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Plastic & Reconstructive Surgery:
doi: 10.1097/PRS.0b013e31829d1d40
Cosmetic: Original Articles

Biophysical Characteristics of Hyaluronic Acid Soft-Tissue Fillers and Their Relevance to Aesthetic Applications

Sundaram, Hema M.D.; Cassuto, Daniel M.D.

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Erratum
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Erratum

In the October 2013 Supplement, Clinical Introduction to the Hyaluronic Acid Dermal Filler Using Cohesive Polydensified Matrix Technology, in the article by Sundaram and Cassuto “Biophysical Characteristics of Hyaluronic Acid Soft-Tissue Fillers and Their Relevance to Aesthetic Applications” (Plast Reconstr Surg. 2013;132(Suppl 4S-2):5S–21S), the first sentence of the Methods paragraph of the abstract is incorrect. The sentence should read as follows (corrections in italics): “Six U.S. Food and Drug Administration–approved, cross-linked, nonanimal-derived hyaluronic acid filler products and one hyaluronic acid product approved in Europe and elsewhere were studied: one cohesive polydensified matrix hyaluronic acid (Belotero Balance, also known as Belotero Basic), two Hylacross hyaluronic acids (Juvéderm Ultra and Juvéderm Ultra Plus), one Vycross hyaluronic acid (Juvéderm Voluma), and three nonanimal stabilized hyaluronic acids (Perlane, Restylane and Restylane SubQ).

Plastic and Reconstructive Surgery. 132(5):1378, November 2013.

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Author Information

Rockville, Md.; Fairfax, Va.; and Milan, Italy

From private practice.

Received for publication March 20, 2012; accepted May 8, 2013.

Disclosure: Dr. Sundaram serves as a consultant and/or clinical investigator for Allergan, Anteis, CosmoFrance, Ipsen, Medicis/Valeant, Mentor/Johnson & Johnson, Merz, Q-Med/Galderma, and Suneva. Dr. Cassuto serves as a consultant and/or clinical investigator for Mentor/Johnson & Johnson, Merz, Myoscience, and Q-Med/Galderma. Merz Aesthetics provided the logistical and financial support for execution of this study. Unless stated otherwise, the soft-tissue fillers discussed in this article were purchased from commercial sources.

Hema Sundaram, M.D., Dermatology, Cosmetic & Laser Surgery, 11119 Rockville Pike, Suite 205, Rockville, Md. 20852, hemasundaram@gmail.com

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Abstract

Background: The purpose of this study was to present new rheologic data for hyaluronic acid filler products, correlate them with recent tissue integration studies, and provide a scientific rationale for selecting appropriate products for volume replacement within different tissue levels and anatomical zones. A brief overview of the methodology of filler rheology studies and data analysis is provided.

Methods: Seven U.S. Food and Drug Administration–approved, cross-linked, nonanimal derived hyaluronic acid filler products were studied: one cohesive polydensified matrix hyaluronic acid (Belotero Balance, also known as Belotero Basic), three Hylacross hyaluronic acids (Juvéderm Ultra, Juvéderm Ultra Plus, and Juvéderm Voluma), and three nonanimal stabilized hyaluronic acids (Perlane, Restylane, and Restylane SubQ). The elastic modulus, complex viscosity, and viscous modulus of each filler gel were quantified. Tan delta for each filler gel and also for calcium hydroxylapatite filler (Radiesse) was calculated at 0.7 Hz.

Results: Cohesive polydensified matrix hyaluronic acid (Belotero Balance) has the lowest elasticity and viscosity and the highest tan delta. This predicts its soft, flowing qualities and correlates with its homogeneous pattern of tissue integration after intradermal implantation. Nonanimal stabilized hyaluronic acid (Perlane and Restylane) has the highest elasticity and viscosity and low tan delta. This predicts its firm, less flowing qualities and correlates with a bolus-like pattern of tissue integration. Hylacross hyaluronic acid (Juvéderm) has intermediate elasticity, viscosity, and tan delta, correlating with its intermediate pattern of tissue integration.

Conclusions: Rheologic evaluation reliably predicts tissue integration patterns and appropriate clinical applications of the studied fillers. Paradigms of layered filler placement can be designed to optimally address individual patient need.

The portfolio of fillers available for soft-tissue augmentation has expanded rapidly. Hyaluronic acid fillers that are available in the United States include Restylane (QMed/Galderma, Uppsala, Sweden; Medicis/Valeant, Bridgewater, N.J.), which was approved by the U.S. Food and Drug Administration in 2003; Juvéderm Ultra and Ultra Plus (Allergan, Inc., Irvine, Calif.), approved in 2006; Perlane (QMed/Galderma), approved in 2007; Prevelle Silk (Genzyme Corp., Cambridge, Mass.; Mentor Corp., Santa Barbara, Calif.), approved in 2008; Belotero Balance (Merz Pharmaceuticals, Greensboro, N.C.), approved in 2011 and available outside the United States under the brand names Belotero Basic (Merz) and Esthélis Basic (Anteis, Geneva, Switzerland); and Juvéderm Voluma (Allergan), approved in 2013. These products are non–animal-derived and cross-linked for longevity. Non–cross-linked (unmodified) hyaluronic acid has a half-life of only a few weeks following intradermal injection.

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EVOLUTION IN USE OF HYALURONIC ACID FILLERS

The enduring popularity of hyaluronic acid fillers is founded on their ability to produce immediate, predictable, and natural-appearing results when injected appropriately. They are well-suited to tissue contouring. They are reversible, and therefore correctable by enzymatic digestion with exogenous, injected hyaluronidase, and have excellent safety and tolerability profiles. Their longevity in tissue makes them more cost effective than the previously available collagen products and allows the injection of larger volumes. These advantages, coupled with cumulative clinical experience, have catalyzed a paradigm shift from individual wrinkle filling to volumization of facial zones, and also of nonfacial areas such as the hands and décolletage.

A further impetus—toward analyzing the aging face in three dimensions, understanding the appearance it adopts, and restoring volume accordingly—has been provided by seminal research into age-related changes in facial anatomy. Lambros observed that the primary process in the aging face may be deflation rather than descent, and that this may be ameliorated most effectively by volume restoration.1,2 He is currently studying this process further.3 The cadaver studies of Rohrich et al. clearly delineated the partitioning of facial subcutaneous fat into discrete compartments, within which age-related volume loss and volume shifting occur.4–7 The computed tomographic scans obtained by Pessa et al. of the midface at different ages showed the importance of remodeling of the underlying bone as the face ages.8 The computed tomographic scans obtained by Shaw et al. provided further insight into age-related patterns of facial bone resorption.9.10 Its effects on the appearance of soft tissue have been well described by Mendelson and Wong.11

The shift from filling wrinkles to volumizing facial zones began with a trend toward reinflating the aging midface with fillers for secondary effacement of the nasolabial folds. This strategy addressed the primary cause of nasolabial folds and produced more natural-appearing results than filling the nasolabial folds and leaving the midface deflated. The trend has been extended to the lower and upper face, including the periocular region, with the rationale that panfacial volume restoration is indicated to correct the panfacial volume loss that occurs with age.

When hyaluronic acid fillers were used for nasolabial folds, product differences were not so apparent. Filling of a nasolabial fold entails simple, low-precision implantation into soft tissue of sufficient thickness that it is quite anatomically forgiving. The expansion of filler use to other facial areas brought the realization that different products could manifest different clinical behavior. Restylane and Perlane were relatively firm and did not spread much after implantation; in retrospect, these effects reflected their higher elastic modulus (G′) and viscosity. Juvéderm Ultra and Juvéderm Ultra Plus were softer and tended to spread more after implantation; this is largely attributable to their lower G′ and viscosity.

Many clinicians continued to use a single product for several different facial zones. However, some began to select different products for distinct clinical applications, based on anecdotal experience and instinct. For example, Perlane and Restylane might be used for the midface, where less filler spread conferred postimplantation precision and contour stability and filler firmness was not a problem. Juvéderm and Juvéderm Ultra Plus might be preferred for lips, where palpability after implantation is less desirable and some filler spread into the tissue might be considered aesthetically appealing.

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RHEOLOGIC STUDY OF HYALURONIC ACID FILLERS

The inception of a scientific rationale for the clinical distinctions between hyaluronic acid products came with an article by Kablik et al. in 200912 that presented data pertaining to the rheologic and other physicochemical characteristics of Juvéderm Ultra Plus, Perlane, Prevelle Silk, Restylane, and two products that are no longer used (Hylaform and Hylaform Plus; Inamed Corp., Santa Barbara, Calif.).

Rheology is defined as the study of flow-related properties. [The term “rheology” was coined by Bingham of Lafayette College and Reiner of Technion, Israel, from the aphorism of the Neoplatonist Greek philosopher, Simplicius, that “everything flows” (panta rhei).13,14 Rheologic theory and measurements are considered crucial for the manufacture of topical medications, paints and inks, concrete, and even chocolate.] Differences in the rheologic properties of filler products reflect their specific manufacturing processes and resultant physicochemical characteristics. The basic methodology of rheologic studies is to place a gel between two nondeformable plates, one fixed and the other mobile, which are adjusted so that there is complete contact between the gel and the plates. This device, known as a rheometer, measures how specimens flow in response to applied forces (Fig. 1). Oscillating pressure, applied to the gel by circular rotation of the mobile plate across it at varying frequencies, generates a variable, translational shear force that is detected with a piezoelectric force transducer. Measurements of elasticity and viscosity are obtained at different oscillation frequencies, which correspond to different levels of shear force. Typically, a relative humidity of close to 100 percent is maintained within the rheometric chamber to prevent dehydration of the gel, and temperature is also controlled during testing.

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The analysis by Kablik et al. showed that total hyaluronic acid concentration (comprising insoluble and soluble hyaluronic acid) was higher for Juvéderm Ultra Plus, Restylane, and Perlane (24, 20, and 20 mg/ml, respectively), which classifies them as high-concentration products. Prevelle Silk, by contrast, had a total hyaluronic acid concentration of 5.5 mg/ml. Insoluble hyaluronic acid gel concentration, a measure of the amount of cross-linked hyaluronic acid, was approximately the same for Juvéderm Ultra Plus, Perlane, and Restylane (14.4, 15, and 15 mg/ml, respectively), whereas Prevelle Silk had 36 to 37 percent of this concentration (5.4 mg/ml). Rheologic study at an oscillation frequency of 5 Hz showed that Restylane and Perlane have a higher elastic modulus (G′) than Juvéderm Ultra Plus and Prevelle Silk. Another article, by Sundaram et al.,15 compared the G′ and viscosity of a calcium hydroxylapatite filler (Radiesse; Merz) and hyaluronic acid fillers (Juvéderm Ultra, Juvéderm Ultra Plus, Juvéderm Voluma, Perlane, Restylane, and Restylane Sub-Q). Measurements over a range of 0.1 to 10 Hz and interpolated at 0.7 Hz support the division of these products into three groups. Radiesse is in the group with the highest G′ and viscosity; Radiesse mixed with 0.3% lidocaine, Perlane, and Restylane in the medium group; and Juvéderm Voluma, Ultra Plus, and Ultra in the low- G′ and low-viscosity group. This grouping is not a ranking of these products, but simply a parsing of their rheologic properties to understand better their behavior during and after injection with the aim of optimizing their clinical use. This article presents new rheologic data for Belotero Balance and for the previously studied products.

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MATERIALS AND METHODS

Seven cross-linked hyaluronic acid soft-tissue fillers—Belotero Basic (Merz, Frankfurt, Germany); Juvéderm Ultra, Juvéderm Ultra Plus, and Juvéderm Voluma (Allergan, Pringy, France); Perlane and Restylane (Medicis, Scottsdale, Ariz.); and Restylane SubQ (Q-Med, Uppsala, Sweden)—were subjected to viscoelastic analysis in a Thermo Haake RS600 Rheometer (Newington, N.H.). The elastic modulus (G′), complex viscosity (η*), and viscous modulus (G″) of each filler gel specimen were measured with a gap between the parallel rheometer plates of 1.2 mm. Oscillatory shear deformation measurements were performed at 30°C using a 35-mm titanium sensor, with a tangential shear stress (tau) of 5 Pa over a frequency range of 0.1 to 10 Hz. Testing was repeated several times. Because there are slight variations in all filler products from batch to batch, analysis was performed on data obtained from a representative rheometric testing session on the same batch of each specimen. These data were consistent with repeated testing. They were interpolated at an oscillation frequency of 0.7 Hz because the resultant shear force fell within the linear viscoelastic range and was considered physiologically relevant for stresses that are common to the skin.

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RESULTS

Figure 2 shows the variation of elastic modulus (G′) with applied force for each of the evaluated hyaluronic acid fillers. The vertical (y) axis is scaled logarithmically; thus, absolute numerical differences in G′ between the products are larger than they appear. Figure 3 shows the variation of complex viscosity (η*) with applied force for each hyaluronic acid filler and Figure 4 shows the variation of viscous modulus (G″) with applied force. The vertical axes for these graphs are also scaled logarithmically. Figure 5 shows the tan delta calculated at 0.7 Hz for each of the hyaluronic acid fillers.

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Table 1 summarizes the interpolated values at 0.7 Hz of G′, η*, G″, and tan delta for each hyaluronic acid filler. Belotero, Juvéderm, and Restylane/Perlane products all have high total hyaluronic acid concentrations, between 20 and 24 mg/ml.

Table 1
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RHEOLOGIC DEFINITIONS

The elastic (storage) modulus, known as G prime and abbreviated to G′, is a quantitative measurement of gel stiffness and thus its ability to resist deformation under applied pressure—such as when the filler is extruded through an injection needle or cannula, and after implantation when the filler is subjected to movements of the facial musculature and overlying skin. The higher the G′ of a gel, the less it deforms under pressure and the more energy it can retain and store. In the article by Sundaram et al., a molded gelatin was given as an example of a gel with a high G′, and chocolate pudding was given as an example of a gel with a low G′. High-G′ products have been described as possessing high tissue-lifting capacity. Although this concept is helpful, it is open to anatomical and functional misinterpretation. As we discuss later in this article, an advanced understanding of volume restoration may be better served by the concept of tissue support rather than tissue lift.

Viscosity, quantified as complex viscosity and symbolized as η*, measures the gel’s ability to resist shearing forces, which are exerted on a filler both during and after injection. In the article by Sundaram et al., peanut butter was given as an example of a high-viscosity gel, whereas room-temperature butter was an example of a low-viscosity gel, and the shear force applied when spreading these gels on toast was discussed. Within a certain range of applied shear force (the linear viscoelastic range), the gel will thin out (the η* will decrease) in a manner that is proportional to applied force. This phenomenon, known as shear thinning, is controlled and predictable. If shear force is increased beyond the linear viscoelastic range, the η* of the gel decreases in an uncontrolled and unpredictable manner in a phenomenon known as yield stress. While exhibiting yield stress, the gel no longer has an elastic behavior. If shear force is increased to a sufficiently high level beyond the linear viscoelastic range, it may actually disrupt the physicochemical structure of the gel. A high-viscosity gel spreads less easily and is less susceptible to shear thinning and yield stress than is a gel of low viscosity.

Viscosity can be quantified instead as the viscous (loss) modulus, known as G double prime and abbreviated as G″. This is a measure of a gel’s ability to dissipate energy when shear force is applied to it. G″ is reciprocally related to G′, which measures the ability of a gel to store energy. G″ is equivalent to complex viscosity (η*) when shear force falls within the linear viscoelastic range. We and other researchers consider η* to be more clinically relevant than G″, because we believe it gives a clearer picture of how a filler might be affected by shear forces during and after injection. This may be particularly germane to Restylane and Perlane, which have a prominent particulate component and behave in some respects like biphasic gels within which a third, distinctly solid phase is suspended. G″ may not be as accurate an indicator as complex viscosity of the behavior of filler products that can display these multiphasic characteristics.

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DESIGN AND REPRODUCIBILITY OF RHEOLOGIC STUDIES

Direct numerical comparison between values of G′ and viscosity can be made only if the rheometric testing conditions are the same. This includes oscillation frequency, which should be such that the applied shear force falls within the linear viscoelastic range that produces consistent, reproducible changes in G′ and η*. When evaluating filler gels, a further, important consideration is that the oscillation frequency should be consistent with the expected range of physiologic stress to which the fillers are subjected when injected into the skin. We define a rheometric oscillation frequency of between 0.1 and 2 Hz as physiologically relevant. The study by Kablik et al. was performed at a higher frequency of 5 Hz. However, the selection of 0.1 to 2 Hz is consistent with previous analyses that consider movement of the facial musculature and gravity to subject the skin to low-frequency stresses,15–17 and in agreement with the conclusions from a consensus session at the International Master Course on Aging Skin 2013 Annual Meeting.18 Support for use of the lower oscillation frequency is also provided by data regarding the application of shear forces to Quorn (Marlow Foods, Ltd., North Yorkshire, United Kingdom), a mycoprotein-derived meat substitute that is engineered to have a texture and consistency resembling mammalian tissue.19 In contrast, a rheometric oscillation frequency as high as 250 Hz has been considered relevant when evaluating fillers for injection into the vocal cords, which are subject to much higher frequency stresses.20

Although the absolute values of G′ for the products common to the studies by Kablik et al. and Sundaram et al. vary because of different oscillation frequencies, the general pattern is consistent, with the same products being found to have relatively high or low G′.

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SECONDARY RHEOLOGIC CALCULATIONS

Tan delta is the ratio of viscous modulus to elastic modulus (G″/G′). It is a measure of the presence and extent of elasticity. A gel with high tan delta will have a predominance of fluidity over elasticity, whereas low tan delta indicates a predominance of elasticity over fluidity.

The complex modulus, abbreviated as G*, is the square root of the sum of the elastic modulus squared plus the viscous modulus squared:

Equation (Uncited)
Equation (Uncited)
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The complex modulus measures the gel’s overall resistance to deformation, which comprises a recoverable component because of the gel’s elasticity and a nonrecoverable component because of the gel’s viscosity.

The Deborah number is calculated as the ratio of the time it takes for the gel to adjust to applied stresses (relaxation time), to the time scale of the study. (The Deborah number, proposed by Reiner and inspired by a verse from the Song of Deborah in the Torah and the Bible, is based on the thesis that, given sufficient time, even the hardest material such as a mountain will flow.) At lower Deborah numbers, the gel behaves in a fluid-like manner with associated Newtonian viscous flow, whereas its behavior becomes more solid-like or elastic at higher Deborah numbers.

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EVIDENCE LEVEL AND CLINICAL CORROBORATION OF RHEOLOGIC DATA

Rheologic testing is performed in vitro and is therefore classified as evidence level V. Care must be taken when extrapolating from testing in a partially open rheometer to the in vivo situation, where the filler is enclosed in the syringe and needle during extrusion and then passes into the confines of tissue. Histopathologic studies (described below) bridge the evidence gap by demonstrating a direct correlation between rheologic properties and the distribution pattern of hyaluronic acid fillers when they are implanted into living tissue. Clinical corroboration is provided by two controlled, split-face studies of evidence level II, which demonstrate that optimal nasolabial fold correction requires a significantly smaller volume of a higher than a lower G′ filler product.21,22 These clinical data support the concept that high G′ is a predictor of greater tissue-supporting capacity (“lift”) and thus better volume efficiency. The relationship between in vitro rheologic data and clinical evidence for fillers might be analogized to the relationship between the x-ray crystallographic data that were key to elucidating the double helix structure of DNA and the corroborating in vivo evidence.

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RHEOLOGIC PROFILES OF TESTED PRODUCTS AND RELATIONSHIP TO MANUFACTURING METHODS

The measurements obtained in this study are consistent with those in the articles cited above12,15 and provide new data pertaining to Belotero Balance and the relative proportions of fluidity and elasticity in each of the tested products. Belotero Balance has the lowest G′ and viscosity and the highest tan delta. These values predict that it is a soft, spreading filler that, although elastic, has a greater component of fluidity than Restylane and Juvéderm. This makes it appropriate for superficial injection, as it will flow readily through the intradermal or superficial subdermal tissue planes and can be molded easily after implantation to produce a smooth result. Belotero Balance is the first filler available in the United States with longevity comparable to Juvéderm and Restylane that can be injected so superficially.

Restylane and Perlane, with the highest G′ and viscosity of the tested hyaluronic acid products, are firm, less spreading fillers with a predominance of elasticity. Juvéderm Voluma, Ultra Plus, and Ultra are intermediate in G′ and viscosity and have intermediate firmness, tendency to spread, and balance of elasticity versus fluidity. The Restylane, Perlane, and Juvéderm products are therefore better placed at the deeper subdermal level, in the subcutaneous and preperiosteal tissue, where they can provide deep tissue support. The noticeable difference between tan delta values for Radiesse mixed with lidocaine and for Restylane is interesting and the subject of a future communication.

During the manufacture of the nonanimal stabilized hyaluronic acid fillers (Restylane and Perlane), blocks of gel are passed through sizing screens. This sieving creates cross-linked hyaluronic acid particles of the desired size that are then dispersed within a lubricant, soluble hyaluronic acid phase. Juvéderm products (classified as Hylacross hyaluronic acid) and Belotero Balance (classified as cohesive polydensified matrix hyaluronic acid) are nonsieved. No particle sizing occurs, and they consist of homogeneous masses of cross-linked hyaluronic acid with particles of variable shape and size.23 They are described as cohesive gels. The term, “monophasic,” sometimes applied to cohesive polydensified matrix hyaluronic acid in an attempt to describe its cohesivity, is not scientifically accurate, as a gel must contain at least two phases by definition. It may be more accurate to think of nonanimal stabilized hyaluronic acid as behaving in some respects like a triphasic gel; whereas cohesive polydensified matrix hyaluronic acid is biphasic, and its cohesivity causes its solid and fluid phases to behave in concordance under physiologic conditions. During the consensus session at the International Master Course on Aging Skin 2013 Annual Meeting, panelists from all six of the participating filler companies, including the manufacturers of Restylane, Juvéderm, and Belotero products, agreed on this key point.18

The manufacture of nonanimal stabilized hyaluronic acid (Restylane) and Hylacross (Juvéderm) products starts with shorter strands of hyaluronic acid for cross-linking (approximately 200 to 300 kDa), whereas manufacture of cohesive polydensified matrix hyaluronic acid (Belotero) begins with longer strands (approximately 800 kDa). Therefore, the hyaluronic acid strands in Belotero that do not become cross-linked (soluble hyaluronic acid) are longer and of higher molecular weight. Belotero Balance differs from Restylane, Perlane, and Juvéderm products in that it has nonuniform cross-linking, which is achieved by means of a two-step process. This makes some areas of the hyaluronic acid molecule softer because the cross-linking is less dense and some areas firmer because of denser cross-linking. Variable cross-linking of Belotero Balance is intended to confer resilience and retention of structural integrity during adaptation to distorting forces. This may be useful in facial zones with uneven pressure, such as the perioral and periocular regions with their sphincteric facial muscles. Resilience is also of value in superficial implantation, because it allows the product to withstand intradermal shearing forces—which may be more acute than those that occur in deeper tissue levels.24

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HISTOPATHOLOGIC CORRELATION OF RHEOLOGIC DATA

Histopathologic studies after intradermal implantation of hyaluronic acid fillers into buttock skin reveal patterns of tissue spread that are a direct manifestation of the fillers’ different viscosities.25 Belotero Balance, which has the lowest viscosity and therefore the greatest tendency to spread, distributes homogeneously within the superficial and deep reticular dermis. Restylane, which has the highest viscosity and therefore the least tendency to spread, distributes as fairly well-defined boluses within the deep reticular dermis. Juvéderm, with intermediate viscosity, distributes with an intermediate pattern within the superficial and deep reticular dermis (Fig. 6). These patterns of intradermal distribution have been confirmed by real-time ultrasound imaging during and after implantation.26

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Belotero Balance has been reported not to cause the Tyndall effect (more accurately termed Rayleigh scattering)—the phenomenon by which a particulate bolus of hyaluronic acid implanted into the superficial dermis scatters the light striking it so that blue light, which has a shorter wavelength, is preferentially reflected back to an observer’s eye. This imparts an aesthetically unappealing bluish discoloration to the implanted filler, even though it is actually colorless27,28 (Fig. 7). Lack of the Tyndall effect with Belotero Balance is inferred to be a manifestation of its homogeneous intradermal distribution pattern, because the absence of discrete particulate filler boluses precludes the preferential scattering of blue light. It is a further reason that this product is appropriate for superficial implantation.

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CLINICAL IMPLICATIONS

Filler longevity is of significant concern to patients. Clinical studies with evidence level II show that the longevity of cohesive polydensified matrix hyaluronic acid (Belotero Balance) is comparable to that of nonanimal stabilized hyaluronic acid (Restylane) and Hylacross (Juvéderm Ultra) when injected into the nasolabial folds. A randomized split-face controlled study that directly compared cohesive polydensified matrix hyaluronic acid to nonanimal stabilized hyaluronic acid and Hylacross found that they all provided equivalent clinical results 12 months after mid to deep dermal implantation.29 An 18-month open-label extension trial of the original split-face double-blind study that resulted in U.S. Food and Drug Administration approval of Belotero Balance showed that nasolabial fold correction persisted for at least 48 weeks in approximately 80 percent of subjects.30

Although study protocols typically call for hyaluronic acid fillers to be implanted in the mid to deep dermis, resection and histopathologic evaluation of nasolabial fold skin in 16 subjects have shown implanted hyaluronic acid (Juvéderm Ultra) to be predominantly localized to the subcutis, with some hyaluronic acid present in the deep dermis.31 These data have been cited on occasion as indicating that intradermal injection of hyaluronic acid filler is impossible. We feel that this is a misinterpretation, as the histopathologic and ultrasonic studies described above25,26 plus others currently in process clearly show that intradermal injection is possible. The authors, who each have over 10 years’ experience with intradermal filler placement, find that it takes a conscious and deliberate effort. The injecting needle tents the skin upward, and there is transient skin blanching at the site of implantation. When filler is laid down in intradermal sheets, the hub of the needle grazes the surface of the skin at an acute angle, and the silver-gray of the needle may even be visible through translucent skin. Retrograde injection technique allows precise placement of filler within the tunnel created as the needle is slowly withdrawn at the appropriate tissue level. Stretching of the skin to be injected with the noninjecting fingers also facilitates filler placement (Fig. 8).

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We may infer from the investigation by Arlette and Trotter that Belotero Balance, like other hyaluronic acid fillers, has actually been implanted subdermally in some studies, rather than intradermally as was intended. The longevity data cited above indicate that the product has good efficacy whether it is implanted within the dermis or below it. However, the biophysical characteristics of Belotero Balance and the clinical behavior they confer make the product appropriate for superficial implantation, whereas it is difficult to inject the other high-concentration hyaluronic acid fillers that are currently available in the United States intradermally unless they are modified. This is most commonly accomplished by product dilution with lidocaine and/or saline—a strategy that can produce impressive results in skilled hands but essentially has the objective of adapting Juvéderm or Restylane, which are best placed subdermally, so that they are less unsuitable for superficial implantation.32

It may be considered a simpler and more direct injection paradigm to use filler products for the purposes that they can best fulfill because of their inherent characteristics. Belotero Balance—a soft, spreading filler that integrates homogeneously into tissue—can be injected superficially to fill fine lines and can be flowed in an intradermal or superficial subdermal sheet through the perioral and submalar cheek regions, the décolletage, and other areas of atrophic, crepey skin. We conceptualize this as “superficial flow volumetry.” Belotero Balance is also suited to the anatomically unforgiving periocular region and to the lips when soft products are considered desirable (e.g., when tissue quality is compromised because of age-related loss of volume and elasticity).33 Juvéderm Ultra and Ultra Plus, Restylane, and Perlane are firmer, less spreading fillers that remain more defined in the tissue; they can be implanted deeply at the subcutaneous and preperiosteal levels, for contouring and sculpting of the midface, lower face, temples, and nose—and also into the periocular region and lips when tissue quality is appropriate. Calcium hydroxylapatite (Radiesse) can also be used with success for deep implantation, by virtue of its high G′ and viscosity.34 We conceptualize this as “deep support volumetry.” Layering of fillers in the superficial and deep tissue planes has been described in Europe as a “sandwich” technique. For most injectors in the United States, it is a new paradigm of volume restoration. It represents a refinement of rheologic tailoring—the process by which filler products are selected for specific clinical applications based on their rheologic attributes.35 These product indications are relative and certainly are not mandatory to achieve good results. Product selection ultimately rests in the hands of the injector.

Layered implantation of fillers makes sense, given our current understanding of age-related volume loss as a multilevel process. Previous rhetoric has focused on the notion that volumetry is a deep, subdermal procedure, characterized by tissue “lift,” with high elastic modulus (G′) being the hallmark of a “lifting” filler. We now propose that volumetry can have both deep and superficial components, and that it is more anatomically and functionally accurate to think of fillers as having the potential to provide layered tissue support rather than tissue lift. If volume restoration reinflates faces rather than lifting them per se, facial reinflation may be visualized as a three-dimensional vectoring. This vectoring is perpendicular, tangential, and/or horizontal to the skin surface—rather than being unidirectional, as would occur if a face were actually lifted.36 Although filler elasticity (G′) is an important contributor to tissue support, cohesivity is also a consideration, and its role remains to be clearly defined.

Both superficial and deep volumetry can provide tissue support by means of three-dimensional vectoring. Because the volume of filler that is injected superficially tends to be smaller than the volume that is injected deeply, the outward vectoring effect is less dramatic. Nonetheless, superficial flow volumetry can contribute significantly to tissue support by virtue of its tangential and horizontal vectoring. It has the potential to synergize with deep support volumetry to optimize results, and it meets several key patient needs (Figs. 9 through 15). Fagien and Cassuto have described the cumulative, restorative clinical improvement that can be observed with repeated superficial hyaluronic acid injection.32

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CONCLUSIONS

As the palette of soft-tissue fillers for aesthetic use in the United States expands, clinicians can better address age-related volume loss, understood to be a multilevel process, with paradigms of layered volumetry that incorporate both new and already available products. A recently approved cohesive polydensified matrix hyaluronic acid product, Belotero Balance, has a distinct manufacturing process and, consequently, a unique biophysical profile that suits it to superficial tissue implantation. It can be used alone or in combination with other fillers that are appropriate for deeper implantation, such as Restylane, Perlane, Juvéderm, and Radiesse. The effects of panfacial, layered volume replacement are profound. It allows a global rejuvenation encompassing restoration or enhancement of youthful contours, together with improvement of fine rhytides and crepey skin, skin reflectance, and skin texture. This can optimize results and patient satisfaction.

The impetus for the original studies of filler rheology was to find scientific explanations for clinical observations. Filler rheology is now driving the design of novel products with biophysical characteristics that fit them to particular clinical applications. Clinical and scientific studies are occurring in tandem. As this coordinated work advances, we can expect significant progress in our understanding of volumetry. We can also anticipate specific issues of clinical importance to be clarified by scientific investigation. Those that we will address in the future include the role of the high-molecular-weight soluble hyaluronic acid that is unique to cohesive polydensified matrix hyaluronic acid, and the quantitative and qualitative contributions of cohesivity to tissue support.

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PATIENT CONSENT

Patients provided written consent for the use of their images.

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ACKNOWLEDGMENTS

The authors express their deep appreciation to David J. Howell, Ph.D., R.R.T., and to Bob Voigts (Merz Aesthetics) for assistance with formatting of the manuscript and figures and with fact-checking.

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©2013American Society of Plastic Surgeons

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