Rheologic and Physicochemical Characteristics of Hyaluronic Acid Fillers: Overview and Relationship To Product Performance
Rheologic and Physicochemical Characteristics of Hyaluronic Acid Fillers: Overview and Relationship To Product Performance
Rheologic and Physicochemical Characteristics of Hyaluronic Acid Fillers: Overview and Relationship To Product Performance
THIEME
116 Original Article
1 Medical Affairs, Allergan Aesthetics, an AbbVie company, Marlow, Address for correspondence Michael B. Silberberg, MD, MBA, Medical
United Kingdom of Great Britain and Northern Ireland Affairs, Allergan Aesthetics, an AbbVie company, Marlow
2 Clinical Development, Allergan Aesthetics, an AbbVie company, International, Ground Floor, Parkway, Marlow, Buckinghamshire
Rome, Italy SL71YL, United Kingdom of Great Britain and Northern Ireland
3 Allergan Aesthetics, an AbbVie company, Pringy, France (e-mail: michael.silberberg@abbvie.com).
Abstract Injections with hyaluronic acid (HA) fillers for facial rejuvenation and soft-tissue
augmentation are among the most popular aesthetic procedures worldwide. Many
HA fillers are available with unique manufacturing processes and distinct in vitro
physicochemical and rheologic properties, which result in important differences in the
fillers’ clinical performance. The aim of this paper is to provide an overview of the
Keywords properties most widely used to characterize HA fillers and to report their rheologic and
► aesthetics physicochemical values obtained using standardized methodology to allow scientifi-
► hyaluronic acid fillers cally based comparisons. Understanding rheologic and physicochemical properties will
► elastic modulus guide clinicians in aligning HA characteristics to the facial area being treated for
► rheology optimal clinical performance.
Hyaluronic acid (HA) filler injections for facial rejuvenation crosslinking conditions (temperature, pH), molecular weight
and soft-tissue augmentation were the second most popular of the starting HA, and post-crosslinking modifications
nonsurgical aesthetic procedures in 2019, with 4.3 million (sieving/homogenization, addition of lidocaine, etc.), can
procedures performed worldwide, an increase of 16% from impact filler characteristics.3,9–12
the previous year.1 Features that may contribute to the Understanding the range of HA filler products from the
popularity of HA filler treatments include their biocompati- standpoint of their rheologic and physicochemical character-
bility and degradability, overall safety and tolerability, high istics can provide an initial framework for predicting treat-
hydrophilicity, ease of administration, minimal recovery ment outcomes13 and assist clinicians in selecting the
time, immediate results, and low incidence of immunologic appropriate attributes for each treated facial area.11,14 Rheo-
reactions.2–6 HA fillers used in aesthetic indications typically logic and physicochemical properties of HA fillers impact
consist of chemically crosslinked HA molecules, resulting in a performance characteristics (i.e., lift capacity, resistance to
hydrogel that is less susceptible to enzymatic degradation deformation, and tissue integration), which, together with
(i.e., has longer duration) and has improved rheologic prop- injection technique (i.e., injection plane, location, volume)
erties compared with uncrosslinked HA.7,8 Variations in and the interaction of the filler with the surrounding tissue,
manufacturing processes, such as degree of crosslinking, may affect clinical outcomes.15
There are different methodologies for measuring and provided in ►Table 1 7,11,14,17,20,24 and discussed in greater
characterizing the rheologic and physicochemical proper- depth below.
ties of crosslinked HA fillers; the use of standardized in vitro
assays can provide the basis for understanding how differ- Complex Modulus (G)
ent fillers may perform under different situations.7,16 This Complex modulus, or G, measures the overall viscoelastic
article presents data on rheologic and physicochemical properties of a gel and is commonly referred to as “hard-
characteristics of HA fillers using consistent methodology ness.”17 G describes the global response of the filler to
to allow a scientifically based comparison. Guidance on deformation, takes into account both the elastic component
appropriately aligning HA rheologic and physicochemical (G′) and the viscous component (G″), and is derived through
characteristics to the facial area being treated follows, with the equation .17,20 This parameter repre-
the goal of helping clinicians make informed decisions sents the strength of the material (hardness) or the total
about HA filler selection. energy needed to deform it.25
Fig. 1 Schematic representation of a rheometer in oscillation mode. The gel is placed between two plates of defined geometry to assess
elasticity (solid behavior) quantified by the elastic modulus, or G′, indicating how much the gel can recover its shape after shear stress. The same
experiment also measures G″, the viscous modulus. From these measured parameters, G and tan delta (d ) can be calculated. 11,17,20
Viscous Modulus (G″) mostly elastic filler.18 Most HA crosslinked fillers have tan d
Viscous modulus, or G″, measures the viscous properties of <1 (i.e., G′ > G″).17 While tan d allows an understanding of
the gel and represents the energy lost during deformation.26 whether the filler is more elastic or more viscous, it is
Hence, it is also known as the “loss modulus.”26 G″ describes important to note that it does not provide information on
the inability of the filler to recover its shape after the sheer the actual magnitudes of G′ and G″.32
stress is removed, and it is linked to the liquid behavior of the
gel, allowing the gel to deform and flow to some extent Gel Cohesion (cohesivity)
during injection.11,17,20 HA fillers tend to have low G″.14 For Gel cohesion (also called cohesivity) represents the adhesion
any HA filler to be effective, it needs to be viscoelastic, i.e., forces within the gel and characterizes how a filler behaves as a
viscous enough to be injected and initially molded, but gel deposit once injected, which makes cohesivity an impor-
elastic enough to resist shear deformation forces and provide tant property to consider in the overall behavior of a filler.17 At
a durable correction once implanted into soft tissue.11,17,20 It the time of injection, HA fillers with lower cohesivity tend to be
is important to note that G″ is distinct from viscosity, which easier to mold and spread more easily.17 However, when
relates to the flow of the filler during injection and does not subjected to the compressive forces of the face, fillers with
impact clinical performance.8,17 lower cohesivity do not maintain their shape and projection as
well as fillers with higher cohesivity and similar G′.17 When
Tan Delta (tan d) high compression is applied to a low-cohesivity gel, there is a
Tan d is the ratio between the viscous (G″) and elastic (G′) risk of detachment/separation of gel from the original deposit,
components of the HA gel (i.e., tan d ¼ G″/G′) and evaluates which can result in filler migration.17 When high compression
the relative contributions of each property.11,17,20 Tan d >1 is applied to a high-cohesivity gel, the gel deposit resists this
signifies a mostly viscous filler, whereas tan d <1 indicates a force more easily and retains its original shape.17 Cohesivity is
Table 2 Rheologic and physicochemical characteristics of HA fillers (data from Hee et al13 and data on file, Allergan Aesthetics, an
AbbVie company). All products were tested under the same conditions using the same methodologies13
Filler product namea HA (mg/mL) G’5Hz (Pa) G’’5Hz (Pa) Tan d Cohesivity/ Maximum
Fn (gmf) water uptake, %
Belotero Softþ 20 40 42 1.050 16 <100
Belotero Balanceþ / Lips Contour 22.5 128 82 0.641 69 664
Belotero Intenseþ / Lips Shape 25.5 255 110 0.431 115 700
Belotero Volumeþ 26 438 103 0.235 97 370
Juvéderm Ultra 24 156 68 0.436 96 580
Juvéderm Ultra XC 24 207 80 0.386 96 622
Juvéderm Ultra Plus 24 214 74 0.346 116 515
Juvéderm Ultra Plus XC 24 263 79 0.300 112 454
Juvéderm Ultra 2 24 188 75 0.399 95 574
Juvéderm Ultra 3/Smile 24 238 71 0.298 104 426
Juvéderm Ultra 4 24 164 66 0.402 105 614
Juvéderm Volite 12 166 30 0.181 12 <100
Juvéderm Volbella with lidocaine 15 271 39 0.144 19 133
Juvéderm Volift with lidocaine 17.5 340 46 0.135 30 184
Juvéderm Voluma with lidocaine 20 398 41 0.103 40 227
Juvéderm Volux 25 665 49 0.074 93 253
Restylane Fynesse 20 134 58 0.433 30 677
Restylane Refyne 20 116 50 0.431 49 516
Restylane Kysse 20 236 50 0.212 85 373
Restylane Defyne 20 342 47 0.137 60 318
Restylane Volyme 20 239 50 0.209 91 354
Restylane Vital Light 12 84 49 0.583 12 <100
Restylane Vital 20 667 172 0.258 27 <100
Restylane 20 864 185 0.214 29 <100
Restylane Lyps 20 976 166 0.170 31 <100
Restylane Lyft 20 977 198 0.203 32 <100
Restylane SubQ 20 1055 123 0.117 42 <100
Teosyal Puresense Redensity II 15 114 43 0.372 16 239
Teosyal Puresense First Lines 20 105 44 0.419 18 250
Teosyal Puresense Kiss 25 314 66 0.209 74 380
Teosyal Puresense Deep Lines 25 301 64 0.214 82 300
Teosyal Puresense Ultra Deep 25 348 54 0.155 87 250
Teosyal RHA1 15 133 54 0.406 22 260
Teosyal RHA2 23 319 99 0.310 77 420
Teosyal RHA3 23 264 67 0.254 109 427
Teosyal RHA4 23 346 62 0.179 115 366
and bumps.12,17,20 Because the aesthetics of the periorbital The zygomatic and submalar areas are subject to dynamic
area are highly sensitive to minimal volume changes, a filler contraction forces of the lip and cheek elevators. Therefore,
with low water uptake should be used to minimize the risk of the fillers used in these areas need to have a medium to high
swelling and puffiness under the eyes.40,43 elastic modulus (G′) to resist shearing and medium to high
cohesivity to withstand compression forces of the overlying Nose, Jawline, and Chin
tissue and maintain projection.44,45 The chin, jaw, and nasal dorsum are areas of low shear stress
This degree of cohesivity is essential to ensure minimal but are characterized by high compression, with taut skin
separation and avoid product displacement that may occur and muscle over bony structures. Thus, the filler of choice to
after repetitive contraction of the overlying musculature.46 enhance contouring and provide structure should have high
To provide projection, the fillers to be used in the midface elasticity (G′) and medium to high cohesivity42 and provide
should have a high lift capacity. Several HA filler products with high lift capacity and resistance to deformation. Such a filler
the described rheologic and physicochemical properties have would minimize lateral spreading and maintain a sharp
demonstrated effectiveness for the treatment of the midface.14 vertical projection over time. Different products with the
appropriate balance of these rheologic properties have dem-
Lower Face onstrated effectiveness for these regions in clinical trials.14,42
The lower face is an area characterized by a high degree of
dynamic movement; loss of volume and structural support in Fine Lines and Improvement of Skin Quality Attributes
this area, resulting in marionette lines, nasolabial folds, or HA filler products can improve superficial wrinkles by filling
accordion lines, requires consideration of distinct rheologic in shallow lines, thus smoothing the skin and leading to an
characteristics, such as medium elasticity (G′) and low to appearance of improved skin quality. Fillers with low HA
medium cohesivity,17,47,48 with a moderate lift capacity. The concentration that exhibit low to medium elasticity (G′)
ideal filler for this region would need to be easily moldable, combined with low cohesivity are best suited to treat super-
have low projection, be nonpalpable, and integrate well with ficial fine lines, such as those in the periorbital and perioral
facial movement, as it will be subjected mostly to shearing areas.14,53,54 As mentioned earlier, HA fillers with low
and mild compression forces. However, to correct severe cohesivity are generally easier to mold and have increased
folds, a filler with higher cohesivity is recom- spread in tissues. As these fillers are usually injected super-
mended,14,17,47,48 although it could be harder to mold after ficially, they require low lift capacity, low resistance to
injection.17 deformation, and good tissue integration. This type of filler
will integrate well with the surrounding tissue, will perform
Lips well with dynamic movement, and will be less likely to result
To enhance the lips, fillers are usually described as soft, i.e., in visible edges and bumps or palpabality.14
having low to medium elasticity (G′) and low to medium
cohesivity, since the challenge in this area is to avoid edges
Conclusion
and bumps. Also, a low swelling factor is usually recom-
mended to avoid unnatural-looking results.11,49 For a The face is a dynamic and complex structure, and therefore the
smoothing effect, lip fillers require lower lift capacity and requirements for each area of the face should be taken into
easy moldability.50,51 Increasing the cohesivity from low to consideration when choosing a filler. This overview of the
medium or even to high will contribute to projection and rheologic and physicochemical properties of HA fillers, togeth-
volumization.9,50,52 There are several HA fillers with the er with a summary of rheologic and physicochemical values for
appropriate combination of elasticity, cohesivity, softness, multiple products measured using the same methodologies,
and water uptake that have been shown to be effective for will provide a valuable resource for clinicians. Aligning the
treating the lips.14,50,51 rheologic and physicochemical properties of HA fillers to the
facial area being treated, along with using the appropriate 16 Edsman KL, Wiebensjö AM, Risberg AM, Öhrlund JA. Is there a
injection technique, can help clinicians select the right product method that can measure cohesivity? Cohesion by sensory eval-
to achieve optimal aesthetic results. uation compared with other test methods. Dermatol Surg 2015;
41(Suppl 1):S365–S372
17 Pierre S, Liew S, Bernardin A. Basics of dermal filler rheology.
Note Dermatol Surg 2015;41(Suppl 1):S120–S126
Medical writing and editorial assistance were provided to 18 Heitmiller K, Ring C, Saedi N. Rheologic properties of soft tissue
the authors by Mayuri Kerr, PhD of Allergan Aesthetics fillers and implications for clinical use. J Cosmet Dermatol 2021;
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19 Goldman MP, Few J, Binauld S, Nuñez I, Hee CK, Bernardin A.
Health company, and funded by Allergan Aesthetics. All
Evaluation of physicochemical properties following syringe-to-
authors met the ICMJE authorship criteria. No honoraria
syringe mixing of hyaluronic acid dermal fillers. Dermatol Surg
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20 Lorenc ZP, Öhrlund Å, Edsman K. Factors affecting the rheological
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