Hyaluronic Acids: The Fillers of the Decade
Wednesday, October 13, 2010
Hyaluronic acid (HA) is a linear polysaccharide composed of
disaccharide units of glucouronic acid and
N-acetyl-glucosamine.1-3 It is the main polysaccharide
in the extracellular matrix of human connective tissue, and serves
as the ground substance of the dermis, fascia, and most fluid
mediums.1,2,4 HA produces a viscoelastic framework where
collagen and elastin are able to bind, and it plays the role of a
structure-stabilizing, space-occupying, and cell-protecting
connective matrix filler.1,2,4 In addition to humans, HA
is found in other organisms, being homogeneous across nature. It
shows no antigenic specificity for species or tissues, hence it
presents a low potential for allergic or immunogenic
reactions.1,2 During the aging process, the HA content
in skin diminishes, resulting in decreased cell hydration,
elasticity and movement. Cell hydration can be affected by the
imbalance between the intra- and extracellular fluid. Therefore,
according to Bray et al.,4 the reduction in HA
that occurs with aging may thus influence cell hydration.
At the present time, HA is one of the most frequently applied
dermal fillers for aesthetic uses. HA dermal fillers are used to
correct facial wrinkles, folds and grooves, for volume augmentation
of facial regions, and for lip eversion (Figure 1).1,5
There are two main raw materials from which HA can be obtained: the
comb of roosters and non-pathogenic bacterial
fermentation.6,7 The use of non-animal sources, however,
reduces the chance of antigenic contamination and subsequent
Figure 1. Injection technique for lip eversion with a
hyaluronic acid (HA) filler.
Chemical Modification of HA Fillers
HA shows excellent biocompatibility and affinity for water in
its natural state, but it exhibits poor biomechanical properties as
a dermal filler: its half-life is 1-2 days and it undergoes rapid
enzymatic degradation and reabsorption when injected into
skin.1-4,9 For that reason, chemical modification is
required to produce stabilized HAs and to improve their mechanical
properties and residence time at the implant site.10
Although HA fillers have similar features, they are submitted to
varying manufacturing processes, which results in them having
different physicochemical characteristics.11 The
clinical performance of HA fillers is also affected by the degree
of cross-linking, the concentration of HA, particle size, and the
extent of gel swelling or hydration capacity.12
No single parameter defines the use of a HA filler. A careful
review of the gel characteristics, together with its properties and
composition, is essential to understand the performance of each
filler. Moreover, different anatomic areas require different HA
fillers with different properties. These two factors together are
important determinants when selecting the correct filler, with the
aim of optimizing results and setting correct expectations in order
to meet the patients' needs.7,9,11
Chemical modifications of HA result in formation of either a
cross-link (a bond between two strands of HA) or a pendant group
(with a bond connecting only one strand and leaving the other
extremity free). Kablik et al. reported that a pendant
group is more likely to contribute to gel swelling than to its
longevity.9 A higher concentration of cross-linked HA
results in a more viscous gel, which is suitable for adding volume
and correcting deeper facial grooves and furrows.13 Kono
et al. observed that double cross-linked hyaluronic acid
(DCHA) provides a more durable aesthetic improvement when compared
with single cross-linked hyaluronic acid (SCHA) in the treatment of
The total HA concentration consists of insoluble HA gel and
soluble-free HA, and may influence the product's duration. However,
the amount of cross-linked HA gel also plays an important role in
the performance of the dermal filler. Both the concentration and
degree of cross-linking are important determinants of a product's
ability to resist deformation. With the same degree of
cross-linking, low HA concentrations will produce soft gels,
whereas higher concentration gels are stiffer.9
Particle size is related to the filling process, but it does not
alter the durability. Fillers with a large particle size are
preferred for filling deep wrinkles, whereas those with a small
particle size are used for superficial lines. According to Bogdan
and Baumann,13 a HA dermal filler can be "sized" or "not
sized". "Sizing" is the process by which cross-linked HA is pushed
through a specially-sized screen and broken into pieces. Neither
the effect of this process on filler performance nor the advantage
of the HA sizing process has been established.
The swelling capacity of HAs refers to their ability to bind
water; it is important to observe that products that are not
completely saturated will have a high ability to bind water and
will expand their volume after injection.9,13 Thus, care
should be taken not to produce an over-response with these
products, especially when they are used for lip
All of these chemical characteristics influence the clinical
performance of HAs and, as previously mentioned, different HAs are
suitable for treating different areas. Thus, the choice of product
depends on several factors, including the site being injected, the
required extent of correction, and the personal preference of the
clinician.14 For example, superficial wrinkles, such as
those found in the lower eyelids, are best treated with softer and
small-particle-size fillers, whereas large-particle-size HA fillers
are suitable for deep wrinkles.9,15 It is also reported
that a flexible product, such as small gel particle HA, is
considered preferable for areas that need structural support,
including the oral commissure, whereas a product such as large gel
particle HA is better suited for deeper injections to create volume
in the deep dermis.14 Currently, there are many
different dermal fillers on the market.
The nasolabial folds are the most commonly treated area,
followed by the lips (Figure 2 and 3), marionette lines, oral
commissures, and tear troughs. Nasolabial folds and oral
commissures should generally be considered together as one anatomic
area. They are also often treated simultaneously with the
Figure 2. Before lip augmentation with a hyaluronic acid
Figure 3. Two weeks after lip augmentation with a
hyaluronic acid (HA) filler.
Soft-tissue augmentation offers patients a younger appearance
and is currently, together with the use of botulinun toxin, one of
the most frequently performed aesthetic procedures in the world.
Although the physicochemical characteristics of HA fillers are,
indeed, relevant when choosing a product, it should be remembered
that a filler's persistence will depend not only on its physical
characteristics 17,18 but also on the patient's
response. Degradation of the implant occurs owing to the action of
enzymes or free radicals, and varies from patient to
Knowledge of the chemical characteristics of the different HA
products on the market allows doctors to make a better choice
regarding the most appropriate dermal filler for tissue
augmentation, optimizing results and therefore benefiting both
doctors and patients.
- Monheit GD, Coleman KM. Hyaluronic acid fillers.
Dermatologic Therapy 2006;19:141-150.
- Tierney EP, Sengelmann RD, Sattler G, Hanke CW. Soft tissue and
augmentation. In: Robinson JK, Hanke CW, Siegel DM, Fratila A, eds.
Surgery of the Skin - Procedural Dermatology, 2nd edn. Edinburgh,
UK: Mosby Elsevier; 2010:363-391.
- Kono T, Kinney BM, Groff WF, et al. Randomized,
evaluator-blind, split-face comparison study of single cross-linked
versus double cross-linked hyaluronic acid in the treatment of
glabellar lines. Dermatol Surg 2008;34(Suppl
- Bray D, Hopkins C, Roberts DN. A review of dermal fillers in
facial plastic surgery. Curr Opin Otolaryngol Head Neck
- Alam M, Gladstone H, Kramer EM, et al. ASDS guidelines
of care: injectable fillers. Dermatol Surg 2008;34(Suppl
- Graf J. Fillers: A dermatologic perspective. In: Saltz R, ed.
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- Cantisano-Zilkha M, Haddad A. Facial fillers and volumizers.
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Rejuvenation. Cidade: Elsevier; 2010:97-118.
- DeLorenzi C, Weinberg M, Solish N, Swift A. The long-term
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stabilized hyaluronic acid-based gel of nonanimal origin in
esthetic facial contouring. Dermatol Surg 2009;35(Suppl
- Kablik J, Monheit GD, Yu L, Chang G, Gershkovich J. Comparative
physical properties of hyaluronic acid dermal fillers. Dermatol
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- Collins MN, Birkinshaw C. Physical properties of crosslinked
hyaluronic acid hydrogels. J Mater Sci Mater Med
- Beer K, Lupo MP. Making the right choices: attaining
predictable aesthetic results with dermal fillers. J Drugs
- Ahmad J, Rozen SM, Rohrich RJ. The role of soft tissue fillers
in cosmetic medicine: A plastic surgical perspective. In: Saltz R,
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- Bogdan Allemann I, Baumann L. Hyaluronic acid gel (Juvéderm)
preparations in the treatment of facial wrinkles and folds.
Clin Interv Aging 2008;3:629-634.
- Weinkle S. Injection techniques for revolumization of the
perioral region with hyaluronic acid. J Drugs Dermatol
- Donath AS, Glasgold RA, Meier J, Glasgold MJ. Quantitative
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- Matarasso SL, Carruthers JD, Jewell ML; Restylane Consensus
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