Skin Fillers

Skin Fillers Shana Kusin, MD, and Jonathan Lippitz, MD Introduction The search for eternal youth and beauty is a theme found throughout human history. The 14th century French alchemist Nicholas Flamel is said to have uncovered the secret of the Philosopher’s Stone and, with it, to have bestowed himself and his wife Perenelle with immortality. Ponce de Leon’s fabled quest to find the Fountain of Youth led to the discovery of Florida in 1513. It was in 1890 that Oscar Wilde’s Dorian Gray sacrificed his mortal soul to remain eternally young and beautiful by having a portrait age in his stead. Although less epic in the scope of tales engendered, legitimate medical attempts at discovering interventions to enhance or preserve youth date to 1893, when Neuber first reported performing autologous fat transfer to reconstruct a facial depression caused by tuberculosis osteitis.1 At the turn of the 20th century, the cosmetic use of injected paraffin was popularized, but this was often complicated by the formation of paraffinomas.2 The 1960s saw the emergence of the worldwide use of liquid silicone for a number of varied applications, including soft tissue augmentation.3 However, it was in 1981 that the FDA approval of the cosmetic use of injectable bovine collagen ushered in the modern era of nonsurgical cosmetic enhancement. The currently available injectable skin fillers can be divided into three categories: those that function to replace tissue lost by the aging process (collagen, hyaluronic acid, and biologic fillers); those that stimulate endogenous connective tissue growth (poly-L lactic acid and calcium hydroxyapatite); and permanent fillers (polymethylmethacrylate, silicone, and hydroxyethylmethacrylate). The properties and characteristics of each of these agents will be described and then the complications associated with each filler will be discussed.

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Types of Fillers: Replacement Collagen It has long been known that collagen loss is a key factor in skin aging. The amount and character of collagen in the skin changes with age, and exposures to agents such as sun, tobacco, and pollution increase collagenase levels.4 It thus makes logical sense that collagen replacement was one of the first techniques employed for nonsurgical rejuvenation procedures. Commercially available collagen preparations are either bovine or human in origin and consist of a given percentage of collagen by weight suspended in saline with lidocaine (see Table 1). As the saline is absorbed, the collagen fibrils form a network that restores the contour of the skin and which subsequently serves as a scaffold for the infiltration of native connective tissue cells. Eventually, the network will be detected by the host’s immune system and degraded by collagenases and the inflammatory process.2 The inflammatory response and associated edema may serve to provide an additional degree of volume augmentation.5 Eventually, the material will be cleared by the host’s foreign body reaction; treatments have been reported to last as long as 18 months but generally last 6 months or less, depending on the site of injection.2 There are two principal types of collagen available commercially: bovine or human. Bovine collagen was the original nonautologous skin filler and has been on the market since the 1970s. The best known agent, Zyderm, has been available since 1976 and was approved in 1981 for use as an injectable filler of facial lines and wrinkles. It is available as Zyderm I (3.5% collagen by weight) or Zyderm II (6.5% collagen by weight). Zyplast, a longer-lasting formulation in which the collagen fibrils are crosslinked with glutaraldehyde in order to slow degradation by collagenase, has been FDA-approved since 1985.5 The collagen in Zyplast and Zyderm is derived from the hides of an isolated, US-raised cow herd.2 Other formulations of bovine collagen include Resoplast, which consists of bovine collagen suspended at two concentrations (3.5% or 6.4%) in a solution of phosphate buffer, sodium chloride, lidocaine, and water; and Kokken Atelocollagen, a mononuclear solution of collagen molecules, currently available only in Japan and some of Europe.6 Artecoll, a suspension of polymethylmethacrylate microspheres in partially denatured collagen with lidocaine, will be discussed later. Because bovine collagen contains a number of species-specific markers, a high rate of allergenicity is seen to these products, with reported rates of DM, April 2009

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TABLE 1. Replacement fillers Chemical

Trade Name

Action

Formation of a collagen fibril Bovine network that restores the Zyplast, Zyderm contour of the skin Resoplast Kokken Atelocollagen Porcine Fibrel Human (donor) Cosmoderm/Cosmoplast Dermalogen Human (autologous) Isolagen Autolagen Hyaluronic acid Bacterial Hygroscopic properties lead Restylane to space-occupying effect Captique and water retention during Juvederm product degradation Avian Hylaform Dermal matrix Cymetra Space-occupying effect, stimulation of ingrowth of fibroblasts and collagen Autologous fat n/a Space-occupying effect by injection of fat harvested Collagen

Durability

Advantages

3-6 months Well studied, low rate of serious adverse effects

Disadvantages/ Complications Requires skin testing; hypersensitivity; granuloma formation; cyst or abscess formation

3-6 months Well studied, well tolerated Bruising; delayed granulomas; No skin testing required; skin discoloration (Tyndall low rate of effect); injection-site hypersensitivity necrosis

12 months

Variable

Longer duration, decreased Inflammation; theoretical risk rate of hypersensitivity of transmission of pathogens from donor Autologous (no risk of Unpredictable results hypersensitivity)

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anywhere from 3% to 10% of the population displaying delayed hypersensitivity reactions.2,7 As an alternative for patients intolerant of bovine products, human collagen products were developed. The best known of these products are Cosmoderm and Cosmoplast, which consist of purified collagen from human fibroblast cell culture lines2 that are processed to remove immunological cells and melanocytes.4 These products, FDA-approved in 2003, differ from one another in that Cosmoplast is crosslinked with glutaraldehyde for longer duration. These products are felt to be technically easier to inject but may be of shorter treatment duration than bovine collagen.2 Dermalogen is another human-based collagen product in which collagen is derived from the dermis of cadaveric skin.6 A number of autologous donor techniques are under investigation to provide an alternative for individuals with concerns regarding the use of collagen derived from donated human tissue. Isolagen is a product composed of collagen cultured from dermal fibroblasts biopsied from the patient’s own skin,6 the cosmetic use of which has not yet been approved by the FDA. Autolagen is a product in which collagen is cultured from discarded specimens obtained in routine surgical procedures. Obviously, the use of this product requires that the patient have surgery for other reasons and that a relatively large specimen of tissue be preserved (2 inches squared of skin produces 1 mL of Autolagen).7 Brief mention can be made of a third class of collagen product. Fibrel, derived from porcine collagen, is an alternative for patients with a hypersensitivity to bovine collagen and who are unwilling to attempt human-derived products. Fibrel is derived from porcine type I collagen and is reconstituted with the patient’s own plasma prior to injection. A smaller percentage of patients (1.8%) have positive skin test reactions to Fibrel.6 Fibrel may be difficult to inject into finer lines or thinner skin.8 Technical considerations for collagen products differ based on products. Zyderm I must be injected into the papillary dermis; Zyderm II into the mid-dermis; Zyplast into the deep dermis.5 Zyderm I requires overcorrection of the defect by 100% due to initial volume loss from saline absorption, whereas Zyderm II requires only 50% overcorrection and Zyplast none.5 Human collagen products are felt to be generally easier to inject than bovine with less lumping of the skin seen after injection; however, these agents likely exhibit less longevity.2

Hyaluronic Acid Hyaluronic acid is one of the most popular forms of replacement skin fillers. It is a naturally occurring linear polysaccharide found in numerous tissues throughout the body, such as extracellular matrix, hyaline cartilage, DM, April 2009

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and synovial fluid, and consists of polyanionic dissacharide units of glucuronic acid and N-acetyl glucosamine connected by alternating b 1-3 and b 1-4 bonds.9 This structural chemical is identical across species, from bacteria to humans, and as such, possesses no antigenic specificity, giving it a low potential for allergic reaction.5 Aged skin possesses lower levels of hyaluronic acid, which results in loss of tissue hydration and may be responsible for the disorganization of collagen and elastin seen with aging.2 Unique chemical properties of hyaluronic acid make it a highly effective agent for use as an injectible skin filler. In aqueous solution, hydrogen bonding between adjacent carboxyl and N-acetyl groups leads to conformational stiffness and water retention; but, beyond merely retaining water, hyaluronic acid is hygroscopic and actively absorbs water from its surroundings.9 This gives it the property of isovolemic degradation; a given amount of injected material will continue to occupy the same volume despite ongoing local degradation.2 Hyaluronic acid also exhibits dynamic viscosity, or viscosity that decreases with the application of increased shear force.10 It injects with relative ease through a small-gauge needle but then expands once in tissue and is unlikely to migrate.5 In its native form, hyaluronic acid is degraded locally quite quickly, exhibiting a half-life of approximately 20 hours and producing a cosmetic effect of only 1 to 2 days’ duration.2 Commercial preparations are therefore crosslinked into macromolecules to enhance duration.9 A number of formulations of hyaluronic acid are available for cosmetic use (see Table 1). Restylane, FDA-approved in 2003, is a hyaluronic acid product derived from cultures of the bacteria Streptococcus equi and stabilized by 1% crosslinking with epoxides. Restylane has a product concentration of 20 mg/mL and consists of small gel particles (400 nm). A randomized, double-blind, multicenter trial comparing Restylane with Zyplast showed Restylane to produce superior results with less injection volume required.11 Two additional formulations of Restylane, Fine Lines and Perlane, consist of different particle sizes with subsequently different viscosities; Perlane was FDA-approved in May 2007, but Fine Lines has not yet been approved for use in the US. Hylaform and Hylaform Plus represent a second major class of hyaluronic acid skin fillers. These products are derived from rooster combs and are 20% crosslinked with divinyl sulfone. Hylaform, which was FDA-approved in 2004, has a lower hyaluronic acid concentration than Restylane (5.5 mg/mL) and is more highly crosslinked, which may result in lower biocompatibility and overall shorter duration of effect.12 It also contains a small amount of avian protein and therefore has a theoretically increased risk of hypersensitivity. Hylaform Plus differs in that it has a larger particle size (750 nm), 240

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which allows for deeper injection. A small, randomized, double-blind study of 8 subjects found higher efficacy and greater patient satisfaction with Restylane compared with Hylaform after 12 weeks.12 Other hyaluronic acid formulations warrant mention. Captique is a hyaluronic acid filler that, similar to Restylane, is produced by bacterial fermentation but has a concentration and crosslinkage profile similar to Hylaform. Juvederm is a bacteria-derived hyaluronic acid filler recently submitted to the FDA for premarket approval; it is a homogenous gel rather than a particulate suspension.5 Dermalive and AC Hyal are similar products available in Europe and in Japan, respectively6; Dermalive will be discussed elsewhere. Overall, hyaluronic acid fillers have a duration of up to 6 months, whereas some clinical trials have indicated that more than two-thirds of the initial correction may remain at the 6- to 8-month mark.13 From a technical standpoint, all hyaluronic acid products are injected intradermally. If injected too deeply or intramuscularly, they may have reduced duration; if injected superficially, they may produce excess fullness or discoloration. Unlike collagen, these products require no overcorrection. As hyaluronic acid is not packaged with lidocaine, these injections may be painful. In addition, hyaluronic acid has a similar chemical structure to heparin, which may lead to excess bruising and in turn may decrease the product’s duration by invoking inflammatory mediators.14

Biologic Fillers Two other human-derived replacement filler products warrant brief mention. Cymetra, a micronized form of the product Alloderm, is an acellular dermal matrix derived from donated human skin that contains collagen as well as dermal elements, such as elastin and proteoglycan. In addition to a filling effect, Cymetra provides a scaffolding for infiltration of fibroblasts and collagen. At least partial duration of effect has been demonstrated to persist 12 months after implantation,15 but the extent of correction is partly determined by the effectiveness of the response mounted by the host’s cells. Autologous fat implantation is another option for patients who prefer to use products derived from their own tissues. In fact, autologous fat is considered the “original filler material,”5 with its use in tissue augmentation extending back nearly a century.6 A patient’s own adipose tissue is harvested from the abdomen, thighs, buttocks, or other areas of the body and then injected into the desired area. The effect has been shown to last as long as 7 years in some cases,2 but the degree of local resorption and, subsequently, the cosmetic results, are unpredictable. In general, autologous fat is less successful in highly dynamic areas of the face, such as the lips. DM, April 2009

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TABLE 2. Stimulatory fillers Chemical

Trade Name

Action

Durability

Poly-L lactic acid Sculptra, New Fill

Transient Months mechanical filling, followed by stimulation of foreign body reaction of collagen ingrowth Calcium Radiesse/ Foreign body 2-5 years hydroxyapatite Radiance reaction leading to collagen ingrowth

Advantages

Disadvantages/ Complications

Longevity, Granuloma or correction nodule of large formation area defects (eg, HIV lipoatrophy)

longevity

Nodule formation, injection material visible under the skin

Types of Fillers: Stimulatory Poly-L Lactic Acid Poly-L Lactic Acid is a synthetic polymer in the alpha-hydroxy acid family that is immunologically inert, biocompatible, and biodegradable. It is related to vicryl resorbable sutures and resorbable microplate and is metabolized to lactic acid monomers and, eventually, to carbon dioxide and water. The commercially available preparation consists of microparticles (40-63 nm) suspended in sodium caboxymethylcellulose and mannitol; the particle size allows for evasion of phagocytosis but still permits injection through a small gauge needle.16 Poly-L Lactic Acid initially causes a transient mechanical filling effect, and, over time, the implant stimulates a foreign body reaction and collagen ingrowth, which leads to the gradual increase in implant volume over a period of a few months.17 Because the effect is progressive, it is preferable to perform several injections spaced out over time. Poly-L Lactic Acid is available commercially under the name Sculptra in the US and New-Fill in Europe (see Table 2). It was approved by the FDA in 2004 for the correction of facial lipoatrophy associated with HIV; as such, its use in non-HIV-associated cosmetic procedures is off label. Two clinical trials investigating Sculptra in HIV patients have suggested that the effect may last at least 96 weeks17 and has a positive subjective result for patients along with decreasing depression and anxiety scores.18 242

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From a technical standpoint, Sculptra works best as a generalized volume enhancer rather than as a wrinkle filler.5 It is injected into the subcutaneous tissue or deeply into the dermis. Because the effect is progressive, overcorrection is not advised, and post-injection massage is generally recommended.5

Calcium Hydroxyapatite Calcium Hydroxyapatite is the mineral component of bone, and a microspherical formulation has been used for cosmetic corrections. The currently available commercial formulation consists of microspheres (25-45 nm) suspended in a glycerin and sodium hydroxycellulose gel (see Table 2). The carrier substance is absorbed and phagocytosed over a period of 6-8 weeks, during which time a local foreign body reaction encapsulates the hydroxyapatite microspheres and prevents their migration.19 These fixed particles will then serve as a scaffold for local ingrowth of collagen. The effect can last as long as 2-5 years,5 with radiographic evidence of the implant noted at up to 6 years.20 Over time, the hydroxyapatite particles are degraded to calcium and phosphate ions.5 The viscous gel is denser than surrounding tissue and may be palpable under the skin for 2-3 months; however, as collagen ingrowth progresses, injected areas will regain the feel of normal tissue.20 Commercially, calcium hydroxyapatite is available as Radiesse, formerly known as Radiance or Radiance FN. It is FDA-approved for the correction of oral and maxillofacial defects, vocal cord insufficiency, and radiographic tissue marking. It has received pre-market approval for use in the treatment of HIV-associated lipoatrophy, but its use as a cosmetic filler is currently off label. From a technical standpoint, the extent of cosmetic effect produced by Radiesse is directed related to injection volume.20 In addition, calcium hydroxyapatite’s viscosity necessitates subdermal or intramuscular injection with subsequent digital massage for contouring. Overcorrection should be avoided, especially in light of the palpable nature of the implant. Calcium hydroxyapatite has a relatively high rate of formation of lip nodules, and its use is generally indicated for treatment of deeper folds.5

Types of Fillers: Permanent PMMA Microspheres Polymethylmethacrylate (PMMA) microspheres represent a more permanent option for cosmetic correction by injection. Commercially, DM, April 2009

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TABLE 3. Permanent fillers Chemical

Trade Name

Action

Polymethylmethacrylate

Arte-Fill (in combination with collagen) Silikon, AdatoSil

Permanent filling of defects with nondegradable microspheres Permanent filling of defects with viscous, nondegradable gel

Dermalive/Dermadeep (in combination with hyaluronic acid)

Permanent filling of defects with permanent acrylic hydrogel, stimulation of collagen ingrowth

Silicone

Hydroxyethylmetacrylate

PMMA is currently available under the trade name Arte-Fill in a combination formulation with bovine collagen (see Table 3). The collagen, which comprises 80% of the injected material, has an effect typical of other collagen formulations and produces an initial cosmetic result lasting 2-4 months. During this initial time period, the PMMA microspheres invoke a host foreign body response and become encapsulated by native collagen fibers, which prevents particle migration.5 The spheres themselves are nondegradable, allowing for 50-75% long-term duration of the initial cosmetic correction, and there are reports of results lasting 10 years or longer.5 However, the effectiveness of the injection is partly dependent on native fibroblast response, so results can be variable and are partly dependent on patient age.21 Arte-Fill was FDA-approved in 2003, but a similar product has been used under the name Artecoll in Europe since 1993. As the product incorporates bovine collagen, it requires allergy testing prior to use.2 From a technical standpoint, due to the permanence of PMMA microspheres, overcorrection should be avoided, and best practice is to perform multiple smaller injections spaced out over time. Patients are advised to strictly limit facial movements for 3 days following injections due to the risk of pushing the permanent substance deeply into the subcutaneous tissues.10

Silicone The term silicone refers to polymers synthesized from the element silicon, which can exist in any number of forms depending on the degree of polymerization.3 Injectable silicone is a clear, oily, liquid form of polymerized dimethylsiloxane.2 Its designation as “medical grade” refers to the particle purity of a sterile preparation of known viscosity.6 Silicone disperses locally following injection and is encapsulated by fibrous tissue 244

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TABLE 3. (continued) Durability

Advantages

Disadvantages/Complications

Permanent (50% of initial Duration of effect, minimal Requires allergy testing, granuloma correction remains) hypersensitivity formulation Permanent Duration of effect, well Granuloma or nodule formation, studied/extensive rosacea-like syndrome, severe medical experience inflammation, necrosis Permanent Does not require allergy Inflammation, granuloma formation testing

over a course of weeks. The extent of fibrous tissue deposition can be manipulated by controlling the size of injection; in general, a microdroplet injection technique is recommended to limit granuloma formation.6 Two forms of injectable liquid silicone, Silikon and AdatoSil, are currently FDA-approved for medical use (see Table 3). However, it should be noted that these agents are only approved for vitreoretinal surgery, and their cosmetic use is currently off label and controversial.2 The viscosity of these products differs, and Silikon is generally the preferred agent for soft tissue augmentation.5 Several studies evaluating the these two products are currently underway.5 From a technical standpoint, the preferred microdroplet technique consists of injecting tiny quantities of silicone (0.01-0.02 mL/droplet) in a grid with 1-3 mm between injections. Injections are repeated every 4-6 weeks, and, due to the small quantities used in microdroplet injections, it generally takes two to three treatments to grossly appreciate results. Due to the permanent nature of the filler, overcorrection is not recommended.

HEMA Microspheres Hydroxyethylmethacrylate (HEMA) fragments represent another permanent injectable skin filler option. Commercially, this product is currently available as an acrylic gel in combination with hyaluronic acid under the names Dermalive and Dermadeep (see Table 3). Forty percent of the filler material consists of a permanent acrylic hydrogel composed of copolymer fragments (45-65 ␮m) of HEMA and ethylmethacrylate (EMA). These are non-biodegradable, intentionally irregularly shaped particles whose morphology stimulates enhanced neocollagenesis but also leads to an increased potential for inflammatory reaction.22 The remaining 60% of the filler consists of bacterial fementation-derived hyaluronic acid DM, April 2009

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with similar cosmetic and chemical properties to other hyaluronic acid products. From a technical standpoint, this product requires injection into the deeper dermis or the subcutaneous tissues because more superficial injections have an increased risk of side effects, such as inflammation or nodule formation. As with other permanent and stimulatory products, multiple sessions are preferable in order to augment the overall effect slowly over time.

Complications Overview In his review of the longer-lasting injectable skin fillers, Pierre Nicolau suggests that, “The ideal filling agent should be well tolerated by the tissues, with no allergic reaction and no immediate or delayed inflammatory reaction, and should either give an immediate permanent or longlasting filling effect, or induce the stimulation of the host’s fibroblasts and fibrocytes, with a long-lasting effect.”22 This statement encapsulates the difficulty with creating the “ideal” skin filler because the majority of cosmetically adverse reactions comprise elements of a normal immune response to injury and the introduction of foreign material. The balance between adverse effect and desired response is delicate, because the mechanisms of action employed by many injectable fillers directly exploit the body’s foreign body reaction. First and foremost in these expected yet undesirable adverse effects is allergic reaction; that the body would launch a hypersensitivity response to foreign material, in particular to products with animal components, is a natural function of the body’s defense system. Second is the process of normal healing and foreign body reaction. Upon violation of the epidermis by a syringe, platelets come into contact with the extracellular matrix and release hemostatic factors and chemotactic agents that attract inflammatory cells.22 This acute inflammatory phase begins within 2 hours and is dominated by neutrophils, which, upon activation, begin phagocytosis of foreign particles and inflammatory debris generated by proteolysis as well as secretion of cytokines that will further direct the inflammatory reaction.22 As the acute reaction progresses, monocytes develop into macrophages that will phagocytose apoptotic debris and also particles too large for neutrophilic ingestion. The macrophages also secrete growth factors that regulate progression towards the proliferative phase of healing. Activated fibroblasts secrete extracellular matrix components such as type I and, 246

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eventually, type III collagen, with collagen reticulation progressing to the contraction of mature collagen.22 This end pathway is the aim of several of the skin fillers that direct their effect toward stimulating collagen production and maturation. Nonetheless, there are clearly many steps along this pathway of inflammation and healing where the body’s response can produce cosmetically undesirable effects. The foreign body reaction comprises a spectrum ranging from generalized inflammation, to generation of small amounts of fibrous tissue, to full-blown granuloma formation with encapsulated foreign bodies. Activated monocytes adhere to the foreign body, an action which triggers cellular responses for proliferation and differentiation. More protein deposition leads to more efficient cellular spreading, adhesion, and proliferation23; however, increased protein deposition also leads to enhanced cellular recognition and a stronger acute inflammatory reaction. Conversely, a lesser degree of initial reaction leads to a more vigorous response by foreign body macrophages.22 Macrophages coalesce into two kinds of giant cells in an attempt to phagocytose larger particles24,25: Langerhans cells, which are associated with inflammation and seen more commonly in inflamed granulomas or autoimmune disease and are histologically comprised of a collar of mostly lymphocytic mononuclear cells around foreign material; or foreign body giant cells, which consist of more irregularly positioned nuclei found clustered at the host-implant interface.26 These foreign body giant cells will remain in place until the implant is degraded, which has been demonstrated as far as 20 years from initial implantation.26 This persistent giant cell reaction is in inverse relation to the success of the acute inflammatory reaction at clearing debris. The importance of this cellular reaction in the durability of longer-term injectable fillers as well as in the formation of undesirable granulomas is clear. Foreign body reactions are thought of more commonly with the stimulatory and permanent skin fillers, but they can be demonstrated in the replacement fillers as well. The type and extent of reaction is governed primarily by the reaction the specific foreign body elicits. There are implant-specific factors that can be manipulated by manufacturers to direct the intended foreign body response. For example, particle size and volume play a role in the nature of physiologic response. Particles under 20 ␮m will be phagocytosed,27 whereas larger particles will be surrounded by connective tissue, macrophages, and giant cells.28 Particles may also be transported remotely or migrate in the body and can lead to inflammation at the site of transport.29 Similarly, gel or liquid implants DM, April 2009

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may reactivate an inflammatory reaction if a droplet separates from the body of injected material.30 Implant morphology also plays a role in body response. For example, it has been shown that angular-shaped implants induce greater acid phosphatase activity than rounded.31 This is because smoother surfaces give rise to thicker, more regular fibrous capsules with less adhesion and, therefore, less inflammation. Similarly, it has been shown that there is a critical surface area above which the inflammatory response goes up significantly.32 A rounded shape has the smallest surface area for a given volume, which provides another reason why this shape of implant provokes a smaller inflammatory reaction.22 Futhermore, for a given mass of implant, a mixture of fewer larger spheres will tend to provoke the formation of less fibrous tissue than a greater number of smaller spheres.33 Chemical composition and charge of the implanted material also affect the body’s response. For example, hydrophobic compounds generally invoke fibronectin adsorption, which promotes cellular adhesion and inflammation, whereas carboxylic compounds such as HEMA activate the C3 component of the complement cascade, which induces macrophage recognition.34 Similarly, cellular adhesion seems to be stronger on polymer/ hydroxyapatite combination compounds than on polymer alone.35 Positively charged particles tend to attract and activate macrophages, which in turn increases the deposition of connective tissue.36 Finally, the site of implantation itself plays a role in the extent of complications associated with a given injection.22 Thinner skin, such as that found over the nose or the ears, tends to have a higher rate of morbidity, at least in part because the skin may be placed under tension by the implant. The chin and malar regions tend to have a lower rate of complication.

Replacement Fillers: Complications Collagen Overwhelmingly, allergic reaction is the biggest concern with collagen implants, and skin testing is required prior to administration. Anywhere from 3-5% of the population may have delayed hypersensitivity to collagen products, with some authors giving rates as high as 10%.2,7 For this reason, many practitioners will perform a second skin test, which leads to sensitization in up to 2% of patients.37 Typically, allergic patients will experience erythema or whealing that develops 48 to 72 hours following exposure, although the possibility exists of developing hypersensitivity after having undergone several injections without previous 248

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reaction.7 The majority of patients exhibiting hypersensitivity have been shown to have circulating antibodies against bovine collagen.38 Ultimately, these localized allergic reactions generally do not produce long-term morbidity. They can be treated by interlesional steroids, systemic steroids, or antihistamines. Local granulomatous reactions have been reported to occur with collagen products at a rate of 0.05%.2 Granulomas are generally selflimited and resolve on the order of weeks, but have been shown in some cases to persist longer than 1 year.39 Other rarer complications include local tissue necrosis or abscess formation.40 Local cysts or abscesses have been seen to occur at any time following injection at a rate of 4 in 100,000.6 The treatment of this complication is drainage or steroids, administered either intralesionally or systemically.

Hyaluronic Acid Typical adverse reactions following hyaluronic acid injection include erythema, induration, edema, and pain, and these typically resolve spontaneously within a few days.41 Topical or low-dose oral steroids may be used if patient discomfort is significant. Bruising, sometimes extensive, has also been noted to occur due to the chemical and structural similarity of hyaluronic acid to heparin.14 Bruising generally resolves within 7 days but, if excessive, may adversely affect the duration of the injection by attracting inflammatory mediators.14 One of the major benefits of hyaluronic acid when compared with collagen is that its lack of antigenicity obviates a need for skin testing, although there does remain a comparatively small risk of hypersensitivity. In general, there have been no reports of significant allergy from either the bacterial or the avian products.9 A retrospective review of reactions to Restylane in 2000 reported that 1 in 1400 patients exhibited localized hypersensitivity with induration and swelling at the injection site, but none of these patients had systemic allergic responses.42 Another restrospective review of adverse reactions to Restylane in Europe from 1997 to 2001 found an overall rate of sensitivity of 0.8%, with a rate of 0.6% after 2000 when Restylane was reformulated, using a lower amount of protein.43 Half of these hypersensitivity reactions occurred immediately and resolved within 3 weeks. However, case reports do exist of hypersensitivity reactions occurring after multiple injections.44 Delayed granulomatous reactions and “angry red bumps” have been reported in the literature. These sometimes tender erythematous nodules have been attributed alternately to allergic reaction, foreign body reaction, infection, or sterile abscess formation.41 In one report, the author was able DM, April 2009

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to histologically demonstrate granulomatous features of a patient’s nodules, which had persisted for 5 months despite treatment with injected and oral steroids and tacrolimus cream.45 Another author biopsied 8 of his patients who experienced localized reactions to hyaluronic acid injections and histologically demonstrated granulomatous reactions in 4 of these.46 A third author describes nodules that drained pus-like, culture-negative material.47 In general, the notion of an immunological basis for these lesions has been challenged and the histologic evidence seems be most suggestive of foreign body reaction as the underlying cause of such reactions.41 Reports of these reactions indicate that treatment with hyaluronidase may be a therapeutic option for lesions refractory to steroid injection.45 An idiosyncratic complication of overly superficial injection of hyaluronic acid is the development of bluish-grey discoloration surrounding the injection site. This discoloration occurs because of the Tyndall effect, where light of different wavelengths is scattered differentially based on the substances it encounters; this effect is similar to what causes the blue appearance of the sky.48 This effect can be managed by massage or by needle aspiration of injected product,41 and there have also been case reports of successful treatment with laser therapy and with hyaluronidase.49 A more serious complication that has been reported is focal injectionsite necrosis. This relatively rare complication has been attributed to intradermal bleeding or arterial occlusion from compression or vessel obstruction by injection material or hematoma expansion, or from direct vessel injury.50 Acutely, occlusion during injection can be managed by stopping the injection, massaging the area, and applying topical nitroglycerin paste to facilitate vasodilation.41 A case report suggests that hyaluronidase may be used successfully to treat even delayed presentations of impending injection site necrosis.51

Stimulatory Fillers: Complications Poly-L Lactic Acid (Scupltra) Specific properties of Sculptra cause it to be particularly prone to granuloma formation. The particles in Sculptra vary in size, ranging from 2 ␮m to 50 ␮m, and those too large for phagocytosis may become porous during enzymatic degradation.22 This leads to a two-phase inflammatory reaction: an initial, moderate inflammatory response and a later, more severe inflammatory phase involving numerous foreign body giant cells.52 The rate of nodule or papule formation has been reported to range from less than 1% to as high as 10%,53 with a propensity of these to form 250

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periorally.22 These hardened granulomas have been seen to appear up to 12 months following injection and may require surgical excision.16

Calcium Hydroxyapatite (Radiesse) The most frequently reported complication of calcium hydroxyapatite injection is nodule formation, occurring at a rate of 20% or higher when injected periorally.54 These nodules usually form locally at the site of injection, but there is one report of a nodule appearing 2 cm distant from the nearest injection site, 2 weeks after the injection was administered.55 This nodule slowly resolved over several weeks following several steroid injections and a failed attempt to extrude it. Another reported complication of calcium hydroxyapatite injections is that the injection body itself may occasionally remain visible as a white paste under the skin, particularly in patients with thinner skin.22

Permanent Fillers: Complications PMMA (Arte-Fill/Artecoll) Although this product uses a bovine collagen product, a multicenter study performed in 1998 demonstrated a rate of allergy of less than 0.1%, which prompted the manufacturer to announce that the product did not require skin pretesting.6 However, a theoretical risk of allergy still exists, and at least one author feels that skin testing remains obligatory.6 Beyond this risk of hypersensitivity, Arte-Fill/Artecoll has been reported to cause delayed granulomatous reactions which can appear months or even years after injection.56 These granulomas may respond to triamcinolone injections, but they often require surgical excision.57 The permanent nature of Arte-Fill/Artecoll makes it subject to beading, ridging, or nodule formation if placed improperly.58 These purely cosmetic complications generally require correction by surgical excision of the implant.

HEMA (Dermalive) EMA is very hydrophobic and favors fibronectin adsorption, which tends to provoke cell adhesion. HEMA, on the other hand, is hydrophilic and favors activation of C3 complement. In combination, these properties cause the particles in Dermalive to be highly stimulatory to macrophages.22 This effect induces neocollagenesis but also has the potential to induce a strong inflammatory reaction. The reports of rates of granuloma formation with Dermalive are somewhat conflicting, ranging from an overall 11% rate of complications with half of these representing secondary granulomas57 to a reported long-range side effect rate of only DM, April 2009

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1.2 in 1000.59 In addition to granulomas, one author reports that, out of 200 patients, 11% reported “dramatic hardening” of the skin overlying the injection site at 1-year follow up, and the number increased to 25.5% at 2-year follow up.57

Silicone Silicone particles are too large for phagocytosis, and the irregular shape leads to a more robust foreign body reaction.22 This leads to the formation of extremely “active” granulomas with significant cell load and connective tissue formation surrounding the particles.22,60 The rate of nodule formation has been reported to vary from 1 in 100,000 to 1 in 1000.3,6 Despite the large particle size, silicone particles have been shown to be transported to lymph nodes following urethral injection.22 There have been reports of delayed granulomatous reactions and rosacea-like syndromes, although in general this phenomenon has not been well studied.3 Granulomatous complications can arise years after treatment.3 Over the years, there have been isolated reports of severe inflammatory reaction and necrosis following silicone injections; interestingly, a number of these reports involve patients with Weber-Christian Disease, but similar complications have been seen in patients without specific comorbidities or risk factors.61,62 In general, it is thought that proper use of small volumes of medical-grade silicone by qualified medical professionals minimizes these more serious complications.3

Skin Fillers and Autoimmune Disease In the past, concerns have risen about the use of potentially immunogenic injectable skin fillers—particularly collagen, with its well-described antigenic properties and high rates of allergic reaction—in patients with underlying autoimmune or connective tissue disease. The literature on this specific topic is surprisingly thin, despite claims made in the early 1990s of a correlation between collagen injections and the development of polymyositis and dermatomyositis.63 In general, no clear association has been demonstrated between injectable skin fillers and the development of immune-mediated disorders, and the FDA has dismissed any correlation between collagen and autoimmune disease.63 Provided that a patient’s wound healing is otherwise normal, skin fillers are not contraindicated in patients with lupus, rheumatoid disease, or scleroderma.63

Granulomas: Treatment In general, there are a number of approaches to the treatment of nodules associated with injectable skin fillers. Steroids may be injected into the 252

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lesion, although these are less effective in nodules associated with Dermalive or silicone.22 5 Fluorouracil can be used to suppress macrophage and fibroblast activity and may be more successful with Dermalive, but it has been shown to cause a violaceous discoloration of the surrounding skin.22 Allopurinol may be similarly effective and has been used in the treatment of granulomas associated with Artecoll.64 Pulsed dye laser may be used to reduce erythema and angiogenesis of superficial lesions.22 Laser therapy is contraindicated in silicone nodules, however, because of the risk of burns in the setting of the injection’s oil medium.65 Finally, surgical excision of nodules may be required for particularly unsightly nodules, although there is a risk of scar formation or that the nodule may not be fully removable. When selecting a treatment, it is important to keep in mind that not all nodules are inflammatory and may result from mechanical compression of the implant itself due to suboptimal location. Histologic examination of nodules can help identify the skin-filling agent involved in cases where more than one filler has been used historically and may theoretically help to guide treatment.66

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