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Understanding the safety and

tolerability of facial filling
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 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.

unbranched chain [6]. The longevity of the respective product

Article highlights. depends on the muscular activity, concentration of the prod-
. Types of dermal fillers: their characteristics and uct and amount of cross-linking and may last from 6 up to
indications. 18 months and more [1,14-16]. Naturally occurring HA (not
. Side effects of dermal fillers: their causes, clinical signs cross-linked, native HA) is rapidly degraded with a half-life
and consequences.
of 12 -- 24 h [17]. Therefore, the manufacturing goal is to cre-
Current diagnostic tools and treatment of dermal filler
complications: State of the art. ate an HA with increased tissue residency and elasticity while
maintaining its biocompatible nature. The process of cross-
This box summarizes key points contained in the article. 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,
before-hand properly. Safety and tolerability of injected and its stability, biodegradability and long-term safety records
materials are until today not fully understood and therefore have been demonstrated for > 15 years [18]. The degree of
should be studied more intensively. The following review
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cross-linking enhances the persistence of the HA filler, but

gives an overview of nowadays most frequently used injectable excessive cross-linking may reduce the biocompatibility of
materials, their properties, indications, possible complications the filler, causing foreign body reaction and encapsulation [13].
and the appropriate diagnostics and treatment options of Cross-linking will also change the rheological properties of the
associated adverse events. gel. Depending on the grade of cross-linking, the filler’s per-
sistence, elasticity and resistance during injection are being
2. Facial filling therapeutics influenced. An important characteristic of the HA molecule
is that it is hydrophilic, which has a major influence on hydra-
2.1 Types of dermal fillers tion and turgor of the skin [13,19]. Higher concentrated HA
It is currently estimated that around 160 different filling and/or large particle products will tend to absorb more water,
products are being available worldwide manufactured by and may thus produce more tissue swelling after injection [1].
For personal use only.

> 50 companies [1,4]. Unfortunately, only the minority is being HA fillers can also be characterized by its homogeneity.
supported by well-designed studies with regard to their prop- Monophasic monodensified fillers are synthesized by mixing
erties, efficacy parameters and potential side effects. Many the HA and cross-linking polymers in a single step. This pro-
products of no-name distributors have no license. Also, an cess results in a product that, for the first 4 -- 5 months after
increasing number of beauticians and other non-licensed injection, has a slower resorption. Biphasic gels consist of
individuals inject dermal fillers uncontrolled or illegally on a HA ground into particles. These particles are suspended in a
daily basis. Internet sources are available to everybody. This non-cross-linked HA, which acts as a lubricant that facilitates
accessible market poses a major risk to patients [5]. extrusion of the gel from the syringe into the skin [13,20].
The substances most commonly used for facial soft-tissue Examples of product names are listed in Table 1. HA is
augmentation are hyaluronic acid (HA), calcium hydroxylapa- degraded by native hyaluronidase. This fact is widely used in
tite (CaHa), collagen, poly-L-lactic acid (PLLA), polymethyl treating complications linked to injected HA fillers [6].
methacrylate (PMMA), silicone and autologous fat [1,6,7]. Collagen fillers can be of bovine, human or porcine origin.
Dermal fillers can be categorized by several methods [1,8,9]. One of the advantages of collagen fillers is that they are less
However, when discussing associated complications, a viscous and thus well suitable for the correction of fine lines
categorization in terms of biodegradable (temporary) versus and wrinkles because they are less likely to produce irregular-
non-biodegradable (permanent) fillers may be most useful [9-12]. ities when injected superficially. The collagen products are
broken down over time by enzymatic mechanisms and fre-
2.1.1 Temporary (biodegradable) fillers quently show shorter duration (2 -- 6 months) of effect
Temporary fillers, such as HA and collagen fillers, are when compared to HA fillers [7,21].
naturally occurring substances that are being reabsorbed by Autologous fat represents the original filler. Fat can fill
the human body, and are associated with ‘temporary’ results, large and small soft-tissue defects of the face and body in
thereby requiring patients to receive periodical top-up any permanent indication. The use of the patient’s own fat
injections. Since its FDA approval in 2003, HA has become as a filler is a safe and natural method. However, fat grafting
the ‘gold standard’ of safe injectable fillers. It is the most does not seem to work equally for all techniques, body areas
important polysaccharide in human extracellular matrix, nor for all patients. The drawback of this technique is that it
which acts as a scaffold for collagen and elastin [13]. Nowa- must be performed in an operating theater environment
days, most of the HA fillers used worldwide are derived with local anesthesia and/or sedation; specific instruments
from the fermentation of Streptococcus equi bacterium, which and materials are also required. The longevity of injected
are referred to as non-animal--stabilized HA or [6]. The chem- autologous fat ranges from 8 months to several years [22].
ical formula consists of linear polymeric dimers of N-acetyl-D- Filling therapeutics with biodegradable particles that stim-
glucosamine and D-glucuronic acid cross-linked into a long ulate the body to produce its own collagen represents another

1216 Expert Opin. Drug Saf. (2014) 13(9)

Safety of fillers

Table 1. Examples of product names of biodegradable hyaluronic acid dermal fillers, describing their main

Brand name and manufacturer Main component

Restylane/ RestylaneFine lines/Restylane Touch/ Restylane Perlane (Q-Med/Medicis) HA gel

Captique (Genzyme/Inamed/AllerganMentor) HA gel
Juvederm Ultra (2, 3 and 4) and Juvederm Ultra XC (Inamed/Allergan) HA gel
Juvederm Ultra Plus and Juvederm Ultra Plus XC (Inamed/Allergan) HA gel
Juvederm Voluma (Inamed/Allergan) HA gel
Belotero Soft/Belotero Basic/Belotero Intense (Merz Pharmaceuticals) (Inamed/Allergan) HA gel
Varioderm (Adoderm GmbH/Medical Aesthetics group) HA gel
Emervel Touch/Emervel Classic/Emervel Deep/Emervel Volume (Galderma) HA gel
Teosyal range (Deep Lines, Global Action, Ultra Deep, First Lines, Meso, HA gel
Touch Up, Ultimate) (Lifestyle Aesthetics)
Cosmoderm (Inamed/Allergan) Human collagen
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Cosmoplast (Inamed/Allergan) Human collagen

Zyderm (Inamed/Allergan) Purified bovine collagen with 0.3% lidocaine
Zyplast (Inamed/Allergan) Purified bovine collagen with 0.3% lidocaine

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 Main component

Sculptra (Dermik aesthetic/Sinclair Pharma) Poly-L-lactic acid

For personal use only.

Radiesse (Merz Pharmaceuticals) Calcium hydroxylapatite microspheres suspended in a carrier gel

group of temporary fillers and include CaHA (RadiesseÒ) and collagen deposition and vascularization [25,26]. Patient
PLLA (SculptraÒ, Table 2) [12,13]. CaHA is a mineral present counseling is especially important when using PLLA due to
in bone and teeth. As a naturally occurring substance, it is its delayed effect. Each injection session with PLLA provides
inherently biocompatible and is metabolized into calcium gradual improvements. Based on the current recommenda-
and phosphate. Radiesse is composed of microspheres of tions three treatment sessions (approximately every 6 weeks)
CaHA (25 -- 45 µm) at 30% concentration suspended in a are generally required, but once the final correction is
gel composed of water, glycerin and sodium carboxymethyl- achieved, volumetric results may last up to 2 -- 3 years [27].
cellulose. This formulation provides a l:1 volumetric correc- The most common adverse effects are injection related. Small,
tion without the need for overcorrection. Once injected, the palpable, subcutaneous nodules, as well as visible nodules, can
gel is slowly absorbed over a period of months. During this result from uneven distribution or superficial placement of
interval, there is ingrowth of fibroblasts into the scaffold of the product [28].
microspheres that will gradually replace the carrier gel [6]. As
these cells replace the gel, they will increase endogenous colla- 2.1.2 Permanent (non-biodegradable) fillers
gen synthesis, which will anchor the microspheres in place. Available permanent fillers include PMMA microspheres in a
The microspheres, stabilized at the injection site by new colla- solution of 3.5% collagen and 0.3% lidocaine, polyacryl-
gen formation, will then slowly be reabsorbed by macro- amide hydrogel, which contains 2.5% of cross-linked poly-
phages over several months [23]. This filler remains in tissue acrylamide and 97.5% of water, and silicone oil. Product
for 12 -- 18 months [24]. It is indicated for correction of severe examples of the three mentioned different compositions are
facial folds and maxillofacial defects mainly associated with ArtecollÒ, AquamidÒ and SilikonÒ, respectively (Table 3).
volume loss and/or lipoatrophy [11]. These types of fillers Their action is based mostly on a foreign body reaction
must be injected deeply -- into the hypodermis or deeper -- around the nonabsorbable microspheres with a new deposi-
in order to avoid visible nodules. The incidence of associated tion of collagen [29]. The collagen solution keeps the spheres
complications is low, and there are no reports of calcification from clumping together, and during its absorption, fibrin
or osteogenesis at injection sites [23]. PLLA is a biodegradable, and new collagen deposition takes its place. At the end of
nontoxic, synthetic material derived from corn starch. It has this process, the augmented volume is about 20% PMMA
been used in suture material and other biomedical implants. and 80% autologous connective tissue [30].
PLLA provides soft-tissue augmentation through stimulation Silicone is produced from silica, which was approved for
of an inflammatory tissue response with subsequent native retinal detachment, and its use as a cosmetic soft-tissue filler

Expert Opin. Drug Saf. (2014) 13(9) 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 lowered by cooling and use of regular analgesics.
Mild infection Migration of implant material Bruising is caused by traumatization of small vessels while
Asymmetry 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-
is off-label. Silicone disperses into tissue to become encapsu-
tal is associated with the lowest risk of bruising [1]. Bruising
lated and it is used as a volumizer for the facial areas. Studies
usually disappears shortly after the procedure; nevertheless,
of injectable silicone in the face vary in regard with results
cooling methods such as application of cold compresses,
and complications.
ointments containing heparinoid or vitamin K [35] together
Complications after permanent fillers may appear after
with camouflage can ameliorate the process.
many years [31], and may be of permanent nature. Long-
Punctual bleeding is produced by transepidermal puncture
term complications include nodules, granuloma formation,
and shows usually a very short duration. Erythema and edema
gel migration or accumulation, persistent redness or pain,
are related to the trauma caused by the injections but may be
swelling, infection and chronic inflammatory reactions [7,9].
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
3. Side effects of dermal fillers and treatment to an injection is physiological, in many cases, and if it persists
for few days allergy or hypersensitivity should be excluded [1].
Mild to severe complications may occur after treatment with Products that are highly reactive (products containing bovine
fillers of various kinds. Nevertheless, unlike permanent filler collagen) require skin testing prior to application [36]. Forma-
materials, temporary dermal fillers are associated with a very tion of new vessels may be seen in all treated areas but based
low incidence of complications. Mild, transient and, therefore, on our experience it is most frequently observed in the naso-
less significant side effects include pain, redness, minor bleeding labial folds and may be caused by tissue trauma as a result
or hematoma; severe ones include product accumulation, asym- of tissue expansion by the material itself (predominantly
metry, transient edema, increased sensitivity, infections and HA) or excessive massage. Depending on the vessel diameter
abscesses but also foreign body granulomas, recurrent edema different wavelengths may be employed (532-nm diode cop-
and inflammation, induration, tissue necrosis and scarring [32]. per vapor, 585-nm pulsed dye laser and intense pulsed light)
Complications may occur immediately or delayed and for their improvement [1].
show both short- and long-term duration. Each reaction and Short-term swelling often does not disturb and can
side effect has to be interpreted individually. be treated by simple cooling. Longer-lasting edema and

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

Safety of fillers

A. B.

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.
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angioedema may be resolved by prescribing antihistamines when filler procedure is targeting the mouth area or the
and oral prednisone. If bacterial infection cannot be excluded, patient reports a history of recurrent herpes simplex or/and
antibiotic treatment should be added. Successful treatment cold sores [7].
of persistent edema with oral steroids in combination with For bacterial infections therapy includes topical, oral or
the leukotriene receptor antagonist montelukast has been even intravenous antibiotics, such as cephalexin, dicloxacillin
previously published [1]. or nafcillin, if indicated. Abscesses are treated with incision,
Tendency for hyperpigmentation following dermal filler drainage and antibiotics. The treatment agent should be cho-
procedures may be seen in all skin types without any preferences sen appropriately according to the obtained antibiogram [47].
and is frequently challenging to improve [37-39]. First-line treat- Hyaluronidase should not be used in the primary phase of
ment includes bleaching agents such as topical hydroquinone treatment, due to the risk of spreading the infected material
(2 -- 8%) and Retin-A (tretinoin) combined with daily full-
For personal use only.

diffusely into the tissues if active cellulitis is present. Many

spectrum sunscreen application [1]. Treatment with intensed bacteria (e.g., staphylococci, streptococci and anaerobes)
pulse light, pulsed dye light or potassium titanyl phosphate naturally produce this enzyme, which plays a role in their path-
lasers has been also reported [1] and may be successful in some ogenicity and allows them to spread quickly through the
cases. Long-wavelength Nd:YAG laser is available also for subcutaneous tissues, consuming HA as they go. The infection
individuals with darker skin types [40]. should first be controlled with incision and drainage, followed
Bluish dyspigmentation appears as a result of the Tyndall by hyaluronidase if necessary [45].
effect and has been reported after superficial injections of In patients with ongoing herpetic infection triggered after
some HA products [41]. Treatment options include intrale- dermal filler treatment (Figure 1A and 1B), two doses of 2 g
sional injection of hyaluronidase or small incision with of valaciclovir for 1 day should be given. Alternatively, pro-
subsequent mechanical expressing of the material [42,43]. phylactic treatment with valaciclovir for 3 -- 5 days may be
started prior to injection to reduce the likelihood of occurring.
3.2 Long-term und severe complications
3.2.1 Infection 3.2.2 Malar edema
Local reactions at the injection site represent the most Malar edema has been observed after filler injections placed
common adverse event associated with fillers [36]. Bacterial, into the infraorbital hollow and tear troughs [48,49]. It is con-
fungal or viral infections may cause post-filler procedure com- sidered a serious complication presenting as long-persisting
plications in the form of diffuse inflammation, erysipelas, swelling in periorbital area after placement of dermal fillers,
phlegmonas or even sepsis. The bacteria are typically intro- most usually HA gel to the infraorbital hollows. The anatomy
duced to the site during injection, most of them originating of this region is complex including fatty tissue with two
from hair follicles passed by the injection needle (Staphylococ- compartments, sept and muscles [50].
cus epidermidis and Propionibacterium acnes) [44,45]. Candida The malar fat pad is described as a triangular area of
species may also be present and should be kept in consider- thick subcutaneous fat. Its base is located at the nasolabial
ation especially when treating immunocompromised patients fold, its apex at the malar eminence of the the zygomatic
or those not responding to treatment with antiviral and bone, usually to be found as the highest and central point of
antibiotic agents alone [46]. the cheakbone. There are several fibrous septae in the malar
Differential diagnosis includes delayed hypersensitivity fat pad fusing with the malar sept. The overlying skin is super-
reactions, which may also cause erythema, but additionally ficially connected with the malar fat pad. An important role in
pruritus and an absence of fever [1]. developing malar edema plays the almost impermeable malar
Most frequently observed viral infections include reactiva- sept, which divides the suborbicularis oculi fat into upper
tion of herpes. Appropriate prevention is therefore essential and lower part [51]. The lower component merges with the

Expert Opin. Drug Saf. (2014) 13(9) 1219

D. Kulichova et al.

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
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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
Figure 2. Material accumulation in the nasolabial fold after injection [53]. Filler visibility occurs very rarely with HA for-
incorrect placement of an HA filler.
mulations but may be associated with a bluish discoloration.
Patient attended the Department of Dermatology and Allergology, Ludwig
Maximilian University, Munich, Germany and provided signed permission for
Nodules appear rather frequently after treatment with CaHa,
For personal use only.

the photograph to be printed. particularly in the lips, and they can migrate superficially due
HA: Hyaluronic acid. 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
Figure 3. Recurrent inflammatory nodule on the left side of
the upper lip after HA filler lip augmentation.
residual effects [56]. Injection in patients with focal or systemic
Patient attended the Department of Dermatology and Allergology, Ludwig infections is contraindicated. Smaller needles naturally impose
Maximilian University, Munich, Germany and provided signed permission for less trauma and bacterial penetration [57].
the photograph to be printed. Granulomas are the product of an immune host reaction
HA: Hyaluronic acid. (type IV hypersensitivity reaction) to inserted foreign material.
The rate of foreign body granuloma has been reported to range
cheek fat and the upper component is known as the malar from 0.01 to 0.1% [58]. Granulomas can occur after several
mound [48]. months or even years post-treatment, presenting therefore
The skin in this area is extremely thin and any disturbance diagnostic difficulties [59]. Although very rare, granulomas
in lymphatic drainage is immediately visual. Some individuals present a serious problem in aesthetic filling therapeutics
already have a predisposition of compromised lymphatic because of its longevity and resistance to treatment. Longer
drainage in the superficial compartment of the superficial periods of latency are observed especially in fillers of
suborbicularis oculi fat even without having any filler material permanent nonabsorbable nature. The clinical picture shows

1220 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

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Vascular compromise by either injecting filler material into a

vessel or compression of vessels by false placement of material
Figure 4. Foreign body granuloma presenting as firm may lead to vessel occlusion with subsequent tissue necrosis.
nodules on the upper lip after contour lip correction with Areas most vulnerable are those in which blood supply depends
HA filler. strongly on a single arterial branch, such as the glabellar and
Patient attended the Department of Dermatology and Allergology, Ludwig
Maximilian University, Munich, Germany and provided signed permission for
nasolabial folds [68,69]. Clinical warning signs during injection
the photograph to be printed. include severe pain, signs of blanching and violet discoloration
HA: Hyaluronic acid. followed by subsequent erosion and ulceration [68]. There have
been a few reports of acute vision loss and hemiplegia after
erythematous to skin colored nodules or plaques that become autologous facial fat injection as a result of ocular and cerebral
firm with time (Figure 4). Ulceration may occur [60,61]. Histo- embolism [65,69-73]. Acute fatal stroke has also been reported
For personal use only.

logically, a granulomatous infiltrate including macrophages, after autologous fat injection into the glabella [74]. As recently
epitheloid histiocytes and multinucleated foreign body giant summarized by Lazzeri et al., central retinal artery embolization
cells that surround the foreign particles is seen (Figure 5A and can be related to retrograde arterial displacement of the
5B) [62]. Fibrosis can be found in later stages. It is believed injected products from peripheral vessels into the ophthalmic
that not only injector-related but also patient- and product- arterial system proximal to the central retinal artery and follows
related characteristics have an influence on forming granulo- the subsequent anterior movement of the injected sub-
mas [58]. It appears that the development of granulomas does stance [75]. Accidental perforation of the wall of a distal branch
not depend on the volume of material injected or the biocom- by the injecting needle or cannula, an injection pressure higher
patibility of the compound, but rather on its chemical proper- than systolic arterial pressure and a sufficient amount of mate-
ties, surface structure and the greater or lesser presence of rial delivered into the vessel increases the risk of embolization
impurities. For example, granulomatous reactions are found of filler into the ophthalmic artery.
more frequently in association with fillers that have an irregu- Treatment of vascular compromise should be initiated as
lar surface (permanent fillers) [63]. The exact pathophysiology soon as possible. First step is to stop injecting the filling mate-
and etiology underlying granuloma formation, however, are rial and administer intralesional hyaluronidase regardless of
still poorly understood. the filler used. Directly thereafter 2% nitroglycerin paste
Nodules caused by HA fillers can be resolved by massage or should be massaged into the affected area and warm com-
in case of resistance by intralesional injection of hyaluroni- presses may be applied in order to increase vasodilation [76].
dase. In case of overcorrection the material may be extruded Subcutaneous injection of low-molecular-weight heparin has
through manual pressure massage directly after the treatment. also been used successfully in a case of severe necrosis [77].
Successful treatment of non-inflammatory nodules by injec- Oral administration of methylprednisolone and aspirin, use
tion of lidocaine or saline combined with massage has also of Sildenafil, as well as antibiotic and antiviral prophylaxes
been reported [64]. are advisable [65]. Currently, no safe, feasible and reliable treat-
If biofilms are suspected, administration of broad-spectrum ment exists for iatrogenic retinal embolism. Nonetheless,
antibiotics, for example, ciprofloxacin together with macro- therapy should theoretically be directed to lowering intraocu-
lides, for example, clarithromycin, for several weeks is lar pressure to dislodge the embolus into more peripheral
indicated. If the biofilm persists, intralesional production of vessels of the retinal circulation, increasing retinal perfusion
heat through radiofrequency or laser leading to a decrease of and oxygen delivery to hypoxic tissues [75].
bacterial counts and liquefaction of the filler microparticles
has been published [65]. 3.2.5Neural complications
The treatment of granulomatous inflammation should Neural complications in patients treated with dermal fillers
start with identifying the injected agent. Hyaluronidase is are extremely rare. Piercing and laceration of nerves by the

Expert Opin. Drug Saf. (2014) 13(9) 1221

D. Kulichova et al.

A. B.

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 by CDL-UC San Diego on 12/29/14

graph to be printed.
HA: Hyaluronic acid.

needle, tissue compression, excessive molding and massage the type of foreign material (e.g., acrylate based bone cement,
may lead to nerve injury and to transient or permanent sen- metal debris, polyethylene particles) [81]. Lymphocyte-
sory or motor deficits. Some refer that it is more often seen dominated peri-implant inflammation together with patch
in cases of intraoral injection approach [65]. 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
4. Diagnostic tools of biopsy material), histopathology and assessment of poten-
tial biomarkers linked to bacterial infection is recommended.
For personal use only.

The most important and relevant diagnostic tool for the

In particular, analysis of the pattern of antimicrobial peptides
assessment of filler complications remains biopsy with histo-
and cytokines represents a promising tool [83]. Finally, the
logical examination. However, other diagnostic tools such as
characterization of local tissue expression of proinflammatory
ultrasound, MRI, CT and in vivo confocal microscopy have
cytokines further helps to differentiate hyperergic from
been proposed in the past.
infectious type of complications [83,84].
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 5. Conclusion
to radiation.
The in vivo confocal laser microscopy is still under investi- Minimally invasive procedures for the improvement of wrin-
gation with regard to possibilities in order to visualize patho- kles and volume loss of the human face utilizing off-the-shelf
logical processes after injecting a filler material and may fillers and biostimulators can create a more youthful appear-
present a novel option for the future. ance and help correct some of the major changes associated
In case of infection, bacterial cultures are indicated. If a lesion with the aging process. Due to the increasing number of
is fluctuating, a needle aspiration should be performed; samples procedures and raising indications, an increase in side effects
should be cultured for 21 days in order to identify the atypical can be expected. Although an in-depth understanding of the
species [56]. If a biofilm is suspected and a bacteriological culture individual characteristics of available products, their indica-
comes out negative, the technique of fluorescence in situ hybrid- tions, their tissue responses, benefits and drawbacks are key
ization and scintigraphy with radiolabeled autologous white for safe and successful achievement of cosmetically pleasing
blood cells may help to define the causing agent [78]. results, adverse events can occur with any dermal filler.
Adverse reactions to orthopedic metal implants, in particu- A profound knowledge of the facial anatomy as well as exten-
lar arthroplasty, have led to diagnostic approaches [79] being sive experience with the various filling techniques and suitable
potentially useful also in understanding filler complications. materials for the respective areas remains crucial for the pre-
A consensus classification has defined four major peri-implant vention of adverse events related to filling procedures of the
reaction types [80]: A particle dominated foreign body like face. Since side effects such as malar edema and foreign
response (type I), the infectious type with predominant gran- body granuloma do affect patients physically and psychologi-
ulocyte response (type II), the mixture of type I and II (com- cally to a significant extent and their successful treatment
bined type, type III) and a fibrotic, paucicellular reaction remains till today challenging, further in depth studies on
(type IV, indifferent type). Further steps are the identification the tolerability of many filling materials utilized are definitely
and description of histopathological characteristics linked to needed. Since the ideal filler does not exist yet, difficulties in

1222 Expert Opin. Drug Saf. (2014) 13(9)

Safety of fillers

treating severe side effects caused by non-resorbable fillers filler and inject it very superficially and slowly, while con-
should encourage us all to utilize only degradable products. stantly moving the needle [85]. Characterizing type and fre-
quency of adverse reactions to injectable filler substances,
6. Expert opinion Zielke et al. [86] recently demonstrated that while adverse reac-
tions are documented with all injectable fillers, time until
With the rise of aesthetic filling therapeutics, higher incidence reaction and the type of adverse reaction varied between the
of side effects and complications associated with these proce- different fillers. Interestingly, substance-specific adverse event
dures is observed and expected. New techniques of prevention profiles could be elucidated, demonstrating that, for example,
as well as ways of treatment evolve. The demand of HA-based fillers were mainly associated with swelling, ery-
high-quality products and the pressure on high experience thema and nodules, while PLLA patients mainly developed
and professionalism is growing. Till to date, the question granulomas, as did patients treated with PMMA plus colla-
whether it is the material and its properties or the injector gen. A retrospective study on prolonged infraorbital swelling
and his/her injection technique that accounts for complica- after HA treatment showed that 12 out of 51 treated patients
tions such as granulomas or malar edema remains in many
Expert Opin. Drug Saf. Downloaded from by CDL-UC San Diego on 12/29/14

presented significant malar edema lasting over a month [49].

cases controversial. Obviously, different injectable products Even though more data are warranted before drawing final
are characterized by widely varying properties, associated risks conclusions, the percentage of affected patients is alarming
and injection requirements. Thus, based on these characteris- and highlighting the periorbital region as an area of increased
tics products have to be chosen accordingly, which will neces- risk, which should be treated by experienced injectors only.
sitate a detailed understanding of facial anatomy, proper Why some patients develop granulomas and others not,
patient selection, appropriate material selection for the respec- what is the reason that some react to the treatment and others
tive anatomical site, correct placement of the product and fight the complications over years are topics of ongoing
appropriate preparation and injection techniques. Taking research. Being able to detect patients prone to these compli-
patient’s history (including previously injected materials), cations and to recognize individual risk factors would be one
consulting the planned procedures with the patient and sign- of the ways how to proactively precede these adverse events.
For personal use only.

ing the informed consent represent absolute musts. Inspection More research in this field in order to develop safe and
of the treated area should be accompanied with palpation. complications-free filling materials is warranted. Till then a
Proper disinfection, use of gloves throughout the procedure, profound knowledge of the facial anatomy as well as extensive
careful and sterile manipulation with the needle should be experience with the various filling techniques remains critical
common praxis. If a patient has a history of cold sores, pro- for the prevention of adverse events. Here, the development of
phylactic treatment with aciclovir or its equivalent prior to blunt-tipped cannulas in order to prevent vascular damage
injections in the perioral area is recommended [7]. Bruising and its associated side effects has been one of the main contri-
can be minimized by avoiding all blood-thinning medications butions during the last years in the field of minimally invasive
and use of local anesthesia combined with adrenaline. Patient volumizing of the face. Slow and low-pressure injections of
should avoid bending of the upper part of their body as well as only little material further contribute to tolerability. With
extreme physical strain right after the treatment. Use of thin the many products on the market available, one should focus
needles or blunt cannulas, together with slow, low-pressure on those supported by well-designed studies and use them
injections of only bit of material, as well as lowest possible according to their indications in the suitable areas and layers
number of punctures also lower the risk of hematoma. Proper for best possible and safest outcomes. In case of existing
management of high blood pressure is advisable. To prevent adverse events a broad consensus is urgently needed on the
complications in the sense of nodules and granulomas, right best course of therapy if filler-associated complications occur.
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- Declaration of interest
ment. Risk of vascular compromise may be lowered by plac-
ing the needle tip in contact with bone, smaller volume The authors do not have relevant affiliations or financial
bolus injections and low-pressure injections in order to involvement with any organization or entity with a financial
prevent from anterograde flow. The site of the highest risk interest in or financial conflict with the subject matter or
for this complication is the glabella since this region is sup- materials discussed in the manuscript. This includes employ-
plied by the suptratrochlear artery, which does not have a ment, consultancies, honoraria, stock ownership or options,
strong collateral circulation. To avoid this complication, it is expert testimony, grants or patents received or pending, or
recommended not to inject this area or at least use a less-dense royalties.

Expert Opin. Drug Saf. (2014) 13(9) 1223

D. Kulichova et al.

Papers of special note have been highlighted as outcomes. J Cutan Aesthet Surg masked, randomized, within-subject
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() to readers. 13. Tezel A, Fredrickson GH. The science of 2007;33(Suppl 2):S128-35

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1226 Expert Opin. Drug Saf. (2014) 13(9)