Hyaluronic acid has become quite the buzz ingredient over the past couple of years. I personally love it, but a fellow cosmetic chemist has challenged me in believing in its efficacy. This chemist believes that at the current levels it’s normally used in cosmetics, ~0.1 - 10% w/w*, it has little to no benefit for the skin. So! The purpose of this blog post is to look at current literature and a) understand what the molecule is, b) understand how it works on skin, and c) see what amount is considered efficacious.
What is hyaluronic acid?
Hyaluronic acid is a high molecular weight carbohydrate. How heavy? Think several thousands of sugars in one chain! It occurs naturally in all living organisms and is produced in our Golgi apparatus. One link in this chain is a dimer of D-glucuronic acid and N-acetylglucosamine.
It serves many purposes in our body, one of them being keeping our joints lubricated. The main feature of this molecule is that it’s extremely hygroscopic, aka it looooooves water. In fact, it’s one of the most hydrophilic molecules in nature. Why is that?
That’s because of the oxygens on the chains. If you recall from high school chemistry, oxygens can bond to hydrogen via hydrogen bonds. Thus, these oxygens on hyaluronic acid are attracted to the hydrogens in a water molecule. What happens when this molecule binds with water? It stiffens and expands into a random coil that traps about 1,000 times its weight in water.
Need a review of high school chemistry spoken in terms of cosmetic chemisTRY? I got you covered.
Hyaluronic acid occurs as the salt form, hyaluronate, in our skin. Why? Skin pH is at about 4.3 - 4.5, but hyaluronic acid’s pKa is 3 - 4. Remember that if the environment the molecule is in is higher than its pKa, it becomes ionized and the oxygens in hyaluronic acid lose their hydrogens to become O-. However, hyaluronate isn’t just found there! It’s also found in the umbilical cord, synovial fluid, vitreous humor, lung, kidney, brain and muscle tissues!
How does hyaluronic acid work?
Hyaluronic acid is a humectant. For skincare, its main function is to help the skin maintain moisture when it’s applied topically. This is possible due to its aforementioned hygroscopic nature. Since it attracts water toward it, it reduces the likelihood that the skin will lose water. It may also bring extra water to the skin, but how much varies a lot with the formula it’s in and the environment you’re in when you apply it. For example, a more humid environment will have more water in the atmosphere for hyaluronic acid to attract toward your skin. This attraction to water helps to prevent transepidermal water loss (TEWL), meaning that it helps to reduce the amount of water that evaporates from your skin.
Another thing to consider is the effect of hyaluronidase on the skin. Hyaluronidase is a class of enzymes which break down hyaluronic acid into smaller parts. Now remember, hyaluronic acid is a chain of carbohydrates. Hyaluronidases break up these large chains into smaller parts. The question then becomes, is this a good thing or a bad thing? Milani et al (2017) found that the effects of hyaluronic acid could be limited due to the existence of hyaluronidase since it isn’t easily measured and understood how long hyaluronic acid stays on your skin before it’s degraded, and this assumes that the formula delivers all of the hyaluronic acid to your skin without you rubbing it off.
I couldn’t find literature commenting on how much and which type of hyaluronidase is on your skin to render this point appreciative, but it is something to consider when thinking about the efficacy of hyaluronic acid. Also, not all skin is created equal. Do certain people have a greater concentration of hyaluronidases on their skin compared to others? Who has more and who doesn’t? Does hyaluronic acid work better on people who have less hyaluronidases in their stratum corneum? Or does it not make an appreciative difference? One of the hyaluronidases in humans is Hyal-2 which works in pH 6 - 7. Since the skin is more acidic (pH 4.3 - 4.5), how does this affect the functionality of Hyal-2? What is the optimal pH for the other four hyaluronidases that exist in humans?
On the flip side, smaller molecular weight hyaluronic acid could better penetrate the skin to draw in water into deeper layers of the stratum corneum. Laugier et al (2001) tested an unknown molecular weight of hyaluronic acid in both cadaver and synthetic human skin and found that hyaluronic acid did not appreciably penetrate the stratum corneum. I would love to know which hyaluronic acid salt they used from Sigma so we could see if their conclusion corroborates with other research. Meanwhile, Brown et al (1999) found that 400 kDa hyaluronic acid could penetrate to the dermis.
Does hyaluronic acid need to penetrate (incorporate into) the skin?
A paper from Bos et al (2000) talks about how chemical compounds can’t penetrate the skin unless they are 500 Da, which is way smaller than the molecular weights of hyaluronic acid chains typically out on the market (e.g. Making Cosmetics sells an 8000 Da one). Although this paper acknowledges that molecules larger than 500 Da have been demonstrated to penetrate the skin, can we be sure the hyaluronic acid out on the market is actually penetrating? Does it need to?
It can probably make a difference if it penetrates the skin since it’ll be able to bring moisture in at a deeper level, but it can still be helpful sitting on top of your stratum corneum. Some research has suggested that lower molecular weight hyaluronic acid can penetrate the stratum corneum, but what is not clear to me is how helpful that is. Even if you had a small enough molecule, it’d only be able to penetrate the skin through a polar pathway. Is that amount appreciable enough to show improved moisturization?
Need a refresher on skin penetration? Check out my blog post here!
Can hyaluronic acid improve wrinkles?
There’s evidence that wrinkle reduction can be improved via injection of hyaluronic acid, but based on present literature, topical hyaluronic acid is an anti-aging ingredient in the sense that it maintains your skin’s health by keeping it moisturized. Pavicic et al (2011) suggests that it may have anti-inflammatory effects which relate to anti-aging, but they haven’t published any studies that I can find which demonstrate this. In general, research suggests that moisturization helps to maintain homeostasis of your skin, and thus the health and integrity of it too (aka less wrinkles).
So is hyaluronic acid or sodium hyaluronate better for your skin?
Depending on the pH of the actual product, you will generally have one or the other form in your product. Why? Let’s not forget the pKa! If a formulator were to add hyaluronic acid in a formula but its final pH is above 4, most likely the hyaluronic acid has deprotonated to turn into the salt form, hyaluronate.
Thinking about the acid versus the salt form, both forms should be able to hydrogen bond with water. The salt form should also be able to have an ion-dipole interaction with water due to the negative charge on oxygen. Since ion-dipole interactions are stronger than hydrogen bonds, does this mean that sodium hyaluronate is better for your skin since the chemistry says it should have a stronger attraction to water? I don’t know! Is there even a difference? I couldn’t find any literature out there which points out which form of hyaluronic acid is better, but please share with me if you have found otherwise!
Do you need a mix of molecular weights to achieve optimal moisturization?
Pavicic et al (2011) tested different 0.1% w/w hyaluronic acid creams, each containing either 50, 130, 300, 800, and 2000 kDa chains. The test subjects were 30 - 60 year old Caucasian women, the experimental design seemed sound, and their base formula was a pretty basic cream. Overall based on their published data from this in vivo study, it does look like the 50 kDa cream showed the best results over a period of 30 and 60 day period.
Jegasothy et al (2014) demonstrated that nano-sized hyaluronic acid has even more efficacy, but this study holds no weight for me. They did not describe the type of formula they used and they had no control, so what am I really looking at when there’s nothing to compare or asses?
I haven’t found any data that proves that a mix of molecular weights is optimal like The Ordinary claims, but I can see the logic in it. If you have some lower molecular weight hyaluronic acid that penetrates deeper into the stratum corneum and then some higher molecular weight ones that sit on top, then you have a variety of hyaluronic acid molecules distributed across different layers of your stratum corneum to bring more moisture throughout the skin. Is this better than concentrating hyaluronic acid in one layer? Not sure. I’d like to see a study on that, though.
Is hyaluronic acid natural? Where does our hyaluronic acid come from? Humans!?
No, it doesn’t. You can produce hyaluronic acid by the fermentation of glucose and yeast extract. Making Cosmetics supplies a hyaluronic acid made from glucose, soy peptone and yeast extract.
Is hyaluronic acid safe?
The last published report by the CIR in 2009 concluded that hyaluronic acid and its salts are safe when looking at cosmetics with up to 2% w/w. They acknowledge that there are data gaps and other concentrations they need to consider. It was discussed during the December 9-10, 2019 expert panel meeting, so I look forward to seeing more conclusions from them. I think it was important for the panel to reconvene considering that many cosmetic products in the market are definitely over 2% w/w.
Formulation Tips
Lower molecular weight hyaluronic acid is easier to mix than higher molecular weight ones since the higher molecular weight one has a thickening effect. When a formula, namely the water phase, is thickened by hyaluronic acid, it tends to have a psuedo-plastic rheology. If you’re working with hyaluronic acid powder, you need to carefully sprinkle it into the vortex of your water with mixing to prevent clumping of the powder. If you’re an at home formulator, Making Cosmetics sells a 8 - 15 kDa hyaluronic acid that should be easier to mix. I think though if you just want to make your life easier, get a sodium hyaluronate solution and put that in your water phase.
Final Opinion--is Hyaluronic Acid Bullshit or Not?
After my personal research, I do feel that including hyaluronic acid in your skin care routine can have a positive impact more or less. I don’t feel, however, it’s the super ingredient brands will have you believe it is. I personally love The Ordinary’s Hyaluronic Acid Serum, but also keep in mind that from anecdotal experience, I’ve been genetically blessed with low maintenance skin (a lot of times I don’t wear a lot of products). I do feel that using the serum before moisturizing gives my skin more relief when it’s really dry.
I can see where my friend’s doubt lies as I haven’t come across a lot of literature with good experimental design to demonstrate hyaluronic acid’s efficacy aside from some pieces of literature above. I think hyaluronic acid can help reduce TEWL and help with dry skin. Is it an anti-aging ingredient? Well, it moisturizes you. That’s about my main takeaway from what we know about the ingredient.
If you have any interesting data to share with me, I’d love to see it!
*w/w = weight per weight. Formulas are written by cosmetic chemists by how much they weigh, not by volume.
References
Miller, William H. Muller and Kirk's Small Animal Dermatology. 7th ed., Elsevier Health Sciences, 2013.
Milani, M. and Sparavigna, A. “The 24-hour skin hydration and barrier function effects of a hyaluronic 1%, glycerin 5%, and Centella asiatica stem cells extract moisturizing fluid: an intra-subject, randomized, assessor-blinded study.” Clinical, Cosmetic and Investigational Dermatology. 2017 Aug 11;10:311-315. doi:10.2147/CCID.S144180
Harada, H. and Takahashi, M. “CD44-dependent intracellular and extracellular catabolism of hyaluronic acid by hyaluronidase-1 and -2.” J Biol Chem. 2007 Feb 23;282(8):5597-607. doi: 10.1074/jbc.M608358200
Pavicic, T. et al. “Efficacy of cream-based novel formulations of hyaluronic acid of different molecular weights in anti-wrinkle treatment.” J Drugs Dermatol. 2011 Sep;10(9):990-1000. PMID: 22052267
Jegasothy, S Manjula et al. “Efficacy of a New Topical Nano-hyaluronic Acid in Humans.” The Journal of clinical and aesthetic dermatology vol. 7,3 (2014): 27-9.
Bukhari, SNA et al. Int J Biol Macromol. 2018 Dec;120(Pt B):1682-1695. doi: 10.1016/j.ijbiomac.2018.09.188.
Bos, J.D. and Meinardi, M.M.H.M. “The 500 Dalton rule for the skin penetration of chemical compounds and drugs.” Exp Dermatol. 2000;9:165-169. doi: 10.1034/j.1600-0625.2000.009003165.x
Laugier, J.P. et al. “Topical hyaluronidase decreases hyaluronic acid and CD44 in human skin and in reconstituted human epidermis: evidence that hyaluronidase can permeate the stratum corneum.” Br J Dermatol. 2001 Dec 24;142(2):226-233. doi:10.1046/j.1365-2133.2000.03289.x
Brown, T.J. et al. “Absorption of hyaluronan applied to the surface of intact skin.” J Invest Dermatol. 1999;113:740-746.
Becker, L.C. et al. “Final report of the safety assessment of hyaluronic acid, potassium hyaluronate, and sodium hyaluronate.” Int J Toxicol. 2009 Jul-Aug;28(4 Suppl):5-67. doi: 10.1177/1091581809337738.