Clinics in Dermatology (2008) 26, 160–176

Non–hyaluronic acid fillers

Daphne Thioly-Bensoussan, MD⁎
St. Louis University, Paris, France

Abstract Fillers are numerous, and the products currently available have effects that may last from a few
months to many years. These are used to treat facial wrinkles, and some of the new fillers exert a
stimulatory effect, restoring volume in focal areas of the face by inducing collagen fibers. The
dermasurgeon should thoroughly understand the indications and uses of these fillers to meet fully a
patient's expectations. Some fillers are biodegradable (12-18 months), others slowly biodegradable
(2-5 years), whereas others are permanent implants.The disadvantage of the traditional biodegradable
fillers is their short duration (6-12 months). Over the past decade, semipermanent fillers (polylactic acid
and ceramics) have been used: they do have a longer effect, but they might induce granulomas
especially on the lips. Also, permanent fillers are traditionally linked to a higher incidence of
granulomas and extrusions, although with the new formulations, the adverse events are decreased.
© 2008 Published by Elsevier Inc.

Introduction volume restorers, and stimulatory fillers and some mixed

fillers representing the new generation to offer more
In the 19th century, with the first use of grease aiming at thorough information to professionals.
filling defects, the search for useful materials concerned
biodegradable materials, such as collagen and hyaluronic
acid, as well as nonbiodegradable materials, such as silicone Choosing the appropriate filler and the
oil. Patients usually desire both a sure product and a durable appropriate technique
correction. Filling substances abound, and currently avail-
able products have effects that may last from a few months to
The choice of the filling substance to use is perhaps the
many years: today, there are a number of soft tissue
most important one once it has been decided that soft tissue
augmentation products to choose from, particularly in
augmentation is to take place. The injection technique is
Europe, each with its own strengths, drawbacks, and
different according to depth of the injection, the gauge needle
indications. These are classified as replacement fillers
used (from 26 G for thick implants to 30 G for the thinnest)
(collagens, hyaluronic acids) or stimulatory fillers (Radiesse,
and the defect to correct. The procedure is performed under
Atléan, Sculptra, and other mixed permanent implant), which
routine aseptic conditions while the patient is in a seated
restore volume and produce new collagen.
position. Before injection, the treatment area should be
This article is in no way a complete list of all the existing
swabbed with alcohol or another antiseptic substance.
fillers but rather aims to discuss the topics of new collagens,
Because lidocaine is present in the most commonly used
⁎ 15, rue Chateaubriand, 75008 Paris, France. Tel.: +33 1 53 75 12 00; collagen-containing dermal fillers, patients tolerate the
fax: +33 1 53 75 15 00. injection without block anesthesia (except for the lips),
E-mail address: drdaphnetb@free.fr. whereas other implants need topical or block anesthesia.

0738-081X/$ – see front matter © 2008 Published by Elsevier Inc.

doi:10.1016/j.clindermatol.2007.09.017
Non–hyaluronic acid fillers 161

As with any injection, patients using substances that Achyal (Filorga) 1% 1 kD

may reduce coagulation, such as aspirin and nonsteroidal Juvelift (Leaderm) 1%
Non-cross-linked 2,5 kDhyaluronic acid (for mesolift)
or native
anti-inflammatory drugs, may experience increased bruis- IalAchyal
System(Filorga)
(Phytogene) 1% 11,8%
kD 1 kD
ing or bleeding at the injection site. Be aware of Hyaluderm (LCA) 2%
Juvelift (Leaderm) 1%2,2,5
4 kDkD
Restylane Vital ⁎(Q Med)1,8% 2% 1 kD
bruising when using vitamin C, ω-3 and ω-6, and Ial System (Phytogene)
Teosyal meso(LCA)
Hyaluderm (Teoxane)2% 2,1,5%
4 kD 1 kD
Ginkgo biloba. The safety of fillers in pregnant and
lactating women has not been yet established. Ultimately,
Surgilift
Restylane Vital ⁎(Q
(Corneal) 1,35%
Med) 2, 2%
5 kD
Elastence (Inamed)
Teosyal meso 3% 0,91,5%
(Teoxane) kD 1 kD
the patient is the paramount consideration, and we are Mesolis
Surgilift (Corneal) 1,35% 2, 5(Antheis)
1,4%, Mesolis+ 1,8% kD 1 kD
responsible for what we do and what we inject to obtain R-fine, 1%, (centrale
Elastence (Inamed) 3% 0,9 kDdes peelings) 2 kD
the best results. Polyvinylic
Mesolis 1,4%, Alcool Mesolis+ 1,8% (Antheis) 1 kD
Bioinblue
R-fine, 1%, lips,(centrale
DeepBlue des(Polymekon)
peelings) 2 kD
Slowly biodegradable
Polyvinylic Alcool fillers (used in volumetric augmentation
Classification of fillers of face and folds)
Bioinblue lips, DeepBlue (Polymekon)
Polylactic acid
Slowly biodegradable fillers (used in volumetric augmentation
New-Fill
of face -Sculptra
and folds)(Sanofi-Aventis), FDA approval
A very confusing array of biodegradable, slowly degrad- August ’04acid
Polylactic
able, and permanent fillers are available: it is important to Hydroxy apatite gel (Sanofi-Aventis), FDA approval
New-Fill -Sculptra
understand which are replacement fillers (wrinkles) and Radiesse
August(Bioform)
’04
which are stimulatory fillers (volume restoration by inducing Phosphate
Hydroxy tricalcique
apatite gel gel
collagen production) those being either slowly biodegradable Atlean (ABR
Radiesse (Bioform)-development)
or permanent. Nonbiodegradable
Phosphate tricalcique implants
gel
Polymethylmetacrylate:
Atlean (ABR -development) (+ collagèn)
Artecoll, Artefill (Artes
Nonbiodegradable implantsInc.)
Acrylic hydrogel: (+ hyaluronic
Polymethylmetacrylate: (+ collagèn) acid)
Collagens
Collagens Dermalive, Dermadeep
Artecoll, Artefill (Artes(Dermatech)
Inc.)
Bovine collagen
Bovine collagen Silicones
Acrylic hydrogel: (+ hyaluronic acid)
Zyderm 1 and 2
Zyderm 1 and 2 Bioplastique
Dermalive, (Uroplasty)
Dermadeep (Dermatech)
Zyplast
Zyplast (Allergan) Silikon
Silicones 1000 (Alcon)
Résoplast
Résoplast (Allergan) SilSkin (Richards–James,
Bioplastique (Uroplasty) Inc.)
Human collagen
Human collagen AdatoSil
Silikon 5000
1000 (Bausch
(Alcon) and Lomb)
Cosmoderm and Cosmoplast (Allergan)
Cosmoderm Polyacrylamide gel
Fascian (Fasciaand Cosmoplast (Allergan)
Biosystems) SilSkin (Richards–James, Inc.)
Fascian (Fascia Biosystems) Outline,
AdatoSil Evolution (Procytech)
5000 (Bausch and Lomb)
Cymectra (US)
Cymectra Aquamid (Contura gelInternational A/S)
Porc collagen(US) Polyacrylamide
Porc collagen Amazingel (Fuhua High
Outline, Evolution Molecular Matter Company, Ltd.)
(Procytech)
Evolence (Colbar LifeScience, Ltd.)
Evolence (Colbar LifeScience, Ltd.) Alkylamides
Aquamid (Contura International A/S)
Autologue
Autologue Bio-alcamid,
Amazingel (Fuhua face, lips,
Highbody (Polymekon)
Molecular Matter Company, Ltd.)
Auto-collagène Isolagen (Isolagen)
Auto-collagène Isolagen type
(Isolagen) Zirconium
Alkylamides beads: Embosphere, Durasphere (Coloplast Corp.)
Synthetic human collagen 111 (Fibrogen Inc.)
Synthetic
Hyaluronic acid human collagen type 111 (Fibrogen Inc.) Bio-alcamid, face, lips, body (Polymekon)
Hyaluronic acid
Animal Zirconium beads: Embosphere, Durasphere (Coloplast Corp.)
Animal
Hylaform
HylaformPlus (Inamed)
Hylaform Adverse reactions can be evaluated in terms of:
MacHylaform
DermolPlus (Inamed) Orgev)
(Laboratories
Mac Dermol (Laboratories Orgev) ▪ Clinical seriousness
Touchline
Touchline ▪ Esthetic relevance
Nonanimal hyaluronic acid (bacterial fermentation)
Nonanimal hyaluronic
Restylane, Restilane acid Perlane,
touch, (bacterialRestilane
fermentation)
sub-Q ▪ Immediate vs delayed onset
Restylane,
(Q-Med AB) Restilane touch, Perlane, Restilane sub-Q ▪ Causality:
(Q-Med
Juvederm 18,AB) 24 and 30 (HV 24 and 30) (Allergan) ○ Expected procedure-related events
Hydrafill 1 218,
Juvederm 3, 24 and 30and
Softline (HV 24 andmax
Softline 30) (Allergan)
(Allergan) ○ Events related to improper technique
Hydrafill 1 2 3, Softline and Softline max
Surgiderm 18, 24 and 30 (24 and 30 HV) (Allergan) (Allergan) ○ Reactions to the product
Surgiderm
Matridur, 18, 24 Matridex
Matrigel, and 30 (24(with
and dextran)
30 HV) (Allergan)
(Biopolymer
Matridur,
GmbH&Co.KG) Matrigel, Matridex (with dextran) (Biopolymer
GmbH&Co.KG)
Esthelis Soft, Basic, Fortelis extra (Anteis SA) Collagens
Esthelis Soft, Basic, Fortelis extra (Anteis SA)
Teosyal (Teoxane)
Teosyal (Teoxane)
Puragen , Puragen +, Prevelle , Prevelle + with Lidocaine Traditional fillers (bovine collagen and hyaluronic acid) are
PuragenCorporation-Genzyme
(Mentor , Puragen +, PrevelleCorporation)
, Prevelle + with Lidocaine biodegradable. Although these fillers can lead to hypersensi-
Hyaluderm (LCA Pharmaceutical) Corporation)
(Mentor Corporation-Genzyme
tivity reactions, they have proven to be safe; their disadvantage
Hyaluderm
Hyaluronic acid(LCA
with Pharmaceutical)
dextran is their short duration (but cross-linking of hyaluronic acid has
Hyaluronicbeautysphere
Matridex, acid with dextran
Matridex, beautysphere improved its duration). Human collagen has recently been
Non-cross-linked or native hyaluronic acid (for mesolift) introduced: it does not require any skin test and has the same
162
longevity as bovine collagen. Other types of collagen derive
from corpses or from pig tendon or from fibroblast culture (the
last one is very expensive and not very well distributed). These
fillers can be used in several sites because of ease of injection of
these fillers and their malleability. Bovine-derived collagens,
including Zyderm and Zyplast, are less used because of the
need of double testing and the risk of allergic reactions. In
general, human-derived collagen implants are safer and present
lower risk of adverse effects but cannot demonstrate increased
duration when compared to bovine collagens.
Cosmoderm and Cosmoplast
Type 1 collagen loss in the dermis is one of the primary
causes of the wrinkles observed in aged skin. Dermal fillers
using type 1 collagen derived from bioengineered skin are
now being used to treat facial wrinkles, alone or in
combination with hyaluronic acid fillers. The benefit of
collagen-based dermal fillers is reduced downtime, reduced
bruising, small pain during injection, and ability to return lost
structural components to aged skin.
Context and structure
Replacement fillers include Cosmoderm I and II, and
Cosmoplast. Approved by the Food and Drug Administra-
tion (FDA) in 2003, these contain type III and I collagen.
Cosmoderm I contains 35 mg/mL of human-based collagen
dispersed in a phosphate saline solution and 0.3% of
lidocaine. Cosmoderm II contains twice as much collagen
as Cosmoderm I. With Zyplast and Zyderm, these must be
kept in the refrigerator. Cosmoplast has the same ingredients
as Cosmoderm I but is cross-linked with glutaraldehyde,
making it more resistant to degradation and allowing the
implant to be placed deeper. No skin test is required for any
of the human collagen products, and adverse reactions are
limited to bruising, erythema, and swelling.
Indications
Cosmoderm is an excellent choice for superficial defects
but also for areas where the deeper dermal injection could
cause complications, such as the glabellar area. It is also an
excellent choice for the perioral rhytids, which may be
superficial. In this case, the vermillion border is filled with
Cosmoplast (which has a slightly stiffer consistency) and at
the same time may elevate the corner of the mouth.
Cosmoplast (like Zyplast) is used for slightly deeper defects
and is placed from mid to deep dermis. Injections should be
performed with a 30-G needle at a 45° angle with the skin.
The filler should be placed medially to the wrinkle and can
be injected with either the serial puncture technique or the
linear threading technique. Cosmoplast has been a major
component of lip enhancement in our practice.
Duration of action
The cosmetic effects of Cosmoderm and Cosmoplast are
immediate and last 4 to 7 months, depending on the area of
D. Thioly-Bensoussan
treatment, injection technique, and amount of product
injected. It is believed that the collagen in the product
contains platelet-aggregating effects that may decrease the
risk of bruising; in addition, because these contain lidocaine,
the risk of swelling and bruising is further reduced by
inhibition of eosinophils' action.
Injection techniques
These agents are injected into the papillary dermis using a
serial puncture technique or a linear withdrawal technique. A
slight temporary blanching of the skin is noted at the injection
sites and demonstrates accurate placement of the implant in the
papillary dermis. Compared to Zyderm, where overcorrection is
important, overcorrection with Cosmoderm should be mini-
mal. Massage on the areas of injection may be performed.
Contraindications
Hypersensitivity to these products and allergy to lidocaine
are some risks in using these fillers.
Cymetra
Available since 2000, it is the injectable form of
Alloderm, (an acellular dermal matrix derived from donated
human skin tissue; the freeze-drying process eliminates the
cellular component of human skin, leaving collagen, laminin,
elastin, and proteoglycans), containing micronized human-
derived collagen. The product is supplied as a powder and
needs to be rehydrated and mixed with lidocaine. The mixing
process needs to be carried out properly and takes about
10 minutes. Cymetra has been used for soft tissue
augmentation and has shown to have more durability than
Zyderm in lip augmentation. Alloderm and Cymetra are both
provided by the American Association of Tissue Banks after
appropriate screenings for infectious agents and teratogeni-
city. These products are contraindicated in patients with
ongoing infection in the treated site, allergy to gentamicin,
and collagen vascular disease.
Evolence
The major disadvantage of other collagen-based fillers is
their limited durability; maintenance of results requires
repeated injections, usually 2 to 3 times a year. Evolence
has taken the established safety profile of collagen and has
set a new standard in biodegradable facial filler technology,
using a novel cross-linking procedure (Glymatrix technology,
Fig. 1) to overcome the limitation of collagen's rapid biode-
gradability, with effects lasting at least 12 months.
Context
This technology is based on ribose-induced cross-linking
of collagen that mimics the natural cross-linking pathway of
collagen in the body, known as glycation. Evolence collagen
can mimic the properties of the natural collagen found in the
skin. Unlike most other cross-linking techniques, the
Non–hyaluronic acid fillers
Fig. 1 Glymatrix technology.
Glymatrix technology does not require the use of potentially
toxic chemicals such as glutaraldehyde and obtains cross-
linked collagen with a long-lasting effect that closely
resembles that of natural collagen of the skin.
Structure
The highly purified collagen used in the manufacture of
Evolence is derived from porcine tendons. Because of their
high degree of immunocompatibility, porcine collagen
materials are favored for use in human medicine. The
evidence for the safety and efficacy of Evolence comes from
a randomized, blinded-assessor, clinical trial that compared
Evolence 30 (a formulation of Evolence at 30 mg/mL used
only in the initial clinical trial) with Zyplast for the reduction
of nasolabial folds over 15 months.
Pretest
Therefore, although an allergic reaction is theoretically
possible, it is extremely rare. Pretesting is not a prerequisite
for treatment with Evolence. Patients with a history of
hypersensitivity and allergy to collagen should be tested.
Technique and indications
To ensure uniform correction, a linear or threading
injection technique and a longitudinal compartment are
created beneath the fold, using a technique called “tunnel-
ing,” into which it is injected. No overcorrection is needed. It
is recommended to limit the use of Evolence collagen
implant to 10 mL in individual patients over a 1-year period.
Evolence is intended for correction of:
• Wrinkles;
• Nasolabial folds;
• Scars;
163
• Atrophy from disease or trauma;
• Defects secondary to rhinoplasty, skin graft, or other
surgically induced irregularities;
• Other soft tissue defects or deficiencies.
Contraindications
This implant is not recommended for use in the periorbital
area, and caution is advised when using Evolence in the lips.
A new “Evolence Breeze” is much more suitable for the lips
(perioral rhytids and vermillion border).
Evolence is contraindicated in the following cases:
• Patients with known hypersensitivity to collagen products;
• Patients with a history of anaphylactic reactions or
serious recurrent allergic reactions;
• Patients undergoing or planning to undergo desensiti-
zation injections to porcine meat products because
these injections can contain porcine collagen.
In patients on immunosuppressive therapy or those with
known connective tissue diseases, it is advisable to choose
another implant.
Side effects
No treatment-related adverse events were reported,
except for transient erythema that was observed after
the injection.
Autologen
It is an autologous collagen suspension, made with a
patient's own tissue, containing 3.5% collagen. The process
takes 6 to 8 weeks and includes harvesting skin from the
patient, usually from abdominoplasty or mammoplasty,
164
which is then sent to a laboratory for culture and processing.
About 2 in of donor skin is needed to produce 1 mL of
Autologen. The advantage of this type of autologous
injectable is that there is no risk of hypersensitivity to the
product, and the correction may last up to 18 months—
considerably longer than other collagens. The disadvantage
includes the delay of harvesting and processing the skin, as
well as the need for a relatively large skin specimen and the
cost of the culture and processing. Autologen can be used for
lip augmentation in addition to scars and furrows. It is no
longer available in the United States.
Isolagen
It is composed of cultured autologous fibroblasts. A
3-mm punch biopsy is obtained from the patient and sent to
the laboratory as a frozen specimen. In about 6 weeks, the
living cultured fibroblasts with their extracellular matrix are
sent back to the physician for the treatment.
Injections should be performed within 24 hours after
receiving the product. There is a minimal risk of hypersensi-
tivity and, therefore, a 2-week pretreatment skin test is
required before injection. It should be noted that the fibroblast
culture may be cryostored and used for additional injections.
Disadvantages of this product are cost, processing time, and
painful injections. Also, because fibroblasts require time to
produce collagen, immediate correction is not observed with
this product, which can be a problem with certain patients.
The duration of the correction is less than 18 months.
Stimulatory fillers (slowly biodegradable)
Radiesse
Context
Radiesse consists of a product made of calcium hydro-
xyapatite (ceramics) approved in the United States for use in
laryngoplasty and craniofacial defects. Its use for soft tissue
augmentation was an off-label indication, and the FDA
approved it in December 2006. The product has gained
popularity among certain esthetic surgeons because it can be
used as a long-term filling product. Calcium hydroxyapatite
is the matrix material found both in bones and in tissue. This
bioengineered product serves as a scaffold for native cells,
particularly osteoblasts and fibroblasts, to form a long-term
soft tissue correction.
Structure
Radiesse consists of 2 components: a gel carrier and a
matrix particle aqueous gel containing glycerin, sodium
carboxymethyl cellulose, and water. Not only are the
components nonallergenic and nontoxic, but also the calcium
hydroxyapatite is inert. Preliminary skin tests before using
the product are not necessary. According to the FDA, all
D. Thioly-Bensoussan
components used are classified as “generally recognized as
safe.” Each bioceramic sphere of hydroxyapatite ranges
between 25 and 45 μm in size. During the manufacturing
process, the spheres are washed free of any dust particle as
well as the presence of nonuniform spheres. The molecular
calcium hydroxyapatite is identical to the skeleton of the
human bone, and this material has a history of biocompat-
ibility for use in maxillofacial surgery and urology.
Migration risk is minimized as the structure allows for
native tissue regrowth once the carrier gel is absorbed.
Mechanism of action
Once injected in the subcutaneous space, the gel is
absorbed. What remains is a matrix of the material, which
will take the characteristics of the cells that populate it. As
the cells of the surrounding tissue develop in the scaffold of
the biologic matrix, they produce their respective materials.
When it is injected in the subperiosteal space, the material
stimulates bone production. When injected into tissue
spaces, fibroblasts produce collagen. This property, consist-
ing of adapting the characteristics of the adjacent tissue,
requires a precise placement of this product to allow
permanent correction. Because the produced collagen is
native and the injected material is inert, the formed filler
has the potential to be stable and permanent.
Selection of patients
Selection of patients is extremely important when
injecting Radiesse. Previous surgery or trauma on the areas
to be treated, as well as former silicone or permanent filler
injections, constitute relative contraindications. The most
important criterion of selection concerns the patient himself
or herself who must have realistic expectations and under-
stand the limits of the procedures. Patients who are likely to
feel unhappy if they can palpate the implant are bad
candidates for this intervention.
Indications
Physicians with experience with various fillers, includ-
ing collagen hyaluronanes and fat, should use Radiesse.
Aside from allergy, which is rare, there are no contra-
indications. Radiesse has several specific indications. These
include acne scars, nasolabial fold, marionette lines, and
glabellar lines; other less common areas include cheeks and
chin augmentation.
Technique
I believe Radiesse should be considered not a filler but a
remodeling agent or a volume enhancement product such as
Sculptra or fat. The material is provided in sterile 1-mL
syringes and is a milky white suspension. Because of its
viscosity, Radiesse should be injected with a 25- or 26-G
needle to obtain a regular flow with low resistance. Another
possibility consists of using an RJ MaxFlow needle. Before
the injection, a thick layer of topical anesthetic under plastic
film must be applied to the site. The technique for
Non–hyaluronic acid fillers
administering Radiesse is subdermal injection, most com-
monly at the junction of deep dermis and subcutaneous tissue.
If injected into mid or superficial dermis (particularly with
patients with clear or thin skin), placement will result in
visible material. While withdrawing the syringe, fine threads
of material are deposited uniformly along the surface. Each
injection must contain approximately 0.05 mL of material.
Radiesse provides excellent results in the nasolabial folds.
The typical quantities used for a moderately deep nasolabial
crease are about 0.5 to 1 mL. Deeper wrinkles obviously
require more material. The retrotracing linear technique can
also be used with Radiesse, although it is technically more
difficult because of the importance of precision during the
injection of this material. Repeated treatment sessions must
be planned for moderate or deep wrinkles, each approxi-
mately 6 weeks apart.
Isolated marionette lines constitute areas that also
respond well. The material is deposited using the serial
puncture technique, with an approximate deposit of 0.5 mL.
When injecting the marionette lines, it is important to
support the corners of the mouth. A small amount of material
(0.05 mL) may be placed in the lateral aspect of the lower lip
to help support the area. The total quantity of material
necessary is approximately 0.5 mL per side. A second
treatment session (approximately 6 weeks later) may be used
to obtain optimal results.
Radiesse must be used with the greatest precaution for the
increase and the correction of the upper and lower lip.
Indeed, the constant movement of the mouth tends to cause
migration of the filler. Other possible problems include
clusters and bumps likely to occur rather frequently in this
zone. Moreover, a superficial injection causes visible bumps,
whereas there is a risk of reaching the orbicular muscle with
an extremely deep injection. In the 88 patients of the Tskicas
fold study, 36% of minimal nodules were found and 8%
moderate nodularity within 6 months.1 In my personal
experience, the benefits-risk ratio means Radiesse should not
be injected in the lips.
Chin furrows and atrophic chins are good candidates for
treatment with Radiesse, with the help of a local anesthetic.
The serial puncture technique should be used, each puncture
depositing approximately 0.1 mL of material. To treat a
furrow in a moderately deep chin, approximately 0.3 to
0.5 mL of materials is used. The treatment of an atrophic chin
is likely to require from 0.5 to 1 mL of material. For chin
augmentation, the material is initially injected and then
gently molded with the fingers to give a symmetrical form to
the chin.
One of the techniques that offers good results within
the framework of a joint use with Radiesse in the
treatment of the chin consists of injecting 2 to 3 U of BX
botulinum toxin in the muscle of the bunch of the chin.
This additional injection minimizes the risks of migration
of material.
In the glabellar rhytids, very small quantities of material
(0.05 mL) should be deposited by puncture, without
165
overcorrection. It might be an adjunctive treatment to
Botox. The quantity of material used for the glabellar area
is approximately 0.25 mL for moderate wrinkles.
I believe there are other biodegradable implants that offer
fewer risks for the glabellar area and give excellent results
when associated with Botox.
Duration of the effect
Radiesse is considered a longer-lasting agent than
collagen and hyaluronic acid, with correction duration of
up to 2 years because of the CaHA microspheres that slowly
degrade into Ca 2+ and PO 3− ions via normal tissue
metabolism. The advantages of Radiesse as a filling
substance are its longevity, nonimmunogenicity, injectabil-
ity, and long shelf life without the need for reconstitution or
refrigeration. Radiesse may not be optimal filler for certain
areas, lip mucosa, and tear troughs/nasojugal groove2
because no product is appropriate for treating all areas.
There are no data available suggesting that this material is
permanent. During an evaluation of the effectiveness of
Radiesse on the nasolabial fold over 6 months, results of
the study suggested that there always remains a significant
obliteration of the SNG but that patients might need
another treatment between 6 and 9 months later to preserve
the effect obtained.2,3
Complications
In all areas, bruises and swelling are common; a light
erythema along the injection site may be resolved
spontaneously from 48 to 72 hours. The most disconcerting
complications for the patients are the persistence of palpable
areas in the skin and the formation of nodules. Formation of
nodules, which is light and limited to the injection points,
occurs at approximately one third of the patients submitted
to the injections. Nearly 10% of the nodules will require
intralesional steroids or incision and drainage, using a no.
11 needle.2 No reports of embolism or arterial occlusion are
actually available with this application, but these undesir-
able effects are foreseeable given the characteristics of
the implant.
Atléan
Context
Atléan βTCP is a new resorbable tricalcic (ceramics)
facial implant with long-lasting correction for the aging face.
This new filling implant for wrinkles that has been patented
by the European Office of Patents has obtained its CE mark
in July 2006.
The acceptability, tolerance, and performances of the gel
have been tested with multicenter clinical trials under the
HURIET law, in accordance with EN 540 standards.
Structure
Atléan βTCP contains βTCP and hyaluronic acid: the
βTCP is in the shape of microparticles with an average
166
diameter of 40 μm suspended in a hyaluronic acid gel. This is
a synthetic material whose basic elements are phosphate ions
and calcium. The atomic relationship determines the stability
of the crystalline structures and provides the molecules with
very different absorption kinetics. Because of this character-
istic, βTCP is known for being rapidly and totally resorbable.
The molecular weight of the sodium hyaluronate used is
between 2 and 3 million daltons. It is produced by bacterial
fermentation and, hence, without animal proteins. It plays
2 roles: as a vector for the βTCP particles and as an
immediate filling effector by mechanical action.
Description
The finished product is presented in a ready-to-inject
syringe of 1 mL, as a white odorless gel.
Atléan βTCP has a high stability throughout time and an
optimal syringability with fine gauge needles (26-27 G).
Mechanism of action
The mechanism of action of this product is mechanical
(through the volume of injection) and, on the other hand,
active by tissue regeneration (stimulation of the production
of endogen collagen).
Clinical studies
The evaluation of the acceptability, innocuousness, and
the intrinsic performances of Atléan have been carried out
by a phase II test, with a direct individual benefit, on
patients of both sexes, in accordance with Good Clinical
Practices and the Helsinki declaration. The protocol was
proofread and received before authorization from the
committee of protection of human individuals as well as
from the French Sanitary Security Agency for Health
Products. The results of this study, conducted with the
objective profilometric method, indicates that the micro-
spheres of βTCP, in suspension and applied by means of
intradermal injections, are well accepted by patients. The
level of efficiency in reducing deep wrinkles has been
significantly demonstrated and proved to be hopeful. No
adverse reaction has been observed. The whole file has
obtained the CE mark from the French notifying body in
July 2006.
Indications
Nasolabial folds and marionettes lines are local actions;
global actions are the modeling and the sculpting of the
face (cheek, chin line, cheek bone, etc). Because Atléan
contains particles, it is necessary to avoid the lips and the
fine lines.
Technique
Atléan βT is provided in sterile 1-mL syringes; it
should be injected with a 26- or 27-G needle. For the
sculpting, a possibility consists of using 27 G, 42 mm
to minimize the introduction of the needle (close to
Coleman's technique).
D. Thioly-Bensoussan
The product should be injected in the deep dermis where
the fibroblasts are numerous. For the treatment of the
cheekbone, the injection has to be at the junction of the bone.
Each injection must contain 0.05 to 0.1 mL of material. The
typical quantity used for a moderately deep nasolabial crease
is about 0.5 to 1 mL; deeper wrinkles obviously require
more material.
The retrotracing linear technique as well as the serial punc-
ture technique may be used, depending on the indications.
Duration of the effect
The treatment and duration may vary depending on
individual factors (age, type of skin, lifestyle) with persis-
tence of 12 to 18 months. After administration or implanta-
tion, βTCP undergoes phagocytosis by the macrophages of
the body and is progressively degraded into phosphate and
calcium ions by chemical hydrolysis (hydration by water).
The half-life of βTCP is related with the size of the particles
and the porosity; the complete degradation of the product is
estimated around 10 months. This degradation is totally
“absorbed” within a year, thus minimizing the risk of specific
inflammatory reaction such as granulomas.
Side effects
Very limited bruises and swelling appear after injec-
tion; some rare erythemas along the injection site may
appear, with a total spontaneously resorption from 48 to
72 hours.
Polylactic acid
Introduction
Polymerised lactic acid (PLLA), marketed with the trade
names of NewFill (Sculptra) in Europe and Sculptra in the
United States, was introduced for the first time in Europe for
the treatment of AIDS-related face lipoatrophy. The
experience gained during the last 2 years confirmed the
value of this product as a dermal stimulator for the correction
of facial fat loss in subjects not infected by the HIV and
therefore places itself as a volume restorer or enhancer.
It is probably preferable not to refer to this product as a
simple dermal filling product, insofar as the data not
published show that this agent stimulates increased collagen
regeneration. The regeneration mechanism probably implies
fibroblast activity stimulation.
Structure
NewFill is a poly-L-lactic polymerized acid in the form of
a freeze-dried powder. It presents a great similarity with
stitching threads (Vicryl). The powder material is recon-
stituted with sterile water in a suspension, and after 24 hours
it is ready to be injected.
Treatment technique
During the last 2 years, Lowe4 carried out an experiment
with more than 130 patients in London (UK). He
Non–hyaluronic acid fillers
successfully treated wrinkles, atrophic scars, nasolabial
folds, cheek hollowing (when there is fat atrophy due to
age or an atrophy of pathologic fat such as an atrophy of
posttraumatic fat), malar areas, and zygomatic arcade. The
use of PLLA in the lips has a high risk of nodules due to
the action of the orbicular muscle of the lips, which causes
the material to move and binds it in bumps during the
normal activities of the mouth.
In my opinion, it should be avoided in the lips, neck, and
face wrinkles; the periorbital area may be injected with
caution and a “light” hand.
Dilution technique
The dilution currently used implies the dilution of each
vial (containing 350 μg of PLLA) in 5 mL of sterile water.
The product then gradually takes the shape of a suspension
that must remain at room temperature for at least 24 hours
before the injection. Immediately before the injection,
1 additional milliliter of Xylocaine (lidocaine) (Astra-
Zeneca, Rueil-Malmaison, France) is added to this suspen-
sion, for a total dilution of 6 mL per vial. When hand
injections are needed, the dilution is 8 to 10 mL serum +
1 mL lidocaine. The suspension is vigorously shaken and
taken in a 1 mL Luer-Lock syringe with an 18-G needle.
The PLLA suspension is injected using a 26-G needle. The
syringes should be shaken and turned over before the
injection to ensure a suspension as uniform as possible.
Technique of injection
The injection is performed in the subreticular dermis.
The idea consists in depositing a smooth layer of
polymerized lactic acid, which stimulates the fibroblasts
of the dermis to produce skin conjunctive tissue, including
collagen. In general, the best technique is the retrograde
injection: the needle is placed at the dermis-hypodermis
junction, and then the plunger is withdrawn to minimize the
risk of an intravascular injection. Several injections using
0.01 to 0.02 mL of suspension are then injected into
various areas. It is essential not to overcorrect because the
injection is followed by a delayed fibroblastic reaction. If
excessive volume has been administered, this reaction
could result in an overcorrection. Moreover, overcorrection
increases the risk of a delayed formation of bumps. If
bumps are noticed after the injection of PLLA, the
concerned areas should be massaged carefully throughout
the following week.
Possible problems
Early problems include the risks of bruises and initial
swelling. If a patient presents a history of possible sensitivity
to lidocaine, dilution should then be 5 mL of water without
Xylocaine to avoid the risk of an allergic reaction.
Problems noticed with PLLA include the appearance of
reactive nodules that have mainly disappeared since the use
of higher dilutions, as provided above (viz, a dilution in 5 or
6 mL of volume). During the treatment of 132 patients,
167
Cohen and Holmes 5 noticed only 5 transitory subcutaneous
nodules that dispersed in a few weeks.
An earlier technique, which used a dilution in 2 mL,
produced a much more viscous and less smooth suspension.
Certain patients injected with this viscous suspension
developed nodules.
Even with the new dilution, it is possible to find nodules
(when the amount injected in one area is too much or too
superficial). Most of them disappeared several weeks after
the treatment with the injection of intralesional steroids and
massage of the concerned areas.
Duration of the effect
Reports published in the European literature suggest
benefit duration of 2 to 4 years. According to the experiment
of Lowe,4 patients continue to present signs of improvement
2 years after PLLA injection.
It is mandatory to take detailed photographs of the face to
precisely evaluate the duration of the correction induced by
PLLA and, moreover, to carry on long-term studies
recording histopathologic analysis or ultrasound images.
Permanent fillers
Artecoll
Context
Artecoll is a permanent injectable soft tissue filler, a
“mixed implant,” made of polymethylmethacrylate (PMMA)
microspheres measuring from 30 to 42 μm of diameter,
suspended in a 3.5% partially denatured bovine collagen
solution. This product has been used in Europe since 1994
and in Canada since 1998, mainly for the treatment of face
wrinkles. It is currently on standby, awaiting the FDA's
authorization for use in the United States, under the
commercial name of Artefill.
The attraction of Artecoll/Artefill lies in their permanent
character. Unlike bovine collagen, which serves as vehicle
for PMMA beads and is degraded in 1 to 3 months, the
microspheres themselves consist in a synthetic non-reab-
sorbable material. These beads induce a foreign-body
reaction and become encapsulated in fibrous connective
tissue, producing a long-lasting augmentation.
Structure
Artecoll has a biphasic nature; it is composed of a solid
phase made up of PMMA microspheres suspended in a
collagen vehicle, representing the liquid phase in a 1:4 ratio.
The microspheres consist of PMMA (Plexiglas) used in bone
cement, dental prostheses, and rigid lenses. The collagen
component is a solution of bovine atelocollagen denatured to
3.5%; the absence of the immunogenic telopeptides adds a
less antigenic character to the collagen molecule. Artecoll
also contains hydrochlorate of lidocaine at 0.3%, making it
possible to reduce the pain. PMMA has appeared to be
168
biocompatible, nonallergenic, and chemically inert during its
use in the last 40 years in bone cement, such as in hip and
teeth implants. The collagen contained in Artecoll is also
known as biocompatible, although it is more likely to induce
an allergic reaction than PMMA. Because of the possibility
of an oversensitiveness reaction to collagen, skin tests are
necessary. An intradermal injection of the collagen of
Artecoll at least 4 weeks before the date planned for the
establishment should be done.
The round PMMA particles present in Artecoll have a
diameter ranging between 30 and 42 μm, with smooth and
polymerized surfaces. This size enables them to be
sufficiently large to avoid phagocytosis and small enough
to support optimal incapsulation by conjunctive tissue.
Because the irregularity of sphere shape is related to the
formation of granulomas, it is necessary to take care of well-
leveling surfaces and eliminate any trace from dust or load by
washing and complex filtering (ultrasound technology).
Artecoll is supplied in a 1.0-mL syringe filled with
approximately 0.5 mL of product and equipped with a
Luer-Lock. The syringe is also supplied with a 26 needle
(preferably) or 27 G, 0.5 in. It is also possible to use a 30-G
RJ Maxflow needle with an internal diameter similar to the
27-G needle. This needle is generally better tolerated by the
person receiving the injections but tends to get blocked from
time to time. Although the suspension of PMMA-freezing of
collagen is stable at room temperature, it must be preserved
in the refrigerator before use. With a good technique, the
material can be used in a satisfactory manner as soon as it is
out of the refrigerator.
Mechanism of action
Gradually, during 1 to 3 months after injection, the
component of 80% collagen contained in Artecoll is
degraded. During this time, PMMA spheres are not
biodegradable and too large to undergo phagocytosis by
macrophages and giant cells. Thus, they form a frame to
support the deposit of conjunctive tissue and end up being
encapsulated by fibroblasts and collagen. The fibrous
conjunctive tissue of the organization then replaces the
volume of the vehicle formed by collagen during the first
4 months. Nevertheless, to avoid overcorrection and to obtain
the desired results, 2 to 4 sessions of injections are generally
necessary, separated by an interval of at least 2 months.
Indications
Artecoll consists of a durable filling substance used in
indications as varied as face wrinkles and folds, acne scars,
contour increases, and defects of soft tissues of similar size to
the face and other areas. It is preferable to use it in areas
where the skin is thick so that the implant is neither visible
nor palpable.
Contraindications
People presenting with known allergy to collagen or
lidocaine, positive results to skin test, atrophic affections of
D. Thioly-Bensoussan
the skin, autoimmune diseases should not be injected with
this product.
Duration of action
The manufacturer describes the correction as being in the
“long term,” taking into consideration the continuous aging
process. At present, the longest duration is 10 years.
Selection of patients
The permanent nature of this implant justifies a careful
selection of patients. They should be in good health, and
pregnant women should be excluded. Previous reactions to
other injections, former surgical operations, or trauma in the
area to be injected constitute relative contraindications. Ideal
patients are those with wrinkles and well-defined folds, with
little excess skin. A good candidate must perfectly include/
understand the possibility of the permanence of an implant of
Artecoll and is often a patient with other temporary implants
and wishing a long-term increase. The patient must under-
stand the need of several injections to obtain the desired
correction, and that, more particularly during the first
6 months, the implant has to change before the final result is
apparent. Ideally, 2 to 4 injections with a 1-month interval
are necessary. It is essential to avoid too large quantities
of Artecoll during a single session to avoid the risk of
adverse events.
Technique
If a local block is desired, anesthesia or at least a topical
anesthetic can be applied 30 to 60 minutes before the
intervention. In general, Artecoll is injected only in the
subreticular dermis, in the limit of the subcutaneous fat layer,
using a needle of 26 G, 0.5 in. Before the injection, it is
necessary to check that the needle is not blocked while gently
pressing on the plunger to let out part of the product from the
extremity. The needle must be inserted horizontally under
the wrinkle and, while maintaining constant pressure on the
plunger and carrying out a continuous motion of the needle,
fill the tunnel while withdrawing the needle. As this product
is 3 times more viscous than collagen, Artecoll requires a
more constant and higher pressure throughout the injection.
If the filling product is injected too superficially, namely, in
the papillary dermis, an effect of undesirable bleaching is
observed. The outline of the needle, but not its silver color,
must always be visible under the skin. After the injection, the
implant must be massaged to eliminate possible bumps and
ensure equal distribution. The patient must avoid muscular
mimic movements during the first days after the injection. It
is possible to help immobility by applying adhesive plaster
on the site of the implant or by injecting botulinum toxin.
A first maximum injection of 0.5 mL of Artecoll is
generally enough to correct one of the following defects:
glabellar area, nasolabial folds, and the corners of the mouth.
Certain patients may wish more correction than what can be
safely obtained with Artecoll at the time of the first session.
In these cases, one may inject a biodegradable implant very
Non–hyaluronic acid fillers
superficially. When these substances are dissipated, volume
could be supplemented by additional injections of Artecoll.
In February 2003 the FDA classified the injection of
Artecoll in the lips as a contraindication because of reports of
nodules due to the movement of the lips. It is difficult to
prevent the migration and the aggregation of the filler. The
treatment, if lip granulomas do not disappear, consists in
carrying out a small incision on the surface of the lip to
extract the foreign-body granuloma. This complication
seems to be more due to the limits of the technique and the
product rather than to an immunologic response. In my
opinion, lip granulomas are difficult to treat and the use of
Artecoll in the lips should be avoided.
Complications
The total rate of complications of Artecoll used in the
wrinkles was estimated at 3% in 1994. Frequent acute
adverse effects include redness, swelling, and pain (2 days
after). Bruises are rare but can last up to 1 week, and
itching may appear during the first months. These effects
can be countered by using corticoid creams or injections.
Other technical adverse effects include unequal distribution,
an excessive amount of filling product, or accidental
displacement due to a marked expression of the face. The
first two can be corrected with the help of another injection
of Artecoll, whereas the last can be prevented by keeping
the site as motionless as possible using adhesive plaster for
approximately 3 days. Allergic reactions with the collagen
component present in Artecoll are rare (3 cases on more
than 4280 patients) but possible and are treated with
intralesional steroid injections. Small veins can appear on
thin skin, but they usually disappear in 6 months; if
resolution is incomplete, it is possible to treat them with
laser. Hypertrophic scarring due to excessive fibrous
conjunctive tissue reaction may be treated with intralesional
steroid injections. Lastly, the formation of granulomas,
although dreaded and being the object of great media
beating, is rare and occurs in less than 0.01% of patients.
No granuloma was reported among 251 patients of 8
centers distributed throughout the United States during the
course of clinical trials carried out to obtain FDA
authorization, although the follow-up was limited to 1
year.5 Granulomas generally appear from 6 to 24 months
after the treatment with Artecoll and are histologically
different from a foreign-body reaction because of the long
distance among macrophages filled with microspheres,
giant cells, fibroblasts, and broadband of collagen fibers.6,7
The treatment of choice is a series of intralesional corticoid
injections. Local steroids function by inhibiting the activity
of fibroblasts and macrophages, therefore preventing
collagen deposit and the formation of giant cells. Up to
20 mg of lidocaine and triamcinolone in a mixture of 1:1 or
5 mg of betamethasone can be injected using a 1-mL
syringe and a 30-G needle in the accused nodule. Two to
five injections with about 3-week intervals are likely to be
necessary. Excision is also part of the options to carry out
169
the ablation of the undesired nodules in the worst cases of
granulomas, hypertrophic scars, or displacement.
Dermalive/Dermadeep
Context
Dermalive and Dermadeep are mixed permanent soft
tissue implants composed of acrylic hydrogel in a hyaluronic
acid vehicle. In Dermadeep, the acrylic hydrogel particles are
larger for deeper injections, whereas in Dermalive, particles
are smaller because the product is injected less deeply. Since
1998, Dermalive and Dermadeep have been marketed in
France and Europe, mainly for long-term corrections of face
wrinkles and for the creation of volume. In the United States,
this product is presently not approved by the FDA for an
aesthetic use.
Although the body absorbs the vehicle made of hyaluronic
gel in 3 or 4 months, the nonbiodegradable acrylic hydrogel
component remains in place for more than 12 months.
Acrylic hydrogel and the foreign bodies' tissue reaction to the
implant are at the origin of its long-term effects.
Structure
Dermalive and Dermadeep consist of 2 phases: a liquid
vehicle and a solid phase for 60% and 40% of volumes,
respectively. Both components are of nonanimal origin and,
consequently, less likely to cause allergies. The liquid
vehicle consists of hyaluronic acid, produced by Strepto-
coccus equi in a bacterial fermentation and later purified for
its use. Hyaluronic acid is nonallergenic and is approved by
the FDA and used in the synovial liquid and in implants
intended for wrinkles. The solid phase of the implant, acrylic
hydrogel, is a copolymer of hydroxylethyl methacrylate and
ethyl methacrylate. Hydroxylethyl methacrylate and ethyl
methacrylate are largely used and well tolerated in other
medical applications such as intraocular lenses and burn
dressings. Acrylic hydrogel solids are polygonal, translucent,
and of intentionally irregular shape with smooth walls.
Dimensions of the particles range from 45 and 65 μm for
Dermalive and between 80 and 110 μm for Dermadeep, too
large for phagocytosis.
Dermalive are Dermadeep are supplied in single packa-
ging, in syringes prefilled with varying quantities: 0.8-mL
syringes with a 27.5-G needle for Dermalive and 1.2-mL
syringes with a 26.5-G needle for Dermadeep. Its viscous
consistency makes it easy to control and inject.
Mechanism of action
Dermalive and Dermadeep are permanent biphasic im-
plants. Mostly composed of hyaluronic acid vector, which
accounts for 60% of its volume, these are reabsorbed
during the first 3 months after the injection. The remaining
40% consist of non-reabsorbable acrylic hydrogel. Hydro-
gel particles are nonspherical in shape, preventing long-
range migrations and concentric fibrosis, and are smooth
walled, acting as a scaffold for collagen fibers to form a
170
loose network around the particles. It is precisely the laxity
of these fibers that generates natural results. In practice,
approximately 50% of the implant remains in place after
the reabsorption because of the neocollagen development
around the acrylic hydrogel particles. This fibrotic reaction
requires approximately 3 months, the recommended
interval between injections. Several injections of Dermalive
and Dermadeep are often necessary, with a maximum of
3 to 4 injections.
Indications
Dermalive and Dermadeep are semipermanent filling
substances preferably used in long-term corrections of
natural or acquired skin depressions due to aging or
trauma, or to create volume. Dermalive should be used
primarily to fill deep depressions such as the nasolabial
fold, the glabellar area, marionette lines, or face scars, and
to correct skin adherences after rhinoplasty. The use of
Dermadeep is only indicated in the reduction of marked
SNG and creation of volume in the cheeks, the sunken
malar eminence, and the chin.
Contraindications
The contraindications for Dermalive and Dermadeep are
of 2 types—the first related to the site of injection and the
second related to the patient. Contraindicated sites include
the mucous part of the lips, the periorbital zones, horizontal
lines on the forehead, and perioral wrinkles. Patients with
previous history of hypertrophic scar, autoimmune or
inflammatory diseases, multiple allergies, and (seldom)
known allergy to sodium hyaluronate or hyaluronic acid
should not be injected.
Duration of action
Dermalive and Dermadeep are considered semipermanent
implants; their effects should last at least 12 months. While
the hyaluronic acid component is reabsorbed, nonbiodegrad-
able acrylic hydrogel particles remain in place and induce a
tissue response to yield long-lasting results.
Selection of patients
Given the long-lasting effects of Dermalive and Derma-
deep, careful selection of patients is important. Patients
should be in good health, and pregnant or breast-feeding
women should not be accepted. In addition to the contra-
indications listed above, the dermatologist should verify
former injections of long-lasting implants such as silicone,
Artecoll, or Gore-Tex. Good candidates are patients present-
ing with obvious wrinkles with little laxity. Patients with thin
skin are not ideal because the risk of complications such as
overcorrection, bleaching at the site of treatment, and implant
visibility is increased in this population. Age is also a factor
to be considered because younger patients have more
tendencies to form scars. Also, the patient must be conscious
that it could be necessary to carry out more than one injection
of Dermalive and Dermadeep to obtain the desired effects of
D. Thioly-Bensoussan
increase and that the implant will change at least during the
first 3 months.
Technique
Dermalive and Dermadeep do not have any element of
animal origin and are generally nonallergenic; therefore, no
preliminary test is necessary. A topical anesthetic cream
may be applied before the injection. These are preferably
injected using the technique of retrotracing linear infiltra-
tion in the dermal-hypodermic junction. It is essential not
to inject too superficially and not to use the multipuncture
technique because it may cause an accumulation of the
implant in a site. On the contrary, Dermadeep must be
injected into the subcutaneous layer. Injecting Dermalive
and Dermadeep too deeply presents little risk of complica-
tion; in such a case, the main consequence is an
insufficient reduction of the wrinkles. Patients generally
require 2 to 3 injections 3 months apart to allow the
implant to stabilize.
Complications
In 2001, the total rate of complications for Dermalive and
Dermadeep was estimated at 1.2 per 1000 patients. Sixty-one
percent of these cases were estimated to be due to
inappropriate technique, excessively superficial injection,
and involved the presence of a contraindication (former
injections of silicon or Artecoll, use on multiallergic patients
or patients with auto-immune or inflammatory disease,
excessive filling, or insufficient interval between 2 injec-
tions). Short-term adverse effects are pain after the injection,
itching, discoloration, sensitivity to touch, palpable bumps,
redness, and edema. Delayed hypersensitivity with hyaluro-
nic acid, which appears from several weeks to months after
the injection, has been documented and should constitute a
contraindication for a subsequent use of this material. Long-
term side effects include nodules, swelling, and redness at the
point of injection that appear on average 6 months after the
injection. Serious complications such as granulomas are
estimated at less than 1 per 15,000 treatments. In my opinion,
these are underestimated, particularly in France, because not
all cases were reported. The remaining cases were generally
treated with intralesional betamethasone injections. As soon
as a nodule or another complication is detected, a series of
corticoid injections 1 to 3 weeks apart is generally effective.
However, it seems that the treatment of Dermalive
granuloma is much more difficult than the ones related to
Artefill. Surgical excision, carried out as a last resource, is
seldom necessary.
Bioplastique
Context
Bioplastique is a biphasic and permanent soft tissue
implant. It consists of solid silicone particles in suspension
in a polyvinylpyrrolidone gel. Since its development in
1987, the applications of Bioplastique in Europe and in
Non–hyaluronic acid fillers
other parts of the world have included soft tissue
augmentation of the face and other parts of the body, such
as the hands or the chest, as well as the treatment of urologic
affections, namely, effort incontinence. The use of Bioplas-
tique in the United States has not been approved by the
FDA. Its uses are rather varied, even for the category of
permanent filling products. The injection of Bioplastique
results in a low inflammatory reaction. This phenomenon,
associated to the nonbiodegradable nature of solid silicone,
produces permanent effects.
Structure
Bioplastique consists of permanent polymer particles
(silicone) in a polyvinylpyrrolidone gel carrier. The biocom-
patible gel vehicle of polyvinylpyrrolidone (CHNO) is a
water-soluble homopolymer with an average molecular
weight of 13,600 d. The solid phase of the implant, dimethyl
siloxane, or silicone, consists of a polymer similar to rubber
used in cardiac valves, vascular shunts, and prostheses of the
nose and the chin since 1960. It is a nonbiodegradable inert
substance. The silicone particles are spheroid and measure
from 100 to 600 μm (150 μm on average) to prevent
migration toward the lymphatic ganglia or other parts of the
body, as well as phagocytosis by macrophages directed
against foreign bodies. This size also means that surface
irregularities are too small to be perceived at palpation.
These polymer particles are manufactured with a textured
surface to lead to the development of tissue ingrowth,
which in turn prevents micromotion. Moreover, the use of
structured particles is considered to reduce rigidity and
contracture of scar tissue by improving the symmetry of
collagen formation around the particle. Bioplastique is
supplied in 1-mL syringes with 20-G, blunt-tipped needles,
including a 4-in cannula fixed at a high-pressure lever gun.
The blunt-tipped cannulas are specifically designed to draw
aside important structures such as nerves, arteries, and veins.
The injection gun delivers precise quantities of gel in a
reliable manner.
Mechanism of action
The permanent nature of Bioplastique is due to its
nondegradable silicone particles and to tissue response to the
implant. During the injection the gel behaves as a lubricant to
suspend the silicone particles equally, to preserve a certain
distance between them, and to prevent any movement after
the injection. Within about 4 days, most of the vehicle in the
gel is absorbed and replaced by fibrin in the first phase of the
subject's immune response. During this period, the foreign-
body reaction continues, this process being essential to the
durable effects of Bioplastique. Fibrin is used as an
intermediate spacer and matrix during the 3 to 4 weeks
needed for fibroblasts to form collagen and for collagen to
organize itself around the silicon. The textured surface of the
implant is conceived to stimulate the fibrous response and to
reinforce connections in the subject. In fact, the subject's
collagen replaces the vehicle in the gel in a volume slightly
171
higher than 1/1 and tends to develop over time, unlike other
temporary and permanent products fillers. It is always
essential to take care not to overcorrect the defect. It is better
to use Bioplastique in several sessions to avoid over-
correction. The minimal interval between 2 injections is
6 weeks, the greatest part of the fibrous reaction of tissue
being in theory concluded after this time.
Indications
Bioplastique is a permanent filler with multiple uses in
soft tissue augmentation. Indications for facial use includes
chin and cheeks, depressed scars, glabellar area, rhinoplasty
cases of saddle nose, and the repair of cleft lip and nose.
Bioplastique is not limited to applications on the face and can
also be used in cases of skull defects, lipoatrophy areas, and
lipoatrophy defects due to liposuction and pectus excavatum.
Bioplastique is contraindicated in patients with from kidney
disease, presenting hypertrophic scarring history, hemor-
rhagic disorders, autoimmune, or inflammatory diseases.
Duration of action
Bioplastique is a permanent implant. Its silicone particles
remain in place and generate a fibrous tissue reaction that
results in long-term effects. Consequently, it is essential to
carry out progressive increase and to avoid overcorrection
because the results are not as easy to correct as to prevent.
Selection of patients
Patients must be in good health, and pregnant or
lactating women must not be included. A patient presenting
a large volume defect would be better. Patients with thin
skin present a higher risk of complications such as
overcorrection, bleaching at the injection site, and seeing
or palpating the implant. Patients must expect to return once
or twice for additional injections of Bioplastique to obtain
the desired results.
Technique
The area to treat should firstly be delimited using a
surgical marker. A regional anesthesia for a nervous block is
suitable for a better anesthetic effect. Bioplastique must be
mainly placed in the subdermic level at the dermis-
hypodermis junction; it is important not to inject it too
superficially. The cannula is then inserted through the
puncture and passed back and forth along the previously
formed channels. The injection must be performed slowly in
a withdrawal manner. A 20-G-wide line of material must be
injected into each channel. The defect is rinsed using a local
anesthetic, and an elastic band is applied to the defect and the
puncture site.
Complications
During the Bioplastique study (6-year follow-up), Ersek8
observed that in 8 (5%) of 127 cases, the material had to be
removed, probably due to overcorrection. Infection was
suspected in 2 (1%) of 127 cases, although cultures were
172
negative. In all 8 cases, an excessive quantity of filler was too
superficial, particularly in the area of the lips. No incidence
of migration of particles or loss of substance was reported. At
least 3 cases of foreign-body granuloma caused by the
injection of Bioplastique were reported. These granulomas,
seen as nodules that appeared between several weeks and
several months after the initial session, were excised and
confirmed by histology. In case of complication, it is possible
to remove Bioplastique using sharp cannulas or biopsy
needles. Direct surgical excision is a last resource but never-
theless part of the possibilities.
Aquamid
Polyacrylamide gel represents a new generation of
soft tissue fillers: it is a biocompatible, non-reabsorb-
able hydrogel.
Structure
Aquamid is the result of a newly patented production
method called “in-line cross-linking technology.” Aquamid
gel contains 2.5% PAAG and a very high concentration of
water (97.5%). It is homogenous, perfectly stable and
nonbiodegradable, and has optimal viscosity and elasticity.
The high water contents allow a continuous water exchange
between the hydrogel and the surrounding tissue and
prevents biofilm formation, thereby reducing the risk of
long-term complications. Used in the former Soviet Union
for more than 15 years, Aquamid has been authorized in
Europe since March 2001 as a new medical device (CE mark
0543) with no guarantee that the product does not have side
effects. It was not launched as a drug (in France, an market
launching autorisation in Europe is needed, which is the
same procedure carried out for FDA approval after numerous
investigations on patients).
Injection technique
Because of infections reported as side effects, antisepsis
must be perfect and on a 5-cm radius from the injection site.
Aquamid (in a 1-mL syringe) must be injected subcuta-
neously, with a 27-G needle. Perform the injection using the
fine multiline retrograde technique. Correction is not needed
at the first injection: more sessions may be performed at a
15-day interval. The first pilot study was carried out on
50 patients in Sweden.9 The plasticity of PAAG is similar to
that of silicon, but PAAG is hydrophilic and has a high
capacity of exchanging water molecules with the surround-
ing tissue fluid. Lip augmentation was the most frequent
procedure (72%), in groups of ages from 20 to 25 years and
from 50 to 60 years; cheekbone enlargement was carried out
in 13% of the cases. The remainder concerned augmentation
of deep nasolabial folds, glabellar area, and chin, account-
ing for 5% of each. In this study, patient's satisfaction was
almost 100% in terms of esthetic results, and neither short-
time nor long-time side effects were reported during a
period of 2 to 16 months.
D. Thioly-Bensoussan
A multicentric study was carried out on 251 patients10
with a 12-month follow-up. Common sites of injection
were nasolabial folds (48%), lips (25%), glabellar folds
(8%), and other sites. The amount of injected gel ranged
from 0.2 to 12 mL. Two hundred twenty-eight patients
were followed up for 12 months after the treatment. In 93%
of them, the results were judged to be good or very good by
investigators, and satisfactory to very satisfactory by
patients. Adverse events, which could be ascribed to the
treatment, were observed in 37 cases, most commonly
transient bruises, swelling, redness, and pain or itching. In
one case, a slight change of skin color at the site of
injection was reported, but no severe events related to the
gel were observed. The transient local tissue reactions
observed were attributable to the injection procedure rather
than the chemical properties of the gel. Nevertheless, long-
term results need to be evaluated in the future because
granuloma in foreign bodies' reactions may take place after
more than 1 year.
Adverse events
The gel is well tolerated by human tissue for up to at least
9 years postoperatively, but adverse reactions of infectious
nature may occur within the first year after injection. Patients
must avoid touching the injection site for at least 6 hours and
using cosmetics on the site 24 hours after the injection. A
small risk of transient erythema or swelling may occur within
1 to 2 weeks after the treatment: if not caused by infection,
these are self-limited and disappear after 5 to 6 days.
Infection is the most common adverse event: microbiologic
and cytological examination should be performed with
cultures. It is advisable to initiate a strong broad-spectrum
antibiotic as early as possible, before culture results
(fluoroquinolone/ciprofloxacin) (500-700 mg BID and for
7 days after complete remission). The sooner the infection is
suspected and a high dose of broad-spectrum antibiotic is
prescribed, the faster the patient will recover. Negative
bacterial cultures rule out bacterial infection, and in this case,
steroids are contraindicated. Foreign-body reaction present
in cytological examination is a normal part of tissue reaction
to the implant and not an allergy indicator. One case reported
an inflammatory reaction after injection of polyacrylamide
for zygomatic facial augmentation.11 An inflammatory
reaction at the site of PAAG injection was noted at
1 month after the initial injection. Despite 2 broad-spectrum
antibiotics, the patient presented persistent draining nodules
that were treated with intralesional steroids, resulting in
prompt resolution and no recurrence. Histologically, PAAG
has been demonstrated to elicit a moderate foreign-body
response, but little or no resulting fibrosis. Gel migration has
not been reported, but PAAG has been found within some
site-related macrophages and giant cells. Inflammatory
nodules showed an increased foreign-body reaction and
bacterial infection. According to the literature, those nodules
occur no later than after 1 year. Inflammatory reactions have
been noted in patients receiving PAAG for breast
Non–hyaluronic acid fillers
augmentation. Very stony and indurated granulomas have
been described with Outline (another PAAG).
Bio-Alcamid
It is a non-reabsorbable polymeric material composed of
alkylimide-amide groups. This cosmetic agent has been used
for the treatment of numerous patients in a multicentric trial led
by different hospitals and universities in Italy. Very serious
defects such as pectus excavatum, Poland syndrome, post-
operative trauma, in addition to common esthetic results such
as lip, cheekbone, and chin hypovolumetry and relaxing of
nasolabial sulcus, have been treated with surgical implants of
Bio-Alcamid. Esthetics results were excellent: tissues felt soft
and the implants were uniformly distributed. No migration or
dislocation of the implants, granuloma, allergic response, or
intolerance of any kind were observed. Only 12 of 2000
patients had postoperative complications such as Staphylo-
coccus infections, and only 3 of 12 cases could be ascribed to
the implanted material. Serrano and Serrano,11 in Spain,
described a case of localized infection in one of the injection
sites, 3 months after implant placement in nasolabial furrows
and lips. Bio-Alcamid could be defined a sort of endoprosth-
esis, suitable for soft tissue augmentation and for the correction
of deficiencies in different tissues. In a recent study, Karim
et al12 from the Netherlands reported 18 cases of Bio-Alcamid
side effects. The onset of complications can be between
1 month to 3 years, presenting as excessive capsule formation,
dislocation, or migration of this implant and infection. Capsule
formation is induced by fibroblast reaction and is unpredict-
able: capsular contraction changes the shape of the polyalk-
ylimide into a sphere, feels unnaturally hard to the touch, and
may severely diminish the cosmetic effect. Large amounts of
material may be removed using a large gauge needle and
squeezed; smaller amounts cannot be squeezed and surgery
may be needed. Infection is a more serious complication
because infected foreign material can hardly ever be
clinically treated. Systemic or intralesional steroids and
antibiotics may temporarily relieve the symptoms but will not
cure them: the foreign material must be surgically removed to
treat the infection properly; healing by secondary intention is
sometimes needed. Given the potentially disfiguring therapy
needed to treat these complications, the authors warn against
its use for cosmetic wrinkles: it may be indicated for severe
reconstructions, such as filling a facial soft tissue deficit such
as facial lipodystrophy.
Injectable silicone
Introduction
Liquid injectable silicone (LIS) is a permanent filler used
for a great number of cutaneous and subcutaneous atrophies.
The term permanent is not to be taken literally. Although the
material remains permanently in the skin without undergoing
significant loss due to degradation, permanent results are
generally not possible in areas prone to additional losses of
173
volume due to mimic movements and gravity. When it is
correctly managed, patients can expect from it a permanent
correction of scars, a permanent increase in contours of lips
and face, and a long-lasting correction of wrinkles and
depressions. Moreover, it is also particularly advantageous
from a cost-benefit point of view. Liquid injectable silicone is
not the filler of choice for those who need immediate
correction because the increase takes place gradually over
several treatment sessions, distributed over 3 to 9 months.
The term silicone refers to synthetic polymers containers
of elementary silicon. These polymers do not represent a
single substance but a family of compounds with specific
chemical and physical properties, and these are varied in
terms of purity, sterility, and biocompatibility. Among the
large and very varied family of silicones, this article will
concentrate only on LIS, or polydimethylsiloxane. The term
centistokes (cSt), which refers to the viscosity of silicone oil,
is directly related to the length of the chain of repeated units
for dimethylsiloxane. Whereas a product of 1 cSt is
equivalent to water in terms of viscosity, products with
350 cSt have a consistency similar to that of mineral oils.
A certain number of reports establishing a link between
injectable silicone and its undesirable reactions generated
considerable negative publicity. On one side, physicians
affirm that purified silicone oil, if injected correctly, is sure
and effective, and that complications are the result of
injection of an impure substance or a bad injection technique.
They state that complications can be avoided by strictly
observing the following rules:
1. use only pure silicone of medical grade, designed for
injection in the human body;
2. inject volumes keeping 2-month intervals;
3. limit the technique of injection to the microdroplets
multipuncture technique (0.01 mL injected with
intervals from 2 to 4 mm subdermally).
Large volumes of silicone oil injected at the same time
tend to move along the tissue plans; sometimes a collagen
capsule is created around the microdroplets, which is used to
maintain the droplets firmly in place and therefore eliminat-
ing the possibility of a drift. The opponents of this opinion,
however, support that injectable silicone is, in itself,
unforeseeable, some of its undesirable events sometimes
appearing years after the injection and this in spite of the use
of suitable technique and substance.
The FDA clarified its position on injectable liquid
silicone: “the FDA has not authorized liquid silicone
injections intended for cosmetic purpose, including the
treatment of the defects and the wrinkles of the face.” In
1997, for the first time, the FDA let American physicians use
in all legality standardized silicone oils of exceptionally high
purity for soft tissue augmentation.
Expected benefits
One of the most remarkable qualities of LIS is its use as a
preventive treatment of wrinkles. It is possible to foresee an
174
improvement from 30% to 90%, according to the depth of the
original depression. The hands are also well adapted to
treatment with LIS, as well as the lips. The LIS injection is a
little less painful than the other fillers as it has a neutral pH.
However, the great number of necessary punctures might be
painful. A needle with a diameter of 30 G is used.
Application of contact anesthetic may help. The costs of
SLI are markedly lower than that of all other fillers.
Selection of patients
The indications of the LIS include face folds and
depressions such as nasolabial folds, marionette lines, facial
contour depressions, nonfixed depressed scars, AIDS-related
face lipoatrophy, and hemifacial atrophic conditions.
The criteria of exclusion for the administration of
LIS include:
1. Patients who desire breast or eyelid augmentation,
down-bound scars, or an injection in a site presenting
an active ignition or an infection.
2. Patients in search of immediate correction, temporary
correction, or those who are not really certain about
facial enhancement.
3. Pregnant or lactating women.
In addition, even if LIS makes it possible to improve
many skin defects, it is not a surgical redrapage (face lift,
eyebrows lift, blepharoplasty).
Sculptra 2006 (polylactic acid) received marketing author-
ization by the FDA for temporary correction of face
lipoatrophy related to AIDS. However, its use is also limited
by temporary tissue duration and by nodule formation, and by
reaction against foreign bodies on puncture sites. In an
evaluation of the safety and effectiveness of a highly purified
silicone oil of 1000 cSt (Silikon 1000) in the treatment of
AIDS-related lipoatrophy, hundreds of patients were treated
with an average 2 mL of Silikon 1000 injected at 1-month
intervals using the microdroplets technique. The volume of
silicone, the number of treatment sessions, and the time
necessary to obtain correction supplement were directly related
to the initial gravity of the lipoatrophy (P b.0001). Contours of
the face were restored in a routine manner, all patients having
tolerated the treatments well and with no undesirable events.
Instruments
In the United States, the most adapted injectable liquid
silicone for soft tissue augmentation is Silikon 1000.
Adatosil 5000 is too viscous to be injected with 30-G
needles. Using a standard sterile technique, silicone oil is
withdrawn immediately before use by means of a Nokor
needle in a 1-mL Luer-lock syringe. Liquid silicone is more
easily applied with an RJ MaxFlow 30-G needle.
Patient’s preparation
The skin must be thoroughly cleaned using an antiseptic
cleaner. The areas to inject are outlined using a fine-tipped
D. Thioly-Bensoussan
marker or similar. A neat and precise marking is of the
highest importance to obtain precise correction. The marked
areas are usually anesthetized with contact anesthetic under
plastic occlusion for 30 minutes.
Injection methods
The microdroplets multipuncture of Orentreich (MDT)
was developed by Norman Orentreich in 1952 and improved
in 1955. It represents a grouting work that infallibly
generates the best results while minimizing the risk of
side effects. Other techniques, even in expert hands, are
more likely to create adverse effects, such as the tendency
to produce regrouping or pearls of silicone in the injection
pathway. The needle is inserted in the skin with intervals
of 2 to 5 mm, according to the suitable angle for
penetration and optimum deposit. An LIS microdroplet is
defined as a volume from 0.005 to 0.01 mL. It is deposited
in the adequate depth during each insertion of the needle.
It is not necessary to aspire before the injection. If
accidentally injected into a blood vessel, LIS simply
circulates and does not block the vessel but is excreted in
the urine.
Concepts related to the injection
Avoiding any finger pressure on the syringe plunger
while the needle penetrates the skin (on its way in or out)
guarantees a LIS deposit at a suitable depth and minimizes
the possibility of an unintentional surface deposit and the
potential formation of pearls. Unlike many temporary
filling products, the intentional production of overcorrec-
tion immediately after the injection of LIS must be
avoided. With LIS, the defect is deliberately under-
corrected, with gradual augmentation during subsequent
sessions. A useful analogy is the “seed plantation” in the
depressed area to stimulate collagen. Certain scars and
wrinkles lack dermis thickness; in these circumstances, a
controlled intradermal injection is intentional and produces
the desired increase. The total quantity of LIS injected is
dictated by the desired degree of correction. When the
microdroplets technique is used, each puncture and
injection of needle deposits between 0.005 and 0.01 mL
of LIS. The single treatment average for a patient requires a
total from 0.25 to 0.75 mL of LIS. The total number of
punctures depends on the size of the microdroplets and the
total volume of LIS used. When treating facial lipodystro-
phy, 2 mL per session is used. Although strong
accumulated volumes are necessary for important defects,
the use of the microdroplets technique remains essential.
The quantity of newly formed collagen is directly
proportional to the total surface of silicone microdroplets
injected (this implant being composed of hundreds of
microdroplets). Recently, the silicone microdroplets tech-
nique has been recommended with excellent results among
selected patients. The product is currently the object of
tests for the FDA for the enhancing of cheeks in case of
AIDS-related lipoatrophy. According to reported ratios, it is
Non–hyaluronic acid fillers
easy to use and allows excellent esthetic results with a
small profile of adverse effects, but we know that silicones
may give problems many years after its application.
Treatment protocol
The intervals between the sessions are generally 2 months
in the first phases of the treatment. Intervals longer than
1 month do not pose any problem; however, the physician
and the patient must both be aware that the increase will
continue at a lower speed and that the final result will take
proportionally a longer time to obtain.
Adverse effects and complications
Edema. The trauma caused by the insertion of the needle is
at the origin of edema, which is generally reabsorbed in a few
hours to a few days. Edemas resulting from the application of
LIS are usually light compared with the edemas caused by
other filling products.
Bruises. When a bruise occurs, it is usually light and related
to the needle diameter and the vascular condition of the sub-
jacent tissue. Bruises are more prominent in areas equipped
with dense vascular network. When an anticoagulant treatment
cannot be stopped, prolonged manual pressure is advised.
Erythema. A light transitory erythema sometimes appears
immediately after the injection. In rare cases, a persistent
erythema can result from a too superficial injection or impure
materials. Persistent erythema can be treated with local
intradermal corticoid injection (1-2.5 mg/mL of triamcino-
lone acetonide into aliquots from 0.05 to 0.10 mL).
Dyschromia. As an avoidable effect, dyschromia is gen-
erally the consequence of a very superficial LIS deposit or of
the injection of impure material. A bluish shade can result
from a superficial deposit in an extremely thin and
translucent skin.
Texture and feeling. The texture of soft tissue using the
microdroplets technique is quite natural. In the context of a
complete esthetic improvement, this type of texture is usually
acceptable for the patient; the skin will eventually acquire a
quasinormal texture.
Overcorrection. A LIS overcorrection occurs when an
excessive quantity is injected at one occasion or in an accu-
mulated manner over several sessions. Any attempt aiming at
satisfying the immediate wish of a patient by injecting large
volumes is completely contrary to the fundamental principle
of a treatment with LIS-MDT. The term beads is used to
describe small firm papules (1-5 mm) on individual sites of
needle insertion. They might be slightly erythematous or
brownish yellow. These papules are not granulomas but the
result of collagen deposits around superficially implanted
microdroplets. The formation of pearls and overcorrection
require intralesional corticoid injections, such as triamcino-
lone acetonide (from 1.0 to 5.0 mg/mL). The improvement
can be temporary overcorrection, making its reappearance
after the dissipation of corticoid effects. This treatment can be
repeated. Electrodessication, punch excision, dermabrasion,
or tangential excision offer permanent resolution.
175
Granuloma reactions. A meticulous examination of
reports on granulomatous reactions reveals that these cases
have different causes: overcorrection, contraindicated injec-
tion sites, injection of impure silicone, and injection of
substances of unknown chemical composition. Favorable
responses to various types of granulomas have been
observed particularly with the use of Imiquimod (Aldara,
Medapharma, Paris, France) 5%, topic or intralesional
steroids, and antibiotic treatment.
Idiosyncratic reactions to LIS. On very rare occasions,
reactions characterized by moderate swelling with or without
erythema can appear months or years after the injection.
These are frequently preceded by an infection in a distant
site, such as acute sinusitis, furuncle, otitis media, or dental
abscess. When a biopsy is carried out, histopathology is
compatible with a nonspecific chronic inflammatory reac-
tion. Treatment consists of intralesional corticoid injections
and broad-spectrum oral antibiotics for a few days or weeks;
treatment is repeated according to the need until the complete
resolution of symptoms.
Drift. A drift is defined as the movement of a soft tissue
implant toward a site distant from that into which it was
initially injected. A drift of LIS (or any other injectable
implant, in fact) can occur when an important volume (many
times superior to a microdroplet) is injected into one single
site during the same session. The microdroplets technique
eliminates the drift in an effective manner by stimulating a
collagen capsule that retains LIS on the injection site. Face
areas presenting natural ptosis related to age risk an LIS drift.
Gravity exerts its effects in the same manner over all soft
tissue of the face.
Connective tissue disease. Occurrence of connective
disease has been reported after silicone breast implants.
Scleroderma was reported among women after a silicone
breast implant mammoplasty, but no relation of cause and
effect could be established. The incidence of scleroderma
among women with silicone mammoplasty was calculated to
be equivalent to that of the women not having mammoplasty.
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