NASHA™ family

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3 NASHA™ family

Gary D. Monheit, Rhoda S. Narins, Kavita Mariwalla

Summary and Key Features

• NASHA™ are a safe, reliable class of dermal fillers that have low potential for allergic response

• NASHA™ fillers are non-permanent and thus ideal to use for treatment-naïve patients and for beginning injectors as they can be easily dissolved with hyaluronidase

• The type of injection technique selected (serial puncture, linear, fanning or cross-hatching) should be based on anatomical site

• Common areas for injection include the nasolabial folds, followed by the melolabial folds, jowls, and lips. Injection into the glabella is contraindicated owing to the risk of necrosis unless it is used with a tiny needle and injected superficially pulling back on the plunger before injection

• Depth of the fold or amount of volume replacement required are the key components to consider prior to product brand selection

• NASHA™ fillers can be layered on top of each other or on top of other semipermanent fillers

• Hyaluronic acid fillers can last from 3 to 6 months depending on location and amount of product previously injected; they last for longer in areas of low mobility and shorter in areas of greater movement

• Postoperative sequelae are usually edema and bruising lasting only a few days

Introduction

The use of an exogenous material to augment soft tissue can be traced back to Neuber in 1893, who used fat transplanted from the arms to correct facial defects. Since that time, substances used to volumize the face have changed rapidly and include both biodegradable and non-biodegradable products. The class of compounds known as non-animal stabilized hyaluronic acids (‘NASHA™’) comprises biodegradable fillers with an average duration of action of 6–12 months. This chapter will review the current NASHA™ products available in the US marketplace and provide injection tips for the most common facial areas injected. Potential complications will be presented, as will advice on how to manage patient expectations.

Background

NASHA™ are commonly used to correct moderate to severe facial lines and restore volume loss that occurs during the natural course of aging. Since the US Food and Drug Administration (FDA) approval of Restylane® in December 2003, the NASHA™ injectable market has continued to expand. According to the American Academy of Aesthetic Plastic Surgeons, there were approximately 1 315 121 hyaluronic acid (HA) injections performed in 2010 alone, with an estimated $1.9 billion spent on injectables in general. This does not include procedures performed by dermatologists or other healthcare practitioners.

Knowing where to place these fillers is as important as understanding the subtle differences between them. In general, NASHA™ injectables are safe, confer a soft look, and are predictable in their volumizing capacity.

Basic science

HA or hyaluronan is an anionic, hydrophilic, non-sulfated glycosaminoglycan that is abundant in human connective tissue. The chemical structure of this substance is uniform throughout Nature and lacks a protein component allowing it to have little to no potential for immunologic reaction in humans when injected. As one of the chief components of the extracellular matrix, HA stabilizes intercellular structures and forms part of the fluid matrix in which collagen and elastic fibers become embedded. The average 70 kg person has approximately 15 g of hyaluronan in the body, of which one-third is degraded and synthesized daily.

HA contributes to cell proliferation and migration as well as tissue repair. With age, HA concentration in the skin decreases, resulting in reduced dermal hydration, which manifests as an increase in lines and folds. In addition, excessive exposure to ultraviolet B rays causes cells in the dermis to stop producing HA. In its natural form, the half-life of HA is 1–2 days and is metabolized by the liver to carbon dioxide and water. As a compound, it can absorb up to 1000 times its molecular weight in water; its mechanism of action as a filler is mainly through hydration.

The hyaluronic acid molecule is stabilized with cross-linked hydroxyl groups. It is this cross-linking that confers longevity to the product in the skin and the degree of cross-linking one of the distinguishing features of NASHA™ products. Because of this structural matrix, the degradation curve of implanted HA is not linear. Rather, the product retains its effect until the structural complex around the HA molecule is broken down. Once the unbound HA is exposed, efficacy is then lost (Fig. 3.1). As a result, patients will often suddenly notice a change in their appearance rather than experience a gradual loss over time. In addition, patients sometimes feel they look worse after HA injection than they did prior to it; however, this is more of a function of selective memory. This is why taking pre-injection photographs is so important. As with natural hyaluronan, HA fillers can be instantly dissolved with the enzyme, hyaluronidase.

image

Figure 3.1 Conceptual degradation curve of NASHA™ fillers. Note that the line is not linear, which correlates to the cross-linking agents used to stabilize the filler in the skin. Free hyaluronic acid has a half-life of 1–2 days in human skin.

Choosing the right NASHA™

The main difference between commercially available NASHA™ products on the current US market is the viscosity of the product. The higher the concentration of HA, the stiffer is the product and the longer it lasts in tissue (Table 3.1). The larger the particle and the greater the concentration of the filler, the greater the lift you get. It should be noted, however, that not all of the HA in a given filler is cross-linked. Some is free, fragmented or only lightly cross-linked so that the gel can actually flow out of the syringe with ease. As discussed above, the cross-linking is what confers longevity to the product and this does vary between brands. In Restylane® and Juvéderm®, 1,4-butanediol diglycidyl ether is the cross-linking agent, which forms ether linkages in the HA chain. This same type of ether linkage is formed by diglycidyl sulfone found in Prevelle® Silk. In addition to cross-linking, it is worth mentioning that not all HA products are packaged in the fully hydrated state. As mentioned earlier, NASHA™ fillers create volume via hydration and, for this reason, patients will often look better or more filled 24 hours after treatment with products like Restylane® and Juvéderm, which are not completely saturated in the syringe. With that in mind, it is prudent not to overcorrect when using NASHA™ products.

Table 3.1 Hyaluronic acid (HA) concentration of commercially available NASHA™ products

Trade name HA concentration Particle size*
Restylane® 20 mg/mL ~260 µm
Perlane® 20 mg/mL ~1000 µm
Juvéderm® 24 mg/mL 50–500 µm (very cohesive)
Juvéderm® Ultra Plus 24 mg/mL Homogeneous gel
Prevelle® Silk 5.5 mg/mL ~250 µm
Hydrelle® 28 mg/mL Not available
Hylaform® Plus 5.5 mg/mL ~700 µm

* Even very cohesive products are particulate. The particle sizes of commercially available NASHA™ fillers are shown. In comparison, the particulate sizes of non-NASHA™ products are as follows: Radiesse® (25–45 µm), Artefill® (over 30–50 µm), Sculptra® (40–60 µm), Dermalive® (20–120 µm).

Patient evaluation

Prior to injection with any dermal filler, a careful patient history should be obtained. Pertinent items to note in this history include a history of herpes simplex virus, pregnancy or breastfeeding, history of keloid formation, presence of any autoimmune disease, and allergy to lidocaine as most of the fillers now come pre-mixed with lidocaine (Box 3.1). A medication history should include use of multivitamins, fish oil, vitamin E, blood thinners, aspirin, ibuprofen, and Gingko biloba, as all of these can predispose the patient to bruising. Unless medically necessary, the patient should be advised to discontinue these medications 14 days prior to treatment. In addition, alcohol use within 48 hours of injection can cause an increase in bruising tendency.

Box 3.1

NASHA™ products currently available pre-mixed with lidocaine

image Restylane®

image Perlane®

image Juvéderm®

image Juvéderm® Ultra Plus

image Prevelle® Silk

image Hydrelle®

If the patient has had fillers in the past, it is recommended that the physician document how long ago, where the fillers were placed, and if the patient was satisfied with the results. In addition to history, pre-injection photography is a must. These authors prefer at least three views: frontal, left side at an oblique angle, and right side at an oblique angle. If a patient is having a specific area corrected, a closeup picture of that area is also advisable. Informed consent must be obtained and the patient should be aware of the financial cost of the procedure prior to opening the first syringe. We also advise that baseline facial asymmetry be discussed with the patient and noted in the chart. From a physician standpoint, it is important to inform your malpractice coverage carrier of your intention to use fillers as many uses are considered off-label.

Patient preparation

Patients should be asked to remove their makeup and the areas to be injected should be cleansed with alcohol or a skin-cleansing solution that does not stain the skin. If there are any areas of infection, injection should be deferred. If the area is to be marked, these authors recommend using a white eyeliner pencil or an erasable marker. Use of gentian violet can create a tattoo if the needle is inserted through the marked line. Patients should be in a seated or reclined position to maximize comfort while allowing the skin to drape naturally. For this reason, it is not advisable to have the patient lie down as this can distort the natural contours of the face. Hair should be pulled back with a bandana or covered and pulled back with a surgical bonnet. The physician may decide to use a topical or local anesthetic prior to injection. If so, this should be completely removed prior to injection.

Pearl 1

If using a custom-formulated topical anesthetic such as BLT (7% betacaine, 7% lidocaine, and 7% tetracaine) be sure to monitor the amount of surface area that is covered with the medication as toxicity can result with high concentrations of anesthetic over large surface areas.

Physician preparation

A note that includes a detailed facial diagram is helpful to document precisely where filler is placed, and labels from each syringe used should be put in the patient chart for traceability. One should also anticipate adverse events, so we recommend that any physician who is using NASHA™ products carry hyaluronidase in case of arterial occlusion or if the product needs to be dissolved rapidly, nitropaste in the event of purple dusky discoloration upon injection, and juice and crackers in the event a patient has a vasovagal episode. If the decision is made to use a topical numbing medication prior to injection, topical steroids should also be kept on hand in the event of an allergic contact reaction. Lastly, it is helpful to have aluminum chloride at concentrations of 20% or higher available in the event of excessive bleeding at a needle insertion point, although most bleeding can be stopped with pressure alone.

Treatment techniques

Several injection techniques exist for the addition of HA fillers to the face and depend mainly on the area of the face that is to be augmented. The four main techniques are illustrated in Figure 3.2. Each has its own advantages and disadvantages and all are based upon a transcutaneous approach.

image

Figure 3.2 Filler techniques: (A) serial puncture technique from a side view; (B) linear-threading technique from a side view; (C) fanning technique from a frontal view; (D) cross-hatching technique from a frontal view. Key: Orange line is the skin fold.

Serial puncture

In this method (Fig. 3.2A), the bevel of the needle is pointed up and the product is dispensed in a droplet-like fashion along the fold that is to be lifted. Depending on the size of the aliquot, the physician may have to massage the area to prevent nodule formation. A disadvantage of this technique is that the patient will experience multiple needle sticks. Examples of areas to use this method include: depot in the infraorbital area with massage into the medial canthal region, acne scarring, and droplet into the lip tubercles (Table 3.2). Serial puncture is common for superficial dermal injections.

Table 3.2 Recommended injection technique by facial area

Area Technique
Nasolabial folds Serial puncture, threading, fanning or cross-hatching; sharp needle or blunt-tipped cannula can be used
Melolabial folds Fanning or cross-hatching; sharp needle or blunt-tipped cannula can be used
Jowls Serial puncture (depot) or linear threading
Cheeks Fanning or cross-hatching; blunt-tipped cannula can be used
Lips – vermilion border Linear threading
Lips – tubercles Serial puncture

Linear threading

The physician points the bevel of the needle up and through one insertion point that is usually at the inferior pole of the fold, the needle is advanced forward, and the product is dispensed in a retrograde fashion as if laying down a cord (Fig. 3.2B). This technique is suboptimal in deeper folds as it does not address the underlying structural support needed to lift certain areas of the face. Examples of areas to use this method include: nasolabial folds and jawline (Table 3.2). This can also be done using a blunt-tipped cannula.

Fanning

Though the insertion point is similar to the linear-threading technique, in this method the needle is not removed from the skin but rather redirected in various directions in a fan-like motion, laying down product underneath the fold (Fig. 3.2C). A blunt-tipped cannula can be used for this technique, which is excellent to help prop up deep folds by addressing the overhang that occurs from adjacent skin. Examples of areas to use this method include: nasolabial folds, corners of the mouth, and temples (Table 3.2). A combination of linear threading and fanning are commonly used together for volume correction.

Cross-hatching

Several parallel cords are placed in one direction and then overlapped with cords placed perpendicularly creating a strut-like scaffold beneath the fold (Fig. 3.2D). Though the patient will experience several needle sticks and the placement of filler in multiple planes can lead to more bruising, this method is ideal for treatment areas that require significant volume. Examples of areas to use this method include: cheeks, jowls, and marionette lines (Table 3.2). Like the other techniques, this can also be done with a blunt-tipped cannula.

Pearl 2

Injection technique should vary according to the region of the face, the depth and tissue plane of the injection and also on the thickness of the NASHA™ filler being used. Whereas fanning and cross-hatching provide excellent structural support and enhance volume, they can lead to increased bruising. Similarly, the serial puncture technique allows for more precise microdroplet placement of filler, but can be painful for the patient. A blunt-tipped cannula minimizes bruising.

Site-specific treatment strategies

Nasolabial folds

Correction of the nasolabial fold is an FDA-approved on-label indication for all NASHA™ products and is the most common site for correction with NASHA™ fillers. The folds or ‘laughter lines’ occur as a result of movement of the malar fat pads medially and inferiorly with age along with a generalized loss of skin elasticity. Fine lines can appear in this area as early as the third decade of life. It is important when assessing the nasolabial fold to note the presence or absence of a heavy cheek. If the cheek has dropped substantially, or if the patient is overweight with substantial contribution to the fold from the inferomedial cheek, the fold will be very deep and several syringes of NASHA™ will be required before a noticeable result is achieved. If this is the case, consider volumizing the cheek in the area of the zygoma along with filler in the fold. This will result in an overall lifting and pulling of the skin back to its original physiological position. For the deep fold itself, the cross-hatch technique is the best one to employ, or one may consider layering a NASHA™ product over another product that is placed in deeper tissue (e.g. Restylane® over Perlane®). For shallow to medium folds, a NASHA™ product alone can suffice and the fanning technique can be used starting at the inferior pole. In this case, cheek augmentation is not necessary. Whether to start from the superior or inferior portion of the pole is a matter of physician preference. At the completion of injection place a gloved thumb on top of the fold and two fingers on the inside of the mouth on the other side of the fold. Gently mold the product to make sure that no nodules or bumps are present. Hyaluronic acid fillers are maleable and can be molded after injection.

It is important to remember basic anatomy when injecting the nasolabial folds. The nasal artery runs near the ala so it is critical when injecting the superior portion of the nasolabial fold that one pulls back on the syringe plunger to make sure no flash of blood is seen. Injecting slowly with small alloquots helps avoid this problem. This will prevent accidental intra-arterial injection.

Case Study 1

Intra-arterial Occlusion?

A patient presents for correction of medium depth nasolabial folds. She has no notable medical history, takes no medications, and is treatment naïve. After injection of a total of 1 mL of hyaluronic acid filler into each nasolabial fold, the patient seems pleased with the results. She is told to ice the area for 10 minutes in every hour and to expect some mild discomfort the following day with some temporary edema. The following morning the patient calls the office to report a patchy red and blue hue of her nasal tip. She denies any pain.

She comes to the office and on examination she has a livedo pattern on the nasal tip that is dark red with a mild dusky hue.

While one may suspect accidental intra-arterial injection, the delayed discoloration indicates that the cause may be compression of the artery due to edema and product placement rather than overt injection of material into the arterial lumen and embolism, which would be seen by an immediate tissue reaction blanching and then discoloration. Using 12–20 units of hyaluronidase, inject slowly into the nasofacial sulcus making sure to pull back on the syringe prior to injection. Massage gently to enhance dissolution of any hyaluronic acid gel in the area. In addition, apply a small amount of nitrous paste to the nose and advise the patient to use warm compresses to the area for the next 24 hours. The patient should be re-evaluated daily until color returns to normal. Do not replace the hyaluronic acid in the area until full resolution of symptoms is achieved.

Pearl 3

If you see multiple lines lateral to the nasolabial fold, resist the urge to fill them as they are usually due to dynamic movement. Filling each line may improve their appearance at rest but will appear as cords upon animation.

Melolabial folds

With time, the area below the oral commissure hollows, pulling down the corners of the mouth, creating melolabial lines, and contributing to jowls. The loss of volume is due to structural bone changes that occur with age; principally, as a person ages, the maxilla and chin grow away from the face and bone resorption decreases maxillary and mandibular height. Along with skin laxity, the result is a sagging appearance of the lower face that responds well to filler use. This location is especially susceptible to bruising after filler injection and it is important to massage the area after injection to prevent lumps. Because of the need for structural support, the fanning or cross-hatch technique is recommended, as is the use of a thicker HA such as Perlane® or Juvéderm® Ultra Plus. Typically 0.5 mL is adequate to volumize each melolabial fold, though larger amounts are needed to volumize the lower face.

Pearl 4

Although most patients can tolerate injection into the nasolabial folds, the melolabial fold tends to be more sensitive. Consider a mental nerve block which will anesthetize not only this area but also portions of the lower lip. Use 0.2 mL of plain lidocaine 1% and inject in the sulcus next to the second premolar. This injection pain can be reduced with a 15-second application of benzocaine 20% (Hurricane® gel) to the mucosa prior to injection.

Jowls

Fat and soft tissue descent along the mandible obscures the bony definition of the jaw, which is considered a hallmark of the youthful face. HA fillers can be used to fill in the pre-jowl sulcus, thereby minimizing the appearance of the jowls. Filler is placed directly against the mandible and molded in a downward sweeping motion with the fingers around the jawline. The best technique to use for this is either a depot or linear threading. Placement of filler in the jowl area not only gives the illusion of a stronger bone line but also creates a relative tucking of the excess skin in the submental area. Of the available HA products, Juvéderm® Ultra Plus or Perlane® is recommended for treatment.

Pearl 5

In elderly patients, the mental nerve is particularly exposed in this area of the face as it is covered only by thin platysma and skin. Therefore, to prevent nerve injury from the needle tip, be sure to stay in the upper subcutaneous or dermis, which is higher than in other parts of the face owing to the thin skin in the jowl area.

Cheeks

With age, the orbicularis oculi muscle loses both its tone and its ability to act as a sling around the orbital rim. Subsequently, descent of the orbicularis and malar soft tissue complex prevails. Aging of the mid-face is dominated by descent of these malar fat pads (of which there are a total of seven), resulting in a loss of convexity and a flattened or even concave appearance of the cheeks. Filling the cheeks may result in softening of the nasolabial folds but requires injection in a deep subcutaneous or fascial plane. If using NASHA™ products, more than one syringe may be needed. It is important when injecting in this area that the patient be asked to smile so that the physician does not inadvertently create a chipmunk appearance in the patient. It is important to fan or cross-hatch injections and blend the cheeks back towards the temple so that the person does not appear to have implants at rest.

Anatomically, one must keep in mind bony structure and face shape as related to race and gender. It is also important to have a discussion with the patient with regards to the hollow below the zygoma as many people want fuller cheeks but do not want to lose this line of definition on the face. Layering filler in this area is successful, as is use of more viscous HA products. If injecting in the upper part of the cheek near the infraorbital region, a thinner filler such as Restylane® or Juvéderm® Ultra should be used. The tear trough or infraorbital hollow is a special area most responsive to a hyaluronic acid filler. Small alloquots are placed deeply below the obicularis muscle along the orbital rim with a linear threading technique. Care must be taken not to overfill this area as it may lead to eyelid edema and nodularity.

Pearl 6

Though it is possible to fill the cheeks through an intraoral approach caution should be used owing to the resident bacteria present in oral flora. Biofilm can be created, which can lead to severe complications. These authors recommend a transcutaneous approach when using HA products.

Lips

By the second decade of life, lip volume has reached full thickness in both men and women and starts decreasing by the mid-30s. In addition to the lips themselves, the vermilion border tends to thin, the corners of the mouth begin to slope downwards, and fine lines appear on the upper and lower cutaneous lip, which over time elicit the complaint of ‘lipstick bleeding.’ The philtral ridge should not be overlooked either as this flattens with the elongation of the cutaneous upper lip. Injection of the lips is a staged process and should be done with Restylane® or Juvéderm® Ultra rather than the more viscous HA products. Usually an infraorbital nerve block and mental nerve block are required for patient comfort, but it should be noted that it is important to work quickly after these blocks as the numbing will distort the position of the patient’s lips. In addition, expect significant swelling and more bleeding in this area than in other parts of the face, which can cause a physician to overcorrect one area in response to edema rather than actual volume change. It is important to note any baseline asymmetry in the lips as well as the presence of any scars, which can make filling more difficult. Lip injections of hyaluronic acid are placed in 3 planes: 1) volume filling within the lip muscle 2) linear threading of the vermillion line 3) superficial injeciton of rhytides. The vermillion injection gives contour, shape and lift to the lip. Identify the white roll at the border of the lip and, starting at the corner of the mouth, insert the needle and use a linear-threading technique to inject into the white roll in an anterograde fashion. Repeat on the other side making sure to fill to the apex of cupid’s bow. Overfilling of the border will result in a platypus-like appearance of the lips. After crisping of the vermilion border (which by default will evert the lip and create the appearance of fullness) consider a droplet injection into each of the two tubercles of the upper and lower lip to give a more pronounced pout.

Case Study 2

‘I only want to fill my upper lip’

A 56-year-old woman presents for filler of the lips. She is most bothered by her upper lip, which she feels has grown increasingly thin with time. She is insistent that she does not want to fill her lower lip because she is happy with the shape of it.

On examination, she has a flattened philtrum consistent with normal aging changes and has significant volume loss of the upper lip compared with the lower lip.

While one must be considerate of a patient’s request, it is appropriate to offer expert guidance so that the patient is not disappointed with the end result. Though patients may insist that filler be placed in only the top or bottom lip, it is important to maintain the lip ratio so that the result looks as natural as possible. The lower lip should always be more full than the upper lip. The ideal ratio of upper lip to lower lip is 1 : 1.6, which is based on the concept of the Fibonacci proportion. It is important to mention this to the patient so that, once filling of the upper lip is complete, the patient understands if some product must be added to the lower lip to maintain this ratio.

Postoperative care and complication management

In general, NASHA™ fillers are safe, effective and easy to use. Complications are generally limited to edema and bruising. After injection, patients are advised to ice the area for up to 10 minutes in every hour. Reusable ice packs can be given to the patient or they can use a bag of frozen peas, which is easy to mold over the area. In the lips, patients are encouraged not to purse their lips or fold them on top of each other, which may cause product movement in the first 6 hours. The following day, patients are advised to expect additional edema as hydration occurs. This may result in a feeling of soreness, which can be relieved with acetaminophen. Bruising can occur up to 72 hours after treatment. Anecdotally, Arnica forte can be used to prevent bruising, but no definitive evidence exists to suggest that this is always successful. The Tyndall effect is possible if the product is placed too superficially, as are nodules or lumps. The only way to correct this is to dissolve the product with hyaluronidase, keeping in mind that this will deplete some native HA in the epidermal matrix as well. Complications such as intra-arterial injection are possible though rare. Extra care is needed in the glabella where the risk of intra-arterial injection is high. If an entire syringe of product is not used on a patient, some physicians store the product for up to 6 months, carefully labeling the product with the patient’s name. Since a physician cannot guarantee sterility of the product once it has been injected, we do not recommend this approach.

Conclusion

The NASHA™ family of dermal fillers is a good choice for novice injectors, treatment naïve patients, and for patients with moderate aging changes. The range of products available in the marketplace is fairly diverse and, once implanted into the mid-to-deep dermis, creates reproducible results with ease. The success of NASHA™ is as dependent on the injectable as it is on the injector and proper technique.

Further reading

Bachmann F, Erdmann R, Hartmann V. Adverse reactions caused by consecutive injections of different fillers in the same facial region: risk assessment based on the results from the Injectable Filler Safety study. Journal of the European Academy of Dermatology and Venereology. 2011;25:902–912.

Bellew SG, Carroll KC, Weiss MA, et al. Sterility of stored nonanimal, stabilized hyaluronic acid gel syringes after patient injection. Journal of the American Academy of Dermatology. 2005;52:988–990.

Brody HJ. Use of hyaluronidase in the treatment of granulomatous hyaluronic acid reactions or unwanted hyaluronic acid misplacement. Dermatologic Surgery. 2005;31:893–897.

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. Dermatologic Surgery. 2003;29:802–809.

Carruthers A, Carey W, de Lorenzi C, et al. Randomized, double-blind comparison of efficacy of two hyaluronic acid derivatives, Restylane Perlane and Hylaform, in the treatment of nasolabial folds. Dermatologic Surgery. 2005;31:1591–1598.

Cohen JL. Understanding, avoiding and managing dermal filler complications. Dermatologic Surgery. 2008;34:S92–S99.

Day DJ, Littler CM, Swift RW, et al. The wrinkle severity rating scale: a validation study. American Journal of Clinical Dermatology. 2004;5:49–52. 2004

Hamilton RG, Strobos J, Adkinson NF. Immunogenicity studies of cosmetically administered nonanimal-stabilized hyaluronic acid particles. Dermatologic Surgery. 2007;33:S176–S185.

Hanke CW, Rohrich RJ, Busso M, et al. Facial soft-tissue fillers conference: assessing the state of the science. Journal of the American Academy of Dermatology. 2011;64:S66–S85.

Hexsel D, Brum C, Schilling de Souza J, et al. A phase II, randomized, double-blind clinical trial comparing safety and efficacy of a metallic cannula versus a standard needle for dermal filler injections (hyaluronic acid gel) for the treatment of nasogenian folds. Journal of the American Academy of Dermatology. 2011;64:AB164.

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. Dermatologic Surgery. 2007;33:357–360.

Kablik J, Monheit GD, Yu L, et al. Comparative physical properties of hyaluronic acid dermal fillers. Dermatologic Surgery. 2009;35:302–312.

Leonhardt JM, Lawrence N, Narins RS. Angioedema acute hypersensitivity reaction to injectable hyaluronic acid. Dermatologic Surgery. 2005;31:577–579.

Lupo MP, Smith SR, Thomas JA, et al. Effectiveness of Juvéderm Ultra Plus dermal filler in the treatment of severe nasolabial folds. Plastic and Reconstructive Surgery. 2008;121:289–297.

Matarasso SL, Carruthers JD, Jewell ML, et al. Consensus recommendations for soft-tissue augmentation with nonanimal stabilized hyaluronic acid (Restylane). Plastic and Reconstructive Surgery. 2006;117:S3–S43.

Monheit GD, Davis B. Nasolabial folds. In: Carruthers J, Carruthers A. Soft tissue augmentation. 2nd edn. Philadelphia, PA: Elsevier; 2008:105–126.

Monheit GD, Baumann LS, Gold MH, et al. Novel hyaluronic acid derm filler: dermal gel extra physical properties and clinical outcomes. Dermatologic Surgery. 2010;36:1833–1841.

Narins RS, Bowman PH. Injectable skin fillers. Clinical Plastic Surgery. 2005;32:151–162.

Narins RS, Jewell M, Rubin M, et al. Clinical conference: management of rare events following dermal fillers – focal necrosis and angry red bumps. Dermatologic Surgery. 2006;32:426–434.

Narins RS, Coleman WP, Donofrio LM, et al. Improvement in nasolabial folds with a hyaluronic acid filler using a cohesive polydensified matrix technology: results from an 18-month open-label extension trial. Dermatologic Surgery. 2010;36:1800–1808.

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