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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 outcomes 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 humanderived 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 largely anecdotal, with few prospective controlled clinical trials. (Plast. Reconstr. Surg. 118: 98e, 2006.) T he placement of high-flow, low-viscosity materials for soft-tissue enhancement has a long history of use in aesthetic facial alteration. Although bovine collagen injections have long been dominant, the past 5 years have seen the emergence of numerous new fillers of differing compositions. When combined with the increasing popularity of injectable Botox and other office-based procedures, the role of injectable soft-tissue augmentation continues to expand. 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 November 1, 2005. Copyright ©2006 by the American Society of Plastic Surgeons DOI: 10.1097/01.prs.0000232436.91409.30 98e flow behavior through a small-gauge needle), and produce an acceptably long period of volume retention (i.e., months to years). Each current 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 intended filler before its clinical use. XENOGENEIC MATERIALS Zyderm/Zyplast The first widely used injectable filler, whose clinical use continues to decline, remains the standard 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 Aesthetics, Santa Barbara, Calif.) are derivatives of bovine www.PRSJournal.com Volume 118, Number 4 • Injectable Soft-Tissue Fillers collagen. Zyderm I was U.S. Food and Drug Administration approved in 1981, whereas Zyderm II gained U.S. Food and Drug Administration approval 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-buffered 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 injected 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 approved 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-buffered physiologic saline, which is reabsorbed. Results 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 derivatives, 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 administered 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 discoloration. Furthermore, a systemic hypersensitivity reaction 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 Zyderm/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 occlusion. 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 (COLLAGENBASED HOMOLOGUES) Cosmoderm/Cosmoplast In an eventual response to the concerns and problems with bovine-derived collagen, the introduction of human-based collagen homologues has occurred more recently. Similarly named, they offer the promise of decreased immunogenicity and longer lasting results. Composition CosmoDerm I and II and CosmoPlast (Inamed) are injectable implants derived from highly purified human collagen. Both CosmoDerm and CosmoPlast were U.S. Food and Drug Administration 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, retroviruses, and tumorigenicity. CosmoDerm II contains approximately twice the concentration of collagen as CosmoDerm I. Clinical Characteristics CosmoDerm and CosmoPlast are prepackaged in 1-ml syringes. They are opaque and should be refrigerated but must not be frozen. They are typically injected with 30-gauge needles. CosmoDerm is U.S. Food and Drug Administration approved for shallow wrinkles or acne scars and is injected into the superficial papillary dermis. CosmoPlast is injected into the mid to deep dermis for the correction of more pronounced wrinkles or scars. However, the safety and efficacy of CosmoDerm use in lip augmentation has not been established. Its flow characteristics are similar to Zyderm and, like Zyderm, overcorrection is necessary with CosmoDerm because it is diluted with saline, which is reabsorbed. The use of CosmoDerm I should be limited to 30 cc per patient per year. CosmoDerm II and CosmoPlast should 99e 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 Immunogenicity Clinical Study demonstrated that the 95 percent 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 adverse events reported with Zyderm/Zyplast in treated patients who initially had a negative skin test. Unlike bovine collagen implants, these dermal 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% lidocaine, 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 CosmoDerm 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 urinary 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 reconstructive and aesthetic surgery. The conversion of these materials into an injectable form is a logical extension 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 epidermis is completely removed, followed by the removal of dermal cells and stabilization of the dermal matrix through the inhibition of metalloproteinases. The material is then cryofractured, 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 particulate 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 viscous consistency after hydration requires a largecaliber needle for introduction. Cymetra is indicated 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 correction 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 subcutaneous 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 conducted. Reported clinical outcomes are largely anecdotal. There are no clinical trials that demonstrate its longevity to be superior to other collagenbased 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 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 indicated for deep wrinkles, scars, fat atrophy, and prominent nasolabial folds.8 At the time of injection, 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 largebore 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, bacitracin, or gentamicin are present in Fascian implants; patients with known allergies to these antibiotics 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 recipient or nerve blocks may be needed for patient comfort during the procedure. Documentation of the longevity of the material has not been reported 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 injection technology.10 The transition from a protein-based material to one of an extracellular matrix composition is a paradigm shift from two decades of previous clinical experience. Composition Restylane (Medicis, Scottsdale, Ariz.) is produced today by fermentation in cultures of equine streptococci. The fermented material is then stabilized by means of epoxidic cross-links of the glycosaminoglycan chains. As a result of this processing method, the hyaluronic acid, or hyaluronan, 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 microbes. The largest amount of hyaluronan resides in skin, where it is present in both dermis and epidermis. Hyaluronan’s high capacity for holding water and high viscoelasticity give it some unique properties that are useful in various medical and pharmaceutical applications.12 Because it retains moisture, hyaluronan is used in some cosmetics to keep skin young and fresh-looking. As we age, the water-holding capacity of our skin decreases 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 degraded 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 occurs 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 feature is what probably accounts for its longer volume retention effects than bovine collagen (isovolemic 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 hyaluronic acid, which varies in particle size and subsequent 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 applications such as deeper wrinkle reduction and for lip augmentation, nasolabial folds, and glabellar creases.13 Restylane has even been successfully used in the treatment of tear trough deformities.14 Restylane Fine Lines has the highest concentration at 200,000 gel particles per milliliter, can be injected through a 30-gauge needle, and is indi- 101e Plastic and Reconstructive Surgery • September 15, 2006 cated for thin superficial wrinkles. The lowest concentration 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 unnecessary, as the risk for hypersensitivity reactions is minimal.16 It is easily injected and flows nicely through small-gauge needles. Although not permanent, 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 severe pain (3.6 percent versus 1.4 percent) with Restylane. The increased pain is partly because Restylane does not come mixed with local anesthetic. 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 December of 2004. As a competitive analogue to Restylane, 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 30gauge 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 hyaluronic 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, Captique is felt to last significantly shorter than Restylane. 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 injection into symptomatic joints since 1996. This is a more dense form of avian-derived hyaluronic acid because of its intraarticular use. As a facial softtissue 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 temperature. 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 injection 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 puncture injections, or a combination of the two have been demonstrated to be effective. However, overcorrection 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 typically last 3 to 4 months. Advantages No skin test is necessary; thus, it can be used at the initial consultation. 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 hypersensitivity 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 nonresorbable 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 Radiance, is manufactured by Bioform, Franksville, Wis.) and is a proprietary mixture of an aqueousbased gel carrier blended with spherical particles of synthetic calcium hydroxyapatite.13 Although traditionally thought of only as a bone replacement, 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 hydroxyapatite particles allows for consistent mechanical action during injection and stability in situ after injection. As the size of particles that can be phagocytized and migrate through the lymphatic system is approximately 15 m, there is very limited potential for migration. Should any calcium 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 pharmaceuticals and injectable drug products. The gel carrier has the unique characteristic of being highly viscous 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 hydroxyapatite 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 hydroxyapatite 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 solubility is very low, volume retention may theoretically persist for years. Disadvantages There are no published reports on the use or the long-term effects of this calcium hydroxyapatite injectable implant in aesthetic facial treatments. It is not currently U.S. Food and Drug Administration approved for this application, although clinical trials are ongoing. Radiesse has received regulatory clearance for the soft-tissue treatments of vocal cord insufficiency and for radiographic tissue marking. It is also currently under 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 immunodeficiency virus–associated facial lipoatrophy, although 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 injections. Although the nonresorbable calcium hydroxyapatite 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 implantation 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). Furthermore, Radiesse is radiopaque and may interfere with facial radiographs. 103e 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 alphahydroxyacid family.22 It is manufactured from essentially a resorbable “plastic” material from which many of the sutures that are used daily (e.g., Vicryl, Dexon) are composed. These are moderately hydrophilic materials from which postimplantation hydrolysis initiates the slow resorption process. Clearance is eventually achieved by macrophage 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 manufacturer 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 sutures, bone screws, and facial implants. Whereas it is approved in Europe for the treatment of wrinkles, it is U.S. Food and Drug Administration approved (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 implantation. It has only been definitely studied in the United States for human immunodeficiency virus patients. It has been U.S. Food and Drug Administration approved on a compassionate-use basis. Whether the same results, particularly the complication rates, would be greater in a nonimmunocompromised patient population can only be speculated. The potential for long-term tissue reactions, 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 polymethylmethacrylate microspheres that are sus- 104e pended in a transport solution of 3.5% bovine collagen and 0.3% lidocaine. The polymethylmethacrylate 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. Subsequently, 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-themouth wrinkles. Follow-up at 1, 3, 6, and 12 months was completed, and evaluations were performed by the investigators and subjects using linear 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 surprising, 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 Administration 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 marketed 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 date of U.S. Food and Drug Administration approval Volume 118, Number 4 • Injectable Soft-Tissue Fillers Table 1. Injectable Soft-Tissue Fillers Composition Collagen, xenograft Collagen, allograft Cymetra (LifeCell) Fascia lata Hyaluronic acid Types Available How Supplied Bovine collagen, 95% type Zyderm I: 35 mg/ml Syringes, store at I, 5% type III; Zyplast is collagen 4°C; reconstituted glutaraldehyde crosswith PBS and 0.3% linked lidocaine Zyderm II: 65 mg/ml Zyplast (Medicus): 65 mg/ml Derived from fibroblast CosmoDerm I Unlike Zyderm culture, 35 mg /ml family, no skin collagen; CosmoPlast is pretesting is cross-linked required CosmoPlast (Medicus), cross-linked Micronize acellular, 330 mg of micronized 5-cc syringe, freeze-dried dermal particles refrigerated up to tissue 6 mo; reconstituted with 1.0 ml of lidocaine, use within 2 hr Preserved particulate Fascian (Fascia Hydrated in 3–5 cc fascia lata, freeze dried Biosystems) 0.3% lidocaine solution Streptococcal fermentation processed, 20 mg/ml in buffered solution (?) Restylane Fine (Q-Med/Medicus) Reconstituted with physiologic saline Restylane Perlane Hyaluronic acid Hyaluronic acid Streptococcal fermentation processed Processed from rooster combs, cross-linked Radiesse (Bioform Medical) Calcium hydroxylapatite spheres (25–45 m) in a polysaccharide gel with glycerin Poly-L-lactic acid Sculptra (Dermik Laboratories) Artecoll (Artes Medical) 3.5% bovine collagen and PMMA beads with 0.3% lidocaine, PMMA beads ⫽ 30 to 40 m, 25% beads, 75% collagen Captique (Inamed) Hylaform (Inamed), Original ⫽ 5.5 mg/ ml; Fine Line, low viscosity; Plus, high viscosity Previously, Radiance FN Sculptra Ready-for-use, skin pretesting is optional 1-cc syringe 1-cc syringe, no refrigeration Indications for Use Superficial defects Needle 30 gauge Moderate defects Deeper defects Papillary dermal injection 30 gauge Deep reticular dermis, deeper defects Because it is tissue bank material, no FDA restrictions on its use exist Deep wrinkles, scars, fat atrophy, nasolabial folds Thin superficial wrinkles Moderate, nasolabial Deeper scars, prominent rhytides, pronounced nasolabial fold Thin superficial wrinkles; moderate, nasolabial Thin superficial wrinkles; moderate, nasolabial; deeper scars, prominent rhytides, pronounced nasolabial fold Subdermal injections, not FDA-approved yet Reconstituted with 5 HIV-associated cc of sterile water lipoatrophy and lidocaine solution 0.5-ml syringe Injected into the subdermis, deeper wrinkles, glabellar and nasolabial folds 26 gauge Preundermine with 20-gauge needle, inject with 16- to 25-gauge needle 30 gauge 30 gauge 27 gauge 30 gauge 27–30 gauge 27 26 gauge 26, 27 gauge PBS, phosphate-buffered saline; FDA, U.S. Food and Drug Administration; HIV, human immunodeficiency virus; PMMA, polymethylmethacrylate. is late 2005 or early 2006. Skin testing is required despite a less than 0.1 percent incidence of sensitivity reactions to assess for the presence of allergy to bovine collagen. The size of the needle and the viscous nature of the material make dermal implantation impossible. Like all par- ticulated injectable fillers, the risk of clumping and localized foreign body reactions exists. For this reason, and because of the risk of palpability, Artecoll should not be injected into the lips and in areas of thin overlying skin (e.g., rhytides of the lateral eye). 105e Plastic and Reconstructive Surgery • September 15, 2006 CONCLUSIONS With the trend toward less invasive procedures, often in a younger patient population, there is an increasing patient demand for the benefits of soft-tissue injectable filler materials. Given the numerous options that now exist and the different chemical compositions and potential biological behavior of the various materials, it is imperative that plastic surgeons be knowledgeable about contemporary injectable fillers. As there is no single injectable filler that has all of the desired characteristics, understanding the advantages and disadvantages of one filler over another, with an appreciation of their limitations, is extremely helpful in achieving the patient’s goals and minimizing the risk of potential adverse reactions (Table 1). It is also important to understand that although all of the aforementioned injectable fillers are safe, the concepts of their long-term volume persistence and how they compare with each other largely remain anecdotal, with few prospective controlled clinical trials. Furthermore, although they are widely used in many areas of the face, the controlled clinical trials and subsequent U.S. Food and Drug Administration approval of them usually does not include lip augmentation, even though it is one of the more commonly injected facial sites. Barry L. Eppley, M.D., D.M.D. Division of Plastic Surgery Indiana University School of Medicine 702 Barnhill Drive, Suite 3540 Indianapolis, Ind. 46202 [email protected] DISCLOSURE None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this article. REFERENCES 1. Burke, K. E., Naughton, G., and Cassai, N. A histological, immunological, and electron microscopic study of bovine collagen implants in the human. Ann. Plast. Surg. 14: 515, 1985. 2. Narins, R. S., and Bowman, P. H. Injectable skin fillers. Clin. Plast. Surg. 32: 151, 2005. 3. Inamed Corporation. Product Information Sheet on CosmoDerm and CosmoPlast. Santa Barbara Calif.: Inamed Corp, 2003. 4. Maloney, B. 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