10-28 Injectables

SRPS
SELECTED READINGS IN PLASTIC SURGERY

I N J E C T A B L E S A LEXANDER T . N GUYEN, M D J EFFREY M . K ENKEL, M D
VOLUME 10 NUMBER 28
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Editor-in-Chief Editor Emeritus Contributing Editors Je rey M. Kenkel, MD F. E. Barton, Jr, MD
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. Gri n, 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. OBrien, 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
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 Insu ciency 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: Wrist, Joints, Congenital Anomalies, and Rheumatoid Arthritis
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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.
SRPS Volume 10 Issue 28 2010
INJECTABLES
Alexander T. Nguyen, MD Jeffrey M. Kenkel, MD University of Texas Southwestern Medical Center at Dallas, Dallas, Texas
INTRODUCTION The use and number of injectable agents for cosmetic facial rejuvenation and reshaping continue to increase around the world. According to the 2009 American Society for Aesthetic Plastic Surgery (ASAPS) Cosmetic Surgery National Data Bank Statistics,1 more than 2.5 million botulinum toxin type A (BoNTA) and more than 1.3 million hyaluronic acid (HA) injection procedures were performed in 2009, the top two cosmetic procedures performed that year. These numbers do not include the growing popularity of longer lasting soft-tissue fillers. The use of BoNTA accounted for more than one billion dollars in expenditures in 2009, with a 3824% 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.24 Injectable products and their literature are rapidly expanding and evolving. In this new issue of Selected Readings in Plastic Surgery, we present injectables as a new topic, review the current classifications of products approved by the United States Food and Drug Administration (FDA), and provide an overview of the clinical uses.
HISTORY 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 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. THE IDEAL INJECTABLE The ideal injectable should have a safe composition, easy delivery, excellent outcomes, and appropriate 1

sensibility. 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 (Table 1).13,14 CLASSIFICATION Soft-tissue injectables can be classified in various ways. They can be identified by their source (autologous, biological, or synthetic), risk profile, level of expertise needed for injection, or arguably the depth of injection (dermal, subdermal, supraperiosteal). More commonly, soft-tissue injectables and fillers are classified by their longevity of effect: temporary, long-lasting (sometimes this distinction is omitted), semipermanent, and permanent. The designated durations can be defined as less than 6 months, 6 months to 2 years, 2 to 5 years, and more than 5 years, respectively (Table 2).15 Each of these categories is briefly reviewed below. Temporary Injectables Botulinum Toxin Botulinum neuromodulators are produced by various strains of Clostridium botulinum with seven serotypes (A, B, C1, D, E, F, and G), with serotypes C1 and D not affecting humans. Serotypes A and B have been isolated for clinical use.16 Botulinum toxin has a high affinity for uptake by cholinergic neurons, resulting in temporary chemodenervation. 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).1719 Botulism poisoning was first described in 1817 by Kerner.20 The first therapeutic use of botulinum toxin was for the treatment of strabismus by Scott et al.21 in 1973. It has numerous medical uses, 2 including the treatment of essential blepharospasm, migraines, and hyperhidrosis.2224 The first cosmetic use of botulinum toxin is attributed to Carruthers and Carruthers,25,26 who noticed the incidental improvement of glabellar rhytids while treating ophthalmological disease. Cosmetic botulinum toxin use has been noted to improve first impression scores for dating success, attractiveness, and athletic success scales.27 Currently, two BoNTA and one botulinum toxin type B FDA-approved products are available.
Figure 1. Evolution of injectables in the United States.

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 Classification of Soft-tissue Injectables Longevity Temporary 06 months Injectable Botulinum toxin Collagen Hyaluronic acid Poly-l-lactic acid Calcium hydroxylapatite Autologous fat Silicone Polymethylmethacrylate
Long-lasting Semi-permanent Permanent
6 months2 years 25 years >5 years
BoNTA-ONA (Botox/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 FDA-approved for cervical dystonia, 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.
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 syndrome). Patients with neuromuscular disorders might be at increased risk for clinically significant effects, including severe dysphagia and respiratory 3

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.31 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.32,33 Based on these findings, botulinum toxin is labeled to warn 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.30 Antibodies to Botox have been reported and can lead to loss of treatment effect. Antigenicity is a concern regarding long-term use of toxin, which might support the use of botulinum toxin type B formulations as an alternative. 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%.34,35 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, Klein36 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.30 The human LD50 is approximately 40 U/kg, or approximately 3000 U.3739 Vials are available in 100 or 50 U. Each 100-U neuromodulator vial currently
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.19)
compromise. Aminoglycoside co-administration can also potentiate the clinical effects.28 Botox is not recommended for use in children but has shown significant benefit as an adjunct to treatment in children with cerebral palsy spasticity.29 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.30 Botulinum toxin type A precautions are as follows: Infection at injection site Known hypersensitivity Neuromuscular disorders Aminoglycosides Children Pregnancy Lactation 4

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, nonpreserved 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.30 Alam et al.,40 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.41 found no difference in efficacy or safety in a dose-dilution study in which 30 U was reconstituted in 1 to 10 mL. Hexsel et al.42 found that potency can be maintained for up to 6 weeks after reconstitution. The reconstitution, dilution, and storage are matters of personal physician preference.43 BoNTA-ABO (Dysport) AbobotulinumtoxinA, known as BoNTA-ABO, is a BoNTA formulation marketed as Dysport (Medicis Aesthetics, Scottsdale, AZ). It was also previously marketed as Reloxin. 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 the appearance of moderate to severe glabellar lines associated with the procerus and corrugator muscle activity in adult patients younger than 65 years.44 Rubin et al.45 and Baumann et al.46 summarized phase III clinical trials of the safety and efficacy of Dysport. Rubin et al.,47 Kane et al.,48 and Brandt et al.49 conducted multicenter, randomized, placebo-controlled, double-blinded studies. Moy et al.50 and Cohen et al.51 conducted open-label studies. The five studies revealed 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. The median time to onset was 3 days, with a response of 85 days for fixed dosing and 109 days for variable dosing. No tolerances were developed.45,46 In addition, Lawrence and Moy52 found no evidence of neutralizing antibodies in 1554 patients who received Dysport. 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 products manufacturer. They have no relationship to potency and are not interchangeable. 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 cows milk proteins.53 The mean toxin protein content is 4.35 ng per 500 LD50-unit vial.18 Contraindications are the same as for Botox with the addition of allergy to cows milk proteins.44 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.44 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.54,55 Lowe et al.56,57 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 significant treatment prolonged effect at 16 weeks (P = 0.04). 5

Rzany and Nast58 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. 3). 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,31 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.59 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.60 used a 1:2.5 dose conversion ratio and found no significant difference between action sizes. RimabotulinumtoxinB (Myobloc) RimabotulinumtoxinB is botulinum toxin type B marketed as Myobloc (Solstice Pharmaceuticals, San Francisco, CA). 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; 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).54,61
Table 3 Dysport versus Botox Dysport Vial size Composition Total protein Albumin Other Type A strain Complex weight Preparation Clinical generalizations Conversion Onset Spread Duration Price 2.5 U 3 days More Same Less 1U 4 days Less Same More 4.35 ng 125 mg 2.5 mg of lactose NCTC 2916 5 ng 500 mg 0.9 mg of NaCl Hall 300 U Botox 100 U
300 kDa
Freeze-dried
900 kDa
Vacuum-dried

Response Wrinkle Score 0 or 1 at Maximum Frown 90 80 70 60 % Responder 50 40 30 20 10 0 0 20 40 60 Days after Injection Figure 3. 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.58) 80 100 120
Treatment Recommendations Considering the significant variation in techniques, guidelines in the literature, and personal experiences, Carruthers et al.41,62 convened in 2004 to develop consensus guidelines for best practices, which were updated in 2008. The recommendations were briefly summarized in the resulting articles, which should be reviewed for further detail and are recapitulated in Table 4 and Figure 4. After intramuscular treatment, most areas should not be manipulated for several hours.41 The duration of activity should be expected to last approximately 3 to 4 months. Fagien63 and Carruthers and Carruthers64 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 FaceThe upper face is the most common site to receive neuromodulator injections. The literature about treatment to the upper face, particularly the glabellar complex, is extensive. The Botox Cosmetic package insert30 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 eight 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 7
Table 4 Recommendations for the Use of Botulinum Toxin Type A53,62
Region/Target Muscle(s)
Usual No. of Injection Points
Total Dose (Botox)
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)
4-8; more or fewer might be required based on anatomic and aesthetic evaluations
Women: 6-15 U Men: 6 to >15 U
30-60 U
Crows feet (lateral portions of the lateral orbicularis)
2-5 per side (higher in selected patients)
Women: 10-30 U Men: 20-30 U
40-60 U
Midface 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
Lower face 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
6-10 U
Dimpled chin (peau dorange), mentalis
1-2 (start with 1 midline or 2 symmetrical lateral injections) 2-12/band
4-10 U
10-20 U
Neck, platysmal bands, platysma
<10 U/band
40-80 U/ band 100-300 U/ side
Masseteric hypertrophy
12 sites in muscle
25-30 U/side

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.62 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.41 Lateral orbital wrinkles, commonly known as crows 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.36 MidfaceContraction 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.55 Neuromodulators can also be used for dynamic nasal tip ptosis. Dayan and Kempiners65 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 FaceThe 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.41 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.62 The dimpled chin, peau dorange, 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.62 Platysmal bands can be softened with 9
Figure 4. Common botulinum toxin injection sites.

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.66 Oral anticholinesterase (pyridostigmine), up to 60 mg, can be used to counteract the side effects.62 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.62 One study presented injections into the levator labii superioris, zygomaticus minor, and orbicularis oris.67 Hypertrophic masseter reduction has been successful with neuromodulators. Injections should be low, just above the mandible, with one to two sites per side.62 Injection of 25 to 30 U of Botox per side has been shown to be efficacious, lasting up to 6 months.68,69 Fillers Collagen Aging causes a reduction in the collagen content of the skin by 1% per year.70 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.71 Double skin testing via a small skin inoculation is required before the use of bovine-derived products. The test is performed via a subcutaneous injection of 0.1 mL of collagen injectable. The area is observed for signs of hypersensitivity, including erythema, swelling, induration, tenderness, and pruritus, for 2 weeks. Immunogenicity by positive skin tests has been noted in 3% of patients.72 If the test results are negative, a second skin test is performed. Additional adverse reactions have been found to occur in 1.3% of patients.73 Collagen fillers are contraindicated in patients with history of allergy to any bovine collagen product or history of dietary beef allergy. Herds of cattle used specifically for collagen fillers are isolated to reduce the risk of 10 viral or prion contamination.74 The network of injected collagen allows for connective tissue ingrowth. Collagen products have an excellent long-term safety profile and can be truly injected into the dermis. All collagen products typically last 3 to 6 months. Gormley and Eremia75 noted a 75% loss of correction at 6 months. Matarasso14 recommended overcorrecting by 150% to 200% of the desired results. Despite the advent of longer-lasting fillers, collagen has been useful in difficult areas, such as the periorbital, perioral, and especially lip regions, where it is well tolerated and user-friendly with minimal bruising. The following collagen products are no longer available for use. Zyderm 1 (Allergan) was the original injectable bovine collagen, introduced in 1981. It contained a phosphate- buffered saline solution of 35 mg/ mL collagen, with 0.3% lidocaine. It was recommended for the superficial papillary dermis to correct fine lines, wrinkles, and shallow scars. Zyderm 2 (Allergan) had almost twice the concentration, 65 mg/ mL collagen, with 0.3% lidocaine. It was recommended for the mid dermis and used to treat moderate lines, wrinkles, and scars. Zyplast (Allergan), FDA-approved in 1985, had a concentration of 35 mg/mL collagen, with 0.3% lidocaine, and was developed to provide a longer-lasting effect by cross-linking collagen with 0.0075% glutaraldehyde. Glutaraldehyde cross-linking of collagen made it less immunogenic and more resistant to degradation by collagenases, providing a longer-lasting effect.76 It was recommended that Zyplast be injected into the deep dermis without overcorrection.14 CosmoDerm 1, CosmoDerm 2, and CosmoPlast (Allergan), were the human-derived collagen equivalents

of Zyderm and Zyplast. They contained purified human-derived collagen produced from human fibroblast cells; skin testing was therefore not required with use of these products. They were FDA-approved in 2003 for the correction of soft-tissue contour deficiencies, such as wrinkles and acne scars, and overcorrection by up to 150% of the desired results was recommended.77 Evolence (Ortho Dermatologies, Skillmann, NJ), was a 35 mg/mL type I collagen extracted from porcine tendons and cross-linked with ribose. It was approved in 2008 for correction of moderate to deep facial wrinkles and folds, such as nasolabial folds. Porcine collagen is thought to be less immunogenic than bovine collagen. Shoshani et al.78 calculated the hypersensitivity of Evolence to be 0.58%, lower than that of bovine and human collagen. Considering that hypersensitivity to this product was rare, skin testing was not required before treatment. It was recommended that defects not be overcorrected. The clinical effects of Evolence could be seen for up to 1 year.79 It was recommended that Evolence not be injected into the lips because of the high incidence of 80 nodule formation. The manufacturer has discontinued the production of Evolence. Long-lasting Injectables HA HA is a glycosaminoglycan biopolymer that is a part of all 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.81 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.82 HA products were developed as an alternative to collagen because of their longer duration of effect, generally 6 to 9 months, and lower potential for hypersensitivity reactions, 0.6% to 0.8%.83,84 Animal-based HA fillers derived from rooster combs and non-animal based HA fillers produced from bacterial fermentation by Streptococcus species are available for use.83,85 Hyaluronic gels, known as hylans, are crosslinked HA 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.86 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.87 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.87 Animal-Based HA InjectablesHylaform (Allergan), was the first hyaluronic gel. It was approved in 2004 for injection into the mid to deep dermis for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds.77 HA from the dermis of rooster combs is extracted to a concentration of 5.5 mg/mL and 20% cross-linked with divinyl sulfone to create a non-water-soluble gel, making the molecule less susceptible to degradation. It is contraindicated in patients with known history of hypersensitivity to avian proteins. Hylaform Plus (Allergan) has a particle size larger than that of than Hylaform, 750 compared with 500 m. Hylaform Plus is intended for deeper implantation because it has an increased gel hardness and is more resistant to shear forces, making it more capable of deforming surrounding tissues to correct contour defects. When compared 11

with non-animal-based HA fillers, the animalbased fillers have less gel hardness, making them more suitable for areas requiring augmentation in the superficial dermis, such as the wet vermilion of the lips.85 Non-animal-based HA Injectables Restylane (Medicis Aesthetics) was the first HA filler to receive FDA approval for use in the United States, in 2003, for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds. It is produced from bacterial fermentation of Streptococcus equi at a concentration of 20 mg/ mL, with a uniform particle size of 400 mm. It is 1% cross-linked with epoxides, which is less crosslinking than that of other HA injectables. The stabilized cross-linking possibly is attributed to the prolonged efficacy by stimulating collagen synthesis and inhibiting collagen breakdown.88 When compared with Hylaform, Restylane is more viscous and less elastic. The Restylane products, Fine Lines and Perlane, are designed for different depths with different size particles.89 Narins et al.90 found that improvements persisted for up to 18 months with retreatment. In 2006, Matarasso et al.89 provided detailed consensus recommendations for Restylane use to optimize patient outcomes. Juvederm (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. Juvederm is produced from S. equi bacterial fermentation. The particles are non-uniformly shaped for a smoother gel consistency. It is available in Ultra and Ultra Plus with variable cross-linking and particle sizes, and its effects have been reported to last up to 12 months.13 The XC formulations add 0.3% lidocaine and have been found to be associated with less procedural pain in 93% of patients.91 Hydrelle, formally Elevess, (Anika, Bedford, MA) is cross-linked HA produced from S. equi 12 bacterial fermentation and suspended in a buffer solution of 0.3% lidocaine. It is approved for injection into the mid to deep dermis for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds. Elevess was the first FDA-approved soft-tissue injectable to combine HA and lidocaine. Prevelle Silk (Mentor, Santa Barbara, CA) is bacterial-derived HA with 0.3% lidocaine. Its crosslinking makes Prevelle softer than most products. The results of this product, which was approved in 2008, are reported to last approximately 4 months. Poly-l-lactic Acid (PLLA) PLLA is a biodegradable, nontoxic, synthetic, and inactive material derived from corn starch in the alpha hydroxy acid family. It has been used in suture material, stents, and other biomedical implants. Sculptra (sanofi-aventis U.S., LLC, Bridgewater, NJ), 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. It contains PLLA microspheres in a powdered form. PLLA is metabolized to carbon dioxide, glucose, and water for several weeks after injection. 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.92 Sculptra often requires a series of injections to achieve adequate correction. The clinical effects can be seen for 18 to 24 months.13 Semi-permanent Injectables 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.93 Radiesse (Bioform Medical, San Mateo, CA) 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. It 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, in more than 20% of patients.94,95 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 9 to 18 months, but the effects sometimes last 2 to 5 years.96 Radiesse can be safely combined with local anesthetic without loss of efficacy.97,98 Permanent Injectables 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 described in detail by Coleman,99 and various techniques of harvesting, handling, and grafting have been attempted and have resulted in acceptable patient satisfaction.99102 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.100 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 and for use during eye surgery to prevent or treat detached retinae. Microdroplet (0.010.03 mL) injection technique allows for dispersion in tissue to become encapsulated as microparticles.103 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. Narins and Beer104 provided a review of the technical considerations, complications, and polarizing nature of injectable silicone. 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. Artefill (Suneva, San Diego, CA) is a gel suspension of 20% PMMA homogeneous 30- to 42-mm microspheres in 3.5% bovine collagen solution mixed with 0.3% lidocaine.105 Because it contains bovine collagen, patients must undergo skin testing 1 month before injection.13 Artefill received FDA approval in 2006 for correction of the nasolabial folds and should not be used in patients with known susceptibility to keloid formation or hypertrophic scarring. 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.106 13

If possible, patients should discontinue medications, including herbal supplements (arnica, garlic, ginger, ginseng, Gingko biloba, St. Johns Wort, vitamin E, etc.), that might cause bleeding 7 to 10 days before procedures to decrease bruising.107,108 Patients who are taking aspirin, non-steroidal anti-inflammatory drugs, Coumadin (Bristol-Myers Squibb, Washington, DC), or Plavix (Bristol-Myers Squibb and sanofi-aventis U.S.) might have medical indications for which the risk of stopping these medications (50%) could far outweigh the benefit. The American College of Chest Physicians 2008 guidelines recommend continuance of anticoagulation for minor dermatological procedures with low risk of bleeding.109 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.106 The importance of skin preparation with injectables is unknown. Alcohol cleansing is commonly performed. Alternatively, Betadine can be used. Calfee and Farr110 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 antibacterial effect not achieved with alcohol and is currently recommended for use before placement of central venous catheters.111 Of note, chlorhexidine should be avoided in the periorbital region because of the associated risk for keratitis.112 It is important to remember to spread the skin during cleansing to 14 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 significant infections. Topical anesthetics or nerve blocks can be used, and concomitant injection of local anesthetic and fillers has been described.97,98,113 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 PLLA acid to avoid clumping or clogging.106 Lemperle et al.114 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: 1.0 mm in frown lines (facial dermis range, 0.4 to 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.114116 Arlette and Trotter117 reported that despite classic teachings of dermal injection, the majority of product is found in the subcutis. Several injection techniques are commonly described (Fig. 5).118 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 in the glabellar region, for enhancement of the philtral columns, and for correction of fine rhytides. It commonly is used in liquid silicone injection. 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
Figure 5. 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.118)
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.62,95 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 spaced grid pattern. This is effective for large areas, three-dimensional filling, and the oral
commissures.118 Glogau and Kane119 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. 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.95
15

COMBINATION THERAPY With the evolution of the understanding of facial rejuvenation, combination modalities are increasing to address the three-dimensional face.3,120,121 Stacking of fillers, especially permanent on top of permanent, and large-volume injections have been associated with more inflammation and granuloma formation.122 Carruthers and Carruthers123 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.62 published their consensus recommendations for botulinum toxin and HA combination therapies in 2008. COMPLICATIONS Injectables available in the United States have excellent safety profiles with rare side effects.13,14,124 With the difficulty to treat biofilms, initial care should be focused on prevention. The most common complications are procedural or technique-related as opposed to product-based, such as inappropriate placement of injectables, usually too superficially.87,96,97 Adverse reactions to injectables usually are transient and mild.125,126 The more serious complications include foreign body granulomas with an incidence of 0.01% to 0.1%.115,127130 The timing of the onset of complications can be classified to assist in management. Commonly classified as early and late, Rohrich et al.15 suggested that onset of complications be classified as early, late, and delayed. The three time frames are defined as approximately less than 14 days, 14 days to 1 year, and more than 1 year, respectfully, and might correlate with the potential causes of the complications. Early complications commonly are inflammatory in nature, late complications usually are secondary to granuloma formation, and both early and late complications can be infectious in origin and complicated by a phenomenon that is collectively referred to as biofilms (Table 5).15,131,132 Early complications are the most common 16 adverse events, accounting for 93% of adverse events, and generally are inflammatory or technical in nature. Mild early complications include discomfort, bruising, bleeding, erythema, swelling, pain, itching, asymmetry, lumpiness, dimpling, allergic reaction, infection, hematoma, migration, extrusion, and nodules, of which persistent erythema is the most common complaint. Redness and swelling have been noted to occur with approximately 80% of injections.133 Early injection site reactions can be limited by applying ice or cold compresses to minimize bruising and swelling. More serious early adverse events include allergic reactions, infections, vascular compromise, and too superficial placement of product. Hypersensitivity can be as severe as angioedema and anaphylaxis.134 Antihistamines, topical immunomodulators (Aldara [Graceway Pharmaceuticals, LLC, Bristol, TN], tacrolimus), and steroid injections are effective in managing immunological reactions.116 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.135 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.136,137 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.138 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.

Table 5 Complication Timing and Potential Cause15 Timing Early <14 days Potential Cause Inflammatory
Late
14 days1 year
Granuloma formation
Delayed
>1 year
Biofilms
Treat one side at a time. Pinch or tent the skin to provide more space. Occlude the vessels at their origins.136,139 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 disperse the material. Warm gauze and nitroglycerin paste will promote vasodilation. Hyaluronidase injection can be used to decompress the vessels.140 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.141 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. Currently, no products should be placed superficially. Immediate massage of products might minimize nodules or irregularities. Angry red bumps, with and without tenderness, describe delayed erythema at the sites
of injection of various products that are associated with visible or palpable nodules. These occur more often with permanent fillers or collagen. The causes have been thought to vary from hypersensitivity to infections to foreign body reactions.135 If infectious, the majority of contaminating bacteria are nonpathogenic species, such as Propionibacterium acnes, Streptococcus oralis/mirabilis, Staphylococci epidermidis, and mycobacteria, and antibiotic coverage should be considered early.131 Late complications include migration, discoloration, scarring, atrophy, and foreign body granulomas, which is the bodys attempt to remove unfamiliar material. Histologically, the granulomas consist of inflammatory lymphocytes, neutrophils, eosinophils, multinucleated giant cells, and plasma cells. Causes of granuloma formation include the volume of injected material, size of the filler particles used, impurities, and biofilms. The diagnosis of filler foreign body granuloma should be based on clinical findings.105,128,129,131,142 Steroid injections are proven treatments of granulomas.112 We refer the reader to the extensive reviews by Lemperle et al.128 and Lemperle and GauthierHazan129 of the complexity of granuloma formation. Delayed complications associated with injectables potentially occur from biofilms, as reviewed by Rohrich et al.132 Biofilms are defined as a structured community of microorganisms encapsulated within a self-developed polymeric matrix and irreversibly adherent to a living or 17

inert surface. The most common biofilm example is dental plaque. Biofilms have impaired immune system penetration, reduced growth rates and/ or susceptibility by quorum sensing, altered micro-environment, altered gene expression, and display.132,143 Routine culture techniques might be inadequate because they are based in the planktonic as opposed to the biofilm model. Improving culture results with techniques such as pyrosequencing, polymerase chain reaction (PCR),144 fluorescence in situ hybridization,145 or ultrasound sonication146 is an essential advance that should be considered when biofilms are suspected. Complications should be approached in an algorithmic manner, and early recognition is important (Fig. 6).132 If the injection was performed by someone else, every attempt should be made to determine what was injected into the site. In cases with even very mild signs of infection, one should assume infection is present and prove it is not. If the wound is fluctuant, it should be needle-drained and cultured. Cultures should be sent to the laboratory immediately for appropriate handling. Preliminary antibiotic regimens should consist of at least a twodrug 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.147 After a trial of antibiotics, intralesional high-dose steroids should be considered.116 If HA was used, hyaluronidase should also be considered.148 The use of laser-assisted evacuation of filler material as an intermediate step between medications and surgery can be considered.149 Excision should be the last step.132 ETHICS 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.150 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.151 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.152 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.132
Figure 6. Management algorithm of late and delayed complications of soft-tissue injectables (Reprinted with permission from Rohrich et al.132)
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33. 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;42:461469. 34. 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;29:683690. 35. Brin MF, Comella CL, Jankovic J, Lai F, Naumann M. Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay. Mov Disord 2008;23:13531360. 36. Klein AW. Complications, adverse reactions, and insights with the use of botulinum toxin. Dermatol Surg 2003;29:549556. 37. Herrero BA, Ecklung AE, Streett CS, Ford DF, King JK. Experimental botulism in monkeys: A clinical pathological study. Exp Mol Pathol 1967;6:8495. 38. Ting PT, Freiman A. The story of Clostridium botulinum: From food poisoning to Botox. Clin Med 2004;4:258261. 39. Scott AB, Suzuki D. Systemic toxicity of botulinum toxin by intramuscular injection in the monkey. Mov Disord 1988;3:333335. 40. 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;138:510514. 41. 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]:1S22S. 42. 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;29:523529. 43. Klein AW. Dilution and storage of botulinum toxin. Dermatol Surg 1998;24:11791180. 44. Medicis Aesthetics, Inc. Dysport (AbobotulinumtoxinA): Full Prescribing Information. Scottsdale: Medicis Aesthetics, Inc.; 2009. 45. 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. Aesthet Surg J 2009;29[suppl 6]:S50S56. 46. 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]:S57S65. 47. 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;8:439444. 48. 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;124:16191629. 49. 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;35:18931901. 50. 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;11:7783. 51. 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]:S43S49. 52. 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. Aesthet Surg J 2009;29[suppl 6]:S66S71. 53. Matarasso A, Shafer D. Botulinum neurotoxin type A-ABO (Dysport): Clinical indications and practice guide. Aesthet Surg J 2009;29[suppl 6]:S72S79. 54. 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;29:713. 55. Carruthers J, Carruthers A. Botulinum toxin A in the mid and lower face and neck. Dermatol Clin 2004;22:151158. 56. 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;31:16511654. 57. 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;55:975980.
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Reconstr Surg 2009;124:13281329. 114. Lemperle G, de Fazio S, Nicolau P. Artefill: A thirdgeneration permanent dermal filler and tissue stimulator. Clin Plast Surg 2006;33:551565. 115. Ha RY, Nojima K, Adams WP Jr, Brown SA. Analysis of facial skin thickness: Defining the relative thickness index. Plast Reconstr Surg 2005;115:17691773. 116. Lemperle G, Rullan PP, Gauthier-Hazan N. Avoiding and treating dermal filler complications. Plast Reconstr Surg 2006;118[suppl 3]:92S107S. 117. Arlette JP, Trotter MJ. Anatomic location of hyaluronic acid filler material injected into nasolabial fold: A histologic study. Dermatol Surg 2008;34[suppl 1]:S56S62. 118. 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]:41S54S. 119. 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]:S105S109. 120. Coleman KR, Carruthers J. Combination therapy with Botox and fillers: The new rejuvenation paradigm. Dermatol Ther 2006;19:177188. 121. Rohrich RJ, Pessa JE. The fat compartments of the face: Anatomy and clinical implications for cosmetic surgery. Plast Reconstr Surg 2007;119:22192227. 122. Gelfer A, Carruthers A, Carruthers J, Jang F, Bernstein SC. The natural history of polymethylmethacrylate microspheres granulomas. Dermatol Surg 2007;33:614620. 123. 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;29:802809. 124. Alam M, Dover JS. Management of complications and sequelae with temporary injectable fillers. Plast Reconstr Surg 2007;120[suppl 6]:98S105S. 125. Lowe NJ, Maxwell CA, Patnaik R. Adverse reactions to dermal fillers: Review. Dermatol Surg 2005;31:16161625. 126. Andre P, Lowe NJ, Parc A, Clerici TH, Zimmerman U. Adverse reactions to dermal fillers: A review of European experiences. J Cosmet Laser Ther 2005;7:171176. 127. Parada MB, Michalany NS, Hassun KM, Bagatin E, Talarico S. A histologic study of adverse effects of different cosmetic skin fillers. Skinmed 2005;4:345349. 128. 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;123:18421863. 129. Lemperle G, Gauthier-Hazan N. Foreign body granulomas after all injectable dermal fillers: Part 2. Treatment options. Plast Reconstr Surg 2009;123:18641873. 130. Lemperle G, Morhenn V, Charrier U. Human histology and persistence of various injectable filler substances for soft tissue augmentation. Aesthetic Plast Surg 2003;27: 354366. 131. Christensen L, Breiting V, Janssen M, Vuust J, Hogdall E. Adverse reactions to injectable soft tissue permanent fillers. Aesthetic Plast Surg 2005;29:3448. 132. Rohrich RJ, Monheit GD, Nguyen AT, Brown SA, Fagien S. Soft tissue filler complications: The important role of biofilms. Plast Reconstr Surg 2010;125:12501256. 133. Narins RS, Brandt F, Leyden J, Lorenc ZP, Rubin M, Smith S. A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg 2003;29:588595. 134. 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;24:257260. 135. 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;32:426434. 136. Glaich AS, Cohen JL, Goldberg LH. Injection necrosis of the glabella: Protocol for prevention and treatment after use of dermal fillers. Dermatol Surg 2006;32:276281. 137. McCleve DE, Goldstein JC. Blindness secondary to injections in the nose, mouth, and face: Cause and prevention. Ear Nose Throat J 1995;74:182188. 138. Sclafani AP, Fagien S. Treatment of injectable soft tissue filler complications. Dermatol Surg 2009;35[suppl 2]: 16721680. 139. Cohen JL, Brown MR. Anatomic considerations for soft tissue augmentation of the face. J Drugs Dermatol 2009;8:1316. 140. 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. Dermatol Surg 2007;33:357360.
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141. Hirsch RJ, Brody HJ, Carruthers JD. Hyaluronidase in the office: A necessity for every dermasurgeon that injects hyaluronic acid. J Cosmet Laser Ther 2007;9:182185. 142. 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;30:12791286. 143. Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: A common cause of persistent infections. Science 1999;284:13181322. 144. Wolcott RD, Ehrlich GD. Biofilms and chronic infections. JAMA 2008;299:26822684. 145. Bjarnsholt T, Tolker-Nielsen T, Givskov M, Janssen M, Christensen LH. Detection of bacteria by fluorescence in situ hybridization in culture-negative soft tissue filler lesions. Dermatol Surg 2009;35[suppl 2]:16201624. 146. Trampuz A, Piper KE, Jacobson MJ, Hanssen AD, Unni KK, Osmon DR, Mandrekar JN, Cockerill FR, Steckelberg JM, Greenleaf JF, Patel R. Sonication of removed hip and knee prostheses for diagnosis of infection. N Engl J Med 2007;357:654663. 147. Hoffmann N, Lee B, Hentzer M, Rasmussen TB, Song Z, Johansen HK, Givskov M, Hiby 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;51:36773687. 148. Lambros V. The use of hyaluronidase to reverse the effects of hyaluronic acid filler. Plast Reconstr Surg 2004;114:277. 149. Cassuto D, Marangoni O, De Santis G, Christensen L. Advanced laser techniques for filler-induced complications. Dermatol Surg 2009;35[suppl 2]:16891695. 150. Reisman NR. Ethics, legal issues, and consent for fillers. Clin Plast Surg 2006;33:505510. 151. 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]:129S132S. 152. 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/Media/JointASPS-and-ASAPS-Guiding-Principles-Supervision-of-NonPhysician-Personnel-in-Medical-Spas-and-Physician-Offices. pdf Last accessed, June 30, 2010.
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RECOMMENDED READING 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]:S115S148. Bailey S, Cohen J, Kenkel JM. Etiology, prevention and treatment of dermal filler complications. Aesthet Surg J 2010, in press. 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]:S57S65. 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;119:48e66e. Carruthers A, Carruthers J. Clinical indications and injection technique for the cosmetic use of botulinum A exotoxin. Dermatol Surg 1998;24:11891194. 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]:1S22S. 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]:5S30S. Cohen JL. Understanding, avoiding, and managing dermal filler complications. Dermatol Surg 2008;34[suppl 1]: S92S99. Coleman SR. Structural fat grafting. Aesthet Surg J 1998;18:386, 388. 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;124:16191629. Klein AW. Complications, adverse reactions, and insights with the use of botulinum toxin. Dermatol Surg 2003;29:549556. Lemperle G, Gauthier-Hazan N. Foreign body granulomas after all injectable dermal fillers: Part 2. Treatment options. Plast Reconstr Surg 2009;123:18641873. Lemperle G, Gauthier-Hazan N, Wolters M, Eisemann-Klein M, Zimmermann U, Duffy DM. Foreign body granulomas after all injectable dermal fillers: Part 1. Possible causes. Plast Reconstr Surg 2009;123:18421863. Lemperle G, Rullan PP, Gauthier-Hazan N. Avoiding and treating dermal filler complications. Plast Reconstr Surg 2006;118[suppl 3]:92S107S. Rohrich RJ, Monheit GD, Nguyen AT, Brown SA, Fagien S. Soft tissue filler complications: The important role of biofilms. Plast Reconstr Surg 2010;125:12501256. Rohrich R J, Nguyen AT, Kenkel JM. Lexicon for soft tissue implants. Dermatol Surg 2009;35[suppl 2]:16051611. Rohrich RJ, Pessa JE. The fat compartments of the face: Anatomy and clinical implications for cosmetic surgery. Plast Reconstr Surg 2007;119:22192227. 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. Aesthet Surg J 2009;29[suppl 6]:S50S56.
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10-28 Injectables

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10-28 Injectables

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SRPS

SELECTED READINGS IN PLASTIC SURGERY

OUR EDUCATIONAL PARTNERS

Senior Manuscript Editor Business Managers Corporate Sponsorship

Dori Kelly Lynsi Chester Becky Sheldon Barbara Williams

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

Figure 1. Evolution of injectables in the United States.

SRPS Volume 10 Issue 28 2010

Nonantigenic, noncarcinogenic, nonteratogenic, nontoxic

Simple, reproducible, consistent, nonmigratory, safe

Minimal side effects, predictable outcomes, minimal downtime

Cost-effective, versatile, easily stored, durable shelf-life

Long-lasting Semi-permanent Permanent

6 months2 years 25 years >5 years

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

Table 4 Recommendations for the Use of Botulinum Toxin Type A53,62

Usual No. of Injection Points

Total Dose (Botox)

Total Dose (Dysport)

Women: 6-15 U Men: 6 to >15 U

Crows feet (lateral portions of the lateral orbicularis)

2-5 per side (higher in selected patients)

Women: 10-30 U Men: 20-30 U

Midface Radix (nasalis) 1-2 2-4 U 6-15 U

3-5 U to each muscle

Depressor anguli oris

Dimpled chin (peau dorange), mentalis

1-2 (start with 1 midline or 2 symmetrical lateral injections) 2-12/band

Neck, platysmal bands, platysma

40-80 U/ band 100-300 U/ side

SRPS Volume 10 Issue 28 2010

Figure 4. Common botulinum toxin injection sites.

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

SRPS Volume 10 Issue 28 2010

Now Indexed in MEDLINE! Submit Your Manuscript Today

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This is your website.

Register online at prsjournal.com

for their support of plastic surgery education as a Platinum Education Partner.

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