Download Injectable Soft-Tissue Fillers: Clinical Overview

CME
Injectable Soft-Tissue Fillers: Clinical Overview
Barry L. Eppley, M.D.,
D.M.D.
Babak Dadvand, M.D.
Indianapolis, Ind.
Learning Objectives: After studying this article, the participant should be able
to: 1. Know the composition and biology of injectable fillers. 2. Understand the
advantages and disadvantages of each injectable filler. 3. Understand the U.S.
Food and Drug Administration regulatory status of each type of injectable filler,
including their indications.
Background: The use of injectable filling agents for soft-tissue facial defects has
a long history of successful use based on xenogeneic collagen materials. New
materials of differing compositions for injection treatments either are now
available or will soon be available for clinical use.
Methods: A review of the medical literature was performed to provide chemical
compositions, methods of preparation, biological behavior, and clinical outcomes for every known injectable filler material that is either currently used or
being evaluated in clinical trials.
Results: Hyaluronic acid– based materials have now replaced animal or humanderived collagen as the standard injection materials. Synthetic alternatives offer
the potential of longer lasting results, but the long-term outcome with their use
in large numbers of patients is not yet known.
Conclusions: As there is no single injectable filler that has all of the desired
characteristics, understanding the advantages and disadvantages of one filler
over another is extremely helpful in guiding the patient to an informed decision.
Although all of the reviewed injectable fillers are safe, the concepts of their
long-term volume persistence and how they compare with each other remain
largely anecdotal, with few prospective controlled clinical trials. (Plast. Reconstr. Surg. 118: 98e, 2006.)
T
he placement of high-flow, low-viscosity materials for soft-tissue enhancement has a
long history of use in aesthetic facial alteration. Although bovine collagen injections have
long been dominant, the past 5 years have seen
the emergence of numerous new fillers of differing compositions. When combined with the increasing popularity of injectable Botox and
other office-based procedures, the role of injectable soft-tissue augmentation continues to expand. With the advent of various new injectable
fillers, it is important to assess their compositions
and characteristics to make the optimal selection
to achieve the patient’s goals.
Ideally, an injectable implant should have a
lack of any significant inflammatory response
(be highly biocompatible), be easily introduced
into the recipient site by injection (have good
From the Division of Plastic Surgery, Indiana University
School of Medicine.
Received for publication September 26, 2005; accepted November 1, 2005.
Copyright ©2006 by the American Society of Plastic Surgeons
DOI: 10.1097/01.prs.0000232436.91409.30
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flow behavior through a small-gauge needle),
and produce an acceptably long period of volume retention (i.e., months to years). Each current U.S. Food and Drug Administration–
approved filler and those under U.S. Food and
Drug Administration application/study exhibit
differences in these three basic characteristics. It
is incumbent on the physician to understand the
physical and biological properties of the intended filler before its clinical use.
XENOGENEIC MATERIALS
Zyderm/Zyplast
The first widely used injectable filler, whose
clinical use continues to decline, remains the standard to which all other injectable fillers continue
to be compared.
Its animal derivation and short longevity have
led to its decrease in popularity.1 In U.S. Food and
Drug Administration clinical trials, however, its
long history of clinical use and data make it the
frequently used control.
Composition
Zyderm I and II and Zyplast (Inamed Aesthetics, Santa Barbara, Calif.) are derivatives of bovine
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Volume 118, Number 4 • Injectable Soft-Tissue Fillers
collagen. Zyderm I was U.S. Food and Drug Administration approved in 1981, whereas Zyderm II
gained U.S. Food and Drug Administration approval in 1983. Zyplast was U.S. Food and Drug
Administration approved in 1985. Zyderm I is 96
percent type I collagen, with the remainder being
type III collagen. It is 3.5 percent bovine dermal
collagen by weight, suspended in phosphate-buffered physiologic saline.2 Zyderm II is 6.5 percent
bovine dermal collagen by weight. Zyplast is 3.5
percent bovine dermal collagen cross-linked by
glutaraldehyde, which makes it more resistant to
biodegradation. It is more viscous than Zyderm
but less immunogenic.
Clinical Characteristics
Zyderm and Zyplast are prepackaged in 1- or
2-ml syringes. They are opaque and are typically
injected with a 30-gauge needle. Zyderm I is injected in the papillary dermis and is U.S. Food and
Drug Administration approved for fine lines and
shallow acne scars. Zyderm II, which also comes in
0.5-ml syringes, is injected in the papillary dermis
and is U.S. Food and Drug Administration approved for moderate lines and deeper acne scars.
Zyplast is injected into the mid to deep dermis and
the subcutaneous region and is best used for deep
folds and lines. Overcorrection is necessary with
Zyderm because it is diluted with phosphate-buffered physiologic saline, which is reabsorbed. Results typically last 2 to 3 months.
Advantages
With a 25-year history of clinical use, Zyderm
and Zyplast are known to be safe, with very few
local complications. Their clinical effectiveness
and versatility are well established. Also, they come
diluted with 0.3% lidocaine, which may reduce the
pain on injection.
Disadvantages
Because Zyderm and Zyplast are bovine derivatives, they require skin testing and thus should
not be used on the day of consultation, unless it is
an established patient. Two skin tests are administered 2 weeks apart, with the second test being 4
weeks before the procedure. Of note, 3 percent of
patients develop a sensitivity reaction even with a
normal skin test.3 Local adverse effects include
erythema, induration, pruritus, and skin discoloration. Furthermore, a systemic hypersensitivity reaction can occur 48 to 72 hours after injection.
This is manifested by fever, malaise, and urticaria,
which are treated with short-term oral steroids.
Granulomas have also been reported with Zyderm/Zyplast. Reactivation of herpes is possible
with lip injections; thus, patients with a positive
history need antiviral prophylaxis. Other compli-
cations include necrosis of the overlying skin and
unilateral vision loss caused by retinal artery occlusion. They are also contraindicated in patients
with lidocaine allergies. The material starts to be
degraded immediately after injection, with clinical
effects observable for a few months. The reduction
in injection volume is essentially linear over time.
ALLOGENEIC MATERIALS (COLLAGENBASED HOMOLOGUES)
Cosmoderm/Cosmoplast
In an eventual response to the concerns and
problems with bovine-derived collagen, the introduction of human-based collagen homologues has
occurred more recently. Similarly named, they offer the promise of decreased immunogenicity and
longer lasting results.
Composition
CosmoDerm I and II and CosmoPlast (Inamed) are injectable implants derived from highly
purified human collagen. Both CosmoDerm and
CosmoPlast were U.S. Food and Drug Administration approved for use in facial aesthetic surgery
in March of 2003 and are the only U.S. Food and
Drug Administration–approved dermal fillers
made from human collagen.
The collagen is cultured from a single cell line
of human dermal fibroblasts that has been used
for over 10 years to manufacture human-based
tissues; these cells produce natural collagen that is
then isolated and purified for injection. The cell
line undergoes extensive testing for viruses, retroviruses, and tumorigenicity. CosmoDerm II contains approximately twice the concentration of
collagen as CosmoDerm I.
Clinical Characteristics
CosmoDerm and CosmoPlast are prepackaged in 1-ml syringes. They are opaque and should
be refrigerated but must not be frozen. They are
typically injected with 30-gauge needles. CosmoDerm is U.S. Food and Drug Administration approved for shallow wrinkles or acne scars and is
injected into the superficial papillary dermis. CosmoPlast is injected into the mid to deep dermis for
the correction of more pronounced wrinkles or
scars. However, the safety and efficacy of CosmoDerm use in lip augmentation has not been established. Its flow characteristics are similar to Zyderm and, like Zyderm, overcorrection is
necessary with CosmoDerm because it is diluted
with saline, which is reabsorbed. The use of CosmoDerm I should be limited to 30 cc per patient
per year. CosmoDerm II and CosmoPlast should
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Plastic and Reconstructive Surgery • September 15, 2006
be limited to 15 cc per patient per year. Results
typically last 3 to 6 months.
Advantages
The Inamed Human Collagen Immunogenicity Clinical Study demonstrated that the 95 percent upper confidence interval for experiencing a
hypersensitivity reaction against CosmoDerm and
CosmoPlast is less than 1.3 percent. This is less
than the incidence of immunologically related adverse events reported with Zyderm/Zyplast in
treated patients who initially had a negative skin
test. Unlike bovine collagen implants, these dermal fillers do not require a pretreatment skin test
before treatment. This has been established
through their preapproval U.S. Food and Drug
Administration application study. Thus, patients
may undergo treatment at the time of their initial
consultation. They come diluted in 0.3% lidocaine, which may have some benefit in reducing
pain on injection.
Disadvantages
The use of these products is contraindicated in
patients with a known allergy to lidocaine. In a
study to evaluate sensitization to CosmoDerm and
CosmoPlast, 428 patients were injected with CosmoDerm I into the forearm and followed for 2
months; the more common adverse side effects
included the following: cold-like symptoms, 4.1
percent; flu-like symptoms, 2.0 percent; and urinary tract infection, 1.0 percent.3
The longevity of this material appears to be
similar to bovine collagen. No prospective study
has been reported that conclusively demonstrates
superior volume persistence.
Cymetra
AlloDerm has many indications in reconstructive and aesthetic surgery. The conversion of these
materials into an injectable form is a logical extension of their subcutaneous use.4
Composition
Cymetra (LifeCell Corp., Palo Alto, Calif.) is
the injectable form of micronized AlloDerm, a
decellularized processed dermal allograft5 that
was U.S. Food and Drug Administration approved
in 2000. The material is originally obtained from
tissue banks compliant with the guidelines of the
American Association of Tissue Banks and the U.S.
Food and Drug Administration. First, the epidermis is completely removed, followed by the removal of dermal cells and stabilization of the dermal matrix through the inhibition of
metalloproteinases. The material is then cryofractured, breaking down the acellular dermal matrix
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into micronized particles that are packaged into
syringes. At the time of clinical use, it is necessary
to hydrate the powder.
Clinical Characteristics
Cymetra is presented as a 330-mg dry particulate in a 5-cc syringe. It is reconstituted with 1 cc
of 1% lidocaine and is injected through a 26-gauge
needle into the subcutaneous space. Its more viscous consistency after hydration requires a largecaliber needle for introduction. Cymetra is indicated for use in nasolabial folds, lips, and acne and
depressed scars. Results typically last 3 to 9
months.
Advantages
No immune response is elicited because cells
exhibiting major histocompatability complexes I
and II have been removed. Patients can be treated
at initial consultation because no skin testing is
needed.
Disadvantages
Because of Cymetra’s large particle size (⬎100
␮m), injections are less smooth than most other
implants and can be more painful because of the
size of the needle. Patients should also be made
aware of postinjection edema. Furthermore, its
use should be avoided in periocular line correction and glabellar contouring to avoid the risk of
intravascular injection and migration. Cymetra is
supplied in an antibiotic-supplemented medium;
thus, patients with sensitivities to the antibiotic
should not receive this material. The size of the
hydrated particles and the needle do not allow
intradermal injection, limiting its use to the subcutaneous space.
As this is a tissue bank material, formal U.S.
Food and Drug Administration clinical trials and
comparisons to other materials have not been conducted. Reported clinical outcomes are largely anecdotal. There are no clinical trials that demonstrate its longevity to be superior to other collagenbased implants.
Fascian
Tissue bank collagen material, other than
from the dermis, is possible from numerous other
sources. Fascia, with a very tight fibrillar collagen
weave, offers the potential for a more dense form
of collagen implant. Fascian was introduced in
April of 1999.
Composition
Fascian (Fascia Biosystems, Beverly Hills,
Calif.) is preserved, particulate fascia lata derived
from human cadavers obtained from an American
Association of Tissue Banks Guideline– compliant
Volume 118, Number 4 • Injectable Soft-Tissue Fillers
tissue bank.6 Preserved fascia lata has been used
for a long time as a sheet graft material but has
only recently become available in injectable form.7
Clinical Characteristics
Fascian is freeze-dried, irradiated, and then
processed into particle sizes of 0.25, 0.5, 1.0, or 2
mm, of which 80 mg of volume is inserted into
each syringe. The material may be stored at room
temperature for years. Clinically, Fascian is indicated for deep wrinkles, scars, fat atrophy, and
prominent nasolabial folds.8 At the time of injection, the fascia particles are initially hydrated in 3
to 5 cc of 0.3% lidocaine solution. This produces
a thick paste that can be extruded through a largebore needle. The injected area is preundermined
with a 20-gauge needle and the material injected
into the preformed tunnel with a 16- to 25-gauge
needle, depending on the size of the particles
used. Fascia Biosystems reports the duration of
results to be 6 to 8 months, but other anecdotal
reports show Fascian’s duration to be 3 to 6
months.
Advantages
In a study by Burres, 81 patients receiving 109
injections of Fascian over a period of 6 to 9 months
experienced no infections, allergic reactions, or
acute rejections; there have been no reports of
disease transmission.9 No skin testing is necessary,
so the patient may the receive injection at the time
of initial consultation.
Disadvantages
Trace amounts of polymyxin B sulfate, bacitracin, or gentamicin are present in Fascian implants; patients with known allergies to these antibiotics should avoid Fascian accordingly. The
large size of the needle needed for introduction
results in the potential for increased bruising. In
addition, local anesthesia infiltration into the recipient or nerve blocks may be needed for patient
comfort during the procedure. Documentation of
the longevity of the material has not been reported in any prospective or controlled patient
series.
SYNTHETIC MATERIALS
Restylane
The long-term use of this synthetically derived
material in Europe and the very favorable clinical
results represented a fundamental change in injection technology.10 The transition from a protein-based material to one of an extracellular matrix composition is a paradigm shift from two
decades of previous clinical experience.
Composition
Restylane (Medicis, Scottsdale, Ariz.) is produced today by fermentation in cultures of equine
streptococci. The fermented material is then stabilized by means of epoxidic cross-links of the
glycosaminoglycan chains. As a result of this processing method, the hyaluronic acid, or hyaluronan, does not cause immunologic sensitization
and there is virtually no risk of allergic reactions.11
Hyaluronan is a polysaccharide that is an essential
component of the extracellular matrices in which
most tissues differentiate. In certain tissues, such
as the vitreous cavity of the eye and synovial joint
fluid, it is the major constituent. Unlike collagen,
it is identical across all animal species and microbes. The largest amount of hyaluronan resides
in skin, where it is present in both dermis and
epidermis. Hyaluronan’s high capacity for holding water and high viscoelasticity give it some
unique properties that are useful in various medical and pharmaceutical applications.12 Because it
retains moisture, hyaluronan is used in some cosmetics to keep skin young and fresh-looking. As we
age, the water-holding capacity of our skin decreases as hyaluronan depolymerizes. Therefore,
the retention or insertion of hyaluronan into the
skin is theoretically helpful in wrinkle reduction.
Hyaluronic acid can be rather rapidly degraded and is ultimately metabolized in the liver.
Modern processing methods have produced more
stable forms of hyaluronic acid that have much
longer in vivo retention times. As degradation occurs over time, water is attracted to the material at
the site of implantation. As the hyaluronic acid
concentration decreases, more water bonds to it,
thus helping with cosmetic persistence. This feature is what probably accounts for its longer volume retention effects than bovine collagen (isovolemic degradation).
Clinical Characteristics
A variety of differing grades of transparent gels
are available, based on the same type of gel from
highly concentrated (20 mg/ml) stabilized hyaluronic acid, which varies in particle size and subsequent indication. Restylane has a particulate size
of 100,000 gel particles per milliliter, flows
through a 27-gauge needle, and is U.S. Food and
Drug Administration approved for mid-dermal applications such as deeper wrinkle reduction and
for lip augmentation, nasolabial folds, and glabellar creases.13 Restylane has even been successfully
used in the treatment of tear trough deformities.14
Restylane Fine Lines has the highest concentration at 200,000 gel particles per milliliter, can be
injected through a 30-gauge needle, and is indi-
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Plastic and Reconstructive Surgery • September 15, 2006
cated for thin superficial wrinkles. The lowest concentration gel is Perlane at 8000 gel particles per
milliliter, which is injected through a 27-gauge
needle and is intended for shaping facial contours
and correcting deep folds, and for lip
augmentation.15 Restylane was U.S. Food and
Drug Administration approved in December of
2003, Restylane FN and Perlane await eventual
U.S. Food and Drug Administration clearance.
Advantages
Its universal hyaluronic acid composition
makes the need for preinjection skin testing unnecessary, as the risk for hypersensitivity reactions
is minimal.16 It is easily injected and flows nicely
through small-gauge needles. Although not permanent, its persistence is reported to exceed that
of bovine collagen, with estimates of between 6
and 12 months after injection.17
Disadvantages
In a study comparing Restylane with Zyplast,
there was an overall higher incidence of severe
bruising (3.6 percent versus 0.7 percent), severe
swelling (3.6 percent versus 1.4 percent), and severe pain (3.6 percent versus 1.4 percent) with
Restylane. The increased pain is partly because
Restylane does not come mixed with local anesthetic. Common side effects include injection-site
inflammation, with an incidence of 0.02 percent,
and local hypersensitivity reactions (i.e., swelling,
erythema, and induration), with an incidence of
0.02 percent, lasting a mean of 15 days.18 Its cost
is more than that of collagen-based materials.
Captique
Composition
Captique (Inamed) is a nonanimal, stabilized,
hyaluronic acid– based material derived from the
same nonanimal source as Restylane. It was U.S.
Food and Drug Administration approved in December of 2004. As a competitive analogue to Restylane, it offers what appears to be a very similar
hyaluronic acid– composed injection material
from a different manufacturing source. Marketing
information states that it is a “softer” hyaluronic
acid than Restylane, although that exact meaning
of that is not clear. One can speculate that this
means it has less gel particles per milliliter.
Clinical Characteristics
Similar to Restylane, it is a clear, colorless gel
that is indicated for fine lines and wrinkles. It
comes in 1-cc syringes and is typically injected with
a 30-gauge needle, although flow through a 30gauge needle is also possible. The longevity of the
injection is reported to be 3 to 6 months.
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Advantages
No skin test is necessary, as with other hyaluronic acid materials.
Disadvantages
What, if any, differences exist between it and
Restylane are not known. It is assumed that its
clinical performance, in terms of incidence of
postinjection reactions and longevity of volume
persistence, is similar. No controlled clinical trial
comparing it to Restylane and any other injectable
has been reported, although anecdotally, Captique is felt to last significantly shorter than Restylane.
Hylaform
Composition
Hylaform (Inamed) is a sterile, colorless gel
implant that consists of cross-linked molecules of
hyaluronic acid derived from an avian source.19
Extracts of the rooster comb have been widely
used in orthopedic surgery as a viscoelastic injection into symptomatic joints since 1996. This is a
more dense form of avian-derived hyaluronic acid
because of its intraarticular use. As a facial softtissue injection, its density is decreased. It gained
U.S. Food and Drug Administration approval in
April of 2004. Hylaform Plus, which is also a clear,
colorless gel, consists of larger mean hyaluronic
acid particles than Hylaform. Hylaform Plus was
U.S. Food and Drug Administration approved in
October of 2004.
Clinical Characteristics
Hylaform is indicated for moderate to severe
facial wrinkles and folds, but not for lip
augmentation.12 Hylaform comes in prepackaged
sterile syringes that should be stored at room temperature. It is injected into the mid to deep dermis
using a 30-gauge needle. Hylaform Plus is U.S.
Food and Drug Administration approved for injection into the mid to deep dermis for correction
of moderate to severe facial wrinkles and folds.
Subdermal injection will lead to inferior results,
and if it is injected too superficially, it may cause
skin discoloration. Linear threading, serial puncture injections, or a combination of the two have
been demonstrated to be effective. However, overcorrection should be avoided. Patients should be
limited to 20 cc of Hylaform gel per 60-kg body
mass per year. The safety of injecting greater
amounts has not been established. Results typically last 3 to 4 months.
Advantages
No skin test is necessary; thus, it can be used
at the initial consultation.
Volume 118, Number 4 • Injectable Soft-Tissue Fillers
Disadvantages
Results may not be as long as other hyaluronic
acid products, lasting approximately 3 months. It
cannot be used in patients with hypersensitivity to
avian proteins, most notably eggs. Given its avian
derivation, this would suggest that the risk of hypersensitivity reactions is greater than hyaluronic
acid derived from nonanimal sources.
ALLOPLASTIC IMPLANTS
In efforts to improve the longevity of soft-tissue
fillers, the merging of resorbable and nonresorbable components into an injectable compound is
a logical one. The issues of flow behavior of the
nonresorbable synthetic component is the key to
the formulation of such an injectable concept.
Radiesse
Composition
This injectable implant, formerly known as Radiance, is manufactured by Bioform, Franksville,
Wis.) and is a proprietary mixture of an aqueousbased gel carrier blended with spherical particles
of synthetic calcium hydroxyapatite.13 Although
traditionally thought of only as a bone replacement, the high density and low solubility of the
bioceramic particles of calcium hydroxyapatite
provide for long-term durability of the implant
and excellent biocompatibility. The spherical
shape and small uniform size of the calcium hydroxyapatite particles allows for consistent mechanical action during injection and stability in
situ after injection. As the size of particles that can
be phagocytized and migrate through the lymphatic system is approximately 15 ␮m, there is very
limited potential for migration. Should any calcium hydroxyapatite become phagocytized, the
particles are simply degraded into calcium and
phosphate ions. The gel carrier is composed of
cellulose, glycerin, and high-purity water. These
gel components are widely used in pharmaceuticals and injectable drug products. The gel carrier
has the unique characteristic of being highly viscous and elastic while allowing for shear thinning.
The high viscosity and elastic properties keep the
calcium hydroxyapatite particles in suspension
during storage and injection. The shear thinning
property of the gel carrier allows injection
through reasonably small-gauge needles.
Clinical Characteristics
Radiesse is composed of calcium hydroxyapatite particles in the 25- to 45-␮m size range and can
be injected with a 26-gauge or larger diameter
thin-wall needle. The duration of its clinical effects
has been reported to be approximately 2 years.
Radiesse is indicated for correction of nasolabial
folds, vertical lip lines, acne scars, marionette
lines, and restoring volume in and around the
cheeks.
Advantages
With the synthetic formulation of the calcium
hydroxyapatite particles and the use of compatible
gel ingredients, there is no need for skin testing
before treatment. Because the calcium hydroxyapatite is a natural mineral in the body, there is no
concern of antigenic or inflammatory reactions.
Despite the fact that the particles are ceramic (and
not osteoinductive), the implants do not calcify
and remain soft and flexible. Because particle solubility is very low, volume retention may theoretically persist for years.
Disadvantages
There are no published reports on the use or
the long-term effects of this calcium hydroxyapatite injectable implant in aesthetic facial treatments. It is not currently U.S. Food and Drug
Administration approved for this application, although clinical trials are ongoing. Radiesse has
received regulatory clearance for the soft-tissue
treatments of vocal cord insufficiency and for radiographic tissue marking. It is also currently under clinical trials in urology for the treatment of
vesicoureteral reflux and stress urinary
incontinence.20 Studies have also reported using
Radiesse for the treatment of human immunodeficiency virus–associated facial lipoatrophy, although this is yet to be an approved indication.21
The size of the needle used and the viscosity of the
material does not permit for intradermal injections. Although the nonresorbable calcium hydroxyapatite component may persist indefinitely,
the majority of the injectate is the carrier gel (70
percent). As the carrier is rapidly absorbed, much
of the perceived augmentative effect may be gone
quite quickly. Although animal (rat) studies show
persistence for years, this potential benefit has not
been observed or confirmed in human facial implantation sites. The potential for “clumping,” an
aggregate of scar contracture around a collection
of the particles, with formation of a foreign body
reaction has been seen anecdotally. This may be
particularly likely to occur when injected into the
lips. This likely results from irregular injection
techniques (nonsmooth) or superficial locations,
or occurs in very mobile sites (e.g., lips). Furthermore, Radiesse is radiopaque and may interfere
with facial radiographs.
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Plastic and Reconstructive Surgery • September 15, 2006
Sculptra
Composition
Sculptra (Dermik Laboratories, Berwyn, Pa.)
is composed of microparticles of poly-L-lactic acid,
a biodegradable synthetic polymer from the alphahydroxyacid family.22 It is manufactured from essentially a resorbable “plastic” material from
which many of the sutures that are used daily (e.g.,
Vicryl, Dexon) are composed. These are moderately hydrophilic materials from which postimplantation hydrolysis initiates the slow resorption
process. Clearance is eventually achieved by macrophage digestion.
Clinical Characteristics
It comes in the form of a sterile, freeze-dried
preparation that is reconstituted with 5 cc of sterile
water. Lidocaine is recommended by the manufacturer in reconstitution. Sculptra is injected in
the deep dermis or subcutaneous space using a
26-gauge needle. It must be used within 72 hours
of reconstitution.
Sculptra (also known as New-Fill in Europe)
has been used for many years in resorbable sutures, bone screws, and facial implants. Whereas it
is approved in Europe for the treatment of wrinkles, it is U.S. Food and Drug Administration approved (August of 2004) only for the treatment of
human immunodeficiency virus–associated facial
lipoatrophy.23
Advantages
No skin test is necessary. The effects typically
last 1 to 2 years, with some European reports citing
up to 5 years between injections.
Disadvantages
Sculptra must be reconstituted 2 hours before
use. The size of the needle and the flow behavior
of the injectate do not allow for intradermal implantation.
It has only been definitely studied in the
United States for human immunodeficiency virus
patients. It has been U.S. Food and Drug Administration approved on a compassionate-use basis.
Whether the same results, particularly the complication rates, would be greater in a nonimmunocompromised patient population can only be
speculated. The potential for long-term tissue reactions, such as granulomas, is likely much higher
than for most other injectable fillers.
Artecoll
Composition
Artecoll (Artes Medical, San Diego, Calif.) is a
permanent injectable filler composed of polymethylmethacrylate microspheres that are sus-
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pended in a transport solution of 3.5% bovine
collagen and 0.3% lidocaine. The polymethylmethacrylate microspheres are 20 to 40 ␮m in
diameter and are packaged in sterile, preloaded
syringes.
Clinical Characteristics
Artecoll is injected with a 27-gauge needle into
the subdermal space and subcutaneous tissue and
is evenly massaged with thumb and index finger to
eliminate any clumping of material. The collagen
dissipates within 1 to 3 months, whereas the
smooth microspheres become encapsulated
thereafter.
In a study by Lemperle et al. of 118 patients
treated with Artecoll, 90 percent were satisfied
with results of their treatment, and 64 percent
reported lasting results at a 2-year follow-up. Subsequently, Cohen and Holmes compared Artecoll
with Zyderm II/Zyplast in a U.S. Food and Drug
Administration clinical trial that commenced in
2001 and was completed in 2004.24 This was a
prospective, randomized, multicenter trial using
251 subjects. Subjects were randomized to receive
Artecoll or Zyderm II/Zyplast to treat nasolabial
folds and glabellar, upper lip, and corner-of-themouth wrinkles. Follow-up at 1, 3, 6, and 12
months was completed, and evaluations were performed by the investigators and subjects using linear analogue scales. Furthermore, three masked
observers using a Facial Fold Assessment Scale
rated the results on the subject’s photographs.
The results of the study showed that the success
and satisfaction ratings for the Artecoll group were
superior to those of the control group.
Advantages
Polymethylmethacrylate and collagen are two
implant materials that have a long clinical history
of successful human implantation. It is not surprising, therefore, that they were well tolerated in
a prospective human clinical trial. When properly
placed, Artecoll demonstrates a persistence of
augmentation that is unrivaled by other injectable
materials.
Disadvantages
Artecoll is still not U.S. Food and Drug Administration approved for aesthetic use in the
United States, although the clinical trial was
completed in 2004. The study has recently been
updated, showing stability in results after 4 years
of follow-up. The product, which will be marketed as ArteFill in the United States, will be
produced using collagen from a closed herd of
U.S. cows, according to final U.S. Food and Drug
Administration guidelines. The anticipated date
of U.S. Food and Drug Administration approval
Volume 118, Number 4 • Injectable Soft-Tissue Fillers
Table 1. Injectable Soft-Tissue Fillers
Composition
Collagen,
xenograft
Collagen,
allograft
Cymetra
(LifeCell)
Fascia lata
Hyaluronic
acid
Types Available
How Supplied
Bovine collagen, 95% type Zyderm I: 35 mg/ml
Syringes, store at
I, 5% type III; Zyplast is
collagen
4°C; reconstituted
glutaraldehyde crosswith PBS and 0.3%
linked
lidocaine
Zyderm II: 65 mg/ml
Zyplast (Medicus): 65
mg/ml
Derived from fibroblast
CosmoDerm I
Unlike Zyderm
culture, 35 mg /ml
family, no skin
collagen; CosmoPlast is
pretesting is
cross-linked
required
CosmoPlast (Medicus),
cross-linked
Micronize acellular,
330 mg of micronized 5-cc syringe,
freeze-dried dermal
particles
refrigerated up to
tissue
6 mo;
reconstituted with
1.0 ml of
lidocaine, use
within 2 hr
Preserved particulate
Fascian (Fascia
Hydrated in 3–5 cc
fascia lata, freeze dried
Biosystems)
0.3% lidocaine
solution
Streptococcal
fermentation processed,
20 mg/ml in buffered
solution (?)
Restylane Fine
(Q-Med/Medicus)
Reconstituted with
physiologic saline
Restylane
Perlane
Hyaluronic
acid
Hyaluronic
acid
Streptococcal
fermentation processed
Processed from rooster
combs, cross-linked
Radiesse
(Bioform
Medical)
Calcium hydroxylapatite
spheres (25–45 ␮m) in a
polysaccharide gel with
glycerin
Poly-L-lactic acid
Sculptra
(Dermik
Laboratories)
Artecoll
(Artes
Medical)
3.5% bovine collagen and
PMMA beads with 0.3%
lidocaine, PMMA beads
⫽ 30 to 40 ␮m, 25%
beads, 75% collagen
Captique (Inamed)
Hylaform (Inamed),
Original ⫽ 5.5 mg/
ml; Fine Line, low
viscosity; Plus, high
viscosity
Previously, Radiance
FN
Sculptra
Ready-for-use, skin
pretesting is optional
1-cc syringe
1-cc syringe, no
refrigeration
Indications for Use
Superficial defects
Needle
30 gauge
Moderate defects
Deeper defects
Papillary dermal injection 30 gauge
Deep reticular dermis,
deeper defects
Because it is tissue bank
material, no FDA
restrictions on its use
exist
Deep wrinkles, scars, fat
atrophy, nasolabial folds
Thin superficial wrinkles
Moderate, nasolabial
Deeper scars, prominent
rhytides, pronounced
nasolabial fold
Thin superficial wrinkles;
moderate, nasolabial
Thin superficial wrinkles;
moderate, nasolabial;
deeper scars, prominent
rhytides, pronounced
nasolabial fold
Subdermal injections, not
FDA-approved yet
Reconstituted with 5 HIV-associated
cc of sterile water
lipoatrophy
and lidocaine
solution
0.5-ml syringe
Injected into the
subdermis, deeper
wrinkles, glabellar and
nasolabial folds
26 gauge
Preundermine with
20-gauge needle,
inject with 16- to
25-gauge needle
30 gauge
30 gauge
27 gauge
30 gauge
27–30 gauge
27
26 gauge
26, 27 gauge
PBS, phosphate-buffered saline; FDA, U.S. Food and Drug Administration; HIV, human immunodeficiency virus; PMMA, polymethylmethacrylate.
is late 2005 or early 2006. Skin testing is required
despite a less than 0.1 percent incidence of sensitivity reactions to assess for the presence of
allergy to bovine collagen. The size of the needle
and the viscous nature of the material make
dermal implantation impossible. Like all par-
ticulated injectable fillers, the risk of clumping
and localized foreign body reactions exists. For
this reason, and because of the risk of palpability, Artecoll should not be injected into the lips
and in areas of thin overlying skin (e.g., rhytides
of the lateral eye).
105e
Plastic and Reconstructive Surgery • September 15, 2006
CONCLUSIONS
With the trend toward less invasive procedures, often in a younger patient population,
there is an increasing patient demand for the
benefits of soft-tissue injectable filler materials.
Given the numerous options that now exist and
the different chemical compositions and potential biological behavior of the various materials,
it is imperative that plastic surgeons be knowledgeable about contemporary injectable fillers.
As there is no single injectable filler that has all
of the desired characteristics, understanding
the advantages and disadvantages of one filler
over another, with an appreciation of their limitations, is extremely helpful in achieving the
patient’s goals and minimizing the risk of potential adverse reactions (Table 1).
It is also important to understand that although
all of the aforementioned injectable fillers are safe,
the concepts of their long-term volume persistence
and how they compare with each other largely remain anecdotal, with few prospective controlled clinical trials. Furthermore, although they are widely
used in many areas of the face, the controlled clinical
trials and subsequent U.S. Food and Drug Administration approval of them usually does not include
lip augmentation, even though it is one of the more
commonly injected facial sites.
Barry L. Eppley, M.D., D.M.D.
Division of Plastic Surgery
Indiana University School of Medicine
702 Barnhill Drive, Suite 3540
Indianapolis, Ind. 46202
[email protected]
DISCLOSURE
None of the authors has a financial interest in any
of the products, devices, or drugs mentioned in this
article.
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106e
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