Edited by:
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Dr. Alessandro Vecchi, Molecular and Industrial Biotechnologist – Research, formulation and regulatory affairs.
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Arianna Gaudioso, Qualified Cosmetic Informant
Table of Contents
What does molecular weight mean?
To understand why there are different types of hyaluronic acid, we need to start with its structure.
Hyaluronic acid is a polysaccharide, meaning a long molecule composed of repeating sugar units. In its case, these units are alternately formed by glucuronic acid and N-acetylglucosamine.
We can imagine it as a long chain.
The more elements make up this chain, the larger the molecule will be and the higher its molecular weight.
Molecular weight is generally expressed in Dalton (Da) or, more frequently when referring to hyaluronic acid, in kilodaltons (kDa).
1 kDa corresponds to 1,000 Daltons.
A 20 kDa hyaluronic acid is therefore a much smaller molecule than a 1,000 or 2,000 kDa hyaluronic acid.
This difference is not merely numerical.
The size of the molecule influences important properties such as:
- the ability to form a film on the skin's surface;
- interaction with water;
- the ability to cross the stratum corneum;
- distribution in the different layers of the epidermis;
- certain biological interactions with skin cells.
This is precisely why two cosmetics, both containing hyaluronic acid, can behave differently.
Is there an official classification?
There is no universally accepted classification that precisely defines where high molecular weight ends and where medium or low molecular weight begins.
The ranges can vary between scientific publications.
For this reason, rather than rigidly focusing on definitions, it is useful to understand a general principle:
reducing the molecular weight progressively changes the properties of hyaluronic acid and its ability to distribute within the skin.
Skin penetration studies, for example, have directly compared fractions of 1,000-1,400 kDa, 100-300 kDa, and 20-50 kDa, highlighting different behaviors.
Scientific study: Human skin penetration of hyaluronic acid of different molecular weights
High molecular weight hyaluronic acid
High molecular weight hyaluronic acid consists of particularly long chains and, therefore, large molecules.
Precisely because of their size, these molecules have a very limited ability to cross the skin barrier.
Once applied to the skin, they therefore remain predominantly on the surface and in the stratum corneum, i.e., the outermost part of the epidermis.
This does not mean they are less effective. It simply means they perform a different function.
What does it do on the skin?
High molecular weight hyaluronic acid has important film-forming and moisturizing properties.
On the skin surface, it contributes to the formation of a thin hydrophilic film capable of retaining water.
Greater hydration of the stratum corneum makes the skin softer and more flexible and can visibly improve its surface.
The cosmetic result is skin that appears:
- more hydrated;
- softer;
- smoother;
- temporarily more plump.
The effect on fine superficial lines is mainly linked to hydration: when the stratum corneum contains an adequate amount of water, the skin surface appears more uniform.
Does it penetrate the skin?
A study published in Skin Research and Technology used Raman spectroscopy to track the skin penetration of hyaluronic acid with different molecular weights.
Hyaluronic acid at 1,000-1,400 kDa did not show the same ability as smaller molecules to cross the stratum corneum, remaining predominantly in the most superficial layers.
Medium molecular weight hyaluronic acid
As the chain length decreases, the behavior of hyaluronic acid begins to change.
Molecules of intermediate size retain good moisturizing properties, but may show a greater ability to at least partially cross the stratum corneum.
We can therefore consider them an intermediate level between the predominantly superficial action of very large molecules and that of low molecular weight fractions.
What does it do on the skin?
Medium molecular weight hyaluronic acid can contribute to hydration not only on the surface, but also in the most superficial layers of the epidermis.
Increased hydration can help improve:
- elasticity;
- softness;
- turgor;
- smoothness of the skin surface.
What do the studies show?
In the previously cited Raman spectroscopy study, hyaluronic acid molecules between 100 and 300 kDa were able to cross the stratum corneum.
Their behavior was therefore different from that of 1,000-1,400 kDa hyaluronic acid.
Low molecular weight hyaluronic acid
By further reducing the chain length, low molecular weight hyaluronic acid is obtained.
Its smaller size generally allows it to cross the barrier of the stratum corneum more easily and distribute more effectively in the epidermal layers.
It is precisely this characteristic that has attracted particular interest in cosmetological research.
What does it do on the skin?
The action of low molecular weight hyaluronic acid is not limited to forming a film on the surface.
Its greater penetration capacity allows smaller molecules to distribute in the epidermal layers and contribute to hydration at this level.
This can affect cosmetic parameters such as:
- hydration;
- elasticity;
- turgor;
- appearance of fine wrinkles.
Some specific low molecular weight fractions have also been studied for their interactions with keratinocytes and with the cellular structures of the epidermis.
A study on reconstructed human epidermis observed, for example, that an HA of about 50 kDa had different characteristics compared to larger molecules and was associated with changes in the expression of some genes involved in keratinocyte differentiation and intercellular junctions.
However, it is important not to generalize these results.
Simply stating that "all low molecular weight hyaluronic acid stimulates cells" would be scientifically too imprecise: the activity depends on the specific molecular weight, concentration, and experimental model used.
How does penetration change with molecular weight?
One of the most interesting questions is precisely this:
how much can hyaluronic acid, applied through a cosmetic, penetrate the skin?
For a long time, hyaluronic acid was considered a molecule too large to cross the stratum corneum.
This statement is especially true for high molecular weight forms, but it cannot be applied indiscriminately to all HA sizes.
The study by Essendoubi and collaborators compared hyaluronic acids belonging to three different molecular weight ranges:
- 1,000-1,400 kDa
- 100-300 kDa
- 20-50 kDa
Using Raman micro-imaging, researchers observed that hyaluronic acids between 20 and 300 kDa were able to cross the stratum corneum, while the high molecular weight fraction of 1,000-1,400 kDa showed much more limited permeability.
This means that the ability of hyaluronic acid to penetrate the skin depends significantly on the size of the molecule.
| Molecular Weight | Prevalent behavior |
|---|---|
| High MW | Remains predominantly on the surface and in the stratum corneum. |
| Medium MW | Can partially cross the stratum corneum and distribute in the epidermis. |
| Low MW | Shows a greater ability to cross the stratum corneum and distribute in the epidermal layers. |
The table represents a useful simplification for understanding. Skin penetration also depends on the formulation, concentration, characteristics of the raw material, and the experimental model considered.
Which molecular weight is best?
At this point, it might seem logical to conclude that low molecular weight hyaluronic acid is always better.
In reality, this is not the case.
Greater penetration does not necessarily mean greater effectiveness.
Different molecular weights perform different functions.
High molecular weight hyaluronic acid is particularly useful on the skin's surface, where it exerts an important film-forming and moisturizing action, helping to maintain the hydration of the stratum corneum.
Intermediate fractions can combine the moisturizing effect with a greater capacity for epidermal distribution.
Low molecular weight molecules, on the other hand, can more easily reach the layers of the epidermis.
In other words, high and low molecular weight do not necessarily have to be considered competitors.
They can be complementary.
And it is precisely this principle that makes the use of multiple molecular weights within the same formulation interesting.
But do we have evidence that different molecular weights actually produce different results on the skin?
What do clinical studies tell us?
One of the most interesting studies on the subject directly compared the cosmetic efficacy of hyaluronic acids with different molecular weights.
The study, published in the Journal of Drugs in Dermatology, involved 76 women aged between 30 and 60 with periorbital wrinkles.
Formulations containing 0.1% hyaluronic acid with five different molecular weights were used:
- 50 kDa;
- 130 kDa;
- 300 kDa;
- 800 kDa;
- 2,000 kDa.
The formulations were applied twice a day for 60 days.
A vehicle cream was applied to the other eye as a control.
What were the results?
After the treatment period, the formulations containing hyaluronic acid led to an improvement in skin hydration and elasticity.
But the most interesting result concerns the molecular sizes.
Formulations containing 50 and 130 kDa HA showed a significant reduction in wrinkle depth compared to the vehicle cream after 60 days.
The study therefore suggests that molecular weight can influence not only the penetration capacity of hyaluronic acid, but also some of the cosmetic results observable after continuous use.
However, it is important to interpret this data correctly.
Topically applied hyaluronic acid should not be compared to an injectable filler.
The reduction in wrinkle depth observed in the study refers to a continuous cosmetic treatment and may be related to the overall effects on the skin, including hydration, elasticity, and epidermal distribution of HA.
So is it better to use a single molecular weight or multiple molecular weights?
In light of what we know, looking for a single "best molecular weight" is probably too simplistic a way to approach the issue.
High and low molecular weight hyaluronic acid do not perform exactly the same function.
The former acts predominantly on the surface.
The latter can reach the epidermal layers more effectively.
A formulation that rationally uses different molecular weights can therefore exploit complementary mechanisms:
on the surface, promoting hydration of the stratum corneum and film formation;
in the epidermal layers, thanks to smaller molecular fractions capable of crossing the stratum corneum more effectively.
This does not mean, however, that a cosmetic claiming "5 types," "7 types," or "10 types" of hyaluronic acid is automatically better.
The number of forms present in the formula says little if we also don't know:
- their molecular weight;
- their concentration;
- the quality of the raw materials;
- the vehicle in which they are formulated.
From a scientific point of view, therefore, it is not simply how many hyaluronic acids are used, but which ones are used and why.
Conclusions
Simply talking about "hyaluronic acid" only describes one part of the characteristics of this ingredient.
Its molecular weight significantly influences its behavior on the skin.
High molecular weight molecules remain predominantly on the skin surface, where they perform an important film-forming and moisturizing action.
Reducing molecular size increases the ability of hyaluronic acid to cross the stratum corneum and distribute within the epidermis.
Available studies also show that specific molecular weights can lead to different results from a cosmetic perspective.
This does not mean that there is a universally superior molecular weight.
High, medium, and low molecular weights can perform different and complementary functions.
And it is precisely this complementarity, rather than the mere presence of hyaluronic acid in the INCI, that makes the study of different molecular weights in modern cosmetic formulations so interesting.
Cited Scientific Studies
Essendoubi M. et al.
Human skin penetration of hyaluronic acid of different molecular weights as probed by Raman spectroscopy.
Skin Research and Technology, 2016.
PubMed
Pavicic T. et al.
Efficacy of cream-based novel formulations of hyaluronic acid of different molecular weights in anti-wrinkle treatment.
Journal of Drugs in Dermatology, 2011.
PubMed
Farwick M. et al.
Fifty-kDa hyaluronic acid upregulates some epidermal genes without changing TNF-α expression in reconstituted epidermis.
Skin Pharmacology and Physiology, 2011.
PubMed
