Received: 14 June 2018 Revised: 27 June 2018 Accepted: 10 July 2018

DOI: 10.1111/dth.12676

SPECIAL ISSUE ARTICLE

Adverse effects of fillers

Eckart Haneke1,2,3,4

1
Dermatology Practice Dermaticum, Freiburg,
Germany Abstract
2
Department of Dermatology, Inselspital, Filler injections belong to the most frequently performed noninvasive beautifying procedures.
Universitätsspital Bern, Bern, Switzerland When done correctly they are generally well tolerated. However, a number of factors, such as
3
Centro Dermatol Epidermis, Instituto CUF, poor filler quality, and particularly host as well as user dependent filler reactions may lead to
Porto, Portugal
unwanted effects. These may be early, late, or delayed events with characteristics for each of
4
Department of Dermatology, University
them. Temporary fillers almost invariably cause temporary side effects whereas those of perma-
Hospital, Ghent, Belgium
nent fillers may last forever. Some fillers are notorious for their poor safety profile; for example,
Correspondence
Eckart Haneke Dermatology Practice silicone is banned in the European Union and the United States but nevertheless used by many
Dermaticum, Freiburg, Germany. practitioners and beauticians. Many fillers can be identified in histopathologic sections allowing
Email: haneke@gmx.net specific measures to be instituted.

KEYWORDS

adverse effects, calcium hydroxyl apatite, histopathology, hyaluronic acid, permanent fillers,
poly-L-lactic acid, soft tissue fillers

1 | I N T RO D UC T I O N Concerning the fillers themselves, it is the substance on one hand

The injection of fillers for soft tissue augmentation is one of the most
frequently performed cosmetic procedures with many millions of
injections worldwide. As with all procedures in medicine, most of
them are tolerated without any adverse effects, but some may cause
side effects. These are a catastrophe for a person who seeks a beauti-
fying treatment and ends up with a result worse than before.
To avoid this a complete patient history has to be taken, particu-
larly concerning previous injections, allergies, immune reactions and
diseases, drugs with an immunomodulatory potential, and chronic
infections. A family history as to serious diseases, collagenoses,
immune defects, and genetic disorders is necessary. It is known that
some fillers are not well tolerated when injected next to, or above,
another one.
It is self-evident that a physician injecting the filler must be expe-
rienced to avoid gross mistakes concerning the site of injection, the
volume, the speed and the depth, and the best post-injection treat-
ment has to be known. The doctor should be available after the injec-
and its chemistry, its purity, homogeneity, particle size, shape and
roughness, its electrical charge, its ability to biointegration, and to
react with other substances that matter (Ionescu et al., 2012).
Filler adverse effects are classified according to their time course
and whether they are user dependent, due to the filler itself or host
factors (Haneke, 2006, 2009). Technical errors concern too much or
too little volume, incorrect depth of filler placement, wrong location,
and inappropriate product choice (DeLorenzi, 2013). Many side
effects are unpredictable, some may be anticipated before injection,
and prior training and experience could have avoided others. Further,
adverse effects are classified according to their time of appearance
and time course into immediate, late and delayed events. In general,
temporary fillers cause temporary side effects whereas permanent
fillers may cause permanent adverse effects (Haneke, 2004).
Changes took place in the injection technique. Whereas linear
threading, fan technique, and criss–cross injections with needles were
preferred until about 10 years ago, the development of blunt cannulas

tion. Never should a patient’s concerns be dismissed. Treating a of fine diameters has revolutionized the injection technique and made

patient with empathy has avoided many lawsuits. The nature of com- inadvertent intravascular injections even less frequent (Iwayama et al.,
plication is checked and can be classified into light and disappearing 2018). However, the cannulas should not be too thin as they may then
by itself, moderate and requiring treatment, or severe necessitating nevertheless pierce a blood vessel. For volume restoration, the tower
immediate intervention. technique is now preferred. A depot of a malleable filler is injected

Dermatologic Therapy. 2018;e12676. wileyonlinelibrary.com/journal/dth © 2018 Wiley Periodicals, Inc. 1 of 9

https://doi.org/10.1111/dth.12676
2 of 9
directly on the periosteum and gently massaged to turn it into the
required shape (Sattler, 2012).
Most immediate adverse effects are short lived, usually not sub-
stance dependent, but due to the manipulation associated with the
injection, such as erythema, some swelling, hematoma, itching, and
pain. They are inevitable consequences of virtually all injections. Itch-
ing and pain lasting for some hours may be prevented or avoided by
the addition of a local anesthetic agent as is now done by many manu-
facturers. Applying cold compresses alleviates erythema and swelling.
Using a blunt cannula reduces the risk of hematoma. Localized swell-
ing of the lip may be due to inadvertent puncture of a blood vessel
and occur hours after the injection. Hematomas can be treated with
arnica or vitamin K ointment; whether Aloe vera often recommended
in publications is really a preventive drug has not been convincingly
confirmed by controlled studies.
Vascular occlusion is commonly thought to be technique-depen-
dent; however, it may happen even to the most experienced injector
(see below) as the course of the facial arteries varies among persons
with only the most frequent variants being shown in the text books
(Pilsl & Anderhuber, 2016; André & Haneke, 2016). The ala nasi and
glabella regions are particularly risky. In most cases of direct intravas-
cular injection, it is seen immediately as a blanching of a circumscribed
skin area, and if occlusion is due to compression from outside it is
seen the next day. When blanching is seen during the injection it must
immediately be stopped. Immediate injection of hyaluronidase as
close to the occluded vessel as possible is recommended, but still the
outcome cannot be predicted (Sattler, 2012; Iwayama et al., 2018); no
such antidote is available for other fillers than hyaluronic acid. In a
case of ocular complications after rhinoplasty with calcium hydroxyl
apatite, the filler was visible in the vessels of the conjunctiva bulbi in
split light examination (Sung, Tsai, & Chen, 2018). Although ultrasound
has been used to explore vascular complications (Kwon, Kim, Ko, &
Choi, 2017) it has not yet been widely used as a tool to prevent inad-
vertent intravascular injections or compression of vessels. Aggressive
massage, warm compresses, and nitroglycerol application have been
recommended but there are no controlled studies concerning their
efficacy (Hirsch, Cohen, & Carruthers, 2007; Kleydman, Cohen, &
Marmur, 2012). The use of blunt cannulas has made intravascular
injections less frequent, but the cannula should not be too thin as this
may perforate a vessel wall (Fulton, Caperton, Weinkle, & Dewandre,
2012). We prefer #23 to #25 cannulas. However, they are not useful
when the injection requires extreme precision such as redefining the
vermilion border or philtrum.
Lumps and bumps may be the immediate result of a wrong tech-
nique and then occur with any filler; however, some fillers are not
suitable for certain regions, for example, calcium hydroxylapatite, and
poly-L-lactic acid should not be used for lip augmentations as they
may clump due to muscle action. In the eye lids, they may be seen as
nodules.
Infections such as cellulitis are usually seen a few days after injec-
tion, abscesses often considerably later. The cause is a breach of the
skin barrier and inoculation of bacteria; as most injections are per-
formed in the face this is rare since the face has an excellent blood
supply making it a safe haven against postprocedural infections. In a
series of over 2,000 filler injections, 4 of 231 calcium hydroxylapatite
HANEKE
injections developed cellulitis with no such infection being observed
after poly-L-lactic acid and hyaluronic acid injections (Daines & Wil-
liams, 2013). Generous disinfection and meticulous removal of
makeup before injection are strongly advised. Infections may be seri-
ous in patients who got permanent fillers.
True allergic reactions are rare, but unforeseeable. A short per-
sonal history of the patient may avoid this.
Granuloma formation, chronic infection, fibrosis, scarring, and loss
of function are usually late complications. Particulate fillers are the
main source of granulomas, particularly in cases where the filler parti-
cles have sharp edges and are crystalloid as in poly-L-lactic acid or
hydroxyethyl methacrylate (HEMA). Chronic infection may develop
from inadvertent corticosteroid injections into suspected granulomas
that were in fact infections. For this reason, a two-week course of
antibiotics is recommended before injecting steroids. Fibrosis may be
inherent to a particular filler, such as poly-L-lactic acid. Scarring is the
result of necrosis and most cases of loss of function are due to inad-
vertent intravascular injection.
2 | SOFT TISSUE FILLERS
The number of different agents available for soft tissue augmentation
is huge. Not all brands are different and sometimes, different sub-
stances may have the same name. It is therefore strongly recom-
mended to use products that have proven their quality during
rigorous testing and have been in use for at least several years. It is
important to note that the appearance of adverse effects does not
permit the diagnosis of the filler used to be made.
Fillers are categorized as being of human origin, biologic, or syn-
thetic products. Biologic products are not necessarily biodegradable
by the human body as was shown in the case of granulomatous reac-
tions to an alginate filler (Novabel®) (Schuller-Petrovic, Pavlovi, Schul-
ler, Schuller-Luki, & Neuhold, 2013).
The best augmentation material is autologous fat. It is relatively
easy to harvest and often present in large amounts. However, collect-
ing and preparing the fat as well as storing excess fat are sometimes
more complicated, and often unpredictable take has made it less used.
One case of death from probable inadvertent intravascular injection
was reported (Gleeson, Lucas, Langrish, & Barlow, 2011). Other autol-
ogous materials such as fibroblasts or fascia are no longer in use.
Bovine collagen was the first marketed filler. As it is a foreign pro-
tein there is a risk of allergy and a pre-injection test had to be per-
formed. Human collagen was developed, but even though no previous
testing was necessary it caused as much inflammation and had the
same short life span like bovine collagen (Sclafani & Romo, 2001).
Curiously, porcine collage turned out to be the best tolerated of the
collagens (Saray, 2003).
Hyaluronic acid (HA) is a linear, unbranched, high molecular
weight glycosaminoglycan. It consists of alternating d-glucuronic acid
and N-acetyl-d-glucosamine. It is claimed to be a biologic substance
without species specificity; however, the natural glycosaminoglycan
moiety is linked to species-specific proteins and also the production
process is critical. In addition to being a biologic and naturally occur-
ring filler it also has a variety of different biologic effects that depend
HANEKE
on its molecular size (Clifford & Clark, 2007). Small fragments are
proinflammatory whereas long chains inhibit inflammation (Mummert,
2005; Wright & Day, 2005; Stern, Asari, & Sugahara, 2006). For its
use as a filler, it has to be stabilized and the way and degree of stabili-
zation are important for the tolerability of HA (Goomer, Leslie,
Maris, & Amiel, 2005). The more HA is cross-linked and thus stable
the more its tolerability is reduced.
Polycaprolactone (PCL)-1 dermal filler (Ellansé TM, AQTIS Medi-
cal, Utrecht, the Netherlands) is a soft tissue dermal filler based on
totally smooth spherical-shaped PCL microspheres (25–50 μm). The
PCL microspheres are homogenously suspended in an aqueous car-
boxymethylcellulose (CMC) gel carrier. PCL in CMC has been used in
many medical devices. It is biodegradable, nontoxic, and completely
excreted from the human organism. The CMC gel carrier is gradually
resorbed by macrophages over a period of several weeks, during
which the PCL microspheres trigger a natural response of the skin and
stimulate a wound-healing process with neocollagenesis. The new col-
lagen replaces the volume of the resorbed carrier. The microspheres
are not phagocytosed because of their size and surface characteristics.
The PCL dermal filler is indicated for deep dermal and subdermal
implantation including hand rejuvenation (Figueiredo, 2013; De
Melo & Marijnisse-Hofsté, 2012).
Adverse effects, such as xanthelasma-like lesions when injected
under the eyes are very rare (De Melo et al., 2017).
Two long-lasting fillers are on the market, poly-L-lactic acid
(PLLA) and calcium hydroxyl apatite (CHA). PLLA has been used for
more than 50 years as suture material and is well tolerated. CHA has
been used as bone cement with excellent tolerance. Both products
may cause granulomas though this is rare.
Permanent fillers are made of a variety of chemical compounds.
Their number is vast and none of them is without risk. Except for sili-
cone, they are particulate and as such are prone to induce granulomas.
The main chemical classes are polymethylmethacrylate (PMMA) as
beads and needles, methacrylate as fibers, acrylic hydrogels as small
crystalloid particles, polyacrylamide and polyalkylamide gel as very
small particles, polyethylene beads, and many more, of which several
are illegal in the United States and European Union. Silicone oil is also
banned. Although not particulate it may induce both lymphocytic
inflammation as well as granulomas.
Many adverse effects are not substance, but class-specific. They
may be due to wrong indication, placement site or injection needle, to
infection due to contaminated ice or water, or “tattooing” of makeup
particles during injection. Infections can be differentiated from granu-
lomas and other nodules by radiolabeled leukocyte scintigraphy
(Grippaudo, Pacilio, Di Girolamo, Dierckx, & Signore, 2013).
Autologous fat usually yields excellent results when adhering to
key principles, including sterile technique and low-volume injection
throughout layers of tissue. Adverse outcomes are infrequent. How-
ever, early adoption of surgical procedures by those without a sound
understanding of the underlying principles and techniques can have
disastrous consequences. Physicians operating on any patient must
understand the potential for complications and be able to manage
them appropriately when they occur (Talbot, Parrett, & Yaremchuk,
2010). Fat longevity depends on handling and preparation of the fat.
Poor fat viability produces an inadequate result and is considered as a
3 of 9
complication (Sykes, Tapias, & Pu, 2010). Deterioration of the aes-
thetic results after a significant weight gain due to corticosteroids, oral
contraception and a change of lifestyle was seen in a patient with
Romberg’s syndrome (Taupin, Labbé, Nicolas, Debout, & Benateau,
2010). Lipomodeling of the breast was performed in 880 cases, and
approximately 140 mL had to be injected for a desired volume of
100 mL, which remained stable for 3–4 months. No radiological prob-
lems occurred at mammography after the procedure. Fat necrosis
occurred in only 3%, but serious complications included one case of
infection at the harvest site, six cases of infection at the injection site,
and one case of intraoperative pneumothorax (Delay, Garson,
Tousson, & Sinna, 2009). There are also case reports on abscess for-
mation, life-threatening sepsis, and residual deformity (Talbot et al.,
2010). Neurological complications were repeatedly reported with
2 patients developing unilateral loss of vision after fat injection into
the glabella, 2 patients with loss of vision, aphasia, and hemiparesis
and 1 patient developing sensorimotor hemiparesis after infarction of
the middle cerebral artery (Teimourian, 1988; Dreizen & Framm,
1989; Egido, Arroyo, Marcos, & Jiménez-Alfaro, 1993; Feinendegen
et al., 1998). Death after autologous fat grafting occurred in a
20-year-old women with lupus profundus and hereditary C4 comple-
ment deficiency who had already got 3 fat injections from 1997 to
1999 with approximately 50% resorption. About 35 mL fat were
injected with minimal pressure using an 18-gauge sharp needle
because of scarring at the recipient site. There was dizziness immedi-
ately after injection of the left cheek and a vaso-vagal syncope sus-
pected. Another 35 mL of fat were subsequently injected. The patient
became increasingly unwell over the next 2 hr, eventually developed
progressive refractory hypoxic respiratory failure and cardiovascular
decompensation. Despite emergency treatment in a critical care unit,
she developed fulminant pulmonary edema, right ventricle dilatation,
and died due to cardiac arrest 4 hr after fat transfer (Gleeson et al.,
2011). Whether or not using a blunt cannula would have prevented
the death of this patient is not clear. Apparently, these side effects
were technique-dependent and not due to the fat itself.
Autologous human collagen is well tolerated, both when derived
from cultured fibroblasts as well as autologous injectable dermis
(Bassetto, Turra, Salmaso, Lancerotto, & Del Vecchio, 2013). Human
allogenic collagen was observed to elicit acute to subacute inflamma-
tory reactions (Sclafani et al., 2000) but no serious long-term side
effects were reported. The duration of the cosmetic effect was
between 4 and 7 months and thus disappointing.
Nonhuman collagens are foreign proteins. They have a propensity
to induce allergies and granulomas, particularly bovine collagen
whereas human and porcine collagens are better tolerated. These
adverse effects are commonly temporary until all collagen has been
resorbed, but one patient developed stone-hard granulomas not dis-
appearing with any treatment over more than a decade (De Coninck,
2008). Usually, the granulomas are palisaded around amorphous
eosinophilic material representing bovine collagen. This is character-
ized by very thick bundles, pale gray-violet staining with Masson tri-
chrome stain, and lack of birefringence (Requena et al., 2011).
Whether the injection of collagenase (Tutrone & Cohen, 2009) would
be successful has not yet been tried. The most common side effects
were temporary granulomas at the site of injection in about 4% of the
4 of 9
patients. Testing and double testing before treatment was recom-
mended, but nevertheless, granulomas did occur.
Hyaluronic acid (HA) is universally present in all animal species.
This carbohydrate macromolecule is nonspecies specific, however,
during their biosynthesis, hyaluronans are linked to proteins that are
species specific. Good preparations are now free from foreign pro-
teins. They have a low propensity to induce granulomas, but show a
variety of transitory side effects, including rare granulomas and infec-
tion (André, 2004; Rodrigues-Barata & Camacho-Mart, 2013). At pre-
sent, there are approximately 200 preparations on the market. In
order to prevent untoward adverse effects well-known brands with
high quality should be preferred, as their complication rate has been
shown to be much lower.
Untested cheap products should never be used.
HA preparations are currently the most widely used fillers. Their
longevity is approximately 6 months, but this is highly variable
depending on molecular size and cross-linking. Differences among
them are due to the size of the molecule, the protein content, the
chemical bonding, the fluidity, whether they are monophasic or
biphasic, injection pain, and longevity (Buntrock, Reuther, Prager, &
Kerscher, 2013). A good preparation must not clump as this may give
rise to granulomas. Whereas granulomas were not rare in the begin-
ning of the nonanimal derived synthetic HAs they are now exceed-
ingly rare, except for one product marketed roughly 6 years ago,
which induced foreign body giant cell granulomas with a high content
of eosinophils, and HA can be seen in giant cells.
Reactions interpreted to be hypersensitivity were observed in the
early period of HA fillers (André, 2004; Micheels, 2001; Lupton &
Alster, 2002). Very rare side effects are a multiform rash and systemic
anaphylactoid reactions after intra-articular injection of HA (Altman,
Moskowitz, & The HaylganO Study Group, 1998; Calvo et al., 2007),
with native HA having a lower sensitizing potential (André, 2004).
Side effects due to the substance are usually short-lived and can
be reversed by injecting hyaluronidase. The dose depends on the spe-
cific drug and may also vary according to the HA used and its degree
of cross-linking. This enzyme cleaves both natural as well as cross-
linked HA. Three sources are available: bovine, ovine and recombi-
nant. As they are proteins they have the potential of causing an
anaphylactic shock in sensitized individuals. It is therefore necessary
to question the patient about possible protein allergies. Hyaluronidase
has also been used to treat HA granulomas (Brody, 2005).
Technique-dependent side effects may occur as with other
fillers. When HA is injected too superficially it may shine through
with a bluish-grayish color, giving rise to the so-called Tyndall
effect. It has to be used with care in the eyelids as it may cause
swelling due to its ability to attract water. Accidental intracapillary
injection may cause livedo reticularis (Bachmann, Erdmann,
Hartmann, Wiest, & Rzany, 2009).
Histopathology of grayish-glassy nodules after superficial injec-
tion just shows HA deposits without any further tissue changes.
Granulomas may show a very dense lymphocytic infiltrate with abun-
dant eosinophils and many foreign body giant cells often containing
basophilic amorphous material that corresponds to HA.
Dextranomer beads were added to HA to improve the longevity
of the filler. They consist of cross-linked dextran molecules with a
HANEKE
positive surface charge and a diameter of 80–120 μm. They attract
macrophages releasing tumor growth factor-β and interleukins, which
stimulates collagenesis around the dextranomer beads, maintaining
the volume correction effect after the resorption of HA (Eppley,
Summerlin, Prevel, & Sadove, 1994). The material is apparently well
tolerated with three reports of granulomas, one of which was suppu-
rative (Massone et al., 2009) and the other two were foreign body
giant cell rich granulomas (Huh et al., 2010; Yang et al., 2012). The
dextranomer beads stain dark bluish or purplish, or may even look like
empty spaces giving a “Swiss cheese” aspect in histopathology slides.
Incision of the nodules and treatment with cephalexin and methyl-
prednisolone aceponate lead to complete resolution in one case
(Massone et al., 2009).
PLLA has been used for decades in medicine and surgery and was
well tolerated. PLLA as a filler comes as a powder of crystalloid parti-
cles that has to be reconstituted before injection. Subcutaneous nod-
ules are either fibrotic or granulomas. They can form because of
insufficient time during reconstitution of the material, inadequate dilu-
tion, overcorrection, superficial injection techniques, inappropriate
concentration of PLLA molecules, or secondary to muscle movement.
Granulomas are thought to be due to allergic or inflammatory host
responses (Apikian, Roberts, & Goodman, 2007). Since most physi-
cians use 10 mL or more of physiologic saline for reconstitution, often
with some lidocaine added, this has become rare. After injection, the
water is resorbed and the PLLA particles induce a fibroblastic reaction
lasting for 24 months or longer. This may cause fibrotic nodules,
which may be visible in thin skin like around the eyes and in the hands
(Palm, Woodhall, Butterwick, & Goldman, 2010), and the substance
may clump in the lips; these are adverse effects of faulty technique.
PLLA granulomas are classical giant cell granulomas with many epithe-
lioid cells and relatively few lymphocytes. The PLLA particles are oval,
fusiform or spiky and seen in epithelioid and giant cells as well as in
between. They are birefringent in polarized light (Requena et al.,
2011). The granulomas last at least 18 months (Zimmermann & Clerici,
2004).
Calcium hydroxyl apatite (CHA) is an inorganic material. It has
long been used successfully as bone cement. The currently available
preparation consists of microspheres (30%) of 25–45 μ suspended in
a gel made of water, glycerol and sodium carboxymethylcellulose
(70%). It is inert and nonantigenic, but stimulates collagen production.
It is very well tolerated when injected as a suspension for soft tissue
augmentation (Marmur, Al Quiran, De Sa Earp & Yoo, 2012). The
duration of correction is between 9 and 12 months, but may also be
longer. Most adverse effects are due to technical faults. When
injected into the lips, CHA tends to clump and produces palpable nod-
ules. In one study, postinjection cellulitis was observed at a frequency
of 1.7% (Daines & William, 2013). However, granulomas also occur
with a higher frequency in elderly women (Daley, Damm, Haden, &
Kolodychak, 2012). They consist of tightly packed, dark bluish micro-
spheres with a diameter of 25–40 μ and giant cells (Dadzie et al.,
2008). The nodules were shown to rapidly decrease after fractional
CO2 laser treatment (Reddy et al., 2012). Recently, a grade 3 systemic
reaction was observed 30 min after injection of CHA vocal cord filler
prompting the authors to recommend a 30 min post-procedure obser-
vation period (Cohen, Reisacher, Malone, & Sulica, 2013).
HANEKE
Polyacrylamide gel (PAAG) is a suspension of 2.5%–5% PAAG in
sterile water. It is produced in different countries and marketed under
many various names: PAAG (Sinocos Eastcos, Hong Kong, China),
Amazing gel, Aqualift, Aquamid, (Contura International, Söborg, Dan-
mark), Argiform, Bioformacryl, Formacryl, and Outline, which are
slightly different in minute additional components (Haneke, 2009).
The material is widely resistant to enzymatic degradation and phago-
cytosis. The particles allow bacteria to grow on their surface and give
rise to late infections, biofilms, and abscesses (Christensen, Breiting,
Aasted, Jörgensen, & Kebuladze, 2003). PAAG does not induce allergic
reactions or interfere with the hemodynamic system. It can hold
300–400 times its weight in water. It was widely used for breast aug-
mentation in Eastern countries. The results are immediate and over-
correction is not necessary. Its major advantage is that it remains soft
and pliable after injection (Leung, Yeoh, & Chan, 2007). However, the
products should not be injected over other ones. PAAG is generally
well tolerated, but severe adverse effects such as swelling, lumps,
abscesses, facial disfigurement, gel dislocation, and respiratory distress
have been described (Kalantar-Hormozi, Mozafari, & Rasti, 2008).
Breast deformity, lumpiness, intermittent swelling, pain, and gel extru-
sion were observed in other series (Reda-Lari, 2008; Cheng, Wang,
Wang, Zhang, & Zhong, 2002; Lee, Kim, Kim, Choi, & Lee, 2004). The
gel is exceedingly biocompatible and thus an excellent medium for
bacteria (Zarini et al., 2004). The main risk is infection often develop-
ing after 8–12 months or even later, but cultures frequently remain
negative and only PCR could identify bacteria that are normally not
pathogenic. Histopathology shows foci of neutrophils and karyorrhec-
tic material, numerous macrophages, and foreign body giant cells
around a gel that appears somewhat similar to hyaluronic acid. Often
giant cells contain vesicles full of PAAG and the material frequently
shows small empty blebs both in the giant cells as well as when pre-
sent in large lakes. PAAG is positive with Alcian blue and not
birefringent.
Polyalkylimide gel 4% in water (Bio-Alcamid, Polymekon, Milan,
Italy) is a large volume filler to be injected into the deep dermis or
under the dermis. A thin collagen capsule forms after injection pre-
venting migration and keeping it apart from the surrounding tissue.
Aspiration or punching a small hole over it allows its removal. Side
effects were edema, bruising, nodules, infections, severe inflammatory
reactions, and migration despite the capsule-like fibrosis around it,
unsatisfactory appearance and late abscesses. Migration is rare (Malik,
Mehta, Adesanya, & Ahluwalia, 2013). Histopathology shows baso-
philic amorphous material surrounded by neutrophils and erythro-
cytes. Gram stain may reveal bacteria. The infections are very difficult
to treat and require high-dose long-term antibiotics, incision, drainage,
and irrigation (Jones, Carruthers, Fitzgerald, Sarantopoulos, & Binder,
2007; Goldan et al., 2007).
Polyacrylamide gel with polyvinylhydroxide microspheres is a sus-
pension of 6% microspheres in 25% PAAG hydrogel (Evolution®, Pro-
Cytech SA). It is apparently well tolerated though it is not often used
(Lemperle, Morhenn, & Charrier, 2003).
A suspension of ethylmethacrylate and hydroxyethylmethacrylate
particles in hyaluronic acid was marketed under the brand names of
® ®
DermaLive and DermaDeep . Initially reported as being well toler-
ated (Bergeret-Galley, Latouche, & Illouz, 2001) it soon turned out
5 of 9
that this biphasic filler caused late granulomas in a very high percent-
age of cases (Sidwell, Dhillon, Butler, & Rustin, 2004; Rossner, Ross-
ner, Bachmann, & Wiest, 2009) so that it had to be withdrawn from
the market. However, granulomas still occur (González-Vela, Armesto,
González-López, Fernández-Llaca, & Val-Bernal, 2008). They usually
present as nodules that are first palpable and then often become
visible. Fistulation may develop, and even a keratoacanthoma-like
appearance was seen (Gamo et al., 2008). The granulomas are well
delimited and relatively easy to remove surgically; however, new gran-
ulomas continue to develop. Other treatments are intralesional corti-
costeroids, 5-fluorouracil and allopurinol. Antibiotics have to be given
before if an infection is suspected (Weyand & Menke, 2008). Histopa-
thology shows a dense granuloma with fibrous pseudocapsule con-
taining masses of crystalloid acrylate particles. The granulomas are
made up of epithelioid and foreign body giant cells that try to engulf
the particles. Some areas become necrotic and contain cholesterol
clefts. Epidermal ridges may grow down and try to surround the for-
eign material giving rise to fistule formation. Some granulomas may
become sclerotic with time.
Polymethylmethacrylate (PMMA) (Artecoll®, Artefill®, and
Artesense®) are round polished PMMA beads suspended in bovine col-
lagen. Testing of bovine collagen is necessary before use to avoid an
immune reaction. Individuals with a history of keloids should not be
treated (Hoffman, 1984). The injection should be juxtaperiosteal, lips are
contraindicated (Blanco Souza, Colom, Bender, & Lemperle 2018).
Approximately 3 weeks after injection, the body starts depositing own
collagen around the microspheres, which get virtually encapsulated by
it. Overcorrection is not performed. Artefill has polished microbeads
being thought to attract fewer impurities and thus being less prone to
induce granulomas (Dansereau et al., 2008). Methacrill and Metrex are
also PMMA particles though not round and polished. Although granulo-
mas are rare with 0.01% reported (Cohen et al., 2006; Solomon, Sklar, &
Zener, 2012) they do occur and are difficult to treat (Haneke, 2004).
Lumps often form, particularly in the lips, but most are just palpable and
not visible. Granulomas may develop several years after the injection
(Wu, Chayavichitsilp, & Hata, 2012). Granuloma precipitation many
years after injection when a patient was treated with interferon because
of hepatitis C (Fischer, Metzler, & Schaller, 2007) or laser skin resurfa-
cing was performed over the area of injection (D Vochelle, personal
communication) is possible. The granulomas appear suddenly with indu-
ration, swelling, tenderness, and erythema. Histopathology shows a typi-
cal granuloma with round empty-appearing clear spaces in a fibrotic
tissue. Treatment was performed with intralesional corticosteroids and
5-fluorouracil (Conejo-Mir, Sanz Guirado, & Angel Muñoz, 2006) as well
as allopurinol and surgery. Methacrill granulomas were melted with high
frequency “endocoagulation” leaving a residue of burnt plastic with a
characteristic smell (Odo, Odo, Nemoto, & Cucé, 2008). Intralesional
laser treatment is another option.
Silicone is another irreversible filler. It is a highly polymerized
hydrophobic oil (Silikon 1,000, Adatosil 5,000, Biopolimero), gel (MDX
4–4,011) or solid rubber consisting of dimethylsiloxane units. Silicone
is generally well tolerated, but the occasional side effects may be dra-
matic and irreversible; this is the reason why it is banned for cosmetic
use both in the European Union as well as the United States. Those
still using silicone off-label claim that pure silicone (Seward & Meara,
6 of 9
2013) and proper microdroplet technique prevent adverse effects, but
this is not generally accepted. Medical grade silicone oil is pure and
sterile. The secret of good long-term results appears to be the injec-
tion of truly minute amounts (Webster, Fuleihan, Hamadan, Gaunt, &
Smith, 1986; Benedetto & Lewis, 2003; Zappi, Barnett, Zappi, &
Barnett, 2007). A mixture of silicone with hyaluronic acid was recently
described as “the optimal filler” (Fulton & Caperton, 2012).
Side effects are local and systemic. Minor complications are small
nodules seen within a year after injection. They are mainly due to too
much substance. However, indurations and erythema with swelling
are silicone granulomas that often only appear 2–12 years after injec-
tion. The differentiation between siliconoma, which consists almost
exclusively of macrophages containing small droplets of silicone oil
and contains virtually no inflammatory cells, and silicone granuloma
with silicone containing macrophages, lymphocytes, and giant cells is
somewhat artificial. Both respond to intralesional corticosteroids in
most cases. Major complications are systemic with pneumonitis, acute
respiratory distress syndrome, sudden death after intravascular injec-
tion, migration of large volumes of low-viscosity silicone oil,
erysipelas-like reactions, blindness, loss of neurologic functions, and
death after silicone oil had been inadvertently injected into the oph-
thalmic or meningeal vessels.
Vaseline, paraffin, lanolin, cod liver oil, beeswax, and other crude
substances were used in the late 19th and early 20th century. Despite
initial satisfying results, long-term results were usually appalling due to
skin hardening, swelling, granuloma formation, ulceration and fistulation,
infections, abscesses, and even cancer development (Haneke, 2004).
Paraffin is irreversible and no longer legally used as a filler
although highly inflammatory granulomas after fraudulent use of par-
affin or other oils containing vitamin E, sometimes also D and A, are
still seen (Kamouna et al., 2014). Injection of paraffin into the penis
caused sclerosing lipogranuloma characterized by fibrosis and defor-
mation (Foucar, Downing, & Gerber, 1983). Histopathologically, the
deep reticular dermis and subcutaneous fat are involved with a pre-
dominantly lobular panniculitis with a Swiss cheese appearance. The
cystic spaces are surrounded by foamy histiocytes and giant cells. The
collagen bundles in-between are sclerotic. Vaseline and other mineral
oils cause a very similar reaction (Hohaus, Bley, Köstler, Schönlebe, &
Wollina, 2003; Akkus, Iscimen, Tasli, & Hattat, 2006; Nyirady et al.,
2008; Al-Ansari, Shamsodini, Talib, Gul, & Shokeir, 2010).
Whether ultrasound liquefaction of the fat where the inappropri-
ate substance had been injected, and subsequent extraction by a suc-
tion cannula helps to eliminate this material remains to be seen
(Maxwell & Gingrass, 1998; Zocchi, 1996).
Silicone elastomer particles (Bioplastique®) suspended in polyvinylpyr-
rolidone plasdone hydrogel were mainly used in urology and for vocal cord
augmentation. Both lumps and granulomas occurred (Eppley, Sidner, &
Sadove, 1992; Baijens, Speyer, Linssen, Ceulen, & Manni, 2007).
3 | D I A G N O S I S OF A D V E R S E FI LL E R
EFFECTS
A number of imaging techniques were applied to aid in the diagnosis
of filler complications, particularly in the diagnosis of suspected
HANEKE
abscesses. Further indications are overfilling, migration, foreign-body
granulomas, and scarring (Ginat & Schatz, 2013). High-frequency
ultrasound complemented with magnetic resonance imaging and leu-
kocyte scintigraphy, allowed the distinction between infections, fibro-
sis, granulomatous inflammation, and product migration (Grippaudo,
Di Girolamo, Mattei, Pucci, & Grippaudo, 2014). Calcium hydroxylapa-
tite is radio-opaque and can be seen in normal radiographs
(El-Halaby & Furtado Araújo, 2014); however, its injection may cause
local hypermetabolism and thus be a source of false-positive findings
in PET scans (Damrose, 2008; Feeney, Fox, & Akhurst, 2009). Conven-
tional X-ray films, CT, and MRI techniques often allow different mate-
rials to be distinguished (Ginat & Schatz, 2013).
Many fillers have a specific morphology and/or staining pattern in
the skin (Requena et al., 2011). This is both true for acute reactions
when the filler is still visible as well as for late reactions like granulo-
mas and infections with abscesses.
4 | G E N E RA L TR E A T M E N T RE M A R K S
Prevention is always better and easier than treatment—this rationale
is also true for filler side effects. After identifying the exact nature of
an adverse side effect, the appropriate therapy has to be chosen. Early
side effects like injection pain, immediate swelling and edema usually
do not require specific treatment. Cooling is often sufficient to allevi-
ate the immediate postinjection pain; however, this is rarely seen any-
more since more and more preparations contain a local anesthetic.
Swelling may respond to acetylosalicylic acid (Aspirin®) or another
nonsteroidal antiinflammatory drug. Placement of too much material
or in the wrong area requires immediate massage or removal, if possi-
ble. Lump formation after CHA injection in the lip is a technical fault
as well as too superficial an injection. Proper training before starting
to inject is mandatory.
Blanching that extends beyond the immediate area of the injec-
tion volume may be a sign of vascular occlusion. Nitroglycerin cream
and warming may be sufficient in mild cases (Kleydman et al., 2012).
Hyaluronic acid can be dissolved with hyaluronidase. Most prepa-
rations are of animal origin and there is the theoretical possibility of a
sensitization. It is wise to use one preparation to get experience with
it as the dosage may vary among the different drugs. The effect is usu-
ally seen within hours, and re-injection is possible after 24 hr, so small
doses are recommended in the beginning.
The problem is the treatment of late and delayed adverse effects.
First, the responsible substance has to be identified. This is often impos-
sible as the patients do not know, or are reluctant to disclose, which
filler had been injected. Once a granuloma has developed it is to be
assumed that granulomas will continue to develop as long as the foreign
material is in the skin. Whether attenuated total reflectance/Fourier
transform infrared analysis spectroscopy really allows fillers to be reli-
ably identified remains to be seen (Persichetti et al, 2013). Another vali-
dated method is the histological examination of sections, which yield
quite specific changes with most different fillers (Eversole, Tran,
Hansen, &Campbell, 2013; Haneke, 2014; Requena et al., 2011).
The differentiation of infection from noninfectious granulomas is
possible with radioactive labeled leukocytes. In case of infection,
HANEKE
antibiotics have to be given long enough and in doses capable of con-
taining the infection. Staphylococcus-fast antibiotics such as cephalo-
sporins are given intravenously (Choi, 2014). Vancomycin is
administered for Staph epidermidis.
Granulomas often respond to intralesional injection of a mixture
of 250 mg 5-fluorouracil/mL, 10 mg triamcinolone acetonide/mL plus
mepivacaine 1 mL, which is given first twice, then once weekly, plus
allopurinol 300–600 mg/d (Wiest, Stolz, & Schroeder, 2009; Reisber-
ger, Landthaler, Wiest, Schröder, & Stolz, 2003). TNF-α inhibitors have
not yet gained much acceptance in the treatment of granulomas.
5 | CO NC LUSIO N
Fillers belong to the most frequently used substances in aesthetic
medicine. The “consumers” are not sick patients, but healthy persons
expecting to look better after the procedure. Any adverse effect,
whether immediate, late or delayed, temporary or irreversible, is a
catastrophe for them and potentially for the treating physician. All
measures have to be taken to avoid them: The physician must be well
trained, use the best product, respect indications, contraindications,
proper aseptic injection techniques, and adequate localization for each
specific filler. The patient has to follow the physician’s recommenda-
tions after treatment. The best would be to give a “filler pass” to the
patient that notes which filler was when and where injected. Despite
all precautions, adverse effects may occur. Take them seriously and
never dismiss a patient’s concerns. Treatment should be instituted as
soon as possible.
CONF LICT OF IN TE RE ST
The authors declare no conflict of interest.
ORCID
Eckart Haneke http://orcid.org/0000-0001-9957-1441
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How to cite this article: Haneke E. Adverse effects of fillers.
Dermatologic Therapy. 2018;e12676. https://doi.org/10.1111/
dth.12676