Cosmetic - Medical University of South Carolina

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Volume 11 • Issue C6
NEUROMODULATORS
AND INJECTABLE FILLERS
Jordan E. Ireton, MD
Alexander T. Nguyen, MD
Cosmetic
www.SRPS.org
Editor-in-Chief
Jeffrey M. Kenkel, MD
Editor Emeritus
F. E. Barton, Jr, MD
Contributing Editors
R. S. Ambay, MD
R. G. Anderson, MD
S. J. Beran, MD
S. M. Bidic, MD
G. Broughton II, MD, PhD
J. L. Burns, MD
J. J. Cheng, MD
C. P. Clark III, MD
D. L. Gonyon, Jr, MD
A. A. Gosman, MD
K. A. Gutowski, MD
J. R. Griffin, MD
R. Y. Ha, MD
F. Hackney, MD, DDS
L. H. Hollier, MD
R. E. Hoxworth, MD
J. E. Janis, MD
R. K. Khosla, MD
J. E. Leedy, MD
J. A. Lemmon, MD
A. H. Lipschitz, MD
R. A. Meade, MD
D. L. Mount, MD
J. C. O’Brien, MD
J. K. Potter, MD, DDS
R. J. Rohrich, MD
M. Saint-Cyr, MD
M. Schaverien, MRCS
M. C. Snyder, MD
M. Swelstad, MD
A. P. Trussler, MD
R. I. S. Zbar, MD
Senior Manuscript Editor
Dori Kelly
Business Manager
Becky Sheldon
Corporate Sponsorship
Barbara Williams
30 Topics
Grafts and Flaps
Wound Healing, Scars, and Burns
Skin Tumors: Basal Cell Carcinoma, Squamous Cell
Carcinoma, and Melanoma
Implantation and Local Anesthetics
Head and Neck Tumors and Reconstruction
Microsurgery and Lower Extremity Reconstruction
Nasal and Eyelid Reconstruction
Lip, Cheek, and Scalp Reconstruction
Ear Reconstruction and Otoplasty
Facial Fractures
Blepharoplasty and Brow Lift
Rhinoplasty
Rhytidectomy
Injectables
Lasers
Facial Nerve Disorders
Cleft Lip and Palate and Velopharyngeal Insufficiency
Craniofacial I: Cephalometrics and Orthognathic Surgery
Craniofacial II: Syndromes and Surgery
Vascular Anomalies
Breast Augmentation
Breast Reduction and Mastopexy
Breast Reconstruction
Body Contouring and Liposuction
Trunk Reconstruction
Hand: Soft Tissues
Hand: Peripheral Nerves
Hand: Flexor Tendons
Hand: Extensor Tendons
Hand: Fractures and Dislocations, the Wrist, and
Congenital Anomalies
Selected Readings in Plastic Surgery (ISSN 0739-5523) is a series of monographs
published by Selected Readings in Plastic Surgery, Inc. For subscription
information, please visit our web site: www.SRPS.org.
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SRPS • Volume 11 • Issue C6 • 2015
NEUROMODULATORS
AND INJECTABLE FILLERS
Jordan E. Ireton, MD*
Alexander T. Nguyen, MD†
*University of Texas Southwestern Medical Center at Dallas,
Dallas, Texas
†M. D. Anderson Cancer Center, Houston, Texas
INTRODUCTION
HISTORY
The use and number of injectable agents for cosmetic
facial rejuvenation and reshaping continues to
increase around the world. According to the 2014
American Society for Aesthetic Plastic Surgery
(ASAPS) Cosmetic Surgery National Data Bank
Statistics,1 more than 3.5 million botulinum toxin
type A (BoNTA) and more than 1.6 million
hyaluronic acid (HA) injection procedures were
performed in 2014. For physicians and extenders
combined, the number of BoNTA injections tops
4.6 million and HA injections are more than 2
million. The use of BoNTA accounted for more
than 1.1 billion dollars in expenditures in 2014,
with a 5407% increase since 1997.1 With increased
comprehension of aging and the associated loss of
volume of soft tissue and bone, the use of injectables
is no longer limited to wrinkles alone. Wrinkles are
sometimes a manifestation of volume loss; therefore,
injectable agents can be used in several different
roles.2−4 Injectable products and their literature
are rapidly expanding and evolving. In this issue
of Selected Readings in Plastic Surgery, we present
neuromodulators and injectables fillers, review the
current products approved by the United States Food
and Drug Administration (FDA), and provide an
overview of the clinical uses.
The history of tissue augmentation began when
Neuber5 used autologous free fat from arms to
reconstruct depressed facial defects in 1893 (Fig.
1). The first cosmetic injection was performed
by Gersuny6 in 1899. He injected paraffin into
a scrotum as a testicular prosthesis to correct the
cosmetic deformity after testicular resection for
advanced tuberculosis. Injectable paraffin and
mineral oil were popular in the United States (US)
and Europe until about 1920. Miller,7 in his 1926
book, Cannula Implants and Review of Implantation
Technics in Esthetic Surgery, described the use of
various materials, including “bits of braided silk,
bits of silk floss, particles of celluloid, gutta percha,
vegetable ivory, and several other insoluble foreign
materials,” injected into the facial tissues to correct
depressions, pits, and lines.8 Liquid silicone became
popular in the 1940s and has been associated with
numerous complications.9,10 Modern autologous
fat transplantation emerged with the evolution of
liposuction. In 1986, Illouz11 presented a report
on the reinjection of fat from liposuction. Klein
and Elson12 detailed the history of soft-tissue
augmentation in 2000.
1
1893–1920s
•  Fat grafting
1900–1920s
•  Paraﬃn oil
1940s
•  Liquid silicone
1980s
•  Fat grafting revival
1981
•  Bovine collagen (Zyderm)
2002
•  OnabotulinumtoxinA (Botox Cosmetic)
2003
•  Human-derived collagen (CosmoDerm)
•  Hyaluronic acid (Restylane, Zyderm,* CosmoDerm,* Captique,* Evolence*)
2004
•  Hyaluronic acid (Hylaform, Captique)
•  Poly-L-lactic acid (PLLA) (Sculptra)
2006
•  Hyaluronic acid (Juvéderm Ultra, Juvéderm Ultra Plus, Elevess)
•  Calcium hydroxylapatite (CaHA) (Radiesse)
•  Polymethylmethacrylate microspheres (PMMA) (ArteFill)
2007
•  Perlane
2008
•  Hyaluronic acid (Prevelle Silk)
•  Porcine collagen (Evolence)
2009
•  AbobotulinumtoxinA (Dysport), poly-L-lactic acid (PLLA) Sculptra Aesthetic
2010
•  Juvéderm Ultra Plus XC/ Ultra Plus XC, Restylane-L, Perlane-L
2011
•  Xeomin, Belotero
2013
•  Juvéderm Voluma XC
2014
•  Restylane Silk
2015
•  Radiesse Plus
Figure 1. Evolution of injectables in the US. *, no longer available.
2
THE IDEAL INJECTABLE
The ideal injectable should have a safe composition,
easy delivery, excellent outcomes, and appropriate
sensibility (Table 1). The material composition should
not be antigenic, carcinogenic, teratogenic, or toxic.
Administration of the injectable should be simple,
reproducible, consistent, without migration, and safe.
Patients should have minimal side effects, predictable
outcomes, and minimal downtime. The product
should also be practical, affordable, versatile, easily
stored, and have a durable shelf life.13,14
DIFFERENTIATORS
Although no universally accepted classification system
for fillers exists, product features and attributes
differentiate one from another. The most common
differentiators include the source of the product,
mechanism of action, and length of duration.
Duration of action is somewhat arbitrary in that
it can be affected by multiple factors such as age,
gender, animation characteristics, metabolism, and
number of past treatments. In addition, injector
technique affects the longevity of a product. Placing
a product too deeply can dramatically shorten its
duration simply because the results are not visible.
We present a review of the most commonly
used FDA-approved soft-tissue fillers, categorized
by product type. These include HA fillers, non-HA
fillers, and permanent synthetic fillers (Table 2).
NEUROMODULATORS
Botulinum Toxin
Botulinum neuromodulators are produced by various
strains of Clostridium botulinum with seven serotypes
(A, B, C1, D, E, F, and G). Serotypes A and B have
been isolated for clinical use.15 Botulinum toxin has
a high affinity for uptake by cholinergic neurons,
resulting in temporary chemo-denervation. It reduces
muscular contractions by binding to receptor sites
on presynaptic autonomic nerve terminals and
temporarily inhibiting acetylcholine release at the
neuromuscular junction via four steps: binding,
internalization, translocation, and intracellular
proteolysis (Fig. 2).16-18
Botulism poisoning was first described in 1817
by Kerner.19 The first therapeutic use of botulinum
toxin was for the treatment of strabismus by Scott
et al.20 in 1973. It has numerous medical uses,
including the treatment of essential blepharospasm,
migraines, and hyperhidrosis.21−23 The first cosmetic
use of botulinum toxin is attributed to Carruthers
and Carruthers,24,25 who noticed the incidental
improvement of glabellar rhytides while treating
ophthalmological disease. Cosmetic botulinum toxin
use has been noted to improve first impression scores
for dating success, attractiveness, and athletic success
scales.26 Currently, three BoNTA-Type A and one
botulinum toxin type B FDA-approved products
are available.
BoNTA-ONA (Botox and Botox Cosmetic)
OnabotulinumtoxinA, known as BoNTA-ONA and
previously known as BoNTA, is marketed as Botox
and Botox Cosmetic (Allergan, Irvine, CA). When
first studied, it was named Oculinum. Botox is FDAapproved for cervical dystonia, chronic migraine,
urinary incontinence, severe primary axillary
hyperhidrosis, strabismus, and blepharospasm.
In 2002, it received FDA approval for temporary
improvement in the appearance of moderate to severe
glabellar lines associated with corrugators and/or
procerus muscle activity in adult patients younger
than 65 years. In 2013, the FDA granted approval
of Botox Cosmetic for temporary improvement in the
appearance of moderate to severe lateral canthus lines,
known as crow’s feet, in adults.
According to the full prescribing information,
Botox is contraindicated in the presence of infection
at the proposed injection site(s) and in persons with
known hypersensitivity to any botulinum toxin
preparation or to any of the components in the
formulation. Caution is advised for patients with
peripheral motor neuropathic diseases, amyotrophic
lateral sclerosis, or neuromuscular junctional
disorders (e.g., myasthenia gravis or Lambert-Eaton
3
Table 1
The Ideal Injectable
Characteristics
Composition
Nonantigenic, noncarcinogenic, nonteratogenic, nontoxic
Delivery
Simple, reproducible, consistent, nonmigratory, safe
Outcomes
Minimal side effects, predictable outcomes, minimal downtime
Sensibility
Cost-effective, versatile, easily stored, durable shelf-life
Table 2
United States Food and Drug Administration-Approved Neuromodulators and Injectable Fillers
Trade Name
Company
Composition
Date of
FDA Approval
Radiesse Plus
Merz Aesthetics
Calcium hydroxylapatite + lidocaine
2015
Restylane Silk
Galderma
Hyaluronic acid + lidocaine
2014
Juvéderm Voluma XC
Allergan
2013
Belotero Balance
Merz Aesthetics
Hyaluronic acid
2011
Allergan
2010
Restylane-L
Galderma
2010
Sculptra Aesthetic
Galderma
Poly-L-lactic Acid
2009
Prevelle Silk
Mentor
2008
Perlane
Galderma
Hyaluronic acid
2007
ArteFill
Suneva Medical, Inc.
Polymethylmethacrylate
2006
Hydrelle (Elevess)
Anika Therapeutics
2006
Juvéderm
Allergan
2006
Radiesse
Merz Aesthetics
Calcium hydroxylapatite
2006
Restylane
Galderma
Hyaluronic acid
2003
Juvéderm Ultra XC
Juvéderm Ultra Plus
4
Neuromuscular disorders
Aminoglycosides
Children
Pregnancy
Lactation
Figure 2. Botulinum toxin mechanism of action. A, Release
of acetylcholine at neuromuscular junction is mediated by
assembly of synaptic fusion complex. B, Botulinum toxin
binds to neuronal cell membrane at nerve terminus and
enters neuron by endocytosis. (Reprinted with permission
from Arnon et al.18)
syndrome). Patients with neuromuscular disorders
might be at increased risk for clinically significant
effects, including severe dysphagia and respiratory
compromise. Aminoglycoside co-administration can
also potentiate the clinical effects.27
Botox is not recommended for use in children
but has shown substantial benefit as an adjunct to
treatment in children with cerebral palsy spasticity.28
Application of Botox is not recommended during
pregnancy, and without adequate studies, it is
considered to be in pregnancy category C. It is not
known whether it is excreted in human milk.29
BoNTA precautions are as follows:
Infection at injection site
Known hypersensitivity
Botulinum toxin can spread or diffuse after
injection. “Spread” refers to the process after the
injection itself, which is related to technique, volume
of injection, and needle size. This is fast and active.
“Diffusion” refers to the process as toxin moves away
from the injection site. This is slow and passive,
taking several days.30 Remote migration of botulinum
toxin to the central nervous system has been reported
to occur in animal studies but has not been shown
to occur in human study participants.31,32 Based
on these findings, all FDA-approved botulinum
toxin products include a box label warning of the
possibility and complications of distant spread.
Symptoms can include generalized muscle weakness,
diplopia, blurred vision, eyebrow and/or eyelid
ptosis, dysphagia, dysphonia, dysarthria, urinary
incontinence, and breathing difficulties. Such
symptoms have been reported to occur hours to
weeks after injection, and there have been reports
of death. Hypersensitivity reactions including
anaphylaxis, urticaria, soft-tissue edema, and dyspnea
have also been reported.29
Antibodies to Botox have been reported and
can lead to loss of treatment effect. Antigenicity
is a concern regarding long-term use of toxin,
and, although rare, several case reports have
identified secondary resistance after multiple
BoNTA injections.33,34 These reports support the
use of botulinum toxin type B formulations, or
Incobotulinum toxin (BoNTA-INCO) (Xeomin;
Merz Aesthetics, Raleigh, NC), which does not have
any bound proteins, as alternatives. Botox underwent
a formulation change in 1997 to decrease protein
content from approximately 25 ng/100 U
to approximately 5 ng/100 U, which was found to
result in a decrease in antibody formation from 9.5%
to 1.2%.35,36
5
Common adverse events occur within the first
week and are transient. The events include localized
pain, infection, inflammation, tenderness, swelling,
erythema, bruising, and local weakness. In 2003,
Klein37 provided a review of the complications of
botulinum toxin, most of which are related to poor
injection techniques.
Botox is produced from the Hall strain of C.
botulinum. One unit corresponds to the calculated
median intraperitoneal lethal dose (LD50) in mice.29
The human LD50 is approximately 40 U/kg, or
approximately 3000 U.38−40 Vials are available in 100
or 50 U. Each 100-U neuromodulator vial currently
contains 0.5 mg of Albumin Human and 0.9 mg of
sodium chloride, vacuum-dried without
a preservative.
According to the package insert, Botox is to be
reconstituted with 0.9% sterile, non-preserved saline
before intramuscular injection at a concentration
of 4 U/0.1 mL. The reconstituted solution should
be clear, colorless, and free of particulate matter.
After opening, the product should be stored in a
refrigerator and used within 24 hours. Unopened
vials can be refrigerated for up to 36 months.29
Figure 3. Dysport (abobotulinumtoxinA). (Image courtesy
of Galderma.)
the appearance of moderate to severe glabellar lines
associated with the procerus and corrugator muscle
activity in adult patients younger than 65 years.45
BoNTA-ABO (Dysport)
Rubin et al.46 and Baumann et al.47 summarized
phase III clinical trials of the safety and efficacy of
Dysport. Rubin et al.,48 Kane et al.,49 and Brandt et
al.50 conducted multicenter, randomized, placebocontrolled, double-blinded studies. A series of openlabeled trials have concluded that single treatment,
variable dosing, and multiple cycles of treatment
with Dysport is well tolerated, has a safety profile
comparable to that of placebo, and significantly
improves glabellar lines compared with placebo.50−54
The median time to onset is 3 days, with results
reported to last as long as 36 months.53 No tolerances
have been described.46,47 In addition, Lawrence and
Moy55 found no evidence of neutralizing antibodies
in 1554 patients who received Dysport.
AbobotulinumtoxinA, known as BoNTA-ABO, is a
BoNTA formulation marketed as Dysport (Galderma,
Fort Worth, TX) (Fig. 3). BoNTA-ABO has been
used in the United Kingdom and other parts of
Europe since 1991 and was FDA-approved in 2009
for cervical dystonia and temporary improvement in
Dysport is produced from a different type
A strain of bacteria, C. botulinum NCTC 2916,
with different manufacturing processes and is not
equivalent to Botox (Table 3). The units are specific
to each product’s manufacturer. They have no
relationship to potency and are not interchangeable.
Alam et al.,41 in a prospective, double-blinded,
randomized controlled trial, found significantly
(P < 0.001) decreased patient discomfort at the
time of injection with preserved compared with
nonpreserved saline reconstitution. Carruthers et al.42
found no difference in efficacy or safety in a dosedilution study in which 30 U was reconstituted in 1
to 10 mL. Hexsel et al.43 found that potency can be
maintained for up to 6 weeks after reconstitution.
The reconstitution, dilution, and storage are matters
of personal physician preference.44
6
Vials for cosmetic use contain 300 U (500 U for
cervical dystonia), which appears as a powder cake
at the bottom of the vial as opposed to Botox, which
appears as dust at the bottom of the vial. Each vial
contains 125 mcg of human serum albumin, 2.5
mg of lactose, with trace amounts of cow’s milk
proteins.56 The mean toxin protein content is 4.35 ng
per 500 LD50-unit vial.17 Contraindications are the
same as for Botox with the addition of allergy to cow’s
milk proteins.45
According to the package insert, Dysport is to
be reconstituted with 0.9% sterile, non-preserved
saline with either 1.5 or 2.5 mL, resulting in a
concentration of 10 U/0.05 mL and 10 U/0.08
mL, respectively. The reconstituted solution should
be clear, colorless, and free of particulate matter.
After opening, the product should be stored in a
refrigerator and used within 4 hours.45
An approximate conversion factor between
Dysport and Botox might provide guidance and
level of comfort for practitioners, but the products
should be viewed as different products. One unit of
Botox is approximately equivalent to 2.5 to 5 U of
Dysport.57,58
Lowe et al.59,60 used a 1:2.5 unit ratio and
compared Botox (20 U) to Dysport (50 U) in a
randomized, double-blinded study for the treatment
of glabellar lines. The authors found a relapse
incidence of 23% for Botox versus 40% for Dysport
and concluded that Botox provided a significantly
prolonged effect at 16 weeks (P = 0.04). Rzany and
Nast61 plotted the results of different Dysport and
Botox studies on the same graph and concluded that
the response curves for both products are very similar
(Fig. 4). Kassir et al.62 compared Dysport with Botox
in a triple-blind, prospective, internally controlled
study in 2013 for the treatment of facial rhytides
using a dose ratio of 2.5:1 and 3:1 Dysport: Botox.
The study concluded that Dysport had a faster time
to improvement and longer duration of improvement
compared with Botox for glabellar wrinkles and
crow’s feet when used in these ratios. A single study
reported successful treatment of masseter hypertrophy
using 100 to 140 units of Dysport per side in 121
patients, with the majority requiring four to five
injections over time.63
Botox is exclusively 900 kDa, whereas Dysport
is a mixture of smaller complex sizes, 300 to 900
kDa, with the core neurotoxin protein being 150
kDa. Concern regarding diffusion caused by the
smaller complex size of Dysport over Botox has been
disproved by Pickett,30 who showed that the complex
dissociates immediately after injection, negating
the effect of complex size. Two studies compared
the diffusion of Dysport and Botox by measuring
anhydrotic halos. Trindade de Almeida et al.64 used
variable dose ratios and found Dysport to have a
larger area of action in 93% of patients at all dose
ratios. Hexsel et al.65 used a 1:2.5 dose conversion
ratio and found no significant difference between
action sizes. A 2:1 ratio of Dysport:Botox in a recent
study66 resulted in a significantly greater diameter of
effect for Dysport compared with Botox, although
the difference was described as “clinically irrelevant”
considering the difference was greater than individual
variations in field effects. Recent data on the topic
stems from a 2013 prospective, single center,
randomized, double-blinded study of 19 patients.67
Each patient received 2 units of Botox on one side
and Dysport on the other. When the same dose was
administered on each side, Botox resulted in a greater
field of diffusion; however, the clinical effect was
statistically comparable for both products at the
same dose.
BoNTA-INCO
BoNTA-INCO was FDA approved for the treatment
of glabellar lines, blepharospasm, and cervical
dystonia in 2011. With its first use in Germany,
BoNTA-INCO is currently approved for use in
more than 20 countries and is marketed under
the trade names Xeomin (in the US, Canada, and
Mexico) (Merz Aesthetics) (Fig. 5) and Bocouture
outside of the US.68 The product is available in
100-U vials containing 0.6 ng total protein and 4.7
mg sucrose.69 It is the first formulation of BoNTA
without complexing proteins. It was theorized that by
eliminating complexing proteins, the predictability of
7
Table 3
Type A Botulinum Toxin Preparations
Dysport
Botox
Xeomin
300 U
100 U
100U
Total protein
4.35 ng
5 ng
0.6ng
Albumin
125 mg
500 mg
1000 mg
2.5 mg of lactose
0.9 mg of NaCl
4.7 mg of Sucrose
NCTC 2916
Hall
Hall
≥300 kDa
≈900 kDa
150 kDa
Lyophilized
Vacuum dried
Lyophilized
2.5 U
1U
1U
Onset
3−5 days
4−5 days
3 days
Spread
More
Less
Same
Duration
Same
Same
Longer
Vial size
Composition
Other
Type A strain
Complex weight
Preparation
Clinical generalizations
Conversion
product spread and clinical effect would be enhanced;
however, clinical and pharmacological studies have
shown that the presence of complexing proteins
does not influence diffusion of the products.70,71
Eliminating complexing proteins has, however, been
shown to reduce antigenicity and to prevent or reduce
host inflammatory response to injections.72,73
In 2010, an international, non-inferiority phase
III clinical trial showed that 24 units of BoNTAINCO was non-inferior to 24 units of Botox for
treating moderate to severe glabellar lines.74 Adverse
events and patient satisfaction are statistically
comparable between Botox and BoNTA-INCO.75,76
When all three formulations of botulinum toxin
8
were compared head to head in a 2013 randomized,
double blinded, prospective study, BoNTA-INCO
was found to have a faster onset of action and longer
duration of effect compared with Botox at a 1:1
dose ratio and compared with Dysport at a 1:3 dose
ratio.77 BoNTA-INCO showed a mean onset of effect
at 3.02 days compared with 5.29 and 5.32 days for
Botox and Dysport, respectively. No association was
observed between time of onset and duration
of effect.
According to the package insert, BoNTAINCO should be reconstituted with 0.9% normal
saline. Reconstitution using 2 to 2.5 mL per 100-U
vial is commonly recommended.78 Once the vacuum
has drawn the saline onto the vial, the vial must
Response Wrinkle Score 0 or 1 at Maximum Frown
90
80
70
% Responder
60
50
40
30
20
10
0
0
20
40
60
80
100
120
Days after Injection
Figure 4. Comparison of results of 50 U of Dysport (blue lines) versus 20 U of Botox (black lines) injected to treat glabella
wrinkles in five studies. The curves are notably similar. (Modified from Rzany and Nast.61)
be inverted two to four times.79 This is because the
product is not freeze-dried and can therefore stick to
the inside of the stopper and walls of the vial. The
reconstituted product should be clear and colorless,
not cloudy. Although all formulations of BoNTA
must be refrigerated once reconstituted, Xeomin can
be stored at room temperature for up to 36 months
before reconstitution.80 Once reconstituted, it should
be used within 24 hours.79
KY). In Europe, this product is known as Neurobloc.
Myobloc was FDA-approved for cervical dystonia
in 1995. When compared with Botox, Myobloc has
an earlier onset of action by 1 to 3 days; a briefer
duration of effect;70,81,82 less predictable results,
possibly because of a greater radius of diffusion; and
more discomfort at the time of injection, possibly
caused by the lower pH value (pH value, 5.6) as
compared with Botox (pH value, 7.3).57,83
RimabotulinumtoxinB (Myobloc)
SPECIAL TOPIC: HYPERHIDROSIS
RimabotulinumtoxinB is botulinum toxin type B
marketed as Myobloc (Solstice Neurosciences, LLC,
a subsidiary of US WorldMeds, LLC, Louisville,
In 2004, Botox received FDA approval for the
treatment of severe axillary hyperhidrosis in patients
older than 18 years after failed topical treatment.84
9
confirming the efficacy and safety of Botox,23,88−93
Dysport,24,86,94 and Xeomin.88 Dosing ranged from 50
to 100 U/axilla total for Botox, 120 to 250 U/axilla
for Dysport, and 50 U/axilla for Xeomin. Duration
of effect is generally 5 to 6 months but has been
reported to last as long as 1 year in some studies using
Botox. Lakraj et al.87 presented a detailed review of
the clinical trials.
The use of botulinum toxins for palmar
hyperhidrosis has also been well established, with
several double-blinded studies confirming the
efficacy and safety of Botox,95−99 Dysport,97,100 and
Xeomin95 for the treatment of palmar hyperhidrosis.
Intradermal injection of 2 to 2.5 U/site (total,
approximately 100 U/palm for Botox or Xeomin and
120 U/palm for Dysport), with a small-gauge needle
is currently recommended for palmar hyperhidrosis.
In the noted studies,95−100 duration of effect ranged
from 3 to 8 months for all botulinum formulations.
Figure 5. Xeomin (incobotulinumtoxinA). (Image courtesy
of Merz Aesthetics.)
Botox is also used off-label for the treatment of
palmar hyperhidrosis. The basis of using Botox for
hyperhidrosis stems from the physiology of eccrine
glands: the sweat-producing glands present in high
concentration in the axillae, palms, and soles.85 These
glands are innervated by postganglionic sympathetic
neurons that are stimulated by acetylcholine.86
Clinical diagnosis of hyperhidrosis requires at least 6
months of excessive sweating, with episodes occurring
at least once per week, not occurring during sleep,
beginning before the age of 25 years, impairing
daily activities, and occurring in a symmetric and
predictable pattern.87
Currently, Level B evidence exists for the
use of Botox and Dysport for the treatment of
hyperhidrosis, Level C for Xeomin, and level U for
Myobloc.87 Only Botox is FDA approved for this
indication; Dysport and Xeomin are currently being
used off-label in comparative studies. The use of
botulinum toxin for axillary hyperhidrosis has been
well established, with several double-blinded trials
10
FUTURE PRODUCTS
A novel application of botulinum toxin is a topical
formulation of the type A toxin, known as RT001,
currently in development by Revance Therapeutics,
Inc. (Newark, CA). The product is in phase III
clinical trials for the treatment of crow’s feet. Its use
for hyperhidrosis and migraine headaches has reached
phase II clinical trials.101 Efficacy and safety of the
product for the treatment of lateral canthal lines were
assessed in a randomized, double-blind, placebocontrolled study in 2012.102 At the 4-week follow-up
time point, 44% of the treated lateral canthal areas
showed at least 2 points of improvement in the
severity scale used by the investigator compared with
0% of those in the placebo group. No treatmentrelated adverse events were reported.
In September 2014, Alphaeon Corporation
received FDA approval of its Investigational New
Drug (IND) Application to conduct clinical trials
for Evosyal, its botulinum toxin type A product.
Evosyal is a 900 kDa neurotoxin molecular complex
with high purity. Enrollment in the clinical trials is
expected to begin in January 2015.
TREATMENT RECOMMENDATIONS
Considering the substantial variations in techniques,
guidelines in the literature, and personal experiences,
Carruthers et al.42,103 convened in 2004 to develop
consensus guidelines for best practices, which were
updated in 2013.78 The recommendations are
recapitulated in Table 456,78,103 and Figure 6. After
intramuscular treatment, most areas should not be
manipulated for several hours.42 The duration of
activity should be expected to last approximately 3 to
4 months. Fagien104 and Carruthers and Carruthers105
presented a report of pretreatment with Botox 1 to 2
weeks before laser resurfacing, which might improve
results by eliminating the hyperfunctional component
during healing.
Upper Face
The upper face is the most common site to receive
neuromodulator injections. The literature regarding
treatment to the upper face, particularly the glabellar
complex, is extensive. The Botox Cosmetic package
insert29 recommends five injection sites for the
glabellar complex and vertical frown lines. Men, in
general, might require more injection sites and more
product, considering the male muscle mass is larger,
on average.
For horizontal forehead lines, the goal should
be to weaken but not completely paralyze the frontalis
muscle. Usually, four to six injection points are used.
Overtreatment of the frontalis will result in brow
ptosis or asymmetry and can be avoided by keeping
injections no closer than 1 to 2 cm above the bony
orbital rim at the lateral corrugators and staying above
the first horizontal line above the brow. Lower doses
of neuromodulator should be used in older patients
to avoid brow ptosis.103 Injections should be lateral
enough to avoid a “quizzical” eyebrow appearance.
To avoid upper eyelid ptosis from diffusion through
the septum to the levator muscle, injections should be
avoided under the mid brow.42
Lateral orbital wrinkles, commonly known as
crow’s feet, are addressed by injections to the lateral
orbital portions of the orbicularis muscle. Injections
range from two to five per side and should be
performed superficially. Diplopia, ectropion, and
smile asymmetry can occur. These conditions can be
avoided by injecting 1 cm outside the bony orbit,
thus avoiding the lateral rectus muscle. Also, to avoid
the zygomaticus, injections should not approach the
inferior margin of the zygoma.37
Midface
Contraction of the nasalis across the bony dorsum
results in “bunny lines” at the nasal radix. Injection
into the nasalis as it transverses the nasal bone
should be performed superficially to avoid bruising.
Injections should also stay high on the lateral nasal
wall, above the nasofacial groove, to avoid the levator
labii superioris, which would result in upper
lip ptosis.58
Neuromodulators can also be used for dynamic
nasal tip ptosis. Dayan and Kempiners106 injected 5
U of Botox into each depressor septi nasi and 3 U
into each levator labii superioris alaeque nasi muscle,
after which the excessive action of these muscles was
attenuated at 2-week follow-up. The nasal tip became
less ptotic with maximal smile effort.
Lower Face
The perioral area is essential to the lower face,
and inappropriate treatment can cause significant
dysfunction, such as drooling, speech difficulties, and
oral incompetence. Knowledge of the anatomy and
patient selection are critical, especially for those who
use their lips as a profession (e.g., musicians, singers,
public speakers). Treatments should be conservative,
avoiding the corners for drooping and drooling and
the midline upper lip for flattening. The number of
injection sites varies considerably.42
The depressor anguli oris pulls down the corner
of the mouth in opposition to the zygomaticus
muscles. Palpation of the muscle should be
performed, and medial or high injections should be
avoided. Injections too high on the lips can affect
the orbicularis oris and worsen asymmetry. This can
be prevented by not injecting higher than halfway
between the lips and the mandible.103
11
Table 4
Recommendations for the Use of Botulinum Toxin Type A56,78,103
Usual No. of
Injection Points
Region/Target Muscle(s)
Total Dose
(Botox/Xeomin)
Total Dose
(Dysport)
Upper face
Vertical frown lines, glabellar complex
(procerus, depressor supercilii, corrugator supercilii)
5–7; men might
require more sites
Women: 10–30 U
Men: 20–40 U
40–80 U
Horizontal forehead lines (frontalis, but consider
interactions with procerus, corrugators, and
orbicularis oculi in overall facial shape)
4–6; more or fewer
might be required
based on anatomic
and aesthetic
evaluations
Women: 10–20 U
Men: 10 to >20 U
20–50 U
Lower eyelid (junction between tarsal and orbital
orbicularis)
1
Women: 0.5–2.5 U
1–6 U
2–5 per side (higher
in selected patients)
Women: 8–16 U
Men: 20–30 U
16–40 U
Radix (nasalis)
1–2
2–4 U
6–15 U
Nasal tip (depressor septi nasi, levator labii
superioris alaeque nasi)
2–4
3–5 U to
each muscle
10–15 U
Perioral area, orbicularis oris
2–6; 4 sites, 1 site
per lip quadrant
4–5 U
10–20 U
Depressor anguli oris
1–2
2–3 U (2.5 U/side)
6–10 U
Dimpled chin (peau d’orange), mentalis
1–2 (start with
1 midline or
2 symmetrical
lateral injections)
4–5 U
10–20 U
Neck, platysmal bands, platysma
2–12/band
<10 U/band
40–80 U/
band
Masseteric hypertrophy
1–2 sites in muscle
25–30 U/side
100–300 U/
side
Crow’s feet (lateral portions of the lateral orbicularis)
Midface
Lower face
*Dosages reflect 1:1 ratio for onabotulinumtoxin and incobotulinumtoxin; for abobotulinumtoxin, a conversion factor of 2:1 or
2.5:1 is recommended.
12
Excessive gingival display, gummy smile, can
be addressed with small amounts of neuromodulators
into the lip elevators. Botox injection of 1 to 2
U per side or 2 to 3 U in the depressor septae are
conservative options.103 Other studies present the
results of injections into the levator labii superioris,
zygomaticus minor, and orbicularis oris.108,109
Hypertrophic masseter reduction has been
successful with neuromodulators. Injections should
be low, just above the mandible, with one to two
sites per side.103 Injection of 25 to 30 U of Botox per
side has been shown to be efficacious, lasting up to 6
months (Table 4).56,78,82,103,110,111
INJECTABLE FILLERS
Figure 6. Common botulinum toxin injection sites.
The dimpled chin, peau d’orange, can be
controlled with conservative injection into the
mentalis. The mentalis protrudes the lower lip and
wrinkles chin skin. Injection into the mentalis in
addition to soft-tissue augmentation is recommended.
When treating the mentalis, it is important to avoid
the depressor labii muscles.103
Platysmal bands can be softened with
neuromodulators in patients with good skin
elasticity and minimal fat descent. Conservative
injections at least 1 cm apart on each band while
grasping the bands or by using electromyographic
guidance will result in more accurate placement.
Judicious treatment should be performed to avoid
dysphagia or voice changes.107 Oral anticholinesterase
(pyridostigmine), up to 60 mg, can be used to
counteract the side effects.103
The use of soft-tissue fillers has greatly increased
during the past 10 years, with more than 3.2 million
injectable filler procedures performed by physicians
and physician extenders in 2013.1 The number of
products continues to increase as well, with each
having subtle biochemical differences. This makes it
imperative but challenging for the cosmetic clinician
to remain up-to-date on the literature. Rohrich et
al.,112 in 2011, and Cohen et al.,113 in 2013, provided
in-depth systematic reviews of the literature regarding
these products.
Collagen Fillers
Aging causes a reduction in the collagen content of
the skin by 1% per year.114 Bovine collagen was the
first nonautologous filler to be approved by the FDA,
in 1981, for the treatment of wrinkles, smile and
frown lines, acne, and postsurgical scars.115 Because
of the availability, success, and longer effect of HA
fillers, the manufacture of collagen-based fillers has
largely been discontinued and the products are no
longer available in the US. Animal-based collagen
fillers required double skin testing, and most collagen
filler products lasted 3 to 6 months, with 75% loss
of correction occurring by 6 months.14,116−121 The
following collagen filler products are no longer
available in the US: Zyderm 1 and 2 (Allergan),
13
Zyplast (Allergan),120 CosmoDerm 1 and 2
(Allergan), Cosmoplast (Allergan),121 Evolence (Ortho
Dermatologies, Skillmann, NJ).122−124
HA Fillers
HA is a glycosaminoglycan biopolymer that is a
natural component of connective tissue in living
organisms. It is chemically the same for all species and
has reduced risk for allergic reactions, so skin testing
is not required with this product.125 HA is hydrophilic
and provides a structural matrix to retain moisture
within the dermis, where collagen can develop. One
gram of HA can bind up to 6 L of water.126 HA
products were developed as an alternative to collagen
because of their longer duration of effect and lower
potential for hypersensitivity reactions, a reported
rate of 0.6% to 0.8%.127,128 Animal-based HA fillers
derived from rooster combs are available but no
longer marketed in the US; we therefore limit our
discussion to non-animal-based HA.127
FDA-approved HA fillers for aesthetic use are
derived from Streptococcus equi. Hyaluronic gels,
known as hylans, are cross-linked at varying degrees
to improve stability and increase longevity. Naturally
occurring HA has a half-life of approximately 20 h.
Hyaluronic gels are 95% water by weight.129 Dynamic
viscosity, a unique attribute of hyaluronic gels, refers
to decreasing viscosity as shear rate increases. At the
time of injection, high-shear-rate hyaluronic gels
pass through needles more easily. At the time of
removal of shearing forces, the viscosity increases and
the gel thickens at its implanted site, minimizing
migration.130 Another unique property of hyaluronic
gels is isovolemic degradation. As the product
degrades, the remaining HA binds more water,
such that the overall volume remains the same. This
process can maintain 95% of the initial filling volume
until all of the material is resorbed.130
The distinction between HA products is related
to their molecular composition and biophysical
properties. The viscosity and elastic modulus (G`) of
the HA dictate the physiological behavior of the gel.
Viscosity refers to the ability of a gel to resist shear
14
forces. For example, peanut butter is highly viscous
compared with mustard in that it requires more force
to spread peanut butter.131 Viscosity is dictated by the
ability of the molecules within the gel to move past
one another, which relates to the size and molecular
weight of the particles (Fig. 7).
The elastic modulus (G`) refers to the
stiffness of a substance, which is its ability to resist
deformation.131 For example, gum has a greater G`
than does pudding and if used to fill a space would
be more resistant to deformation if an external force
were applied. G` is a function of bond strength,
which determines the degree that the bonds can
stretch when stressed. In other words, G` reflects
the ability of the bonds to resist expansion and
contraction (Fig. 8). Clinically, a higher G` translates
into greater tissue lift.
A product with lower G` and viscosity (e.g.,
Juvéderm; Allergan) is associated with a softer feel,
greater spread, and less tissue lift. A higher G` and
viscosity (e.g., Restylane; Galderma) is associated with
greater firmness, more limited spread, and greater
tissue lift. A ranking of these properties for available
HA agents is presented in Figure 9.
Figure 7. Viscosity is dictated by the ability of the molecules
within the gel to move past one another, which relates to
the size and molecular weight of the particles.
Figure 8. G` is a function of bond strength, which determines the degree to which the bonds can stretch when stresses. G`
therefore reflects the ability of the bonds to resist expansion and contraction.
A greater degree of cross-linking of the HA
gel correlates to a longer duration of effect, and the
overall charge of the gel influences how hydrophilic it
behaves. The number of HA products on the market
reflects the ability to chemically engineer varying
degrees of these parameters. Because of these factors,
it is generally accepted that these products are not
only distinguished by trade name but by important
molecular properties that must be understood by the
clinician using them.
FDA-Approved HA Fillers
Figure 9. Viscosity rankings. A product with lower G` and
viscosity (e.g., Juvéderm, Allergan) is associated with a
softer feel, greater spread, and less tissue lift. A higher G`
and viscosity (e.g., Restylane, Galderma) is associated with
greater firmness, more limited spread, and greater tissue lift.
Restylane was the first HA filler to receive FDA
approval for use in the US (2003), for the correction
of moderate to severe facial wrinkles and folds, such
as nasolabial folds. In 2010, the FDA approved
Restylane-L which contains 0.3% lidocaine (Fig.
10). In June 2014, the FDA approved Restylane
Silk (Fig. 11) for submucosal implantation for lip
augmentation and for dermal implantation for the
correction of perioral rhytides. Restylane Silk also
contains 0.3% lidocaine. Restylane and Restylane-L
are produced from bacterial fermentation of S. equi
at a concentration of 20 mg/mL, with a uniform
15
particle size of 400 mm. Restylane is 1% cross-linked
with epoxides, which is less cross-linking than that of
other HA injectables yet the bond is more stable. The
stabilized cross-linking is thought to contribute to
prolonged efficacy by stimulating collagen synthesis
and inhibiting collagen breakdown.132
In 2006, Matarasso et al.133 provided detailed
consensus recommendations for Restylane use
to optimize patient outcomes. Restylane has
been directly compared with a number of other
commercially available HA products. A detailed
summary of those trials was presented by Rohrich et
al. in 2011.112 Additional Restylane products have
been designed for different depths with different
size particles.133
Figure 10. Restylane-L and Perlane-L. (Image courtesy
of Galderma.)
Perlane (Galderma) is designed for deeper
injection for coarser wrinkles. It was FDA approved
in 2007 for the correction of moderate to severe facial
folds and wrinkles. Similar to Restylane, Perlane has
a higher G` and viscosity and is therefore firmer than
other HA products, has less spread, and provides
greater tissue lift. Its efficacy and safety have been well
established for injection into mid to deep dermis for
correction of nasolabial folds,80,134−139 marionette lines
and perioral wrinkles,134,140 tear trough deformities,141
and lipoatrophy.142 Results have been reported to
last up to 7 months.135 In 2010, the FDA approved
Perlane-L, which contains 0.3% lidocaine (Fig. 10).
Figure 11. Restylane Silk. (Image courtesy of Galderma.)
Juvéderm Ultra and Ultra Plus (Allergan) has
a higher concentration of HA, 24 mg/mL, when
compared with Restylane, with more cross-linking in
an attempt to increase longevity. It was approved by
the FDA in 2006 for injection into the mid to deep
dermis for correction of moderate to severe facial
wrinkles and folds, such as nasolabial folds. In 2010,
the FDA approved Juvéderm Ultra XC and Ultra
Plus XC, both containing 0.3% lidocaine. Juvéderm
is produced from S. equi bacterial fermentation. The
particles are non-uniformly shaped for a smoother gel
consistency. The Ultra and Ultra Plus formulations
are made with variable cross-linking and particle sizes,
with effects reported to last up to 12 months.13 These
formulations are recommended for the treatment of
the perioral and nasal areas.
Juvéderm Voluma XC (with 0.3% lidocaine),
approved in 2013, was developed to address facial
volume loss, and it is the first HA filler to be FDA
approved for injecting deep into the malar area for
volume enhancement. It consists of a 20 mg/mL
concentration of HA and is highly viscous. Its efficacy
was established in European clinical trials published
in 2009143 and was confirmed by a recent randomized
clinical trial in the US144 and by non-randomized
trials assessing its efficacy and durability.145,146 Voluma
has been reported to last up to 24 months144,145,147
and has high rates of patient and physician
satisfaction.146−148
16
The Volbella formulation is manufactured to
be less hydrophilic, thereby reducing water uptake
and swelling. This feature is desirable when injecting
the lips. The product is available in Canada and
is currently in clinical trials for FDA submission
and approval. The addition of lidocaine (XC
formulations) has been associated with less procedural
pain (93% of patients).149,150
Prevelle Silk (Mentor Worldwide, LLC, Santa
Barbara, CA) is indicated for injection into the mid
to deep dermis for correction of moderate to severe
facial wrinkles and folds, such as nasolabial folds.
Belotero Balance (Merz Aesthetics) (Fig. 12) was
FDA approved in 2011 to correct moderate to severe
facial wrinkles and folds, such as nasolabial folds.
Belotero is derived from S. equi, and does not contain
lidocaine. It is distinctive in that it uses varying
degrees of cross-link density, a feature referred to as a
polydensified matrix.78 The result of this is a prolonged
duration of effect with preservation of a soft texture,
allowing for more precise corrections of fine lines. The
product consists of high- and low-molecular-weight
polymers, with a mean size of 1196 kDa and 297
kDa, respectively.151 It has the highest mean molecular
weight and greatest proportion of high- versus lowmolecular-weight polymers when compared with
Restylane and Juvéderm Ultra.151 Because of this
molecular composition, the viscosity of the product
is low, providing for easier injection and improved
natural distribution. This is supported by histological
examination that revealed Belotero Balance diffused
evenly throughout the non-papillary dermis without
clumping.152 This was in contrast to Restylane, which
deposited in large pools exclusively in the reticular
dermis, and to Juvéderm, which formed clumps
throughout the reticular dermis. A recent study
using high-resolution ultrasound to investigate filler
distribution supports these findings.153
The safety and efficacy of Belotero Balance was
established in a series of studies beginning in 2006.
A detailed review of these articles was presented
by Lorenc et al. in 2013.154 Longevity of Belotero
Balance is most often 6 to 8 months but has been
shown to last as long as 14 months.155−157 In a headto-head prospective, rater-blind, randomized trial
comparing Restylane with Belotero for the treatment
of nasolabial folds, Belotero resulted in markedly
greater improvement in subjective skin assessment
scores and was preferred by patients.158 Downie et
al.159 presented a series of 93 patients with Fitzpatrick
skin types IV, V, and VI and concluded that Belotero
Balance is safe for use in patients with those
skin types.
Based on a 2013 roundtable discussion of the
use of Belotero, it is recommended that Belotero
be injected into the intradermal and superficial
subdermal plane using a 13-mm sharp, 27-gauge
needle, or 30-gauge needle.160 Lidocaine can be mixed
with Belotero in a 10:1 or 10:3 lidocaine:Belotero
ratio, although this use is off-label and adequate
mixing should be achieved to ensure proper
dilution.161,162 A series of videos demonstrating the
recommended injection techniques of Belotero in
various anatomic locations was presented by Lorenc
et al.160
A number of new HA fillers are available
outside the US, and although they might find a
place in the US market, we recommend that they
not be imported until their clinical efficacy and
safety have been evaluated. In addition, it is strongly
recommended that any facial injectable product be
purchased directly from the manufacturing company
or a designated outlet to ensure that they are
manufactured under approved FDA conditions that
adhere to strict quality control requirements.
Figure 12. Belotero Balance. (Image courtesy of
Merz Aesthetics.)
17
Non-HA Fillers
Soft-tissue fillers referred to as non-HA fillers contain
synthetic, biodegradable materials. Products in this
group, including Radiesse and Radiesse Plus (Merz
Aesthetics) and Sculptra Aesthetic (Galderma)
contain synthetic material that stimulates endogenous
tissue growth. The advantage of these products is that
the duration of action is typically longer than with
most HA fillers, in some cases reportedly up to 2
years. The disadvantage of a longer duration of action
is that if results are not acceptable, the product has to
be removed, which can be inherently difficult.
Poly-L-lactic Acid (PLLA)
to reach the desired effect after initial injection,
and it is recommended that patients be adequately
counseled regarding this feature.164,168 Once the
desired result is achieved, the clinical effect can be
seen for 18 to 24 months.13,169−171 The long-term
soft-tissue augmentation is caused by the stimulation
of fibroblasts and growth of type I collagen into
areas of accumulated PLLA microspheres. It is best
used as a three-dimensional volumetric filler, as
opposed to a superficial line filler.172,173 Sculptra often
requires a series of injections to achieve adequate
correction. Palm and Chayavichitsilp,164 Fitzgerald
and Vleggaar,174 and Lorenc.175 provided detailed
reviews of injection techniques and recommendations
for Sculptra use.
PLLA is a biodegradable, nontoxic, synthetic, and
inactive material derived from cornstarch in the
alpha hydroxy acid family. It has been used in suture
material, stents, and other biomedical implants.
Sculptra (Galderma) (Fig. 13), known as
New-Fill in Europe, was FDA approved in 2004
for restoration and/or correction of the signs of
lipoatrophy (facial fat loss) in people with or
receiving treatment for human immunodeficiency
virus. The lipoatrophy is thought to result from the
use of highly active antiretroviral therapy. In 2009,
Sculptra Aesthetic received FDA approval for the
correction of shallow to deep nasolabial fold contour
deficiencies and other facial wrinkles in which deep
dermal grid pattern (cross-hatch) injection technique
is appropriate. Injection of 0.05 to 0.1 mL per square
centimeter has been recommended by Schierle
and Casas.163
Sculptra consists of microspheres in a powdered
form containing 150 mg of PLLA, 127.5 mg of
non-pyrogenic mannitol, and 90 mg of sodium
carboxymethylcellulose. Because of the hydrophobic
nature of PLLA, the product requires reconstitution
at least 3 hours before use, with some clinicians
reporting up to 1 month of reconstitution with
bacteriostatic water.164−167
PLLA is metabolized to carbon dioxide, glucose,
and water for several weeks after injection. This results
in a delayed effect, often taking up to 2 months
18
Figure 13. Sculptra Aesthetic. (Image courtesy of Galderma.)
Calcium Hydroxylapatite (CaHA)
CaHA is found naturally in the body as the mineral
component of bone and is highly biocompatible. It
has been used in dental, orthopaedic, urological, and
vocal cord applications. It acts as a biostimulatory
scaffold for collagen ingrowth.176
Radiesse (Fig. 14A) was approved by
the FDA in 2006 to restore and/or correct the
signs of lipoatrophy in people with the human
immunodeficiency virus and for the correction of
moderate to severe facial wrinkles and folds, such
as nasolabial folds. Radiesse is composed of 24 to
45 mm CaHA spheres suspended in a 70% aqueous
carboxymethylcellulose gel. It is highly viscous
and predisposed to nodule formation, especially
on the lips, a complication reported to occur in
more than 20% of patients in some studies.161,177−179
Deep injection subdermally or intramuscularly is
recommended. The gel matrix is absorbed in 6 to 8
weeks, and over time, the CaHA microspheres are
metabolized while serving as a scaffold for collagen
ingrowth. Longevity is generally 9 to 18 months,
but the effects have been reported to last as long
as 2 to 5 years.180−183 A multicenter, blinded, splitface, randomized clinical trial found Radiesse to be
superior to Juvéderm and Perlane for improvement in
nasolabial fold depth.139 A similarly designed study by
the same authors concluded superiority of Radiesse
over Restylane.184 Radiesse can be safely combined
with local anesthetic without loss of efficacy.185−187
Dallara et al.188 provided detailed consensus
recommendations for the use of Radiesse. In January
2015, the FDA approved Radiesse Plus, which
contains 0.3 mL of lidocaine (Fig. 14B)
SPECIAL TOPIC: HAND REJUVENATION
A topic of recent interest is the use of fillers for hand
rejuvenation. Aging hands are characterized by dermal
thinning and loss of subcutaneous fat, which leads
to prominence of the musculoskeletal and venous
structures of the hand. Injection of HA products
into the subcutaneous tissue and mid dermis of the
hand has been reported, with results lasting 6 to 9
months.189−191 The efficacy and safety of Scupltra for
hand rejuvenation when injected into subcutaneous
tissue has been published, with some studies finding
sustained results at 15 months.192−195 Radiesse has
become a popular option for hand rejuvenation and
has been more extensively studied for this purpose
Figure 14. A, Radiesse; B, Radiesse Plus. (Images courtesy of
Merz Aesthetics.)
19
compared with HA and Sculptra. Its safety and
efficacy for volume restoration of the aging hand
have been well established, with results lasting from
1 to 2 years.185,196−200 To receive hand rejuvenation
fillers, patients are placed in the Trendelenburg
position to reduce venous pressure. The injections
proceed parallel to the metacarpals or in a fanning
pattern. Massage of the area is recommended to
prevent nodule formation, particularly with the use
of Sculptra.191 Patients are asked to keep their hands
elevated for 24 hours after the procedure to minimize
edema, particularly with Radiesse.191 A randomized
study to validate a hand grading scale was conducted
(supported by Merz Aesthetics). The results of the live
validation study showed consistent inter- and intrarater agreement. The hand grading scale is considered
suitable for live assessment in clinical studies to
grade dorsal hand conditions.201 After reviewing
data presented in March 2015, the FA Advisory
Panel recommended approval of Radiesse for hand
rejuvenation.202 Approval is expected later in the year.
Permanent Injectables
Polymethylmethacrylate (PMMA)
PMMA, developed in 1928, is also known as
Plexiglas, Acrylite, Lucite, and acrylic glass. It has been
used in numerous medical applications for years,
including bone cement, lenses, dental work, and
pacemakers. Bellafill (formerly called Artefill; Suneva
Medical, San Diego, CA) (Fig. 15) is a gel suspension
of 20% PMMA homogeneous 30- to 42-mm
microspheres in 3.5% bovine collagen solution mixed
with 0.3% lidocaine.210 Because it contains bovine
collagen, patients must undergo skin testing 1 month
before injection.13 Bellafill received FDA approval
for the correction of moderate to severe atrophic,
distensible facial scars on the cheeks in patients older
than 21 years.
described in detail by Coleman,201 and various
techniques of harvesting, handling, and grafting
have been attempted and have resulted in acceptable
patient satisfaction.201−204 Successful fat grafting
involves diffuse infiltration using multiple passes
while grafting small aliquots of fat with each pass.
This is thought to increase the contact area of the
grafted fat with the recipient tissue vascular bed,
improving long-term viability. The grafted fat seems
to stabilize at approximately 4 months but can
continue to lose volume for up to 1 year.202 Shuck et
al.205 provided a review of safety, efficacy, and longterm outcomes of autologous fat grafting for human
immunodeficiency virus-associated lipoatrophy.
Autologous Dermis
The use of autologous dermis as an injectable
filler is currently under investigation. Bassetto et
al.206 presented a series of 16 patients undergoing
concomitant cosmetic procedures who were later
injected with morselized autologous dermis for lip or
nasolabial fold correction. Volume was maintained
in all 16 patients at 1 year. Two patients experienced
6 months of palpable firmness over the injected area.
This technique has not been studied extensively and
is available only to patients who are undergoing
concomitant procedures requiring excision of dermis.
Autologous Fat
Autologous fat is the original injectable.5 It is fully
biocompatible and plentiful. Unfortunately, the
degree of permanency varies. A technique has been
20
Figure 15. Bellafill treatment kit. (Image courtesy of Suneva.)
Silicone
Injectable silicone is produced from silica and
polymerized dimethylsiloxane and is inert. It is
FDA-approved for use in the eye for severe retinal
detachment. A microdroplet (0.01-0.03 mL)
injection technique allows for dispersion in tissue,
where the material can become encapsulated as
microparticles.207 The two brands available are
Silikon 1000 (Alcon, Fort Worth, TX) and Adaptosil
5000 (Bausch & Lomb, Rochester, NY). The
numbers 1000 and 5000 correlate to the viscosity in
centistokes (cSt), with water having a viscosity of 1
cSt at 20 degrees Celsius. The use of these products as
injectable fillers for cosmetic purposes is off-label.
Narins and Beer208 provided a review of
the technical considerations, complications, and
polarizing nature of injectable silicone. Fulton and
Caperton.209 presented a series of 95 patients who
underwent injection with Silikon emulsified in crosslinked HA and concluded that the combination is
safe, effective, and permanent.
Its use in Europe has been extensively studied,
with the results of more than 15,000 patients
represented in clinical trials and data indicating a
duration of effect lasting up to 15 years.211 High
patient satisfaction is consistently reported along with
low rates of adverse effects.212 A detailed review of
injection techniques, indications, and applications of
ArteFill can be found in a paired series by Lemperle
et al.211,213 Considering that ArteFill is a permanent
product, proper technique is critical to prevent
complications such as ridge formation, nodules, and
long-lasting erythema.214,215
PATIENT SELECTION
Satisfaction is a priority considering that injectables
for facial rejuvenation are elective cosmetic
procedures. Proper patient counseling should include
goals, limitations, complications, and the realistic
financial commitment associated with injectables.
Photographs assist in documenting and addressing
areas to be treated.
Before placing injectables, a complete patient
history should be obtained, including current
medications and herbals, previous allergic reactions
and sensitivities, previous facial rejuvenation
(procedures, implants, or injectables), and
personal medical history, including acne, keloids,
dental abscesses, herpes simplex infections, and
immunocompromised states.216
If possible, patients should discontinue
medications, including herbal supplements (arnica,
garlic, ginger, ginseng, Gingko biloba, St. John’s Wort,
vitamin E, etc.), that might cause bleeding 7 to 10
days before procedures to decrease bruising.217,218
Patients who are taking aspirin, non-steroidal antiinflammatory drugs, Coumadin (Bristol-Myers
Squibb, Washington, DC), or Plavix (Bristol-Myers
Squibb; and Sanofi US, Bridgewater, NJ) might have
medical indications for which the risk of stopping
these medications (≤50%) could far outweigh the
benefit. The guidelines put forth by the American
College of Chest Physicians recommend continuance
of anticoagulation for minor dermatological
procedures with low risk of bleeding.219
INJECTION TECHNIQUES
It is important to realize that practitioners are
performing procedures that implant foreign materials.
Contamination should be avoided to reduce
infectious adverse events. Hands should be washed.
Make-up should be removed and reapplication
delayed at least 4 hours. Skin should be cleansed
before injection. A sterile technique should be used
during reconstitution and dilution of product. One
should consider changing gloves after intra-oral
manipulation. Injection during active skin infections
should be avoided. Use of the smallest needles to
achieve the desired effect is recommended.216
The importance of skin preparation with
injectables is unknown. Alcohol cleansing is
commonly performed. Alternatively, Betadine can
be used. Calfee and Farr220 found no difference
in contamination of blood cultures between 10%
iodine, 70% alcohol, or a combination of the two,
concluding that alcohol be used considering cost.
Chlorhexidine might have the benefit of a residual
21
antibacterial effect not achieved with alcohol and is
currently recommended for use before placement of
central venous catheters.221 Of note, chlorhexidine
should be avoided in the periorbital region because
of the associated risk for keratitis.222 It is important
to remember to spread the skin during cleansing to
get into wrinkles. Prophylactic antibiotics have been
suggested to prevent biofilms in situations in which
semi-permanent or permanent fillers are used initially
or later during notable infections.
Topical anesthetics or nerve blocks can be used;
however, concomitant injection of local anesthetic
and fillers has been described185,186,223 and is gaining
popularity. Needle gauge and length vary depending
on the product, dilution, and application location.
Smaller needles might reduce pain, injection site
trauma, adjacent tissue trauma, and risk of infection.
As a general rule, the smallest needle that allows
accurate injection with optimal results should be
used: 30-gauge for less viscous, 27-gauge for more
viscous, such as CaHA, or 25-gauge for poly-L-lactic
acid to avoid clumping or clogging.216 Lemperle
et al.214 recommended using a 26-gauge needle,
which acts as a guide to dermal thickness. The outer
diameter of the needle is 0.5 mm, whereas the
dermis is two needle diameters in thickness: 1 mm
in frown lines (facial dermis range, 0.4−1.2 mm).
General visual clues regarding needle depth include
the following: intradermal, see the gray of the needle;
superficial subdermal, see the shape of the needle;
and deep subdermal, fat is pressed down with the tip
of the needle.214,224,225 Arlette and Trotter226 reported
that despite classic teachings of dermal injection, the
majority of product is found in the subcutis. Several
injection techniques are commonly described (Fig.
16).227
The serial puncture and droplet technique
deposits small aliquots by using multiple injections
along the wrinkle or fold. Injections are placed close
together to allow the filler to blend into a smooth,
continuous line that lifts the wrinkle or fold, which
can be assisted by molding and massage. The
technique is useful for enhancement of the philtral
columns and for correction of fine rhytides.
22
Linear threading deposits the injectable as
the needle is advanced (anterograde) or withdrawn
(retrograde). Anterograde injection might be less
painful; theoretically, it minimizes trauma by
hydrodissection and might cause less bruising by
pushing blood vessels out of the way. This technique
might be useful for enhancing the nasolabial folds and
the vermiliocutaneous border by finding the potential
spaces with limited needle movement. Retrograde
injection might avoid intravascular injection, as in the
glabellar region, and does not create additional tracks
or dissection planes.103,161
Fanning involves multiple passes in different
directions without withdrawing the needle. The
needle can also be passed several times, superimposing
deep and superficial layers of fillers, which is thought
to achieve superior results for the nasolabial fold.
Cross-hatching involves linear injection in
an evenly sp aced grid pattern. This is effective for
large areas, three-dimensional filling, and the oral
commissures.228
Glogau and Kane134 conducted a prospective,
blinded, controlled study of injection techniques.
They found that techniques that increase the
dissection of the subepidermal plane (fanlike needle
use, rapid injection, rapid flow rates, and higher
volumes) increase the incidence of local adverse events
whereas injection techniques that increase epidermal
damage (multiple punctures, deep subcutaneous
injection) have no effect on adverse events.
A recent enhancement to injection of softtissue fillers is the use of a blunt-tip cannula. Because
of the nature of a blunt tip versus a sharp needle,
these devices produce less trauma to the tissues and
decrease the risk for blood vessel rupture. The result
is less bruising and less pain.229 In addition, the use of
blunt-tip cannulae allows the physician to treat larger
areas with fewer injection points. Blunt-tip cannulae
are available in many sizes from a variety
of companies.
Post-procedure management can include
cold compresses or ice to help reduce swelling and
tenderness. Reduced facial expression for the first 48
hours might minimize migration.161
Figure 16. Injection techniques: serial puncture (above, left), linear threading (above, right), fanning (below, left) and
cross-hatching or radial (below, right). (Reprinted with permission from Rohrich et al.227)
COMBINATION THERAPY
COMPLICATIONS
With the evolution of the understanding of facial
rejuvenation, combination modalities are increasing
to address the three-dimensional face.3,230,231 Stacking
of fillers, especially permanent on top of permanent,
and large-volume injections have been associated with
more inflammation and granuloma formation.232,233
Carruthers and Carruthers232 conducted a prospective,
randomized study of Botox in combination with HA
filler and observed improved outcomes in comparison
with those of HA filler alone for glabellar rhytides.
The combination treatment almost doubled the
duration of response. Carruthers et al.103 published
their consensus recommendations for botulinum
toxin and HA combination therapies in 2008.
Injectables available in the US have excellent
safety profiles with rare side effects.13,14,234 The
most common complications are procedural or
technique-related as opposed to product-based,
such as inappropriate placement of injectables,
usually too superficially.130,180,185 Adverse reactions
to injectables generally are transient and mild
and include redness, swelling, bruising, and
itching.80,128,137,142,155−159,162,163,170,181,234−238 Early
injection site reactions can be limited by applying ice
or cold compresses to minimize bruising and swelling.
Nodule formation is a complication that can
occur with all fillers but is particularly common
23
with Sculptra and Radiesse because of their
molecular characteristics.163,170,181,236−238 A nodule
formation rate of up to 52% has been reported
for Sculptra;163,170,236,237 however, a low nodule rate
of 4.2% was published in a study by Schierle and
Casas.163 The authors attribute the low rate to their
reconstitution technique.
Hypersensitivity to fillers can be as severe as
angioedema and anaphylaxis.239 Antihistamines,
topical immunomodulators (Aldara; Graceway
Pharmaceuticals, LLC, Bristol, TN), tacrolimus,
and steroid injections are effective in managing
immunological reactions.225
Injections around the lips can trigger herpetic
outbreaks. If the patient has a history of herpes,
prophylactic antiviral treatment should be considered,
especially when injecting around the lips.240
Intra-arterial injection can cause injection site
necrosis and has been reported to occur in both the
supraorbital artery during glabellar injection and
the angular artery during injection of the nasolabial
folds.241-243 The glabella is thought to be at highest
risk because the supratrochlear artery provides a
watershed area. It is always important to remember
the anatomy when using injectables. Specifically, the
supratrochlear artery runs deep (therefore, injections
should be superficial) whereas the angular artery
runs superficially (thus, injections should be deep).
Venous occlusion can also occur if excessive product
placement results in venous external compression.
This might present as dull aching pain and swelling
with violaceous discoloration.244
Vascular embarrassment can be minimized by
simple techniques. Always aspirate before injection.
Use lower volumes in high-risk areas. Remember
knowledge of vascular anatomy and depth planes.
Treat one side at a time. Pinch or tent the skin to
provide more space. Occlude the vessels at their
origins.241,245
Early intervention when encountering vascular
compromise might prevent necrosis, with the goal
of increasing blood flow. The procedure should
immediately be aborted and the area massaged to
24
disperse the material. Warm gauze and nitroglycerin
paste will promote vasodilation. Hyaluronidase
injection (for HA fillers) can be used to decompress
the vessels.246 Hyperbaric oxygen can be considered.
Essential products to have available when using
injectables include ice, heat, nitroglycerin, and
hyaluronidase. Hyaluronidase might result in
sensitivity, especially in patients with bee venom
allergies.
The Tyndall effect refers to the blue
discoloration seen when soft-tissue fillers are injected
too superficially. This occurs because of light
scattering differently depending on the diameter
of particles encountered.247 Visible blanching and
immediate appearance of lumps and bumps are
technical errors of product placement, such as filler
placement that is too superficial, which can be
avoided by slowing down the injection and using
finer-gauge needles. This will avoid inflammatory
nodules or hypertrophic scarring. Although Belotero
has been reported to not cause a Tyndall effect, even
with superficial injections, care should be taken
when injecting fine rhytides. Immediate massage of
products might minimize nodules or irregularities.
Late complications include migration,
discoloration, scarring, atrophy, biofilm
development,248-250 and foreign body granulomas,
which is the body’s attempt to remove unfamiliar
material. Foreign body granulomas occur
at an incidence of 0.01% to 0.1% for most
fillers.224,251-257 Histologically, the granulomas
consist of inflammatory lymphocytes, neutrophils,
eosinophils, multinucleated giant cells, and plasma
cells. Causes of granuloma formation include
using high-viscosity fillers, large-particle fillers,
impure products, and biofilms. The diagnosis of
filler foreign body granuloma should be based on
clinical findings.210,249,252,253,258 Steroid injections are
proven treatments of granulomas.222 Cassuto and
Sundaram259 provided an overview of the classification
and recommendations for treatment of nodular
complications after HA and CaHA filler injections.
Complications should be approached in
an algorithmic manner, and early recognition is
important (Fig. 17).250 If the injection was performed
by someone else, every attempt should be made to
determine what was injected into the site. A recent
study argued for the use of infrared spectroscopy
as an imaging modality to identify the specific
filler injected into tissue in cases of severe adverse
reactions.260 In cases with even very mild signs of
infection, one should assume infection is present and
prove it is not.
ETHICS
If the wound is fluctuant, it should be needledrained and cultured. Cultures should be sent to the
laboratory immediately for appropriate handling.
Preliminary antibiotic regimens should consist of
at least a two-drug therapy, such as administration
of a quinolone and third-generation macrolide,
to prevent further biofilm deposition. Macrolides
have been shown to be uniquely effective, which
seems to be related to improved accumulation
in the subcutaneous fat (where the filler material
typically resides), and they might also block quorum
sensing.261 After a trial of antibiotics, intralesional
high-dose steroids should be considered.225 If HA was
used, hyaluronidase should also be considered.262 The
use of laser-assisted evacuation of filler material as an
intermediate step between medications and surgery
can be considered.263 Excision should be the
last step.250
Three models for delivery of injectables by
qualified providers are available: physician delivery
model, physician extender delivery model, and
combined delivery model. The individual physician
of record is ultimately responsible to ensure that any
non-physician administering injectables possesses
the proper education and training.265 The American
Society of Plastic Surgeons (ASPS) and the ASAPS
published the Joint ASPS & ASAPS Guiding
Principles: Supervision of Non-Physician Personnel in
Medical Spas and Physician Offices.266 This publication
provides guiding principles to protect patients and
improve quality of care. A central registry, or filler
passport, has been suggested to maintain records
while also minimizing unqualified practitioners and
unregulated products.250
The majority of cosmetic injectable use is off-label,
and it is illegal to commercially advertise any nonapproved or off-label use. Off-label use must not be
experimental and should have general acceptance
by the medical community in peer-approved
publications or presentations. The patient must be
informed of the off-label use.264
Figure 17. Management algorithm of late and delayed complications of soft-tissue injectables (Reprinted with permission from
Rohrich et al.250)
25
REFERENCES
1.American Society for Aesthetic Plastic Surgery. Cosmetic
Surgery National Data Bank Statistics. http://www.surgery.
org/media/statistics Last accessed, April 9, 2014.
M, Lillibridge S, Osterholm MT, O’Toole T, Parker G, Perl
TM, Russell PK, Swerdlow DL, Tonat K, Working Group
on Civilian Biodefense. Botulinum toxin as a biological
weapon: medical and public health management. JAMA
2001;285:1059−1070.
2.Donath AS, Glasgold RA, Glasgold MJ. Volume loss versus
gravity: New concepts in facial aging. Curr Opin Otolaryngol
Head Neck Surg 2007;15:238–243.
19.Kerner J. Vergiftung durch verdorbene Würste [in
German]. Tübinger Blätt Naturwissenschaften Arzneykunde
1817;3:1–25.
3.Rohrich RJ, Pessa JE, Ristow B. The youthful cheek and
the deep medial fat compartment. Plast Reconstr Surg
2008;121:2107–2112.
20.Scott AB, Rosenbaum A, Collins CC. Pharmacologic
weakening of extraocular muscles. Invest Ophthalmol
1973;12:924–927.
4.Gonzalez-Ulloa M, Flores ES. Senility of the face: Basic
study to understand its causes and effects. Plast Reconstr
Surg 1965;36:239–246.
21.Scott AB. Botulinum toxin injection into extraocular
muscles as an alternative to strabismus surgery. J Pediatr
Ophthalmol Strabismus 1980;17:21–25.
5.Neuber F. Fettransplantation [in German]. Chir Kongr
Verhandl Dsch Gesellch Chir 1893;22:66.
22.Lowe NJ, Glaser DA, Eadie N, Dagget S, Kowalski JW,
Lai PY. Botulinum toxin type A in the treatment of primary
axillary hyperhidrosis: A 52-week multicenter double-blind,
randomized, placebo-controlled study of efficacy and safety.
J Am Acad Dermatol 2007;56:604–611.
6.Gersuny R. Ueber eine subcutane prothese [in German].
Ztschr Heilkunde 1900;199–204.
7.Miller C. Cannula Implants and Review of Implantation
Technics in Esthetic Surgery. Chicago: The Oak Press; 1926.
8.Rogers BO. A brief history of cosmetic surgery. Surg Clin
North Am 1971;51:265–288.
9.Ellenbogen R, Rubin L. Injectable fluid silicone therapy:
Human morbidity and mortality. JAMA 1975;234:308–309.
10.Achauer BM. A serious complication following medicalgrade silicone injection of the face. Plast Reconstr Surg
1983;71:251–254.
11.Illouz YG. The fat cell “graft”: A new technique to fill
depressions. Plast Reconstr Surg 1986;78:122–123.
12.Klein AW, Elson ML. The history of substances for soft
tissue augmentation. Dermatol Surg 2000;26:1096–1105.
13.Broder KW, Cohen SR. An overview of permanent and
semipermanent fillers. Plast Reconstr Surg 2006;118[suppl
3]:7S–14S.
14.Matarasso SL. Injectable collagens: Lost but not
forgotten: A review of products, indications, and injection
techniques. Plast Reconstr Surg 2007;120[suppl 6]:17S–26S.
15.Huang W, Foster JA, Rogachefsky AS. Pharmacology of
botulinum toxin. J Am Acad Dermatol 2000;43:249–259.
16.Simpson LL. The origin, structure, and pharmacological
activity of botulinum toxin. Pharmacol Rev 1981;33:155–188.
17.Wortzman MS, Pickett A. The science and manufacturing
behind botulinum neurotoxin type A-ABO in clinical use.
Aesthet Surg J 2009;29[suppl 6]:S34–S42.
18.Arnon SS, Schechter R, Inglesby TV, Henderson DA,
Bartlett JG, Ascher MS, Eitzen E, Fine AD, Hauer J, Layton
26
23.Heckmann M, Ceballos-Baumann AO, Plewig G.
Botulinum toxin A for axillary hyperhidrosis (excessive
sweating). N Engl J Med 2001;344:488–493.
24.Carruthers A, Carruthers J. History of the cosmetic use of
botulinum A exotoxin. Dermatol Surg 1998;24:1168–1170.
25.Carruthers A, Carruthers J. Clinical indications and
injection technique for the cosmetic use of botulinum A
exotoxin. Dermatol Surg 1998;24:1189–1194.
26.Dayan SH, Lieberman ED, Thakkar NN, Larimer KA,
Anstead A. Botulinum toxin A can positively impact first
impression. Dermatol Surg 2008;34[suppl 1]:S40–S47.
27.Wang YC, Burr DH, Korthals GJ, Sugiyama H. Acute
toxicity of aminoglycoside antibiotics as an aid in detecting
botulism. Appl Environ Microbiol 1984;48:951–955.
28.Hoare BJ, Wallen MA, Imms C, Villanueva E, Rawicki
HB, Carey L. Botulinum toxin A as an adjunct to treatment
in the management of the upper limb in children with
spastic cerebral palsy (UPDATE). Cochrane Database Syst Rev
2010;1:CD003469.
29.Allergan, Inc. Botox Cosmetic (OnabotulinumtoxinA) for
Injection: Full Prescribing Information. Irvine: Allergan, Inc.;
2009.
30.Pickett A. Dysport: Pharmacological properties and
factors that influence toxin action. Toxicon 2009;54:683–689.
31.Antonucci F, Rossi C, Gianfranceschi L, Rossetto O,
Caleo M. Long-distance retrograde effects of botulinum
neurotoxin A. J Neurosci 2008;28:3689–3696.
32.Tang-Liu DD, Aoki KR, Dolly JO, de Paiva A, Houchen
TL, Chasseaud LF, Webber C. Intramuscular injection of
125I-botulinum neurotoxin-complex versus 125I-botulinumfree neurotoxin: Time course of tissue distribution. Toxicon
2003;42:461–469.
33.Borodic G. Immunologic resistance after repeated
botulinum toxin type a injections for facial rhytides. Ophthal
Plast Reconstr Surg 2006;22:239−240.
Full Prescribing Information. Scottsdale: Medicis Aesthetics,
Inc.; 2009.
46.Rubin M, Dover J, Maas C, Nestor M. An analysis of safety
data from five phase III clinical trials on the use of botulinum
neurotoxin type A-ABO for the treatment of glabellar lines.
34.Lee SK. Antibody-induced failure of botulinum toxin
type A therapy in a patient with masseteric hypertrophy.
Dermatol Surg 2007;33[suppl 1]:S105−S110.
47.Baumann L, Brandt FS, Kane MA, Donofrio LM. An
analysis of efficacy data from four phase III studies of
botulinum neurotoxin type A-ABO for the treatment of
glabellar lines. Aesthet Surg J 2009;29[suppl 6]:S57–S65.
35.Yablon SA, Brashear A, Gordon MF, Elovic EP, Turkel
CC, Daggett S, Liu J, Brin MF. Formation of neutralizing
antibodies in patients receiving botulinum toxin type A for
treatment of poststroke spasticity: A pooled-data analysis of
three clinical trials. Clin Ther 2007;29:683–690.
48.Rubin MG, Dover J, Glogau RG, Goldberg DJ, Goldman
MP, Schlessinger J. The efficacy and safety of a new U.S.
botulinum toxin type A in the retreatment of glabellar
lines following open-label treatment. J Drugs Dermatol
2009;8:439–444.
36.Brin MF, Comella CL, Jankovic J, Lai F, Naumann M. Longterm treatment with botulinum toxin type A in cervical
dystonia has low immunogenicity by mouse protection
assay. Mov Disord 2008;23:1353–1360.
49.Kane MA, Brandt F, Rohrich RJ, Narins RS, Monheit GD,
Huber MB. Evaluation of variable-dose treatment with a
new U.S. botulinum toxin type A (Dysport) for correction of
moderate to severe glabellar lines: Results from a phase III,
randomized, double-blind, placebo-controlled study. Plast
Reconstr Surg 2009;124:1619–1629.
37.Klein AW. Complications, adverse reactions, and
insights with the use of botulinum toxin. Dermatol Surg
2003;29:549–556.
38.Herrero BA, Ecklung AE, Streett CS, Ford DF, King JK.
Experimental botulism in monkeys: A clinical pathological
study. Exp Mol Pathol 1967;6:84–95.
39.Ting PT, Freiman A. The story of Clostridium botulinum:
From food poisoning to Botox. Clin Med 2004;4:258–261.
40.Scott AB, Suzuki D. Systemic toxicity of botulinum
toxin by intramuscular injection in the monkey. Mov Disord
1988;3:333–335.
41.Alam M, Dover JS, Arndt KA. Pain associated with
injection of botulinum A exotoxin reconstituted using
isotonic sodium chloride with and without preservative: A
double-blind, randomized controlled trial. Arch Dermatol
2002;138:510–514.
42.Carruthers J, Fagien S, Matarasso SL. Consensus
recommendations on the use of botulinum toxin type
A in facial aesthetics. Plast Reconstr Surg 2004;114[suppl
6]:1S–22S.
43.Hexsel DM, De Almeida AT, Rutowitsch M, De Castro
IA, Silveira VL, Gobatto DO, Zechmeister M, Mazzuco
R, Zechmeister D. Multicenter, double-blind study of
the efficacy of injections with botulinum toxin type
A reconstituted up to six consecutive weeks before
application. Dermatol Surg 2003;29:523–529.
44.Klein AW. Dilution and storage of botulinum toxin.
Dermatol Surg 1998;24:1179–1180.
45.Medicis Aesthetics, Inc. Dysport (AbobotulinumtoxinA):
50.Brandt F, Swanson N, Baumann L, Huber B. Randomized,
placebo-controlled study of a new botulinum toxin type A
for treatment of glabellar lines: Efficacy and safety. Dermatol
Surg 2009;35:1893–1901.
51.Moy R, Maas C, Monheit G, Huber MB. Long-term safety
and efficacy of a new botulinum toxin type A in treating
glabellar lines. Arch Facial Plast Surg 2009;11:77–83.
52.Cohen JL, Schlessinger J, Cox SE, Lin X. An analysis of
the long-term safety data of repeat administrations of
botulinum neurotoxin type A-ABO for the treatment of
glabellar lines. Aesthet Surg J 2009;29[suppl 6]:S43–S49.
53.Schlessinger J, Dover JS, Joseph J, Monheit G, Nelson
DB, Albright CD, Axford-Gatley RA, Cohen JL; Dysport
Study Group. Long-term safety of abobotulinumtoxinA for
the treatment of glabellar lines: Results from a 36-month,
multicenter, open-label extension study. Dermatol Surg
2014;40:176−183.
54.Cavallini M, Cirillo P, Fundarò SP, Quartucci S, Sciuto C,
Sito G, Tonini D, Trocchi G, Signorini M. Safety of botulinum
toxin A in aesthetic treatments: A systematic review of
clinical studies. Dermatol Surg 2014;40:525−536.
55.Lawrence I, Moy R. An evaluation of neutralizing
antibody induction during treatment of glabellar lines with
a new U.S. formulation of botulinum neurotoxin type A.
56.Matarasso A, Shafer D. Botulinum neurotoxin type
A-ABO (Dysport): Clinical indications and practice guide.
27
57.Matarasso SL. Comparison of botulinum toxin types A
and B: A bilateral and double-blind randomized evaluation
in the treatment of canthal rhytides. Dermatol Surg
2003;29:7–13.
58.Carruthers J, Carruthers A. Botulinum toxin A in the mid
and lower face and neck. Dermatol Clin 2004;22:151–158.
59.Lowe PL, Patnaik R, Lowe NJ. A comparison of two
botulinum type A toxin preparations for the treatment
of glabellar lines: Double-blind, randomized, pilot study.
Dermatol Surg 2005;31:1651–1654.
60.Lowe P, Patnaik R, Lowe N. Comparison of two
formulations of botulinum toxin type A for the treatment of
glabellar lines: A double-blind, randomized study. J Am Acad
Dermatol 2006;55:975–980.
61.Rzany B, Nast A. Head-to-head studies of botulinum
toxin A in aesthetic medicine: Which evidence is good
enough? J Am Acad Dermatol 2007;56:1066–1067.
62.Kassir R, Kolluru A, Kassir M. Triple-blind, prospective,
internally controlled comparative study between
abobotulinumtoxinA and onabotulinumtoxinA for
the treatment of facial rhytids. Dermatol Ther (Heidelb)
2013;3:179−189.
63.Kim NH, Park RH, Park JB. Botulinum toxin type A for
the treatment of hypertrophy of the masseter muscle. Plast
Reconstr Surg 2010;125:1693−1705.
64.Trindade de Almeida AR, Marques E, de Almeida J,
Cunha T, Boraso R. Pilot study comparing the diffusion of
two formulations of botulinum toxin type A in patients
with forehead hyperhidrosis. Dermatol Surg 2007;33[suppl
1]:S37–S43.
65.Hexsel D, Dal’Forno T, Hexsel C, Do Prado DZ, Lima MM.
A randomized pilot study comparing the action halos of
two commercial preparations of botulinum toxin type A.
Dermatol Surg 2008;34:52–59.
66.Hexsel D, Brum C, do Prado DZ, Soiremann N, Rotta FT,
Dal’Forno T, Rodrigues TC. Field effect of two commercial
preparations of botulinum toxin type A: A prospective,
double-blind, randomized clinical trial. J Am Acad Dermatol
2012;67:226−232.
67.Hexsel D, Hexsel C, Siega C, Schilling-Souza J, Rotta
FT, Rodrigues TC. Fields of effects of 2 commercial
preparations of botulinum toxin type A at equal labeled
unit doses: A double-blind randomized trial. JAMA Dermatol
2013;149:1386−1391.
68.Merz Aesthetics Inc. Xeomin, incobotulinumtoxinA:
Important safety information, full prescribing information,
and medication guide. www.xeominaesthetic.com Last
accessed, October 20, 2014.
28
69.Pickett A, Perrow K. Formulation composition
of botulinum toxins in clinical use. J Drugs Dermatol
2010;9:1085−1091.
70.Brodsky MA, Swope DM, Grimes D. Diffusion of
botulinum toxins. Tremor Other Hyperkinet Mov (N Y) 2012;2.
71.Kerscher M, Roll S, Becker A, Wigger-Alberti W.
Comparison of the spread of three botulinum toxin type A
preparations. Arch Dermatol Res 2012;304:155−161.
72.Wang L, Sun Y, Yang W, Lindo P, Singh BR. Type A
botulinum neurotoxin complex proteins differentially
modulate host response of neuronal cells. Toxicon
2014;82:52−60.
73.Brown M, Nicholson G, Ardila MC, Sartorius A, Broide RS,
Clarke K, Hunt T, Francis J. Comparative evaluation of the
potency and antigenicity of two distinct BoNT/A-derived
formulations. J Neural Transm 2013;120:291−298.
74.Sattler G, Callander MJ, Grablowitz D, Walker T, Bee
EK, Rzany B, Flynn TC, Carruthers A. Noninferiority of
incobotulinumtoxinA, free from complexing proteins,
compared with another botulinum toxin type A in
the treatment of glabellar frown lines. Dermatol Surg
2010;36[suppl 4]:2146−2154.
75.Roggenkämper P, Jost WH, Bihari K, Comes G, Grafe S;
NT 201 Blepharospasm Study Team. Efficacy and safety of
a new botulinum toxin type A free of complexing proteins
in the treatment of blepharospasm. J Neural Transm
2006;113:303−312.
76.Benecke R, Jost WH, Kanovsky P, Ruzicka E, Comes G,
Grafe S. A new botulinum toxin type A free of complexing
proteins for treatment of cervical dystonia. Neurology
2005;64:1949−1951.
77.Rappl T, Parvizi D, Friedl H, Wiedner M, May S,
Kranzelbinder B, Wurzer P, Hellbom B. Onset and duration
of effect of incobotulinumtoxinA, onabotulinumtoxinA, and
abobotulinumtoxinA in the treatment of glabellar frown
lines: A randomized, double-blind study. Clin Cosmet Investig
Dermatol 2013;6:211−219.
78.Lorenc ZP, Kenkel JM, Fagien S, Hirmand H, Nestor
MS, Sclafani AP, Sykes JM, Waldorf HA. Consensus panel’s
assessment and recommendations on the use of 3
botulinum toxin type A products in facial aesthetics. Aesthet
Surg J 2013;33[suppl 1]:35S−40S.
79.Merz North America, Inc. Xeomin, incobotulinumtoxinA:
Cervical dystonia blepharospasm and moderate to severe
frown lines between the eyebrows. www.xeomin.com Last
80.Carruthers A, Carey W, De Lorenzi C, Remington
K, Schachter D, Sapra S. Randomized, double-blind
comparison of the efficacy of two hyaluronic acid
derivatives, Restylane Perlane and Hylaform, in
the treatment of nasolabial folds. Dermatol Surg
2005;31:1591−1598.
81.Chapman MA, Barron R, Tanis DC, Gill CE, Charles PD.
Comparison of botulinum neurotoxin preparations for the
treatment of cervical dystonia. Clin Ther 2007;29:1325−1337.
82.Lee DH, Jin SP, Cho S, Feneran A, Youn CS, Won CH, Park
GH, Kim BW, An J, Chang SE, Lee MW. RimabotulinumtoxinB
versus onabotulinumtoxinA in the treatment of masseter
hypertrophy: A 24-week double-blind randomized split-face
study. Dermatology 2013;226:227−232.
83.Flynn TC, Clark RE II. Botulinum toxin type B (MYOBLOC)
versus botulinum toxin type A (BOTOX) frontalis study: Rate
of onset and radius of diffusion. Dermatol Surg 2003;29:
519–522.
84.Allergan. Botox onabotulinumtoxinA and Botox
Cosmetic. www.botox.com Last accessed, October 20, 2014.
85.Sato K, Kang WH, Saga K, Sato KT. Biology of sweat
glands and their disorders: II. Disorders of sweat glad
function. J Am Acad Dermatol 1989;20:713−726.
86.Schnider P, Binder M, Auff E, Kittler H, Berger T,
Wolff K. Double-blind trial of botulinum A toxin for the
treatment of focal hyperhidrosis of the palms. Br J Dermatol
1997;136:548−552.
87.Lakraj AA, Moghimi N, Jabbari B. Hyperhidrosis:
Anatomy, pathophysiology and treatment with emphasis on
the role of botulinum toxins. Toxins (Basel) 2013;5:821−840.
88.Dressler D. Comparing Botox and Xeomin for axillar
hyperhidrosis. J Neural Transm 2010;117:317−319.
89.Naumann M, Lowe NJ. Botulinum toxin type A in
treatment of bilateral primary axillary hyperhidrosis:
Randomised, parallel group, double blind, placebo
controlled trial. BMJ 2001;323:596−599.
90.Odderson IR. Long-term quantitative benefits of
botulinum toxin type A in the treatment of axillary
hyperhidrosis. Dermatol Surg 2002;28:480−483.
91.Vadoud-Seyedi J, Simonart T. Treatment of axillary
hyperhidrosis with botulinum toxin type A reconstituted in
lidocaine or in normal saline: A randomized, side-by-side,
double-blind study. Br J Dermatol 2007;156:986−989.
92.Güleç AT. Dilution of botulinum toxin A in lidocaine
vs. in normal saline for the treatment of primary axillary
hyperhidrosis: A double-blind, randomized, comparative
preliminary study. J Eur Acad Dermatol Venereol
2012;26:314−318.
93.Talarico-Filho S, Mendonça DO Nwscimento M,
Sperandeo DE Macedo F, DE Sanctis Pecora C. A doubleblind, randomized, comparative study of two type A
botulinum toxins in the treatment of primary axillary
hyperhidrosis. Dermatol Surg 2007;33[suppl 1]:S44−S50.
94.Montaser-Kouhsari L, Zartab H, Fanian F, Noorian N, Sadr
B, Nassiri-Kashani M, Firooz A. Comparison of intradermal
injection with iontophoresis of abobotulinum toxin A for the
treatment of primary axillary hyperhidrosis: A randomized,
controlled trial. J Dermatolog Treat 2014;25:337−341.
95.Campanati A, Giuliodori K, Martina E, Giuliano A,
Ganzetti G, Offidani A. Onabotulinumtoxin type A (Botox)
versus incobotulinumtoxin type A (Xeomin) in the
treatment of focal idiopathic palmar hyperhidrosis: Results
of a comparative double-blind clinical trial. J Neural Transm
2014;121:21−26.
96.Lowe NJ, Yamauchi PS, Lask GP, Patnaik R, Iyer S. Efficacy
and safety of botulinum toxin type A in the treatment of
palmar hyperhidrosis: A double-blind, randomized, placebocontrolled study. Dermatol Surg 2002;28:822−827.
97.Simonetta Moreau M, Cauhepe C, Magues JP, Senard JM.
A double-blind, randomized, comparative study of Dysport
vs. Botox in primary palmar hyperhidrosis. Br J Dermatol
2003;149:1041−1045.
98.Saadia D, Voustianiouk A, Wang AK, Kaufmann H.
Botulinum toxin type A in primary palmar hyperhidrosis:
Randomized, single-blind, two-dose study. Neurology
2001;57:2095-2099.
99.Kavanagh GM, Shams K. Botulinum toxin type A by
iontophoresis for primary palmar hyperhidrosis. J Am Acad
Dermatol 2006;55[suppl 5]:S115−S117.
100.Davarian S, Kalantari KK, Rezasoltani A, Rahimi A. Effect
and persistency of botulinum toxin iontophoresis in the
treatment of palmar hyperhidrosis. Australas J Dermatol
2008;49:75−79.
101.Revance Therapeutics, Inc. Leveraging development
across multiple aesthetic and therapeutic applications.
www.revance.com/product-pipeline Last accessed, October
20, 2014.
102.Glogau R, Blitzer A, Brandt F, Kane M, Monheit GD,
Waugh JM. Results of a randomized, double-blind, placebocontrolled study to evaluate the efficacy and safety of a
botulinum toxin type A topical gel for the treatment of
moderate-to-severe lateral canthal lines. J Drugs Dermatol
2012;11:38−45.
103.Carruthers JD, Glogau RG, Blitzer A. Advances in
facial rejuvenation: Botulinum toxin type A, hyaluronic
acid dermal fillers, and combination therapies: Consensus
recommendations. Plast Reconstr Surg 2008;121[suppl
5]:5S–30S.
104.Fagien S. Extended use of botulinum toxin type A in
facial aesthetic surgery. Aesthet Surg J 1998;18:215–219.
29
105.Carruthers J, Carruthers A. The adjunctive usage of
botulinum toxin. Dermatol Surg 1998;24:1244–1247.
106.Dayan SH, Kempiners JJ. Treatment of the lower third
of the nose and dynamic nasal tip ptosis with Botox. Plast
Reconstr Surg 2005;115:1784–1785.
107.Carruthers A, Carruthers J. Botulinum toxin type A:
History and current cosmetic use in the upper face. Semin
Cutan Med Surg 2001;20:71–84.
108.Polo M. Botulinum toxin type A (Botox) for the
neuromuscular correction of excessive gingival display on
smiling (gummy smile). Am J Orthod Dentofacial Orthop
2008;133:195–203.
Aesthetic Plast Surg 1985;9:145–151.
118.Carruthers J, Carruthers A. Mad cows, prions, and
wrinkles. Arch Dermatol 2002;138:667–670.
119.Gormley DE, Eremia S. Quantitative assessment of
augmentation therapy. J Dermatol Surg Oncol 1990;16:
1147–1151.
120.Bailey AJ. Perspective article: The fate of collagen
implants in tissue defects. Wound Repair Regen 2000;8:5–12.
121.Rohrich RJ. Semipermanent and permanent
dermal/subdermal fillers supplement. Plast Reconstr Surg
2006;118[suppl 3]:1S–3S.
109.Mangano A, Mangano A. Current strategies in the
treatment of gummy smile using botulinum toxin type A.
Plast Reconstr Surg 2012;129:1015e.
122.Shoshani D, Markovitz E, Cohen Y, Heremans A,
Goldlust A. Skin test hypersensitivity study of a cross-linked,
porcine collagen implant for aesthetic surgery. Dermatol
Surg 2007;33[suppl 2]:S152–S158.
110.Kim HJ, Yum KW, Lee SS, Heo MS, Seo K. Effects of
botulinum toxin type A on bilateral masseteric hypertrophy
evaluated with computed tomographic measurement.
123.Narins RS, Brandt FS, Lorenc ZP, Maas CS, Monheit GD,
Smith SR. Twelve-month persistency of a novel ribose-crosslinked collagen dermal filler. Dermatol Surg 2008;34[suppl
1]:S31–S39.
111.Park MY, Ahn KY, Jung DS. Botulinum toxin type A
treatment for contouring of the lower face. Dermatol Surg
2003;29:477–483.
124.Braun M, Braun S. Nodule formation following lip
augmentation using porcine collagen-derived filler. J Drugs
Dermatol 2008;7:579–581.
112.Rohrich RJ, Hanke CW, Busso M, Carruthers A, Fagien S.
Fitzgerals R, Glogau R, Greenberger PE, Lorenc ZP, Marmur
ES, Monheit GD, Pusic A, Rubin MG, Rzany B, Sclafani A,
Taylor S, Weinkle S, McGuire MF, Pariser DM, Casas LA,
Collishaw KJ, Dailey RA, Duffy SC, Edgar EJ, Greenan BL,
Haenlein K, Henrichs RA, Hume KM, Lum F, Nielsen DR,
Poulsen L, Shoaf L, Seward W, Begolka WS, Stanton RG,
Svedman KJ, Thomas JR, Sykes JM, Wargo C, Weiss RA. Facial
soft-tissue fillers conference: Assessing the state of the
science. Plast Reconstr Surg 2011;127[suppl 4]:22S−S.
125.Larsen NE, Pollak CT, Reiner K, Leshchiner E, Balazs
EA. Hylan gel biomaterial: Dermal and immunologic
compatibility. J Biomed Mater Res 1993;27:1129–1134.
113.Cohen JL, Dayan SH, Brandt FS, Nelson DB, AxfordGatley RA, Theisen MJ, Narins RS. Systematic review of
clinical trials of small- and large-gel-particle hyaluronic acid
injectable fillers for aesthetic soft tissue augmentation.
Dermatol Surg 2013;39:205−231.
128.André P. Evaluation of the safety of a non-animal
stabilized hyaluronic acid (NASHA: Q-Medical, Sweden) in
European countries: A retrospective study from 1997 to
2001. J Eur Acad Dermatol Venereol 2004;18:422–425.
114.Bauman L. CosmoDerm/CosmoPlast (human
bioengineered collagen) for the aging face. Facial Plast Surg
2004;20:125–128.
115.Knapp TR, Kaplan EN, Daniels JR. Injectable collagen for
soft tissue augmentation. Plast Reconstr Surg 1977;60:
398–405.
126.Monheit GD. Hyaluronic acid fillers: Hylaform and
Captique. Facial Plast Surg Clin North Am 2007;15:77–84.
127.Carruthers A, Carruthers J. Non-animal-based
hyaluronic acid fillers: Scientific and technical
considerations. Plast Reconstr Surg 2007;120[suppl
6]:33S–40S.
129.Fagien S, Klein AW. A brief overview and history of
temporary fillers: Evolution, advantages, and limitations.
Plast Reconstr Surg 2007;120[suppl 6]:8S–16S.
130.Narins RS, Bowman PH. Injectable skin fillers. Clin Plast
Surg 2005;32:151–162.
116.Kamer FM, Churukian MM. Clinical use of injectable
collagen: A three-year retrospective review. Arch Otolaryngol
1984;110:93–98.
131.Sundaram H, Voigts B, Beer K, Meland M. Comparison
of the rheological properties of viscosity and elasticity in
two categories of soft tissue fillers: Calcium hydroxylapatite
and hyaluronic acid. Dermatol Surg 2010;36[suppl
3]:1859−1865.
117.Cooperman LS, Mackinnon V, Bechler G, Pharriss
BB. Injectable collagen: A six-year clinical investigation.
132.Wang F, Garza LA, Kang S, Varani J, Orringer JS, Fisher
GJ, Voorhees JJ. In vivo stimulation of de novo collagen
30
production caused by cross-linked hyaluronic acid dermal
filler injections in photodamaged human skin. Arch
Dermatol 2007;143:155–163.
133.Matarasso SL, Carruthers JD, Jewell ML. Consensus
recommendations for soft-tissue augmentation with
nonanimal stabilized hyaluronic acid (Restylane). Plast
Reconstr Surg 2006;117[suppl 3]:3S–34S.
viscous 20-mg/mL hyaluronic acid volumizing filler:
Prospective European study. BMC Dermatol 2009;9:9.
144.Jones D, Murphy DK. Volumizing hyaluronic acid filler
for midface volume deficit: 2-year results from a pivotal
single-blind randomized controlled study. Dermatol Surg
2013;39:1602−1612.
134.Glogau RG, Kane MA. Effect of injection techniques on
the rate of local adverse events in patients implanted with
nonanimal hyaluronic acid gel dermal fillers. Dermatol Surg
2008;34[suppl 1]:S105–S109.
145.Callan P, Goodman GJ, Carlisle I, Liew S, Muzikants P,
Scamp T, Halstead MB, Rogers JD. Efficacy and safety of a
hyaluronic acid filler in subjects treated for correction of
midface volume deficiency: A 24 month study. Clin Cosmet
Investig Dermatol 2013;6:81−89.
135.Nast A, Reytan N, Hartmann V, Pathirana D, Bachmann
F, Erdmann R, Rzany B. Efficacy and durability of two
hyaluronic acid-based fillers in the correction of nasolabial
folds: results of a prospective, randomized, double-blind,
actively controlled clinical pilot study. Dermatol Surg
2011;37:768−775.
146.Philipp-Dormston WG, Eccleston D, De Boulle K, Hilton
S, van den Elzen H, Nathan M. A prospective, observational
study of the volumizing effect of open-label aesthetic use of
Juvéderm VOLUMA with lidocaine in mid-face area. J Cosmet
Laser Ther. 2014;16:171−179.
136.Ascher B, Bayerl C, Brun P, Kestemont P, Rzany B, Poncet
M, Guennoun M, Podda M. Efficacy and safety of a new
hyaluronic acid dermal filler in the treatment of severe
nasolabial lines: 6-month interim results of a randomized,
evaluator-blinded, intra-individual comparison study. J
Cosmet Dermatol 2011;10:94−98.
137.Hamilton RG, Strobos J, Adkinson NF Jr.
Immunogenicity studies of cosmetically administered
nonanimal-stabilized hyaluronic acid particles. Dermatol
Surg 2007;33[suppl 2]:S176−S185.
138.Lindqvist C, Tveten S, Bondevik BE, Fagrell D. A
randomized, evaluator-blind, multicenter comparison
of the efficacy and tolerability of Perlane versus Zyplast
in the correction of nasolabial folds. Plast Reconstr Surg
2005;115:282−289.
139.Moers-Carpi M, Vogt S, Santos BM, Planas J, Vallve
SR, Howell DJ. A multicenter, randomized trial comparing
calcium hydroxylapatite to two hyaluronic acids for
treatment of nasolabial folds. Dermatol Surg 2007;33[suppl
2]:S144−S151.
140.Brandt F, Bassichis B, Bassichis M, O’Connell C, Lin X.
Safety and effectiveness of small and large gel-particle
hyaluronic acid in the correction of perioral wrinkles. J Drugs
Dermatol 2011;10:982−987.
141.Morley AM, Malhotra R. Use of hyaluronic acid filler for
tear-trough rejuvenation as an alternative to lower eyelid
surgery. Ophthal Plast Reconstr Surg 2011;27:69−73.
142.Denton AB, Tsaparas Y. Injectable hyaluronic acid
for the correction of HIV-associated facial lipoatrophy.
Otolaryngol Head Neck Surg 2007;136:563−567.
143.Hoffmann K; Juvéderm Voluma Study Investigators
Group. Volumizing effects of a smooth, highly cohesive,
147.Raspaldo H. Volumizing effect of a new hyaluronic acid
sub-dermal facial filler: A retrospective analysis based on
102 cases. J Cosmet Laser Ther 2008;10:134−142.
148.Fischer TC. A European evaluation of cosmetic
treatment of facial volume loss with Juvéderm Voluma in
patients previously treated with Restylane Sub-Q. J Cosmet
Dermatol 2010;9:291−296.
149.Weinkle SH, Bank DE, Boyd CM, Gold MH, Thomas
JA, Murphy DK. A multi-center, double-blind, randomized
controlled study of the safety and effectiveness of Juvéderm
injectable gel with and without lidocaine. J Cosmet Dermatol
2009;8:205–210.
150.Levy PM, De Boulle K, Raspaldo H. A split-face
comparison of a new hyaluronic acid facial filler containing
pre-incorporated lidocaine versus a standard hyaluronic
acid facial filler in the treatment of naso-labial folds. J
Cosmet Laser Ther 2009;11:169−173.
151.Flynn TC, Thompson DH, Hyun SH. Molecular weight
analyses and enzymatic degradation profiles of the softtissue fillers Belotero Balance, Restylane, and Juvéderm
Ultra. Plast Reconstr Surg 2013;132:22S−32S.
152.Flynn TC, Sarazin D, Bezzola A, Terrani C, Micheels
P. Comparative histology of intradermal implantation of
mono and biphasic hyaluronic acid fillers. Dermatol Surg
2011;37:637−643.
153.Goh AS, Kohn JC, Rootman DB, Lin JL, Goldberg RA.
Hyaluronic acid gel distribution pattern in periocular area
with high-resolution ultrasound imaging. Aesthet Surg J
2014;34:510−515.
154.Lorenc ZP, Fagien S, Flynn TC, Waldorf HA. Clinical
application and assessment of Belotero: A roundtable
discussion. Plast Reconstr Surg 2013;132[suppl 2]:69S−76S.
31
155.Narins RS, Coleman WP III, Donofrio LM, Jones DH,
Maas C, Monheit G, Kaur M, Grundy SL, Pappert EJ, Hardas B.
Improvement in nasolabial folds with a hyaluronic acid filler
using a cohesive polydensified matrix technology: Results
from an 18-month open-label extension trial. Dermatol Surg
2010;36[suppl 3]:1800−1808.
156.Kühne U, Imhof M, Kirchmeir M, Howell DJ. Fiveyear retrospective review of safety, injected volumes,
and longevity of the hyaluronic acid Belotero Basic
for facial treatments in 317 patients. J Drugs Dermatol
2012;11:1032−1035.
157.Micheels P, Sarazin D, Besse S, Sundaram H, Flynn TC.
A blanching technique for intradermal injection of the
hyaluronic acid Belotero. Plast Reconstr Surg 2013;132[suppl
2]:59S−68S.
158.Prager W, Steinkraus V. A prospective, rater-blind,
randomized comparison of the effectiveness and tolerability
of Belotero Basic versus Restylane for correction of
nasolabial folds. Eur J Dermatol 2010;20:748−752.
159.Downie JB, Grimes PE, Callender VD. A multicenter
study of the safety and effectiveness of hyaluronic acid with
a cohesive polydensified matrix for treatment of nasolabial
folds in subjects with Fitzpatrick skin types IV, V, and VI. Plast
Reconstr Surg 2013;132[suppl 2]:41S−47S.
160.Lorenc ZP, Fagien S, Flynn TC, Waldorf HA. Review of
key Belotero Balance safety and efficacy trials. Plast Reconstr
Surg 2013;132[suppl 2]:33S−40S.
161.Alam M, Gladstone H, Kramer EM, Murphy JP Jr, Nouri
K, Neuhaus IM, Spencer JM, Spenceri E, Van Dyke S, Ceilley
RI, Lee KK, Menaker G, Monheit GD, Orentreich DS, Raab
B, Smith KC, Solish NJ. ASDS guidelines of care: Injectable
fillers. Dermatol Surg 2008;34[suppl 1]:S115–S148.
168.Rotunda AM, Narins RS. Poly-L-lactic acid: A new
dimension in soft tissue augmentation. Dermatol Ther
2006;19:151−158.
169.Duracinsky M, Leclercq P, Armstrong AR, Dolivo M,
Mouly F, Chassany O. A longitudinal evaluation of the
impact of a polylactic acid injection therapy on health
related quality of life amongst HIV patients treated with
anti-retroviral agents under real conditions of use. BMC
Infect Dis 2013;13:92.
170.Lowe NJ, Maxwell CA, Lowe P, Shah A, Patnaik R.
Injectable poly-L-lactic acid: 3 years of aesthetic experience.
Dermatol Surg 2009;35[suppl 1]:344−349.
171.Mest DR, Humble GM. Duration of correction for
human immunodeficiency virus-associated lipoatrophy
after retreatment with injectable poly-L-lactic acid. Aesthetic
Plast Surg 2009;33:654−656.
172.Sherman RN. Sculptra: The new three-dimensional
filler. Clin Plast Surg 2006;33:539–550.
173.Rose AE, Day D. Esthetic rejuvenation of the temple.
Clin Plast Surg 2013;40:77−89.
174.Fitzgerald R, Vleggaar D. Facial volume restoration
of the aging face with poly-L-lactic acid. Dermatol Ther
2011;24:2−27.
175.Lorenc ZP. Commentary on: Complications after Facial
Injections with Permanent Fillers: Important Limitations
and Considerations of MRI Evaluation. Aesthet Surg J
2014;34(6):924−925.
176.Drobeck HP, Rothstein SS, Gumaer KI, Sherer
AD, Slighter RG. Histologic observation of soft tissue
responses to implanted, multifaceted particles and discs of
hydroxylapatite. J Oral Maxillofac Surg 1984;42:143–149.
162.Lowe NJ, Maxwell CA, Patnaik R. Adverse reactions to
dermal fillers: Review. Dermatol Surg 2005;31:1616–1625.
177.Sklar JA, White SM. Radiance FN: A new soft tissue filler.
163.Schierle CF, Casas LA. Nonsurgical rejuvenation of the
aging face with injectable poly-L-lactic acid for restoration
of soft tissue volume. Aesthet Surg J 2011;31:95−109.
178.Moulonguet I, Arnaud E, Bui P, Plantier F. Foreign
body reaction to Radiesse: 2 cases. Am J Dermatopathol
2013;35:e37−e40.
164.Palm M, Chayavichitsilp P. The “skinny” on Sculptra: A
practical primer to volumization with poly-L-lactic acid. J
Drugs Dermatol 2012;11:1046−1052.
179.Assi, Pope, Kessler. Oral and maxillofacial pathology
case of the month: Foreign body giant cell reaction to
cosmetic filler material Radiesse. Tex Dent J 2013;130:582,
620−621.
165.Vleggaar, D. Facial volumetric correction
with injectable poly-L-lactic acid. Dermatol Surg
2005;31:1511−1517.
180.Flaharty P. Radiance. Facial Plast Surg 2004;20:165–169.
166.Fitzgerald R, Vleggaar D. Using poly-L-lactic acid (PLLA)
to mimic volume in multiple tissue layers. J Drugs Dermatol
2009;8[suppl]:s5−s14.
181.Alam M, Havey J, Pace N, Pongprutthipan M, Yoo
S. Large-particle calcium hydroxylapatite injection for
correction of facial wrinkles and depressions. J Am Acad
Dermatol 2011;65:92−96.
167.Lacombe V. Sculptra: A stimulatory filler. Facial Plast
Surg 2009;25:95−99.
182.Vagefi MR, McMullan TF, Burroughs JR, Georgescu
D, McCann JD, Anderson RL. Orbital augmentation with
32
injectable calcium hydroxylapatite for correction of
postenucleation/evisceration socket syndrome. Ophthal
Plast Reconstr Surg 2011;27:90−94.
183.Bass LS, Smith S, Busso M, McClaren M. Calcium
hydroxylapatite (Radiesse) for treatment of nasolabial
folds: Long-term safety and efficacy results. Aesthet Surg J
2010;30:235-238.
184.Moers-Carpi MM, Tufet JO. Calcium hydroxylapatite
versus nonanimal stabilized hyaluronic acid for the
correction of nasolabial folds: A 12-month, multicenter,
prospective, randomized, controlled, split-face trial.
Dermatol Surg 2008;34:210−215.
185.Busso M, Applebaum D. Hand augmentation with
Radiesse (Calcium hydroxylapatite). Dermatol Ther
2007;20:385–387.
186.Busso M, Voigts R. An investigation of changes in
physical properties of injectable calcium hydroxylapatite in
a carrier gel when mixed with lidocaine and with lidocaine/
epinephrine. Dermatol Surg 2008;34[suppl 1]:S16–S23.
187.Busso M. Calcium hydroxylapatite (Radiesse):
Safety, techniques and pain reduction. J Drugs Dermatol
2009;8[suppl]:s21−s23.
188.Dallara JM, Baspeyras M, Bui P, Cartier H, Charavel MH,
Dumas L. Calcium hydroxylapatite for jawline rejuvenation:
Consensus recommendations. J Cosmet Dermatol
2014;13:3−14.
189.Sadick NS, Anderson D, Werschler WP. Addressing
volume loss in hand rejuvenation: A report of clinical
experience. J Cosmet Laser Ther 2008;10:237−241.
190.Lacarrubba F, Tedeschi A, Nardone B, Micali G.
Mesotherapy for skin rejuvenation: Assessment of
the subepidermal low-echogenic band by ultrasound
evaluation with cross-sectional B-mode scanning. Dermatol
Ther 2008;21[suppl 3]:S1−S5.
191.Fabi SG, Goldman MP. Hand rejuvenation: A review and
our experience. Dermatol Surg 2012;38:1112−1127.
192.Vleggaar D. Soft-tissue augmentation and the role of
poly-L-lactic acid. Plast Reconstr Surg 2006;118:46S−54S.
196.Edelson KL. Hand recontouring with calcium
hydroxylapatite (Radiesse). J Cosmet Dermatol 2009;8:44−51.
197.Bank DE. A novel approach to treatment of the aging
hand with Radiesse. J Drugs Dermatol 2009;8:1122−1126.
198.Gargasz SS, Carbone MC. Hand rejuvenation using
Radiesse. Plast Reconstr Surg 2010;125:259e−260e.
199.Sadick NS. A 52-week study of safety and efficacy of
calcium hydroxylapatite for rejuvenation of the aging hand.
J Drugs Dermatol 2011;10:47−51.
200.Marmur ES, Al Quran H, De Sa Earp AP, Yoo JY. A fivepatient satisfaction pilot study of calcium hydroxylapatite
injection for treatment of aging hands. Dermatol Surg
2009;35:1978−1984.
201.Cohen JL, Carruthers A, Jones D. A randomized study
to validate the Merz hand grading scale for live assessments
[poster]. Presented at the Annual Meeting of the American
Academy of Dermatology, San Francisco, 2015.
202.Goldman M, Moradi A, Katz B, Gold M, Alizadeh K,
Adelglass J. Safety and efficacy of calcium hydroxylapatite
dermal filler for hand treatment: A 12-month follow-up
study [poster]. Presented at the Annual Meeting of the
American Academy of Dermatology, San Francisco, 2015.
203.Coleman SR. Structural fat grafting. Aesthet Surg J
1998;18:386, 388.
204.Coleman SR. Structural fat grafting: More than a
permanent filler. Plast Reconstr Surg 2006;118[suppl
3]:108S–120S.
205.Smith P, Adams WP Jr, Lipschitz AH, Chau B, Sorokin E,
Rohrich RJ, Brown SA. Autologous human fat grafting: Effect
of harvesting and preparation techniques on adipocyte
graft survival. Plast Reconstr Surg 2006;117:1836–1844.
206.Kaufman MR, Bradley JP, Dickinson B, Heller JB, Wasson
K, O’Hara C, Huang C, Gabbay J, Ghadjar K, Miller TA.
Autologous fat transfer national consensus survey: Trends
in techniques for harvest, preparation, and application, and
perception of short- and long-term results. Plast Reconstr
Surg 2007;119:323–331.
193.Palm MD, Woodhall KE, Butterwick KJ, Goldman MP.
Cosmetic use of poly-L-lactic acid: A retrospective study of
130 patients. Dermatol Surg 2010;36:161−170.
207.Shuck J, Iorio ML, Hung R, Davison SP. Autologous
fat grafting and injectable dermal fillers for human
immunodeficiency virus-associated facial lipodystrophy:
A comparison of safety, efficacy, and long-term treatment
outcomes. Plast Reconstr Surg 2013;131:499−506.
194.Lam SM, Azizzadeh B, Graivier M. Injectable poly-Llactic acid (Sculptra): Technical considerations in soft-tissue
contouring. Plast Reconstr Surg 2006;118[suppl 3]:55S−63S.
208.Bassetto F, Turra G, Salmaso R, Lancerotto L, Del
Vecchio DA. Autologous injectable dermis: A clinical and
histological study. Plast Reconstr Surg 2013;131:589e−596e.
195.Redaelli A. Cosmetic use of polylactic acid for hand
rejuvenation: Report on 27 patients. J Cosmet Dermatol
2006;5:233−238.
209.Ersek RA, Gregory SR, Salisbury AV. Bioplastique
at 6 years: Clinical outcome studies. Plast Reconstr Surg
1997;100:1570–1574.
33
210.Narins RS, Beer K. Liquid injectable silicone: A review
of its history, immunology, technical considerations,
complications, and potential. Plast Reconstr Surg
2006;118[suppl 3]:77S–84S.
211.Fulton J, Caperton C. The optimal filler: Immediate
and long-term results with emulsified silicone (1,000
centistokes) with cross-linked hyaluronic acid. J Drugs
Dermatol 2012;11:1336−1341.
212.Lemperle G, Romano JJ, Busso M. Soft tissue
augmentation with Artecoll: 10-year history, indications,
techniques, and complications. Dermatol Surg 2003;29:
573–587.
213.Lemperle G, Sadick NS, Knapp TR, Lemperle SM.
ArteFill permanent injectable for soft tissue augmentation:
II. Indications and applications. Aesthetic Plast Surg
2010;34:273−286.
214.Mills DC, Camp S, Mosser S, Sayeg A, Hurwitz D, Ronel
D. Malar augmentation with a polymethylmethacrylateenhanced filler: Assessment of a 12-month open-label pilot
study. Aesthet Surg J 2013;33:421−430.
215.Lemperle G, Knapp TR, Sadick NS, Lemperle SM.
ArteFill permanent injectable for soft tissue augmentation:
I. Mechanism of action and injection techniques. Aesthetic
Plast Surg. 2010;34:264−272.
216.Lemperle G, de Fazio S, Nicolau P. ArteFill: A thirdgeneration permanent dermal filler and tissue stimulator.
Clin Plast Surg 2006;33:551–565.
217.Conejo-Mir JS, Sanz Guirado S, Angel Muñoz M.
Adverse granulomatous reaction to Artecoll treated by
intralesional 5-fluorouracil and triamcinolone injections.
Dermatol Surg 2006;32:1079-1081.
218.Bailey S, Cohen J, Kenkel JM. Etiology, prevention and
treatment of dermal filler complications. Aesthet Surg J 2010,
in press.
219.Broughton G II, Crosby MA, Coleman J, Rohrich RJ. Use
of herbal supplements and vitamins in plastic surgery: A
practical review. Plast Reconstr Surg 2007;119:48e–66e.
220.Dinehart SM, Henry L. Dietary supplements: Altered
coagulation and effects on bruising. Dermatol Surg
2005;31:819–826.
221.Douketis JD, Berger PB, Dunn AS, Jaffer AK,
Spyropoulos AC, Becker RC, Ansell J. The perioperative
management of antithrombotic therapy: American College
of Chest Physicians Evidence-Based Clinical Practice
Guidelines (8th Edition). Chest 2008;133[suppl 6]:299S–339S.
222.Calfee DP, Farr BM. Comparison of four antiseptic
preparations for skin in the prevention of contamination of
percutaneously drawn blood cultures: A randomized trial. J
34
Clin Microbiol 2002;40:1660–1665.
223.O’Grady NP, Alexander M, Dellinger EP, Gerberding JL,
Heard SO, Maki DG, Masur H, McCormick RD, Mermel LA,
Pearson ML, Raad II, Randolph A, Weinstein RA, Healthcare
Infection Control Practices Advisory Committee. Guidelines
for the prevention of intravascular catheter-related
infections. Am J Infect Control 2002;30:476–489.
224.Cohen JL. Understanding, avoiding, and managing
dermal filler complications. Dermatol Surg 2008;34[suppl
1]:S92–S99.
225.Rohrich RJ, Herbig KS. Minimizing pain, maximizing
comfort: A new technique for facial filler injections. Plast
Reconstr Surg 2009;124:1328–1329.
226.Ha RY, Nojima K, Adams WP Jr, Brown SA. Analysis of
facial skin thickness: Defining the relative thickness index.
Plast Reconstr Surg 2005;115:1769–1773.
227.Lemperle G, Rullan PP, Gauthier-Hazan N. Avoiding
and treating dermal filler complications. Plast Reconstr Surg
2006;118[suppl 3]:92S–107S.
228.Arlette JP, Trotter MJ. Anatomic location of hyaluronic
acid filler material injected into nasolabial fold: A histologic
study. Dermatol Surg 2008;34[suppl 1]:S56–S62.
229.Rohrich RJ, Ghavami A, Crosby MA. The role of
hyaluronic acid fillers (Restylane) in facial cosmetic surgery:
Review and technical considerations. Plast Reconstr Surg
2007;120[suppl 6]:41S–54S.
230.Fulton J, Caperton C, Weinkle S, Dewandre L. Filler
injections with the blunt-tip microcannula. J Drugs Dermatol
2012:11:1098−1103.
231.Coleman KR, Carruthers J. Combination therapy with
Botox and fillers: The new rejuvenation paradigm. Dermatol
Ther 2006;19:177–188.
232.Rohrich RJ, Pessa JE. The fat compartments of the face:
Anatomy and clinical implications for cosmetic surgery. Plast
Reconstr Surg 2007;119:2219–2227.
233.Gelfer A, Carruthers A, Carruthers J, Jang F, Bernstein
SC. The natural history of polymethylmethacrylate
microspheres granulomas. Dermatol Surg 2007;33:614–620.
234.Carruthers J, Carruthers A. A prospective, randomized,
parallel group study analyzing the effect of BTX-A (Botox)
and nonanimal sourced hyaluronic acid (NASHA, Restylane)
in combination compared with NASHA (Restylane) alone in
severe glabellar rhytides in adult female subjects: Treatment
of severe glabellar rhytides with a hyaluronic acid derivative
compared with the derivative and BTX-A. Dermatol Surg
2003;29:802–809.
235.Alam M, Dover JS. Management of complications and
sequelae with temporary injectable fillers. Plast Reconstr
Surg 2007;120[suppl 6]:98S–105S.
236.André P, Lowe NJ, Parc A, Clerici TH, Zimmerman U.
Adverse reactions to dermal fillers: A review of European
experiences. J Cosmet Laser Ther 2005;7:171–176.
237.Friedman PM, Mafong EA, Kauvar AN, Geronemus RG.
Safety data of injectable nonanimal stabilized hyaluronic
acid gel for soft tissue augmentation. Dermatol Surg
2002;28:491−494.
238.Kates LC, Fitzgerald R. Poly-L-lactic acid injection for
HIV-associated facial lipoatrophy: Treatment principles,
case studies, and literature review. Aesthet Surg J
2008;28:397−403.
239.Valantin MA, Aubron-Olivier C, Ghosn J, Laglenne E,
Pauchard M, Schoen H, Bousquet R, Katz P, Costagliola D,
Katlama C. Polylactic acid implants (New-Fill) to correct
facial lipoatrophy in HIV-infected patients: Results of the
open-label study VEGA. AIDS 2003;17:2471−2477.
240.Bernardini FP, Cetinkaya A, Devoto MH, Zambelli A.
Calcium hydroxyl-apatite (Radiesse) for the correction of
periorbital hollows, dark circles, and lower eyelid bags.
Ophthal Plast Reconstr Surg 2014;30:34−39.
241.Mullins RJ, Richards C, Walker T. Allergic reactions to
oral, surgical and topical bovine collagen: Anaphylactic risk
for surgeons. Aust N Z J Ophthalmol 1996;24:257–260.
242.Narins RS, Jewell M, Rubin M, Cohen J, Strobos J.
Clinical conference: Management of rare events following
dermal fillers: Focal necrosis and angry red bumps. Dermatol
Surg 2006;32:426–434.
243.Glaich AS, Cohen JL, Goldberg LH. Injection necrosis of
the glabella: Protocol for prevention and treatment after use
of dermal fillers. Dermatol Surg 2006;32:276–281.
244.McCleve DE, Goldstein JC. Blindness secondary
to injections in the nose, mouth, and face: Cause and
prevention. Ear Nose Throat J 1995;74:182–188.
245.Kim YJ, Kim SS, Song WK, Lee SY, Yoon JS. Ocular
ischemia with hypotony after injection of hyaluronic acid
gel. Ophthal Plast Reconstr Surg 2011;27:e152−e155.
246.Sclafani AP, Fagien S. Treatment of injectable soft tissue
filler complications. Dermatol Surg 2009;35[suppl 2]:
1672–1680.
247.Cohen JL, Brown MR. Anatomic considerations for
soft tissue augmentation of the face. J Drugs Dermatol
2009;8:13–16.
248.Hirsch RJ, Cohen JL, Carruthers JD. Successful
management of an unusual presentation of impending
necrosis following a hyaluronic acid injection embolus and
a proposed algorithm for management with hyaluronidase.
249.Hirsch RJ, Brody HJ, Carruthers JD. Hyaluronidase in
the office: A necessity for every dermasurgeon that injects
hyaluronic acid. J Cosmet Laser Ther 2007;9:182–185.
250.Rohrich R J, Nguyen AT, Kenkel JM. Lexicon for soft
tissue implants. Dermatol Surg 2009;35[suppl 2]:1605–1611.
251.Christensen L, Breiting V, Janssen M, Vuust J, Hogdall E.
Adverse reactions to injectable soft tissue permanent fillers.
Aesthetic Plast Surg 2005;29:34–48.
252.Rohrich RJ, Monheit GD, Nguyen AT, Brown SA, Fagien
S. Soft tissue filler complications: The important role of
biofilms. Plast Reconstr Surg 2010;125:1250–1256.
253.Parada MB, Michalany NS, Hassun KM, Bagatin E,
Talarico S. A histologic study of adverse effects of different
cosmetic skin fillers. Skinmed 2005;4:345–349.
254.Lemperle G, Gauthier-Hazan N, Wolters M, EisemannKlein M, Zimmermann U, Duffy DM. Foreign body
granulomas after all injectable dermal fillers: Part 1. Possible
causes. Plast Reconstr Surg 2009;123:1842–1863.
255.Lemperle G, Gauthier-Hazan N. Foreign body
granulomas after all injectable dermal fillers: Part 2.
Treatment options. Plast Reconstr Surg 2009;123:1864–1873.
256.Lemperle G, Morhenn V, Charrier U. Human histology
and persistence of various injectable filler substances for
soft tissue augmentation. Aesthetic Plast Surg 2003;27:
354–366.
257.Cecchi R, Spota A, Frati P, Muciaccia B. Migrating
granulomatous chronic reaction from hyaluronic acid skin
filler (Restylane): Review and histopathological study with
histochemical stainings. Dermatology 2014;228:14−17.
258.Shahrabi Farahani S, Sexton J, Stone JD, Quinn K, Woo
SB. Lip nodules caused by hyaluronic acid filler injection:
Report of three cases. Head Neck Pathol 2012;6:16−20.
259.Sage RJ, Chaffins ML, Kouba DJ. Granulomatous foreign
body reaction to hyaluronic acid: Report of a case after
melolabial fold augmentation and review of management.
Dermatol Surg 2009;35[suppl 2]:1696−1700.
260.Jones DH, Carruthers A, Orentreich D, Brody HJ, Lai MY,
Azen S, Van Dyke GS. Highly purified 1000-cSt silicone oil
for treatment of human immunodeficiency virus-associated
facial lipoatrophy: An open pilot trial. Dermatol Surg
2004;30:1279–1286.
261.Cassuto D, Sundaram H. A problem-oriented approach
to nodular complications from hyaluronic acid and calcium
hydroxylapatite fillers: Classification and recommendations
for treatment. Plast Reconstr Surg 2013;132[suppl
2]:48S−58S.
262.Persichetti P, Palazzolo D, Tenna S, Poccia I, Abbruzzese
F, Trombetta M. Dermal filler complications from unknown
35
biomaterials: Identification by attenuated total reflectance
spectroscopy. Plast Reconstr Surg 2013;131:597e−603e.
266.Reisman NR. Ethics, legal issues, and consent for fillers.
Clin Plast Surg 2006;33:505–510.
263.Hoffmann N, Lee B, Hentzer M, Rasmussen TB, Song
Z, Johansen HK, Givskov M, Høiby N. Azithromycin blocks
quorum sensing and alginate polymer formation and
increases the sensitivity to serum and stationary-growthphase killing of Pseudomonas aeruginosa and attenuates
chronic P. aeruginosa lung infection in Cftr(-/-) mice.
Antimicrob Agents Chemother 2007;51:3677–3687.
267.American Society of Plastic Surgeons, American
Society for Aesthetic Plastic Surgery. Injectables and fillers:
Legal and regulatory risk management issues. Plast Reconstr
Surg 2006;118[suppl 3]:129S–132S.
264.Lambros V. The use of hyaluronidase to reverse
the effects of hyaluronic acid filler. Plast Reconstr Surg
2004;114:277.
265.Cassuto D, Marangoni O, De Santis G, Christensen L.
Advanced laser techniques for filler-induced complications.
Dermatol Surg 2009;35[suppl 2]:1689–1695.
36
268.American Society of Plastic Surgeons, American
Society for Aesthetic Plastic Surgery. Joint ASPS & ASAPS
Guiding Principles: Supervision of Non-Physician Personnel
in Medical Spas and Physician Offices. Arlington Heights:
ASPS Executive Committee; New York: ASAPS Executive
Committee; 2006. http://www.plasticsurgery.org/
Documents/medical-professionals/health-policy/guidingprinciples/Joint-Medical-Spas-Guiding-Principles.pdf Last
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