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Surgery and Cosmetics

Doris M. Hexsel, MD

Hyaluronic Acids: The Fillers of the Decade

Doris M. Hexsel, MD

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 hypersensitivity reactions.8


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 glabellar lines.3

HA Concentration

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

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.

Swelling Capacity

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 augmentation.13 

Product Choice

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 lips.16


Figure 2. Before lip augmentation with a hyaluronic acid (HA) filler.


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 patient.9

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.


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  2. 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.
  3. 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 1):S25-S30.
  4. Bray D, Hopkins C, Roberts DN. A review of dermal fillers in facial plastic surgery. Curr Opin Otolaryngol Head Neck Surg 2010;18:295-302.
  5. Alam M, Gladstone H, Kramer EM, et al. ASDS guidelines of care: injectable fillers. Dermatol Surg 2008;34(Suppl 1):S115-S148.
  6. Graf J. Fillers: A dermatologic perspective. In: Saltz R, ed. Cosmetic Medicine and Aesthetic Surgery: Strategies for Success. St. Louis, MO: Quality Medical Publishing; 2009:311-324.
  7. Cantisano-Zilkha M, Haddad A. Facial fillers and volumizers. In: Cantisano-Zilkha M, Haddad A, eds. Aesthetic Oculofacial Rejuvenation. Cidade: Elsevier; 2010:97-118.
  8. DeLorenzi C, Weinberg M, Solish N, Swift A. The long-term efficacy and safety of a subcutaneously injected large-particle stabilized hyaluronic acid-based gel of nonanimal origin in esthetic facial contouring. Dermatol Surg 2009;35(Suppl 1):313-321.
  9. 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.
  10. Collins MN, Birkinshaw C. Physical properties of crosslinked hyaluronic acid hydrogels. J Mater Sci Mater Med 2008;19:3335-3343.
  11. Beer K, Lupo MP. Making the right choices: attaining predictable aesthetic results with dermal fillers. J Drugs Dermatol 2010;9:458-465.
  12. Ahmad J, Rozen SM, Rohrich RJ. The role of soft tissue fillers in cosmetic medicine: A plastic surgical perspective. In: Saltz R, ed. Cosmetic Medicine and Aesthetic Surgery: Strategies for Success. St. Louis, MO: Quality Medical Publishing; 2009:325-343.
  13. 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.
  14. Weinkle S. Injection techniques for revolumization of the perioral region with hyaluronic acid. J Drugs Dermatol 2010;9:367-371.
  15. Donath AS, Glasgold RA, Meier J, Glasgold MJ. Quantitative evaluation of volume augmentation in the tear trough with a hyaluronic acid-based filler: a three-dimensional analysis. Plast Reconstr Surg 2010;125:1515-1522.
  16. Matarasso SL, Carruthers JD, Jewell ML; Restylane Consensus Group. Consensus recommendations for soft-tissue augmentation with nonanimal stabilized hyaluronic acid (Restylane). Plast Reconstr Surg 2006;117(Suppl 3):3S-34S; discussion 35S-43S.
  17. Falcone SJ, Berg RA. Temporary polysaccharide dermal fillers: a model for persistence based on physical properties. Dermatol Surg 2009;35:1238-1243.
  18. Edsman K, Näsström J. Re: temporary polysaccharide dermal fillers: a model for persistence based on physical properties. Dermatol Surg 2010;36:569-571.