge needle using aserial puncture technique into the super-ficial dermis; overcorrection is to beavoided.66 Postimplantation massage isadvised to enhance molding.

Benefits Without prior allergy testingneeded, these products can be injectedon the first visit. Special cross-linkingtechnology, Glymatrix, yields a morestable collagen product that createsimmediate effects potentially lastingfor up to 1 year. Evolence products maybe used in combination with otheragents such as HA fillers. This collagenfiller is stored at room temperature. Arecent study comparing the safety andefficacy of Evolence and Restylaneshowed that Evolence performed simi-larly to Restylane.67

Drawbacks Evolence does not containlidocaine as other collagen fillers do. It ismore difficult to inject than Restylaneand Juvéderm. Needle jamming hasbeen noted on occasion, which makesinjections a bit awkward.60 Religiousbeliefs have to be considered prior toimplantation because this product con-tains porcine collagen, which may berejected on religious grounds by Jewishand Muslim patients. This product hadnot yet been approved by the FDA atthe time of publication, but approval isexpected shortly. Although postproce-dure side effects of porcine collagenfillers are comparable to HA fillers(e.g., transient edema, erythema, pain,ecchymoses), the development ofinfrequent lumps and nodules that lastseveral months has also been noted.60

These papules can be treated withmassage and intralesional corticos-teroids. Because of these side effects,injecting Evolence into thin skin areasshould be avoided.60 This filler is newand does not have the years of experi-ence associated with other collagenand HA fillers. Its use should beapproached with caution.

ISOLAGEN

Overview Although presently approvedin the UK, Isolagen (Isolagen Inc., Exton,PA) is undergoing clinical studies in theUS to obtain FDA approval. Utilizingthe patient’s skin, fibroblasts are cul-tured and stimulated to generateinjectable material for aesthetic augmen-tation. The appeal of Isolagen is that ituses a minimally invasive harvestingtechnique, employing very little tissue (a 3-mm skin punch biopsy from a non-cosmetic area), to produce an individual,immunologically inert supply of vol-ume-enhancing product.68 About 2months after harvesting, a 1 to 2 cm3

amount of product is created andinjected at about 2-week intervals inseveral sessions to provide longer-lastingresults. This product may containfibroblasts that could confer long-termbenefits not found with other fillers.

Benefits The crucial benefits of Isolagenare biocompatibility and safety. Thisproduct contains the donor’s ownfibroblasts, which may provide amelio-rative effects by increasing the produc-tion of desired cytokines and growthfactors, stimulating collagen and elastinproduction. Correction is believed, butnot proven, to last about 6 to 12 months.As other collagen fillers, it is injected atsuperficial and moderate dermal depthto treat rhytides and nasolabial folds aswell as the lips.

Drawbacks This product is particularlyexpensive because of the specific engi-neering technique of cultured autolo-gous fibroblasts and collagen. There is awaiting period of 2 months and theproduct derived from the biopsy is rela-tively sparse. However, this product canbe used in conjunction with other fillersto make up the volume difference.Special product shipping, handling andstorage, as well as a narrow time-frameof implantation (within 24 h of Isolagendelivery) are limitations. The side effectsof the product have not been clarified,but are likely similar to other fillers onthe market.

LARESSE

Overview Laresse is a novel dermal fillercomposed of two polymers in solution,carboxymethyl cellulose (CMC) andpolyethylene oxide (PEO), both ofwhich are hydrophilic. The product is aviscoelastic gel that is injected into thedermis as a space-filling substance.Although the clinical data are limited, ithas been available in the UK since mid-2006 and has become a competitor to


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cross-linked HA products. Since Laresseis not cross-linked, it is smoother toinject than HA fillers and imparts a softcontour to the dermis.

Benefits Skin testing is not requiredwith this product. The componentshave been used in numerous injectabletherapeutics and medical devices andare known to be immunologically inert.Laresse is easily injected and is reportedto produce less pain on injection thanother fillers. The product is particularlysmooth and natural feeling in the skinand it has been used in nasolabial foldsand other superficial wrinkles. Becauseof its ability to stabilize and compact inhigher concentrations without a needfor cross-linking, it is hypothesized thatLaresse will have longer durability thanHA fillers.69 However, no studies havebeen published in the US to supportthese claims.

Drawbacks Although studies haveshown that Laresse lasts 6 months insome patients, limited clinical studieshave been performed so its duration willbecome evident as it becomes availablein the marketplace. The extent of itspotential applications in facial augmen-tation is unclear as the product has beenused clinically only since 2007 and itsuse in the hands of practitioners is stillbeing evaluated. Laresse does not con-tain lidocaine and, therefore, preproce-dure anesthesia is usually topical or anerve block, similar to HA fillers. Sideeffects are analogous to the HA fillersand consist mainly of transient swelling,bruising, and redness. Other adverseevents are yet to be revealed as Laresseis being investigated by the FDA.

AQUAMID

Overview A novel permanent filler,Aquamid (Ferrosan A/S-Contura Inter-national SA, Cophenhagen, Denmark)has been approved and used in Europe,South America, and the Middle East forthe past few years.33 Aquamid is com-posed of 97.5% pyrogenic water linkedto 2.5% cross-linked polyacrylamidepolymer. When it is introduced into skintissue, acrylamide stimulates fibroticand localized foreign-body reactions.The gel is packaged in a 1-mL syringeand stored at room temperature. It isinjected through a 27-gauge needleusing a threading technique withoutovercorrection.

Benefits The material is inert, obviatingprior sensitivity testing. Aquamid is bio-compatible and nonabsorbable, which

� FIGURE 23-13 Patient with prolonged facial swelling one month after Aquamid injections.

yields an inert and durable device thatcan last indefinitely. Aquamid hasshown efficacy in lip augmentation, cor-rection of nasolabial folds, depressedmouth commissures, as well as glabellarand perioral rhytides.33

Drawbacks Lacking lidocaine content,Aquamid requires local or regionalanesthesia prior to the procedure.

Although postimplantation side effectsare similar to those of HA fillers (e.g.,temporary erythema, edema, redness),rare long-term and more severe adverseeffects are more prominent withAquamid. The primary author has seenseveral patients treated in SouthAmerica with prolonged swelling andedema (Fig. 23-13). The exact durationof Aquamid in the skin is still unclear,

TABLE 23-6

The A, B, C, D Approach to Choosing the Appropriate Filler

A—Assess the patient

a. Which areas show aging or asymmetry?

b. Which areas can be easily corrected?

c. Imagine how the patient will look if various areas are corrected.

d. Determine the best areas of injection and proceed to next step.

B—Budget

a. Determine the patient’s financial budget.

b. Determine the patient’s time budget.

c. Refine plan in your mind about which areas are most important to treat.

C—Considerations

a. Learn more about the patient.

b. What bothers the patient most?

c. Ask about prior experience with fillers.

d. Are there any religious restrictions?

e. Can the patient return for future treatments?

f. Does the patient have an event coming up?

g. Is the patient on anticoagulants?

h. Are there any concerns about outcome?

i. Are there any product promotions going on?

D—Device

a. Assess pros and cons of available fillers.

b. Match attributes of fillers to what was learned in steps A, B, and C.

c. Choose the appropriate device.

d. Discuss the plan with the patient.


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with most recent studies demonstrat-ing about 2-year durability.70 Rarehematomas, lumps, granulomas, andindurations do occur with the use ofAquamid.33 Use of this filler should bediscouraged until more safety data aregathered.

HOW TO SELECT A FILLER

There are many filler options available,so deciding on which filler to use is dif-ficult. The A, B, C, D approach can help(Table 23-6). “A” stands for assess thepatient. Determine which areas can betreated with the greatest potential forimprovement. Look at the entire faceand decide where to get the “best bangfor the buck.” For example, if thepatient has prominent nasolabial folds,there are two main options: treating thenasolabial folds, or treating the cheekor cheekbone area to add volume thatwill improve the fold by pulling theskin back. A patient with large roundcheeks would do better to have thenasolabial fold treated (Fig. 23-14),while a patient with thin cheeks andfacial volume loss would have a betterresult if the cheeks were treated (Figs.23-15 and 23-16). As a practitioner, it isimportant to form your own impres-sion first before the patient tells youtheir thoughts. In some cases you maynotice factors that the patient does noteven realize are contributing to an agedappearance (Figs. 23-17 and 23-18).These observational skills are devel-oped with experience. Table 23-7 pro-vides an overview of which fillers arebest suited for each facial area. Onceyou have an idea of what areas wouldmake the most significant impact iftreated, then move to the “B” section,which is budget. It is crucial to deter-mine how much money the patient iswilling to spend. It is often the case thatthe budget is lower than what is neces-sary, so the physician must determinewhat areas to treat to achieve the bestcosmetic effect possible within thepatient’s budget. In addition, the practi-tioner must consider the patient’s timebudget or schedule. For example, if apatient is visiting from another countryand planning to leave the followingday, a course of Sculptra injections isnot an option. Once the time and finan-cial budget have been determined, thepractitioner should talk to the patientabout other considerations. The mostimportant question is what bothersthem about their face. It is often differ-ent than what the physician sees.

A B

� FIGURE 23-14 A. Those with a normal to large buccal fat pad are best treated with injections

directly into the nasolabial folds and marionette lines. B. Immediately after treatment of nasolabial folds

and marionette lines.

� FIGURE 23-15 This patient has thin cheeks from buccal fat pad wasting; therefore, she is a good can-

didate for a filler such as Sculptra, Juvéderm Ultra, or Restylane to the cheek area below the cheekbones.

A B

� FIGURE 23-17 (A and B) Soft tissue loss around the mental area is often one of the first signs of

facial aging. It is hard to capture on film and patients do not really notice it until it is pointed out to them.

� FIGURE 23-16 This patient appears to have buccal fat pad wasting, but actually is missing a tooth on

this side, leading to the defect.A dental consult is more appropriate for this patient rather than a dermal filler.


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Patient happiness is contingent onimproving what they see as the prob-lems on their face, not what bothers thephysician. The following or similarquestions may be appropriate to framesuch a discussion, then, in the attemptto identify the most suitable filler for apatient: What have you tried before?Were you satisfied with the results?Why or why not? What concerns doyou have? Are you a frequent bruiser?Are you worried that your lips will looktoo big? Do you hate it when your lip-stick bleeds up into the lines on the toplip? Do you have any religious restric-tions? Do you have any events comingup? What amount of downtime canyou tolerate? These are all criticalissues in determining the most appro-priate filler. Once all this informationhas been gathered, the physician mustchoose a filling device that meets all thecriteria. It is a relatively easy choiceafter the preceding questions have beenanswered. In addition, the physicianshould have many filler choices onhand to give the patient the best result.

Injection Technique

Injection technique varies from filler tofiller. Most physicians use either ananterograde, retrograde, or serial punc-ture technique. Most collagen and HAfillers are injected at a 45-degree angle(Fig. 23-19). It is important to be individ-ually trained on the injection techniquesof each filler. Fillers can be used in com-bination with botulinum toxins andother cosmetic procedures (Fig. 23-20).Although this chapter focused on facialuse, fillers can also be injected in otherareas of the body such as the hands (Fig. 23-21). Many injection techniquescan be used. However, it is difficult toteach various techniques without videoand live demonstrations. In the future,instructional videos will be available atwww.derm.net and training courses willbe offered at the University of Miami. Inaddition, the American Academy ofDermatology and the American Societyof Dermatologic Surgeons offer trainingcourses for dermatologists.

SUMMARY

Filling agents for soft issue augmenta-tion procedures are now widely avail-able, based on the long-standing suc-cessful track records of the earliestproducts. Most agents in the soft tissueaugmentation armamentarium can besafely used alone or in combination. The

TABLE 23-7

Fillers by Region (Listed from the Top of the Face Down)

Forehead lines Nasolabial folds

CosmoDerm I CosmoPlast

Restylane Fine Lines, Juvéderm18, or Prevelle Silk Evolence

Zyderm I Juvéderm Ultra

Raising lateral brows (almost any will work) Juvéderm Ultra Plus

CosmoPlast Perlane

Evolence Prevelle Silk

Juvéderm Ultra Prevelle Dura

Juvéderm Ultra Plus Radiesse

Perlane Restylane

Prevelle Silk Sculptra

Prevelle Dura Zyplast

Radiesse Vermilion border of the lip

Restylane CosmoPlast

Zyplast Evolence

Glabella (use with caution) Juvéderm Ultra

CosmoDerm I Prevelle Silk

Zyderm I Restylane

Tear trough (soft fillers preferred) Zyplast

Hylaform Body of the lip

Juvéderm 18 Hylaform

Prevelle Silk Prevelle Silk

Restylane Touch Restylane Lip

Crow’s feet Marionnette lines

CosmoDerm I CosmoPlast

Juvéderm 18 Evolence

Prevelle Silk Juvéderm Ultra

Restylane Touch Juvéderm Ultra Plus

Zyderm I Perlane

Cheek bones Prevelle Silk

Juvéderm Ultra Prevelle Dura

Juvéderm Ultra Plus Radiesse

Perlane Restylane

Prevelle Dura Zyplast

Prevelle Silk Pre-jowl sulcus

Radiesse CosmoPlast

Restylane Evolence

Sculptra Juvéderm Ultra

Juvéderm Ultra Plus

Perlane

Prevelle Silk

Prevelle Dura

Radiesse

Restylane

Sculptra

Zyplast

A B

� FIGURE 23-18 (A and B) Once the soft tissue around the mental bone has been filled, the face looks

more youthful. An HA filler was used in this patient.


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most frequently used agents are thosethat contain HA. Given the widespreadpopularity of soft tissue augmentationand the ever-present need to developsafer fillers that last longer than the cur-rent products, new fillers frequentlyenter the market. Soon to be made avail-able in the US is an HA filler that con-tains lidocaine as well as more durableand safer synthetic agents. In short, thedemand for soft tissue augmentationprocedures has steadily increased sincetheir inception and research is ongoingto develop products that address theshortcomings of the earlier productswhile incorporating and expanding ontheir advantages. Moreover, the “cou-pling” of fillers with other cosmeticinterventions (e.g., Botox injections)enhances their longevity and efficacy,and creates an overall realistically aes-thetic appearance.71 To keep astridewith the rapidly changing cosmetic der-matology arena, it behooves the aes-thetic practitioner to be aware of thecurrent availability, application, andfuture potential of dermal fillers.

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� FIGURE 23-21 The hand on the left is before Radiesse treatment. The image with the dark nail is

after Radiesse. (Photos courtesy of Lisa Grunebaum, MD.)

� FIGURE 23-19 Most collagen and HA fillers are injected using a 45-degree angle. Injecting over the

thumb can help ensure this angle.

A B

� FIGURE 23-20 (A and B) A patient treated with Radiesse to several facial areas and with Botox to

the platysma. (Photos courtesy of Lisa Grunebaum, MD.)


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