Introduction

Although dozens of hyaluronic acid (HA) fillers are available for soft tissue augmentation, each has its own unique characteristics. The Juvéderm^® family of fillers are well known to physicians as soft and ‘easy to inject’ gels. Juvéderm^® products are distributed in the USA by Allergan Inc., Santa Barbara, CA. They were approved by the US Food and Drug Administration (FDA) in September 2006 and began to be marketed at the beginning of 2007.

All Juvéderm^® products are composed of hyaluronic acid, or hyaluronan, a polymer found naturally in human skin, eye, muscles, and joints, as well as in the connective tissue of all mammals. It is the most abundant glycosaminoglycan in human tissue, and plays a role in dermal water retention while binding collagen and elastin fibers. Thus, HA contributes to the integral structure of the skin. HA is not species specific, regardless of its source, so bacterial-derived HA is well tolerated by humans. In its natural form, HA breaks down within hours when injected into the skin. To produce longevity, it must be cross-linked. Although there are many methods for cross-linking HA, Juvéderm^® features a proprietary cross-linking process called Hylacross^®, which results in a concentration of 24 mg/mL of HA. This unique process results in a soft, viscous, non-beaded gel and is designed to improve the durability of this filler.

Juvéderm^® was approved by the FDA after a multicenter double-blind, randomized clinical trial by Baumann and co-workers in which it was compared with bovine collagen; the 24-week study revealed superior persistence in patients injected in the nasolabial areas with Juvéderm^®. After a subsequent FDA-approved clinical trial by Pinsky et al demonstrating that, after a single treatment, the effects could last up to 12 months, the FDA granted a label extension in June 2007. More recently, Allergan released a formulation of Juvéderm^® that was pre-mixed with lidocaine (XC) to diminish the pain of injection. Levy and colleagues determined that this new mixture was more comfortable for patients in a split-face comparison. Subsequent research by Raspaldo et al confirmed that the addition of lidocaine did not reduce the long-term durability of the product.

Juvéderm formulations

Juvéderm^® is available in a variety of formulations. In the USA, it is distributed as Juvéderm^® Ultra, Juvéderm^® Ultra Plus, Juvéderm^® Ultra XC, and Juvéderm^® Ultra Plus XC (Table 4.1). Juvéderm^® Ultra Plus contains a cross-linked composition of 8% versus 6% in Juvéderm^® Ultra, making it a more robust filler. The two XC Juvéderm^® products contain 0.3% lidocaine but are otherwise identical to the Ultra formulations. In some countries Juvéderm^® Voluma^® is also available. Voluma^® is a 20 mg/mL smooth HA preparation with high cohesivity and viscosity. These features provide extra ‘lift’ when injected into tissue.

Juvéderm^® injectable gel is a sterile, biodegradable, non-pyrogenic, viscoelastic, clear, colorless, homogenized gel implant (Fig. 4.1). It consists of cross-linked HA produced by bacterial fermentation by Streptococcus equus. The gel is formulated to a concentration of 20–24 mg/mL and suspended in a physiological buffer. The package insert states that the product is approved for ‘injection into the mid- to deep dermis for correction of moderate to severe facial wrinkles and folds (such as nasolabial folds)’ but is commonly used by physicians for a variety of soft tissue augmentation indications.

Figure 4.1 Syringes of Juvéderm^® Ultra and Ultra Plus.

Contraindications and safety considerations

The package insert states that Juvéderm^® is contraindicated in patients with severe allergies and in those sensitive to bacterial proteins, since trace amounts survive the manufacturing process. The gel must not be injected intravascularly and if done so may lead to embolization and tissue necrosis. It should also not be injected into sites of obvious inflammation, such as active acne or where infection is present.

The safety of injecting more than 20 mL per 60 kg of body weight has not been established nor has injection into patients prone to keloids, hypertrophic scars or pigmentary abnormalities. However, clinical experience by Taylor et al in injecting HA fillers into patients of color has been demonstrated to be similar to Caucasians; and in the original clinical trial (described on the package insert), more than one-third of subjects were of Fitzpatrick skin phototypes IV, V, or VI. No safety studies have been done on pregnant females, on those breast feeding, or on children under 18; so, caution is prudent in considering the timing of treating these individuals. Bleeding and bruising are increased in patients on aspirin, non-steroidal inflammatory agents, fish oil, or warfarin.

Laser and/or chemical peeling procedures of many depths may or may not affect the longevity of Juvéderm^® injections, especially if performed close to the time of the injection. The package insert also warns of inflammatory reactions if these procedures are performed soon before or after the filler injection, but there are no good clinical studies to support or refute this. Theoretically, the deeper the peel or laser (or dermabrasion) penetrates the dermis, the more likely it is that there will be an effect on the performance of a filler injected soon before or after. In addition, swelling due to treatments performed immediately prior to injections may skew contour and lead to unwanted results.

Minor problems such as redness, pain, tenderness, itching, firmness, swelling, bumps/lumps, and discoloration have been reported; but all of these can be easily treated and often resolve spontaneously. Like all HA fillers, Juvéderm^® can also be dissolved using hyaluronidase. So, this provides a convenient way to remove visible bumps/lumps and also persistent allergic nodules or biofilm formation, as was described by Brody.

Using Juvéderm^®

The most common areas for treatment with Juvéderm^® products are the lips, nasolabial furrows, commissures, chin, and nasojugal depressions (Box 4.1). Prior to treatments the patient should undergo detailed informed consent with the physician, reviewing all the risks and benefits of using this filler. After answering all questions and obtaining written permission, the physician can begin treatment. A topical anesthetic cream applied to the skin for at least 10 minutes (longer if possible) makes the process more comfortable. For the perioral area, injectable local anesthesia such as a submucosal field block is also helpful in reducing discomfort. However, if too much volume of anesthetic is injected, it may distort the contours enough to confuse the injector. Niamtu states that, after application of a topical dental anesthetic, small aliquots of plain lidocaine can be injected at several locations at the sulcus produced by the attached gingival and the unattached mucosa in the upper and lower lips. Additional injection points on the undersurface of the nasolabial fold between the mucosa and the skin extend the field of anesthesia. This normally gives excellent anesthesia for infiltration of Juvéderm^® into the nasolabial furrows, commissures, and lips.

Because infection is a risk of any injection, sterility should be maintained as far as possible. After marking the intended injection sites, an antibacterial scrub should be applied such as 4% w/v chlorhexidine gluconate. Alcohol is an inferior choice and provides only a brief period of antisepsis.

Before approaching the patient, the physician should confirm that the needle is firmly locked into the syringe; then the plunger should be depressed (while pointing it away from the patient) until a small amount of gel flows out of the needle to prime the needle and ensure adequate flow. Typically, a combination of serial puncture and linear-threading injection techniques is used. The Juvéderm^® gel should be placed deep enough in the dermis that surface lumps are not produced. If the material flows too superficially, the lumps can usually be massaged into the proper contour. Juvéderm^® gel is quite soft and can be molded quite easily immediately after injection, using fingers and/or cotton-tipped applicators. Determining the end point of the filling injection takes experience, but overcorrection is discouraged. Generally, it is better for the physician to undercorrect and then have the patient return for a secondary injection than to overcorrect. This is especially true of treatment of the periocular area where overfilling can result in visibility of the injected product. Injections should create a more youthful appearance to the treated area (Fig. 4.2).

Figure 4.2 (A) Before and (B) after treatment with Juvéderm^® Ultra XC to the infraorbital hollows. Notice the decrease in shadowing and the more youthful appearance to the area.

If blanching occurs, the physician should stop injecting and immediately massage the treated area. If blanching remains, a vessel may be occluded and topical nitroglycerin paste should be applied and/or hyaluronidase injected. Grunebaum et al found that delayed treatment of occluded vessels may lead to skin necrosis.

Immediately afterward, the patient should apply ice to the treated areas and should be instructed to avoid making extensive facial expressions, which may make the gel move from its intended location, for at least 2 hours. This includes excessive chewing or talking. Heavy exercise or exposure to excessive heat may increase swelling and bruising. It is wise to have patients avoid alcoholic beverages and anticoagulant medications such as aspirin, non-steroidal inflammatory agents, fish oil, or warfarin for 1 day after treatment. Most patients can return to social occasions the following day (see Case study 1).

Case Study 1

A 42-year-old female patient calls the office 12 days after injection of Juvéderm^® Ultra to the periocular area complaining of persistent bruising. When she arrives in the clinic, you examine the patient. There is a noticeable bluish discoloration bilaterally at the lower margin of the lower lid.

The Juvéderm^® Ultra was placed too superficially and is visible owing to the Tyndall effect. This is more common in the area of the eye owing to the thinness of the skin. The area needs to be treated with hyaluronidase to resolve the discoloration. Future injections should be carried out deep to the orbicularis muscle to avoid this complication.

Clinical choices

Many dermatologists prefer Juvéderm^® for the perioral areas, especially the lips, over other HA fillers. Juvéderm^® has a well-deserved reputation as a ‘soft’ filler that feels more natural to the patient in sites where a hard texture would be more discernable. More often, patients are looking for subtle improvements that do not appear ‘overdone’ (Fig. 4.3). The choice to use the Ultra or the Ultra Plus gel is more personal since there is no good clinical evidence that one performs significantly better than the other in specific sites. One might theorize that the more robust Ultra Plus would last longer and feel firmer in the tissues; however, there is no compelling evidence to support this.

Figure 4.3 (A) Before and (B) after treatment with Juvéderm^® Ultra Plus to the lips. Notice the excursion produced and the natural appearance of the philtrum and border.

A more controversial clinical debate revolves around the XC formulations of Juvéderm^®. Before introduction of this product, dermatologists were commonly pre-mixing lidocaine with Juvéderm^® products. Although this practice helped with pain during injection, it had the unintended beneficial consequence of changing the flow characteristics of the gels. Juvéderm^® mixed with lidocaine in a ratio anywhere from 1 : 0.3 to 1 : 1 allowed the physician to modulate the texture and ease of flow of the material to suit clinical situations. Even now, more dilute formulations are being used by many dermatologists in the USA to replace the discontinued Cosmoderm^® and Zyderm^® collagen, which could be used superficially in the dermis to fill fine lines. Also, lidocaine could be employed in a variety of concentrations to achieve more or less anesthesia, and using lidocaine with epinephrine conferred the additional benefit of vasoconstriction and was potentially less bruising. After becoming accustomed to these advantages, many dermatologists did not embrace the pre-mixed lidocaine-loaded XC Juvéderm^® gels, which did not allow the flexibility of onsite lidocaine mixing. Still others would argue that potential complications could occur from onsite mixing, including contamination, mixing errors, etc., and that the pre-mixed formulation is proven to be safe and effective. Raspaldo et al also confirmed that ‘no significant drop in rheology (flow and deformation of the gel under stress) or extrusion force was noted with the addition of lidocaine, thus confirming that lidocaine does not degrade HA or the gel network’. This would suggest that there is some suspicion that onsite mixed Juvéderm^® gels might have diminished longevity compared with the pre-mixed preparations; however, this has not been satisfactorily confirmed.

Volumizing with Juvéderm^® gels

Although Juvéderm^® Ultra, Juvéderm^® Ultra Plus, Juvéderm^® Ultra XC, and Juvéderm^® Ultra Plus XC are used by some dermatologists for replacing volume loss of soft tissue, the most common applications are to treat wrinkles and folds. Juvéderm^® Voluma^® has been developed specifically for treating the three-dimensional aspects of facial aging (see Case study 2; Fig. 4.4). Available in Canada and other countries, the 20 mg/mL is positioned as a ‘smooth, cohesive HA filler’, according to Carruthers et al. Allergan uses a unique manufacturing process, mixing both low and high molecular weight HA polymer chains, to increase cross-linking and produce a product of both high viscosity and high cohesivity. This process theoretically reduces migration from deep injection sites. Because of its increased viscosity, Juvéderm^® Voluma^® is packaged with two 23-gauge 1-inch (25 mm) ultra-thin wall needles and two 18-gauge 70 mm cannulas. There is a known incompatibility between sodium hyaluronate and quaternary ammonium salts such as benzalkonium chloride. The package insert therefore advises the user never to put Juvéderm^® Voluma^® in contact with these products, or with substances treated with these products.

Figure 4.4 (A) Before and (B) after treatment of the lips with Juvéderm^® Voluma^®.

Reproduced with permission from Dermatologic Surgery: Carruthers J, Carruthers A, Tezel A, et al 2010 36:1886-1892

Case Study 2

A thin, 49-year-old female comes to the clinic with a complaint of ‘looking old’. Examination of the patient reveals good skin quality with atrophy of the cheek and mid-face. Pictures are taken of the patient for pre-treatment documentation.

Using the pictures, the patient is shown the areas that are atrophic and the resultant effect on her face as a whole. Given all the options for facial volumization, she chooses treatment with Juvéderm^® Voluma^® because of its longevity and its ability to be reversed with hyaluronidase.

You explain to the patient that she should avoid alcohol, aspirin and other blood thinners. The patient is marked for treatment. After topical anesthesia has been in place for at least 10 minutes, the area is cleansed with chlorhexidine. Injections are carried out deeply in the cheek to create lift and volume. After treatment patient is given an ice pack and advised to avoid strenuous exercise or excessive use of facial muscles for 24 hours.