Animal collagen

Bovine collagen (BC) has been used as a transitory injectable filler to correct depressed scars, deep nasolabial folds, age-related rhytides, and soft tissue augmentation. The duration of the effect from an injection of BC is usually less than 6 months. Skin tests are required before injection of these products because 3% of the population develops a delayed hypersensitivity response. Histopathology of these hypersensitive reactions includes the formation of foreign body granulomas, palisading granulomas resembling granuloma annulare at the test site injections ( Fig. 4 A ), and cyst or abscess formation. Rare examples of disseminated and recurrent sarcoid like granulomatous panniculitis caused by BC injection have also been described. More uncommon side effects include bruising, reactivation of herpetic infection, verified bacterial infection, and local necrosis. The last one is mostly seen with BC injected at the glabellar area because of vascular interruption; injections should, thus, be avoided in this region. Histopathologically, BC appears different from human collagen (HC) because bundles of BC are thicker and show a homogeneous appearance nearly devoid of spaces between them. Furthermore, HC is birefringent under polarized light and stains green with Masson trichrome stain, whereas BC is not birefringent with polarized light and stains with a pale gray-violet color with Masson trichrome stain. The inflammatory infiltrate around the implant is denser when the BC is injected in the deep reticular dermis or partially infiltrates the subcutaneous fat, but panniculitis is not usually seen when the implant is confined to the dermis. To avoid the hypersensitive adverse reactions to BC, human-based collagen implants have been produced in recent years. No skin tests for hypersensitive reactions are required with human-derived collagen products. Local adverse reactions include bruising, erythema, and swelling at the site of injection. However, a few cases of granulomatous reactions at the injection site or at the skin test site after injection of acellular HC have also been reported.

Histopathologic morphology of filler particles. ( A ) BC ( H&E ×200). ( B ) Porcine collagen (H&E ×200). ( C ) HA (H&E ×400). ( D ) Purified polysaccharide alginate (Novabel) (H&E ×400). ( E ) Dextranomer microparticles (Matridex) (H&E ×400). ( F ) Poly- l -lactic acid (New-Fill) (H&E ×400). ( G ) Calcium hydroxylapatite + carboxymethylcellulose and glycerin (Radiance) (H&E ×400). ( H ) Paraffin (H&E ×400). ( I ) Silicone (H&E ×400). ( J ) Elastomer particles + polyvinylpyrrolidone (Bioplastique) (H&E ×400). ( K ) Polymethyl-methacrylate microspheres and BC (Artecoll) (H&E ×400). ( L ) Hydroxyethylmethacrylate/ethylmethacrylate fragments and HA (Dermalive) (H&E ×400). ( M ) Polyacrylamide hydrogel (Aquamid) ( H&E ×200). ( N ) Polyalkylimide gel (Bio-Alcamid) (H&E ×400).

Fillers with porcine collagen (PC) have also been used with good cosmetic results and few adverse reactions. It seems that PC does not require previous skin testing; it induces less inflammatory response than BC; histopathologic evaluation demonstrates that PC seems integrated within the host tissue, being difficult to distinguish by conventional histopathology between porcine and HC bundles (see Fig. 4 B).

Hyaluronic acid

Injections of HA gel are now used as resorbable filler for filling out wrinkles of the face, soft tissue augmentation, and correction of all types of defects, such as scars and facial lipoatrophy. The longevity of the injected gel lasts for about 6 months. HA has no organ or species specificity; thus, in theory there is no risk of an allergic reaction. Very few adverse hypersensitivity reactions secondary to injections of HA 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 (see Fig. 4 C), which was the injected HA gel. Scant amounts of HA may also be seen within multinucleated giant cells. The HA stains positively for alcian blue at a pH of 2.7 and is negative when examined under polarized light. Rarely described histopathologic findings at the injection sites of HA include a prominent eosinophilic granulomatous reaction and a suppurative granuloma without evidence of infection. Sonographically, pure HA appears as scattered anechoic round structures (pseudocysts), whereas the mixed formulation (HA and lidocaine) presents pseudocysts with inner echoes (debris) and septa. The most serious complication of HA injections is the iatrogenic blindness as a direct consequence of filler embolization into the ophthalmic artery following cosmetic injections.

Purified polysaccharide alginate

Five cases of granulomatous reactions to a new resorbable filler consisting of the purified polysaccharide alginate (Novabel) have been described when injected into tear troughs and/or the dorsa of hands. No systemic complications have been described as secondary to the injections of this filler. Histopathologically, the granulomatous reaction was confined to the deep dermis and subcutaneous fat, which were involved by numerous multinucleated giant cells and histiocytes. Within this granulomatous reaction, a nonpolarizing exogenous material was identified consisting of slightly bluish deposits of variable size and shape, some of which were well delineated, others with a blurred or spiky perimeter, and frequently showed retraction in a clear vacuole (see Fig. 4 D). These particles of Novabel reacted weakly with periodic acid-Schiff (PAS) and alcian blue but were intensely stained with toluidine blue.

Hyaluronic acid + dextranomer microparticles

A mixture of nonanimal-stabilized HA and dextranomer microspheres (Matridex, Reviderm Intra) has also been used as a resorbable filler. Only one case of a granulomatous reaction caused by this filler has been described in the literature. Histopathology of that case demonstrated a suppurative granuloma surrounding the HA and the spherical dark bluish particles that represented the dextranomer microparticles (see Fig. 4 E).

Poly- l -lactic acid

Poly- l -lactic acid (PLLA) is a resorbable filler that has been used to correct the signs of lipoatrophy in human immunodeficiency virus (HIV)–infected patients receiving antiprotease treatment as well as for facial cosmetic augmentation. It induces tissue augmentation that lasts up to at least 24 months. This filler frequently develops nodules at the site of injection, which are palpable but generally nonvisible. Histopathology of the nodules demonstrates a foreign-body granulomatous reaction, with numerous multinucleated giant cells surrounding translucent particles of different sizes, most of them showing a fusiform, oval, or spiky shape, which are birefringent under polarized light examination (see Fig. 4 F).

Calcium hydroxylapatite

Calcium hydroxylapatite (CH) is another resorbable filler composed of CH microspheres that stimulate the endogenous production of collagen. These microspheres induce almost no foreign body reaction and they show a bluish color and a round or oval shape. When this agent is injected in the lips, it tends to be associated with a high incidence of nodules. However, in some patients, CH microspheres may induce a foreign body granulomatous reaction, and blue-gray microspheres in the extracellular matrix or within multinucleated giant cells can be seen ( Fig. 4 G). On ultrasound, CH appears as hyperechoic deposits with variable degrees of posterior acoustic shadowing.

Paraffin

Paraffin is no longer used as filler because of its frequent adverse reactions; but because it is a nonresorbable material, it is still possible to see granulomatous reactions secondary to injections performed many years ago. These granulomatous reactions, also named paraffinomas, consist histopathologically of 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. The surrounding dermis and the connective tissue of the subcutaneous septa show considerable sclerosis. Sclerosing lipogranuloma is a specific form of paraffinoma, which results from injection of paraffin in the penis causing fibrosis and deformity of the penis body (see Fig. 4 H).

Silicone

Silicone is the most widely used filler material for soft tissue augmentation. Recently, it has also been injected as a filler to circumvent facial lipoatrophy in HIV infected patients receiving antiprotease treatment. Silicone gel is capable of migrating to distant sites, where it may give rise to an inflammatory reaction and hamper clinical diagnosis. Although 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, there seems to be little scientific basis for any association between silicone breast implants and any well-defined connective tissue disease. Recently, 4 cases of a new type of adverse reaction to injected silicone simulating orofacial granulomatosis have been described. The reaction consisted of recurrent episodes of unilateral, asymmetric facial edema of the cheek. Histopathology demonstrated a granulomatous reaction around silicone particles. Histopathologic findings in local reactions to implants of silicone are variable depending mainly 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, and the particles are not birefringent under polarized light (see Fig. 4 I). Sonographically, silicone oil appears as hyperechoic deposits snow storm with a high degree of sound scattering, similar to the pattern reported in patients with ruptured breast implants whereby the initially anechoic silicone is suddenly expelled and can freely mix and/or spread through the fat lobules of the subcutaneous tissue. Pure silicone appears anechoic when injected without pressure in the porcine skin.

Polyvinylpyrrolidone

A permanent filler, composed of particles of polymerized silicone elastomer dispersed in a carrier of polyvinylpyrrolidone (PVP) (Bioplastique), has been recently introduced for correction of facial rhytides and lip augmentation. Granulomas secondary to this filler are uncommon but when develop consist of irregularly shaped cystic spaces containing translucent, jagged pop corn, nonbirefringent particles of varying size dispersed in a sclerotic stroma, surrounded by abundant multinucleated foreign body giant cells (see Fig. 4 J). Although the material is nonbirefringent, crystalloid particles are better seen when lowering the microscope condenser.

Polymethyl-methacrylate microspheres and bovine collagen

Another permanent biphasic filler, composed of polymethylmethacrylate microspheres suspended in a degradable BC solution as a carrier (Artecoll), is used mostly in Europe as a cosmetic microimplant for correction of facial wrinkles and furrows, perioral lines, small scars, and other subdermal defects. Because this filler contains BC, it is mandatory to perform an intradermal test 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, which mimic normal adipocytes and correspond to the implanted polymethylmethacrylate microspheres (see Fig. 4 K). The microspheres may be distinguished from normal adipocytes because they are markedly homogeneous in size and shape. Recently, a study analyzed the biological behavior of Artecoll injected into the mouse ear. Histopathologic analyses of the ear, liver, and kidney were performed revealing the development of an intense granulomatous reaction of the foreign body type in the right ear, periportal and intralobular infiltrates in the liver, and interstitial nephritis and chronic pyelonephritis in the kidney. Sonographically, polymethylmethacrylate deposits at early stages are generally small (<1 cm), appearing as multiple bright hyperechoic dots producing a mini comet-tail-shaped artifact (posterior reverberance); later on (more than 6 months after injection), some of the larger filler deposits acquire posterior acoustic shadowing artifacts.

Hydroxyethylmethacrylate/ethylmethacrylate fragments and hyaluronic acid

Another permanent biphasic filler is composed of ethylmethacrylate and hydroxyethylmethacrylate particles suspended in an HA gel (Dermalive). 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 (see Fig. 4 L). Transepidermal elimination of the product may occur.

Polyacrylamide hydrogel

An injected hydrophilic gel of polyacrylamide (Aquamid) 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 treatment of antiretroviral-related facial lipoatrophy in HIV-infected patients as well as for correction of acquired or congenital malformations with depressed skin. This permanent filler may cause nodules after the injections that frequently develop secondary 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 polyacrylamide hydrogel (see Fig. 4 M). This material shows some histopathologic similarity to HA, although granulomas secondary to HA usually show 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.

Polyalkylimide gel

Bio-Alcamid is a permanent translucent gel filler made of a hydrophilic biopolymer composed of sterile water and polyalkylimide polymer. It has been used to increase volume in the cheeks in HIV-infected patients with facial lipoatrophy related to antiretroviral therapy as well as for buttock augmentation, correction of scar depressions, and posttraumatic subcutaneous atrophy. Few histopathologic studies describing the adverse reactions to this filler have been reported, and they described basophilic amorphous material corresponding to the implanted material, surrounded by epithelioid histiocytes, foreign body multinucleated giant cells, neutrophils, and red cells (see Fig. 4 N).

Immediate-onset complications

Immediate-onset complications include undercorrection and overcorrection, implant visibility, and vascular compromise. Venous obstruction is typically associated with shallower skin breakdown, whereas arterial occlusion may lead to sudden iatrogenic blindness and broad and deep skin loss. In the case of HA injection, firm massage can be used to disperse excessive, superficial, or unaesthetic filler placement; in some cases, hyaluronidase can also be of help. Other filling agents may require reduction of the product using several methods, including simple unroofing with a needle tip or superficial dermabrasion. Treatment of vascular occlusion should be swift and aggressive. Injection should be stopped and aspiration attempted; the area should be massaged and warm compresses applied to increase vasodilatation. Additionally, 2% nitroglycerine paste can be considered to cause further vasodilatation. The use of hyperbaric oxygen can also be considered in the case of dramatic vascular compromise and impending necrosis. Localized skin breakdown should be treated with topical or systemic antibiotics, and conservative debridement should also be performed when necessary.

Early onset complications

Early onset (3–14 days) complications include noninflammatory and inflammatory persistent nodules and angioedema. Noninflammatory nodules can be treated with observation, gentle massage, patient reassurance, and, sometimes, hyaluronidase. Inflammatory nodules can be treated with incision and drainage (with culture) and empiric treatment with a macrolide or tetracycline antibiotic (which also have antiinflammatory and immunomodulatory effects). Antibiotic treatment should be continued for a total of 4 to 6 weeks; if the inflammatory nodule persists, intralesional corticosteroids may also be used. Angioedema can be related to the material or to host factors; true immune-mediated angioedema is rare, estimated as less than 1 to 5 in 10,000, and thought to be related to protein contaminants present in the material. HA-related angioedema can be treated with hyaluronidase or removal of the HA derivative.

Delayed-onset complications

Delayed-onset (>14 days) complications include persistent erythema and telangiectasias at the site of injection that can be treated with hyaluronidase and a 532- or 1064-nm laser. However, the more problematic delayed-onset complications are inflammatory nodules, granulomas, and sterile abscesses. These complications can be managed with multidrug oral antibiotic therapy and intralesional corticosteroid injection using ultradilute solutions and treating repeatedly. Sometimes, surgical excision or destruction of the injected agent is the only therapeutic possibility, resulting in worse cosmetic results than those that were attempted to correct by filler in the first place. Anecdotic reports have described improvement of the foreign body granulomas with colchicine, laser therapy, allopurinol, cyclosporin, tacrolimus, ascomycin, and isotretinoin.