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Neuromodulators and Injectable Soft Tissue Substitutes


Chapter 28: Neuromodulators and Injectable Soft Tissue Substitutes

Corey S. Maas MD FACS, 1,2 Kenneth C.Y. Yu, 3 Kristin Egan MD 1

1 Division of Facial Plastic Surgery, University of California at San Francisco, CA

2 The Maas Clinic, San Francisco, CA

3 Department of Otolaryngology-Head & Neck Surgery, Travis Air Force Base, CA

Introduction

Attitudes on the use of injectable agents for rejuvenation of the face have changed dramatically over the past decade. This is particularly true for the upper third of the face where the impact of botulinum neuromodulator had its first application. In the senior author’s opinion, no technique, device or pharmaceutical has had a greater impact on aesthetic surgery than the now widely employed use of botulinum neuromodulator as an injectable agent. Botulinum neuromodulator , while widely used in cosmetic indications over the past decade, received approval for a single cosmetic indication in 2002 and has become both an “entry level” treatment and a mainstay of therapy in cosmetic surgery.

Soft tissue augmentation holds a significant role in addressing treatment options for aging effects and camouflaging scars in particular for the mid and lower face. The past decade has witnessed a tremendous increase in consumer, professional and corporate interest in injectable agents capable of eliminating or reducing the signs of aging and undesirable facial expression. The resultant advances in filler agents have expanded the options available for achieving soft tissue augmentation.

Until the past few years, the Food and Drug Administration (FDA) approved injectable fillers for use in the Unites States were limited to the collagen family of products. These included the bovine collagen products Zyderm and Zyplast (McGhan Medical, Santa Barbara, CA) and, more recently, human derived recombinant products (Cosmoderm and Cosmoplast, Inamed, Santa Barbara, CA). Recent action by the FDA and keen corporate interest in capturing part of what is considered to be well in excess of a billion dollar market have led to the development of a series of new products. These include biologic nonpermanent implants (i.e. hyaluronic acid gels, human recombinant collagen, micronized acellular human cadaveric dermis, preserved connective tissue) and the permanent alloplastic implants (i.e. silicone, Gore-Tex). The biologic products offer the advantages of selective bioactivity, ease of use and greater longevity than currently available collagen based products.

Selective bioactivity is, in the authors’ opinion, the central characteristic of successful injectable biomaterials. Selective bioactivity can be characterized by limited and/or selective inflammatory response, a measurable and predictable effective half life or reversibility, and biocompatibility. Biocompatibility is defined as non-carcinogenic, non-toxic and non-immunogenic. Non-immunogenic can be labeled a misnomer since any injected material elicits some inflammatory (and thus immunogenic) response. The pressure to market various new fillers led some companies to not apply for the standard FDA “device” approval process; soft tissue fillers are considered devices and not pharmaceutical agents. Instead, some companies sought clearance by defining their products as transplantable devices. Examples of such “transplant devices” include Cymetra, Fascion, and Dermalogen.

In this chapter we review the currently available neuromodulators and soft tissue fillers, their mechanisms of action, techniques for use and clinical characteristics. In addition, current data on certain products under FDA review for these applications will be discussed. While this family of products has grown, there are still limitations to available filler agents, as well as those undergoing clinical investigation and FDA approval process. Although are a number of ways to classify these soft tissue augmentation materials and neuromodulators, we employ a system that is based on selective bioactivity.

Botulinum neuromodulators

1. Botulinum toxin type A
1. Botox
2. Purtox
3. Reloxin
2. Botulinum toxin type B
1. Myobloc

Soft Tissue Fillers

1. Biologic materials
1. Tissue derived injectable
1. Bovine collagen (Zyderm, Zyplast)
2. Porcine collagen (Evolence)
3. Human collagen (Demalogen)*
4. Avian hyaluronic acid (Hylaform)
5. Human particulate “dermal matrix” (Cymetra)*
6. Human particulate connective tissue (Fascion, Tutoplast)
7. Cultured autologous fibroblasts (Isologen)
2. Synthesized injectable
1. Hyaluronic acid (Restylane, Perlane, Juviderm, Captique)
2. Collagen (Cosmoderm, Cosmoplast)
3. Implantable soft tissue fillers
1. Human acellular dermis (Alloderm)
2. Porcine acellular dermis (Surgicis)
4. Autologous tissue transfer materials
1. Fat
2. Dermal fat grafts
3. fascia
2. Synthesized selective bioactive (resorbable) injectable materials
1. Calcium hydroxlyappetite particles (Radiesse)
2. Polylactic acid particles (Scuptra)
3. Synthesized non-resorbable injectable polymers
1. Silicone (Silkon)
2. Polymethylmethacrylate (PMMA) (Artecoll, Artefill)*
3. Others *(over half of the 63 “regulated” fillers world-wide are microparticulate synthetic polymers
4. Implantable synthetic polymers
1. Extruded polytetrafluoroethylene (ePTFE) – solid (Advanta, Gore-tex) Ultrasoft)
2. Extruded polytetrafluoroethylene (ePTFE) – tube (Softform, UltraSoft)

*Unavailable or FDA trials ongoing

BOTULINUM NEUROMODULATORS

First employed by Dr. Allen Scott of San Francisco in the 1980s, botulinum neuromodulator showed promise in laboratory chick models for selective weakening of treated muscles and soon thereafter was used in the management of strabismusstrabismus 1. Under the trade name Oculinum this product was picked up by Allergan Inc ( Irvine, CA), primarily an ophthalmic pharmaceutical company, for this and other neuromuscular disorders around the eye.

Botulinum neuromodulator is found in nature in seven serotypes (A-G) defined by their specific biologic action in cleaving the particular proteins in the active transport of acetylcholine into the neurosynaptic cleft responsible for muscle contraction (and other autonomic functions) 2. These naturally occurring proteins were originally described as toxins due to the illness botulism, which is associated with ingestion of large amounts of Clostridium botulinum contaminated food stuffs. They are better described, with respect to their now widespread medical use, as neuromodulators. Their distinct beneficial action is selective weakening, relaxation or paralysis of treated muscles or muscle groups. By selective weakening of certain hypertrophic muscle groups in the face and neck, unwanted lines and facial expressions can be suppressed or even eliminated.

While the B serotype neuromodulator (Myobloc, Solstice Neurosciences, San Francisco, CA) has demonstrated benefit in the treatment of hyperfunctional frown lines (HFL), its benefit under current formulations is limited by the shorter duration of effect of the product 3, 4..

The A serotype has demonstrated the longest duration of effect (90 to 120 days) and least discomfort with injection. The standard for neuromodulators has been set by Botox™ (BTX) (Allergan, Inc; Irvine, CA), which has demonstrated safety and efficacy record of over 15 years. The techniques and dosages described herein are in reference to the use of this medicinally original botulinum neuromodulator.

Reloxin (Inamed Inc., Santa Barbara, CA), known as Dysport in Europe, is in current phase III FDA clinical trials and shows promise, as does Purtox (Mentor Corp., Santa Barbara CA) which is in its early phase FDA trials.

An understanding of how to use BTX relies on a clear understanding of the facial muscular anatomy. (Fig. 28–1) While many techniques and surface points of injection have proven effective, it is clear that optimal response with minimal effective dosages requires precise placement in the selected muscle or muscle group.

The senior author has demonstrated the upper facial anatomy in controlled large population anatomic studies 5. The interest in lower facial applications reinforces the need for a fundamental understanding of this muscular anatomy 6. It is clear, however, that due to diffusion effects and the relative safety of BTX, the variability in points of injection and dosages has not significantly reduced the product’s overall satisfactory clinical results. In the opinion of the senior author, required dosages for a given anatomic area can be reduced by precise localization and direct injection into the targeted muscle or muscle groups. Diffusion is helpful for those who lack a solid understanding of muscle location and general anatomy. In some cases, this has been perpetuated by inaccurate published anatomic drawings.

It is imperative that one keep in mind not only the specific muscle locations when providing neuromodulator treatment, but also the functional interrelationships of the muscle action. Many of these act as antagonist-protagonists in the position of the brow. (Fig. 28–1). The use of BTX in general has evolved with experienced and thoughtful injectors from a simple wrinkle treatment to means of reshaping, contouring and softening the facial features associated with aging and the stigmata of the frowning, angry or worried facial form.

The glabellar complex

Furrows created at the base of the nose (radix) are created by the procerus muscle which is statistically larger in women than men. While this muscle has limited action as a brow depressor, it is a powerful “wrinkler” of the nose which with chronic activity creates deep furrows. Many patients seeking treatment for vertical glabellar furrows have very limited procerus activity and do not require concurrent treatment. It is safe to say that not all patients are the same and thus treatment formulas that are universal are wasteful and unnecessary. Three to five units placed in one or two aliquots in the area of radix are sufficient for most patients to achieve a satisfactory reduction in procerus activity. (Fig. 28–1)

The corrugator supercilii and its accompanying depressor orbicularis oculi muscle are clinically indistinguishable. Their anatomy is poorly understood as it relates to that position. In contrast to many schematic and/or figurative diagrams showing the tail (or insertion) of the corrugator muscle one centimeter above the brow, the corrugator in the vast majority of patients follows the course of the eyebrow and delicately interdigitates with the orbiularis oculi muscle laterally and the frontalis muscle superiorly. Thus, injections well above the mid-pupillary brow are of little value in targeting corrugator function and primarily disable lower portions of frontalis muscle. Such injections would be expected to result in medial brow ptosis.

Proper targeting requires the bulk of dosing for the corrugator at the clubhead of the eyebrow. We employ a minimum of 7.5 units in this area and 2.5 units in the scant muscle of the lateral brow to address “recruitment” of this lateral portion and some of the horizontally oriented orbicularis. These injections are directed at or slightly (within 1 or 2 mm) above the level of the eyebrow as the musculature descends with the aging ptotic brow. (Fig. 28–1)

The Lateral Orbital Region (LOR)

The orbiularis oculi (O.o.) muscle and the “Crow’s feet” are also seemingly poorly understood. While primary emphasis is focused by many on the softening of lines in this area, the lateral O.o. is the most powerful depressor of the brow and, as such, has the greatest potential with neuromodulation to reshape the upper face. The emphasis on lateral orbicularis muscle is paramount as the muscle is a sphincter and its superior and inferior portions create vectors of force that are in the horizontal plane. Treating these regions provides for softening vertically oriented supraorbital lines and “crepey” lines in the infraorbital region. Contrary to popular belief, the treatment of these areas has limited impact on horizontal brow position, in the senior author’s opinion.

Treatment strategies therefore are stratified (although not mutually exclusive) around treatment of hypertrophic lines and reshaping the brow. While single point limited dosing at the lateral brow margin may provide some benefit in elevating brow position, it is advisable to keep in mind the entire lateral O.o. is responsible for brow depression and, as shown in the senior author’s previous work 7, 8 treatment of this large and powerful depressor can have a profound impact on brow position. In contrast, the supra and infraorbital lines of expression can be substantively impacted by small doses in these regions. Concerns about effects on extra ocular movements and the elevators of the lip have not proven problematic in our experience where lower eyelid injections are targeted outside the orbital rim and in the immediate subcutaneous plane.

Starting doses for the LOR are in the range of 10 units per side and one can quite comfortably go as high as 20 units per side in our experience without impact on sphincteric function. Small 2.5 units aloquiots are placed at roughly 1cm intervals in a “half-moon” configuration from the infralateral brow to the inferior extent of horizontally oriented lines. (Fig. 28–1) Extension for the crepey skin in the infraorital region is easily done up to the area of the nasojugal groove.

The Forehead

The forehead is probably the most variably and poorly treated region of the upper face with neuromodulators. Injectors must balance the benefit of hyperfunctional line improvement with relaxation of the only brow elevator, the frontalis, and attendant ptosis of the brow that will occur. Dosages exceeding 20 units in the forehead are rarely warranted, in the senior author’s opinion, as complete line effacement is not worth the side effect of noticeable brow ptosis. In addition, many strategies for treating the forehead region leave lateral frontalis muscle action unattenuated, resulting in a “Dr. Spock-like” forehead deformity (Fig. 28-2) that is both a hallmark of treatment and unattractive. The key to success in forehead treatment is modest dosing (enough to soften the lines with minimal impact on brow position) and uniform distribution of injections to avoid asymmetries and an artificial appearance of brow position.

Typical starting doses are around 5 units per side in 4 or 5 2.0 to 2.5 unit aliquots. (Fig. 28–1) Extension areas (E) may also be treated with similar dosing strategies deposited just through the galea aponeurosis. This layer can be “felt” as a gentle pop of the needle with insertion and is well above the frontal periosteum.

Perioral lip lines

Historically, fillers have been the primary therapy for perioral lip lines and, along with resurfacing for longer term results, remain the mainstay for treatment of these dynamic lines. The lines, often referred to as “smoker’s lines” are the result of repetitive muscle action of the Orbicularis oris muscle and photoaging. With the etiology of these lines of facial expression in mind, one can use sparing amounts of BTX to suppress pursing expressions. Generally, 4-6 units of Botox are placed with precise symmetry at the vermillion border in 4-6 one unit aliquots for the upper and lower lips. Beyond these doses one risks significant early problems with dysarthria and oral competence.

Marionette Lines

The depressor anguli oris (D AO) arises from the oblique line of the mandible, and inserts, by a narrow fasciculus, into the angle of the mouth (Fig. 28-3). At its origin, it is continuous with the platysma; at its insertion, it is continuous with the Orbicularis oris. Contraction of this muscle over time results in melomental folds or “marionette lines” which may be treated with by injecting botulinum toxin directly into the DAO muscle at one location. Typically, 3 U are injected into each muscle, located where the nasolabial fold intersects the mandible. One must take care to avoid injecting the lip depressors.

Dimpled chin

The mentalis muscle originates from the mandible, covers the chin and inserts into the skin below the lower lip. Its action can cause wrinkles and dimpling (Fig. 28-4). 2-5 U is injected into one or more sites. The injection is targeted low or just below the prominence of the chin. After injecting, the muscle is massaged in a lateral direction. One should take care not to inject too high or risk weakening the orbicularis oris, causing lower lip incontinence and possible drooling. One must also avoid injecting the depressor labii, which can cause the lower lips to depress.

Platysmal bands and neck contouring

Hypertrophic or flaccid platysmal muscle can be one etiology of the aging neck. Other potential causes include lipodystrophy, ptotic submandibular glands, or excess skin. Consequently, proper patient selection for BTX is critical and the greatest challenge. Using BTX to address platysmal bands work best for younger patients with good skin elasticity or postoperative residual bands. 9 Number of injections and injection dosages vary among practitioners; from three to five sites per band and dosages varied from 6 to 40+ U total doses per band. The senior author prefers to inject 10 U per band, and targets those bands at the cervicomental area. Usually two bands are treated in one session and repeat treatments typically occurred after 3 to 4 months. (Fig. 28-5) When injecting the platysmal bands, care must be taken to avoid the strap muscles. 10 Complications may include ecchymosis, headaches, dyspnea, and neck weakness. 11 While BTX can produce temporary satisfactory results, the optimal and longest lasting results can only be achieved through surgery. 12 BTX will not correct skin laxity or fat deposits. 9 There is general consensus that BTX should be limited to patients who are poor surgical candidates. 10,12

SOFT TISSUE FILLERS

Historically, soft tissue fillers, namely Zyderm (Inamed Corporation, Santa Barbara, CA), were the only available injectable agents for management of the aging face. This legacy has largely been supplanted by the use of BTX. However, there is still a role for the use of these materials in upper as well as lower facial rejuvention. Despite BTX’s excellent results and established track record, there remain shortcomings to the use of BTX alone in the upper face; namely, the inability to correct dermal resting lines particularly deeper lines and those in older patients. The predominant use of fillers in upper portions of the face is in the management of fine dermal lines, commonly in combination with BTX. Historically, Zyderm was used to treat “crow’s feet”, horizontal forehead lines, and glabellar lines. The effectiveness of BTX in management of these regions has largely limited the use of fillers to deep dermal lines in the glabellar area refractory to the muscle atony induced by BTX.

Soft tissue fillers hold a more useful role in rejuvenating the mid and lower thirds of the face. Increased nasolabial and melolabial folds are commonly seen during the aging process. In addition, loss or contracture of tissue resulting from surgery, trauma, or acne can be improved with fillers. The hypoplastic lip is another common cosmetic concern that can be treated with soft tissue fillers.

Historical Background

The ideal filler agent is one that is easy to use, creates reproducible long lasting results, is biocompatible, nonallergenic noncarcinogenic, and nonmigratory. In addition, it can be transported and stored at room temperature and has a long shelf life. The search for an ideal soft tissue augmentation product has been continuing with varying degrees of success since the end of the nineteenth century. Autologous fat was first reported as a soft tissue filler by Neuber in 1893. 13 Paraffin was later used, but the high incidence of inflammatory reaction and foreign body granuloma formation made it unsafe, and its use was abandoned around the time of World War I. 13,14 The ensuing years brought the use of vegetable oils, mineral oil, lanolin, and beeswax; however, all exhibited problems that continue to be associated with fillers in use today, namely chronic inflammation, infection and/or migration. 15-18

In the 1960’s, interest turned to new highly purified polymers and their potential application for soft tissue augmentation. Pure injectable liquid silicone was embraced as ideal among these synthetic polymers. Despite caution suggested in a number of reports, silicone became widely used to augment many soft tissue defects by direct injection. 19,20 Severe complications can occur with large volume injections. For instance, late term granulomas are not uncommon, and large volume injection (greater than 0.5ml) particularly in the lips can have irreversible consequences. Yet, controversy persists regarding the efficacy and safety of the so called microdroplet injection technique popularized by Webster and Orentreich et al 21,22 They argue that silicone is both an effective and safe filler when used in limited amounts mandated by the microdroplet technique. If limited siliconoma develop, corticosteroids may be helpful. 23 Another synthetic polymer, polytetrafluoroethylene (Teflon) paste, was initially thought to be a useful soft tissue filler. However, the technical difficulties encountered when injecting this thick paste, as well as an exaggerated inflammatory reaction, prevented its widespread use. 24

Over the next four decades, investigations and development produced many alternative materials such as injectable collagen, human acellular dermis, and synthetic selective bioactive materials. In just the past 2 years we have witnessed the introduction of an extraordinary number of soft tissue augmentation fillers in response to the public’s ever increasing demand for minimally invasive cosmetic procedures. Table 1 summarizes the current most popular soft tissue fillers.

I. BIOLOGIC MATERIALS

The use of biologic materials for injection is, in general, advantageous as infection rates are less than synthetic materials which, regardless of biocompatibility, are foreign bodies. However, infection has not been eliminated altogether and biologic fillers are, without exception, subject to variable degrees of remodeling and/or resorption. The rates of biologic degradation of these materials are determined by a number of factors and have been fairly clearly characterized for certain biologic fillers. Historically, manufacturers of commercially available products have exaggerated the duration of clinical effect leaving physicians with difficulty with patient expectations. Hypersensitivity responses are generally uncommon and well described for bovine collagen products.

Bovine collagen

Bovine collagen was the first material approved by the FDA for use as an injectable soft tissue filler in 1981. 15 Injectable collagen is a reconstituted, purified, enzyme-digested, bovine dermal collagen suspended in a phosphate buffered saline with 0.3% lidocaine. 25 Commercial products include Zyderm I, Zyderm II, and Zyplast (Inamed Corp., Santa Barbara, CA). Zyderm I was the first approved agent for use as a soft tissue filler in the United States in 1981. 26 Zyderm I contains a collagen concentration of 35 mg/ml and is made up of 95% type I collagen and 5% type III collagen. 27 The processing of Zyderm removes the immunogenic telopeptide regions of the molecule without disrupting the natural helical structure. Zyderm II is similar to Zyderm I, but contains a higher concentration of collagen (65 mg/ml) 27 . Zyplast differs from Zyderm in that it contains glutaraldehyde cross-linked collagen, making it less susceptible to collagenase degradation and less immunogenic. 27 Patients considering bovine collagen injection must be skin tested prior to treatment. 0.1 ml of the material is injected subdermally in the volar forearm area. The site is examined after 48 to 72 hours and at one month. A positive test, exhibited by erythema and/or induration, is a contraindication to use this product. 3 to 3.5% of the population demonstrate a hypersensitivity to bovine collagen and after one negative skin test, one percent (or less) of patients will demonstrate hypersensitivity to a second challenge . 28 Consequently, a repeat test in 2 to 4 weeks is usually recommended, and treatment may proceed after a second negative skin test.

Zyderm and Zyplast have a good safety record andcome prepackaged in a one milliliter syringe. Zyderm I has very favorable flow characteristics and as such is excellent for treating fine lines. The duration of effect with bovine collagen is highly variable (generally three months) is dependent on the injection site the patients metabolism. Disadvantages include the need for refrigeration, possibility of allergic reaction, the short duration of improvement, and treatment can be expensive if increased amounts need to be injected for older patients. 29

Zyderm and Zyplast are injected intradermally, and the effects are immediate. Results with the use of Zyderm and Zyplast are good but can be modified by delayed hypersensitivity. Zyderm is infiltrated into the superficial papillary dermis and its effect makes it an excellent filler for addressing fine lines. Zyplast is placed into the midreticular or deep reticular dermis at the dermal subcutaneous interface. Zyplast should not be injected into the superficial papillary dermis or in areas of thin skin because it can form beads on placement. 27 Since Zyplast is injected into the deep reticular dermis, it can be used to address deep folds, wrinkles, as well as augmenting the lips. Provided the patient has been skin tested, Zyplast is an excellent option for those who desire a quick enhancement prior to a social event. Zyderm and Zyplast contain lidocaine for more comfortable administration, however, additional topical anesthetic may be useful.

Human collagen

The success of injectable bovine collagen led to the development of a myriad of alternative injectable biologic fillers including, in the US, Autologen and Dermalogen (Collagenesis, Beverly, MA). these products gained limited popularity and are mentioned for historical purposes. Autologen was an injectable autologous human tissue matrix processed from skin harvested during skin excision surgery (i.e. rhytidectomy, blepharoplasty). For theoretical long-term results, at least three injections were required spaced two weeks apart to satisfactorily augment a soft tissue defect. As autologous tissue there was little risk of disease transmission or allergic reaction however, the results were not been shown to last longer than bovine collagen. Since Autologen was material harvested from the patient’s own body,. the time,expense, equivocal duration and delayed treatment doomed Autologen..

Dermalogen was developed to overcome the obstacle of surgical harvesting, and used cadaveric banked tissue which had been aseptically processed, acellular, and was structurally similar to Autologen. 30 The cosmetic results of both Autologen and Dermalogen demonstrated a natural, softer appearance like the result seen with bovine collagen. One study by Sclafani et al 31 evaluated a direct comparison of Dermalogen and Zyplast in 20 patients over a 12-week period. It demonstrated that the clinical persistence and histological behavior of Dermalogen was comparable to Zyplast. The product is no longer available.

Human Recombinant Collagen (Cosmoderm and Cosmoplast)

The delay time from presentation to treatment and measurable delayed hypersensitivity response seen with bovine collagen led the to development a human derived “tissue engineered” collagen product. The emphasis on this technology was underscored by diminishing sales of bovine based products, particularly in Europe, where the Bovine Spongiform Encephalopathy (BSE) or “mad cow disease” left much of public concerned about transmissibility of this disease through bovine collagen injections. No such cases have been reported. CosmoDerm I / II and CosmoPlast (Inamed, Santa Barbara, CA) are the only currently available dermal fillers made from natural human collagen grown under controlled laboratory conditions. They contain purified collagen derived from cell cultures of human fibrocytes. The cell lines are obtained from the foreskin of a newborn and are screened for viruses, tumerigenicity, and other potential pathogens. Since these products contain the basic human collagen molecule stripped of antigenic determinants, no skin testing is required. This is an advantage over Zyderm and Zyplast, allowing one to inject this product at the initial consultation. The disadvantages are similar to Zyderm and Zyplast: need for refrigeration, the cost, and duration of effect.

Human particulate “connective tissue”

Fascian (Fascia Biosystems, Beverly Hills, CA) and Tutoplast are preserved irradiated human cadaver fascial issue in particulate form that can be injected for soft tissue augmentation. 32 They are supplied in various particle sizes and must be rehydrated with lidocaine or saline before injection. The implant is injected subdermally with a 16- to 26 gauge needle, depending on the particle size selected. Fascian should not be injected into the dermis because inflammation with lumpiness can occur.

The promoted advantages of fascial tissue are that they may last longer than collagen, it can be stored at room temperature, and no skin testing is required. Disadvantages include the requirement for rehydration prior to use, local anesthetic must be used, and is contraindicated in patients with allergies to polymyxin sulfate, bacitracin, or gentamycin since there may be trace amounts of these substances in these implants. These products are not useful for superficial lines. Clinical reports with these products have been limited and, in general reported by company principles. The general impression of the clinical and academic community is the behavior of this product is similar to Cymetra (swelling and short duration).

Hyaluronic acid derivatives

hyaluronic acid (hyaluronan, sodium hyaluronate; HA), a natural biopolymer of glycosaminoglycan chains which coil on themselves resulting in elastic and viscous matrix. It exhibits no species or tissue specificity and its chemical structure is uniform throughout nature. Thus, there is limited potential for immunogenicity. It is found naturally in the dermis and has a high affinity for water thereby serving to hydrate the skin. 22 33 The loss of HA as we age leads to dermal dehydration and the formation of rhytides. 23 34 Cross-linking can serve to lengthen the half-life of HA but cannot eliminate its degradation. current FDA approved hyaluronic acid fillers are limited to Hylaform (Biomatrix, Ridgefield, NJ), Restylane (Q-Med, Upsala, Sweden) and Captique (Inamed Corp., Santa Barbara, CA) Hylaform is a xenogenic variety derived from rooster combs. Restylane and Captique are partially cross-linked and processed from Streptococcus fermentation. 33 .Restylane and Captique, non-animal products,s, have a theoretical lower risk of delayed hypersensitivity reaction. In side by side comparison with Restylane, Hylaform showed a higher incidence of skin reaction. 35 Both forms are reabsorbed, albeit at a slower rated than the collagen products. It has been reported that effects last up to 6 months. 36

Restylane, Captique Hylaform do not require skin testing, although early studies did not demonstrate hypersensitivity or allergic reactions, several case series have reported delayed reactions 37,38. A study of 709 patients over four years showed positive skin testing in patients who developed delayed skin reactions to these materials. The manufacturer does not recommend skin testing for these materials but these reports may suggest otherwise. 39 Case reports have also shown the potential for granuloma formation with the use of hyaluronic acid derivatives. 40 Positive skin tests have demonstrated chronic inflammatory reactions at up to 11 months and serum IgG and IgE antibodies to hyaluronic acid however, these reactions are quite rare. 38 HA is contraindicated in patients with severe allergies manifested by history of anaphylaxis or history of multiple severe allergies. Restylane, Captique and Hylaform are contraindicated for breast augmentation and implantation into bone, tendon, or ligament. It must not be injected in blood vessels since it may occlude vasculature, leading to infarction or embolism.

Restylane is approved for mid to deep dermal injections and can be used in all areas of the face. The most commonly treated areas include the lips and nasolabial folds, while perioral areas (e.g. Marionette lines, oral commissure), glabellar complex and brows are also potential targets. In the senior author’s experienceOlenius and Duranti, et al demonstrated encouraging results, with majority of patients reporting good results up to 8 months. 57,58 A randomized study of 138 patients comparing Restylane and Zyplast on the correction of nasolabial folds (Fig. 28–6) demonstrated that a more durable aesthetic improvement was found with Restylane. 59 Less injection volume was required with Restylane, and it was superior to Zyplast in retaining its shape. A comparison of Restylane with and without the addition of Botox (Allergan Inc., Irvine, CA) demonstrated that glabellar rhytides responded better to the combination of Restylane and Botox. 60 Those patients who present with deep vertical glabellar lines at rest may not be able to achieve the elimination of those lines with the use of Botox alone. Restylane can serve to fill the resting lines, and the addition of Botox delays the deformation of the filler residing in the dermis, thereby performing a protective function. Restylane is also well used as a soft tissue filler for microchelia (Fig. 28-7). Finally, Restylane is being used more and more as a soft tissue filler in areas such as the submalar areas, temporal areas, and the nasal jugal groove ( Fig. 28-8). The rationale behind using Restylane to replace or enhance volume is based on injecting into the subdermis area. There is a growing sense that Restylane in this area may last longer (the duration of effect may not even be an issue) and is possibly safer. , HA fillers such as Restylane are not ideal in addressing the perioral fine lines due visible ridges and bluish tint seen (Tindel effect) (Fig. 28-9).

These fillers also have the potential for reabsorption and may require repeat injections at 2-4 weeks. 33 Restylane is more viscous than Hylaform and it has been postulated that a decreased concentration may allow the material to absorb more water and lead to a more long-term correction. None of the HA fillers contain lidocaine and pre-injection with local anesthetic is recommended. No overcorrection is necessary. These fillers can be stored at room temperature for at least a year but must be used within 24 hours when opened. Restylane has demonstrated excellent clinical results with softness,durability and patient acceptance since its introduction in the US market. These features and an admirable marketing campaign have resulted in Restylane capturing some 50% of the total injectable filler market. In contrast, the limited duration of effect seen other HA fillers have limited their success.

Juvederm is in U.S. FDA trials and is another hyaluronic acid in the form of viscoelastic gel, which is transparent and homogeneous and which has four major benefits. It is obtained by biosynthesis and is of non-animal origin and does not require any prior skin testing. The molecule is highly biocompatible and is obtained by bacterial fermentation. Juvederm is presented in the form of a pre-filled syringe, containing a viscoelastic, transparent hyaluronic acid gel and is available in three different concentrations, their use depending on the nature of the depression, needed to be corrected. Juvederm 18 is used for fine wrinkles such as peri-oral wrinkles, Juvederm 24 for glabellar lines, mild to moderate nasal furrows and cheek wrinkles. Juvederm 30 is used for deep nasolabial folds and lip volume. Data from European and other experience suggests that Juvederm compares favorably to Restylane in ease of use and patient satisfaction.

Collagen

Cultured autologous fibroblasts

Isolagen (Isolagen Tech., Metuchen, NJ) is currently under FDA investigation. It consists of injectable autologous fibroblasts derived from an autologous source. It has been advocated for the treatment of facial rhytids, nasolabial folds, glabellar furrows, scars, and hypoplastic lips. Recommended treatment consists of three to four injections over a 3 to 6 month period. Theoretically, Isolagen has the advantage of low immunoreactivity; there has been no report of major complications or hypersensitivity reactions. Isolagen’s manufacturer attempted several years ago to achieve approval as a transplant material and was temporarily on the market, but was subsequently required to perform standard FDA device clinical research. Currently, this research in ongoing and Isolagen remains under clinical investigation.

Human acellular dermis

Skin Derivatives

Alloderm (LifeCell Corp., Branchburg, NJ) is an acellular, freeze dried dermal graft harvested from screened cadavers. Alloderm is processed from cadaveric skin preserving the basement membrane and dermal collagen matrix. After the fibroblasts are extracted, the material is cryoprotected, enabling it to be freeze dried in a two-step procedure. Like all other materials harvested from cadavers, Alloderm is screened for contaminants before it is shipped. To date, no reported cases of disease transmission exist. It is stable for 2 years under refrigeration, and must be rehydrated for 10 to 20 minutes in normal saline or lactated Ringer’s solution immediately prior to use. The various size and thicknesses available make it an excellent material for repairing large tissue defects. If infection occurs, it may not be necessary to remove the implant, only to treat the infection. 28 Zyplast was studied in direct comparison with Alloderm with follow-up at 1 year by Sclafani, et al. Superior results were seen with Alloderm which stabilized in resorption at six months while Zyplast was progressively absorbed. 42 Unfortunately, Alloderm does not appear to last as long or be as consistent as originally described. The reduced duration of effect and its high cost have decreased its use and popularity.

Cymetra (LifeCell, Branchburg, NJ) is micronized Alloderm designed as an injectable soft tissue filler. Cymetra must be reconstituted with 1 mL of lidocaine before injection and used within 2 hours. Some reports suggest that Cymetra does not reabsorb as Zyplast is observed to do, and therefore repeated treatments are more effective. 43 In addition, Cymetra carries an increased incidence of inflammatory reactions and has not shown to last longer than Zyplast. It also requires mixing with 1% or 2% lidocaine; the resultant thick paste can be difficult to inject. The senior author’s experience with Cymetra has been variable, but the marked swelling and shorter than advertised duration of effect have limited the clinical use of this product.

Porcine acellular dermis

Surgisis (Cook Biotech Inc., West Lafayette, IN) is a sterile acellular graft material extracted from the small intestine submucosa of pigs. The submucosa is processed to retain the natural composition of matrix of collagen (Type I, III,VI), glycosaminoglycans (hyaluronic acid, heparin, heparin sulfate, and chondroitin sulfate), proteoglycans, and fibronectin. The material acts as a natural extracellular matrix which acts as a scaffold for host tissue remodeling. The manufacturing process is also carefully validated to ensure any potential virus in host animals is inactivated. Like Alloderm, it must be hydrated in sterile normal saline or lactated Ringer’s prior to use. Surgisis has a long shelf life (about 18 months) and can be stored at room temperature. Its main use continues to be for nasal reconstructive surgery, but increasing experience may broaden its applications.

Autologous fat injection

Since Neuber first introduced free fat autografts in 1893, the use of fat as a filler agent has fallen in and out of favor due to its high resorption rate and unpredictability. In 1950, Peer reported an average loss of 45% in the weight of the free fat implant by one year. 45 The arrival of liposuction has renewed interest in autologous fat injection. 46

Fat is harvested aseptically into a sterile container, using local anesthesia and tumescent technique with a blunt tipped microcannula or a syringe. Donor site choices include the submental, lateral thigh, hips, or umbilical regions. The harvested fat can also be frozen in liquid nitrogen for future use. The harvested fat is then washed with sterile saline, although some believe that washing the fat can lead to increased mechanical trauma and decreased fat survival. 47 Currently, there is no gold standard for autologous fat injection. 48 The fat is injected into the subcutaneous tissue with a large bore needle (i.e. 16 or 18 gauge needle). After injection, the area is massaged so that the fat fills the injected fields smoothly. Fat injection may be used to address nasolabial and melolabial folds, glabellar furrows, lips, and hemifacial atrophy. Due to the expected resorption, overcorrection of 30 to 50% is usually recommended. The role of fat transplantation, like many fillers, has changed over the past decade. Its primary role is now well established as a volume restoration product in the brow, midface and lower facial areas. In these areas, the variable results that are often described when filling lines and borders are largely eliminated. Fat has truly found its role due to work of Coleman and others in volume restoration.

Autologous fat injection offers certain advantages. Since it is from the patient’s own body, there is no risk of allergic reaction. Fat is abundant in the body, making it versatile (able to fill large and small areas over much of the body). 29 Disadvantages include donor site morbidity, and the unpredictable resorption rate.

II. SYNTHETIC SELECTIVE BIOACTIVE INJECTABLE FILLERS

Calcium hydroxyapatite particles

Radiesse, formerly Radiance FN, (Bioform, Franksville, WI) is composed of microscopic calcium hydroxyapatite particles (ranging in size from 25-40?m) suspended in a carboxymethyl-cellulose gel.. The mechanism action of Radiesse is both in volume restoration and to act as a framework for fibroblastic ingrowth in soft tissue. Radiesse is FDA approved and used for years in dental reconstruction, as well as bone, bladder, and neck implants, and is also approved for oral-maxillofacial defects.

Radiesse also does not require skin testing because it contains no animal products. Its effects are reported to last from 2 to 5 years in urologic studies. In facial applications its duration is in the range of 6 –12 months depending on the site of the injection and the technique used. In the senior author’s and others’ experience, Radiesse looks and feels quite natural. 29

In histologic studies, Radiesse microspheres were gone at nine months but they stimulated almost no foreign body reaction. 49 Few macrophages were visualized surrounding the microspheres of Radiesse, suggesting that they are degraded by enzymatic processes rather than cellular processes.

Radiesse is in late phase clinical trials for cosmetic indications, namely, the nasolabial fold where side by side comparisons with an HA control demonstrated patient and physician preference for Radiesse. This product may well have a significant impact our choices and methodologies when using fillers with FDA approval.

Radiesse can produce excellent results for deeper folds, wrinkles, and lip enhancement, when used judicially, but should not be used for superficial lines. 29 Its applications, too, has expanded into the role of volume enhancement. More and more practioners are using Radiesse to enhance nasolabial folds, naso jugal groove, and inframalar areas. The attraction of Radiesse is its longer duration of effect (8-18 months) and hypoallergenic characteristics. While Radiesse has been used in the lip, we do not recommend its use in lip augmentation as the microspheres will be compressed into strands during the act of mastication. Others have also noted problems with its use in the lip. 62 Injections with Radiesse are painful and require local anesthesia. Swelling can occur for two days after injection

Polylactic acid particles (Sculptra)

Sculptra (Dermik Aesthetics, Berwyn, PA) is an injectable form of poly-L-lactic acid, a compound that has been used in absorbable suture material for over 40 years. It is a nontoxic, synthetic, immunologically inactive, biodegradable lactic acid polymer. It is approved in Europe for the treatment of scars and wrinkles and was recently approved by the FDA for treating facial lipoatrophy associated with HIV disease. Sculptra comes in powdered form and must be reconstituted with sterile water with or without lidocaine. The reconstituted form must then sit for 2 hours to ensure complete hydration of the product. It requires a 26-gauge or larger needle for injection and must be used within 72 hours. Theoretically, Sculptra can be injected into the deep dermis or subcutaneous tissue. However, in the senior author’s experience, this product must be placed in deep subcutaneous tissue to avoid the reported complications of visible and palpable granulomas and draining fistulas. Multiple sessions at 2 week intervals are needed for significant improvement. Initial studies demonstrated skin thickness increase as early as 6 weeks after injection, which remained for up to 96 weeks. 50

Advantages of Sculptra are that it does not require refrigeration and no skin test is necessary. However, it must be reconstituted 2 hours before injection and a local anesthetic is usually required. In Europe, the current opinion of Sculptra is variable. While it may produce some improvement initially, the fluid is absorbed after a week and the effect is diminished. Multiple repeat injections are required to stimulate the proposed collagen growth before the desired effect is achieved, which may take up to 3-4 months. The advertised duration of months to years must be interpreted with caution since many injections spaced months apart are necessary to achieve this. Finally, granulomas, nodule formation and drainage have all been reported, and these complications can be difficult to manage.

III. SYNTHETIC NON-RESORBABLE INJECTABLE POLYMERS

Silicone

Silicone is a polymer of dimethylpolysiloxane that can come in various forms, ranging from liquid to solid. 51 Silicone may be used off label, but since it is classified as a device and not a drug, it may not be advertised in the office, phone book, internet, or in other media.

Silicone is injected through a 30-gauge needle in microdropletsof 0.01 mL into the subdermis. 51,52 Serial injections should be separated by 1 to 2 mm of tissue. Each microdroplet produces augmentation via a fibroblastic response; a fibrous capsule forms around each capsule of silicone. This process takes several weeks. One should inject microamounts and undercorrect. 51 When considering injectables, there are basically three techniques used to deliver material to the deep dermis or subcutaneous level: linear threading, serial puncture and droplet (Fig. 28-10). Linear threading is a technique by which an agent is delivered in a uniform fashion while the needle is slowly withdrawn from the tissue. The linear threading is a technique that is particularly effective when performing lip augmentation along the mucocutaneous border. The serial puncture technique is used to deliver small aliquots of filler at multiple spots to achieve even distribution over a two-dimensional area. Finally, the droplet technique is used in a manner similar to that in linear threading. However, instead of an even distribution of filler as the needle is withdrawn, micro-droplets of filler are delivered into the tissue by gentle pumping on syringe as the needle is withdrawn. The droplet technique has been advocated for use when injecting silicone. The depth of injection, however, is dependent on the injectable used. Multiple treatments may be necessary, and should be performed at 6 or more week intervals.

Silicone is permanent, does not require skin testing (there are no antibodies to liquid silicone), can be stored at room temperature, does not support bacterial growth, and can be used to treat many areas. However, its disadvantages are numerous, including inflammation, induration, discoloration, ulceration, migration, and formation of silicone granulomas. 51. Silicone is also very difficult to remove after it’s injected into soft tissue. There are those who believe the complications seen with silicone are caused by improper injection technique, injecting too much silicone, or the quality of silicone. 25,52

Polymethylmethacrylate (PMMA)

Synthetic Polymers

Artecoll (Artes Medical Inc., San Diego, CA) is a suspension of polymethylmethacrylate (PMMA) microspheres 30-40?m in diameter in 3.5% bovine collagen solution and is the most advanced synthetic permanent injectable. Artecoll works by microgranuloma formation which may not be controllable. This product produces immediate correction with collagen and also permanent replacement with new collagen produced as part of the inflammatory response. 28 Artecoll, unlike the other microspheres, does not become reabsorbed, and histologically new collagen deposits are visible at one month. 49

The smooth surface of the microsphere decreases a foreign body reaction and its size prevents migration and phagocytosis. 53 It should not be used in areas of fine skin as the implants may be more visible and should be avoided in those prone to keloids as any foreign material may serve to increase the incidence of keloids. However, Artecoll demonstrates a much lower incidence of immunological response (0.06%) as compared to Zyderm which has an incidence of 3%. 49 A concern with the use of permanent filler is the potential for migration to other areas outside of the injection site which can lead to potential deformities. Migration has only been observed when the material is injected into the dermis in trials with guinea pigs and has not been observed with correct placement of the material. 54 Granulomas may also occur, and while it is impossible to predict which patients may face this consequence, those fillers which are composed of microspheres with a smooth surface, such as Artecoll and New-Fill, are less likely to cause this reaction than fillers with irregularly surfaced microspheres, such as Dermalive. 14 Reviderm (Rifol Medical International, Netherlands), available in Europe, is a suspension of 2.5% dextran microspheres of 40?m in 2.0% hyaluronic acid. The microspheres of Reviderm produced the greatest amount of granulation tissue but were also disintegrated at nine months.

Artecoll may be used to treat facial rhytids or scars. We do not advocate its use in lips due to the potential development of granulomas, which are difficult to remove. In addition, thin skin areas (i.e. crow’s feet) should be avoided because the implant may be visible or palpable; hence, the implant should not be injected into the dermis. Artecoll is injected into the subdermis with a 27-gauge needle under constant pressure using the needle to create tunnels. The patient is also encouraged to massage the area for 3-5 days. 53 Slight overcorrection is recommended and repeat injections may be performed 1 to 3 months later.

Combinations of materials are also available outside the .U.S. including Dermalive and Dermadeep (Dermatich, Paris, France). Dermalive, a 40% hyaluronic acid, and Dermadeep, a 60% hyaluronic acid, are combinations of hyaluronic acid and the active constituent acrylic hydrogel (contact lens material) which have been studied in Europe. They, along with over 50 other permanent microparticulate synthetic products world-wide, were for sustained (irreversible soft tissue augmentation. The tolerance to Dermalive, like silicone or PMMA beads ifor patients who demonstrate no early or late-term chronic inflammatory response to the acrylic polymer, is good and it has been supplemented with injections of Juvederm or Restylane for fine line and superficial defects. 41 A three year study of this combination therapy in 455 patients demonstrates a 88% patient satisfaction rate with limited side effects. 41 Experience with these permanent bead products demonstrates a measurable incidence of deforming side effects requiring surgical intervention.

IV. IMPLANTABLE SYNTHETIC POLYMERS

Expanded polytetrafluroethylene (ePTFE)

Implantable expanded polytetrafluoroethylene (e-PTFE) (W.L. Gore and Assoc., Flagstaff, AZ) has been used in the field of vascular surgery for over 30 years, a testament to its safety and reliability. 55 Tissue in-growth is marginal into the material, but when shaped into a tube, longitudinal growth occurs. This serves to strengthen the filler and secure it to the site of implantation. 56 The tubular form, marketed under the name SoftForm (Collagen Corp., Palo Alto, CA), was used as a soft tissue filler for lip augmentation. There still exists a risk of extrusion or exposure of the ends of the material at the entrance wound where the implant is delivered. SoftForm showed wall stiffening due to the abundance of ePTFE and will shorten and harden with time. This can create an “accordion effect”. The risk of extrusion at the insertion sites creates a potential source of infection. If complications do arise, the implant is always removable. Because of these limitations, SoftForm has been improved and is now marketed under the new name Ultrasoft, a thinner and softer form.

Ultrasoft is dispensed alone or within an included trocar. A stab incision is made where the implant is to be inserted after obtaining local anesthesia. The implant is tunneled parallel to the defect at the level of the deep reticular dermis or subdermis. The implant is cut at the remaining end and the entrance wound is closed in layers. Careful attention is paid to insure symmetric and even soft tissue distribution over the implant prior to removing the tunneling trocar.

TECHNIQUES

When considering injectables, there are basically four techniques used to deliver material to the deep dermis or subcutaneous level: linear threading, serial puncture and the subcutaneous techniques of fanning and cross-hatching(Fig. 28-10).

Linear threading is a technique by which an agent is applied in a uniform fashion while the needle is slowly advanced or withdrawn from the tissue. Uniformity in the depth of deposition is the challenge when placing products intradermally using this technique. Subcutaneous or deep intradermal applications however, can be reliably performed using linear threading. This technique is commonly employed (along with fanning) for nasolabial fold and oral commissure augmentation as well as volume enhancement and contouring. The HA fillers and Radiesse are commonly applied using this technique.

The linear threading is a technique that is particularly effective when performing lip augmentation along the mucocutaneous border. By placing the needle in the proper plane along the vermillion border and applying steady and light plunger pressure the injector can achieve an effective and uniform placement of the product effectively by hydrodissection. The anatomic plane filled employing this technique can provide a natural lip roll and substantial natural augmentation.

The serial puncture technique is used to deliver small aliquots of filler at multiple spots to achieve even distribution over a two-dimensional area It is particularly effective in accurately delivering product at the more superficial levels of the mid to upper dermis and thus is ideal for correcting fine lines. The flow characteristics and color of Cosmoderm I and Zyderm I make these product more suitable for this technique although some author’s have reported success using fine (30ga) needles and HA products for fine lines. The skin is punctured superficially and gentle plunger pressure applied to achieve a visible blanching effect that elevates the line and spreads circumferentially beyond its confines. 4-8 mm of wheal are thus created and the needle is withdrawn and topographically reinserted at approximately the radius of the previous wheal. The linear defect is followed as such to achieve complete correcton.In general, while HA products are theoretically designed and approved for intradermal injection, many expert providers are injecting these products subdermally and demonstrating excellent results and longevity. Examples of applications where subdermal injections are required and have shown good results and longevity include the tear through deformity, mandibular border, lips and even the nasolabial fold.

The senior author has witnessed many “expert” demonstrations of injection in which the instructor represented that the injections were in the “deep dermis” while plunging the needle 5-8 mm or more below the skin surface. While anatomically incorrect in the discription of placement, subdermal sudermal injections may be an ideal level for many areas. It is understandable that companies cannot promote off-label use of products, however as practioners we should take care to more accurately represent the level of place, which in the case of HA products, may not need to be placed in the dermis to provide excellent and lasting cometic effect.

As such, when using HA products we use both a topical and nerve block anesthesia to achieve high levels of patient comfort. After proper anesthesia the skin is prepared with topical alcohol. The patient is general in the lounge chair position, although for gravity dependent areas such as the nasolabial fold, one may need to place the patient more upright for accuracy. A linear threading technique is used in the deep dermal-subcutaneous junction for nasolabial folds starting inferiorly and moving superiomedially. The lips are injected from lateral to medial in the subcutaneous plane along the vermillion border by gentle pressure and “hydrodissection”. Upper and lower lips and treated similarly with focus on the central one third of the lower lip. Further plumping and eversion can be achieved by everting the lip and placing several linear “beads” caudal to the wet lip border.

The mandibular border and tear through deformity are treated in the deep subcutaneous tissues with linear threading and serial point and aggressive massage. Care must be taken and consent for the potential risk of periorbital vascular occlusion. While the author is not aware of intracranial or intraorbital occlusion complications, such complications have been reported with steroid injections and are theoretically possible.

One unique benefit of the HA products is the immediate reversibility or correction of this product with hyaluronidase. Using 25-150 units of hyaluronidase injected directed into the irregularity can improve contour within 24 hours in the author’s experience.

Collagen products

In contrast to HA products, the collagen products should be used intradermallyas they have in general very short effective half-lives when placed subcutaneously. Zyderm and Cosmoderm remain the most effective fine line fillers in the author’s opinion and as such play a large role in minimally invasive cosmetic enhancements. For fine line treatments are provided using a 30-gauge needle placed at 30 -45 degrees to the skin surface and injected slowly in a serial point fashion along the generally linear defects. A blanching effect is seen as the collagen slowly expands in rhw mid to upper dermis with an overcorrection of 150 to 200% recommended.. Standard recommendations urge against overcorrection when using Zyplast or Cosmoplast; however, reports show better results with slight overcorrection. 48

An emerging strategy gaining popularity is utilizing CosmoDerm in conjunction with other fillers such as HA. An HA filler such as Restylane can be used to address deeper lines and enhance volume while CosmoDerm is used to treat the more superficial lines. 61

Radiesse

Calcium hydroxyappetite is injected subcutaneous using a linear threading or fanning technique. The deeper placement provides a softer feel and does not seem to impact the longevity generally seen to be the 6-12 month range. Slight over correction is recommended as the carboxymethylcellulose carrier provides

CONCLUSION

The introduction of the Botulinum neurotoxin,injectable fillers and other minimally invasive techniques has changed the treatment paradigm for the aging face. The choice of which to use can be based on a number of factors, including desires of the patient, cost to the patient, and experience of the clinician. Caution must be exercised, however, when considering the use of newly introduced “permanent” soft tissue fillers which have not undergone long term observation and study. The new fillers work great alone but the current trend seems to be using them in combination and in particular with Botulinum toxin for relaxation of hyperfunctional muscles and dynamic lines, volume restoration and line and border filling.

Results with this combination of products can be remarkable, even stunning and now represents a true alternative to surgical intervention in many selected patients.

While the products and technologies for rejuvenation and contouring are rapidly evolving, it is advisable to employ comprehensive management and approaches that include combinations of the available injectable agents.

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Figure 28-1. Anatomy of face demonstrating recommended injection sites and dosages.

Figure 28-2. Excessive dosage of Botulinum neuromodulator in the forehead can result in the “Dr. Spock-like” deformity.

Figure 28-3. Lower facial musculature pertinent to treatment of the Marionette lines.

Figure 28-4. Lower facial musculature pertinent to dimpled chin treatment.

Figure 28-5. Before (A) and after (B) photos of platysmal bands treated with BTX injections.

Figure 28-6. Nasolabial folds injected with Restylane???

Figure 28-7. Before and after photos of nasolabial folds treated with Restylane injection.

Figure 28-8. Before and after photos of Restylane injection of the nasal jugal groove area.

Figure 28-9. Unpleasant bluish tint (Tindel effect) seen in the nasolabial folds from Restylane injection.

Figure 28-10. Various injection techniques.