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Plastic & Reconstructive Surgery:
doi: 10.1097/PRS.0b013e31829a0bfc
Cosmetic: Original Articles

Clinical Application and Assessment of Belotero: A Roundtable Discussion

Lorenc, Z. Paul M.D.; Fagien, Steven M.D.; Flynn, Timothy C. M.D.; Waldorf, Heidi A. M.D.

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New York and Nanuet, N.Y.; Boca Raton, Fla.; and Cary and Chapel Hill, N.C.

From private practice; Cary Skin Center; the Department of Dermatology, University of North Carolina at Chapel Hill; and Mount Sinai School of Medicine.

Received for publication March 7, 2013; accepted April 30, 2013.

Disclosure: Dr. Lorenc is a consultant for Mentor, Merz Aesthetics, Medicis, and Johnson & Johnson. Dr. Fagien is an advisory board member and investigator for Allergan, Medicis, Merz Aesthetics, and Galderma. Dr. Flynn is a consultant for Merz and Canfield Scientific; he has received research support from Merz Aesthetics. Dr. Waldorf is an advisory board member, consultant, and speakers’ bureau member for Merz Aesthetics, Medicis, Allergan, Valeant, Solta, Bropelle, P&G, Johnson & Johnson, Unilever, and Kythera.

Z. Paul Lorenc, M.D., Lorenc Aesthetic Plastic Surgery Center, 983 Park Avenue, New York, N.Y. 10028, lorenc@lorenc.com

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Abstract

Summary: In this final article for the Supplement, the authors address the physical and aesthetic characteristics of the latest hyaluronic acid, Belotero Balance. Topics include unique characteristics of the hyaluronic acid, aesthetic indications, administration techniques, adverse events, and differences between Belotero and other hyaluronic acids. The article closes with a brief discussion about nomenclature of hyaluronic acid products.

Belotero Balance (Merz Aesthetics, Greensboro, N.C.) is the latest hyaluronic acid approved by the U.S. Food and Drug Administration (2011). Although similar in some of its common properties to other approved hyaluronic acids, Belotero has unique properties that make it particularly suitable for superficial injection. Belotero is a hyaluronic acid of high cross-link density and uses a cohesive polydensified matrix technology that results in a cohesive gel with zones of greater and lesser density.1 Belotero is softer (lower G′) than other hyaluronic acids, making it highly suitable for injection into fine lines and other superficial injections. It also has a low viscosity, allowing the material to be spread evenly into surrounding tissues, allowing for a soft, smooth fill.

A roundtable panel of experts representing plastic surgery, oculoplastic surgery, and dermatology gathered in February of 2013 to review the properties of Belotero and to discuss its clinical application and associated aesthetic considerations. This article summarizes key discussions from the meeting and provides recommendations on the use of Belotero Balance. This article represents the combined opinions of the panel based on the discussion. The views represented here are those of the panelists and do not necessarily reflect those of the Journal or authors of other articles in this Supplement. These opinions are based on a combination of clinical experience and the scientific literature, when available. Readers are advised to consider these viewpoints in combination with their own clinical experience, evidence from the literature, and product labeling.

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PROPERTIES OF BELOTERO

Perhaps because of similarities among hyaluronic acids, there is a tendency for some clinicians to consider the fillers as largely the same, amendable mostly through reconstitution of the products. To some physicians, manufacturing differences between the products are not considered significant but rather are perceived as subtle changes among the manufacturers for purposes of marketing their products. The roundtable panel disagrees with this perception; the manner in which a hyaluronic acid is manufactured is significant and has clinical relevance. In this Supplement, for example, Sundaram and Cassuto discuss the physiochemical characteristics of hyaluronic acids and their clinical significance, Flynn describes the dermal integration behavior of Belotero Balance, and Micheels et al. address injection technique and depth of dermal injection and injection technique for this particular hyaluronic acid.

One way in which hyaluronic acids differ is in their molecular weight distributions and nuances in the manufacturing process such as cross-linking. Because a pure non–cross-linked hyaluronic acid degrades rapidly when injected because of tissue enzymes, hyaluronic acid products are cross-linked to resist enzymatic degradation and to increase the stiffness of the gel.2 Belotero Balance has a higher concentration of non–cross-linked molecules; the degree to which the filler is cross-linked is not uniform, making it softer in some areas and stiffer in others (polydensified). In addition, these non–cross-linked molecules (and their varying length) cause the filler to behave differently when injected, producing lower G′ and lower viscosity among some of the characteristics of the product. Even when diluted and compared with other diluted products, from a structural perspective, Belotero Balance is a different product; it also behaves differently than other hyaluronic acids such as Juvéderm (Allergan, Inc., Irvine, Calif.) and Restylane (Q-Med, Uppsala, Sweden), which have higher viscosity.

A comparative histologic evaluation of several hyaluronic acids has been described by Flynn and colleagues.3 They found that Restylane deposits in large pools, deep in reticular dermis, with the papillary and superficial reticular dermis free of hyaluronic acid. Juvéderm is deposited throughout the thickness of the reticular dermis but in clumps, with papillary dermis free of filler. Belotero Balance diffuses into the dermis in a diffuse, evenly distributed manner, except in papillary dermis (which remains free of exogenous material).3 Results typically last 6 to 8 months with Belotero Balance, and are prolonged in many patients. The article by Micheels et al. in this Supplement provides evidence of effect lasting 15 months in one patient and 21 months in another.4 Volume loss may start to return after this period even though some hyaluronic acid product remains in the dermis, as patients and skin continue to age. (Editor’s note: More details about the manufacturing process and a review of the safety and efficacy data of Belotero are provided in the article “Review of Key Belotero Balance Safety and Efficacy Trials” elsewhere in this Supplement.)

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Aesthetic Considerations

Because of its unique physiochemical properties, Belotero Balance is particularly suited for superficial injection into the dermis or the superficial subdermal plane. The filler is easily and evenly integrated, which produces a smooth distribution into the dermis as described by Flynn and colleagues. It is the first product in some time that is particularly useful for very fine lines such as forehead lines. It is also well suited for use in the tear trough and the vermillion border, although these uses are off label. Neither this hyaluronic acid nor any other need necessarily be the single product in the aesthetic physician’s clinical setting, however. Members of the panel frequently use Belotero Balance as combination therapy with other hyaluronic acids and/or neurotoxin for a panfacial approach to aesthetic correction.

Selection of product for particular anatomical areas and aesthetic goals are based on the characteristics of the hyaluronic acids as described above. Increasingly, the panelists are using two or more fillers at the same session to achieve different goals. Although there is no one standard of care recommended by the panelists, they recommend layers of soft-tissue fillers, using clinical judgment and knowledge of the characteristics of each. Many feel that products with higher G′ [e.g., Restylane, Perlane (Q-Med), or Radiesse (Merz; calcium hydroxylapatite, which is not a hyaluronic acid but often is used for facial and hand volume)] would be injected deeply for revolumization, and products with low viscosity and lower G′ (e.g., Belotero Balance) would be injected superficially. [See Video, Supplemental Digital Content 1, in which participants (left to right) Timothy C. Flynn, M.D., Steven Fagien, M.D., Heidi A. Waldorf, M.D., and Z. Paul Lorenc, M.D., discuss their preferences on the use of specific hyaluronic acid fillers for use in different areas of the face and their rationale as to why certain products might be better suited for one area of the face versus another, available in the “Related Videos” section of the full-text article on PRSJournal.com or, for Ovid users, at http://links.lww.com/PRS/A859.]

Some panelists use neurotoxin in the same visit; others do not. The decision regarding whether to inject neurotoxin and filler at the same visit must be informed by the desired clinical outcomes and an overall correction strategy. For many patients, injecting neurotoxin and filler in a single visit is appropriate and might be an important timesaver for the patient. In other cases, however, characteristics of the chosen filler may interfere with the neurotoxin, and vice versa. For example, a lidocaine-containing filler may inhibit muscle movement and the ability to assess facial muscle use. Optimal injection of neurotoxin should be delayed until after the filler is placed.

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Regardless of the combination of fillers and the general approach a clinician uses for aesthetic correction of lines and folds, the panelists strongly emphasize the importance of taking preoperative and postprocedure photographs (especially before the procedure). Photographs taken from multiple views are even more useful. Pretreatment photographs can be beneficial in managing expectations, and posttreatment photographs are helpful in reviewing outcomes with patients and in planning future treatment sessions.

In addition to photographs, the panelists suggest documenting which product (or products) are used on what area of the face, when the product was injected, and whether the product was customized. A schematic of the facial anatomy has been invaluable to several roundtable panel participants, both for documentation purposes and to describe treatment plans to patients (Fig. 1). The visual aid of the schematic can be useful in describing the treatment strategy and desired outcomes. In some electronic medical records, physicians can draw on top of the schematic with an electronic pen to indicate what was done where (and when).

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Finally, conversations with patients should be empathetic regarding their aesthetic goals, but also clear and realistic. Some patients will need multiple treatments using multiple facial aesthetic options. Others may not benefit sufficiently from dermal fillers and/or neurotoxin and are more suitable candidates for surgery. It is important that patients understand limitations of the dermal products they and their physicians are considering as part of the management of patient expectations discussions.

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Administration of Belotero

Injectors will place Belotero Balance at different anatomical sites depending on desired outcome, point of injection, and clinical experience. The following general recommendation applies: Belotero Balance can be injected into the intradermal and superficial subdermal planes of the nasolabial, perioral, and submalar regions, and into the vermilion borders, lower eyelid, and glabella with a 30-gauge or 27-gauge, 13-mm sharp needle (Fig. 2). (See Video, Supplemental Digital Content 2, which demonstrates difficult-to-treat areas with a new hyaluronic acid soft-tissue filler. Miles Graivier, M.D, a plastic surgeon from Roswell, Ga., demonstrates injection technique using Belotero in more difficult-to-treat areas of the face, including turning up the corners of the mouth, crow’s feet, and the glabella area. This video is available in the “Related Videos” section of the Full-Text article on PRSJournal.com or, for Ovid users, at http://links.lww.com/PRS/A860.) A 27-gauge blunt cannula is useful for injection into the tear trough.5 (See Video, Supplemental Digital Content 3, which demonstrates treating the tear trough with a new hyaluronic acid soft-tissue filler. Dr. Graivier demonstrates an injection technique using Belotero to correct tear trough deformities. He demonstrates the correction he can achieve by combining both a deep and a superficial injection technique. He also shows how he uses blunt tip cannulas to achieve his outcomes. This video is available in the “Related Videos” section of the full-text article on PRSJournal.com or, for Ovid users, at http://links.lww.com/PRS/A861.) For fine lines anywhere, intradermal injection should be performed; because this injection is superficial in nature, a 30- or 32-gauge needle should be used. Individual clinician technique and preference will vary. (See Video, Supplemental Digital Content 4, which demonstrates fine lines being treated with a new hyaluronic acid soft-tissue filler, available in the “Related Videos” section of the full-text article on PRSJournal.com or, for Ovid users, at http://links.lww.com/PRS/A862. Timothy C. Flynn, M.D., a dermatologist from Cary, N.C., gives his perspective on the use of Belotero. Dr. Flynn demonstrates mixing the product with lidocaine as well as the blanching technique for treating fine lines.)

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Today’s patients have come to expect a nearly pain-free procedure, perhaps in part because other dermal fillers are commonly premixed with lidocaine. Consequently, many clinicians will mix lidocaine with Belotero Balance, even if doing so is off-label. The panelists use a ratio of 10:1 or 10:3 lidocaine. For a 10:1 dilution with 0.1 cc of 1% to 2% lidocaine, mix 1 ml of Belotero using a female-to-female Luer-Lok (BD, Franklin Lakes, N.J.) transfer. Thirty passes are used to completely mix the lidocaine solution into the Belotero. This reconstitution creates a very smooth homogenous product that can be injected using a 32-gauge needle. Injectors may notice that it takes a little extra force to push the reconstituted product through the needle. Using a steady, slow flow of injection has been shown to produce superior results and to decrease the likelihood of adverse events, such as patient pain and the formation of temporary nodules.6,7 The panel wishes to reiterate that reconstitution of Belotero with lidocaine is an off-label use, and its use must be disclosed to the patient and documented in the medical record and, perhaps, on the aforementioned facial schematic. [See Video, Supplemental Digital Content 5, which discusses considerations in technique with soft-tissue fillers, available in the “Related Videos” section of the full-text article on PRSJournal.com or, for Ovid users, at http://links.lww.com/PRS/A863. Participants (left to right) Timothy C. Flynn, M.D., Steven Fagien, M.D., Heidi A. Waldorf, M.D., and Z. Paul Lorenc, M.D., review different injection techniques with hyaluronic acid fillers, including mixing with lidocaine, needle versus cannula use, and technique for intradermal injections.]

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Adverse Events
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Adverse events associated with Belotero Balance include those commonly associated with dermal fillers (i.e., erythema, edema, and ecchymosis), all of which generally are of short duration. In one of the pivotal trials of Belotero Balance, the only adverse event that occurred with an incidence of greater than 5 percent was injection-site nodules.8 However, as with any dermal filler, serious adverse events can occur and can be of long duration. They include nodules, contour irregularities, product migration, malar edema, discoloration, infection, numbness, and vascular events.

Vascular events associated with dermal fillers include necrosis, embolization, retinal occlusion, and infection. Risk of vascular occlusion is greatest with the small lumen arteries common in facial injection, such as the forehead rhytides, the nasolabial and nasojugal folds, and the glabella.9

In the event of vascular adverse events, physicians who inject dermal fillers should have a treatment kit that includes, at a minimum, the following items:

* Hyaluronidase to act at the site of local injection and break down and hydrolyze hyaluronic acid, resulting in increased tissue permeability.

* Warm compresses to increase vasodilation.

* Sildenafil for its vasodilatory properties.

* Aspirin.

* Heparin (subcutaneous).

* Nitropaste.

In addition, some vascular adverse events are managed by local wound care, glucose control, head elevation, sunscreen, and frostbite protection in cold climates. Hyperbaric oxygen may be needed if the compromise does not resolve.

Physicians can be aided in identifying possible delayed vascular adverse events by knowledgeable front office staff and/or nurses. Because these office members will likely be the personnel answering telephone calls from patients and triaging patients for physician follow-up, time spent training them both on protocol and adverse event management is a worthwhile endeavor. Management of adverse events associated with soft-tissue fillers is discussed in more detail in the article by Sundaram and Cassuto in this Supplement. [See Video, Supplemental Digital Content 6, which discusses considerations in managing complications with soft-tissue fillers, available in the “Related Videos” section of the full-text article on PRSJournal.com or, for Ovid users, at http://links.lww.com/PRS/A864. Participants (left to right) Timothy C. Flynn, M.D., Steven Fagien, M.D., Heidi A. Waldorf, M.D., and Z. Paul Lorenc, M.D., review the complications that can occur with the use of hyaluronic acid fillers and methods to manage adverse events.]

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Differences across Products
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Belotero Balance, like other fillers, can be used subdermally, but its novel properties make it uniquely suited for superficial lines, the vermillion border, and the tear trough, provided that the patients are informed that use in these areas is off-label. Belotero Balance fortifies the clinician’s ability to address specific needs of the patients and to use a product with confidence in superficial sites, in ways previously achievable only with collagen products such as Zyderm (McGhan Medical Corp., Santa Barbara, Calif.) and CosmoDerm (Inamed Corp., Santa Barbara, Calif.). Much of the recent clinical excitement about Belotero Balance, according to the panelists, has been the ability to remove the superficial lines around the lips effectively. Patients are happy to have this option again after the withdrawal of collagen products. In addition, patients are pleased with the longevity of Belotero Balance. (See the article “Review of Key Belotero Balance Safety and Efficacy Trials” elsewhere in this Supplement for more details about longevity.) Other sites in which Belotero Balance has been a useful addition are very fine lines, marionette lines, and acne scars. Belotero Balance is very moldable and works well for such atrophic scars.

The authors emphasize the aforementioned optimal uses of Belotero Balance, rather than a one-product-fits-all mindset about soft-tissue fillers in general. This new product works well as part of a toolbox of hyaluronic acids for aesthetic correction of the face. Most clinicians would not inject Belotero Balance into deeper areas where they would more likely inject a product such as Restylane. However, there is the temptation to compare hyaluronic acids for specific uses, such as the correction of nasolabial folds. The authors urge caution in interpreting studies such as the one by Prager et al.10 that showed that aesthetic results were similar when three hyaluronic acids (Juvéderm, Restylane, and Belotero) were compared. Although the panelists recognize the importance of the study by Prager et al. for demonstrating the noninferiority of Belotero compared with other hyaluronic acids, it is their opinion that such comparative studies must be consistent and reproducible. The study had a small number of subjects (n = 40), with two treatment arms of 20 subjects each (Belotero was injected into one nasolabial fold and Juvéderm was injected into the other fold in one comparison, and Restylane was injected into the other fold in the other comparison) and may not have been sufficiently powered. Studies that compare the use of hyaluronic acids at different dosages for different anatomical areas are needed, in the opinion of the panelists, rather than more comparative studies of multiple products injected into nasolabial folds. The panelists acknowledge, however, that cross-product comparisons for even one area of treatment are labor intensive and costly; studies of multiple products in multiple areas and multiple doses are even more so.

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Nomenclature

Unlike drug names, where there are standardized names to refer to molecular agents, hyaluronic acids do not have chemical names. Instead, hyaluronic acids fall within polymer chemistry, a field in which there is no broadly based accepted way of describing the variations in complex molecules through nomenclature. Consequently, proprietary terms that the companies have developed are used, which often refer to the manufacturing process for the particular hyaluronic acid. As a result, we see terms such as nonanimal stabilized hyaluronic acid in the literature to refer to products such as Restylane, Perlane, and Restylane-L. The term Hylacross is used on occasion to refer to Juvéderm to differentiate it from the nonanimal stabilized hyaluronic acid products. Finally, the designation for Belotero is CPM to describe its cohesive polydensified matrix technology and differentiate it from other hyaluronic acids. At other times, the clinical literature has used hyaluronic acid-1, hyaluronic acid-2, hyaluronic acid-3, and so forth, as nomenclature for the products, but doing so requires an intimate familiarity with the hyaluronic acids involved in any particular study under discussion. Even within this Supplement, authors have in several cases added “Balance” to Belotero, to limit confusion of this product with other Belotero products available outside of the United States.

As chemists study the chemical properties of the hyaluronic acids to better understand the chemical structure and reactions of the hyaluronic acids, perhaps more descriptive and consistent terms will emerge. Until such a time, the panelists find that the various terms can contribute to confusion and that the products’ brand names are often clearer and less prone to confusion. Consequently, this article and others in this Supplement use the brand names, where use of brand names results in clarity rather than confusion.

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CONCLUSIONS

Belotero Balance, the latest hyaluronic acid approved in the United States, uses a unique cohesive polydensified matrix technology. The manufacturing process results in a cohesive gel that is softer and has lower viscosity than other hyaluronic acids. The product is one that is well-suited for fine lines and superficial injections. The filler is the first product in some time that is particularly useful for very fine lines such as those of the forehead; it is also well-suited for injection in the tear trough and the vermillion border, although these applications are off-label. Belotero Balance penetrates deep into the dermis in an evenly distributed manner and the results are long-lasting, typically 6 to 8 months, and even longer in many patients. Adverse events include those commonly associated with hyaluronic acids (e.g., erythema, edema, and ecchymosis) and are generally of short duration.

Members of the roundtable panel frequently use Belotero Balance in combination with other hyaluronic acids and other fillers for a panfacial approach to aesthetic correction. Products with higher G′ are ideal for deep injections and revolumization, with Belotero used superficially. Non–hyaluronic acid products such as calcium hydroxylapatite or poly-L-lactic acid can be used as combination therapy with Belotero Balance. Belotero Balance restores the clinician’s ability to inject superficially with confidence in the absence of the previously available collagen products.

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ACKNOWLEDGMENTS

Editorial and writing assistance for this article was funded by Medical Education Associates. The authors acknowledge the editorial and writing assistance of Mark R. Vogel, M.A., a medical communications specialist in San Francisco. Figures 1 and 2 were illustrated by Alexandra B. Hernandez of Gory Details Illustration.

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REFERENCES

1. Bezzola A, Micheels P. Esthélis, hyaluronic acid of Swiss design: First complete study of the physico-chemical characteristics and clinical trials. J Med Esth Chir Derm. 2005;32:11–20

2. Kablik J, Monheit GD, Yu L, Chang G, Gershkovich J. Comparative physical properties of hyaluronic acid dermal fillers. Dermatol Surg. 2009;35(Suppl 1):302–312

3. Flynn TC, Sarazin D, Bezzola A, Terrani C, Micheels P. Comparative histology of intradermal implantation of mono and biphasic acid fillers. Dermatol Surg. 2011;37

4. Micheels P, Sarazin D, Besse S, Sundaram H, Flynn TC. A blanching technique for intradermal injection of the hyaluronic acid Belotero. Plast Reconstr Surg. 2013;132:59–68

5. Sundaram H, Weinkle S, Pozner J, Dewandre L. Blunt-tipped microcannulas for the injection of soft tissue fillers: A consensus panel assessment and recommendations. J Drugs Dermatol. 2012;11:s33–s39

6. Lowe NJ, Maxwell CA, Patnaik R. Adverse reactions to dermal fillers: Review. Dermatol Surg. 2005;31:1616–1625

7. Alam M, Gladstone H, Kramer EM, et al.American Society for Dermatologic Surgery. ASDS guidelines of care: Injectable fillers. Dermatol Surg. 2008;34((Suppl 1):S115–S148

8. Narins RS, Coleman WP III, Donofrio LM, et al. Nonanimal sourced hyaluronic acid-based dermal filler using a cohesive polydensified matrix technology is superior to bovine collagen in the correction of moderate to severe nasolabial folds: Results from a 6-month, randomized, blinded, controlled, multicenter study. Dermatol Surg. 2010;36:730–740

9. Hirsch RJ, Stier M. Complications of soft tissue augmentation. J Drugs Dermatol. 2008;7:841–845

10. Prager W, Wissmueller E, Havermann I, et al. A prospective, split-face, randomized, comparative study of safety and 12-month longevity of three formulations of hyaluronic acid dermal filler for treatment of nasolabial folds. Dermatol Surg. 2012;38:1143–1150

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©2013American Society of Plastic Surgeons

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