What Is Hyaluronic Acid?

What Kind of Molecule Is Hyaluronic Acid?

Hyaluronic acid is a glycosaminoglycan: a long, unbranched chain made of repeating sugar units. It is found widely in the body and is one of the main components of the material that fills the spaces between cells (the extracellular matrix).

The tissue that contains the most of this molecule is the skin: about half of the body's total hyaluronan (another name for hyaluronic acid) is reported to be in the skin. For a long time it was thought to belong only to the dermis (the middle layer of the skin), but it has been shown to be present in the epidermis (the outer layer of the skin) as well.

The molecule's defining property is that it holds water. Because it can hold a large amount of water, it is reported to play a key role in the skin's moisture balance and elasticity. As the chain binds water around itself, the space it takes up grows; what gives tissue its fullness is not the molecule's own mass but the water it holds.

Different sizes of the same molecule do not all do the same job. Hyaluronic acid of different molecular weights is reported to have different effects on cellular processes, which is why specific molecular weight ranges are chosen depending on the purpose. In short, hyaluronic acid is the name not of a single substance but of a family of molecules.

How Long Hyaluronic Acid Stays in the Tissues

The hyaluronic acid in tissue is not a deposit that stays in place; it is constantly being made and constantly being broken down. Hyaluronan in the skin is reported to turn over quickly, with a half-life (the time it takes for the amount to fall by half) of less than one day.

Its breakdown is carried out by enzymes called hyaluronidases. Research has shown hyaluronidase activity in healthy human skin and has mapped in detail where HYAL1 and HYAL2, the proteins that break down hyaluronan, are found in the skin. Contrary to earlier assumptions, proteins called TMEM2 and CEMIP were found not only in the dermis but also in the epidermis.

In practice, these two facts lead to one conclusion: hyaluronic acid placed in tissue in its free form cannot stay there for long, because the tissue quickly breaks it down with its own enzymes. For an injected material to stay in the tissue, the molecule has to be converted into a structure that differs from its natural form.

The amount of hyaluronic acid in the skin is reported to decrease with age, starting around the age of 25, and external factors are reported to affect both its production and its breakdown. What decreases is not just a substance but the water that substance holds.

What Hyaluronic Acid in Creams Does

The hyaluronic acid in creams, serums and masks is a free, non-cross-linked molecule. When applied to the skin, it works mainly at the surface.

The effect of hyaluronic acid applied to the skin is explained not by a single mechanism but by several at once: hydrating the skin, interacting with the skin's outermost horny layer, forming a film that clings to the surface, behaving as both elastic and fluid (viscoelastic), and pathways that work through receptors on the cell surface. Molecular weight and chemical modifications change this behaviour. Separate delivery systems, such as hydrogels, nanoemulsions, microneedles and liposomes, are designed to reach different layers.

From a clinical point of view, hyaluronic acid applied to the skin is reported to be an effective and well-tolerated cosmeceutical ingredient for skin hydration and signs of ageing. A cosmeceutical is a skincare product with active ingredients that sits between a cosmetic and a medicine. So it would not be right to say that creams do not work; what they do is clear.

However, a cream does not add volume beneath the skin; the applied molecule does not form a lasting gel inside the tissue. What a cream does and what an injected gel does cannot be grouped under the same heading, because the difference between them is not a difference in dose but a difference in material.

Why Cross-Linking Is Needed

Most injectable hyaluronic acid products are not a free molecule but a gel. The gel is made by linking the chains to one another with chemical bridges; this process is called cross-linking.

Cross-linking changes two things at once: the material turns from a free-flowing solution into a gel that behaves somewhere between a solid and a liquid, and it becomes more resistant to breakdown by enzymes. Heavily cross-linked gels are reported to have a firmer consistency and greater resistance to enzymatic breakdown.

The manufacturing method also classifies products. Depending on the cross-linking process, gels are divided into biphasic (two-phase) and monophasic (single-phase) gels. Biphasic gels are lightly cross-linked, rely largely on the chains naturally entangling with one another and show greater elasticity; monophasic gels are made with more extensive chemical cross-linking. This difference changes the gel's molecular weight, structure and behaviour in the tissue all at once.

Cross-linking also has a safety aspect: it is emphasised that completely removing any cross-linking agent left in the gel after manufacture is crucial for safety.

In short, the hyaluronic acid in a cream and an injected cross-linked gel share the same chemical backbone but behave differently physically. Seeing the same name on the labels of two products does not make them the same material.

How a Gel's Behaviour Is Measured

Cross-linked gels behave like both a solid and a liquid. The science that studies this dual behaviour is called rheology; rheology measures how a material changes shape and how it flows under force.

The main measurements are:

• Elastic modulus (G′) is the gel's solid-like resistance to changing shape.
• Loss modulus (G″) is the gel's fluid-like component.
• tan δ is the ratio of the two and shows how fluid the material's behaviour is.
• G* is the combination of the two.

Because a gel's behaviour changes with the speed at which stress is applied, comparative studies measure these values over a set frequency range.

Alongside rheology, cohesivity is a separate property: the gel's tendency to hold together. Correcting volume deficits in the face with filler is reported to be linked mainly to the gel's viscoelasticity (its behaviour between that of a solid and a liquid) and its cohesivity. According to research, these two properties determine the gel's resistance to changing shape sideways and vertically; by controlling how the gel spreads in the tissue, they also affect how it integrates with the tissue.

The third important property is the yield point: the threshold at which the gel starts to flow. Hyaluronic acid gels are reported to show viscoplastic as well as viscoelastic behaviour. This behaviour is said to allow the gel, once the yield point is exceeded, to pass through a fine needle, be shaped and integrate with the tissue. In other words, a gel's ability to be injected and its ability to stay in place in the tissue are two sides of the same property.

How G′ and Cohesivity Separate Product Classes

What these measurements mean in practice can be put in one sentence: gels made from the same molecule are not interchangeable.

Gels with a high elastic modulus and a low tan δ value (that is, firm, resistant gels) are reported to suit treatments that need structural support and forward projection. Gels with low elastic resistance and a high tan δ value (that is, more fluid gels) are said to adapt better to the changing shear stress in superficial and mobile tissues.

However, the same properties are said to affect not only the gel's performance but also its tendency to cause complications. These complications include filler migration, the formation of nodules (small lumps under the skin), inflammation and vascular occlusion (a blocked blood vessel). So a firm gel cannot be said to be superior; firmness is not an advantage but a choice about where the gel is placed.

There is not yet a standard way of comparing products with one another. A study that examined 23 commercial gels from five manufacturers using the same methods based its comparison on two groups of measurements: dynamic measurements (rheology and gel content) and consistency measurements (injection force, water uptake and gel particle size). The researchers emphasise that the wide range of products makes objective comparison difficult and that manufacturers should increase transparency by using common test methods.

This is why a G′ value given for a gel is not meaningful on its own if you do not know which method was used to measure it.

Non-Cross-Linked Injectable Products

Not every injectable hyaluronic acid product is cross-linked. There are also non-cross-linked injectable products; these are used not to add volume but to target the skin itself directly.

In a study that compared the rheology of 28 commercial gels (3 non-cross-linked and 25 cross-linked), the two groups had clearly different profiles. Under mechanical stress, the rheological properties of the non-cross-linked products changed much more than those of the cross-linked products. The researchers interpret this as making non-cross-linked products better suited to structural support within the skin (intradermal) and to treatments beneath the skin (subcutaneous), and cross-linked products better suited to volumising injections into deep tissue.

In the clinical results, the limits are clearly visible. An analysis that pooled studies on the effect of hyaluronic acid injections on skin ageing found a significant improvement in hydration and radiance compared with control groups, but no significant difference in elasticity or in the melanin index (a measure of the pigment that gives skin its colour). The researchers note that more research is needed on this subject.

In short, hyaluronic acid does not change every finding. Both what it changes and what it does not change have been measured; it is important to know both.

Face Gels and Body Gels Are Not the Same

The rheological properties expected of a gel vary by area. Gels used on the body are said to face different conditions from gels used on the face: larger volume deficits and a higher mechanical load. Because rheology was for a long time studied mainly in facial tissues, there is a gap in knowledge about the body.

A study that examined four commercial body gels under standard laboratory conditions found no significant difference in physicochemical properties such as pH, osmolality, ion concentration, clarity and swelling factor, but found clear differences in rheological properties. Gels with a high elastic modulus and a high complex modulus were reported to be better suited to treatments under high load; however, the researchers stated that these findings need to be confirmed in a long-term clinical setting.

The practical conclusion is this: a gel chosen for the face is not automatically suitable for the body. When the area changes, the choice of material changes too, and that choice is based on the mechanical conditions of the area, not on a product catalogue.

Reversibility: Hyaluronidase

The most concrete feature that sets hyaluronic acid gels apart from other types of filler is that they are reversible. Hyaluronidase is an enzyme that breaks down hyaluronic acid, and it can dissolve injected gel. This enzyme's ability to reverse complications of hyaluronic acid (HA) fillers is said to have played an important part in these treatments becoming widespread.

However, reversibility is treated not as a convenience but as something that must be managed carefully. Non-urgent situations — the Tyndall effect (a bluish tint under the skin), non-inflammatory nodules, and allergic and hypersensitivity reactions — are treated with a low or moderate dose. Emergencies such as vascular occlusion (a blocked blood vessel) and vision loss need treatment without delay and with a high dose. It is also noted that controlled data on this subject are limited and that knowledge is based largely on clinical experience and expert opinion.

The gel itself is also part of this equation. Heavily cross-linked gels have been reported to be more resistant to enzymatic breakdown; in other words, reversibility is not equally easy with every gel.

Reversibility is an option, not a guarantee. The enzyme also has its own dose, timing and risks; the doctor carrying out the treatment assesses the dose, timing and risks. Filler dissolving is a separate treatment in its own right.

What This Guide Does Not Cover

This guide does not say how long the effect lasts. The US Food and Drug Administration (FDA) states that absorbable fillers are absorbed by the body over time and that the treatment may need to be repeated to keep the effect. It also states that how long the effect lasts depends on both the filler material and the area treated. Giving a single figure would contradict this information.

Brand names are not included either, because there is not yet a common test method that would allow products to be compared objectively; scientific publications also say that transparency needs to improve.

This guide also does not cover who can have this treatment. What the molecule is and whether it can be used for you are separate questions; the second is answered at a consultation, not in an article.

Treatments Offered Here

At the clinic, hyaluronic acid (HA) fillers are used on areas of the face and body. Collagen-stimulating fillers, botulinum toxin, mesotherapy and thread lifting with dissolvable threads are also among the treatments carried out at the clinic. Dissolving filler with hyaluronidase is also included.

Which gel is used in which layer depends on what your doctor finds at your consultation, not on this guide. This guide explains what the material is; it does not tell you what should be done for you. Your consultation shows that, and the decision is yours.