Adverse reactions to injectable soft tissue fillers

CONTINUING MEDICAL EDUCATION Adverse reactions to injectable soft tissue fillers Luis Requena, MD,a Celia Requena, MD,b Lise Christensen, MD,c Ute S...
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CONTINUING

MEDICAL EDUCATION

Adverse reactions to injectable soft tissue fillers Luis Requena, MD,a Celia Requena, MD,b Lise Christensen, MD,c Ute S. Zimmermann, MD,d Heinz Kutzner, MD,e and Lorenzo Cerroni, MDf Madrid and Valencia, Spain; Copenhagen, Denmark; Paris, France; Friedrichshafen, Germany; and Graz, Austria In recent years, injections with filler agents are often used for wrinkle-treatment and soft tissue augmentation by dermatologists and plastic surgeons. Unfortunately, the ideal filler has not yet been discovered and all of them may induce adverse reactions. Quickly biodegradable or resorbable agents may induce severe complications, but they will normally disappear spontaneously in a few months. Slowly biodegradable or nonresorbable fillers may give rise to severe reactions that show little or no tendency to spontaneous improvement. They may appear several years after the injection, when the patient does not remember which product was injected, and treatment is often insufficient. In this review, we discuss the most commonly used fillers, their most frequent adverse reactions as well as the characteristic histopathologic findings that allow the identification of the injected filler agent. In conclusion, histopathologic study remains as the gold standard technique to identify the responsible filler. ( J Am Acad Dermatol 2011;64:1-34.) Learning objectives: After completing this learning activity, participants should be able to recognize the most frequent adverse reactions induced by cosmetic fillers, identify their histopathologic characteristics so that they can be distinguished from each other, and advise their patients with adverse reactions about the different nature of these according to the filler for subsequent successful treatment. Key words: adverse reactions; bovine collagen; calcium hydroxylapatite; dextranomers; fillers; histopathology; hyaluronic acid; paraffin; polyacrylamide; polyalkylimide; poly-L-lactic acid; polymethylmethacrylate; polyvinylhydroxide; polyvinylpyrrolidone; silicone.

uring the last few decades, cosmetic dermatology has been growing with many different techniques for ‘‘rejuvenation.’’ Among them, injection techniques with filler agents are often used for wrinkle treatment and soft tissue augmentation. The treatment of age wrinkles, correction of atrophic scars or small cutaneous defects, and cosmetic soft tissue augmentation of different parts of the body are currently common parts of daily practice for many dermatologists and plastic surgeons. The ideal injectable material for wrinkle treatment or soft tissue augmentation should offer good aesthetic results and have a long-lasting effect. It should also be safe, biocompatible, and stable at the

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implantation site, with minimal complications and no risk of migration.1,2 Unfortunately, the ideal filler has not yet been discovered, although available agents are numerous and varied. Some of them seem to be less risky than others, but all of them can induce adverse reactions. Agents that degrade within months—such as collagen, hyaluronic acid, and agarose gel—may induce severe complications, but these will in general disappear spontaneously in a variable period of time. All other fillers can give rise to severe adverse reactions, and these show little or no tendency to spontaneous improvement. They may appear several years after the injections, when the patient does not remember which product was

From the Departments of Dermatology, Fundaci on Jimenez Dıaz,a Universidad Aut onoma, Madrid, and the Instituto Valenciano de Oncologıa,b Valencia, Spain; Department of Pathology,c Bispebjerg Hospital, University Hospital, Copenhagen, Denmark; Centre de Pathologie Cutanee de la Roquette,d Paris, France; Dermatopathologische Gemeinschaftspraxis,e Friedrichshafen, Germany; and the Department of Dermatology, University of Graz, Graz, Austria.f Robert T. Brodell, MD, JAAD CME Planner, has disclosed the following financial relationship: Medicis - Advisory Board/Honoraria. All other authors, editors, planners, editorial and education staff

involved with this CME activity and all content validation/peer reviewers of this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Reprints not available from the authors. Correspondence to: Luis Requena, MD, Department of Dermatology, Fundaci on Jimenez Dıaz, Avda. Reyes Cat olicos 2, 28040-Madrid, Spain. E-mail: [email protected]. 0190-9622/$36.00 ª 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.02.064

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injected, and treatment is often ineffective. Someassignment of the culpability of the filler or fillers times, surgical excision of the injected agent is the causing the adverse reaction. only therapeutic possibility, resulting in poorer cosmetic results than those which were attempted to BOVINE COLLAGEN correct by filler in the first place. Key points In this review, we will discuss the most commonly d Bovine collagen is a resorbable filler; the used fillers and their most frequent adverse reactions. duration of the effect from an injection of Special attention will be fobovine collagen procused on the characteristic ducts is usually less CAPSULE SUMMARY histopathologic findings that than 6 months d Histopathologically, boallow the identification of the All cosmetic fillers may induce adverse specific filler agent. This is vine collagen fibers are reactions. Complications secondary to necessary because only a much thicker than hubiodegradable or resorbable fillers will dermatopathologic examinaman collagen, have a disappear spontaneously in a few tion can identify precisely homogeneous appearmonths, but nonresorbable fillers may which filler is involved and ance nearly devoid of give rise to severe permanent reactions. therefore determine the type spaces between them, of adverse inflammatory reHistopathologic study of the cutaneous with fewer fibroblasts, action for optimal treatment. lesions is the criterion standard and fail to refract polarIn litigation cases, dermatotechnique to identify the responsible ized light d Skin tests are required pathologic evaluations of filler of the adverse reaction, because the skin specimens have been particles of each filler have specific before the injection of used as proof of association microscopic characteristics. bovine collagen products d Rare hypersensitive rebetween a filler and the paTreatment of cutaneous adverse tient’s subsequent skin reacactions to bovine collareactions to permanent fillers is often tion. This can be determined gen include foreign ineffective, and surgical excision of the because each filler has spebody granulomas and injected agent is typically the only cific histopathologic feapalisading granulomas therapeutic possibility. tures. This is particularly important in cases where a Bovine collagen has been number of different fillers have been injected in the used as injectable filler in human subjects for same site, or where the patients had not been nearly 30 years. Originally, this collagen was correctly informed concerning the procedure and injected into the dermis and subcutaneous tissue filler used. to correct depressed acne scars, viral pockmarks, Some authors have proposed a grading sysand lipoatrophy,4 but shortly thereafter the product tem classification of foreign body reactions was popularized for correcting deep nasolabial induced by injected fillers into four categories3: folds (Fig 1), age-related rhytides,5 and soft tissue grade I, slight reaction with a few inflammatory cells; augmentation, especially lip enhancement.6 The grade II, clear inflammatory reaction with one or two duration of the effect from an injection of bovine giant cells; grade III, fibrous tissue with inflammatory collagen is usually less than 6 months. However, cells, lymphocytes, and giant cells; and grade IV, variations in longevity are frequent depending on granuloma with encapsulated implants and clear collagen gel subtype, amount injected, mechanical foreign body reaction. stress at the treatment site, location, and individual In our experience, however, this classification response.7 system is difficult to apply in a specific case because Animal studies using bovine collagen8 and huthe intensity of the inflammatory response in foreign man histopathologic studies of bovine collagen body granulomas varies from one histopathologic implants in aging human facial skin5 have revealed section to another—or even within different areas of recipient collagen production that gradually rethe same section. places the injected collagen after implantation. Table I lists the most common fillers that are Ultrastructural studies identified fibroblasts within currently used. They have been classified into two the implant with dilated rough endoplasmic reticumain categories, namely transitory biodegradable or lum, which was indicative of active collagen secretresorbable within months and years respectively, ing cells,5 and direct immunofluorescent studies and permanent or nonresorbable. The trademark have also shown the deposition of type III collagen of each filler is also included for a more easy by the host during the bovine collagen resorption.9 d

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Table I. The most common injectable fillers for soft tissue augmentation Category

Resorbable within months

Chemical composition

Trade name*

Bovine collagen

Zyderm and Zyplast

Human-derived collagen

Autologen, Cosmoderm, Cosmoplast, and Cymetra Hylaform, Restylane, Juv ederm, Perlane, and Macrolane Matridex and Reviderm intra

Hyaluronic acid Resorbable within years

Permanent

Hyaluronic acid plus dextranomer microparticles Poly-L-lactic acid microspheres plus sodium carboxymethylcellulose, nonpyrogenic mannitol, and sterile water Calcium hydroxylapatite plus carboxymethylcellulose and glycerine Paraffin Silicone oil Silicone gel Silicone elastomer particles plus polyvinylpyrrolidone Polymethylmethacrylate microspheres and bovine collagen Hydroxyethylmethacrylate/ethylmethacrylate fragments and hyaluronic acid Polyacrylamide hydrogel

Polyalkylimide gel Polyvinylhydroxide microspheres plus polyacrylamide gel

Sculptra and New-Fill

Radiance and Radiesse

Silikon 1000 and Silskin MDX 4-4011 and Dow Corning Bioplastique Artecoll, Arteplast, and Artefill Dermalive and Dermadeep Aquamid, Interfall, OutLine, Royamid, Formacryl, Argiform, Amazingel, Bio-Formacryl, and Kosmogel Bio-Alcamid Evolution

*Trade names are owned by their respective manufacturers as noted in the manuscript.

Histopathologically, bovine collagen can be differentiated from human collagen because bundles of bovine collagen are much thicker and have a homogeneous appearance nearly devoid of spaces between them and with fewer fibroblasts,10 which by the colloidal iron stain have been shown to secrete glycosaminoglycans between the fibrils of the implant.11 Furthermore, human collagen is birefringent under polarized light and stains green with Masson trichrome stain, whereas bovine collagen fails to refract polarized light and stains with a pale gray-violet color with Masson trichrome stain.7,11 Early dermal implants induce a characteristic subepidermal response that consists of edema and fibroplasia of the papillary dermis.11 Within a few weeks, a perivascular lymphohistiocytic infiltrate is observed around the periphery of the implant. Invasion of the implant by neoformed host vessels is not seen.11 The inflammatory response around the implant is usually more dense when the bovine collagen is injected in the reticular dermis or partially infiltrates the subcutaneous fat, but panniculitis is not observed when the implant is confined to the dermis.11

Fig 1. Granulomatous reaction after bovine collagen injections in the nasolabial folds.

Zyderm I (Inamed, Santa Barbara, CA) was the first bovine collagen introduced in the market as injectable filler and is composed of a phosphatebuffered saline solution of 35 mg/mL of collagen with 0.3% lidocaine. Zyderm I was followed by Zyderm II (Inamed), a concentration of 65 mg/mL of collagen with 0.3% lidocaine, and by Zyplast (Inamed), which was developed to provide a longer-lasting effect by cross-linking collagen fibrils with glutaraldehyde. Zyplast is more resistant to

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proteolytic degradation and is less immunogenic.12 In addition, Zyplast has a lower viscosity than Zyderm I and Zyderm II and this makes it applicable for deeper contour defects. Skin tests are required before injection of these products, because 3% of the population develops a delayed hypersensitivity response. This is characterized by local erythema, swelling, and induration occurring 48 to 72 hours following intradermal injection of a 0.1-mL aliquot of collagen injectable in the volar forearm, indicating a preexisting allergy to bovine collagen.13-17 Some authors even recommend a second skin test either 2 or 4 weeks after a negative first test before initiating therapy, because 2% of patients will develop hypersensitivity after repeat exposure despite initial nonreactivity.18-20 Because most treatment-associated allergic reactions to bovine collagen occur shortly after the first treatment, double testing greatly reduces the frequency of this hypersensitivity side effect.21 Additional rare hypersensitive reactions include the formation of foreign body granulomas,7,22-25 palisading granulomas resembling granuloma annulare at the test site injections26,27 (one of these patients had a history of granuloma annulare and the reaction at the site injection might also be caused by Koebner phenomenon27), and cyst or abscess formation.28 Rare examples of disseminated and recurrent sarcoid-like granulomatous panniculitis caused by bovine collagen injection have also been described.29 Some authors differentiated a palisading granuloma (Fig 2), occurring mainly 2 or 3 months after injection and located in the mid to reticular dermis, from a diffusely organized granuloma, which was more frequent within the first 2 weeks and located in the reticular dermis and the subcutaneous tissue.30 Hypersensitivity reactions are associated with antiebovine collagen antibodies,12,31,32 which do not cross-react with human collagen.14,15,28 Allergic reactions to bovine collagen may be treated with topical, intralesional, or a brief course of systemic corticosteroids, and there are also reports of patients who have been successfully treated with oral cyclosporine33 or topical tacrolimus.34,35 Zyderm I is used for correction of superficial wrinkles, whereas Zyderm II is more effective in moderate to deep wrinkles, and both of them should be injected in the superficial dermis. In contrast, Zyplast works best when placed at the mid-dermis and is more valuable in treating deeper lines, such as nasolabial folds, deep acne scars, and lip augmentation through injection in the vermillion border. A slight degree of overcorrection (10%-20%) is sought when injecting bovine collagen, but

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persistent whiteness at the injection site and elevation can be observed with excessive overcorrection or when the injected material is placed too superficially.36-38 Other rare adverse localized effects at the site of the injection consist of ‘‘sterile’’ abscess formation39 (‘‘sterile’’ meaning negative culture), which is histopathologically characterized by numerous neutrophils, lymphocytes, plasma cells, and multinucleated giant cells surrounding particles of injected collagen, cellular debris, and hemorrhage. The inflammatory reaction is either confined to the implant or it can extend to the adjacent tissue, which appears richly vascularized. More uncommon side effects include bruising, the reactivation of herpetic infection, verified bacterial infection, and local necrosis. This is mostly seen with Zyplast injected at the glabellar area because of vascular interruption at the treatment site, and injections of Zyplast should therefore be avoided in this region.39 There have also been two reports of irreversible unilateral or bilateral vision loss after bovine collagen injection, probably resulting from an occlusive event involving the retinal artery.12,40 Rare systemic complications reported after injections of bovine collagen include flulike symptoms, paresthesias or difficulty breathing,41 and severe anaphylactic shock.42 Although some initial studies proposed that there may be a triggering effect of dermatomyositis in patients with injected bovine collagen,43 retrospective studies have found no evidence that bovine collagen induce connective tissue disease in human subjects.31,32,44-47

HUMAN-DERIVED BIOENGINEERED COLLAGEN IMPLANTS Key points d

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Human-based collagen implants have been investigated in recent years to avoid the hypersensitivity adverse reactions to bovine collagen No skin tests for hypersensitive reactions are required for any of these human-derived collagen products

To avoid hypersensitive adverse reactions to bovine collagen, human-based collagen implants have been produced in recent years. Autologen (Collagenesis, Beverly, MA) is an injectable autologous human tissue matrix primarily composed of intact collagen fibrils that are processed from the patient’s own skin and harvested during elective surgery.48,49 Human collagen implants are also obtained from human donor tissues that undergo extensive screening for infectious disease and the

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Fig 2. Histopathologic features of granulomatous reaction to bovine collagen. A, Scanning power showing palisading granulomas in the subcutaneous tissue. B, Higher magnification showing well circumscribed palisading granulomas. C, Bovine collagen at the center of the granulomas reveals a homogeneous eosinophilic appearance. D, Bovine collagen fibers are much thicker than those of human collagen and they have a homogeneous appearance nearly devoid of spaces between them and with fewer fibroblasts. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400. Photographs courtesy of Mark Jacobson, MD, New York, NY.)

material is irradiated before use. Dermal fibroblasts harvested from bioengineered human skin cells produce types I and III human collagen and extracellular matrix proteins. As the counterpart of the bovine collagen products, human-derived collagen implants have been named Cosmoderm I (Inamed), which contains 35 mg/cc human-based collagen dispersed in a phosphate-based saline solution and 0.3% lidocaine, Cosmoderm II (Inamed)—which contains about twice the collagen concentration of Cosmoderm I—and Cosmoplast (Inamed), which has the same ingredients as Cosmoderm I but is cross-linked by glutaraldehyde, making it more resistant to degradation and allowing for deeper placement of the injectable material.50,51 Cymetra (LifeCell, Branchburg, NJ) is another human-derived collagen containing micronized cadaveric-derived collagen.52 The cosmetic effect lasts about 4 to 7 months, depending on the area of treatment, injection technique, and amount of injected collagen.53 No skin test for hypersensitive reactions are required for any of these human-derived collagen products. Local adverse reactions include bruising,

erythema, and swelling at the site of injection. However, there also are few reported cases of granulomatous reaction at the site of the injection48 or at the skin test after injection of acellular human collagen.53

HYALURONIC ACID Key points d

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Hyaluronic acid gel is used as a resorbable filler; the longevity of the injected gel is about 6 months Hyaluronic acid has no organ or species specificity, and therefore in theory there is no risk of an allergic reaction Very few adverse hypersensitivity reactions secondary to injections of hyaluronic acid used as filler have been reported; histopathologically, they consisted of a granulomatous foreign body reaction, with abundant multinucleated giant cells surrounding an extracellular basophilic amorphous material, which was the injected hyaluronic acid gel

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Hyaluronic acid is one of the components of the normal skin forming part of the extracellular matrix of the dermis and providing support for other tissues. Chemically, hyaluronic acid is a glycosaminoglycan polysaccharide composed of alternating residues of the monosaccharide d-glucuronic acid and N-acetyl-d-glucosamine, both normally present in the human body.54 It is produced by dermal fibroblasts, synovial cells, endothelial cells, smooth muscle cells, adventitial cells, and oocytes, and is released into the surrounding extracellular space. Here, it functions as a hygroscopic material because it is capable of capturing large amounts of water, as seen in wound healing55,56 and in the lubrication of joints.57 Hyaluronic acid also acts as an important free radical scavenger,58 and it may indirectly stimulate some neocollagenogenesis after injection through mechanical stretching of the dermis and subsequent activation of dermal fibroblasts.59 Injections of hyaluronic acid gel are used for filling out wrinkles of the face, for soft tissue augmentation, and for the correction of all types of defects, such as scars and facial lipoatrophy. For the majority of patients, the longevity of the injected hyaluronic acid lasts for about 6 months, although slight variations occur depending on quantity, anatomy, and individual characteristics. There are two sources for industrial production of the hyaluronic acid used as a gel filler agent for soft tissue augmentation: an animal hyaluronic acid produced from rooster combs (Hylaform [Biomatrix, Ridgefield, NJ), and a nonanimal stabilized hyaluronic acid produced by bacterial fermentation from specific strains of streptococci (Restylane [Medicis Aesthetics, Scottsdale, AZ], Juv ederm [Allergan, Santa Barbara, CA], Perlane [Medicis Aesthetics], and Macrolane [QMed, Uppsala, Sweden]). Both types contain a small amount of protein, and a stabilization process modifies the hyaluronic acid molecule. Hyaluronic acid has no organ or species specificity, and therefore in theory there is no risk of an allergic reaction if exogenous hyaluronic acid is injected into the skin.60 Therefore, no skin testing is necessary before injecting hyaluronic acid because it is biodegradable. In fact, in spite of its frequent use for cosmetic reasons, there are very few descriptions of hypersensitivity reactions secondary to injections of hyaluronic acid used as a filler into the skin61-77 (Fig 3), and although Micheels78 described circulating antibodies against hyaluronic acid in patients after several injections, these findings could not be confirmed by other investigators.79 It may also be possible that the described hypersensitivity reactions are caused by

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Fig 3. Granulomatous reaction on the right side of the upper lip 2 months after the injection of hyaluronic acid (arrows indicate swollen areas of the upper lip).

impurities from the bacterial fermentation process, such as contaminating DNA, rather than to hyaluronic acid.71 Manna et al80 showed up to four times the quantity of protein in certain lots of Restylane as compared to the same volume of preparation of certain lots of Hylaform. Filion and Phillips81 further confirmed these findings when they studied low molecular weight fragments obtained from different preparations of hyaluronic acid. They revealed that some of these preparations stimulated the synthesis of interleukin-12 and tumor necrosis factorea in human monocytes, and that treatment of these preparations with deoxyribonuclease reduced the induction of proinflammatory cytokines by these cells. These findings might explain the rare reports of delayed hypersensitivity reactions in patients treated with hyaluronic acid gel injections.61-77 Histopathologically, a granulomatous foreign body reaction involves the dermis, with abundant multinucleated giant cells surrounding an extracellular basophilic amorphous material (Fig 4), the injected hyaluronic acid gel.82-85 Scant amounts of hyaluronic acid may be also seen within multinucleated giant cells. The hyaluronic acid stains positively for Alcian blue at a pH of 2.7 and is negative when examined under polarized light.85 A prominent eosinophilic granulomatous reaction has been described at the site of hyaluronic acid injections,77 and in another case,66 the adverse reaction to the injected hyaluronic acid for lip augmentation showed a granulomatous foreign body reaction surrounding a bluish amorphous material intermingled with numerous polymorphonuclear leukocytes. A suppurative granuloma developed, and bacterial infection could not be ruled out. Intralesional hyaluronidase injections are the treatment of choice when local hypersensitivity reactions are to be reversed.86-89 Severe systemic hypersensitivity reactions secondary to injections of hyaluronic acid fillers are even more

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Fig 4. Histopathologic features of a granulomatous reaction to hyaluronic acid. A, Low power view showing basophilic material at different levels of the dermis. B, Higher magnification showing basophilic deposits of variable size and shape that correspond to the injected hyaluronic acid. C, In some areas, the basophilic material is surrounded by histiocytes and multinucleated giant cells. D, Close view of the injected hyaluronic acid. (Hematoxylineeosin stain; original magnifications: A, 320; B, 340; C, 3200; D, 3400)

rare than local side effects.90,91 However, nonallergic local side effects at the sites of injections are frequent, including pain, bruising, and transient edema, but they disappear in a few days and usually do not need any treatment.92 It has been suggested that the reason hyaluronic acid fillers cause more swelling and bruising than collagen fillers is the anticoagulant effect of hyaluronic acid, which has a structural similarity to heparin.93,94 The too superficial placement of hyaluronic acid fillers or an uneven distribution of the injected product can lead to visible, pale nodules in the skin. Uncommon additional nonallergic reactions that have been described secondary to hyaluronic acid injections into the skin include herpes reactivation, bacterial infections, aseptic abscess,95 generalized scleromyxedema,96 scar sarcoidosis,97 interferon-induced systemic sarcoidosis in patients with chronic hepatitis C—who also developed sarcoidal granulomas around the injected hyaluronic acid filler98—and necrosis and livedoid pattern after accidental arterial embolization.99 There are reports describing an outbreak of Mycobacterium chelonae infection after soft tissue augmentation with hyaluronic acid derivate

fillers,100,101 but is not clear whether the injected material was contaminated with the mycobacteria during the manufacturing process or whether they were inoculated during the injection procedure, because the administration was performed in a nonmedical setting.

HYALURONIC ACID PLUS DEXTRANOMER MICROPARTICLES Key points d

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Resorbable filler composed of a mixture of nonanimal stabilized hyaluronic acid and dextranomer microspheres A single case report of foreign body granuloma caused by this filler has been described Histopathologic study showed a suppurative granuloma surrounding the hyaluronic acid and the spherical dark bluish particles that represented the dextranomer microparticles

This is a new resorbable gel suspension filler composed of a mixture of nonanimal stabilized hyaluronic acid, cross-linked hyaluronic acid, and dextranomer microspheres (Matridex [BioPolymer,

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Siershahn, Germany] and Reviderm intra [Rofil Medical International, Breda, Netherlands]). It has been used for the aesthetic treatment of facial lines, wrinkles, folds, and lip augmentation. The main component of Matridex is the dextranomer microspheres, which are composed of cross-linked dextran molecules (80-120 m in diameter) with a positive surface charge.102 A single case report of foreign body granuloma caused by Matridex has been described.103 The patient, a 43-year-old woman, developed erythematous nodules on both cheeks and the periorbital skin 4 weeks after the injection of Matridex (Fig 5). The histopathologic study revealed a suppurative granuloma surrounding exogenous material, composed of bluish-greyish filamentous material of hyaluronic acid particles with bizarre configuration and spherical dark bluish particles, representing the dextranomer microparticles (Fig 6). Surgical incision of the nodules and conservative treatment with systemic cephalexin and topical methylprednisone aceponate allowed complete resolution of the lesions in 6 months.

POLY-L-LACTIC ACID Key points d

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Poly-L-lactic acid is a resorbable filler that induces tissue augmentation that lasts up to at least 24 months The development of nodules at the site of injection is frequent; they are palpable but generally not visible Histopathologically, granulomatous adverse reactions at the sites of injection reveal a foreign body granuloma, with numerous multinucleated giant cells around translucent particles of different sizes, most of them showing a fusiform, oval, or spiky shape; these particles are birefringent in polarized light examination

Injectable poly-L-lactic acid (Sculptra [SanofiAventis, Bridgewater, NJ] and New-Fill [Dermik Laboratories, Berwyn, PA]) is a dermal filler that has been used to correct the signs of lipoatrophy in HIV patients receiving antiprotease treatment and for facial cosmetic augmentation.104-113 Injectable poly-L-lactic acid is a biocompatible, biodegradable, synthetic filler that must be injected into the reticular dermis or subcutaneous fat. In animal models, this synthetic polymer seems to be able to stimulate the activity and proliferation of dermal fibroblasts with subsequent endogenous production of collagen.108,114 Histologic studies in humans have shown gradual dissolution of the injected poly-L-lactic and

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Fig 5. Erythematous nodules on the cheek 4 weeks after the injection of Matridex (BioPolymer, Siershahn, Germany).

dermal ingrowth of type I collagen over 8 to 30 months after injection.115,116 An increase in volume is correspondingly gradual, starting 3 months after the injection and achieving a maximum at approximately 5 to 6 months postinjection. Even though poly-L-lactic is gradually degraded into water and carbon dioxide by nonenzymatic hydrolysis over approximately 9 to 24 months,117,118 neoformed collagen remains and the cosmetic augmentation has been noted to last up to at least 24 months.110,116-120 Nodules at the site of injection, which are palpable but generally nonvisible, are frequently described in about 30% to 40% of patients, and without treatment they tend to persist for months or years.113 Visible papules can also be seen, but they generally resolve spontaneously in a few weeks. A significant reduction of the frequency of the nonvisible but palpable nodules has been achieved with higher reconstitution volume of the injected filler (5 mL of sterile water for injection rather than 3 mL), a longer time between reconstitution and injection (36-48 hours rather than 2-12 hours), injections into the subcutaneous tissue rather into the reticular dermis, and postinjection massage.108,111 Like with other fillers, local shortterm, injection-related adverse events are frequent, including erythema, bruising, swelling, pain, inflammation, and pruritus, but they resolve spontaneously in a few days. Late-onset infections and histopathologically confirmed foreign body granulomas at the sites of injection have also been described121-127 (Fig 7). Severe systemic adverse effects secondary to poly-L-lactic injections are very rare, with only one case being described as

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Fig 6. Histopathologic features of granulomatous reaction to Matridex (BioPolymer, Siershahn, Germany). A, Scanning power showing a suppurative granuloma surrounding exogenous material. B, The exogenous material is composed of bluish-greyish filamentous material of hyaluronic acid and spherical dark bluish particles, which represent the dextranomer microparticles. C, Higher magnification of the filamentous hyaluronic acid. D, Higher magnification of a microsphere of dextranomer. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3400; D, 3400.)

an anaphylactic reaction necessitating treatment interruption.128 Histopathologic study of granulomatous adverse reactions at the sites of injection demonstrates a foreign body granuloma, with numerous multinucleated giant cells around translucent particles of different sizes, most of them showing a fusiform, oval, or spiky shape, similar to cholesterol clefts, but shorter and wider (Fig 8). Some of these particles may also be seen within the cytoplasm of the multinucleated giant cells.87 Poly-L-lactic acid particles are birefringent in polarized light examination (Fig 9). Some of the multinucleated giant cells may contain asteroid bodies within their cytoplasm and there is also a lymphocytic infiltrate intermingled with the foreign body granuloma. Histopathologically, the aspect of the particles of this filler is quite similar to that of suture remains frequently observed in routine skin biopsies, a useful histopathologic diagnostic clue. The granulomatous reaction to poly-L-lactic particles may persist at least 18 months after injection.82 Bacteria

Fig 7. Granulomatous reaction to injections of New-Fill (Dermik Laboratories, Berwyn, PA) for treatment of facial lipoatrophy in a HIV patient.

have been searched for to find etiology of this reaction, but no microorganisms were detected by polymerase chain reaction/DNA analysis in 6 cases of granulomatous reaction to poly-L-lactic particles.129

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Fig 8. Histopathologic features of granulomatous reaction to New-Fill (Dermik Laboratories, Berwyn, PA). A, Scanning power. B, Foreign body granuloma, with numerous multinucleated giant cells around translucent particles. C, Most of the particles show fusiform or oval shape. D, Higher magnification of the New-Fill particles surrounded by multinucleated giant cells. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

CALCIUM HYDROXYLAPATITE Key points d

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Resorbable filler composed of calcium hydroxylapatite microspheres that stimulate the endogenous production of collagen Histopathologically, microspheres of calcium hydroxylapatite stimulate almost no foreign body reaction and they appear bluish in color and round or oval in shape

Injectable calcium hydroxylapatite (Radiance FN and Radiesse [BioForm Medical, San Mateo, CA]) is, like poly-L-lactic acid, a resorbable filler containing microspheres that stimulate the endogenous production of collagen. The product has a texture resembling native soft tissue and migration is minimal.130 Initial augmentation is afforded by the implant itself, but in a few months the palpable implant diminishes further in size and has disappeared clinically at 9 to 12 months. When macrophages begin to degrade the implant, new collagen may form around the calcium hydroxylapatite microspheres.131 Injectable microspheres of calcium hydroxylapatite have been successfully used for correction of lipoatrophy of HIV patients receiving antiprotease

treatment and for smoothing moderate wrinkles.130-136 When this agent is injected in the lips, it tends to be associated with a high incidence of nodules137 (Fig 10). Migration to a distant location from the injection site has also been described.138 Histopathologically, microspheres of calcium hydroxylapatite stimulate almost no foreign body reaction, and because only few macrophages are seen around the particles,139,140 it is suggested that the microspheres of this implant are degraded by enzymatic breakdown rather than phagocytosis. The microspheres appear packed together, with bluish color, round or oval shape, 25 to 40 m in size, and surrounded by some fibrin fibers but little cellular infiltrate. In some patients, however, calcium hydroxylapatite microspheres may induce a foreign body granulomatous reaction (Fig 11), seen as blue-gray microspheres in the extracellular matrix or within multinucleated giant cells.1,85

PARAFFIN Key points d

Paraffin is no longer used as filler because of its frequent adverse reactions, but

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Fig 9. The same section of the previous figure seen under polarized light examination showing birefringent particles of New-Fill (Dermik Laboratories, Berwyn, PA). (Hematoxylineeosin stain and polarized light microscopy; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

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because it is a nonresorbable material, today it is still possible to see granulomatous reactions secondary to injections from many years ago Sclerosing lipogranuloma results from injection of paraffin in the penis causing fibrosis and deformity of the penis body Histopathologically, paraffinoma shows a mostly lobular panniculitis, in which the subcutaneous fat exhibits a Swiss cheese appearance, with cystic spaces of variable size and shape, surrounded by foamy histiocytes and multinucleated giant cells

Paraffin was used in the past as a filler for augmentation of tissues, mostly in the breasts, penis, buttocks, and calves, and it is included here only because of historical interest. Although no longer in use because of frequent adverse reactions and the advent of better fillers, this nonresorbable material may still today induce granulomatous reactions, which are known to appear many years after the injection. Moreover, accidental injections of paraffin and other mineral oils, such as sheep lanolin, petroleum jelly, and vitamin E, can still be seen today, and patients with psychiatric or personality disorders

Fig 10. Nodules in the lower lip after injections of calcium hydroxylapatite microspheres.

may be capable of injecting themselves with a wide variety of substances.141-163 A specific form of paraffinoma is the so-called sclerosing lipogranuloma, which results from injection of paraffin in the penis causing fibrosis and deformity of the penis body143,145,148,150,151,154,156,158,161,162 (Fig 12). The involved areas of paraffinoma appear as erythematous indurated plaques and in rare instances the lesion may ulcerate the overlying epidermis, mimicking a squamous cell carcinoma.145 Some of these patients suffer from psychiatric problems and have

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Fig 11. Histopathologic features of granuloma secondary to injections of calcium hydroxylapatite microspheres. A, Scanning power showing a diffuse involvement of the corium of the oral mucosa. B, The epithelium of the oral mucosa is not involved. C, Granulomas surrounding the calcium hydroxylapatite microspheres. D, Higher magnification showing that microspheres appear bluish in color, are round or oval in shape, and are surrounded by histiocytes and multinucleated giant cells. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400. Photographs courtesy of Mark Jacobson, MD, New York, NY.)

self-administered the injections with resulting factitial panniculitis—an often challenging diagnosis. Adverse effects are typically confined to the sites of injections and adjacent skin, but there are also reports of involvement of lymph nodes and lungs, presumably from lymphatic or hematogenous spread. A case of disseminated lipogranulomas and sudden death from self-administered mineral oil injections has been also reported.147 Histopathologically, lesions of paraffinoma involve the reticular dermis and subcutaneous tissue that shows a mostly lobular panniculitis, in which the subcutaneous fat exhibits a Swiss cheese appearance, with cystic spaces of variable size and shape, surrounded by foamy histiocytes and multinucleated giant cells149,162 (Fig 13). The stroma is composed of bundles of sclerotic collagen between the foamy histiocytes and the cystic spaces. The connective tissue septa show an inflammatory infiltrate of mostly lymphocytes and plasma cells. If frozen sections are available, the mineral oils stain with Oil-red-O, Sudan, Nile blue, and Osmic acid. Infrared absorption

Fig 12. Sclerosing lipogranuloma secondary to paraffin injections for augmentation of the penis.

spectrophotometry and thin layer chromatography can also be used to identify the presence of paraffin in tissue specimens.85

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Fig 13. Histopathologic features of paraffinoma. A, Scanning power showing a mostly lobular panniculitis. B, Subcutaneous fat exhibits a Swiss cheese appearance, with cystic spaces of variable size and shape. C, Cystic spaces are surrounded by foamy histiocytes and multinucleated giant cells. D, Higher magnification revealing foamy histiocytes around the cystic space. Note the sclerotic collagen bundles of the stroma. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

SILICONE Key points d

d

d

d

Silicone is the most widely studied filler material for soft tissue augmentation There are credible reports of silicone gel migrating to sites distant from the injection site There is no scientific basis for any association between silicone breast implants and any well-defined connective tissue disease Histopathologic findings in local reactions to implants of silicone are variable and depend largely on the form of the injected silicone; solid elastomer silicone induces an exuberant foreign body granulomatous reaction, whereas silicone oil and gel induce a sparser inflammatory response; silicone particles appear as groups of round empty vacuoles of different sizes between collagen bundles or within macrophages; silicone particles are not birefringent under polarized light

Silicone is a polymeric hydrophobic compound of dimethylsiloxanes that may be injected as oil (Silikon

1000 and Silskin [both from Richard-James, Peabody, MA]) or gel (MDX 4-4011 [Dow Corning, Midland, MI]), or implanted as solid silicone rubber implants (Silastic [Dow Corning]).164 Dimethylsiloxanes are compounds of methane, oxygen, and elemental silica. In its liquid and gel forms, injections of silicone have been used in more than 100,000 patients for cosmetic correction of small wrinkles or scars of the face (Fig 14) and volume augmentation of soft tissues. More recently, it has also been used as a filler to circumvent facial lipoatrophy in HIV patients receiving antiprotease treatment,165 making this gel the most widely studied of all filler materials for soft tissue augmentation.166,167 Medical-grade silicone refers to a pure and sterile preparation with consistent viscosity of 360 centistokes. Silicone gel is a hydrophobic oil-like compound that has a high affinity for cell membranes,168 entering into the cytoplasm of circulating inflammatory cells, mostly macrophages,169-173 and by this route migrating along the reticuloendothelial system to regional lymph nodes,174,175 the liver,176 and the spleen.177 To avoid the side effects that result from using large amounts of liquid silicone, ‘‘bag-gel’’ implants were introduced, mostly for augmentation of the

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Fig 14. Granulamatous reaction secondary to injections of silicone gel for the treatment of acne atrophic scars. A, Nodules on the chin. B, Lateral view of the nodules on the chin. C, One of the nodules is opened to the skin surface. D, Close-up view of the eroded skin surface.

breasts.178 However, leakage of silicone may also occur through these bags, either by diffusion or after trauma (Fig 15), and silicone gel is capable of migrating to distant sites, where it may give rise to an inflammatory reaction and hamper clinical diagnosis178-182 (Fig 16). It appears, however, as if most cases of migration is favored by gravity in patients with very lax skin and subcutaneous tissue, where the silicone implant has sagged downward distally from the injected site. Several disparate side effects secondary to silicone implants have been described in the literature, but none of them are clearly related to the silicone itself. Localized morphea has been described in the skin adjacent to the site of a leaking silicone gel breast implant,183 and in the past decade there has been considerable controversy in the literature about the relationship between systemic scleroderma and other connective tissue diseases and the use of breast implants containing silicone gel.174,175,184-187 There appears to be little scientific basis for any association between silicone breast implants and any welldefined connective tissue disease.188 A recent report raised the possibility of a relationship between silicone breast implants and mesenchymal tumors of the breast, describing six cases of fibromatoses and one case of pleomorphic

Fig 15. Inflammatory reaction secondary to rupture of a ‘‘bag-gel’’ implant of silicone for breast augmentation.

undifferentiated sarcoma. Nevertheless, the authors concluded that surgical trauma, perhaps occurring in patients with a predisposition to develop desmoid tumors, could account for fibromatosis in this setting and that the relationship between implants and the sarcoma was probably casual.189 The rare finding of an anaplastic large cell lymphoma of the breast and silicone breast implants is probably coincidental.190 Local reactions at the sites of injections include pain, erythema, ecchymosis, hyperpigmentation and hypopigmentation of the overlying skin, induration and inflammatory nodules, also named

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Fig 16. A, Transsexual patient who received injections of liquid silicone for buttock augmentation. B, Five years later, silicone migrated to distant sites of the lower leg, where it produced an inflammatory reaction. C, Nodules and inflammatory reaction to silicone in the lower leg.

‘‘siliconomas,’’ which are sometimes resolved with dystrophic scars.121,178,191-198 The diagnosis is not always clinically suspected, because these reactions may develop many years after the tissue augmentation. Granulomas have also been described in the skin at the point of entry of acupuncture and venepuncture needles coated with silicone and particles of silicone have been detected in macrophages with radiographic microanalysis.199 Although rare, severe local reactions with ulceration of the skin overlying areas of subcutaneous injections of liquid silicone have also been reported.191,200-202 Other complications of solid silicone implants in deeper tissues are rare, but the literature shows descriptions of bone erosion, infection, seroma, and implant extrusion.203 Pulmonary embolism, acute pneumonitis, and granulomatous hepatitis are very rare systemic complications after the fraudulent use of large amounts of liquid silicone in transsexual patients.204,205 Histopathologic findings in local reactions to implants of silicone are variable depending mainly on the form of the injected silicone (liquid, gel, or solid elastomer type) and the amount of product implanted in the tissues.30,178,206 Solid elastomer silicone, both as the outer shell of a breast implant

and as fragments in a gel (see next paragraph), induces an exuberant foreign body granulomatous reaction in the dermis and subcutaneous tissue, with abundant numbers of macrophages and multinucleated giant cells (Fig 17). Often, some of the multinucleated giant cells contain asteroid bodies in their cytoplasm (Fig 18), and the adjacent dermis shows perilesional fibrosis. Silicone oil induces a sparser inflammatory response in the tissues than does solid silicone (Figs 19 and 20), and the implant appears in the form of interstitial vacuoles and cystic spaces of different sizes between collagen bundles, surrounded by a few macrophages, some of them with a foamy cytoplasm as a consequence of engulfed silicone.207 This histopathologic pattern has been named ‘‘Swiss cheese’’elike, and sometimes residual glassy-appearing material is found inside the vacuoles and cystic spaces. Although most of the silicone liquid is removed during paraffin embedding process, small amounts may persist, both inside the cytoplasm of macrophages and interstitially as groups of empty vacuoles of different sizes between collagen bundles. The vacuoles may simulate adipocytes, but they are smaller.178 Also, the histopathologic pattern should be not mistaken for a well-differentiated liposarcoma.208,209 In rare

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Fig 17. Histopathologic findings in a local reaction to a silicone breast implant. A, Diffuse inflammatory infiltrates involving the reticular dermis and subcutaneous tissue. B, Cystic spaces and vacuoles of different sizes in the reticular dermis. C, Cystic spaces and the smaller vacuoles are surrounded by multinucleated giant cells. D, Higher magnification of the vacuoles of different sizes that correspond to the implanted silicone. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

instances, eosinophils may be abundant in the infiltrate. Silicone particles are not birefringent under polarized light and the angulated translucent birefringent particles that occasionally are seen in silicone granulomas probably result from impurities by adulteration of the nonemedical-grade silicone compounds injected by nonprofessionals178 or from deposition of talc introduced at the time of the implant surgery.210 Sometimes, these impurities are nonbirefringent206,211 (Fig 21). Silicone can be detected by spectroscopy, by scanning electron microscopy, and by energy dispersive radiographic analysis.176,212-214 Silicone granulomas have been successfully treated with topical applications of imiquimod,215 intralesional injections of corticosteroids,216 and oral minocycline.217

POLYVINYLPYRROLIDONE-SILICONE SUSPENSION Key points d

This is a permanent filler comprised of particles of polymerized silicone elastomer dispersed in a carrier of polyvinylpyrrolidone

d

Histopathologically, granulomas secondary to this filler consist of irregularly shaped cystic spaces containing translucent, jagged ‘‘popcorn,’’ nonbirefringent particles of varying size dispersed in a sclerotic stroma surrounded by abundant multinucleated foreign body giant cells

This filler is comprised of particles of polymerized silicone elastomer, 100 to 600 m in size, dispersed in a carrier vehicle, polyvinylpyrrolidone (Bioplastique; Uroplasty BV, Geleen, The Netherlands). The suspension should be injected in the subcutaneous tissue and has been mostly used for the correction of facial rhytids and lip augmentation. The large size of the silicone particles prevent them from being phagocytosed by macrophages, and therefore they remain at the injected site, where they produce a local foreign body reaction and fibrosis, which contributes to the filling effect.218 Local side effects that have been described secondary to injections of Bioplastique include induration, swelling (Fig 22), and granuloma formation.219-221 Most investigators1,222,223 believe that granulomas occur more frequently after injection of

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Fig 18. Granulomatous reaction to a silicone breast implant. A, Exuberant foreign body granulomatous reaction. B, The granulomatous reaction is surrounding cystic spaces of variable size. C, This granulomatous reaction shows an abundant number of multinucleated giant cells. D, Some of the multinucleated giant cells contain asteroid bodies in their cytoplasm. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

particles with an irregular surface, such as Bioplastique or Dermalive (Dermatech, Paris, France), than after implantation of microspheres with a smooth surface, such as Artecoll (Artes Medical, San Diego, CA), NewFill, or Radiesse. The histopathologic study of granulomas secondary to Bioplastique injections reveals82,221 irregularly shaped cystic spaces containing translucent, jagged ‘‘popcorn,’’ nonbirefringent particles of varying size dispersed in a sclerotic stroma (Fig 23). The cystic spaces are surrounded by multinucleated foreign body giant cells, some of them containing asteroid bodies within their cytoplasm and many showing cytoplasmic ‘‘arabesque’’ projections into the lumina of the cystic cavities. Usually, some small lymphocytes and eosinophils are also present in the surrounding infiltrate.218,221

POLYMETHYL-METHACRYLATE MICROSPHERES AND BOVINE COLLAGEN Key points d

Biphasic filler composed of permanent implant of polymethylmethacrylate microspheres suspended in a degradable bovine collagen solution as a carrier

d

d

Intradermal tests are mandatory before the first use of this filler Histopathologically, adverse reactions to this filler show a nodular or diffuse granulomatous infiltrate surrounding rounded vacuoles of similar shape and size that mimic normal adipocytes and that correspond to the implanted polymethylmethacrylate microspheres

This is a biphasic filler composed of 30- to 42-m polymethylmethacrylate (PMMA) microspheres suspended at a 3.5% bovine collagen solution in a proportion of 4:1 (Artecoll, Arteplast, and Artefill [all from Artes Medial]).224,225 It also contains 0.3% lidocaine hydrochlorate for pain reduction at injection. This filler has been used in Europe since 1994 as a cosmetic microimplant for the correction of facial wrinkles and furrows, perioral lines, lip and philtrum augmentation, scar revision, and other subdermal defects. It was introduced in 1991 by Lemperle in Germany.226 The solid phase (permanent implant) is represented by PMMA microspheres, whereas the liquid phase is represented by degradable bovine collagen solution.225 The biocompatibility of PMMA has been shown

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Fig 19. Granulomatous reaction to silicone liquid. A, Silicone liquid induces sparser inflammatory response. B, The injected silicone appears in the form of interstitial vacuoles of different sizes between collagen bundles surrounded by a few macrophages. C, Some of the histiocytes show a foamy appearance of their cytoplasm as a consequence of the engulfed silicone. D, Higher magnification of the vacuoles of silicone, both within the cytoplasm of the macrophages and extracellularly. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

previously by its use in bone cement and dental prosthesis.226 Collagen of bovine origin induces allergy reactions in approximately 3% to 4% of the patients,15,227 and it is therefore mandatory to perform an intradermal test before the first use of this filler.228 One case of anaphylactic shock has been observed after the eighth treatment.224 Collagen, however, is merely a carrier substance that eases the injection of the microspheres and prevents them from agglomerating during tissue ingrowth, and 80% of it is gone after 1 to 3 months. The PMMA microspheres, on the other hand, persist for years and induce a granulomatous foreign body reaction, with a deposition of fibrous tissue, which is part of the wanted effect of the filler. A uniform size and shape and smooth surface of the PMMA microspheres—combined with the correct injection technique—seem to be important for obtaining a controlled granulomatous reaction with adequate volume for cosmetic purposes.224,225 The filler must be implanted into the reticular dermis. If the injection is too deep into the subcutaneous fat, the filler will have no effect, and if it is injected too

superficially into the superficial dermis, the filler will result in a whitish nodule and is likely to produce a more evident granulomatous reaction, with undesirable cosmetic effects.90,223,229 It has been claimed that size and the smooth surface of the particles hinder their phagocytosis by macrophages, but some authors disagree.228 Although not very common, this filler may cause some undesirable side effects, with a total rate estimated at 3%, including telangiectasias, hypertrophic scarring, allergic reactions, and granuloma formation.225,230 Granulomas generally appear from 6 to 24 months after the treatment,231 with a 0.6% occurrence rate232,233 (Fig 24), but they may also emerge several years after the injection.129 One patient with chronic hepatitis C infection receiving treatment with peginterferon alfa-2a and ribavirin developed disfiguring facial swelling, requiring plastic surgery in foci where Artecoll had been injected 10 years earlier.234 The histopathologic findings of granulomas related to this filler were first described by Rudolph et al,221 and other cases have since

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Fig 20. Histopathologic features of panniculitis secondary to migration of the liquid silicone in the patient seen in Figure 13. The patient had a history of injections of liquid silicone on the buttocks and 5 years later developed nodular lesions on the lower legs. This biopsy specimen came from the nodule seen in Figure 13, C. A, Scanning power showing a mostly septal panniculitis. B, Higher magnification reveals a thickening of the connective tissue septa with sparse inflammatory infiltrate. C, The septa showed a multivacuolated appearance because of the deposits of liquid silicone. D, Higher magnification showed the multivacuolated appearance of the liquid silicone. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

been added.84,121,220,228,235-238 Some of the cases that were reported as Artecoll granulomas should correctly have been classified as silicone granulomas235,239 or Dermalive granulomas240 (see below). Artecoll-related granulomas may involve the dermis, subcutaneous fat, and, occasionally, adjacent sweat glands241 and the skeletal muscle.221 They are characterized by a nodular or diffuse granulomatous infiltrate, and at higher magnification, rounded vacuoles of similar shape and size mimicking normal adipocytes are easily identified.242 These round bodies correspond to the implanted PMMA microspheres, which are markedly homogeneous in size and shape (Fig 25). They are round, sharply circumscribed, translucent, nonbirefringent, and characteristically extracellular. Epithelioid histiocytes, multinucleated giant cells, lymphocytes, and occasional eosinophils often surround the microspheres, which are individually disposed or arranged in clusters surrounded by sclerotic stroma. In our experience, asteroid bodies are not present in Artecoll

granulomas. This is in consonance with the complex washing procedure and ultrasound technology224 that has been described as part of the purification process. Other authors, however, have described asteroid bodies in their granuloma cases.121,238 Management of this exaggerated granulomatous reactions to Artecoll can be achieved with diluted triamcinolone (1:3 in anesthetic solution) injected inside the nodules. One case report described a positive response of Artecoll-induced granuloma to allopurinol236 and another to intralesional injections of 5-fluorouracil.237

HYDROXYETHYLMETHACRYLATE/ ETHYLMETHACRYLATE FRAGMENTS AND HYALURONIC ACID Key points d

Permanent biphasic filler composed ethylmethacrylate and hydroxyethylmethacrylate particles suspended in a hyaluronic acid gel

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Fig 21. Granulomatous reaction secondary to impurities of silicone. A, Scanning power. B, Numerous angulated translucent particles are present in the dermis. C, Most of the granulomatous reaction and multinucleated giant cells are around the angulated translucent particles. Note that the vacuoles of silicone originated little inflammatory response. D, In this case, the angulated translucent particles of the impurities were not birefringent under polarized light. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3200. Polarized light.)

d

Histopathologically, granulomatous reactions to this filler consist of nodular infiltrates of macrophages and multinucleated giant cells with numerous pseudocystic structures of different sizes and shapes containing polygonal, pink, translucent, nonbirefringent foreign bodies

This is another biphasic cosmetic filler made of 40% acrylic hydrogel composed of ethylmethacrylate (EMA) and hydroxyethylmethacrylate (HEMA) particles with a variable diameter, and 60% hyaluronic acid produced by microbiologic engineering techniques (Dermalive and Dermadeep [Dermatech]). Both components are of nonanimal origin, so allergy reactions are less probable than with Artecoll. The acrylic hydrogel contained in Dermalive is the same as the one used for intraocular lens implants in cataract surgery.243 Hyaluronic acid is used as a carrier; it is broken down by hyaluronidase and disappears in 3 months, whereas fragments of EMA and HEMA persist for years. Acrylic hydrogel particles in Dermalive are

Fig 22. Asymmetric swelling of the upper lip caused by a granulomatous reaction to Bioplastique (Uroplasty BV, Geleen, The Netherlands).

solid, polygonal, translucent, intentionally irregular in shape, but of smooth surface, and sized between 45 and 65 m. Dermadeep is very similar to Dermalive, but with larger particles of EMA and HEMA (80-110 m), and it is used for the correction of larger defects than Dermalive. Indications for the use of Dermalive are similar to those for Artecoll. It must be implanted in the same place: the reticular dermis or at the dermosubcutaneous junction. In a similar way, superficial deposition of

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Fig 23. Histopathologic features of a granulomatous reaction to Bioplastique (Uroplasty BV, Geleen, The Netherlands). A, Scanning power. B, Irregularly shaped cystic spaces containing translucent, jagged ‘‘popcorn,’’ nonbirefringent particles of varying size dispersed in a sclerotic stroma. C, Cystic spaces are surrounded by multinucleated foreign body giant cells. D, Higher magnification of the translucent particles of Bioplastique surrounded by multinucleated giant cells. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

Dermalive can induce overcorrection and granulomatous evident reactions. Like Artecoll, the prolonged cosmetic effect of Dermalive is related to the acrylic hydrogel added to the limited granulomatous reaction, with a deposition of fibrous tissue. The immediate side effects of Dermalive injections are similar to those after other cosmetic fillers and include redness, pain, edema, or hematoma, all disappearing spontaneously within a few days. Long-term side effects have been estimated in 1.2 per 1000 by one publication222 and in 28% by another.244 They appear months after injection and present as indurations (Fig 26), edema, and nodules. A case of keratoacanthoma-like reaction has been recently described at the site of injection of this filler.245 Granulomatous reactions to Dermalive and their histopathologic features have been well described.1,82,121,129,222,223,246-250 They consist of nodular granulomatous infiltrates involving the reticular dermis and superficial hypodermis. The epidermis and superficial dermis are usually spared. At higher magnification, numerous pseudocystic

Fig 24. Granulomatous reaction to Artecoll (Artes Medical, San Diego, CA) involving the lower eyelids and the cheeks.

structures of different sizes and shapes containing polygonal, pink, translucent foreign bodies are easily seen (Fig 27). These extracellular particles look like clear broken glass gravel and they are not birefringent under polarized light microscopy. The granulomatous infiltrate consists of numerous epithelioid histiocytes, many multinucleate giant cells, and some lymphocytes. Abundant asteroid bodies

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Fig 25. Histopathologic features of Artecoll-related granuloma (Artes Medical, San Diego, CA). A, Scanning power showing a nodular or diffuse granulomatous infiltrate. B, With higher magnification, rounded vacuoles of similar shape and size mimicking normal adipocytes are easily identified. C, These round bodies correspond to the implanted polymethylmethacrylate microspheres, which are markedly homogeneous in size and shape. D, Higher magnification of the round, sharply circumscribed, translucent, nonbirefringent, extracellular microspheres of Artecoll surrounded by a sclerotic stroma. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

may be present in the cytoplasm of giant cells. Transepidermal elimination of the product may occur.82 Intralesional injections of corticosteroids or 5-fluorouracil221 have been described to be effective in treating granulomas secondary to Dermalive.

POLYACRYLAMIDE HYDROGEL Key points d

d

d

Permanent filler composed of a hydrophilic gel of polyacrylamide Nodules may develop after the injections that have been found to be localized bacterial infection Granulomas secondary to this filler are composed of macrophages, foreign body giant cells, lymphocytes, and red cells surrounding a basophilic multivacuolated nonbirefringent material, which corresponds to the polyacryalamide hydrogel

Injected hydrophilic gel of polyacrylamide (Aquamid [Contura International, Copenhagen,

Denmark], Interfall [FuHua Aesthetics, Shenzen, China], OutLine [ProCytech SA, Bordeaux, Fance], Royamid [Fluka Chemie AG, Buchs, Switzerland], Formacryl [Bioform, Moscow, Russia], Argiform [Bioform], Amazingel [NanFeng Medical, Shijiazhuang, People’s Republic of China], Bio-Formacryl [Progen, Ancona, Italy], and Kosmogel [Styling Medical Devices, Engelberg, Switzerland]) has been used in large quantities mostly in China, Ukraine, and the former Soviet Union for breast, buttock, and calf augmentation. More recently, it has been used in European countries for the treatment of antiretroviral-related facial lipoatrophy in HIV patients and for the correction of acquired or congenital malformations with depressed skin.251-255 Polyacrylamide hydrogel is a polymer hydrogel consisting of 2.5% polyacrylamide polymer backbone and 97.5% water and should be injected deeply into the subcutaneous fat, the muscle or into the supraperiosteal plane.256 When medium to large quantities of this hydrogel are injected under pressure, a cellular foreign body reaction can be observed histologically, but clinically visible nodules are rarely seen in connection with these large

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Fig 26. Granulomatous reaction in the lips after injections of Dermalive (Dermatech, Paris, France). A, Erythema and diffuse swelling of the upper and lower lips. B, Close view of the erythematous lips. C, Lateral view showing that the induration extended beyond the limit of the upper lip to adjacent skin. D, The lesions eroded the mucous surface of the upper lip.

deposits.257,258 Nodules may develop after injection of small amounts in the face, and these have been found to be related to localized bacterial infection.259 Other side effects of polyacrylamide hydrogel, described mostly in breast augmentation, include pigmentation of the skin surface caused by the periodic exacerbation of the protracted inflammatory process, hematoma, infections (Fig 28), indurations, lumps, mastodynia, unsatisfactory contour results, abnormal skin sensations, gel migration, and axillary lymphadenitis.251-265 More severe, although rare, complications include bone erosion and facial ulceration.266 Two cases of breast cancer occurring after injection of polyacrylamide hydrogel injections in augmented breasts have been also described, and although they did not appear to be etiologically related to the implant, a delayed detection and diagnosis because of its presence were recorded.267 Contraindications to polyacrylamide hydrogel injections include previous injection of any filler at the same site, dental work, face lift or peeling at the same site in the days before the injection, Crohn disease, ulcerative colitis, pemphigus vulgaris, and insulin-dependent diabetes mellitus.259 The histopathologic study of breast tissue bordering the gel has revealed three different patterns: large

collections of gel are surrounded by a thick, softlooking cellular membrane of macrophages and foreign body giant cells; medium-size deposits were surrounded by just a thin layer of macrophages; and small deposits were not associated with any reaction in the surrounding tissue. Granulomas have been seen in some patients and they are composed of macrophages, foreign body giant cells, lymphocytes, and red cells surrounding the polyacryalamide hydrogel (Fig 29). This material shows some histopathologic similarity to hyaluronic acid, although granulomas secondary to hyaluronic acid usually consist of a less dense inflammatory infiltrate than those secondary to polyacrylamide hydrogel. Polyacrylamide hydrogel is positive with Alcian blue stain and it is not birefringent under polarizing microscopy. A thin layer of fibrous connective tissue is occasionally present around the foreign body membrane, but the thick fibrous capsule, as seen with silicone implants, is usually completely absent.82,257,259 Instead, it has been shown in an experimental study in the pig, that vessel in-growth takes place anchoring the gel to its surroundings, and that a 0.2-mL deposit will be completely traversed within 14 months.268 The histopathologic findings of the local reaction at the cheek mucosa after injection

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Fig 27. Histopathologic features of Dermalive-related granuloma (Dermatech, Paris, France). A, Nodular granulomatous infiltrates involving the reticular dermis and superficial hypodermis. B, At higher magnification, numerous pseudocystic spaces are seen. C, These spaces contain polygonal, pink, translucent foreign bodies with different sizes and shapes. D, The extracellular particles of Dermalive are pink in color and they are not birefringent under polarized light microscopy. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

of polyacrylamide hydrogel has in one case been reported to mimic a mucoepidermoid carcinoma.269

POLYALKYLIMIDE GEL Key points d

d

d

Permanent hydrophilic filler composed a polyalkylimide polymer Complications secondary to this filler include edema, bruising, nodules, and infections, but no granulomas have been described Histopathologically, this filler appears as basophilic amorphous material with granular appearance surrounded by sparse numbers of epithelioid histiocytes, foreign body multinucleated giant cells, neutrophils, and red cells

This is a permanent translucent gel made of a hydrophilic biopolymer with 96% sterile water and 45% polyalkylimide polymer (Bio-Alcamid; Polymekon, Brindisi, Italy), and different from polyacrylamide. It has been used to increase volume in the

Fig 28. A pustular reaction secondary to Aquamid (Contura International, Copenhagen, Denmark) injections for treatment of facial lipoatrophy in a patient with HIV. Cultures of the lesions isolated Staphylococcus aureus.

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Fig 29. Histopathologic features of granulomatous reaction to Aquamid (Contura International, Copenhagen, Denmark). A, Scanning power showing granulomas at different levels of the dermis. B, Higher magnification showing macrophages and foreign body giant cells surrounding basophilic multivacuolated material. C, The basophilic material at the center of the foreign body granulomas is the polyacryalamide hydrogel. D, Higher magnification showing the bluish and multivacuolated appearance of the polyacrylamide hydrogel. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

cheeks in HIV patients with facial lipoatrophy related to antiretroviral therapy and for gluteal augmentation, correction of irregularities after liposculpture, scar depressions, and posttraumatic subcutaneous atrophy and filling of pectus excavatum or other malformations of the skeleton.270-278 Complications secondary to the injections of Bio-Alcamid include edema (Fig 30), bruising, and nodules and, in particular, infections.279-286 To our knowledge, no granulomas secondary to Bio-Alcamid have been described. There are few histopathologic studies describing the findings in the local reactions to Bio-Alcamid, and the microscopic study of the material obtained from an indurated nodule has shown basophilic amorphous material corresponding to the implanted material, surrounded by epithelioid histiocytes, foreign body multinucleated giant cells, neutrophils and red cells281 (Fig 31). In accordance with this histology, late-appearing abscesses have been seen in HIV patients treated with this filler for lipoatrophy following antiretroviral therapy.279-286

Fig 30. Edema of the upper lip after injection of BioAlcamid (Polymekon, Brindisi, Italy).

POLYVINYLHYDROXIDE MICROSPHERES SUSPENDED IN POLYACRYLAMIDE GEL Key points d

d

Permanent filler composed of polyvinylhydroxide microspheres suspended in polyacrylamide gel There are not descriptions of adverse reactions to this filler

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Fig 31. Histopathologic features of a late-appearing abscess after injections of Bio-Alcamid (Polymekon, Brindisi, Italy). A, Scanning power. B, Several areas of basophilic amorphous material corresponding to the implanted material, surrounded by neutrophils and red cells. C, The implanted material has a basophilic granular appearance. D, Higher magnification of the polyalkylimide gel. Gram stain revealed the presence of abundant Gram-positive bacteria intermingled with these basophilic granular material. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

This filler is composed of a suspension of 6% polyvinylhydroxide microspheres suspended in 2.5% polyacrylamide gel (Evolution; ProCytech SA) and has been used mostly for lip augmentation. To our knowledge, there are not reports on this rarely used filler other that the observation made by Lemperle et al1 who, in their comparative paper on fillers, injected Evolution (and later excised it from the first author’s forearm) and found the filler to give little local reaction and diminish slowly over 9 months.

CONCLUSION A wide variety of cosmetic fillers are now available worldwide, and new ones will likely appear in the immediate future. The ideal filler is still missing, because all of them known today may cause adverse reactions. These side effects are less severe after injection with quickly biodegradable cosmetic fillers, where most will disappear spontaneously within a few months. Unfortunately, however, after injection with slowly or nonbiodegradable fillers, adverse reactions may appear that need active treatment. If these are related to bacterial infection as seen with

the polyacrylamide gel and if bacterial resistance (biofilm) has developed,287 or if they present as foreign body granulomas, as seen after the other fillers of this category, surgical removal of the implanted material often remains the only effective therapeutic possibility. Because medicolegal problems may arise with the use of these fillers and because they may be implanted in nonmedical settings—not infrequently with incomplete or even fraudulent information about the nature of the implanted filler given to the patients—histopathology remains the criterion standard for identification of the responsible filler. The variation in microscopic morphology of the implanted particles and hydrogels allows dermatologists and dermatopathologists to precisely classify most cases, and this appears to be particularly important in cases where different fillers have been applied over time, so that the filler responsible for the adverse reaction can be identified and treated accordingly.

REFERENCES 1. Lemperle G, Morhenn V, Charrier U. Human histology and persistence of various injectable filler substances for

J AM ACAD DERMATOL VOLUME 64, NUMBER 1

2. 3.

4. 5.

6.

7.

8.

9.

10. 11.

12.

13.

14.

15.

16. 17.

18. 19. 20. 21. 22.

23.

24.

soft tissue augmentation. Aesthetic Plast Surg 2003;27: 354-66. Laeschke K. Biocompatibility of microparticles into soft tissue fillers. Semin Cutan Med Surg 2004;23:214-7. Duranti F, Salti G, Bovani B, Calandra M, Rosati M. Injectable hyaluronic acid gel for soft tissue augmentation. Dermatol Surg 1998;24:1317-25. Knapp TR, Kaplan EN, Daniels JR. Injectable collagen for soft tissue augmentation. Plast Reconstr Surg 1977;60:389-405. Stegman SJ, Chu S, Bensch K, Amstrong R. A light and electron microscopic evaluation of Zyderm collagen and Zyplast implants in aging human facial skin: a pilot study. Arch Dermatol 1987;123:1644-9. Wallace DG, McPherson JJ, Ellingsworth LE. Injectable collagen for tissue augmentation. In: Nimni ME, editor. Collagen, Vol III, Biotechnology. Boca Raton, FL: CRC Press; 1988. pp. 117-44. Robinson JK, Hanke CW. Injectable collagen implant: histopathologic identification and longevity of correction. J Dermatol Surg Oncol 1985;11:124-30. McPherson JM, Sawamura S, Amstrong R. An examination of the biologic response to injectable, glutaraldehyde crosslinked collagen implants. J Biomed Mater Res 1986;20:93-107. Burke KE, Naughton G, Cassai NA. Histological, immunological and electron microscopic study of bovine collagen implants in the human. Ann Plast Surg 1985;14:515-22. Ackerman AB, Guo Y, Vitale P. Clues to Diagnosis in Dermatopathology II. Chicago: ASCP Press; 1992. pp. 385-8. Kligman AM, Armstrong RC. Histologic response to intradermal Zyderm and Zyplast (glutaraldehyde cross-linked) collagen in humans. J Dermatol Surg Oncol 1986;12:351-7. DeLustro F, Smith ST, Sundsmo J, Salem G, Kincaid S, Ellingsworth L. Reaction to injectable collagen: results in animal models and clinical use. Plast Reconstr Surg 1987;79:581-94. Kamer FM, Churukian MM. Clinical use of injectable collagen: a three-year retrospective review. Arch Otolaryngol 1984;110: 93-8. Siegle RJ, McCoy JP, Schade W, Swanson NA. Intradermal implantation of bovine collagen. Humoral immune responses associated with clinical reactions. Arch Dermatol 1984;120: 183-7. Cooperman LS, Mackinnon V, Bechler G, Pharriss BB. Injectable collagen: a six-year clinical investigation. Aesthetic Plast Surg 1985;9:145-51. Castrow FF 2nd, Krull EA. Injectable collagen implant— updated. J Am Acad Dermatol 1983;9:889-93. Stegman S, Chu S, Armstrong R. Adverse reactions to bovine collagen implant: clinical and histologic features. J Dermatol Surg Oncol 1988;14(suppl):39-48. Elson ML. The role of skin testing in the use of collagen injectable materials. J Dermatol Surg Oncol 1989;15:301-3. Klein AW. In favour of double testing. J Dermatol Surg Oncol 1989;15:263. Klein AW, Rish DC. Injectable collagen update. J Dermatol Surg Oncol 1984;10:519-22. Klein AW. Collagen substances. Facial Plast Surg Clin North Am 2001;9:205-18. Brooks N. A foreign body granuloma produced by an injectable collagen implant at a test site. J Dermatol Surg Oncol 1982;8:111-4. Burke KE, Naughton G, Waldo E, Cassai N. Bovine collagen implant: histologic chronology in pig dermis. J Dermatol Surg Oncol 1983;9:889-95. Overholt MA, Tschen JA, Font RL. Granulomatous reaction to collagen implant: light and electron microscopic observations. Cutis 1993;51:95-8.

Requena et al 27

25. Barr RJ, Stegman SJ. Delayed skin test reaction to injectable collagen implant (Zyderm). J Am Acad Dermatol 1984;10: 652-8. 26. Barr RJ, King DF, McDonald RM, Bartlow GA. Necrobiotic granulomas associated with bovine collagen test site injections. J Am Acad Dermatol 1982;6:867-9. 27. Rapaport MJ. Granuloma annulare caused by injectable collagen. Arch Dermatol 1984;120:837-8. 28. McCoy JP Jr, Schade WJ, Siegle RJ, Waldinger TP, Vanderveen EE, Swanson NA. Characterization of the humoral immune response to bovine collagen implants. Arch Dermatol 1985; 121:990-4. 29. Garcia-Domingo MI, Alijotas Rey J, Cistero-Bahima A, Treserra F, Enrique E. Disseminated and recurrent sarcoid-like granulomatous panniculitis due to bovine collagen injection. J Invest Allergol Clin Immunol 2000;10:107-9. 30. Morgan AM. Localized reactions to injected therapeutic materials. Part 2. Surgical agents. J Cutan Pathol 1995;22: 289-303. 31. Cooperman L, Michaeli D. The immunogenicity of injectable collagen. I. A 1-year prospective study. J Am Acad Dermatol 1984;10:638-46. 32. Cooperman L, Michaeli D. The immunogenicity of injectable collagen. II. A retrospective review of seventy-two tested and treated patients. J Am Acad Dermatol 1984; 10:647-51. 33. Baumann LS, Kerdel F. The treatment of bovine collagen allergy with cyclosporine. Dermatol Surg 1999;25:247-9. 34. Moody BR, Sengelmann RD. Topical tacrolimus in the treatment of bovine collagen hypersensitivity. Dermatol Surg 2001;27:789-91. 35. Alam M, Dover JS. Management of complications and sequelae with temporary injectable fillers. Plast Reconstr Surg 2007;120(suppl):98S-105S. 36. Klein AW. Bonfire of the wrinkles. J Dermatol Surg Oncol 1991;17:543-4. 37. Klein AW. Implantation technics for injectable collagen: twoand-one half years of personal clinical experience. J Am Acad Dermatol 1983;9:224-8. 38. Bailin PL, Bailin MD. Collagen implantation: clinical applications and lesion selection. J Dermatol Surg Oncol 1988;14 (suppl 1):49-54. 39. Hanke CW, Hingley HR, Jolivette DM, Swanson NA, Stegman SJ. Abscess formation and local necrosis after treatment with Zyderm or Zyplast collagen implant. J Am Acad Dermatol 1991;25:319-26. 40. McGrew RN, Wilson RS, Havener WH. Sudden blindness secondary to injection of common drugs in the head and neck. Part 1: clinical experiences. Otolaryngology 1978;86:147-51. 41. Douglas RS, Donsoff I, Cook T, Shorr N. Collagen fillers in facial aesthetic surgery. Facial Plast Surg 2004;20:117-23. 42. Mullins RJ, Richards C, Walker T. Allergic reaction to oral, surgical and topical bovine collagen. Anaphylactic risk for surgeons. Aust N Z J Ophthalmol 1996;4:257-60. 43. Cukier J, Beauchamp RA, Spindler JS, Spindler S, Lorenzo C, Trentham DE. Association between bovine collagen dermal implants and a dermatomyositis or a polymyositis-like syndrome. Ann Intern Med 1993;118:920-8. 44. Ellingsworth LR, DeLustro F, Brennan JE, Sawamura S, McPherson J. The human immune response to reconstituted bovine collagen. J Immunol 1986;136:877-82. 45. DeLustro F, Dasch J, Keefe J, Ellingsworth LR. Immune response to allogenic and xenogenic implants of collagen and collagen derivates. Clin Orthop Relat Res 1990;260: 263-79.

28 Requena et al

46. Rosemberg MJ, Reiclin M. Is there an association between injectable collagen and polymyositis/dermatomyositis? Arthritis Rheum 1994;37:747-53. 47. Hanke CW, Thomas JA, Lee WT, Jolivette DM, Rosemberg MJ. Risk assessment of polymyositis/dermatomyositis after treatment with injectable bovine collagen implants. J Am Acad Dermatol 1996;34:450-4. 48. Sclafani A, Romo T, Jacono AA, McCormick SA, Cocker R, Parker A. Evaluation of acellular dermal graft in sheet (Alloderm) and injectable (micronized Alloderm) forms for soft tissue augmentation: clinical observations and histologic findings. Arch Facial Plast Surg 2000;2:130-6. 49. Fagien S. Facial soft-tissue augmentation with injectable autologous and allogenic human tissue collagen matrix (autologen and dermalogen). Plast Reconstr Surg 2000;105: 362-73. 50. Baumann L, Kaufman J, Saghari S. Collagen fillers. Dermatol Ther 2006;19:134-40. 51. Bauman L. CosmoDerm/CosmoPlast (human bioengineered collagen) for the aging face. Facial Plast Surg 2004;20:125-8. 52. Sclafani AP, Romo T, Jacono AA 3rd. Rejuvenation of the aging lip with an injectable acellular dermal graft (Cymetra). Arch Facial Plast Surg 2002;4:252-7. 53. Moody BR, Sengelmann RD. Self-limited adverse reaction to human-derived collagen injectable product. Dermatol Surg 2000;26:936-8. 54. Goa KL, Benfield P. Hyaluronic acid. A review of its pharmacology and use as a surgical aid in ophthalmology, and its therapeutic potential in joint disease and wound healing. Drugs 1994;47:536-66. 55. Taddeucci P, Pianigiani E, Colletta V, Torasso F, Andreassi L, Andreassi A. An evaluation of Hyalofill-F plus compression bandaging in the treatment of chronic venous ulcers. J Wound Care 2004;13:202-4. 56. Gomes JA, Amankwah R, Powell-Richards A, Dua HS. Sodium hyaluronate (hyaluronic acid) promotes migration of human corneal epithelial cells in vitro. Br J Ophthalmol 2004;88: 821-5. 57. Day R, Brooks P, Conaghan PG, Petersen MM, Multicenter Trial Group. A double blind, randomized, multicenter, parallel group study of the effectiveness and tolerance of intraarticular hyaluronan in osteoarthritis of the knee. J Rheumatol 2004;31:775-82. 58. Lym HS, Suh Y, Park CK. Effects of hyaluronic acid on the polymorphonuclear leukocyte (PMN) release of active oxygen and protection of bovine corneal endothelial cells from activated PMNs. Korean J Ophthalmol 2004;18:23-8. 59. Wang F, Garza LA, Kang S, Varani J, Orringer JS, Fisher GJ, et al. In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin. Arch Dermatol 2007;143:155-63. 60. Larsen N, Pollack CT, Reiner K, Leshchiner E, Balazs EA. Hylan gel biomaterial: dermal and immunologic compatibility. J Biomed Mater Res 1993;27:1129-34. 61. Lupton JR, Alster TS. Cutaneous hypersensitivity reaction to injectable hyaluronic acid gel. Dermatol Surg 2000;26:135-7. 62. Raulin C, Greve B, Hartschuh W, Soegding K. Exudative granulamotous reaction to hyaluronic acid (Hylaform). Contact Dermatitis 2000;43:178-9. 63. Lowe NJ, Maxwell CA, Lowe P, Duick MG, Shah K. Hyaluronic acid skin fillers: adverse reactions and skin testing. J Am Acad Dermatol 2001;45:930-3. 64. Friedman PM, Mafong EA, Kauver AN, Geronemus RG. Safety data of injectable non-animal stabilized hyaluronic acid gel for soft tissue augmentation. Dermatol Surg 2002;28:491-5.

J AM ACAD DERMATOL

JANUARY 2011

65. Kavouni A, Stanee JJ. Human antihyaluronic acid antibodies. Dermatol Surg 2002;28:359-60. 66. Fernandez Ace~ nero MJ, Zamora E, Borbujo J. Granulomatous foreign body reaction against hyaluronic acid: report of a case after lip augmentation. Dermatol Surg 2003;29:1225-6. 67. Klein AW. Granulomatous foreign body reaction against hyaluronic acid. Dermatol Surg 2004;30:1070. 68. Andre P. Evaluation of the safety of non-animal stabilised hyaluronic acid (NASHA, Q-Medical, Sweden) in European countries: a retrospective study from 1997 to 2001. J Eur Acad Dermatol Venereol 2004;18:422-5. 69. Andre P. Hyaluronic acid and its use as ‘‘rejuvenation’’ agent in cosmetic dermatology. Semin Cutan Med Surg 2004;23: 218-22. 70. H€ onig JF, Brink U, Korabiowska M. Severe granulomatous allergic tissue reaction after hyaluronic acid injection in the treatment of facial lines and its surgical correction. J Craniofac Surg 2003;14:197-200. 71. Pinheiro MV, Bagatin E, Hassun KM, Talarico S. Adverse affect of soft tissue augmentation with hyaluronic acid. J Cosmet Dermatol 2005;4:184-6. 72. Bardazzi F, Ruffato A, Antonucci A, Balestri R, Tabanelli M. Cutaneous granulomatous reaction to injectable hyaluronic acid gel: another case. J Dermatol Treat 2007;18:59-62. 73. Bisaccia E, Lugo A, Torres O, Johnson B, Scarborough D. Persistent inflammatory reaction to hyaluronic acid gel: a case report. Cutis 2007;79:388-9. 74. Arron ST, Neuhaus IM. Persistent delayed-type hypersensitivity reaction to injectable non-animalestabilized hyaluronic acid. J Cosmet Dermatol 2007;6:167-71. 75. Alijotas-Reig J, Garcia-Gimenez V. Delayed immune-mediated adverse effects related to hyaluronic acid and acrylic hydrogel dermal fillers: clinical findings, long-term follow-up and review of the literature. J Eur Acad Dermatol Venereol 2008;22:150-61. 76. Sanchis-Bielsa JM, Bagan JV, Poveda R, Salvador I. Foreign body granulomatous reactions to cosmetic fillers: a clinical study of 15 cases. Oral Surg Oral Med Oral Pathol Radiol Endod 2009;108:237-41. 77. Okada S, Okuyama R, Tagami H, Aiba S. Eosinophilic granulomatous reaction after intradermal injection of hyaluronic acid. Acta Derm Venereol 2008;88:69-70. 78. Micheels P. Human anti-hyaluronic acid antibodies: is it possible? Dermatol Surg 2001;27:185-91. 79. Hamilton RG, Strobos J, Adkinson NF Jr. Immunogenicity studies of cosmetically administered nonanimal-stabilized hyaluronic acid particles. Dermatol Surg 2007;33(suppl 2): S176-85. 80. Manna F, Dentini M, Desideri P, de Pita O, Mortilla E, Maras B. Comparative chemical evaluation of two commercially available derivates of hyaluronic acid (hylaform from rooster combs and restylane from streptococcus) used for soft tissue augmentation. J Eur Acad Dermatol Venereol 1999;13: 183-92. 81. Filion MC, Phillips NC. Pro-inflammatory activity of contaminating DNA in hyaluronic acid preparations. J Pharm Pharmacol 2001;53:555-61. 82. Zimmermann US, Clerici TJ. The histological aspects of fillers complications. Semin Cutan Med Surg 2004;23: 241-50. 83. Ghislanzoni M, Bianchi F, Barbareschi M, Alessi E. Cutaneous granulomatous reaction to injectable hyaluronic acid gel. Br J Dermatol 2006;154:755-8. 84. Parada MB, Michalany NS, Hassun KM, Bagatin E, Talarico S. A histologic study of adverse effects of different cosmetic skin fillers. Skinmed 2005;4:345-9.

J AM ACAD DERMATOL VOLUME 64, NUMBER 1

85. Dadzie OE, Mahalingam M, Parada M, El Helou T, Philips T, Bhawan J. Adverse reactions to soft tissue fillers—a review of the histological features. J Cutan Pathol 2008; 35:536-48. 86. Brody HJ. Use of hyaluronidase in the treatment of granulomatous hyaluronic acid reactions or unwanted hyaluronic acid misplacement. Dermatol Surg 2005;31:893-7. 87. Soparkar CNS, Patrinely JR. Managing inflammatory reactions to restylane. Ophthal Plast Reconstr Surg 2005;21:151-3. 88. Lambros V. The use of hyaluronidase to reverse the effects of hyaluronic acid filler. Plast Reconstr Surg 2004;114:277. 89. Hirsch RJ, Cohen J. Challenge: correcting superficially placed hyaluronic acid. Skin Aging 2007;15:36-8. 90. Grossman KL. Hyaluronic acid gel fillers: hypersensitivity reactions. Aesthet Surg J 2005;25:403-5. 91. Leonard MM, Lawrence N, Narin RS. Angioedema acute hypersensitivity reaction to injectable hyaluronic acid. Dermatol Surg 2005;31:577-9. 92. Pollack SV. Some new injectable dermal filler materials: Hylaform, Restylane and Artecoll. J Cutan Med Surg 1999;(Suppl 4):527-32. 93. Barbucci R, Lamponi S, Magnani A, Renier D. The influence of molecular weight on the biological activity of heparin like sulphated hyaluronic acids. Biomaterials 1998;19: 801-6. 94. Pandolfi M, Hedner U. The effect of sodium hyaluronate and sodium chondroitin sulphate on the coagulation system in vitro. Ophthalmology 1984;91:864-6. 95. Shafir R, Amir A, Gur E. Long-term complications of facial injections with Restylane (injectable hyaluronic acid). Plast Reconstr Surg 2000;28:359-60. 96. Rongioletti F, Cattarini G, Sottofattori E, Rebora A. Granulomatous reaction after intradermal injections of hyaluronic acid gel. Arch Dermatol 2003;139:815-6. 97. Dal Sacco D, Cozzani E, Parody A, Rebora A. Scar sarcoidosis after hyaluronic acid injection. Int J Dermatol 2005;44: 411-2. 98. Descamps V, Landry J, Frances C, Marinho E, Ratziu V, Chosidow O. Facial cosmetic filler injections as possible target for systemic sarcoidosis in patients treated with interferon for chronic hepatitis C: two cases. Dermatology 2008;217:81-4. 99. Schanz S, Schipper W, Ulmer A, Rassner G, Fierlbeck G. Arterial embolization caused by injection of hyaluronic acid (Restylane). Br J Dermatol 2002;146:928-9. 100. LaGlenne E. Letter to the editor: in response to: case report: episodes of angioedema of the face with nodules and foreign body granulomas two years after injection of a product for filling wrinkles: New-Fill probably the responsible agent. Nouv Dermatol 2004;23:223-4. 101. Pope J Jr, Sternberg P Jr, Mclane NJ, Potts DW, Stulting RD. Mycobacterium chelonae scleral abscess after removal of a scleral buckle. Am J Ophthalmol 1989;107:557-8. 102. Consulting Room. Matridur  and Matridex  information and background. Available at: http://www.consultingroom. com/Treatment_FAQs/Product_Display.asp?Product_ID=26& Matridur--and-Matridex-. Accessed November 4, 2010. 103. Massone C, Horn M, Kerl H, Ambros-Rudolph CM, Brunasso AMG, Cerroni L. Foreign body granuloma due to Matridex injection for cosmetic purposes. Am J Dermatopathol 2009; 31:197-9. 104. Burgess CM, Quiroga RM. Assessment of the safety and efficacy of poly-L-lactic acid for treatment of HIVassociated facial lipoatrophy. J Am Acad Dermatol 2005; 52:233-9.

Requena et al 29

105. Mest DR, Humble G. Safety and efficacy of poly-L-lactic acid injections with HIV-associated lipoatrophy: the US experience. Dermatol Surg 2006;32:1336-45. 106. Moyle GJ, Brown S, Lysakova L, Barton SE. Long-term safety and efficacy of poly-L-lactic acid in the treatment of HIVrelated facial lipoatrophy. HIV Med 2006;7:181-5. 107. Valantin MA, Aubron-Olivier C, Ghosn J, Laglenne E, Pauchard M, Schoen H, et al. Polylactic acid implants (New Fill) to correct facial lipoatrophy in HIV-infected patients: results of the open-label study VEGA. AIDS 2003; 17:2471-7. 108. Lam SM, Azizzadeh B, Graivier M. Injectable poly-L-lactic acid (Sculptra): technical considerations in soft-tissue contouring. Plast Reconstr Surg 2006;118(suppl):55-63S. 109. Guaraldi G, Orlando G, De Fazio D, De Lorenzi I, Rottino A, De Santis G, et al. Comparison of three different interventions for the correction of HIV-associated facial lipoatrohy: a prospective study. Antivir Ther 2005;10: 753-9. 110. Vleggaar D. Soft-tissue augmentation and the role of poly-Llactic acid. Plast Reconstr Surg 2006;118(suppl):46-54S. 111. Butterwick K, Lowe NJ. Injectable poly-L-lactic acid for cosmetic enhancement: learning from European experience. J Am Acad Dermatol 2009;61:281-93. 112. Vochele D. The use of poly-L-lactic acid in the management of soft-tissue augmentation: a five-year experience. Semin Cutan Med Surg 2004;23:223-6. 113. Levy RM, Redbord KP, Hanke CW. Treatment of HIV lipoatrophy and lipoatrophy of aging with poly-L-lactic acid: a prospective 3-year follow-up study. J Am Acad Dermatol 2008;59:923-33. 114. Gogolewski S, Jovanovic M, Perren SM, Dilon JG, Hughes MK. Tissue response and in vivo degradation of selected polyhydroxyacids: polylactides (PLA), poly(3-hydroxybutyrate) (PHB) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB/VA). J Biomed Mater Res 1993;27:1135-48. 115. Vleggaar D. Facial volumetric correction with injectable polyL-lactic acid. Dermatol Surg 2005;31:1511-8. 116. Vleggaar D, Bauer U. Facial enhancement and the European experience with Sculptra (poly-L-lactic acid). J Drugs Dermatol 2004;3:542-7. 117. Athanasiou KA, Niederauer GG, Agrawal CM, Landsman A. Applications of biodegradable lactides and glycolides in podiatry. Clin Orthop Relat Res 1995;315:272-81. 118. Spenlehauer G, Vert M, Benoit JP, Boddaert A. In vitro and in vivo degradation of poly(D, L-lactide/glycolide) acid microspheres made by solvent evaporation method. Biomaterials 1989;10:557-63. 119. Bauer U. Improvement of facial aesthetics at 40 months with injectable poly-L-lactic acid (PLLA). Houston: International Society of Aesthetic Plastic Surgery; 2004. 120. Lewis D. Controlled release of bioactive agents from lactide/glycolide polymers. In: Chasin M, Langer R, editors. Biodegradable polymers as drug delivery systems. New York: Marcel Dekker Inc; 1990. p. 1-41. 121. Lombardi T, Samson J, Plantier F, Husson C, K€ uffer R. Orofacial granulomas after injection of cosmetic fillers. Histopathologic and clinical study of 11 cases. J Oral Pathol Med 2004;33:115-20. 122. Dijkema SJ, van der Lei B, Kibbelaar RE. New-fill injections may induce late-onset foreign body granulomatous reaction. Plast Reconstr Surg 2005;115:76e-8. 123. Bauer U, Vleggaar D. Response to ‘‘New-fill injections may induce late-onset foreign body granulomatous reaction.’’ Plast Reconstr Surg 2006;118:265.

30 Requena et al

124. Apikian M, Roberts S, Goodman GJ. Adverse reactions to polylactic acid injections in the periorbital area. J Cosmet Dermatol 2007;6:95-101. 125. Stewart DB, Morganroth GS, Mooney MA, Cohen J, Levin PS, Gladstone HB. Management of visible granulomas following periorbital injection of poly-L-lactic acid. Ophthal Plast Reconstr Surg 2007;23:298-301. 126. Goldan O, Garbov-Nardini G, Regev E, Orenstein A, Winkler E. Late-onset infections and granuloma formation after facial polylactic acid (New-Fill) injections in women who are heavy smokers. Plast Recontr Surg 2008;121:336e-8. 127. Azizzadeh B. Late-onset infections and granuloma formation after facial polylactic acid (new-fill) injections in women who are heavy smokers. Plast Reconstr Surg 2009;124:316-7. 128. Lafaurie M, Dolivo M, Porcher R, Rudant J, Madelaine I, Molina JM. Treatment of facial lipoatrophy with intradermal injections of polylactic acid in HIV-infected patients. J Acquir Immune Defic Syndr 2005;38:393-8. 129. Christensen L, Breiting V, Jansen M, Vuust J, Hogdall E. Adverse reactions to injectable soft tissue permanent fillers. Aesthetic Plast Surg 2005;29:34-48. 130. Tzikas TL. Evaluation of the radiance FN soft tissue filler for facial soft tissue augmentation. Arch Facial Plast Surg 2004;6: 234-9. 131. Marmur ES, Phelps R, Goldberg DJ. Clinical, histologic and electron microscopic findings after injection of a calcium hydroxylapatite filler. J Cosmet Laser Ther 2004;6:223-6. 132. Broder KW, Cohen SR. An overview of permanent and semipermanent fillers. Plast Reconstr Surg 2006;118(suppl): 7-14S. 133. Silvers SL, Eviatar JA, Echavez MI, Pappas AL. Prospective, open-label, 18-month trial of calcium hydroxylapatite (Radiesse) for facial soft-tissue augmentation in patient with human immunodeficiency virus-associated lipoatrophy: one-year durability. Plast Reconstr Surg 2006;118(suppl): 34-45S. 134. Sklar JA, White SM. Radiance FN: a new soft tissue filler. Dermatol Surg 2004;30:764-8. 135. Jansen DA, Graivier MH. Evaluation of calcium hydroxylapatite based implant (Radiesse) for facial soft-tissue augmentation. Plast Reconstr Surg 2006;118(suppl):22S-30S. 136. Ahn MS. Calcium hydroxylapatite: Radiesse. Facial Plast Surg Clin North Am 2007;15:85-90. 137. Duffy DM. Complications of fillers. Overview. Dermatol Surg 2005;31:1626-33. 138. Beer KR. Radiesse nodule of the lips from a distant injection site: report of a case and consideration of etiology and management. J Drugs Dermatol 2007;6:846-7. 139. Drobeck HP, Rothstein SS, Gumaer KI, Sherer AD, Slighter RG. Histologic observation of soft tissue responses to implanted, multifaceted particles and discs of hydroxylapatite. J Oral Maxillofac Surg 1984;42:143-9. 140. Misiek DJ, Kent JN, Carr RF. Soft tissue responses to hydroxylapatite particles of different shapes. J Oral Maxillofac Surg 1984;42:150-60. 141. Urbach F, Wine SS, Johnson WC, Davies RE. Generalized paraffinoma (sclerosing lipogranuloma). Arch Dermatol 1971; 103:277-85. 142. van der Waal I. Paraffinoma of the face: a diagnostic and therapeutic problem. Oral Surg Oral Med Oral Pathol 1974;38: 675-80. 143. Foucar E, Downing DT, Gerber WL. Sclerosing lipogranuloma of the male genitalia containing vitamin E: a comparison with classical ‘‘paraffinoma.’’. J Am Acad Dermatol 1983;9: 103-10.

J AM ACAD DERMATOL

JANUARY 2011

144. Klein JA, Cole G, Barr RJ, Bartlow G, Fulwider C. Paraffinomas of the scalp. Arch Dermatol 1985;121:82-5. 145. Soyer HP, Petritsch P, Glavanovitz P, Kerl H. Sclerosing lipogranuloma (paraffin-induced granuloma) of the penis with a clinical picture of carcinoma [in German]. Hautarzt 1988;39:174-6. 146. Feldmann R, Harms M, Chavaz P, Salomon D, Saurat JH. Orbital and palpebral paraffinoma. J Am Acad Dermatol 1992;26:833-5. 147. Rollins CE, Reiber G, Guinee DG Jr, Lie JT. Disseminated lipogranulomas and sudden death from self-administered mineral oil injection. Am J Forensic Med Pathol 1997;18:100-3. 148. Steffens J, Kosharskyy B, Hiebl R, Sch€ onberger B, R€ ottger P, Loening S. Paraffinoma of the external genitalia after autoinjection of vaseline. Eur Urol 2000;38:778-81. 149. Darsow U, Bruckbauer H, Worret WI, Hofmann H, Ring J. Subcutaneous oleomas induced by self-injection of sesame seed oil for muscle augmentation. J Am Acad Dermatol 2000; 42:292-4. 150. Cohen JL, Keoleian CM, Krull EA. Penile paraffinoma: selfinjection with mineral oil. J Am Acad Dermatol 2001;45(6 suppl):S222-4. 151. Santos P, Chaveiro A, Nunes G, Fonseca J, Cardoso J. Penile paraffinoma. J Eur Acad Dermatol Venereol 2003;17: 583-4. 152. Eo SR, Kim KS, Kim DY, Lee SY, Cho BH. Paraffinoma of the labia. Plast Reconstr Surg 2004;113:1885-7. 153. Ko CJ, Sarantopoulos GP, Bhuta S, Binder SW. Scalp paraffinoma underlying squamous cell carcinoma. Arch Pathol Lab Med 2004;128:1171-2. 154. Akkus E, Iscimen A, Tasli L, Hattat H. Paraffinoma and ulcer of the external genitalia after self-injection of vaseline. J Sex Med 2006;3:170-2. 155. Markopoulos C, Mantas D, Kouskos E, Antonopoulou Z, Revenas C, Yiacoumettis A. Paraffinomas of the breast or oleogranulomatous mastitis—a rare entity. Breast 2006;15:540-3. 156. Eandi JA, Yao AP, Javidan J. Penile paraffinoma: the delayed presentation. Int Urol Nephrol 2007;39:553-5. 157. Rodrıguez-Martın M, Saez-Rodrıguez M, Carrasco JL, Carnerero A, Cabrera R, Perez-Robayna N, et al. Self-induced paraffinoma in a schizophrenic patient. J Am Acad Dermatol 2007;56(5 suppl):S127-8. 158. Uchida Y, Yoshii N, Kubo H, Kanzaki T, Kanekura T. Facial paraffinoma after cosmetic paraffin injection. J Dermatol 2007;34:798-800. 159. Pehlivanov G, Kavaklieva S, Kazandjieva J, Kapnilov D, Tsankov N. Foreign-body granuloma of the penis in sexually active individuals (penile paraffinoma). J Eur Acad Dermatol Venereol 2008;22:845-51. 160. Balighi K, Farsinejad K, Naraghi ZS, Tamizifar B. Paraffinoma and ulcer of the external genitalia after self-injection of nandrolone. Int J Dermatol 2008;47:1092-4. 161. Oertel YC, Johnson FB. Sclerosing lipogranuloma of male genitalia. Arch Pathol Lab Med 1977;101:321-6. 162. Claudy A, Garcier F, Schmitt D. Sclerosing lipogranuloma of the male genitalia: ultrastructural study. Br J Dermatol 1981; 105:451-5. 163. Hirst AE, Heustis DG, Rogers-Neufeld B, Johnson FB. Sclerosing lipogranuloma of the scalp. A report of two cases. Am J Clin Pathol 1984;82:228-31. 164. Clark DP, Hanke CW, Swanson NA. Dermal implants: safety of products injected for soft augmentation. J Am Acad Dermatol 1989;21:992-8. 165. Mori A, Lo Russo G, Agostini T, Pattarino J, Vichi F, Dini M. Treatment of human immunodeficiency viruseassociated

J AM ACAD DERMATOL VOLUME 64, NUMBER 1

166. 167.

168. 169.

170.

171.

172.

173.

174.

175.

176. 177.

178.

179.

180.

181.

182.

183.

184.

facial lipoatrophy with lipofilling and submalar silicone implants. J Plast Reconstr Aesthet Surg 2006;59:1209-16. Duffy D. Silicone. A critical review. Adv Dermatol 1990;5: 93-109. Bakker-Woudenberg IA, Lokerse AF, ten Kate MT, Melissen PM, van Vianen W, van Etten EW. Liposomes as carriers of antimicrobial agents or immunomodulatory agents in the treatment of infections. Eur J Clin Microbiol Infect Dis 1993; 12(suppl 1):S61-7. Duffy DM. Liquid silicone for soft tissue augmentation. Dermatol Surg 2005;31:1530-41. Barlow R, Torres W, Sones P, Someren A. Sonographic demonstration of migrating silicone. AJR Am J Roentgenol 1980;135:170-1. Wickham MG, Rudolph R, Abraham JL. Silicon identification in prosthesis-associated fibrous capsules. Science 1978;199: 437-9. Winding O, Christensen L, Thomsen JL, Breiting VB, Brandt B. Silicon in human breast tissue surrounding silicone gel prostheses. A scanning electron microscopy and energy dispersive X-ray investigation of normal, fibrocystic and peri-prosthetic breast tissue. Scand J Plast Reconstr Surg Hand Surg 1988;22:127-30. Gregoriadis G. Liposomes as immunological adjuvants: approaches to immunopotentiation including ligandmediated targeting to macrophages. Res Immunol 1992;43: 178-85. Thomsen JL, Christensen L, Nielsen M, Brandt B, Breiting VB, Felby S, et al. Histologic changes and silicone concentrations in human breast tissue surrounding silicone breast prostheses. Plast Reconstr Surg 1990;85:38-41. Silver RM, Sahn EE, Aleen JA, Sahn S, Greene W, Maize JC, et al. Demonstration of silicone in sites of connective tissue disease in patients with silicone gel breast implants. Arch Dermatol 1993;129:63-8. Varga J, Schumacher R, Jimenez SA. Systemic sclerosis after augmentation mammoplasty with silicone implants. Ann Intern Med 1989;111:377-87. Leong AS, Disney AP, Gove DW. Retractile particles in liver of hemodialysis patients. Lancet 1981;1:889-90. Bommer J, Ritz E, Walsherr R. Silicone-induced splenomegaly: treatment of pancytopenia by splenectomia in a patient on hemodialysis. N Engl J Med 1981;305:1077-9. Travis WD, Balogh K, Abraham JL. Silicone granulomas: report of three cases and review of the literature. Hum Pathol 1985; 16:19-27. Anderson DR, Schwartz J, Cottrill CM, McClain SA, Ross JS, Magidson JG, et al. Silicone granulomas in acral skin in a patient with silicone-gel breast implants and systemic sclerosis. Int J Dermatol 1996;35:36-8. Teuber SS, Ito LK, Anderson M, Gershwin ME. Silicone breast implanteassociated scarring dystrophy of the arm. Arch Dermatol 1995;131:54-6. Raso DS, Greene WB, Harley RA, Maize JC. Silicone deposition in reconstruction scars of women with silicone breast implants. J Am Acad Dermatol 1996;35:32-6. Marcusson JA, Bjarnason B. Unusual reaction to silicone content in breast implants. Acta Derm Venereol 1999;79: 136-8. Granel B, Serratrice J, Gaudy C, Weiller-Merli C, Bonerandi JJ, Lepidi H, et al. Localized morphea after silicone-gel-filled breast implant. Dermatology 2001;202:143-4. Ishikawa O, Warita S, Tamura A, Miyachi Y. Occupational scleroderma. A 17-year follow-up study. Br J Dermatol 1995; 133:786-9.

Requena et al 31

185. Fenske NA, Vasey FB. Silicone-associated connectivetissue disease. The debate rages. Arch Dermatol 1993; 129:97-8. 186. Sahn EE, Garen PD, Silver RM, Maize JC. Scleroderma following augmentation mammoplasty. Report of a case and review of the literature. Arch Dermatol 1990;126: 1198-202. 187. Varga J, Jimenez SA. Augmentation mammoplasty and scleroderma. Is there an association? Arch Dermatol 1990; 126:1220-2. 188. H€ olmich LR, Lipworth L, McLaughlin JK, Friis S. Breast implant rupture and connective tissue disease: a review of the literature. Plast Reconstr Surg 2007;120(7 suppl. 1):62S-9S. 189. Balzer BL, Weiss SW. Do biomaterials cause implantassociated mesenchymal tumors of the breast? Analysis of 8 new cases and review of the literature. Hum Pathol 2009; 40:1564-70. 190. de Jong D, Vasmel WL, de Boer JP, Verhave G, Barbe E, Casparie MK, et al. Anaplastic large-cell lymphoma in women with breast implants. JAMA 2008;300:2030-5. 191. Winer LH, Sternberg TH, Lehman R, Ashley FL. Tissue reactions to injected silicone liquids. Arch Dermatol 1964;90: 588-93. 192. Achauer BM. A serious complication following medical-grade silicone injection of the face. Plast Reconstr Surg 1983;71: 251-4. 193. Pearl RM, Laub DR, Kaplan EN. Complications following silicone injections for augmentation of the contour of the face. Plast Reconstr Surg 1983;71:251-3. 194. Pimentel L, Barnadas M, Vidal D, Sancho F, Fontarnau R, Alomar A. Simultaneous presentation of silicone and silica granuloma. Dermatology 2002;205:162-5. 195. Rapaport MJ, Vinnik C, Zarem H. Injectable silicone: cause of facial nodules, cellulites, ulceration, and migration. Aesthetic Plast Surg 1996;20:267-76. 196. Wilkie TF. Late development of granuloma after liquid silicone injections. Plast Reconstr Surg 1977;60:179-88. 197. Veiga DF, Filho JV, Schnaider CS, Archangelo I Jr. Late hematoma after aesthetic breast augmentation with textured silicone prosthesis: a case report. Aesthetic Plast Surg 2005;29:431-3. 198. Khan UD. Bilateral areolar depigmentation after augmentation mammoplasty: a case report and literature search. Aesthetic Plast Surg 2008;32:143-6. 199. Yanagihara M, Fujii T, Wakamatu N, Ishizaki H, Takehara T, Nawate K. Silicone granuloma on the entry points of acupuncture, venepuncture and surgical needles. J Cutan Pathol 2000;27:301-5. 200. Rae V, Pardo RJ, Blackwelder PL, Falanga V. Leg ulcers following subcutaneous injection of a liquid silicone preparation. Arch Dermatol 1989;125:670-3. 201. Mastruserio DN, Pesqueira MJ, Cobb MW. Severe granulomatous reaction and facial ulceration after subcutaneous silicone injection. J Am Acad Dermatol 1996;34: 849-52. 202. Hexsel DM, Hexsel CL, Iyengar V. Liquid injectable silicone. History, mechanism of action, indications, technique, and complications. Semin Cutan Med Surg 2003;22: 107-14. 203. Oliveira VM, Roveda Junior D, Lucas FB, Lucarelli AP, Martins MM, Rinaldi JF, et al. Late seroma after breast augmentation with silicone prostheses: a case report. Breast J 2007;13: 421-3. 204. Restrepo CS, Artunduaga M, Carrillo JA, Rivera AL, Ojeda P, Martinez-Jimenez S, et al. Silicone pulmonary embolism:

J AM ACAD DERMATOL

32 Requena et al

205. 206.

207. 208.

209.

210.

211.

212.

213.

214.

215.

216. 217.

218.

219. 220.

221.

222.

223.

224.

225.

report of 10 cases and review of the literature. J Comput Assist Tomogr 2009;33:233-7. Gurvits GE. Silicone pneumonitis after a cosmetic augmentation procedure. N Engl J Med 2006;354:211-2. Ficarra G, Mosqueda-Taylor A, Carlos R. Silicone granuloma of the facial tissues: a report of seven cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94:65-73. Krayenb€ uhl BH, Panizzon RG. Silicone granuloma. Dermatology 2000;200:360-2. Maly A, Regev E, Meir K, Maly B. Tissue reaction to liquid silicone simulating low-grade liposarcoma following lip augmentation. J Oral Pathol Med 2004;33:314. Mustacchio V, Cabibi D, Minervini MI, Barresi E, Amato S. A diagnostic trap for the dermatopathologist: granulomatous reactions from cutaneous microimplants for cosmetic purposes. J Cutan Pathol 2007;34:281-3. Kasper CS, Chandler PJ. Talc deposition in skin and tissues surrounding silicone gelecontaining prosthetic devices. Arch Dermatol 1994;130:48-53. Ackerman AB, Jacobson M, Vitale P. What is the clue and what is your diagnosis? In: Ackerman AB, Jacobson M, Vitale P, editors. Clues to diagnosis in dermatopathology I. Chicago: ASCP Press; 1990. p. 394-5. Faure M. Complications from silicone implants and other socalled inert materials [in French]. Ann Dermatol Venereol 1995;122:455-9. Haycox CL, Leach-Scampavia D, Olerud JE, Ratner BD. Quantitative detection of silicone in skin by means of spectroscopy for chemical analysis (ESCA). J Am Acad Dermatol 1999; 40:719-25. Bigata X, Ribera M, Bielsa I, Ferrandiz C. Adverse granulomatous reaction after cosmetic dermal silicone injection. Dermatol Surg 2001;27:198-200. Baumann LS, Halem ML. Lip silicone granulomatous foreign body reaction treated with Aldara (imiquimod 5%). Dermatol Surg 2003;29:429-32. Owens JM. Soft tissue implants and fillers. Otolaryngol Clin N Am 2005;38:361-9. Senet P, Bachelet H, Ollivaud L, Vignon-Pennamen D, Dubertret L. Minocycline for the treatment of cutaneous silicone granulomas. Br J Dermatol 1999;140:985-7. Ersek RA, Beisang AA. Bioplastique: a new texture copolymer microparticle promises permanence in soft tissue augmentation. Plast Reconstr Surg 1991;33:693-702. Rudolph CM, Soyer HP, Schuller-Petrovic S, Kerl H. Bioplastiquegranulom. Hautarzt 1997;48:749-52. Hoffmann C, Schuller-Petrovic S, Soyer HP, Kerl H. Adverse reactions after cosmetic augmentation with permanent biologically inert implant materials. J Am Acad Dermatol 1999; 40:100-2. Rudolph CM, Soyer HP, Schuller-Petrovic S, Kerl H. Foreign body granulomas due to injectable aesthetic microimplants. Am J Surg Pathol 1999;23:113-7. Bergeret-Galley C, Latouche X, Illouz YG. The value of new filler material in corrective and cosmetic surgery: DermaLive and DermaDeep. Aesthetic Plast Surg 2001;25: 249-55. Requena C, Izquierdo MJ, Navarro M, Martınez A, Vilata JJ, Botella R, et al. Adverse reactions to injectable aesthetic microimplants. Am J Dermatopathol 2001;23:197-202. Lemperle G, Romano JJ, Busso M. Soft tissue augmentation with Artecoll: 10-year history, indications, techniques, and complications. Dermatol Surg 2003;29:573-87. Lemperle G, Hazan-Gauthier N, Lemperle M. PMMA microspheres (Artecoll) for skin and soft-tissue augmentation.

JANUARY 2011

226.

227.

228.

229. 230. 231. 232. 233.

234.

235. 236.

237.

238.

239.

240.

241.

242.

243.

244.

Part II: Clinical investigations. Plast Reconstr Surg 1995;96: 627-34. Lemperle G, Ott H, Charrier U, Hecker J, Lemperle M. PMMA microspheres for intradermal implantation: part I. Animal research. Ann Plast Surg 1991;26:57-63. Kamer FM, Churukian MM. Clinical use of injectable collagen. A three-year retrospective review. Arch Otolaryngol 1984; 110:93-8. McClelland M, Egbert B, Hanko V, Berg RA, DeLustro F. Evaluation of Artecoll polymethylmethacrylate implant for soft-tissue augmentation: biocompatibility and chemical characterization. Plast Reconstr Surg 1997;100: 1466-74. Alcalay J, Alkalay R, Gat A, Yorav S. Late-onset granulomatous reaction to Artecoll. Dermatol Surg 2003;29:859-62. Lemperle G. Complications from Artecoll are treatable. Aesthetic Surg J 2003;23:469-70. Thioly-Bensoussan D. Non-hyaluronic acid fillers. Clin Dermatol 2008;26:160-76. Lemperle G, Kind P. Biocompatibility of Artecoll. Plast Reconstr Surg 1999;103:338-40. Lemperle G, Gauthier-Hazan N, Lemperle M. PMMA-microspheres (Artecoll) for long-lasting correction of wrinkles: refinements and statistical results. Aesthetic Plast Surg 1998;22:356-65. Fischer J, Metzler G, Schaller M. Cosmetic permanent fillers for soft tissue augmentation: a new contraindication for interferon therapies. Arch Dermatol 2007;143:507-10. Al-Qattan MM. Late artecoll granulomas aggravated by pregnancy. Ann Plast Surg 2007;58:592. Reisberger EM, Landthaler M, Wiest L, Schr€ oder J, Stolz W. Foreign body granulomas caused by polymethylmethacrylate microspheres: successful treatment with allopurinol. Arch Dermatol 2003;139:17-20. Conejo-Mir JS, Sanz Guirado S, Angel Mu~ noz M. Adverse granulomatous reaction to Artecoll treated by intralesional 5fluorouracil and triamcinolone injections. Dermatol Surg 2006;32:1079-81. Kim KJ, Lee HW, Lee MW, Choi JH, Moon KC, Koh JK. Artecoll granuloma: a rare adverse reaction induced by microimplant in the treatment of neck wrinkles. Dermatol Surg 2004;30: 545-7. da Costa Miguel MC, Nonaka CF, dos Santos JN, Germano AR, de Souza LB. Oral foreign body granuloma: unusual presentation of a rare adverse reaction to permanent injectable cosmetic filler. Int J Maxillofac Surg 2009;38:385-7. Sidwell RU, Mc LJN, Francis N, Bunker CB. Cutaneous sarcoidal granulomas developing after Artecoll facial cosmetic filler in a patient with newly diagnosed systemic sarcoidosis. Clin Exp Dermatol 2006;31:208-11. Mang WL, Sawatzaki K. Fremdk€ orperreaktion nach Implantation von PMMA (Polymethylmethacrylat) zur Weichteilaugmentation. Z Hautkrankh 1998;73:42-4. Requena C, Requena L, Sanmartın O, Botella R. Histopathologic findings of granuloma caused by polymethylmethacrylate microspheres. Arch Dermatol 2003;139:1505. Wheeler JC, Woods JA, Cox MJ, Cantrel RW, Watkins FH, Edlich RF. Evolution of hydrogel polymers as contact lenses, surface coatings, dressings, and drug delivery systems. J Long Term Eff Med Implants 1996;6:207-17. Rossner M, Rossner F, Bachmann F, Wiest L, Rzany B. Risk of severe adverse reactions to an injectable filler based on a fixed combination of hydroxyethylmethacrylate and ethylmethacrylate with hyaluronic acid. Dermatol Surg 2009;35 (suppl 1):367-74.

J AM ACAD DERMATOL

Requena et al 33

VOLUME 64, NUMBER 1

245. Gamo R, Pinedo F, Vicente J, Naz E, Calzado L, Ruiz-Genao D, et al. Keratoacanthoma-like reaction after a hyaluronic acid and acrylic hydrogel cosmetic filler. Dermatol Surg 2008;34:954-9. 246. Sidwell RU, Dhillon AP, Butler PE, Rustin MH. Localized granulomatous reaction to a semi-permanent hyaluronic acid and acrylic hydrogel cosmetic filler. Clin Exp Dermatol 2004;29:630-2. 247. Vargas-Machuca I, Gonzalez-Guerra E, Angulo J, Fari~ na MC, Martin L, Requena L. Facial granulomas secondary to Dermalive microimplants: report of a case with histopathologic differential diagnosis among the granulomas secondary to different injectable permanent filler materials. Am J Dermatopathol 2006;28:173-7. 248. Furmanczyk PS, Wolgamot GM, Argenyi ZB, Gilbert SC. Extensive granulomatous reaction occurring 1.5 years after DermaLive injection. Dermatol Surg 2009;35(suppl 1): 385-8. 249. Gonzalez-Vela MC, Armesto S, Gonzalez-Lopez MA, Fernandez-Llaca JH, Val-Bernal JF. Perioral granulomatous reaction to Dermalive. Dermatol Surg 2008;34:986-8. 250. Angus JE, Affleck AG, Leach IH, Millard LG. Two cases of delayed granulomatous reactions to the cosmetic filler Dermalive, a hyaluronic acid and acrylic hydrogel. Br J Dermatol 2006;155:1077-8. 251. Cheng N-X, Wang Y-L, Wang J-H, Zhang X-M, Zhong H. Complications of breast augmentation with injected hydrophylic polyacrylamide gel. Aesthetic Plast Surg 2002;26:375-82. 252. Niachajev I. Lip enhancement: surgical alternatives and histologic aspects. Plast Reconstr Surg 2000;105:1173-83. 253. Von Buelow S, Pallua N. Efficacy and safety of polyacrylamide hydrogel for facial soft-tissue augmentation in a 2-year follow-up: a prospective multicenter study for evaluation of safety and aesthetic results in 101 patients. Plast Reconstr Surg 2006;118(2 suppl):85S-91S. 254. De Santis G, Jacob V, Baccarani A, Pedone A, Pinelli M, Spaggiari A, et al. Polyacrylamide hydrogel injection in the management of human immunodeficiency viruserelated facial lipoatrophy: a 2-year clinical experience. Plast Reconstr Surg 2008;121:644-53. 255. Negredo E, Puig J, Aldea D, Medina M, Estany C, PerezAlvarez N, et al. Four-year safety with polyacrylamide hydrogel to correct antiretroviral-related facial lipoatrohpy. AIDS Res Hum Retroviruses 2009;25:451-5. 256. De Cassia Novaes W, Berg A. Experience with a new nonbiodegradable hydrogel (Aquamid): a pilot study. Aesthetic Plast Surg 2003;27:376-80. 257. Christensen LH, Breiting VB, Aasted A, Jorgensen A, Kebulazde I. Long-term effects of polyacrylamide hydrogel on human breast tissue. Plast Reconstr Surg 2003;111:1883-90. 258. Alijotas-Reig J, Garcia Jimenez V, Mir o Mur F, Vilardel Tarres M. Delayed immune-mediated adverse effects related to polyacrylamide dermal fillers: clinical findings, management, and follow-up. Dermatol Surg 2009;35(suppl 1):360-6. 259. Christensen L, Breiting V, Vuust J, Hogdall E. Adverse reactions following injection with a permanent facial filler polyacrylamide hydrogel (Aquamid): causes and treatment. Eur J Plast Surg 2006;28:464-71. 260. De Bree R, Middelweerd MJ, van der Waal I. Severe granulomatous inflammatory response induced by injection of polyacrylamide gel into facial tissue. Arch Facial Plast Surg 2004;6:204-6. 261. Xie PB, Shi AP. Complications of breast augmentation with injected hydrophilic polyacrylamide gel. Aesthetic Plast Surg 2002;26:375-82. 262. Cheng NX, Xu SL, Deng H, Ding XB, Zhang XM, Wu DH, et al. Migration of implants: a problem with injectable

263. 264.

265. 266.

267.

268.

269.

270.

271. 272.

273.

274. 275.

276.

277.

278.

279. 280.

281.

282.

polyacrylamide gel in aesthetic plastic surgery. Aesthetic Plast Surg 2006;30:215-25. Patrick T. Polyacrylamide gel in cosmetic procedures: experience with Aquamid. Semin Cutan Med Surg 2004;23:233-5. Kawamura JY, Domaneschi C, Migliari DA, Sousa SO. Foreign body reaction due to skin filler: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;101:469-71. Christensen L. Normal and pathologic tissue reactions to soft tissue gel fillers. Dermatol Surg 2007;33:S168-75. Liu HL, Cheung WY. Complications of polyacrylamide hydrogel (PAAG) injection in facial augmentation. J Plast Reconstr Aesthet Surg 2010;63:e9-12. Cheng NX, Liu LG, Hui L, Chen YL, Xu SL. Breast cancer following augmentation mammaplasty with polyacrylamide hydrogel (PAAG) injection. Aesthetic Plast Surg 2009;33:563-9. Christensen LH, Nilesen JB, Mouritsen L, Sorensen M, Lose G. Tissue integration of polyacrylamide hydrogel: an experimental study of periurethral, perivesical and mammary gland tissue in the pig. Dermatol Surg 2008;34 (suppl 1):S68-77. Karagozoglu KH, van der Waal I. Polyacrylamide soft tissue filler nodule mimicking a mucoepidermoid carcinoma. Int J Oral Maxillofac Surg 2008;37:578-80. Pacini S, Rugiero M, Cammarota N, Protopata C, Gulisano M. Bio-alcamid, a novel prosthetic polymer, does not interfere with morphological and functional characteristics of human skin fibroblasts. Plast Reconstr Surg 2003;111:489-91. Claoue BL, Rabineau P. The polyalkylimide gel. Experience with Bio-Alcamid. Semin Cutan Med Surg 2004;23:236-40. Ramon Y, Fodor L, Ullmann Y. Preliminary experiences with Bio-Alcamid in HIV facial lipoatrophy. Dermatology 2007;214: 151-4. Loutfy MR, Raboud JM, Antoniou T, Kovacs C, Shen S, Halpenny R, et al. Immediate versus delayed polyalkylimide gel injections to correct facial lipoatrophy in HIV-positive patients. AIDS 2007;21:1147-55. Margolis DM. Treatment for lipoatrophy: facing the real costs. AIDS 2007;21:1819-20. Nelson L, Stewart KJ. Experience in the treatment of HIVassociated lipodystrophy. J Plast Reconstr Aesthet Surg 2008; 61:366-71. Karim RB, de Lint CA, van Galen SR, van Rozelaar L, Nieuwkerk PT, Askarizadeh E, et al. Long-term effect of polyalkylimide gel injections on severity of facial lipoatrophy and quality of life of HIV-positive patients. Aesthetic Plast Surg 2008;32:873-8. Mallewa JE, Wilkins E, Vilar J, Mallewa M, Doran D, Back D, et al. HIV-associated lipodystrophy: a review of underlying mechanisms and therapeutic options. J Antimicrob Chemother 2008;62:648-60. H€ onig J. Cheek augmentation with Bio-Alcamid in facial lipoatrophy in HIV seropositive patients. J Craniofac Surg 2008;19:1085-8. Serrano C, Serrano S. Delayed infection after Bio-alcamid implantation [in Spanish]. Actas Dermosifiliogr 2006;97:460-2. Karim RB, Hage JJ, van Rozelaar L, Lange CA, Raaijmakers J. Complications of polyalkylimide 4% injections (Bio-Alcamid): a report of 18 cases. J Plast Reconstr Aesthet Surg 2006;59: 1409-14. G omez-de la Fuente E, Alvarez-Fernandez JG, Pinedo F, Naz E, Gamo R, Vicente-Martın FJ, et al. Cutaneous adverse reaction to Bio-Alcamid implant [in Spanish]. Actas Dermosifiliogr 2007;98:271-5. Goldan O, Georgiou I, Farber N, Winkler E, Haik J, Orenstein A. Late-onset facial abscess formation after cosmetic soft

34 Requena et al

tissue augmentation with bio-alcamid. Aesthet Surg J 2007; 27:416-8. 283. Jones DH, Carruthers A, Fitzgerald R, Sarantopoulos GP, Binder S. Late-appearing abscesses after injections of nonabsorbable hydrogel polymer for HIV-associated facial lipoatrophy. Dermatol Surg 2007;33(suppl 2):S193-8. 284. Goldan O, Georgiou I, Grabov-Nardini G, Regev E, Tessone A, Liran A, et al. Early and late complications after a nonabsorbable hydrogel polymer injection: a series of 14 patients and novel management. Dermatol Surg 2007;33(suppl 2): S199-206.

J AM ACAD DERMATOL

JANUARY 2011

285. Ocampo-Candiani J, Sobrevilla-Ondarza S, Velazquez-Arenas L, Vazquez-Martınez OT. Complication of a polyalkylimide implant in a patient with facial trauma. Dermatol Surg 2008; 34:1280-2. 286. Maas CS, Papel ID, Greene D, Stoker DA. Complications of injectable synthetic polymers in facial augmentation. Dermatol Surg 1997;23:871-7. 287. Bjarnsholt T, Tolker-Nielsen T, Givskov M, Janssen M, Christensen LH. Detection of bacteria by fluorescence in situ hybridization in culture-negative soft tissue filler lesions. Dermatol Surg 2009;35(suppl 2):1620-4.