Review

Understanding the safety and

tolerability of facial filling
therapeutics
1. Introduction
Daniela Kulichova†, Alyona Borovaya, Thomas Ruzicka, Peter Thomas &
2. Facial filling therapeutics
Gerd G Gauglitz
3. Side effects of dermal fillers Ludwig Maximilian University, Department of Dermatology and Allergology, Munich, Germany
and treatment
4. Diagnostic tools Introduction: Aesthetic medicine represents an emerging field for many
5. Conclusion specialties. Nowadays, a plethora of approaches are available to rejuvenate
the human body and face, the latter being a frequent target for the place-
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by CDL-UC San Diego on 12/29/14

6. Expert opinion
ment of filling substances to correct wrinkles and volume loss. Nevertheless,
based on the many products on the market, treating clinicians must pay spe-
cific attention to the properties of the respective materials, their associated
side effects and any specific handling requirements to prevent potential
short- and long-term adverse events.
Areas covered: Types of filling materials, including biodegradable and
non-biodegradable products, related complications, their conservative and
invasive treatment options, as well as prevention strategies are described in
this review.
Expert opinion: A profound knowledge of the facial anatomy as well as
For personal use only.

extensive experience with the various filling techniques and suitable materials
for the respective areas remains crucial to prevent adverse events associated
with filling procedures to the human face. Since side effects such as malar
edema and foreign body granuloma do affect patients physically and psycho-
logically to a significant extent and their successful treatment still remains
challenging, further in depth studies on the tolerability of many filling
materials utilized are required.

Keywords: aesthetic medicine, complications, dermal fillers, foreign body granulomas,

malar edema

Expert Opin. Drug Saf. (2014) 13(9):1215-1226

1. Introduction

Soft-tissue augmentation with the use of dermal fillers in order to overcome the signs
of aging, skin defects and scars as an alternative to surgery has become a daily practice
for many dermatologists, plastic surgeons and other specialists. In recent years, indi-
cations and number of procedures performed are continuously increasing. Today,
filling materials are frequently utilized for volume enhancement such as cheek and
chin augmentation, tear trough correction, nose reshaping, lip enhancement, hand
rejuvenation and the correction of facial asymmetry [1].
Facial soft-tissue augmentation and rejuvenation procedures using various filler
materials are widely performed for cosmetic enhancement because of their highly
predictable, convenient and pleasing outcomes [2,3]. Although benefits of successful
filler treatments are obvious, the number of associated complications is likely to
grow during the next years. Unfortunately, many clinicians still lack in depth
knowledge of the anatomic background as well as product- and technique-related
complications associated with minimally invasive procedures. Physicians who offer
therapies with filling materials should be aware of potential adverse events associated
with each type of procedure and should communicate these risks with the patient

10.1517/14740338.2014.939168 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X 1215
All rights reserved: reproduction in whole or in part not permitted
 D. Kulichova et al.
Article highlights.
. Types of dermal fillers: their characteristics and
indications.
. Side effects of dermal fillers: their causes, clinical signs
and consequences.
.
Current diagnostic tools and treatment of dermal filler
complications: State of the art.
This box summarizes key points contained in the article.
before-hand properly. Safety and tolerability of injected
materials are until today not fully understood and therefore
should be studied more intensively. The following review
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by CDL-UC San Diego on 12/29/14
gives an overview of nowadays most frequently used injectable
materials, their properties, indications, possible complications
and the appropriate diagnostics and treatment options of
associated adverse events.
2. Facial filling therapeutics
2.1 Types of dermal fillers
It is currently estimated that around 160 different filling
products are being available worldwide manufactured by
For personal use only.
> 50 companies [1,4]. Unfortunately, only the minority is being
supported by well-designed studies with regard to their prop-
erties, efficacy parameters and potential side effects. Many
products of no-name distributors have no license. Also, an
increasing number of beauticians and other non-licensed
individuals inject dermal fillers uncontrolled or illegally on a
daily basis. Internet sources are available to everybody. This
accessible market poses a major risk to patients [5].
The substances most commonly used for facial soft-tissue
augmentation are hyaluronic acid (HA), calcium hydroxylapa-
tite (CaHa), collagen, poly-L-lactic acid (PLLA), polymethyl
methacrylate (PMMA), silicone and autologous fat [1,6,7].
Dermal fillers can be categorized by several methods [1,8,9].
However, when discussing associated complications, a
categorization in terms of biodegradable (temporary) versus
non-biodegradable (permanent) fillers may be most useful [9-12].
2.1.1 Temporary (biodegradable) fillers
Temporary fillers, such as HA and collagen fillers, are
naturally occurring substances that are being reabsorbed by
the human body, and are associated with ‘temporary’ results,
thereby requiring patients to receive periodical top-up
injections. Since its FDA approval in 2003, HA has become
the ‘gold standard’ of safe injectable fillers. It is the most
important polysaccharide in human extracellular matrix,
which acts as a scaffold for collagen and elastin [13]. Nowa-
days, most of the HA fillers used worldwide are derived
from the fermentation of Streptococcus equi bacterium, which
are referred to as non-animal--stabilized HA or [6]. The chem-
ical formula consists of linear polymeric dimers of N-acetyl-D-
glucosamine and D-glucuronic acid cross-linked into a long
1216
unbranched chain [6]. The longevity of the respective product
depends on the muscular activity, concentration of the prod-
uct and amount of cross-linking and may last from 6 up to
18 months and more [1,14-16]. Naturally occurring HA (not
cross-linked, native HA) is rapidly degraded with a half-life
of 12 -- 24 h [17]. Therefore, the manufacturing goal is to cre-
ate an HA with increased tissue residency and elasticity while
maintaining its biocompatible nature. The process of cross-
linking HA molecules accomplishes this goal and is usually
achieved by using butanediol diglycidyl. It is a cross-linking
agent utilized in the majority of the market-leading HA fillers,
and its stability, biodegradability and long-term safety records
have been demonstrated for > 15 years [18]. The degree of
cross-linking enhances the persistence of the HA filler, but
excessive cross-linking may reduce the biocompatibility of
the filler, causing foreign body reaction and encapsulation [13].
Cross-linking will also change the rheological properties of the
gel. Depending on the grade of cross-linking, the filler’s per-
sistence, elasticity and resistance during injection are being
influenced. An important characteristic of the HA molecule
is that it is hydrophilic, which has a major influence on hydra-
tion and turgor of the skin [13,19]. Higher concentrated HA
and/or large particle products will tend to absorb more water,
and may thus produce more tissue swelling after injection [1].
HA fillers can also be characterized by its homogeneity.
Monophasic monodensified fillers are synthesized by mixing
the HA and cross-linking polymers in a single step. This pro-
cess results in a product that, for the first 4 -- 5 months after
injection, has a slower resorption. Biphasic gels consist of
HA ground into particles. These particles are suspended in a
non-cross-linked HA, which acts as a lubricant that facilitates
extrusion of the gel from the syringe into the skin [13,20].
Examples of product names are listed in Table 1. HA is
degraded by native hyaluronidase. This fact is widely used in
treating complications linked to injected HA fillers [6].
Collagen fillers can be of bovine, human or porcine origin.
One of the advantages of collagen fillers is that they are less
viscous and thus well suitable for the correction of fine lines
and wrinkles because they are less likely to produce irregular-
ities when injected superficially. The collagen products are
broken down over time by enzymatic mechanisms and fre-
quently show shorter duration (2 -- 6 months) of effect
when compared to HA fillers [7,21].
Autologous fat represents the original filler. Fat can fill
large and small soft-tissue defects of the face and body in
any permanent indication. The use of the patient’s own fat
as a filler is a safe and natural method. However, fat grafting
does not seem to work equally for all techniques, body areas
nor for all patients. The drawback of this technique is that it
must be performed in an operating theater environment
with local anesthesia and/or sedation; specific instruments
and materials are also required. The longevity of injected
autologous fat ranges from 8 months to several years [22].
Filling therapeutics with biodegradable particles that stim-
ulate the body to produce its own collagen represents another
Expert Opin. Drug Saf. (2014) 13(9)

Table 1. Examples of product names of biodegradable hyaluronic acid dermal fillers, describing their main
characteristics.
Brand name and manufacturer
Restylane/ RestylaneFine lines/Restylane Touch/ Restylane Perlane (Q-Med/Medicis)
Captique (Genzyme/Inamed/AllerganMentor)
Juvederm Ultra (2, 3 and 4) and Juvederm Ultra XC (Inamed/Allergan)
Juvederm Ultra Plus and Juvederm Ultra Plus XC (Inamed/Allergan)
Juvederm Voluma (Inamed/Allergan)
Belotero Soft/Belotero Basic/Belotero Intense (Merz Pharmaceuticals) (Inamed/Allergan)
Varioderm (Adoderm GmbH/Medical Aesthetics group)
Emervel Touch/Emervel Classic/Emervel Deep/Emervel Volume (Galderma)
Teosyal range (Deep Lines, Global Action, Ultra Deep, First Lines, Meso,
Touch Up, Ultimate) (Lifestyle Aesthetics)
Cosmoderm (Inamed/Allergan)
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Cosmoplast (Inamed/Allergan)
Zyderm (Inamed/Allergan)
Zyplast (Inamed/Allergan)
HA: Hyaluronic acid.
Table 2. Semipermanent fillers with biodegradable particles leading to stimulation of body’s own collagen and
their main components.
Brand name and manufacturer
Sculptra (Dermik aesthetic/Sinclair Pharma)
For personal use only.
Radiesse (Merz Pharmaceuticals)
group of temporary fillers and include CaHA (RadiesseÒ) and
PLLA (SculptraÒ, Table 2) [12,13]. CaHA is a mineral present
in bone and teeth. As a naturally occurring substance, it is
inherently biocompatible and is metabolized into calcium
and phosphate. Radiesse is composed of microspheres of
CaHA (25 -- 45 µm) at 30% concentration suspended in a
gel composed of water, glycerin and sodium carboxymethyl-
cellulose. This formulation provides a l:1 volumetric correc-
tion without the need for overcorrection. Once injected, the
gel is slowly absorbed over a period of months. During this
interval, there is ingrowth of fibroblasts into the scaffold of
microspheres that will gradually replace the carrier gel [6]. As
these cells replace the gel, they will increase endogenous colla-
gen synthesis, which will anchor the microspheres in place.
The microspheres, stabilized at the injection site by new colla-
gen formation, will then slowly be reabsorbed by macro-
phages over several months [23]. This filler remains in tissue
for 12 -- 18 months [24]. It is indicated for correction of severe
facial folds and maxillofacial defects mainly associated with
volume loss and/or lipoatrophy [11]. These types of fillers
must be injected deeply -- into the hypodermis or deeper --
in order to avoid visible nodules. The incidence of associated
complications is low, and there are no reports of calcification
or osteogenesis at injection sites [23]. PLLA is a biodegradable,
nontoxic, synthetic material derived from corn starch. It has
been used in suture material and other biomedical implants.
PLLA provides soft-tissue augmentation through stimulation
of an inflammatory tissue response with subsequent native
Expert Opin. Drug Saf. (2014) 13(9)
Safety of fillers
Main component
HA gel
HA gel
HA gel
HA gel
HA gel
HA gel
HA gel
HA gel
HA gel
Human collagen
Human collagen
Purified bovine collagen with 0.3% lidocaine
Purified bovine collagen with 0.3% lidocaine
Main component
Poly-L-lactic acid
Calcium hydroxylapatite microspheres suspended in a carrier gel
collagen deposition and vascularization [25,26]. Patient
counseling is especially important when using PLLA due to
its delayed effect. Each injection session with PLLA provides
gradual improvements. Based on the current recommenda-
tions three treatment sessions (approximately every 6 weeks)
are generally required, but once the final correction is
achieved, volumetric results may last up to 2 -- 3 years [27].
The most common adverse effects are injection related. Small,
palpable, subcutaneous nodules, as well as visible nodules, can
result from uneven distribution or superficial placement of
the product [28].
2.1.2 Permanent (non-biodegradable) fillers
Available permanent fillers include PMMA microspheres in a
solution of 3.5% collagen and 0.3% lidocaine, polyacryl-
amide hydrogel, which contains 2.5% of cross-linked poly-
acrylamide and 97.5% of water, and silicone oil. Product
examples of the three mentioned different compositions are
ArtecollÒ, AquamidÒ and SilikonÒ, respectively (Table 3).
Their action is based mostly on a foreign body reaction
around the nonabsorbable microspheres with a new deposi-
tion of collagen [29]. The collagen solution keeps the spheres
from clumping together, and during its absorption, fibrin
and new collagen deposition takes its place. At the end of
this process, the augmented volume is about 20% PMMA
and 80% autologous connective tissue [30].
Silicone is produced from silica, which was approved for
retinal detachment, and its use as a cosmetic soft-tissue filler
1217
 D. Kulichova et al.

Table 3. Brand name examples of permanent dermal Appropriate handling of complications associated with
fillers with their main components. dermal fillers requires knowledge of all types of possible adverse
events, their cause, diagnostics and treatment. For standardized
Brand name and Main component evaluation of these complications a systemic overview is pre-
manufacturer sented in Table 4. First, it remains critical to classify the side
effects with regard to magnitude and severity in order to take
Artecoll (Rofilmedical) PMMA enclosed in a solution of
3.5% collagen and 0.3% lidocaine the appropriate action. Also, a differentiation between filler/
Aquamid (Contura) 97.5% sterile water and 2.5% product-related versus technique- and injector-related compli-
polyacrylamide cations can be helpful. Unfortunately, very frequently patients
Silikon 1000-cst liquid injectable silicone oil are not familiar with the product that has been injected when
seeking help for treatment of side effects. Some clinicians in
PMMA: Polymethyl methacrylate.
this field provide patient passports for this matter depicting
the respective products, which have been used during treatment
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Table 4. Types of complications, mild and severe, in sessions. This aspect is particularly important when patients
dermal filler injections. tend to see different doctors for aesthetic improvements.

Mild, short-term complications Severe, persisting

complications 3.1Short-term and mild complications: pain,
bruising, erythema and dyspigmentation
Bruising Long-lasting/severe infection
Bleeding from puncture site Abscess Mild complications do occur relatively frequently, do usually
Erythema Malar edema not significantly deteriorate the quality of patient’s life because
Transient edema Nodule of its short duration and include pain during (and shortly after)
Pain Foreign body granuloma the injection, redness, minor bleeding and/or hematoma [33].
Hyperpigmentation Vascular compromise with Pain may be reduced by using pretherapeutical local anesthesia
tissue necrosis
For personal use only.

Hypopigmentation Scarring in the form of a cream or injection; post-treatment pain can be

Dyscoloration Hypersensitivity
Mild infection Migration of implant material
Asymmetry
is off-label. Silicone disperses into tissue to become encapsu-
lated and it is used as a volumizer for the facial areas. Studies
of injectable silicone in the face vary in regard with results
and complications.
Complications after permanent fillers may appear after
many years [31], and may be of permanent nature. Long-
term complications include nodules, granuloma formation,
gel migration or accumulation, persistent redness or pain,
swelling, infection and chronic inflammatory reactions [7,9].
3. Side effects of dermal fillers and treatment
Mild to severe complications may occur after treatment with
fillers of various kinds. Nevertheless, unlike permanent filler
materials, temporary dermal fillers are associated with a very
low incidence of complications. Mild, transient and, therefore,
less significant side effects include pain, redness, minor bleeding
or hematoma; severe ones include product accumulation, asym-
metry, transient edema, increased sensitivity, infections and
abscesses but also foreign body granulomas, recurrent edema
and inflammation, induration, tissue necrosis and scarring [32].
Complications may occur immediately or delayed and
show both short- and long-term duration. Each reaction and
side effect has to be interpreted individually.
lowered by cooling and use of regular analgesics.
Bruising is caused by traumatization of small vessels while
injecting. It has been reported that bruising appears more
often while injecting into the dermal and immediate sub-
dermal planes [34]. Deposition of a material directly preperios-
tal is associated with the lowest risk of bruising [1]. Bruising
usually disappears shortly after the procedure; nevertheless,
cooling methods such as application of cold compresses,
ointments containing heparinoid or vitamin K [35] together
with camouflage can ameliorate the process.
Punctual bleeding is produced by transepidermal puncture
and shows usually a very short duration. Erythema and edema
are related to the trauma caused by the injections but may be
also associated with the hygroscopic properties of the injected
material. Erythema usually resolves within a few hours, edema
may persist for 2 -- 3 days [7]. Immediate response with redness
to an injection is physiological, in many cases, and if it persists
for few days allergy or hypersensitivity should be excluded [1].
Products that are highly reactive (products containing bovine
collagen) require skin testing prior to application [36]. Forma-
tion of new vessels may be seen in all treated areas but based
on our experience it is most frequently observed in the naso-
labial folds and may be caused by tissue trauma as a result
of tissue expansion by the material itself (predominantly
HA) or excessive massage. Depending on the vessel diameter
different wavelengths may be employed (532-nm diode cop-
per vapor, 585-nm pulsed dye laser and intense pulsed light)
for their improvement [1].
Short-term swelling often does not disturb and can
be treated by simple cooling. Longer-lasting edema and

1218 Expert Opin. Drug Saf. (2014) 13(9)


A.
Figure 1. Herpetic outbreak of upper and lower lip after lip augmentation with HA filler (A,B).
Patient attended the Department of Dermatology and Allergology, Ludwig Maximilian University, Munich, Germany and provided signed permission for the photo-
graph to be printed.
HA: Hyaluronic acid.
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by CDL-UC San Diego on 12/29/14
angioedema may be resolved by prescribing antihistamines
and oral prednisone. If bacterial infection cannot be excluded,
antibiotic treatment should be added. Successful treatment
of persistent edema with oral steroids in combination with
the leukotriene receptor antagonist montelukast has been
previously published [1].
Tendency for hyperpigmentation following dermal filler
procedures may be seen in all skin types without any preferences
and is frequently challenging to improve [37-39]. First-line treat-
ment includes bleaching agents such as topical hydroquinone
(2 -- 8%) and Retin-A (tretinoin) combined with daily full-
For personal use only.
spectrum sunscreen application [1]. Treatment with intensed
pulse light, pulsed dye light or potassium titanyl phosphate
lasers has been also reported [1] and may be successful in some
cases. Long-wavelength Nd:YAG laser is available also for
individuals with darker skin types [40].
Bluish dyspigmentation appears as a result of the Tyndall
effect and has been reported after superficial injections of
some HA products [41]. Treatment options include intrale-
sional injection of hyaluronidase or small incision with
subsequent mechanical expressing of the material [42,43].
3.2 Long-term und severe complications
3.2.1 Infection
Local reactions at the injection site represent the most
common adverse event associated with fillers [36]. Bacterial,
fungal or viral infections may cause post-filler procedure com-
plications in the form of diffuse inflammation, erysipelas,
phlegmonas or even sepsis. The bacteria are typically intro-
duced to the site during injection, most of them originating
from hair follicles passed by the injection needle (Staphylococ-
cus epidermidis and Propionibacterium acnes) [44,45]. Candida
species may also be present and should be kept in consider-
ation especially when treating immunocompromised patients
or those not responding to treatment with antiviral and
antibiotic agents alone [46].
Differential diagnosis includes delayed hypersensitivity
reactions, which may also cause erythema, but additionally
pruritus and an absence of fever [1].
Most frequently observed viral infections include reactiva-
tion of herpes. Appropriate prevention is therefore essential
Expert Opin. Drug Saf. (2014) 13(9)
Safety of fillers
B.
when filler procedure is targeting the mouth area or the
patient reports a history of recurrent herpes simplex or/and
cold sores [7].
For bacterial infections therapy includes topical, oral or
even intravenous antibiotics, such as cephalexin, dicloxacillin
or nafcillin, if indicated. Abscesses are treated with incision,
drainage and antibiotics. The treatment agent should be cho-
sen appropriately according to the obtained antibiogram [47].
Hyaluronidase should not be used in the primary phase of
treatment, due to the risk of spreading the infected material
diffusely into the tissues if active cellulitis is present. Many
bacteria (e.g., staphylococci, streptococci and anaerobes)
naturally produce this enzyme, which plays a role in their path-
ogenicity and allows them to spread quickly through the
subcutaneous tissues, consuming HA as they go. The infection
should first be controlled with incision and drainage, followed
by hyaluronidase if necessary [45].
In patients with ongoing herpetic infection triggered after
dermal filler treatment (Figure 1A and 1B), two doses of 2 g
of valaciclovir for 1 day should be given. Alternatively, pro-
phylactic treatment with valaciclovir for 3 -- 5 days may be
started prior to injection to reduce the likelihood of occurring.
3.2.2 Malar edema
Malar edema has been observed after filler injections placed
into the infraorbital hollow and tear troughs [48,49]. It is con-
sidered a serious complication presenting as long-persisting
swelling in periorbital area after placement of dermal fillers,
most usually HA gel to the infraorbital hollows. The anatomy
of this region is complex including fatty tissue with two
compartments, sept and muscles [50].
The malar fat pad is described as a triangular area of
thick subcutaneous fat. Its base is located at the nasolabial
fold, its apex at the malar eminence of the the zygomatic
bone, usually to be found as the highest and central point of
the cheakbone. There are several fibrous septae in the malar
fat pad fusing with the malar sept. The overlying skin is super-
ficially connected with the malar fat pad. An important role in
developing malar edema plays the almost impermeable malar
sept, which divides the suborbicularis oculi fat into upper
and lower part [51]. The lower component merges with the
1219
 D. Kulichova et al.
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Figure 2. Material accumulation in the nasolabial fold after
incorrect placement of an HA filler.
Patient attended the Department of Dermatology and Allergology, Ludwig
Maximilian University, Munich, Germany and provided signed permission for
For personal use only.
the photograph to be printed.
HA: Hyaluronic acid.
Figure 3. Recurrent inflammatory nodule on the left side of
the upper lip after HA filler lip augmentation.
Patient attended the Department of Dermatology and Allergology, Ludwig
Maximilian University, Munich, Germany and provided signed permission for
the photograph to be printed.
HA: Hyaluronic acid.
cheek fat and the upper component is known as the malar
mound [48].
The skin in this area is extremely thin and any disturbance
in lymphatic drainage is immediately visual. Some individuals
already have a predisposition of compromised lymphatic
drainage in the superficial compartment of the superficial
suborbicularis oculi fat even without having any filler material
1220 Expert Opin. Drug Saf. (2014) 13(9)
injected [52]. Malar edema may occur after introducing filler
superficial to the malar sept [48] or due to injecting large
volumes of material causing pressure on the lymphatic vessels.
Treatment of malar edema after filler injection includes
head elevation with cold compresses. The patient is advised
to perform manual pressure massage several times a day and
administration of an oral methylprednisolone in a decreasing
dosage over a week is prescribed. If HA filler was injected,
intralesional hyaluronidase is indicated.
In case of edema due to delayed hypersensitivity reactions
and failure of above-mentioned treating methods, excision is
the ultimate therapeutical option. Lymphatic drainage and
soft face massage may help to reduce swelling if performed
in a correct way.
3.2.3 Nodules, biofilms and foreign body granulomas
Palpable or visible nodular masses or/and whitish papules are
caused by accumulation of material (Figure 2) in cases of over-
correction and of a superficial or incorrect placement of filler
(e.g., intramuscular). They are usually stable in its size, have
well-defined borders and appear relatively early after the filler
injection [53]. Filler visibility occurs very rarely with HA for-
mulations but may be associated with a bluish discoloration.
Nodules appear rather frequently after treatment with CaHa,
particularly in the lips, and they can migrate superficially due
to the pumping effect of the orbicularis oris muscle; thus, the
use of this type of filler in this area is not recommended [54].
Nodules should be distinguished from inflammatory nodules
(Figure 3) or from formation of biofilms.
Biofilms develop within weeks after the administration of
the filler, and present as erythematous, mildly tender nodules
persisting for months and cause great anxiety to the patient [55].
They are usually culture negative and hence they were previ-
ously thought to be due to an allergic or a foreign body reac-
tion to the filler substance. These reactions are always small,
localized and have no associated antibody formation. Biofilms
are referred to a collection of microorganisms sticking to surfa-
ces and are not recognized by the immune system. They are
considered to be 100 times more resistant to antibiotics [56].
To avoid biofilms, aseptic measures should be fully observed
during injection. Disinfecting the skin with chlorhexidine prior
to injection seems to be more preferable than alcohol for its
residual effects [56]. Injection in patients with focal or systemic
infections is contraindicated. Smaller needles naturally impose
less trauma and bacterial penetration [57].
Granulomas are the product of an immune host reaction
(type IV hypersensitivity reaction) to inserted foreign material.
The rate of foreign body granuloma has been reported to range
from 0.01 to 0.1% [58]. Granulomas can occur after several
months or even years post-treatment, presenting therefore
diagnostic difficulties [59]. Although very rare, granulomas
present a serious problem in aesthetic filling therapeutics
because of its longevity and resistance to treatment. Longer
periods of latency are observed especially in fillers of
permanent nonabsorbable nature. The clinical picture shows

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Figure 4. Foreign body granuloma presenting as firm
nodules on the upper lip after contour lip correction with
HA filler.
Patient attended the Department of Dermatology and Allergology, Ludwig
Maximilian University, Munich, Germany and provided signed permission for
the photograph to be printed.
HA: Hyaluronic acid.
erythematous to skin colored nodules or plaques that become
firm with time (Figure 4). Ulceration may occur [60,61]. Histo-
For personal use only.
logically, a granulomatous infiltrate including macrophages,
epitheloid histiocytes and multinucleated foreign body giant
cells that surround the foreign particles is seen (Figure 5A and
5B) [62]. Fibrosis can be found in later stages. It is believed
that not only injector-related but also patient- and product-
related characteristics have an influence on forming granulo-
mas [58]. It appears that the development of granulomas does
not depend on the volume of material injected or the biocom-
patibility of the compound, but rather on its chemical proper-
ties, surface structure and the greater or lesser presence of
impurities. For example, granulomatous reactions are found
more frequently in association with fillers that have an irregu-
lar surface (permanent fillers) [63]. The exact pathophysiology
and etiology underlying granuloma formation, however, are
still poorly understood.
Nodules caused by HA fillers can be resolved by massage or
in case of resistance by intralesional injection of hyaluroni-
dase. In case of overcorrection the material may be extruded
through manual pressure massage directly after the treatment.
Successful treatment of non-inflammatory nodules by injec-
tion of lidocaine or saline combined with massage has also
been reported [64].
If biofilms are suspected, administration of broad-spectrum
antibiotics, for example, ciprofloxacin together with macro-
lides, for example, clarithromycin, for several weeks is
indicated. If the biofilm persists, intralesional production of
heat through radiofrequency or laser leading to a decrease of
bacterial counts and liquefaction of the filler microparticles
has been published [65].
The treatment of granulomatous inflammation should
start with identifying the injected agent. Hyaluronidase is
Expert Opin. Drug Saf. (2014) 13(9)
Safety of fillers
the method of choice in treating complications after HA fill-
ers [66]. Intralesional administration of corticosteroids mixed
with lidocain, in combination with 5-fluorouracil, is consid-
ered in resistant cases [63,67]. Usually repeated therapy sessions
are needed ranging in between every week to once monthly.
In our department, we usually inject a mixture of 0.5 cc
5-fluorouracil (50 mg/cc), 0.2 xylocaine 2% with adrenaline
1:100000 and 0.3 cc of triamcinolone acetonide 10 mg/cc.
However, before injecting intralesional steroid injections,
an infection needs to be excluded. Surgical excision of the
material represents the last therapeutic option [61].
3.2.4 Vascular compromise
Vascular compromise by either injecting filler material into a
vessel or compression of vessels by false placement of material
may lead to vessel occlusion with subsequent tissue necrosis.
Areas most vulnerable are those in which blood supply depends
strongly on a single arterial branch, such as the glabellar and
nasolabial folds [68,69]. Clinical warning signs during injection
include severe pain, signs of blanching and violet discoloration
followed by subsequent erosion and ulceration [68]. There have
been a few reports of acute vision loss and hemiplegia after
autologous facial fat injection as a result of ocular and cerebral
embolism [65,69-73]. Acute fatal stroke has also been reported
after autologous fat injection into the glabella [74]. As recently
summarized by Lazzeri et al., central retinal artery embolization
can be related to retrograde arterial displacement of the
injected products from peripheral vessels into the ophthalmic
arterial system proximal to the central retinal artery and follows
the subsequent anterior movement of the injected sub-
stance [75]. Accidental perforation of the wall of a distal branch
by the injecting needle or cannula, an injection pressure higher
than systolic arterial pressure and a sufficient amount of mate-
rial delivered into the vessel increases the risk of embolization
of filler into the ophthalmic artery.
Treatment of vascular compromise should be initiated as
soon as possible. First step is to stop injecting the filling mate-
rial and administer intralesional hyaluronidase regardless of
the filler used. Directly thereafter 2% nitroglycerin paste
should be massaged into the affected area and warm com-
presses may be applied in order to increase vasodilation [76].
Subcutaneous injection of low-molecular-weight heparin has
also been used successfully in a case of severe necrosis [77].
Oral administration of methylprednisolone and aspirin, use
of Sildenafil, as well as antibiotic and antiviral prophylaxes
are advisable [65]. Currently, no safe, feasible and reliable treat-
ment exists for iatrogenic retinal embolism. Nonetheless,
therapy should theoretically be directed to lowering intraocu-
lar pressure to dislodge the embolus into more peripheral
vessels of the retinal circulation, increasing retinal perfusion
and oxygen delivery to hypoxic tissues [75].
3.2.5Neural complications
Neural complications in patients treated with dermal fillers
are extremely rare. Piercing and laceration of nerves by the
1221
 D. Kulichova et al.
A.
Figure 5. Granulomatous infiltrate formed by lymphocytes, granulocytes, macrophages and multinucleated foreign body
giant cells surrounding foreign particles following an HA filler (A,B).
Patient attended the Department of Dermatology and Allergology, Ludwig Maximilian University, Munich, Germany and provided signed permission for the photo-
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by CDL-UC San Diego on 12/29/14
graph to be printed.
HA: Hyaluronic acid.
needle, tissue compression, excessive molding and massage
may lead to nerve injury and to transient or permanent sen-
sory or motor deficits. Some refer that it is more often seen
in cases of intraoral injection approach [65].
4. Diagnostic tools
For personal use only.
The most important and relevant diagnostic tool for the
assessment of filler complications remains biopsy with histo-
logical examination. However, other diagnostic tools such as
ultrasound, MRI, CT and in vivo confocal microscopy have
been proposed in the past.
While ultrasound represents a noninvasive, fast, low-cost-
associated and easy method for the examination of adverse
events following dermal filler injections, MRI and CT are rarely
necessary and are associated with high costs and exposition
to radiation.
The in vivo confocal laser microscopy is still under investi-
gation with regard to possibilities in order to visualize patho-
logical processes after injecting a filler material and may
present a novel option for the future.
In case of infection, bacterial cultures are indicated. If a lesion
is fluctuating, a needle aspiration should be performed; samples
should be cultured for 21 days in order to identify the atypical
species [56]. If a biofilm is suspected and a bacteriological culture
comes out negative, the technique of fluorescence in situ hybrid-
ization and scintigraphy with radiolabeled autologous white
blood cells may help to define the causing agent [78].
Adverse reactions to orthopedic metal implants, in particu-
lar arthroplasty, have led to diagnostic approaches [79] being
potentially useful also in understanding filler complications.
A consensus classification has defined four major peri-implant
reaction types [80]: A particle dominated foreign body like
response (type I), the infectious type with predominant gran-
ulocyte response (type II), the mixture of type I and II (com-
bined type, type III) and a fibrotic, paucicellular reaction
(type IV, indifferent type). Further steps are the identification
and description of histopathological characteristics linked to
1222 Expert Opin. Drug Saf. (2014) 13(9)
B.
the type of foreign material (e.g., acrylate based bone cement,
metal debris, polyethylene particles) [81]. Lymphocyte-
dominated peri-implant inflammation together with patch
test reactivity to metals adds to the diagnosis of allergic reac-
tion [82]. To better reveal low-grade infection, combined
approach of microbiology (e.g., bacterial smear and culture
of biopsy material), histopathology and assessment of poten-
tial biomarkers linked to bacterial infection is recommended.
In particular, analysis of the pattern of antimicrobial peptides
and cytokines represents a promising tool [83]. Finally, the
characterization of local tissue expression of proinflammatory
cytokines further helps to differentiate hyperergic from
infectious type of complications [83,84].
5. Conclusion
Minimally invasive procedures for the improvement of wrin-
kles and volume loss of the human face utilizing off-the-shelf
fillers and biostimulators can create a more youthful appear-
ance and help correct some of the major changes associated
with the aging process. Due to the increasing number of
procedures and raising indications, an increase in side effects
can be expected. Although an in-depth understanding of the
individual characteristics of available products, their indica-
tions, their tissue responses, benefits and drawbacks are key
for safe and successful achievement of cosmetically pleasing
results, adverse events can occur with any dermal filler.
A profound knowledge of the facial anatomy as well as exten-
sive experience with the various filling techniques and suitable
materials for the respective areas remains crucial for the pre-
vention of adverse events related to filling procedures of the
face. Since side effects such as malar edema and foreign
body granuloma do affect patients physically and psychologi-
cally to a significant extent and their successful treatment
remains till today challenging, further in depth studies on
the tolerability of many filling materials utilized are definitely
needed. Since the ideal filler does not exist yet, difficulties in

treating severe side effects caused by non-resorbable fillers
should encourage us all to utilize only degradable products.
6. Expert opinion
With the rise of aesthetic filling therapeutics, higher incidence
of side effects and complications associated with these proce-
dures is observed and expected. New techniques of prevention
as well as ways of treatment evolve. The demand of
high-quality products and the pressure on high experience
and professionalism is growing. Till to date, the question
whether it is the material and its properties or the injector
and his/her injection technique that accounts for complica-
tions such as granulomas or malar edema remains in many
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by CDL-UC San Diego on 12/29/14
cases controversial. Obviously, different injectable products
are characterized by widely varying properties, associated risks
and injection requirements. Thus, based on these characteris-
tics products have to be chosen accordingly, which will neces-
sitate a detailed understanding of facial anatomy, proper
patient selection, appropriate material selection for the respec-
tive anatomical site, correct placement of the product and
appropriate preparation and injection techniques. Taking
patient’s history (including previously injected materials),
consulting the planned procedures with the patient and sign-
For personal use only.
ing the informed consent represent absolute musts. Inspection
of the treated area should be accompanied with palpation.
Proper disinfection, use of gloves throughout the procedure,
careful and sterile manipulation with the needle should be
common praxis. If a patient has a history of cold sores, pro-
phylactic treatment with aciclovir or its equivalent prior to
injections in the perioral area is recommended [7]. Bruising
can be minimized by avoiding all blood-thinning medications
and use of local anesthesia combined with adrenaline. Patient
should avoid bending of the upper part of their body as well as
extreme physical strain right after the treatment. Use of thin
needles or blunt cannulas, together with slow, low-pressure
injections of only bit of material, as well as lowest possible
number of punctures also lower the risk of hematoma. Proper
management of high blood pressure is advisable. To prevent
complications in the sense of nodules and granulomas, right
localization and layer together with avoidance of an intramus-
cular injection is necessary. Prevention of hyperpigmentation
is associated with proper usage of sunscreen after the treat-
ment. Risk of vascular compromise may be lowered by plac-
ing the needle tip in contact with bone, smaller volume
bolus injections and low-pressure injections in order to
prevent from anterograde flow. The site of the highest risk
for this complication is the glabella since this region is sup-
plied by the suptratrochlear artery, which does not have a
strong collateral circulation. To avoid this complication, it is
recommended not to inject this area or at least use a less-dense
Expert Opin. Drug Saf. (2014) 13(9)
Safety of fillers
filler and inject it very superficially and slowly, while con-
stantly moving the needle [85]. Characterizing type and fre-
quency of adverse reactions to injectable filler substances,
Zielke et al. [86] recently demonstrated that while adverse reac-
tions are documented with all injectable fillers, time until
reaction and the type of adverse reaction varied between the
different fillers. Interestingly, substance-specific adverse event
profiles could be elucidated, demonstrating that, for example,
HA-based fillers were mainly associated with swelling, ery-
thema and nodules, while PLLA patients mainly developed
granulomas, as did patients treated with PMMA plus colla-
gen. A retrospective study on prolonged infraorbital swelling
after HA treatment showed that 12 out of 51 treated patients
presented significant malar edema lasting over a month [49].
Even though more data are warranted before drawing final
conclusions, the percentage of affected patients is alarming
and highlighting the periorbital region as an area of increased
risk, which should be treated by experienced injectors only.
Why some patients develop granulomas and others not,
what is the reason that some react to the treatment and others
fight the complications over years are topics of ongoing
research. Being able to detect patients prone to these compli-
cations and to recognize individual risk factors would be one
of the ways how to proactively precede these adverse events.
More research in this field in order to develop safe and
complications-free filling materials is warranted. Till then a
profound knowledge of the facial anatomy as well as extensive
experience with the various filling techniques remains critical
for the prevention of adverse events. Here, the development of
blunt-tipped cannulas in order to prevent vascular damage
and its associated side effects has been one of the main contri-
butions during the last years in the field of minimally invasive
volumizing of the face. Slow and low-pressure injections of
only little material further contribute to tolerability. With
the many products on the market available, one should focus
on those supported by well-designed studies and use them
according to their indications in the suitable areas and layers
for best possible and safest outcomes. In case of existing
adverse events a broad consensus is urgently needed on the
best course of therapy if filler-associated complications occur.
Declaration of interest
The authors do not have relevant affiliations or financial
involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or
materials discussed in the manuscript. This includes employ-
ment, consultancies, honoraria, stock ownership or options,
expert testimony, grants or patents received or pending, or
royalties.
1223
 D. Kulichova et al.
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Affiliation
Daniela Kulichova† MD, Alyona Borovaya,
Thomas Ruzicka, Peter Thomas &
Gerd G Gauglitz
†
Author for correspondence
Ludwig Maximilian University, Department of
Dermatology and Allergology, Munich,
Germany,
Frauenlobstr. 9-11, 80337 Munich, Germany
Tel: +011 49 89 5160 6010;
Fax: +011 49 89 5160 6002;
E-mail: daniela.kulichova@med.uni-muenchen.
de