Characteristics of HA Dermal Fillers

In the first of a two-part article, Dr Souphiyeh Samizadeh discusses the basic characteristics of hyaluronic acid fillers to aid product selection

Abstract
Hyaluronic acid (HA) dermal fillers have become very popular agents for facial rejuvenation. There are a number of HA fillers available on the market with continuous evolution of products and product ranges, technology and injection strategies and approaches. The choice of product can become confusing for practitioners with so many different brands, characteristics and strongly marketed unique selling points of each product. In this paper, basic characteristics and rheology of the HA fillers are discussed to aid selection of appropriate products for the correct indications, taking into consideration patient factors.

Introduction
HA is found in nearly all biological fluids and tissues, including synovial fluid and extracellular matrix. Both vertebrates and the capsule of some bacteria contain HA.1 It has a high molecular mass and has unique biological, viscoelastic and rheological properties, making it an attractive biomaterial for various medical applications. It is used in clinical medicine, therapeutics and aesthetic medicine. Examples of use in clinical medicine include use as a diagnostic marker for many diseases (e.g. cancer), as a drug delivery agent, as a gene therapy vector, and in rheumatoid arthritis and liver pathologies. Its other clinical uses include, but are not limited to, use in arthritic patients (intra-articular injection of HA to supplement impaired synovial fluid), neurosurgery, ophthalmological surgeries, reconstruction of soft tissue, otological surgeries, cosmetic regeneration and wound healing.2-5 The highest content of HA in the human body is found in synovial fluid, followed by the umbilical cords, and the eye. The highest concentrations are found in the skin. The HA acts as a matrix and has critical functions that include: increasing dermal volume and compressibility, scavenger of free radicals, protective, structure stabilising and shock absorption, and it also influences cell proliferation, differentiation, and tissue repair.1,6 In medical aesthetics, HA dermal fillers are highly popular as an immediate, predictable, and natural-looking result can be achieved with the use of correct products and correct techniques. In addition, their reversibility via enzymatic digestion with hyaluronidase makes them a favourable product. This makes HA products relatively safer than non-HA dermal fillers with improved tolerability profile.7 With the evolution of the products, readily available scientific information regarding both products and ageing changes, the technique and approaches for the clinical use of HA dermal fillers have also changed. The face has a complex anatomy and is a dynamic structure. Hence, any product that is implanted in the face would be subjected to intrinsic and extrinsic forces that vary in terms of intensity and frequency. Therefore, the characteristics of dermal fillers for various indications and facial regions vary. These characteristics should be taken into consideration when treating other areas such as hands and décolletage.7 There is no general filler that is suitable for every treatment, every facial or body area, or for every individual. There are many factors that may influence HA filler performance and need to be understood by practitioners. Some of these include the total HA concentration (cross-linked and uncross-linked), particle size, the cross-linking method/agent, modulus, swelling/water resorption, and extrusion force.7-10 Prior to being able to compare various available dermal fillers, it is important to understand what various terms used to describe characteristics of HA dermal fillers mean. In this paper, the focus is understanding these terms and in a following paper, these characteristics for commonly available products in the UK will be compared.

Product architecture
Hyaluronic acid (also known as hyaluronan, sodium hyaluronate, HA), is a glycosaminoglycan (a linear water soluble polysaccharide, made up of polymeric carbohydrate molecules – long chains of monosaccharide) that is formed from disaccharide units containing N-acetyl-d-glucosamine and glucuronic acid (Figure 1).1

Properties and characteristics
Rheological properties of dermal fillers may help in understanding the differences between HA products in terms of their physical properties which are correlated to their performance. The basic definition of properties and characteristics used to describe dermal fillers can be found on the next page.7,8

Viscoelastic
Viscoelastic properties can be described by four main rheological parameters:11
• G: overall viscoelastic properties or ‘hardness’ – resistance to distortion • G′: elastic properties • G″: viscous properties • δ: the ratio between the two above characteristics (viscous and elastic) Elastic (solid) and viscous (liquid) components of a gel makes the gel/product viscoelastic (G). Viscoelasticity of a product is determined during the design and manufacturing of the product.8,11

Elastic modulus
This is the measure of the gel’s ability to resist distortion under pressure applied.7,10
• Known as G prime
• Abbreviation: G′
• A quantitative measurement of stiffness/firmness of the gel
• Ability to resist distortion under applied pressure
• Affected by cross-linking (discussed below) and gel concentration
As the G’ increases, the gel deforms less under pressure. Therefore, a product with a high G’ can resist deformation under pressure and external forces much better than those with a low G’. It will also have a higher tissue-lifting capacity.7,10

Viscous modulus/loss modulus
Viscous modulus is the measure of the flow properties of a gel. It is a function of concentration of cross-linked HA.12
• Known as G double prime
• Abbreviation: G″
• Flow properties
This property is an indication of how a product is affected by shear forces during extrusion through the needle, injection and post implantation.7

Viscosity/Complex viscosity
This is the capability of the fluid phase to resist shearing forces.7,10 A
gel with high viscosity is more resistant to flow, or movement, and
is more difficult to spread, meaning that it is likely to stay at the site
of implantation.10
• Symbolised as η*

Cohesive
Cohesivity is the degree of attraction between cross-linked HA units. It characterises behaviour of a product as a gel post implantation.11 Dermal fillers, in particular those injected to the face, are subjected to constant internal and external forces including compressive forces, for example lying on a pillow. HA fillers with higher cohesivity can resist deformation and maintain shape of implanted gel deposit. HA fillers that have lower cohesivity but the same G’ lose projection easier than those with higher cohesivity.11

Cross-linking
Cross-linking refers to the action of creating a bond between two strands of HA. HA is a water soluble polymer and therefore needs to be modified to improve its mechanical properties, prevent rapid degradation and improve longevity.8,13 Non-cross-linked and unmodified HA has a short half-life. Following intradermal injection, the half-life is only a few weeks.7 Various cross-linking strategies aim to improve biomechanical properties without changing the biocompatibility and also the biological activity of HA;8 dialdehydes and disulphides, and diglycidyl ethers are examples of cross-linkers used.14 Diglycidyl ethers are one of the most common cross-linkers (used in Restylane, Juvéderm, and Belotero).8,15 At times, one end of the polymer will not be cross-linked. This results in one end being cross-linked and the other end being a pendant. The pendant groups are more likely to influence and contribute to gel water absorption and swelling than to the longevity of the product.8 Increasing the cross-link density of HA makes the overall polymer network stronger and hence, enhances the gel hardness/stiffness and longevity.8

HA concentration
HA concentration is expressed in mg/ml and it consists of insoluble HA, soluble-free HA (unmodified and modified soluble HA). The soluble-free HA does not contribute towards longevity. It is added as a lubricant that facilitates the extrusion of the gel through fine-bore needles.8 Therefore, the concentration of cross-linked and free H is important to be understood. Higher concentration of HA means a higher volume expansion capacity, and also may be linked with increased longevity.9

Water absorption
HA is a water-loving molecule (strongly hydrophilic).16 Water absorption abilities of HA molecules are dependent on the 3D structure. Therefore, more water gets bound as the length of HA molecules increases. This is clinically relevant as this means the dermal fillers can absorb water and hence swell post injection. This ability is dependent on factors including the HA concentration and amount of cross-linked HA. In addition, the process for HA gel hydration employed by companies has an effect. This should be taken into account, as more water will be absorbed and under-correction maybe needed for dermal fillers that have not been fully hydrated during manufacturing.8

Particle size and particle size distribution
The particle size is one of the factors that influence the extrusion force. The higher average particle size means extrusion of the gel through fine-bore needles becomes more difficult. Distribution of particles is also important. It can result in sporadic flow or an interrupted flow of the product through the needle and less control over product placement can occur. The uniformity of the size of the particles is preferred to avoid the mentioned problems.8

Biphasic gels

Biphasic gels contain cross-linked HA of selectively sized particles and non-cross-linked free HA used as a carrier. The Restylane range is an example of a biphasic product.16,17

Monophasic gels
The molecular weight of HA varies in these gels. They contain
high-molecular-weight HA and low-molecular-weight HA in varying
amounts and, in some cases, varying degrees of cross-linkage.
Monophasic gels contain a single phase of HA with a single density.
An example of monophasic gel is the Juvéderm range. This range of
products consists of smooth hydrogenous gels produced through
the Hylacross technology.16 The proprietary Hylacross technology
refers to the fact that the ‘sizing’ process is not part of the Juvéderm
technology. The sizing process is where cross-linked HA is pushed through a screen that is specially sized and is broken into pieces which are sorted into various dermal fillers.18 Monodensified dermal fillers are cross-linked once. Different ranges and families of monophasic monodensified fillers are available depending on their manufacturing technology. Examples include the Hylacross technology (e.g. Juvéderm Ultra),20 or the Vycross technology (e.g. Juvéderm Volbella), containing mainly low molecular weight HA, some high molecular weight HA with improved crosslinking20 and the cohesive monophasic polydensified gels (Belotero range) with a matrix that contains higher and lower cross-linking concentrations of HA.21 Polydensified dermal fillers comprise a single phase of HA that is cross-linked continuously. The cohesive polydensified matrix (CPM) technology is used for their production, which produces a gel with non-uniform cross-linking and molecular weight and lower viscosity (Belotero products).16,22

Conclusion
There are numerous HA-based dermal fillers available in the UK. These have a wide variety of properties which independently or in combination have direct, indirect and extensive effect on their use, indications, contraindications and clinical outcomes. An understanding of these properties, in addition to clinical experience, will result in the correct choice of product, for the correct indication for each individual patient and hence optimal aesthetic results. No single property or parameter can be used for the choice of a dermal filler, a careful consideration of all gel properties is essential for the correct choice of product, understanding the product’s performance and for helping set and manage patients’ expectations. It should be kept in mind that the clinical results are directly dependant on the HA dermal filler characteristics, patient factors and the response of the patient. Patient satisfaction and the final outcome depends on the product properties, placement technique, and the biological patient response.

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