DERMAL FILLERSOver the last quarter century, we have had several kinds of products suitable for soft tissue augmentation available to us, with intense industry research yielding more dermal filler options with increasing regularity. In 1893, by transplanting fat from the arms into facial defects, Neuber became the first physician to practice soft tissue augmentation. The field of soft tissue augmentation came into its own in the 1970s with the introduction by Stanford University researchers of animal-derived collagen implants.1 By the 1980s, the use of collagen injections for wrinkles had entered the mainstream. While Americans were enjoying the benefits of bovine collagen fillers (i.e., Zyderm and Zyplast), other countries began to experiment with non-bovine dermal fillers such as Restylane and Hylaform. These hyaluronic acid (HA) fillers were available outside the United States and were popular worldwide for several years before the FDA granted approval for their use here. With different forms of collagen and seven HA fillers currently available in the United States — and others in the pipeline — selecting the appropriate filler can pose a challenge for us and our patients alike. In this article, which is part one of a two-part series on dermal filling agents, I will discuss the advantages and disadvantages of the various dermal filling agents currently available in the United States, as well as advice on optimum ways to use each one. COLLAGENThe major structural component of the dermis, collagen is the most abundant protein in the human organism as well as the skin, in particular, and confers strength and support to the skin. Collagen is also one of the strongest natural proteins, imparting durability and resilience to the skin, and comprising 70% of dry skin mass.2 What is known as “collagen” is actually a meshwork of scaffolding-like structures composed of a complex family of over 18 types — 11 of which are found in the dermis. Type I collagen (80% to 85%) and type III collagen (10% to 15%) are the primary collagen constituents in the dermal matrix of adult human skin. Dermal fibroblasts produce a precursor form of collagen, a procollagens, which in turn produce both collagen types I and III, each of which is composed of three collagen chains.Skin fragility and wrinkles result from the collagen loss, which occurs with aging and solar exposure and other insults. UV light, free radicals, and other factors cause the body to produce collagenase, an enzyme that breaks down collagen. Injecting various forms of collagen into the skin helps it regain a youthful appearance, but only temporarily. The range of collagen products has increased in recent years as manufacturers have worked to extend the duration of product effects.BOVINE COLLAGENWith a record of safety and efficacy spanning more than two decades, bovine collagen has been the standard dermal filler agent used to ameliorate undesirable signs of cutaneous facial aging.3 In 1977, Zyderm I was introduced as the first injectable bovine collagen implant; it was approved by the U.S. Food and Drug Administration (FDA) in 1981. Zyderm II and Zyplast were introduced and approved in 1983 and 1985, respectively. Zyderm I and II differ only by collagen concentration (35 mg/cc with the older product and 65 mg/cc with Zyderm II). The difference in concentration is significant insofar as it renders Zyderm II thicker and stiffer than Zyderm I. Like Zyderm I, Zyplast contains 35mg/cc of collagen, but this collagen is crosslinked with glutaraldehyde, which makes it last longer than the other bovine-derived collagen implants. All of the bovine collagen products contain lidocaine to reduce the pain associated with the procedure. Consequently, additional numbing agents are usually unnecessary. However, topical lidocaine or nerve blocks can be used to reduce the risk of pain of injection.Although these products remain the standard to which newer implants are compared, human-derived collagen and HA products have become widely used. AdvantagesBovine-derived collagen dermal filling agents effectively reduce wrinkles and scars. Zyplast is indicated for shaping the vermilion border of the lips and to treat deeper wrinkles, such as nasolabial folds and atrophic scars (e.g., deep post-acne, post-traumatic, post-viral, and post-operative).4 Zyderm I is well suited for treating superficial rhytides (e.g., glabellar lines, horizontal forehead wrinkles, crow’s feet, fine perioral wrinkles, and scars) or for use over Zyplast in deeper wrinkles. The higher concentration of collagen in Zyderm II renders this product more appropriate for moderate-to-deeper lines and scars, but Zyplast lasts longer because it is crosslinked. Collagenase ultimately succeeds in degrading these products, returning the skin to its appearance prior to injection. Zyplast is the most commonly used bovine collagen product and lasts about 4 months, slightly longer than Zyderm I and II. Bovine collagen can be safely re-injected three to four times a year, if needed. Zyderm and Zyplast are the least expensive dermal fillers on the market and typically engender less bruising than products that contain hyaluronic acid.DisadvantagesTwo skin tests, 6 and 2 weeks before the scheduled treatment, are required before the use of bovine collagen agents to reduce the risk of inducing hypersensitive or allergic reactions. Such responses can occur as early as 6 hours after the test, but are more likely to emerge 48 hours to 4 weeks after the test. A positive skin test disqualifies a patient for treatment with bovine collagen. Approximately 3% of the general population is thought to be sensitive to bovine collagen.5 Although a patient is unlikely to react to bovine collagen implants after two negative skin tests, the risk is never completely eliminated. The risk of hypersensitive reaction is 1.3% to 6.2% after one negative test,6,7 and 0.5% after two negative tests. Patients should be advised that should such a reaction occur, it should spontaneously resolve within 4 to 24 months.7,8,9 Allergic reactions also arise, albeit rarely, following multiple treatments. In this scenario, the patient should be advised to monitor the injection site between 48 and 72 hours after treatment and make an appointment to see the treating physician 4 weeks after the procedure. Topical, intralesional, or a brief course of systemic corticosteroids can be effective to treat these reactions. Oral cyclosporine10 and topical tacrolimus11 have also reportedly been used for the successful treatment of hypersensitive reactions to bovine collagen.Non-hypersensitive reactions to bovine collagen fillers can also occur (e.g., abscesses, bacterial infections, beading, cyst formation, ecchymoses, herpes virus infection, and local necrosis). Steps can be taken to reduce the likelihood of such outcomes.

• Zyplast should not be injected into the glabellar region due to reports of local necrosis.12 Further, antiviral medications are recommended for patients with a history of oral herpes infections to reduce the risk of eruptions.

• To reduce the risk of bruising, patients should also be advised not to take NSAIDs, aspirin, vitamin E, or anticoagulants for 10 days before a scheduled procedure.

• Prior to 1990, cysts were reported at the injection site in 0.04% of patients treated with Zyderm or Zyplast.13 Injections should be made only into the dermis to avoid such a reaction.14

• More than a decade ago, there was some speculation that autoimmune diseases, namely polymyositis and dermatomyositis, might be induced by the injection of bovine collagen,15 but studies have demonstrated that antibodies to bovine collagen do not cross-react with human collagen.16,17 Therefore, it is unlikely that bovine collagen causes connective tissue disease in humans.18,19 Furthermore, a study by Hanke et al showed that the incident rate of polymyositis/dermatomyositis in patients receiving bovine collagen was not higher than the control-matched population.20

BIOENGINEERED HUMAN COLLAGENIn recent years, several companies motivated by the drawbacks of bovine-derived collagen, especially the attendant potential for provoking adverse allergic reactions, have developed human-derived soft tissue fillers. The manufacturing process begins with the harvesting of dermal fibroblasts from bioengineered human skin and placement into a three-dimensional mesh. The fibroblasts are then cultured in a bioreactor that simulates the human body. Then, the fibroblasts synthesize collagen and extracellular matrix proteins. Human-bioengineered collagen implants include CosmoDerm I, CosmoDerm II, and CosmoPlast, which contain human collagen types I and III, and were approved by the FDA in March 2003. CosmoDerm I is composed of 35 mg/cc human-bioengineered collagen distributed in a phosphate-based saline solution and 0.3% lidocaine. CosmoDerm II contains twice the collagen concentration of CosmoDerm I. CosmoPlast contains the same ingredients as CosmoDerm I, but is crosslinked by glutaraldehyde, yielding a product more resistant to degradation, thus lasting longer, and more appropriate for treating deeper furrows. CosmoPlast, which exhibits a stiff consistency (even more so than products containing hyaluronic acid), is also well suited to treating the vermilion border of the lips and bridge of the nose, as well as raising the corners of the mouth. CosmoDerm is indicated for superficial wrinkles. CosmoPlast is typically used in combination, usually with a hyaluronic acid agent, to treat medium and deep wrinkles, with the collagen product injected first and the HA filler injected into the same location.AdvantagesGiven the absence of allergy risk associated with these agents, no skin testing is required. This allows for patients to be treated in their initial visit to the physician. The cosmetic effects of CosmoDerm and CosmoPlast are immediate, last about 3 to 4 months, respectively,21 and are typically associated with less bruising than the effects of procedures using agents containing HA. Like Zyderm and Zyplast, CosmoDerm and CosmoPlast must be kept refrigerated. Also similar to the bovine-derived fillers, CosmoPlast and CosmoDerm contain lidocaine to mitigate the pain of injection and lower the risk of edema and ecchymoses by inhibiting the activation of eosinophils.22 Consequently, CosmoDerm and CosmoPlast are contraindicated in patients allergic to lidocaine. DisadvantagesBioengineered human-derived collagen is expensive to produce, rendering these agents as the most costly fillers on the market. Further, their cosmetic effects do not last, on average, any longer than the bovine-derived products. However, these products are associated with less bruising, erythema, and pain than other filling agents and, consequently, remain desirable options.Hyaluronic acid or hyaluronan is a non-sulfated glycosaminoglycans that occurs naturally in the skin and other tissues (specifically, connective, epithelial, and neural tissues). This polysaccharide has the capacity to bind water up to 1,000 times its volume. Such a quality serves to plump up the skin, giving it volume and yielding a more youthful appearance. HA breaks down rapidly in its natural form. As an injectable filling agent, HA is crosslinked to extend the duration of the product. Currently, HA products do not contain lidocaine; therefore, other methods of anesthesia are usually required when using HA injectables. In the last few years, HA filler substances have become the new gold standard, far outpacing in usage the other soft tissue augmentation agents.23 HYALURONIC ACIDHYLAFORMHylaform is an animal HA product derived from rooster combs. The crosslinking of sulfonyl-bis-ethyl in between hydroxyl groups of HA polysaccharide chains yields a gel-like substance ultimately extruded through a sieve in the production process.24 The FDA has approved two products in this family, Hylaform and Hylaform Plus. The moderate number of crosslinks used renders the Hylaform fillers biocompatible, soft, and malleable. These agents contain 5.5 mg/ml of crosslinked HA. Hylaform, which is composed of medium-sized particles, is indicated for medium-depth wrinkles and fine lines. Hylaform Plus is composed of larger particles and is indicated for deep furrows and enhancing lip volume. Both products represent the softest available HA filler substances.AdvantagesSkin testing is not required before using these agents. In addition, these products, which impart a natural feel in the skin, are soft enough to make them ideal for use in the body of the lip and in large areas such as the cheekbones and jowls. Side effects, which are rare and relatively mild, include hypersensitivity, inflammatory and granulomatous reactions, edema, erythema, pruritus, and acneiform lesions.25 The contraindications for Hylaform products are similar to those for bovine-derived fillers (e.g., autoimmune and inflammatory disorders, allergic background, history of anaphylactic reactions, immunosuppressant therapy, pregnancy or breastfeeding). In addition, patients allergic to products of avian origin cannot use these agents.26 DisadvantagesBruising is associated with all HA dermal fillers. The injection of Hylaform can be painful to patients because the product does not contain lidocaine. The use of topical anesthetics and dental nerve blocks is recommended to reduce the pain on injection. The cosmetic effects of Hylaform and Hylaform Plus are believed to last approximately 3 months.CAPTIQUECaptique differs from Hylaform only insofar as the former is derived from bacteria rather than roosters, as the latter is. The bacterial origin of Captique renders it slightly stiffer than Hylaform. This non-animal stabilized HA (NASHA) product is suitable for treating wrinkles, lips and scars.No testing is required and the agent can be injected in the initial physician’s visit. The bacterial origin of the HA in this product results in a stiffer and more difficult to inject product than Hylaform. Anecdotally this product lasts about 4 months.RESTYLANELike Captique, Restylane is a NASHA gel formulated through fermentation, with sugar present, in bacterial cultures of equine streptococci. This highly crosslinked transparent agent, which is stiffer and more rigid than Hylaform, is the most popular and well known of the HA fillers. Because of the higher amount of HA in this product, as well as its bacterial origin, Restylane is the stiffest of all the available HA fillers. However, unlike Captique, it is easy to inject because it has properties that make it flow easily through a 30-gauge needle. Restylane is composed of approximately 100,000 particles/ml and contains 20 mg/ml of stabilized HA, is indicated for the mid-dermis and is the only injectable in the product line (which includes Restylane Fine Lines, Perlane, and SubQ) currently approved by the FDA. However, it is expected that Perlane will soon be approved by the FDA for use in the United States. Restylane is made of medium-sized pieces of HA gel while Perlane is composed of larger HA gel particles, but with the same HA concentration. Perlane, which is known throughout much of the world as Restylane-Perlane, has the largest particles in the product line and is indicated for treatment in the deep dermis. The stiffness of Restylane renders it well suited for deep wrinkles, and it is this quality that is thought to impart greater longevity in human tissue as compared to Hylaform and Captique. However, the stiffness is a drawback if the product is used by a poorly skilled physician, with bumps and blue blebs possibly arising from improper injection technique. Slower injection may limit the risk of inflammation; swelling can be reduced through the use of systemic prednisone.27 AdvantagesNo skin test is required for any of the Restylane line products and none require refrigeration. The cosmetic effects of Restylane are thought to last from 6 to 9 months. Product stiffness makes it more suitable for deep wrinkles than for use in the body of the lips.DisadvantagesAside from the bruising associated with all HA fillers, erythema and swelling are common complaints within the first 24 hours of treatment with Restylane. This agent is stiffer than Hylaform, Captique, and Juvéderm; therefore, it should be used with caution in the body of the lips and around the eyes, where overuse can produce an unnatural look.JUVÉDERMJuvéderm, also known as Hydrafill, is an HA product manufactured by a bacterial fermentation process similar to that used for Restylane, and this product was approved by the FDA in late 2006. There are five products in the Juvéderm line (Juvéderm 18, Juvéderm 24, Juvéderm 24HV, Juvéderm 30, and Juvéderm 30HV), but only Juvéderm 24HV (also known as Juvéderm Ultra) and Juvéderm 30HV (also known as Juvéderm Ultra Plus) are currently sold in the United States. All of the products in the line vary by the amount of HA per cc, the amount of crosslinking, and the regularity of the crosslinking. Both Juvéderm Ultra and Ultra Plus consist of 24 mg/cc of HA, but Juvéderm Ultra Plus has a higher proportion (11%) of crosslinked HA than Juvéderm Ultra, which makes Ultra Plus more suitable for deeper facial folds and wrinkles. Like Restylane, Juvéderm is stiff; but unlike Hylaform and Restylane, which are broken into small particles, Juvéderm is said to be a homogenous gel. Although unproven, it is said that homogenous gels have less surface area exposed as compared to the nonhomogenous products, which is believed to lower hyaluronidase activity thereby prolonging duration correction.28 In addition, gel homogeneity is believed to confer greater biocompatibility because it provokes less friction with dermal tissues on injection, contributing to less inflammation. The duration of Juvéderm injections is currently unknown.AdvantagesNo skin tests are necessary before using the Juvéderm products. The large volume of HA in Juvéderm Ultra Plus and the 11% degree of crosslinking (both of which are higher than the other HA products) results in longer-lasting cosmetic effects as compared to products with less HA, such as Hylaform.DisadvantagesThis product line, like all HA products, can cause erythema, swelling, and bruising. The initial Juvéderm products had a defect in the syringe that caused the needle to pop off during application. New syringes are currently being investigated.STEADY INCREASE IN DEMAND, MORE PRODUCTS AVAILABLEDermal filling agents for soft issue augmentation procedures are now widely available, based on the longstanding successful track record of the earliest products. Most agents used for soft tissue augmentation can be safely used alone or in combination. Given the widespread popularity of soft tissue augmentation and the ever-present need to develop dermal fillers that last longer than the current products, new fillers frequently enter the market. In the future we can look forward to porcine derived collagen fillers and HA fillers that contain lidocaine. In addition, FDA approval is thought to be imminent for Perlane, a bacteria-derived filler similar to Restylane that may last longer than Restylane. In short, the demand for soft tissue augmentation procedures has steadily increased since their inception and research is ongoing to develop products that address the shortcomings of the earlier products while matching or exceeding their advantages. A note from Dr. Baumann: I feel that in order to properly learn how to inject the various fillers, live injections or videos should be shown. It is difficult to portray technique in print only. To help with this, University of Miami’s Web site www.derm.net will have downloadable videos in the future, which you can access athttp://www.derm.net/education.shtml. Come visit us in the next 4 months to learn more.