134 JOURNAL OF COSMETIC SCIENCE “aesthetic,” and “cosmetic techniques.” Any studies using fillers or medicinal products not containing HA were excluded. Research filters were applied for articles published within the last 25 years and written in English or Portuguese. Some of the articles were selected from the reference lists of previously read publications. RESULTS INTRINSIC PROPERTIES OF HA HA is a naturally occurring high-molecular-weight polysaccharide belonging to the glycosaminoglycan family and produced in the inner side of the cell membrane, with a natural lifespan in the human body of less than 3 days (24 hours–48 hours), since in its noncross-linked state it is quickly degraded by hyaluronidase in the liver (enzymatic degradation). Whether it is derived from animal or bacterial cultures, its structure is identical, consisting of repeating units of nonsulphated disaccharide, which include molecules of D-glucuronic acid and N-acetylglucosamine, linked by β-(1–4) and β-(1–3) glycosides.1-3,11,13,18,19 In each monomer, the HA molecule contains a carboxylic acid and a primary alcohol, which are important for recognition by hyaladherins, and an amide, which improves the adhesive properties of the molecule.12 Each disaccharide monomer has a molecular weight of around 400 Da, and the complete polymer can reach a total of 10 MDa. There is a proportionate relationship between molecular weight and the number of repeating disaccharides in a HA molecule, and the higher it is, the higher the gel’s viscosity. The difference between animal or bacterial HA resides solely in the length of the final polymer chain: bacterial-based HA is usually shorter and has a lower molecular weight than animal-based HA.14,16,18 Polymer chains of small and medium length usually hold immunostimulant, proangiogenic, and antiapoptotic properties, while larger polymers hold immunosuppressive and antiangiogenic ones.11,12 Hyaluronic acid’s properties can be divided into rheological and physiochemical. Within rheology, it’s possible to identify both viscoelasticity and cohesivity, while physiochemical properties refer to the cross-linking degree, the concentration of HA, the particle size and the water absorption capacity (as is shown in Figure 1). RHEOLOGICAL PROPERTIES Viscoelasticity. Rheology is the study of the flow and deformation of materials when subjected to certain forces. This study incorporates different manufacturing processes and HA filler Figure 1. The properties of hyaluronic acid.

135 HYALURONIC ACID AESTHETIC FILLERS properties.24 HA is a viscoelastic gel, which means it has a viscous component and an elastic one. These components, along with its cohesivity, are responsible for defining the gel’s capacity to flow through a needle (which decreases with the increase of viscosity) or to return to their original shape after deformation. This means HA will define the filler’s properties, such as malleability, extrusion force, lifting capacity, and tissue integration, which in turn will influence its clinical outcomes.14,25 The selection of a filler with appropriate characteristics corresponding to each patient also depends on the anatomical area as each area of the face is subjected to different mechanical forces that modify the shape, distribution, duration, and level of correction obtained. There are essentially two types of forces that will act upon the HA: the lateral shear/torsion, which acts in the horizontal plane that is parallel to the skin and the compressive or stretching force, which acts in a perpendicular plane to that of the skin.16,19,25,26 The filler’s cohesivity, which is responsible for tissue expansion according to a horizontal vector, is determined by the compressive forces. On the other hand, viscoelasticity and the elastic modulus (G’), which are responsible for tissue projection according to a vertical vector, are determined by the lateral shear forces.24,25 There are four essential parameters that define a HA gel’s viscoelasticity17-19,22,25027: • The shear modulus or complex modulus (G*) is the amount of energy it takes to deform the gel in the horizontal plane. This energy amount determines HA’s hardness. It represents the total resistance to deformation. • The viscous modulus (G’’) is the fraction of energy that dissipates after deformation, which confirms that the filler is unable to completely restore its initial shape after deformation. G’’ is clinically related to the filler’s injectability (the higher the G’’, the more difficult the extrusion). • The elastic/storage modulus (G’), on the other hand, is the fraction of energy that the filler retains after deformation (in other words, its capacity to resist deformation). Fillers with higher G’ values are better suited for deeper areas since they are firmer, unlike those with lower G’ values, which are softer and better suited for more superficial zones. Higher G’ values make a gel harder to inject than lower values. • Lastly, tan δ corresponds to the G’’/ G’ ratio and tells us whether a gel is more elastic or more viscous (if G’ is higher and the tan δ 1, then the elastic component is predominant, but if G’’ is higher and the δ 1, then the viscous component is predominant). Most injectable HAs have a lower tan δ, which means they’re usually more elastic than viscous. The less viscous gels show higher tissue integration and a more natural appearance, and are thus better suited for more superficial areas.25,28 Furthermore, these four parameters are influenced by the level of cross-linking shown by the filler. Higher levels of cross-linking usually mean higher levels of G* and G’ and lower levels of G’’.19,25,26,29 Even though free uncross-linked HA is quickly metabolized (therefore not contributing to the final clinical outcome), it does reduce the filler’s viscosity, allowing for an easier injection.14,18 It is the different rheological and chemical properties that make it possible to divide the HA fillers into two big groups. The monophasic/cohesive fillers (such as the Juvéderm line) are more homogenous and made up of cross-linked HA chains with varying molecular weights, which make them less elastic and more viscous, while the biphasic/granular fillers (such as the Restylane line) have reticulated HA particles dispersed in either noncrosslinked or very low cross-linked HA, which makes them more fluid and easier to inject. However, there is still debate among the scientific community regarding this division: some authors