Hyaluronic Acid and derivatives

Hyaluronic Acid and derivatives


Hyaluronic acid is a naturally-occurring molecule found in the body, first used clinically in the 1960s to treat wound lesions. By 1990 it made its way to the cosmetic industry and today is well known for the claim that it holds “1000 times its weight” in water. Hyaluronic acid and has become increasingly popular in recent years as a ‘hero’ skincare ingredient for its moisturization properties. But what does it actually do, does it actually work and are the products we use today any good?

In the skin, Hyaluronic acid functions as a sponge that can hold a lot of water to keep our skin plump and well hydrated. It can either sit on top of your skin or penetrate into deeper layers. Since it is produced by the body, there is a low chance of it causing allergic reactions.
What is Hyaluronic Acid?

Hyaluronic acid is a glycosaminoglycan (GAG) that is a part of the extracellular matrix (ECM) which lies between the cells but is also present intracellularly in the dermis. These ECMs not only provide structural support to the cells but also exert effects on cellular processes. It is a highly organized structure composed of GAGs, proteoglycans, growth factors, structural proteins such as collagen, and most predominantly Hyaluronic Acid (HA and skin Aging).

Hyaluronic Acid was first discovered in the vitreous body of cows and its name is derived from the greek word Hyalos (meaning glass) and uronic which is a type of sugar acids. It is primarily composed of repeating polymeric dissacharides of D-glucoronic acid and N-acetly-D-glucosamine linked by a glucoronic B (1-3) bond. Its molecular weight varies from lower than 6,000 DaItons to as high as more than 20 Million Daltons. Because of this huge range of its size, it is expected that its penetration and its biologic effect is also varied depending on the size. Both epidermal and dermal cells are able to produce HA throughout lifetime but there is a significant decrease in epidermal HA as you age, which translates to less supple skin.
Does it penetrate the skin?

The penetration of HA was investigated using Raman Spectroscopy on human skin sections and it showed that 20-300 KDa are able to penetrate the stratum corneum. This means that a solution containing different molecular weights of HA is beneficial for the skin compared to a single molecular weight because the different molecular weight HA would penetrate differently in the skin and exert their effect in the various layers.

How is it able to hold water?

Most of you probably read somewhere that a gram of HA can hold up to 6 Liters of water (most likely a HA supplier brochure, which should always be taken with a grain of salt), but how exactly does it do this? HA contains a high density of fixed negative charges from the carboxyl groups. These negative charges facilitates hydrogen bonding with the water where it is held tightly. Aside from that, the junction zones formed by HA can also trap water in it which contributes to HA’s capacity of holding water.

What are the beneficial effects of HA?

It has very diverse functions and effects owing to its polymorphic conformation that is pH, temperature and environment dependent. High molecular weight forms a film on the surface of your skin and prevents water loss; specifically, it forms a viscoelastic film that holds water on the surface of your skin. Owing to its tight grip on water, HA has good water retention properties both at high and low humidity, this means that even in xerotic conditions, it will be hard for it to lose its bound water. There is a very common myth that in non-humid conditions, HA will pull moisture from your skin instead of the environment. HA cannot discern where it pulls moisture from, it simply holds water wherever that may be. It can hold water that it was holding when it was in the solution or it can also hold water from your skin. This is a normal process as, unless dehydrated, your skin always has a fresh supply of water from the blood vessels. Other humectants on the other hand can increase your Trans- Epidermal Water Loss (TEWL) by encouraging the water movement from the dermis to your epidermis where water is easily lost. This is why it is important to use products that have humectants, with occlusive ingredients. High molecular weight HA has also been shown to attenuate the inflammatory response and promotes repair and regeneration of the skin. It is also associated with finer reticular pattern of collagen regeneration which translates to a more even skin.

Low molecular weight HA on the other hand are better at hydrating the skin. However, after month-2, the higher molecular weight 1M had a better degree of hydration. Low HA can also influence keratinocyte differentiation by binding to CD44 and it helps in the formation of intracellular tight junction complexes, which are beneficial for maintaining your skin’s moisture barrier. Low molecular weight is also a potent inducer of def beta 2 which translates to a more potent response to microbes. They are also found to stimulate endogenous synthesis of high molecular weight HA.

Most hyaluronic acid in cosmetics are in the form of Sodium Hyaluronate, which is the stable form of Hyaluronic Acid. Native HA has short half life because it is easily degraded by enzymes and radicals. HA fragments are still active for angiogenesis (growth of new vessels) and supporting proliferation of fibroblast. (Harry’s).

What are the disadvantages of HA?

Hyaluronic acid can cause a-helic to b-sheet conversion of the keratin which leads to a disarranged barrier, leading to more prominent penetration of substances. In simpler terms, they cause a change in the shape of keratin which leads to a more disrupted barrier. This is further proven in a study that showed the effectiveness of HA as a penetration enhancer in damaged epidermal barrier. In this study, a damaged epidermis was produced through multiple tape stripping. Radioactive labeled HA and Bovine Serum Albumin (test protein) was applied to the skin. It showed that HA+albumin penetrated better than albumin on its own, showing that HA can act as a penetration enhancer. This means that when you have a damaged barrier, the HA can further disrupt the organization of the lipids, which causes substances to further penetrate the skin.

When an insult or an injury occurs in your skin, hyaluronidase enzymes are released as a response to the injury. The hyaluronidase enzymes cleave off the HA into Medium Molecular Weight to Low Molecular Weight HA. Smaller fragments can also increase the formation of pre-inflammatory interleukins which are responsible for the generation of free-radicals which are both damaging to the extracellular matrix and the keratinocytes. These smaller fragments serve as chemical messengers as they bridge the cascade of inflammation. They are also associated with a more disorganized reticular pattern of collagen regeneration. For these reasons, application of super low-molecular weight in a skin with damaged barrier is a little questionable and the verdict is still out there.

What to look for in buying products with HA.

Certainly look for products that have varying molecular weight as we’ve learned that HA’s biologic functions and other physical and chemical properties are dependent on its molecular weight. Since the science is still undecided whether super low molecular weight HA is beneficial, prefer those with 100 KDa and above. Sodium Hyaluronate is the more stable and more soluble form of HA while Native HA degrades easily into uncontrolled fragments. Sodium Hyaluronate crosspolymer on the other hand is a cross-linked HA molecules which has infinite possibilities of Molecular Weight. Contrary to what other huge brands claim, it is not more likely for it to penetrate the skin compared to Sodium HA. It forms a more contiguous viscoelastic layer on top of the skin, lowering your moisture loss.

Next HA article: Role of HA in wound repair and inflammation


Note to self: Download and read these:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949149/
https://www.ncbi.nlm.nih.gov/pubmed/15168246
https://www.woundsresearch.com/article/hyaluronic-acid-inflammation-and-tissue-regeneration
https://www.researchgate.net/publication/236084599_Different_molecular_weight_hyaluronic_acid_effects_on_human_macrophage_interleukin_1b_production
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026078
https://www.hindawi.com/journals/mi/2016/8727289/
https://iovs.arvojournals.org/article.aspx?articleid=2357180
http://barefacedtruth.com/2015/03/31/hyaluronic-acid-yes-size-does-matter/