Dr Tatiana Lapa and Mr Rishi Mandavia outline the pharmacology, rheology and application of hyaluronic acid dermal fillers
In 2015, hyaluronic acid (HA) dermal fillers accounted for more than 92% of all filler treatments in the US.2 A growth in HA filler popularity likely reflects their excellent safety profile, efficacy and ease of administration. This article provides a background to HA dermal fillers, including regulation, their physical characteristics and uses, as well as other commonly used FDA-approved classes of dermal filler.
In a report published in 2013, the Department of Health (DOH) highlighted the lack of regulation around dermal fillers as ‘a crisis waiting to happen’.1 In the UK, dermal fillers are classed as a device, rather than drug, and can be used for cosmetic purposes without being subject to CE standards, Care Quality Commission (CQC) regulation or the EU General Product Safety Directive.1
In the absence of regulation, practitioners often look towards guidance provided by the FDA. However, the FDA has only approved 16 HA fillers for specific indications; and it is widely acknowledged that practitioners work on the basis of clinical judgement rather than this guidance.3
HA is a naturally-occurring component of the extracellular matrix. It is a glycosaminoglycan (GAG) polymer consisting of repeat disaccharide units of glucuronic acid and N-acetylglucosamine. HA polymers vary considerably in length. The weight of HA polymers influence their behaviour within the tissues; polymers with high molecular mass are believed to reduce inflammation and angiogenesis, whilst polymers with low molecular mass interact to increase inflammation and angiogenesis.4
Approximately 50% of the body’s total HA is in the skin.5 HA acts as a scaffold for the extracellular matrix, providing rigidity, hydration and turgor whilst allowing cellular movement and regeneration.6 It is also important in protecting the skin from free radical damage, particularly against UVA and UVB.4 HA is rapidly metabolised in the tissues, with one third of total body HA being turned over daily.7,8
Variability in methods used to manufacture HA fillers have given rise to differences in properties such as degree of cross-linkage, particle size and concentration
Levels of HA are determined by the balance between enzymes that create it (synthase HAS1, HAS2 and HAS3) and those that break it down (hyaluronidases HYAL1, HYAL2 and HYAL3).6 Hyaluronidases are enzymes licensed for enhancing penetration of subcutaneous or intramuscular injections, local anaesthetics and infusions and reduce swelling.16
However, they are also widely used ‘off-label’ in aesthetic medicine to dissolve hyaluronic acid fillers. The enzymes can be classified by their mechanism of action: mammalian (endo-Beta- N-acetylhexosaminidase), leech/hookworm (endo-Beta-D-glucuronidase) and microbial (Hyaluronate lyase).17 The most commonly-used preparation in the UK is Hyalase, originating from sheep testes.18 However, microbial and human hyaluronidases appear to have advantages in terms of safety and reduced immunogenicity.16
HA dermal fillers consist of long chains of hyaluronic acid. Most dermal filler products will consist of HA cross-linked with a chemical such as 1,4-butanedioldiglycidyl ether (BDDE) for Restylane, Belotero and Juvéderm, divinyl sulfone (DVX) for Hylaform, 1,2,7,8-diepoxyoctane (DEO) for Puragen, and suspended in a physiological or phosphate-buffered solution.18 The product is then processed as a homogeneous gel or a suspension of particles in gel carriers.
Variability in methods used to manufacture HA fillers have given rise to differences in properties such as degree of cross-linkage, particle size and concentration. These properties are vital in determining the clinical performance of the filler.19 Chains of hyaluronic acid are linked using hydrogen bonds, forming stable complexes.9 This may provide some advantages in limiting the risk of hypersensitivity reactions, because of the lack of chemicals used in the manufacturing process may be more acceptable to some patients.
There is much debate over the clinical effectiveness of monophasic or biphasic hyaluronic acid fillers and it is likely that no single method is superior to another
HA fillers can be classified according to their particulate forms: either monophasic or biphasic gels. Monophasic gels consist of a single ‘phase’ of HA. They can be either monodensified, HA is mixed and cross-linked in a single step e.g. Juvéderm and Teosyal, or polydensified, HA goes through two stages of cross-linking e.g. Belotero. Biphasic gels such as Restylane and Perlane consist of two ‘phases’ of HA, cross-linked HA of a specific size which is then suspended in non-cross-linked HA acting as a carrier.20,21
There is much debate over the clinical effectiveness of monophasic or biphasic hyaluronic acid fillers and it is likely that no single method is superior to another, rather that the different physical properties of dermal fillers are more suitable for different clinical indications.
Rheology is the study of the physical characteristics that influence the way materials behave when subject to deforming forces. Once injected, fillers are subject to shearing, vertical compression and stretch from muscle movements, compression and gravity.22 It is our role as practitioners to understand the way fillers will behave when injected into a particular area or layer of the skin and to choose the most appropriate dermal filler to achieve the desired aesthetic result. Fillers used to treat different parts of the face have very different desirable qualities.
For example, when treating the deep subdermal layers of the cheeks, it is important that the filler gives good volume and projection without spreading too easily through the tissues. Conversely, when injecting into superficial dermal layers, it is important that fillers can easily spread through the tight connective tissue in order to sit smoothly in the upper layers of the skin. A number of factors affect the physical characteristics of HA dermal fillers. These include:
There are other fillers available that are not made from HA. These are outlined below.
Polymethylmethacrylate (PMMA) are non-absorbable microspheres which, when injected into the subdermal plane, stimulate fibroblasts to encapsulate each microsphere and therefore augment tissue volume by fibroplasia.10
Artefill, the only FDA-approved PMMA filler, is a suspension of PMMA beads in bovine collagen. It is approved for the correction of nasolabial folds and acne scars.3 The earlier versions of Artefill caused unacceptably high rates of granuloma formation (up to 2.5%).10 Skin testing is generally advisable prior to treatment due to risk of sensitivity to bovine collagen. Furthermore, the filler is permanent and requires surgical removal in the event of complications or need for correction.
Collagen can be derived from porcine, bovine or human donors. Collagen fillers can be mixed with PMMA or another gel carrier. These fillers are approved for a variety of uses including injection superficially for the correction of scars and wrinkles, as well as deep dermal injections for the correction of deep folds and facial contours.
PLLA is an absorbable polymer which stimulates fibroblast production and generation of collagen, and results usually last for around two years.11 For optimal results, multiple treatment sessions are often required. The main concern with PLLA is a delayed development of palpable nodules. However, a study by Woerle et al. on 300 patients followed-up over five years reported that with adequate dilution, longer hydration time, addition of lidocaine and proper handling of the vials, the incidence of nodule formation is below 1%.27 Similar recommendations were made by Alessio et al.28 The only filler that contains PLLA is Sculptra, which was approved by the FDA in 2004 for the correction of facial lipoatrophy in patients with HIV.12
Radiesse is the only CaHA filler approved by the FDA. It was first approved in 2006 for the correction of facial lipoatrophy in patients with HIV, and for moderate wrinkles and skin folds.3 Radiesse is composed of 30% calcium hydroxylapatite microspheres suspended in a 70% gel carrier. It is a synthetic compound, similar in structure to bones and teeth. Radiesse is non-immunogenic, hence does not require patch testing, and is fully degraded and excreted by the body. The corrective results last for approximately 12 months.11
Whilst this article aimed to address hyaluronic acid fillers and other commonly used FDA-approved classes of fillers, there are other less common types of dermal filler that have not been addressed in this article. Some of these include: polycaprolactone, autologous fat transfer, dextran particles, polyacrylamide gel and agarose gel.
|Area ||Aim|| Desirable properties ||Rheological properties|
• Deep dermal or subdermal injection
• Restoring volume
• Achieving projection
• Withstand shear deformation
• Withstand compression
• Minimal displacement
• Maintain shape
• Low viscosity (for ease of injection)
• High elasticity
• Medium-high cohesivity e.g. Belotero Volume, Juvéderm Voluma, Restylane Lyft, Teosyal Ultimate, Teosyal Ultra Deep
Fine Lines and Lips
• Restoring volume in intradermal and sub-dermal planes
• Easy moulding and spread of product
| Low viscosity (for ease of injection)|
• Low-medium elasticity
• Low cohesivity e.g. Belotero Balance, Juvéderm Volbella, Restylane Kysse, Restylane Refyne, Teosyal RHA 2, Teosyal Global Action
• Restoring volume in deep dermal or subdermal planes
• Easily mouldable
• Minimal projection
• Low viscosity (for ease of injection)
• Moderate elasticity
• Low-medium cohesivity
e.g. Belotero Intense, Juvéderm Volift, Restylane Refyne, Teosyal Global Action, Teosyal RHA 3
Nose and Chin
Nasal and chin projection
• Minimal lateral spread
• Maximal vertical projection
• Low viscosity (for ease of injection)
• High elasticity
• High cohesivity e.g. Belotero Volume, Juvéderm Voluma, Restylane Lyft, Teosyal Ultimate
Table 1: The desirable physical characteristics of dermal fillers according to treatment areas.
Although dermal fillers are widely used and generally considered safe, there are certain considerations prior to treatment. Contraindications such as active infection and known allergy to the filler product or constituents such as lidocaine, should be identified.24
Additional factors that may impact on treatment and recovery following treatment should be identified and optimised if possible. This includes physical (e.g. immunosuppression, autoimmune disease, dermatological problems, diabetes) and psychological health (e.g. body dysmorphia, depression, anxiety) health problems.
To a greater or lesser degree, all dermal fillers are associated with certain risks. Beyond the common complications of redness, bruising and swelling, there are important risks that patients should be consented for. Infections following filler treatment are uncommon25 but may be caused by bacteria, viruses, fungi or even biofilm mediated.13 Infective agents can hide within a biofilm, protected from the reach of the immune system and antibiotics, causing granulomatous inflammation, abscesses, nodules and recurrent infection.13 Biofilms are resistant to penetration with antibiotics, hence treatment often requires surgical debridement or excision of the foreign material, thus highlighting the major advantage of the easily-dissolved HA fillers.
An abnormal tissue reaction can lead to the formation of nodules or granulomatous inflammation. Granulomatous inflammation is a type 4 hypersensitivity reaction, mediated by macrophage or T-cell interaction.14 Treatment may involve cortisone injections, triamcinolone acetonide injections or topical use of 5-florouracil.13 In some cases, surgical excision may be necessary. Anaphylactic reactions, although rare, are a possibility. Prompt action can save patients with anaphylaxis and therefore up-to-date anaphylaxis management training and equipment are vital for any practitioner practising injectable procedures.
A disruption of the blood flow through a tissue compartment due to arterial embolisation (AE) impeding arterial blood flow, can cause pain, blanching, mottling, tissue necrosis and ulceration. Embolisation of filler product has been reported, leading to complications such as extensive necrosis, blindness and stroke.15
Strategies to reduce the risk of intravascular injection of filler include:
Hyaluronic acid is present in abundance in the skin. To make HA a useable product in cosmetic treatments, HA is stabilised with cross-linking proteins, usually 1,4-BDDE. This makes HA more resistant to degradation and therefore enables it to last for several months in the skin.
Different technologies used for manufacturing HA dermal fillers have facilitated the development of fillers with very different properties. Furthermore, non-HA fillers have certain advantages such as a longer duration of effectiveness and generation of collagen in the skin. Using dermal fillers with the most suitable properties for the indication can help clinicians get the best results from their treatments.