- Journal of the American Academy of Dermatology

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
D
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
1
J AM ACAD DERMATOL
2 Requena et al
JANUARY 2011
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
d
d
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Requena et al 3
VOLUME 64, NUMBER 1
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
J AM ACAD DERMATOL
4 Requena et al
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
JANUARY 2011
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
d
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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Requena et al 5
VOLUME 64, NUMBER 1
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
d
d
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
6 Requena et al
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
J AM ACAD DERMATOL
JANUARY 2011
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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Requena et al 7
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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
d
d
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,
8 Requena et al
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
d
d
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
J AM ACAD DERMATOL
JANUARY 2011
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
d
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.)
d
d
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
12 Requena et al
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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
18 Requena et al
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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
22 Requena et al
J AM ACAD DERMATOL
JANUARY 2011
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
J AM ACAD DERMATOL
VOLUME 64, NUMBER 1
Requena et al 23
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
24 Requena et al
J AM ACAD DERMATOL
JANUARY 2011
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.
J AM ACAD DERMATOL
Requena et al 25
VOLUME 64, NUMBER 1
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
26 Requena et al
J AM ACAD DERMATOL
JANUARY 2011
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.
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