CME
`
`Injectable Soft-Tissue Fillers: Clinical Overview
`
`Barry L. Eppley, M.D.,
`D.M.D.
`Babak Dadvand, M.D.
`Indianapolis, Ind.
`
`Learning Objectives: After studying this article, the participant should be able
`to: 1. Know the composition and biology of injectable fillers. 2. Understand the
`advantages and disadvantages of each injectable filler. 3. Understand the U.S.
`Food and Drug Administration regulatory status of each type of injectable filler,
`including their indications.
`Background: The use of injectable filling agents for soft-tissue facial defects has
`a long history of successful use based on xenogeneic collagen materials. New
`materials of differing compositions for injection treatments either are now
`available or will soon be available for clinical use.
`Methods: A review of the medical literature was performed to provide chemical
`compositions, methods of preparation, biological behavior, and clinical out-
`comes for every known injectable filler material that is either currently used or
`being evaluated in clinical trials.
`Results: Hyaluronic acid– based materials have now replaced animal or human-
`derived collagen as the standard injection materials. Synthetic alternatives offer
`the potential of longer lasting results, but the long-term outcome with their use
`in large numbers of patients is not yet known.
`Conclusions: As there is no single injectable filler that has all of the desired
`characteristics, understanding the advantages and disadvantages of one filler
`over another is extremely helpful in guiding the patient to an informed decision.
`Although all of the reviewed injectable fillers are safe, the concepts of their
`long-term volume persistence and how they compare with each other remain
`(Plast. Recon-
`largely anecdotal, with few prospective controlled clinical trials.
`str. Surg. 118: 98e, 2006.)
`
`The placement of high-flow, low-viscosity ma-
`
`terials for soft-tissue enhancement has a
`long history of use in aesthetic facial alter-
`ation. Although bovine collagen injections have
`long been dominant, the past 5 years have seen
`the emergence of numerous new fillers of differ-
`ing compositions. When combined with the in-
`creasing popularity of injectable Botox and
`other office-based procedures, the role of inject-
`able soft-tissue augmentation continues to ex-
`pand. With the advent of various new injectable
`fillers, it is important to assess their compositions
`and characteristics to make the optimal selection
`to achieve the patient’s goals.
`Ideally, an injectable implant should have a
`lack of any significant inflammatory response
`(be highly biocompatible), be easily introduced
`into the recipient site by injection (have good
`
`From the Division of Plastic Surgery, Indiana University
`School of Medicine.
`Received for publication September 26, 2005; accepted No-
`vember 1, 2005.
`Copyright ©2006 by the American Society of Plastic Surgeons
`DOI: 10.1097/01.prs.0000232436.91409.30
`
`flow behavior through a small-gauge needle),
`and produce an acceptably long period of vol-
`ume retention (i.e., months to years). Each cur-
`rent U.S. Food and Drug Administration–
`approved filler and those under U.S. Food and
`Drug Administration application/study exhibit
`differences in these three basic characteristics. It
`is incumbent on the physician to understand the
`physical and biological properties of the in-
`tended filler before its clinical use.
`
`XENOGENEIC MATERIALS
`Zyderm/Zyplast
`The first widely used injectable filler, whose
`clinical use continues to decline, remains the stan-
`dard to which all other injectable fillers continue
`to be compared.
`Its animal derivation and short longevity have
`led to its decrease in popularity.1 In U.S. Food and
`Drug Administration clinical trials, however, its
`long history of clinical use and data make it the
`frequently used control.
`Composition
`Zyderm I and II and Zyplast (Inamed Aesthet-
`ics, Santa Barbara, Calif.) are derivatives of bovine
`
`98e
`
`www.PRSJournal.com
`
`Exhibit 1018
`Prollenium v. Allergan
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`Volume 118, Number 4 • Injectable Soft-Tissue Fillers
`
`collagen. Zyderm I was U.S. Food and Drug Ad-
`ministration approved in 1981, whereas Zyderm II
`gained U.S. Food and Drug Administration ap-
`proval in 1983. Zyplast was U.S. Food and Drug
`Administration approved in 1985. Zyderm I is 96
`percent type I collagen, with the remainder being
`type III collagen. It is 3.5 percent bovine dermal
`collagen by weight, suspended in phosphate-buff-
`ered physiologic saline.2 Zyderm II is 6.5 percent
`bovine dermal collagen by weight. Zyplast is 3.5
`percent bovine dermal collagen cross-linked by
`glutaraldehyde, which makes it more resistant to
`biodegradation. It is more viscous than Zyderm
`but less immunogenic.
`Clinical Characteristics
`Zyderm and Zyplast are prepackaged in 1- or
`2-ml syringes. They are opaque and are typically
`injected with a 30-gauge needle. Zyderm I is in-
`jected in the papillary dermis and is U.S. Food and
`Drug Administration approved for fine lines and
`shallow acne scars. Zyderm II, which also comes in
`0.5-ml syringes, is injected in the papillary dermis
`and is U.S. Food and Drug Administration ap-
`proved for moderate lines and deeper acne scars.
`Zyplast is injected into the mid to deep dermis and
`the subcutaneous region and is best used for deep
`folds and lines. Overcorrection is necessary with
`Zyderm because it is diluted with phosphate-buff-
`ered physiologic saline, which is reabsorbed. Re-
`sults typically last 2 to 3 months.
`Advantages
`With a 25-year history of clinical use, Zyderm
`and Zyplast are known to be safe, with very few
`local complications. Their clinical effectiveness
`and versatility are well established. Also, they come
`diluted with 0.3% lidocaine, which may reduce the
`pain on injection.
`Disadvantages
`Because Zyderm and Zyplast are bovine deriv-
`atives, they require skin testing and thus should
`not be used on the day of consultation, unless it is
`an established patient. Two skin tests are admin-
`istered 2 weeks apart, with the second test being 4
`weeks before the procedure. Of note, 3 percent of
`patients develop a sensitivity reaction even with a
`normal skin test.3 Local adverse effects include
`erythema, induration, pruritus, and skin discolor-
`ation. Furthermore, a systemic hypersensitivity re-
`action can occur 48 to 72 hours after injection.
`This is manifested by fever, malaise, and urticaria,
`which are treated with short-term oral steroids.
`Granulomas have also been reported with Zy-
`derm/Zyplast. Reactivation of herpes is possible
`with lip injections; thus, patients with a positive
`history need antiviral prophylaxis. Other compli-
`
`cations include necrosis of the overlying skin and
`unilateral vision loss caused by retinal artery oc-
`clusion. They are also contraindicated in patients
`with lidocaine allergies. The material starts to be
`degraded immediately after injection, with clinical
`effects observable for a few months. The reduction
`in injection volume is essentially linear over time.
`
`ALLOGENEIC MATERIALS (COLLAGEN-
`BASED HOMOLOGUES)
`
`Cosmoderm/Cosmoplast
`In an eventual response to the concerns and
`problems with bovine-derived collagen, the intro-
`duction of human-based collagen homologues has
`occurred more recently. Similarly named, they of-
`fer the promise of decreased immunogenicity and
`longer lasting results.
`Composition
`CosmoDerm I and II and CosmoPlast (In-
`amed) are injectable implants derived from highly
`purified human collagen. Both CosmoDerm and
`CosmoPlast were U.S. Food and Drug Adminis-
`tration approved for use in facial aesthetic surgery
`in March of 2003 and are the only U.S. Food and
`Drug Administration–approved dermal
`fillers
`made from human collagen.
`The collagen is cultured from a single cell line
`of human dermal fibroblasts that has been used
`for over 10 years to manufacture human-based
`tissues; these cells produce natural collagen that is
`then isolated and purified for injection. The cell
`line undergoes extensive testing for viruses, ret-
`roviruses, and tumorigenicity. CosmoDerm II con-
`tains approximately twice the concentration of
`collagen as CosmoDerm I.
`Clinical Characteristics
`CosmoDerm and CosmoPlast are prepack-
`aged in 1-ml syringes. They are opaque and should
`be refrigerated but must not be frozen. They are
`typically injected with 30-gauge needles. Cosmo-
`Derm is U.S. Food and Drug Administration ap-
`proved for shallow wrinkles or acne scars and is
`injected into the superficial papillary dermis. Cos-
`moPlast is injected into the mid to deep dermis for
`the correction of more pronounced wrinkles or
`scars. However, the safety and efficacy of Cosmo-
`Derm use in lip augmentation has not been es-
`tablished. Its flow characteristics are similar to Zy-
`derm and,
`like Zyderm, overcorrection is
`necessary with CosmoDerm because it is diluted
`with saline, which is reabsorbed. The use of Cos-
`moDerm I should be limited to 30 cc per patient
`per year. CosmoDerm II and CosmoPlast should
`
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`Plastic and Reconstructive Surgery • September 15, 2006
`
`be limited to 15 cc per patient per year. Results
`typically last 3 to 6 months.
`Advantages
`The Inamed Human Collagen Immunogenic-
`ity Clinical Study demonstrated that the 95 per-
`cent upper confidence interval for experiencing a
`hypersensitivity reaction against CosmoDerm and
`CosmoPlast is less than 1.3 percent. This is less
`than the incidence of immunologically related ad-
`verse events reported with Zyderm/Zyplast in
`treated patients who initially had a negative skin
`test. Unlike bovine collagen implants, these der-
`mal fillers do not require a pretreatment skin test
`before treatment. This has been established
`through their preapproval U.S. Food and Drug
`Administration application study. Thus, patients
`may undergo treatment at the time of their initial
`consultation. They come diluted in 0.3% lido-
`caine, which may have some benefit in reducing
`pain on injection.
`Disadvantages
`The use of these products is contraindicated in
`patients with a known allergy to lidocaine. In a
`study to evaluate sensitization to CosmoDerm and
`CosmoPlast, 428 patients were injected with Cos-
`moDerm I into the forearm and followed for 2
`months; the more common adverse side effects
`included the following: cold-like symptoms, 4.1
`percent; flu-like symptoms, 2.0 percent; and uri-
`nary tract infection, 1.0 percent.3
`The longevity of this material appears to be
`similar to bovine collagen. No prospective study
`has been reported that conclusively demonstrates
`superior volume persistence.
`
`Cymetra
`AlloDerm has many indications in reconstruc-
`tive and aesthetic surgery. The conversion of these
`materials into an injectable form is a logical ex-
`tension of their subcutaneous use.4
`Composition
`Cymetra (LifeCell Corp., Palo Alto, Calif.) is
`the injectable form of micronized AlloDerm, a
`decellularized processed dermal allograft5 that
`was U.S. Food and Drug Administration approved
`in 2000. The material is originally obtained from
`tissue banks compliant with the guidelines of the
`American Association of Tissue Banks and the U.S.
`Food and Drug Administration. First, the epider-
`mis is completely removed, followed by the re-
`moval of dermal cells and stabilization of the der-
`mal matrix
`through
`the
`inhibition
`of
`metalloproteinases. The material is then cryofrac-
`tured, breaking down the acellular dermal matrix
`
`100e
`
`into micronized particles that are packaged into
`syringes. At the time of clinical use, it is necessary
`to hydrate the powder.
`Clinical Characteristics
`Cymetra is presented as a 330-mg dry partic-
`ulate in a 5-cc syringe. It is reconstituted with 1 cc
`of 1% lidocaine and is injected through a 26-gauge
`needle into the subcutaneous space. Its more vis-
`cous consistency after hydration requires a large-
`caliber needle for introduction. Cymetra is indi-
`cated for use in nasolabial folds, lips, and acne and
`depressed scars. Results typically last 3 to 9
`months.
`Advantages
`No immune response is elicited because cells
`exhibiting major histocompatability complexes I
`and II have been removed. Patients can be treated
`at initial consultation because no skin testing is
`needed.
`Disadvantages
`Because of Cymetra’s large particle size (⬎100
`␮m), injections are less smooth than most other
`implants and can be more painful because of the
`size of the needle. Patients should also be made
`aware of postinjection edema. Furthermore, its
`use should be avoided in periocular line correc-
`tion and glabellar contouring to avoid the risk of
`intravascular injection and migration. Cymetra is
`supplied in an antibiotic-supplemented medium;
`thus, patients with sensitivities to the antibiotic
`should not receive this material. The size of the
`hydrated particles and the needle do not allow
`intradermal injection, limiting its use to the sub-
`cutaneous space.
`As this is a tissue bank material, formal U.S.
`Food and Drug Administration clinical trials and
`comparisons to other materials have not been con-
`ducted. Reported clinical outcomes are largely an-
`ecdotal. There are no clinical trials that demon-
`strate its longevity to be superior to other collagen-
`based implants.
`
`Fascian
`Tissue bank collagen material, other than
`from the dermis, is possible from numerous other
`sources. Fascia, with a very tight fibrillar collagen
`weave, offers the potential for a more dense form
`of collagen implant. Fascian was introduced in
`April of 1999.
`Composition
`Fascian (Fascia Biosystems, Beverly Hills,
`Calif.) is preserved, particulate fascia lata derived
`from human cadavers obtained from an American
`Association of Tissue Banks Guideline– compliant
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`Volume 118, Number 4 • Injectable Soft-Tissue Fillers
`
`tissue bank.6 Preserved fascia lata has been used
`for a long time as a sheet graft material but has
`only recently become available in injectable form.7
`Clinical Characteristics
`Fascian is freeze-dried, irradiated, and then
`processed into particle sizes of 0.25, 0.5, 1.0, or 2
`mm, of which 80 mg of volume is inserted into
`each syringe. The material may be stored at room
`temperature for years. Clinically, Fascian is indi-
`cated for deep wrinkles, scars, fat atrophy, and
`prominent nasolabial folds.8 At the time of injec-
`tion, the fascia particles are initially hydrated in 3
`to 5 cc of 0.3% lidocaine solution. This produces
`a thick paste that can be extruded through a large-
`bore needle. The injected area is preundermined
`with a 20-gauge needle and the material injected
`into the preformed tunnel with a 16- to 25-gauge
`needle, depending on the size of the particles
`used. Fascia Biosystems reports the duration of
`results to be 6 to 8 months, but other anecdotal
`reports show Fascian’s duration to be 3 to 6
`months.
`Advantages
`In a study by Burres, 81 patients receiving 109
`injections of Fascian over a period of 6 to 9 months
`experienced no infections, allergic reactions, or
`acute rejections; there have been no reports of
`disease transmission.9 No skin testing is necessary,
`so the patient may the receive injection at the time
`of initial consultation.
`Disadvantages
`Trace amounts of polymyxin B sulfate, baci-
`tracin, or gentamicin are present in Fascian im-
`plants; patients with known allergies to these an-
`tibiotics should avoid Fascian accordingly. The
`large size of the needle needed for introduction
`results in the potential for increased bruising. In
`addition, local anesthesia infiltration into the re-
`cipient or nerve blocks may be needed for patient
`comfort during the procedure. Documentation of
`the longevity of the material has not been re-
`ported in any prospective or controlled patient
`series.
`
`SYNTHETIC MATERIALS
`
`Restylane
`The long-term use of this synthetically derived
`material in Europe and the very favorable clinical
`results represented a fundamental change in in-
`jection technology.10 The transition from a pro-
`tein-based material to one of an extracellular ma-
`trix composition is a paradigm shift from two
`decades of previous clinical experience.
`
`Composition
`Restylane (Medicis, Scottsdale, Ariz.) is pro-
`duced today by fermentation in cultures of equine
`streptococci. The fermented material is then sta-
`bilized by means of epoxidic cross-links of the
`glycosaminoglycan chains. As a result of this pro-
`cessing method, the hyaluronic acid, or hyaluro-
`nan, does not cause immunologic sensitization
`and there is virtually no risk of allergic reactions.11
`Hyaluronan is a polysaccharide that is an essential
`component of the extracellular matrices in which
`most tissues differentiate. In certain tissues, such
`as the vitreous cavity of the eye and synovial joint
`fluid, it is the major constituent. Unlike collagen,
`it is identical across all animal species and mi-
`crobes. The largest amount of hyaluronan resides
`in skin, where it is present in both dermis and
`epidermis. Hyaluronan’s high capacity for hold-
`ing water and high viscoelasticity give it some
`unique properties that are useful in various med-
`ical and pharmaceutical applications.12 Because it
`retains moisture, hyaluronan is used in some cos-
`metics to keep skin young and fresh-looking. As we
`age, the water-holding capacity of our skin de-
`creases as hyaluronan depolymerizes. Therefore,
`the retention or insertion of hyaluronan into the
`skin is theoretically helpful in wrinkle reduction.
`Hyaluronic acid can be rather rapidly de-
`graded and is ultimately metabolized in the liver.
`Modern processing methods have produced more
`stable forms of hyaluronic acid that have much
`longer in vivo retention times. As degradation oc-
`curs over time, water is attracted to the material at
`the site of implantation. As the hyaluronic acid
`concentration decreases, more water bonds to it,
`thus helping with cosmetic persistence. This fea-
`ture is what probably accounts for its longer vol-
`ume retention effects than bovine collagen (iso-
`volemic degradation).
`Clinical Characteristics
`A variety of differing grades of transparent gels
`are available, based on the same type of gel from
`highly concentrated (20 mg/ml) stabilized hyal-
`uronic acid, which varies in particle size and sub-
`sequent indication. Restylane has a particulate size
`of 100,000 gel particles per milliliter,
`flows
`through a 27-gauge needle, and is U.S. Food and
`Drug Administration approved for mid-dermal ap-
`plications such as deeper wrinkle reduction and
`for lip augmentation, nasolabial folds, and glabel-
`lar creases.13 Restylane has even been successfully
`used in the treatment of tear trough deformities.14
`Restylane Fine Lines has the highest concentra-
`tion at 200,000 gel particles per milliliter, can be
`injected through a 30-gauge needle, and is indi-
`
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`Plastic and Reconstructive Surgery • September 15, 2006
`
`cated for thin superficial wrinkles. The lowest con-
`centration gel is Perlane at 8000 gel particles per
`milliliter, which is injected through a 27-gauge
`needle and is intended for shaping facial contours
`and correcting deep folds,
`and for
`lip
`augmentation.15 Restylane was U.S. Food and
`Drug Administration approved in December of
`2003, Restylane FN and Perlane await eventual
`U.S. Food and Drug Administration clearance.
`Advantages
`Its universal hyaluronic acid composition
`makes the need for preinjection skin testing un-
`necessary, as the risk for hypersensitivity reactions
`is minimal.16 It is easily injected and flows nicely
`through small-gauge needles. Although not per-
`manent, its persistence is reported to exceed that
`of bovine collagen, with estimates of between 6
`and 12 months after injection.17
`Disadvantages
`In a study comparing Restylane with Zyplast,
`there was an overall higher incidence of severe
`bruising (3.6 percent versus 0.7 percent), severe
`swelling (3.6 percent versus 1.4 percent), and se-
`vere pain (3.6 percent versus 1.4 percent) with
`Restylane. The increased pain is partly because
`Restylane does not come mixed with local anes-
`thetic. Common side effects include injection-site
`inflammation, with an incidence of 0.02 percent,
`and local hypersensitivity reactions (i.e., swelling,
`erythema, and induration), with an incidence of
`0.02 percent, lasting a mean of 15 days.18 Its cost
`is more than that of collagen-based materials.
`
`Captique
`Composition
`Captique (Inamed) is a nonanimal, stabilized,
`hyaluronic acid– based material derived from the
`same nonanimal source as Restylane. It was U.S.
`Food and Drug Administration approved in De-
`cember of 2004. As a competitive analogue to Re-
`stylane, it offers what appears to be a very similar
`hyaluronic acid– composed injection material
`from a different manufacturing source. Marketing
`information states that it is a “softer” hyaluronic
`acid than Restylane, although that exact meaning
`of that is not clear. One can speculate that this
`means it has less gel particles per milliliter.
`Clinical Characteristics
`Similar to Restylane, it is a clear, colorless gel
`that is indicated for fine lines and wrinkles. It
`comes in 1-cc syringes and is typically injected with
`a 30-gauge needle, although flow through a 30-
`gauge needle is also possible. The longevity of the
`injection is reported to be 3 to 6 months.
`
`102e
`
`Advantages
`No skin test is necessary, as with other hyal-
`uronic acid materials.
`Disadvantages
`What, if any, differences exist between it and
`Restylane are not known. It is assumed that its
`clinical performance, in terms of incidence of
`postinjection reactions and longevity of volume
`persistence, is similar. No controlled clinical trial
`comparing it to Restylane and any other injectable
`has been reported, although anecdotally, Cap-
`tique is felt to last significantly shorter than Re-
`stylane.
`
`Hylaform
`Composition
`Hylaform (Inamed) is a sterile, colorless gel
`implant that consists of cross-linked molecules of
`hyaluronic acid derived from an avian source.19
`Extracts of the rooster comb have been widely
`used in orthopedic surgery as a viscoelastic injec-
`tion into symptomatic joints since 1996. This is a
`more dense form of avian-derived hyaluronic acid
`because of its intraarticular use. As a facial soft-
`tissue injection, its density is decreased. It gained
`U.S. Food and Drug Administration approval in
`April of 2004. Hylaform Plus, which is also a clear,
`colorless gel, consists of larger mean hyaluronic
`acid particles than Hylaform. Hylaform Plus was
`U.S. Food and Drug Administration approved in
`October of 2004.
`Clinical Characteristics
`Hylaform is indicated for moderate to severe
`facial wrinkles and folds, but not
`for
`lip
`augmentation.12 Hylaform comes in prepackaged
`sterile syringes that should be stored at room tem-
`perature. It is injected into the mid to deep dermis
`using a 30-gauge needle. Hylaform Plus is U.S.
`Food and Drug Administration approved for in-
`jection into the mid to deep dermis for correction
`of moderate to severe facial wrinkles and folds.
`Subdermal injection will lead to inferior results,
`and if it is injected too superficially, it may cause
`skin discoloration. Linear threading, serial punc-
`ture injections, or a combination of the two have
`been demonstrated to be effective. However, over-
`correction should be avoided. Patients should be
`limited to 20 cc of Hylaform gel per 60-kg body
`mass per year. The safety of injecting greater
`amounts has not been established. Results typi-
`cally last 3 to 4 months.
`Advantages
`No skin test is necessary; thus, it can be used
`at the initial consultation.
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`Volume 118, Number 4 • Injectable Soft-Tissue Fillers
`
`Disadvantages
`Results may not be as long as other hyaluronic
`acid products, lasting approximately 3 months. It
`cannot be used in patients with hypersensitivity to
`avian proteins, most notably eggs. Given its avian
`derivation, this would suggest that the risk of hy-
`persensitivity reactions is greater than hyaluronic
`acid derived from nonanimal sources.
`
`ALLOPLASTIC IMPLANTS
`In efforts to improve the longevity of soft-tissue
`fillers, the merging of resorbable and nonresorb-
`able components into an injectable compound is
`a logical one. The issues of flow behavior of the
`nonresorbable synthetic component is the key to
`the formulation of such an injectable concept.
`
`Radiesse
`Composition
`This injectable implant, formerly known as Ra-
`diance, is manufactured by Bioform, Franksville,
`Wis.) and is a proprietary mixture of an aqueous-
`based gel carrier blended with spherical particles
`of synthetic calcium hydroxyapatite.13 Although
`traditionally thought of only as a bone replace-
`ment, the high density and low solubility of the
`bioceramic particles of calcium hydroxyapatite
`provide for long-term durability of the implant
`and excellent biocompatibility. The spherical
`shape and small uniform size of the calcium hy-
`droxyapatite particles allows for consistent me-
`chanical action during injection and stability in
`situ after injection. As the size of particles that can
`be phagocytized and migrate through the lym-
`phatic system is approximately 15 ␮m, there is very
`limited potential for migration. Should any cal-
`cium hydroxyapatite become phagocytized, the
`particles are simply degraded into calcium and
`phosphate ions. The gel carrier is composed of
`cellulose, glycerin, and high-purity water. These
`gel components are widely used in pharmaceuti-
`cals and injectable drug products. The gel carrier
`has the unique characteristic of being highly vis-
`cous and elastic while allowing for shear thinning.
`The high viscosity and elastic properties keep the
`calcium hydroxyapatite particles in suspension
`during storage and injection. The shear thinning
`property of
`the gel carrier allows
`injection
`through reasonably small-gauge needles.
`Clinical Characteristics
`Radiesse is composed of calcium hydroxyapa-
`tite particles in the 25- to 45-␮m size range and can
`be injected with a 26-gauge or larger diameter
`thin-wall needle. The duration of its clinical effects
`
`has been reported to be approximately 2 years.
`Radiesse is indicated for correction of nasolabial
`folds, vertical lip lines, acne scars, marionette
`lines, and restoring volume in and around the
`cheeks.
`Advantages
`With the synthetic formulation of the calcium
`hydroxyapatite particles and the use of compatible
`gel ingredients, there is no need for skin testing
`before treatment. Because the calcium hydroxy-
`apatite is a natural mineral in the body, there is no
`concern of antigenic or inflammatory reactions.
`Despite the fact that the particles are ceramic (and
`not osteoinductive), the implants do not calcify
`and remain soft and flexible. Because particle sol-
`ubility is very low, volume retention may theoret-
`ically persist for years.
`Disadvantages
`There are no published reports on the use or
`the long-term effects of this calcium hydroxyapa-
`tite injectable implant in aesthetic facial treat-
`ments. It is not currently U.S. Food and Drug
`Administration approved for this application, al-
`though clinical trials are ongoing. Radiesse has
`received regulatory clearance for the soft-tissue
`treatments of vocal cord insufficiency and for ra-
`diographic tissue marking. It is also currently un-
`der clinical trials in urology for the treatment of
`vesicoureteral
`reflux
`and
`stress
`urinary
`incontinence.20 Studies have also reported using
`Radiesse for the treatment of human immunode-
`ficiency virus–associated facial
`lipoatrophy, al-
`though this is yet to be an approved indication.21
`The size of the needle used and the viscosity of the
`material does not permit for intradermal injec-
`tions. Although the nonresorbable calcium hy-
`droxyapatite component may persist indefinitely,
`the majority of the injectate is the carrier gel (70
`percent). As the carrier is rapidly absorbed, much
`of the perceived augmentative effect may be gone
`quite quickly. Although animal (rat) studies show
`persistence for years, this potential benefit has not
`been observed or confirmed in human facial im-
`plantation sites. The potential for “clumping,” an
`aggregate of scar contracture around a collection
`of the particles, with formation of a foreign body
`reaction has been seen anecdotally. This may be
`particularly likely to occur when injected into the
`lips. This likely results from irregular injection
`techniques (nonsmooth) or superficial locations,
`or occurs in very mobile sites (e.g., lips). Further-
`more, Radiesse is radiopaque and may interfere
`with facial radiographs.
`
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`Plastic and Reconstructive Surgery • September 15, 2006
`
`Sculptra
`Composition
`Sculptra (Dermik Laboratories, Berwyn, Pa.)
`is composed of microparticles of poly-L-lactic acid,
`a biodegradable synthetic polymer from the alpha-
`hydroxyacid family.22 It is manufactured from es-
`sentially a resorbable “plastic” material
`from
`which many of the sutures that are used daily (e.g.,
`Vicryl, Dexon) are composed. These are moder-
`ately hydrophilic materials from which postim-
`plantation hydrolysis initiates the slow resorption
`process. Clearance is eventually achieved by mac-
`rophage digestion.
`Clinical Characteristics
`It comes in the form of a sterile, freeze-dried
`preparation that is reconstituted with 5 cc of sterile
`water. Lidocaine is recommended by the manu-
`facturer in reconstitution. Sculptra is injected in
`the deep dermis or subcutaneous space using a
`26-gauge needle. It must be used within 72 hours
`of reconstitution.
`Sculptra (also known as New-Fill in Europe)
`has been used for many years in resorbable su-
`tures, bone screws, and facial implants. Whereas it
`is approved in Europe for the treatment of wrin-
`kles, it is U.S. Food and Drug Administration ap-
`proved (August of 2004) only for the treatment of
`human immunodeficiency virus–associated facial
`lipoatrophy.23
`Advantages
`No skin test is necessary. The effects typically
`last 1 to 2 years, with some European reports citing
`up to 5 years between injections.
`Disadvantages
`Sculptra must be reconstituted 2 hours before
`use. The size of the needle and the flow behavior
`of the injectate do not allow for intradermal im-
`plantation.
`It has only been definitely studied in the
`United States for human immunodeficiency virus
`patients. It has been U.S. Food and Drug Admin-
`istration approved on a compassionate-use basis.
`Whether the same results, particularly the com-
`plication rates, would be greater in a nonimmu-
`nocompromised patient population can only be
`speculated. The potential for long-term tissue re-
`actions, such as granulomas, is likely much higher
`than for most other injectable fillers.
`
`Artecoll
`Composition
`Artecoll (Artes Medical, San Diego, Calif.) is a
`permanent injectable filler composed of polym-
`ethylmethacrylate microspheres
`that are sus-
`
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`
`pended in a transport solution of 3.5% bovine
`collagen and 0.3% lidocaine. The polymethyl-
`methacrylate microspheres are 20 to 40 ␮m in
`diameter and are packaged in sterile, preloaded
`syringes.
`Clinical Characteristics
`Artecoll is injected with a 27-gauge needle into
`the subdermal space and subcutaneous tissue and
`is evenly massaged with thumb and index finger to
`eliminate any clumping of material. The collagen
`dissipates within 1 to 3 months, whereas the
`smooth microspheres become
`encapsulated
`thereafter.
`In a study by Lemperle et al. of 118 patients
`treated with Artecoll, 90 percent were satisfied
`with results of their treatment, and 64 percent
`reported lasting results at a 2-year follow-up. Sub-
`sequently, Cohen and Holmes compared Artecoll
`with Zyderm II/Zyplast in a U.S. Food and Drug
`Administration clinical trial that commenced in
`2001 and was completed in 2004.24 This was a
`prospective, randomized, multicenter trial using
`251 subjects. Subjects were randomized to receive
`Artecoll or Zyderm II/Zyplast to treat nasolabial
`folds and glabellar, upper lip, and corner-of-the-
`mouth wrinkles. Follow-up at 1, 3, 6, and 12
`months was completed, and evaluations were per-
`formed by the investigators and subjects using lin-
`ear analogue scales. Furthermore, three masked
`observers using a Facial Fold Assessment Scale
`rated the results on the subject’s photographs.
`The results of the study showed that the success
`and satisfaction ratings for the Artecoll group were
`superior to those of the control group.
`Advantages
`Polymethylmethacrylate and collagen are two
`implant materials that have a long clinical history
`of successful human implantation. It is not sur-
`prising, therefore, that they were well tolerated in
`a prospective human clinical trial. When properly
`placed, Artecoll demonstrates a persistence of
`augmentation that is unrivaled by other injectable
`materials.
`Disadvantages
`Artecoll is still not U.S. Food and Drug Ad-
`ministration approved for aesthetic use in the
`United States, although the clinical trial was
`completed in 2004. The study has recently been
`updated, showing stability in results after 4 years
`of follow-up. The product, which will be mar-
`keted as ArteFill in the United States, will be
`produced using collagen from a closed herd of
`U.S. cows, according to final U.S. Food and Drug
`Administration guidelines. The anticipated da