Hyaluronic Acid – Yes, Size Does Matter! | BareFacedTruth.com

Hyaluronic Acid – Yes, Size Does Matter!

Being touted by some as a “better” hyaluronic acid (HA) for skin application, low molecular weight  hyaluronic acid (LMW-HA) is in fact a potent stimulus for inflammation and scarring.

We at BFT have found a major disconnect between what the cosmetic industry says is true, and what actual scientists say is true.  So here we go again. We find a number of products claiming to contain a new, improved form of HA that is “low molecular weight”.  As is typical we can trace this myth making back to the ingredient manufacturers, who of course provide “proof”. But, in keeping with  their usual habit, do the wrong experiments and then misinterpret the results to put a positive spin on the matter.
Hyaluronic acid (HA) is ubiquitous in mammals, forming a key component of connective tissue in our bodies.The average person has roughly 15 grams of HA in the body, one-third of which is turned over (degraded and re-synthesized) every day. HA is an important structural molecule in the extracellular matrix of our skin. It is synthesized there by fibroblasts, fibrocytes, and by roving stem repair cells derived from bone marrow(MSC’s)  that show up in case of wounding and other forms of damage.

HA is used therapeutically – it is the stuff of facial fillers, and can be applied topically as a humectant. Being a very large molecule it does not penetrate and instead sits of the skin surface where it binds to water to maintain hydration, and cross links with other HA molecules to knit together a temporary barrier.  Very useful to help maintain skin’s barrier function after minor injuries.  Because our bodies make it – it is completely natural to humans – and therefore very unlikely to cause an allergic reaction.

Diagram showing injury – HA fragmentation into LMW varieties – cytokine induction – inflammation cascade leading to fibrosis and scarring

When wounding or damage (e.g. sunburn) occurs,  there is released early a set of hyaluronidase enzymes, which breaks HAdown into fragments. The size of these can vary from low(LMW-HA) to medium (MMW-HA) molecular weights. HMW-HA has been shown to attenuate the inflammatory response, suggesting that HMW-HA promotes regenerative healing in adult wounds.  On the other hand, LMW-HA and intermediate-weight HA increase the expression of macrophage inflammatory protein-1a and monocyte chemotactic protein-1, which may suggest that LMW-HA is important in the induction of the inflammatory cascade. Other scientific peer-reviewed publications peg LMW-HA as pro-inflammatory by multiple mechanisms: they stimulate macrophages to produce inflammatory chemokines, induce interferons, recruit T-cells, induce IL-12 cytokines, and induce nitric-oxide synthase to produce excess NO2.

In both adults and fetuses, HA levels increase in response to wounding. However, unlike adults, fetuses produce much more HMW-HA in response to injury.  HAS-1 over-expression promotes dermal regeneration in part by decreasing the inflammatory response and by recapitulation of fetal ECM HMW-HA content. (Part of our work involves altering the growth factor and cytokine to more closely resemble a fetal pattern).

The type of collagen produced by to regenerate skin is affected by the relative presence of HMW vs LMW HA. A fine reticular pattern is produced in the non0inflammatory environment of HMS-HA, whereas a more disorganized pattern is seen when HA fragments abound.  The results (scar free vs scarring) has aesthetic implications.

It is of considerable interest that organic “contact sensitizers”  induce production of reactive oxygen species (ROS) and a concomitant breakdown of the extracellular matrix (ECM) component hyaluronic acid (HA) to pro-inflammatory low molecular weight fragments in the skin. So, in some ways, adding LMW-HA topically may replicate that cascade of events.  This makes it especially problematic when you consider the application of HA when the skin barrier has been disrupted, e.g. during microneedling.

Small fragments of the extracellular matrix component hyaluronic acid (sHA) are typically produced at sites of inflammation and tissue injury and have been shown to be associated with tumor invasiveness and metastasis. Exposure of human melanoma cells to small HA fragments leads to nuclear factor kB (NFk-B) activation followed by enhanced expression of matrix metalloprotease (MMP) 2 and interleukin (IL)-8, factors that can contribute to melanoma progression.  This suggests that LMW-HA in melanoma might promote tumor invasiveness by inducing MMP- and cytokine-expression.

According to another study, low molecular weight HA may also play a role in breast cancer metastasis.

There is abundant experimental evidence from the human physiology and biochemistry literature to support the basic notion that LMW-HA is inflammatory, pro-fibrotic, and associated with adult scarring phenotypes rather than fetus-like, scar-free, truly regenerative healing.  The latter is what we want in an any aesthetic procedure, or topical adjunct to a procedure, or just for topical use.

We strongly suggest you review any hyaluronic acid products you may use on yourself or others. Make sure the formulator didn’t fall prey to marketing materials from one of those too-clever-by-half ingredients manufacturers who make up a good story but haven’t a clue about the real science. Caveat emptor!



  1. Nigella Pressland says:

    Hi there, your site is very interesting. I realise this is slightly tangential to the article, but if HA has such big molecules, is there any benefit to applying it externally, other than as a humectant on damaged skin? It seems to be touted by the cosmetic industry as an anti-aging product, but it seems to me that it is just a moisturiser. Your views would be most welcome.

    • drjohn says:

      Excellent question, Nigella. We know that hyaluronic acid (HA) has many functions at all levels within the skin. But since intact (HMW) HA is a very large molecule and not likely to be absorbed in intact skin, what are the benefits to topical application? First, let’s confirm that it is a terrific humectant in that it binds 1,000 times its weight in moisture to the skin. Second, the molecules can be cross-linked to create polymers (films, sheets, or biogels of HA). Third, the HA molecule has binding sites that can hold (and make available) bioactive molecules such as growth factors. Within skin, we have discussed how HA can act as a biosignal and HMW-HA moderates inflammation, but when fragmented in the presence of enzymes those LMW-HA species are inflammatory. In wounded skin, HA is involved in granulation tissue formation and re-epithelialization – critical parts of the healing process. HA also acts as a free radical scavenger deeper in the epidermis and dermis. And all of this also comes with a high degree of “biocompatibility”. Since it is natural, HA is not likely to cause allergic reactions. (If it does, it would be because it is of nonhuman origin and not pure).

      Your question has to do with both normal and “damaged skin” which is a wide spectrum. If the barrier function of the skin is entirely intact, then HA is really a great moisturizer and perhaps nothing more. But even in the presence of small damage (e.g. sun exposure) some of it’s wound healing effects might be taking place. It can provide both a physical protective barrier that protects allowing natural mechanisms to restore from within while preventing dehydration, and also has multiple biochemical roles to play in both minor and more disruptive wounds. We can put microneedling of varying depths on that spectrum as well. Multiple punctate disruptions to the skin’s natural barrier function, or multiple wounds? Which of these descriptors fits is open to debate. But either way, HA can be seen as beneficial. In microneedling, its other benefit is to provide glide when automated pens are being “dragged” across skin.

      As a moisturizer, HA acts quite differently to lipids and other humectants that have better penetration capabilities. But for the very reason of it’s size and molecular weight it perhaps provides a better short term barrier replacement, and of course you mix these types as well. Part of our work is with HA hydrogels which are quite remarkable for covering wounds and delivering growth factors. We are perfecting an HA mask that we like a lot.

  2. Nigella Pressland says:

    Thank you for taking the time to answer. I’m UK based & find it very hard to get any genuine scientific evaluation of the creams (often very expensive) that are sold to be put on the skin. The advertising of most of the cosmetic products is outrageous, in my opinion. I watched a commercial for a cream yesterday that was referred to as “bouncy” and would work over night to help skin appear “well-rested” and “satin smooth”. None of those descriptors actually mean anything, so it is very much a case of caveat emptor, which is easier said than done as an ordinary mortal! However, now I’ve found your site, hopefully I shall be better informed.

  3. Lucas says:


    This is really interesting and what you’re saying makes a lot of sense. But I have rosacea and there have been those in online forums which experienced improvement in their symptoms using a low molecular weight hyaluronic acid gel (bionect), which is marketed towards irritated skin. Have you heard of this product?
    Also, this link (http://jddonline.com/articles/dermatology/S1545961613P0664X/1#close) has been going around, and I don’t have the technical background to judge it.

    Thank you,

    • drjohn says:

      Hi Lucas – great question. We have seen this report, and it makes no sense to us, logically speaking. Let’s start with these two quotes:

      “Rosacea is a chronic cutaneous disorder that is usually found on the face. The disorder is most commonly characterized by flushing, erythema, telangiectasia, edema, papules, and pustules.1 The cause of this inflammatory disorder is unknown, but is thought to include multiple contributing factors…”

      OK, we can agree with that. Rosacea is an inflammatory disorder. Now they go on to say …

      “As high molecular weight hyaluronic acid (HMW-HA) is depolymerized in sites of inflammation or tissue injury, low molecular weight hyaluronic acid (LMW-HA) fragments result…. In addition, LMW-HA has the ability to alter the innate immune response partly stimulating the production of cytokines and chemokines by macrophages and activating T cells and dendritic cells. Effects on cell behavior include leukocyte, fibroblast, and endothelial cell migration and activation.

      Notice this bolded bit: leukocyte, fibroblast, and endothelial cell migration and activation is the very definition of inflammation.. So, we must ask, how can it be that an inflammatory condition (rosacea) is improved by inflaming skin further? Makes no sense, right?

      Maybe this offers some clue: “Lastly, LMW-HA induces the production of β-defensin 2 (DEFβ2) by stimulating a tissue injury response, ultimately creating an antibacterial effect that allows for regeneration of the cutaneous epithelium and reduction in antigen load”. To the extent that LMW-HA induces defensins (natural antibiotics), and rosacea sometimes responds to antibiotics, this may offer a putative explanation?

      What is also confusing to us is that we in our research clinic see dramatic improvements within days (not 8 weeks as in the study) in rosacea signs and symptoms using a product made with anti-inflammatory cytokines & growth factors derived from mesenchymal stem cells. Tamping down the inflammation works wonders. We should get Dr George to comment on this – he has personal experience.

      Maybe the study above demonstrates a hormesis principle in action – many cells getting killed off due to oxidative stresses results in rapid turnover of fresh epidermis. What doesn’t doesn’t kill you makes you tougher?

      • Firefox7275 says:

        Do you have any comments on the angiogenic effect of low MW hyaluronic acid when it comes to rosacea? Is the eight week duration of that study just not long enough to see this occurring?

        If that is an issue presumably one would want to give low MW hyaluronic acid a particularly wide berth right after IPL treatment for rosacea?

        Thank you.

        • drjohn says:

          Rosacea is a different beast. Recent work on its pathophysiology suggests defects in toll like receptor pathways, and defensins. Now we do know that LMW-HA stimulates those things. That can help in self-defense against bacteria. We know that bacterial overgrowth is part of the rosacea complex. Another place where defensins are critical is vaginal epithelium. We also know that toll like receptor induction with LMW-HA, helping to protect against bacterial overgrowth. So, it may be the same or similar in rosacea. Induction of defensins has benefit. But chronically – not good to hold off aging.

          Vaginal TLR & LMW-HA: http://www.ncbi.nlm.nih.gov/pubmed/21102537

          Rosacea cytokines: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3704141/

          This review focuses on the crucial role of HA in vascular integrity and how HA degradation promotes vascular barrier disruption, with low molecular weight fragments causing damage to the endothelial
          glycocalyx.: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253523/pdf/ajcd0001-0200.pdf

    • drgeorge says:

      Hi, Lucas. I echo Drjohn’s comment that the use of LMW-HA to reduce an inflammatory condition such as rosacea is at odds with published studies that show otherwise i.e. LMW-HA tends to promote inflammation. As he suggests, there may be other mechanisms at work. Seldom is something in medicine, particularly a physiologic process with so many contributory components as inflammation, a black or white issue. Confounding variables abound. Perhaps that is why studies often show conflicting results. What he also mentioned is how the net anti-inflammatory pattern of cytokines and growth factors produced by bone marrow mesenchymal stem cells in culture can attenuate inflammation. In that case, the story holds together nicely since they play that role physiologically in the healing and rejuvenation process throughout life. In fact, fetal wound healing is the paradigm of inflammation-free healing, felt to be the result of abundant anti-inflammatory cytokines during the early months of gestation, particularly abundant quantities of TGF-beta3, the quintessential anti-inflammatory cytokine. In my personal experience, my decades-long saga dealing with rosaces (oral doxycycline, topical Metroget and occ. steroids) can to an abrupt and most pleasing end when I started using the skincare product Drjohn and I developed using the cells mentioned above. I discontinued all prescription meds when I started our prototype formula and within a week my issue with rosacea became part of my past. My wife, whose makeup was often purloined to make my face more presentable for social events, was thrilled. I have not had a flare-up since July 1, 2011, the day I started our product. We have since heard numerous other instances of improvements in rosacea symptoms and our products now are used to reduce inflammation and shorten downtime following ablative and semi-ablative facial aesthetic procedures. It’s gratifying when the theory and real-life experience line up so nicely.

  4. Lucas says:


    Thank you for that! It certainly doesn’t make sense to promote inflammation on an already inflammatory process.

    I inadvertently have been using a toner with three (!) different kinds of low molecular weight hyaluronic acid derivatives. I know that because the company has provided that information, but is there anyway to know whether I’m buying something with LMWHa or not? The most common hyaluronic acid salt I see everywhere is sodium hyaluronate. What do you think of that ingredient? What should I look for in the INCI list to make sure I’m not getting the wrong kind of hyaluronic acid?

    Thank you again,

    • drjohn says:

      Sodium hyaluronate generally is HMW-HA (the good stuff) which is the natural form. If HA has been processed (enzymatically degraded) to produce LMW fragments (extra steps taken in the lab, at extra cost), the company selling it should say so. They use it as a marketing ploy, so it makes no sense for them to put in something that costs more if they aren’t going to advertise it as such. Pure unadulterated sodium hyaluronate or HA is natural, physiologic, so no worries, we like it a lot and use it in our own microneedling solution.

  5. kflab says:

    Dr. John,

    What about taking HA internally via pill form?

    • drjohn says:

      You can take it orally, and yes indeed some of it is absorbed intact and gets into your bloodstream. A small amount gets filtered into e.g. joints, eyes, etc. and some may even make it to skin. About 95% is lost in the urine. Not compelling evidence that it helps skin, but then nothing to suggest it is not safe also. You do get HA (along with other matrix elements & fragments) from gelatin an bone broth and the like – anything derived from animal connective tissues. But in skin care, the best studied role of HA is to sit on the top of skin and draw water to itself to moisturize. best way to get it there is to slather it on.

  6. Luke says:

    This is interesting as almost everything I read points to the low-molecular weight being superior. I’m not sure what to think. Have you seen this study? https://personal-care.evonik.com/product/personal-care/en/media-center/downloads/publications/Documents/sofw-hyacare-50.pdf

    • drjohn says:

      Yes, we have seen that study by the manufacturer. Not published in a peer reviewed journal. It says LMW penetrates better (makes sense). And that it gives quick results by ameliorating wrinkles (which is always our first clue that the mechanism of action is inflammation – since true collagenesis and elastogenesis takes longer than 4 weeks). They call it anti-aging. I call it “pro-aging with benefits”. Analogy: like getting a sun tan. Bronzing by ultraviolet rays may make you look better for a while – but eventually catches up with you and actually accelerates aging in the long run.

      These papers (amongst many others in the medical literature ) paint a different picture:


      To put it succinctly – HMW-HA associated with scar free healing & regeneration while LMW-HA associated with inflammation & scarring.

  7. Louise B Andrew says:

    Very interesting.
    FWIW, the above citations both refer to the same article.

    The cited article also defines TGF to mean “Tumor Growth Factor”.
    I believe it should be Transforming Growth Factor? Surely these are not synonyms.

    Unless I missed something, nothing was said about the advantage of healing in a nice bath of amniotic fluid. Perhaps we should be capturing this liquid gold? (JK—apparently it would have to be had at an early period of gestation to get the best healing—so lots of moral reservations)

    But seriously, where does TGF beta 3 come from (other than fetal platelets)? Is that the miracle cure for scarless healing?

    • drjohn says:

      Fixed the refs. Good find Louise and you are 100% correct about TGF (T = “transforming” not “tumor”). TGF beta3 is indeed the key to scarless healing. And while human amniotic fluid may be a good place to find some, that source has issues. meanwhile, we now know that mesenchymal stem cells in culture can produce this en masse. That is also part of the answer “where does TGF-beta3 come from? During embryonic life, many different types of cells are behaving like these stem cells (indeed embryos are by their nature mainly stem cells – makes sense from a developmental perspective). So during fetal life skin and other tissues make a lot of their own TGF beta-3 driven by the genetic imperative to develop into a infant human capable of surviving outside the womb. We gradually lose that capability over time (a strong correlate of aging itself). In adults, much of human regenerative capacity resides in these very special cells that live in the bone marrow but patrol the whole body looking for problems to solve (e.g. wound healing). And because cytokines are a communication molecule, these stem cells not only tell other =cells what to do (e.g.make new healthy tissue) but also tell them to make more of the same molecule. Sort of a “tell a friend” scheme that amplifies the message in that tissue. There are other cytokines that tell tissue to grow, but TGF beta3 is unique in its ability to create scar-free (fetal-like) regeneration. Hope this sheds more light on the “where does it come from” question.

  8. Elizabeth says:

    Is hydrolized hyaluronic acid the same as the LMW stuff talked about here? Also, HA serums being so popular are readily available in so many different price points that you eventually want to believe when one person says it’s such a “high quality” one that you should pay $150 for it; for example, Bakel HA serum. When you see most of the Japanese toning lotions and milks containing hydrolized hyaluronic for the low price point, on the other end, of course butylene glycol being a main ingredient in a lot of those products too which I’m not convinced helps.

    • drjohn says:

      Elizabeth – yes, the way to break up HA into fragments is by hydrolysis. And you are right about the price. You can buy “pure HA” on Amazon for about $5/oz. But read the label to make sure it is in fact pure and not containing other stuff. Remember, HA sits on the surface of the skin and provides a moisture barrier. But it also can be a superb carrier or delivery system for molecules that normally attach to HA (e.g. many growth factors and cytokines). I also like HA masks.

  9. Neil Mosunic says:

    Hello Dr. John,

    Thank you so much for your work and replying to comments. I’m considering taking HA to see if it would help with what I believe to be the early stages of elbow tendonitis (from climbing, which I’ve gathered is medial, like golfer’s elbow, opposed to lateral, which is tennis elbow).

    Are there any specific brands of HA capsules you would recommend for this? Is low molecular the best option for this? I’ve seen claims that some brands have low molecular from sodium, is this just marketing or is it as effective as low molecular from animal sources? I would like to get non-animal source if I can find one that is as effective, but if not, I would go for an animal sourced version.

    Thanks in advanced. Have a great day and keep up the research for those of us who really try to inform ourselves!

  10. Sam says:

    I’ve read some articles (nothing scientific) stating that pure HA can dehydrate the skin in certain climates because if there isn’t enough moisture in the air that the HA draws moisture from your skin to itself. Is there any truth to these claims and if so is it possible to avoid. Second question, if using other oils topically, like vitamin, is it best to put HA on first or afterward?

    • drjohn says:

      Sam, we have seen this a lot too, but you are right – nothing scientific. Welcome to the skin trade. While it is true that HA loves water, once it is saturated it is not going to act as a desiccant (drying agent). Generally the HA you buy is actually less than 1% HA and the rest is water (and maybe other stuff). If you pace pure diluted HA on skin, some water will evaporate at the surface. This can make skin feel dry, but the HA is still acting as a water loss barrier, keep the skin underneath happy. The proof would be found in a TEWL meter (trans-epidermal water loss). We should do an experiment. HA also can spontaneously cross link (form natural weaves), which can lead to some temporary tightening as the molecules actually form matrix-like meshes on the skin surface. BTW – you can always put a moisturizing cream on top of HA (not after microneedling though).

  11. Jae Z says:

    Hi Drs. John and George,

    Dr. John says in response to Lucas that you guys use HA in your microneedling solution. I think you’re referring to the Palmitoyl tetrapeptide-7 in Ante AGE MD, right?

    I would REALLY REALLY love clarification on some of the info on the Ante AGE MD product line website:

    On the Accelerator MD page, it says “Its powerful ingredients also make it the perfect post-procedure topical adjuvant following laser, microneedling, abrasive, and other ablative or collagen inducting medical esthetic treatments.” But when I look at the ingredients list, it doesn’t seem to have what you’ve recommended in your blog, e.g. only physiologic ingredients, in particular cytokines and GF derived from adult human mesenchymal bone marrow stem cells and HMW HA. Those ingredients do appear in the Serum MD page, which makes me think that actually THAT is intended as the immediate post-needling product? The Serum MD page also features the quote “Its powerful ingredients also make it the perfect post-procedure topical adjuvant following laser, microneedling, abrasive, and other ablative or collagen inducting medical esthetic treatments.”. I’m wondering if the appearance of that quote on the Accelerator MD page is a copy-pasta typo/ error? Would you mind clarifying, is Ante AGE MD Serum recommended for immediate post-needling application, even after more intense medical needling? Only after more shallow depths? Or is it recommended for later application, after the window of highest post-needling absorption closes? When should Ante AGE MD accelerator be applied?Additionally, I’ve been wondering about this – the MD formulations seem like better, stronger versions of the regular Ante AGE products. Is that true? If so, why sell the regular Ante AGE line at all? Why not only sell the more effective version (MD)?

    Thank you very much!

    • drjohn says:

      Hi Jae Z. There is HA (high molecular weight only) in the microneedling solution, along with cytokines and growth factors, but no peptides. AnteAge MD is a different (daily use, twice a day) product. The only ingredients we allow during and for 4 hours after microneedling are those which are entirely natural (native) to the human body. Peptides are not.

      The AnteAge MD line is only available through physicians. Consider it like a prescription strength medication where a lower dose is available as an over the counter version (regular AnteAge).

      There is not yet an AnteAge consumer version of microneedling solution but I think there is one coming soon.

      AnteAge (serum and accelerator) whether MD or not, is applied twice a day, morning and evening. For microneedling we now recommend using AnteAge for as few weeks before starting medical microneedling. The microneedling solution is applied during the needling session, and then again (by you) about an hour after the procedure. You wait another few hours before putting AnteAge (or anything other than the MN solution) on your face.

      We are seeing spectacular results with microneedling plus stem cell derived growth factors and cytokines for all sorts of skin conditions as well as general anti-aging effects.

  12. Leeanne says:

    When you say HA or hyaluronic acid, are you also saying that sodium hyaluronate is a bad thing and that because it is low molecular weight, it should be avoided? What is the difference between hyaluronic acid and sodium hyaluronate? Isn’t SH the salt of hyaluronic acid so SH would be considered a safe alternative?

    • drjohn says:

      Hi Leeanne. No, sodium hyaluronate is merely the sodium salt. It’s not which salt is involved that matters, it is the size of the HA itself. If it has been enzymatically broken into smaller bits (a process called hydrolysis), e.g. using hyaluronate, that is when it becomes problematic. The other cells consider these fragments to be danger signals, and go into retreat mode, including slowing down or stopping protein production. Such enzymes are part of tissue breakdown, not tissue building. Any salt of HA (sodium or potassium) is quite safe. It’s the HA fragments that are the issue, not salt type.

      • Astral Aly says:

        I’m glad I discovered this site before I wasted gobs of money on hyaluronic acids that seem to do more harm than good in the long run. My question is, can these products (The Ordinary hyaluronic acid 2% +B5 and The Chemistry Brand’s Hyaluronic Concentrate “A Big Tub of Hyaluronic acid to be more specific) be used under ANY circumstances? Also, I have read in some far-off part of the internet that retinol can accelerate the aging process in the long run. Is this true? Is this also true about anything that encourages high cell turnover rate, like topical vitamin C? Should we all just leave our skin alone when it comes to these anti-aging products? Also, with does “suspension 23% HA spheres 2%” mean? It’s on my tube of vitamin c from The Ordinary brand. How would you rate this company?

        • drgeorge says:

          Our opinion about HA is high molecular weight product is preferable to low molecular weight because of the issue of resulting inflammation. We acknowledge it is very difficult to discern what kind of HA is in a given product. Many companies won’t say, and perhaps don’t even know. Certainly, applying LMW HA to broken or inflamed skin is something we do not advocate. HA does have a role in improving skin hydration. “High molecular weight HA displays anti-inflammatory and immunosuppressive properties, whereas low molecular weight HA is a potent proinflammatory molecule.” Citation below.

          Litwiniuk M, Krejner A, Speyrer MS, Gauto AR, Grzela T. Hyaluronic Acid in Inflammation and Tissue Regeneration. Wounds. 2016 Mar;28(3):78-88. PMID: 26978861.

          As to retinol, “Inside the body, retinoids bind to several classes of proteins including retinoid-binding proteins and retinoid nuclear receptors. This eventually leads to the activation of specific regulatory regions of DNA – called the retinoic acid response elements – involved in regulating cell growth, differentiation and apoptosis.” Also, “The mechanism of UVR-induced photodamage is multifactorial. Retinoids have demonstrated efficacy in the treatment of photoaged skin”, and “Furthermore, two split-face, randomized, double-blinded clinical trials were conducted, one for 12 months to compare treated vs. untreated and the other for 6 months followed by a 2-month regression to compare treated vs. commercially marketed products. In both studies, rotational regimen showed superior results to its matching comparison as assessed by clinical grading and image analysis of crow’s feet wrinkles. In conclusion, rotational regimen using retinol and PGA is effective in treating facial photoaging signs with long-lasting benefits.” Citations below.

          Khalil S, Bardawil T, Stephan C, Darwiche N, Abbas O, Kibbi AG, Nemer G, Kurban M. Retinoids: a journey from the molecular structures and mechanisms of action to clinical uses in dermatology and adverse effects. J Dermatolog Treat. 2017 Dec;28(8):684-696.

          Kong R, Cui Y, Fisher GJ, Wang X, Chen Y, Schneider LM, Majmudar G. A comparative study of the effects of retinol and retinoic acid on histological, molecular, and clinical properties of human skin. J Cosmet Dermatol. 2016 Mar;15(1):49-57. doi: 10.1111/jocd.12193. Epub 2015 Nov 18. PMID: 26578346.

          DiNatale L, Idkowiak-Baldys J, Zhuang Y, Gonzalez A, Stephens TJ, Jiang LI, Li W, Basson R, Bayat A. Novel Rotational Combination Regimen of Skin Topicals Improves Facial Photoaging: Efficacy Demonstrated in Double-Blinded Clinical Trials and Laboratory Validation. Front Med (Lausanne). 2021 Sep 17;8:724344.

          As to the brand, The Ordinary, we must plead ignorance. After looking online and finding the bargain basement pricing for these products, and being in the business of formulating and producing cosmeceuticals for a decade, we must caution our readers. These products are dirt cheap for a reason, making us believe the quality and quantity of their “active ingredients” must be far below what one would desire. Quality active ingredients add costs to production, and skimping on quality and quantity will produce inferior products. We’d stay away but that’s because we doubt there is much “oomph” in anything they are selling.

  13. Hi. I am about to make my own HA 1% serum (using water with the HA). I bought HMW-HA because I had heard of the inflammation low molecular weight could cause in the skin. I’m guessing my serum is not going to penetrate the skin though. Am I just making a barrier that will set on top of my skin? Will any of it penetrate? I’m looking for added moisture as well as some anti aging benefits and I’m starting to think HA isn’t the answer. Thanks!

    • drjohn says:

      You don’t want HA to penetrate your skin. The value of HMW-HA applied topically is that it is too big to be absorbed but holds water like crazy for hydration while forming an effective barrier. Damaged barrier function is the culprit in many common skin irritations, allergies, and the like. It also leads to an aged appearance. LMW-HA is more likely to be absorbed, but has the negative effects mention in the post. HA alone may not be anti-aging in the true, regenerative sense of the word. But keeping skin well hydrated is a big part of the battle at any age. It’s not the whole answer, but is a great start. Bravo for mixing your own – its relatively simple and inexpensive. But keep in mind that without a preservative it is going to have a limited shelf life. Best to mix small batches regularly, paying attention to a clean environment and tools. Keep your DIY mixture in the refrigerator between uses.

  14. Kristi says:

    Hi Dr. John,
    Does your company sell HMW-HA yet? If not, what brand is reliable to use during and post needling? I have looked on Amazon and its very overwhelming. Thanks in advance!

    • drjohn says:

      Cellese only sells growth factor and stem cytokine based products, although we find HA to be a superior molecular host and hydration factor in our products. You can buy The Original Hyaluronic Acid Serum 100% Pure 2 oz. from Timeless Skin Care on Amazon for $9.98 with free delivery. A bargain. It’s not hydrolyzed so it is all HMW. The preservatives are not ones we consider to be troublemakers.

  15. Curious says:

    I have never seen this before. I went at looked at some products that I have and I am wondering if a product says that it has short and long chain HA are they saying the same thing? That short chain HA = low molecular weight HA and long chain HA is regular or high molecular weight HA?

  16. Kristi says:

    Thanks for your reply, Dr. John! Also wanted your thoughts on the micro current device Nuface and led red light for increased collagen. Seems that there are claims of research of accumulative effects of micro current by increasing ATP in the cells. And some studies seem to support led red light therapy. Many thanks!!!!!

    • drjohn says:

      Kristi, we have read many user reviews of NuFace that raise red flags: burns, landing strips, hyperpigmentation and the like. Of course electrical stimulation (ES) has a long track record in wound healing, and higher current RF devices in medical aesthetics (physician offices) product stellar results. . Microcurrent ES (MES) is less well established and in fact there is little clinical evidence for efficacy. Here is an excellent published review that says the same thing. Of note, NuFace doesn’t tell you their current parameters, and their study results or not anywhere to be found, so making comparisons with known science is difficult. However, low level current is also the basis for iontophoresis, which is a process whereby ionic molecules (actives) in a topical serum can be drawn into the skin (much better absorption). So, what does NuFace sell to go along with its iontophoretic MES device? Plant stem cell malarky – worthless nostrums based on blatant pseudoscience. Our advice is that you should never trust a purveyor of skin care who cannot tell the difference.

      Of note on a theoretical level: ES works by stimulating growth factors associated with early stages of wound healing, most prominently VEGF. VEGF promotes angiogenesis (new blood vessels) tends to be inflammatory. You may get more collagen, but it won’t be the pretty basket weave kind.

      We like iontophoresis, but we don’t like plant stem cell fiction, burns, inflammation and hyperpigmentation. If anyone has the wave form, pulsing, current type and other data for NuFace please send it our way.

  17. Kristi says:

    Wow!!! Thanks for the info, now could I please bother you on your thoughts about the red led light home units? Helpful or harmful? Different models have different wavelengths of light. I started using AnteAge skincare and wanted to do something non invasive to up the ante!!! Thought about micro needling and I have some autoimmune issues and am a bit hesitate to open those skin channels after reading about all the immune issues some folks are having with products. Even wondering if the preservatives in the pure HA could be bothersome.

    • drjohn says:

      The literature on LED therapy is generally quite good. Here is a recently published excellent review of the scientific literature on the matter of LED’s in dermatology. Red light can be both anti-inflammatory and regenerative. The effect is amplified in the presence of biochemical stimuli. Indeed we have had reports of users of red light plus AnteAge who found the combination to be quite effective. We are contemplating a clinical trial to document the effects of combined GF plus red light.

      Have I mentioned yet that there is now a research clinic in Newport Beach, CA devoted to aesthetics clinical research, with an emphasis of combining stem cytokine and growth factors with other modalities such as microneedling, laser, RF, LED, iontophoresis, ultrasound?. Any folks who live in the Orange County area who are interested can contact docs@barefacedtruth.com for information about ongoing studies. There is one starting up this week that studies hair restoration using a special cytokine/GF mixture along with microneedling with a new type of pen.

  18. Curious says:

    Thank you so much Dr. John! I was confused because of the way they worded that.

    • drjohn says:

      BTW – there is new research out that furthers the argument we make about the inflammatory nature of LMW-HA, and the mechanism of action includes the activation of macrophages (tissue eating white cells). Also if you look at fetal wounds vs adult wounds you see a marked difference. Fetal wounds (scare free non-inflammatory healing) have essentially zero LMW-HA present, while older adult wounds (scarring, inflammatory) have a mix of LMW and HMW hyaluronic acid molecules. The evidence is overwhelming.

  19. JM says:

    This is going to sound far fetched probably, but, I was researching LMW HA because after using it one time on my face, neck, and hands I experienced sore joints and nerve type pain in my hands and up through my wrists; and my face felt numb. It was bizarre. I have experienced this type of sensation once before while taking the supplement quercetin. It turned out that quercetin can cause inflammation so I had an answer for my pain which I was beginning to worry was RA. I am going to assume the LMW HA I used caused instant inflammation; but that almost seems impossible. Thank you for the information. It’s disappointing to find out that the miracle wrinkle cure isn’t a miracle after all.

    • drjohn says:

      JM, not so far fetched. Injection of HA into joints for therapeutic effects has been investigated quite a bit. The consensus is that HMW-HA is clinically more beneficial than LMW-HA. Further, if you look at inflammatory markers you see that they are much higher when LMW-HA is used. HA with a high molecular weight is more effective in downregulating proinflammatory cytokines such as interleukin-1beta and tumor necrosis factor-alpha. Quercitin has well known anti-inflammatory properties so i cannot make sense of that reaction.

  20. KK says:

    What about HA for vaginal dryness and absorption in your stomach?
    Somewhere, I read HA is good. Now I am reading this and I am confused with the technical words.
    Please, Is it HA good for Vaginal dryness?, What works the best, oral or topically? Can you recommend a brand? where can I get it?

    • drjohn says:

      Hi KK, HA is well proven in medical studies to be an excellent antidote to vaginal dryness. Both oral and intravaginal work, but intravaginal gets you higher exposure so works better. Hyalofemme is a product with HA only, available on Amazon.

      It is also well known that a particular growth factor (KGF) has a remarkable effect on thinned vaginal epithelium to regenerate it to a more normal state (safely). We have in fact now put together a product combining HA with KGF for vaginal rejuvenation (also for vulva). We call if RejuVV, currently in clinical testing.

  21. LW says:

    Thank you for all of this information. So please correct me if I have misunderstood but from what I have gathered from the article and comments that it is better to avoid the use of LMW HA and just stick with the HMW HA as a way to improve the moisture in the skin? Because the LMW HA can cause inflammation to occur. Also, I am very confused by the percentage amounts different companies quote for their HA. One will say theirs is 25% (professional use, not sold retail) while another is 2%. They seem so far apart, do you have any insight into this?

    • drjohn says:

      Yes, yes, and … hyaluronic acid comes in bulk as a solid which is then dissolved in water to become an HA solution. The standard solution for HA is 1% (that is, 1 gm per 100 ml) and anything much higher than that makes a solution that is too viscious to be usable. I believe that when folks say 25% HA they really mean 25% of a 1% solution (i.e. 1% diluted 4:1 with water). 50% would be a 2:1 dilution, etc. Nothing else makes sense.

  22. gm says:


    Thank you for sharing your knowledge with us.

    Are there certain cosmetic ingredients or environmental conditions that may cause HMW-HA to fragment into the inflammatory LMW-HA species? E.g.s: (1) Does combining HMW-HA with AHAs present this risk? (2) Does wearing HMW-HA in sunlight present this risk?

    • drjohn says:

      The fragmentation is caused by enzymes call hyaluronidases. Things that cause inflammation in the dermis would increase the production of these enzymes. So, to the extent sunlight or acids cause inflammation they would indirectly cause fragmentation through production of hyaluronidases. Ascorbyl palmitate variants have been shown to inhibit hyaluronidase. The work is early but if true would be a good reason to put this in anti-aging skin care formulations.

  23. gm says:

    Thanks for your reply – your knowledge is much appreciated.

    Is degradation of HMW-HA into LMW-HA, via oxidising agents, worth considering?

    Also, is degradation of HMW-HA by ascorbic acid worth considering?

    Often, HA skin care products contain many ingredients, and I am concerned that some of these don’t play nicely with HMW-HA.

    • drjohn says:

      It really is an enzymatic process (proteases) so I’m not worried about oxidation per se causing HA fragments. Although oxidation can cause release of proteases within the matrix. Vit. C as an antioxidant in a non-inflammatory form and dose could only help. The things that don’t play well are things causing inflammation.

  24. Yves says:

    I would be curious to hear your response to the comment from “jm” dated Dec 8, 2015. Thanks!

  25. yolly says:

    I am curious as to what you think of this company and their serums? Are they really what they say they are on the tin?!

    • drjohn says:

      http://episilkserum.com/pha_serum.html. I think this company is completely “science impaired”. I have no trust in anything they sell. Here’s why: They hawk a product called Renu-Age. Said product is claimed to “improve microcirculation”. They source the ingredient from Pentapharm, one of those dubious Swiss cosmeceutical houses. Here is what Pentapharm has to say: Efficacy tests – In vitro tests (aPTT-activated Partial Thromboplastin Time and TT-Thrombin Time) have shown that REGU®-AGE improves the microcirculation. Oh, really? Any 1st year med or nursing pharm student will tell you that PTT and PT are tests that measure blood clotting, not microcirculation. If they indeed are modifying PT and PTT then they are causing blood clots or a tendency to bleed. Either would be dangerous. Of course it is unlikely that the substance does so, but it shows the total and complete lack of even basic knowledge of physiology, or a tendency to deceive by just pulling some acronym test name out of a hat and pretend they even know what it means. This is the worst kind of example of the snake oil salesmen of the cosmetic industry. I point to those egregious European ingredients suppliers and marketers who think we are all too stupid to know anything, so they can say whatever they want. Sheep being led to the slaughter. Really niggles me. Can you tell?

  26. KL says:

    If HA is degraded into smaller fragments at the site of inflammation, wouldn’t applying topical HMW HA to an inflamed skin instigate the inflammatory cascade, particularly in a rosacea skin or skin that has been microneedled?

    • drjohn says:

      Great nerdy question. Here is the ultra nerdy answer. No – because HWM-HA actually counteracts the effects of LMW-HA. Here’s why – the skin is abundant in cells that express CD44. This is a cell surface receptor involved with inflammation on/off through TLR (toll like receptors). While LMW-HA can attach, stimulating inflammation, HMW-HA attaches but forma a sort of film that coats the surface to then prevent LMW-HA from attaching. It’s very cool! Now, if you have a lot of hylaluronidase around (the natural enzyme that breaks down HMW into LMW-HA) some will become fragmented. But it’s a game of numbers. If the balance is in favor of HMW-HA, anti-inflammation wins over inflammatory responses. Small puncture wounds don’t require much in the way of inflammation for healing. You want to tip the balance there quickly. Rosacea is a chronic self-perpetuating inflammatory disorder, and there you want to tamp it down permanently.

      If you want really nerdy you may want to scan this paper: http://www.woundsresearch.com/article/hyaluronic-acid-inflammation-and-tissue-regeneration#sthash.CyuN08Ys.dpuf


      “In physiological conditions, the activation of immune system cells is crucial for proper wound healing. In acute wounds, small hyaluronan fragments accumulating at the site of injury activate the immune system to manage rupture in tissue integrity; however, in chronic wounds a constant excessive inflammatory response proves to be a negative phenomenon that actually prevents that wound from healing. ”

      “Several studies have concentrated on TLRs and TLR signaling as a key player responsible for proinflammatory properties of LMWHA. Several authors have confirmed, using in vitro studies, that LMWHA is able to bind to TLR receptors and consequently initiate the signaling cascade, leading to the production of proinflammatory cytokines and chemokines in various types of cells.46 In immune cells from injured tissues, TLR2 and TLR4 activation by LMWHA leads to initiation of MyD88-dependent NFκB signaling cascade and pro-inflammatory cytokine gene expression.14,47 Iwata and coauthors48 have shown that LMWHA stimulates B lymphocytes via TLR4 receptor to IL-6 and TGF beta production. Induction by LMWHA TLR-related myeloid differentiation primary response gene 88 (MyD88)/NFκB signaling was also confirmed in breast tumor cells. Bourguignon et al49 have shown that small HA fragments stimulate CD44 association with TLR2, TLR4, and MyD88, leading to NF-κB-specific transcriptional activation and the expression of proinflammatory cytokines IL-1β and IL-8 in the human breast cell line. Taken together, these reports suggest that LMWHA induces inflammation via activation of TLR receptors and initiation of MyD88/NFκB signaling which leads to production of proinflammatory cytokines and chemokines.”

  27. KL says:

    I was playing devils advocate. I’m writing an article on the benefits of HMW HA in rosacea skin, and was looking for any possible argument against its use by a clinician 🙂 Thanks for talking nerdy to me.. lol

    • drgeorge says:

      KL, in checking Google Scholar and PubMed, there are numerous articles wherein HA is described as part of topical formulations for various topical treatments for rosacea. The issue, then, is there an optimal molecular weight HA to use for this purpose. As Drjohn pointed out in his article, low molecular HA is pro-inflammatory whereas high molecular weight HA has the opposite effect. Based on that fact, it seems high molecular weight HA is preferable in rosacea skin. That is, however, not the complete story. Two studies cited below, demonstrated improvement in rosacea and seborrheic dermatitis using low molecular weight HA salt gel. We do not, however, see studies arguing against the use of high molecular HA in rosacea.

      JJ Drugs Dermatol. 2013 Jun 1;12(6):664-7.
      Efficacy and tolerability of low molecular weight hyaluronic acid sodium salt 0.2% cream in rosacea.Clin Aesthet Dermatol. 2014 May;7(5):15-8.

      J Clin Aesthet Dermatol. 2014 May;7(5):15-8Efficacy and safety of a low molecular weight hyaluronic Acid topical gel in the treatment of facial seborrheic dermatitis final report.

  28. Bj says:

    Hi, I am a little confused.
    I stumbled on this article due to skincare product confusion. I have been using devita skin care natural vegan products. I use pretty much the whole skin care line and love them. I’m using a particular product by devita skincare that I really enjoy atleast it feels good on my skin it is the hyaluronic surugel it is supposed to be 1percent hyaluronic acid and it just says vegan source. Well I just turned 30 and as we humans do when we reach age milestones I am imagining my face is falling,my pores are enlarging,my wrinkles are starting and I must turn back the clock lol:) So I started investigating stronger more chemically laden beauty products and I am so confused by alot of things because all of these companies have their own hook. “Use mine cause its natural, use mine because its scientifically advanced, use mine because its expensive or inexpensive” you get the picture. Even the simple thing like hyaluronic acid…
    I found a bellevolve advanced hyaluronic serum containing both hydrolized nano form and a sodium hylaronate they make it sound terrific but that’s marketings job so I’m confused is that bad or good. Is it ok to stick with natural skin care products and vegan sources of hyalauronic acid or are they ripping me off?should I step up to more advanced science and “proven” chemically laden products?

    • drgeorge says:

      For many reasons, the topical skincare world is perhaps the most crowded and confusing of them all. It’s the perfect alignment of demand (everyone wants to look better and slow the aging clock, particularly women), unwary consumers (very few people have the knowledge and background to make informed discerning judgments about ingredients), marketing chicanery (outright lies and fantasies, admittedly once in a while with an occasional kernel of truth), and HUGE profit opportunities (even if the consumer only buys your product once.) Throw in the fact that every famous pretty face wants in on the action, and it makes the wild west look tame.

      Hyaluronic acid, in one form or another is found in many products because it is such a great hydrator, and plump moist skin looks better than dry skin with less volume. It’s also a natural molecule easily tolerated by everyone. Drjohn discussed the molecular size aspect, and the potential for promoting inflammation, so his advise is a good reference regarding HA. But your question goes further.

      Active ingredients that have proven published benefits when used on the skin are the direction you want to go, especially as you head into your 30’s and beyond. Spend some time reading about the ones that comprise the dermatologists’ pyramid of skin health and beauty. Of course, sun protection is #1 regardless of age and use it everyday! Then comes AHA and BHA (acids that promote exfoliation), Vit A (Retin-A, retinol, etc.), Vit C, Vit E, niacinamide, green tea, resveratrol grape seed oil, curcuminoids (from tumeric), isoflavones, ceramides, linoleic acid, and most recently added, growth factors and cytokines from human stem cell culture.

      Getting them all and using them will break the bank and eat up half your day, so look for products that contain multiple actives. Your BFT hosts, drjohn and drgeorge, developed one you may want to consider that we think is best in breed. Email us if you want to learn more about it.

  29. CR says:

    I do microneedling and use SkinCeuticals Hydrating B5 Gel as a glide. Would this be appropriate and safe? The ingredients in order are Water, Sodium Hyaluronate, Panothenic Acid, and Phenoxyethanol.

    • drgeorge says:

      We are not fans of using anything for microneedling that in not found naturally WITHIN the skin so HA and normal saline make the cut. So do microneedling solutions formulated for that purpose that contain natural growth factors and cytokines with the caveat being they should REDUCE inflammation. For a deep dive into microneedling science, we strongly recommend The Concise Guide to Dermal Needling by Dr. Lance Setterfield.

      Here at BFT, we see some nasty reactions from people who have tried non-physiologic ingredients like the so-called snail growth factors, covered in depth in posts here on BFT. We are also aware of skin reactions to serums containing copper peptides and Vitamin C. We can’t say for certain which ingredient in these products is the culprit because there are several that are NOT physiologic nor found naturally in the skin. I suggest you read our posts here and stay cautious. If you would like to learn more about the product your BFT hosts formulated in consultation with Dr. Setterfield, send us an email. We are not aware of any reactions and the number of applications is approaching 100,000.

  30. Kim says:

    Hi Dr John/George

    I have eczema and ligament inflammation in the knee (arthritis?) and degeneration of the metarsophalangeal joints.

    1) for eczema = what type of HA to apply (HMW?)
    2) for arthritis and degeneration of joints = what type of HA to
    consume and how much at one time?

    3) There is a type of HA Oliga = Is it better than HMW?

    4) Any side effects for consuming Na Hyaluronate powder?
    I read that Stanford Chemicals is selling them but I do not know
    their quality?

    Also, Bulk supplements are selling Sodium Hyaluronate powder with numerous good reviews.
    Any idea?

    I have not bought any yet as I want to buy the correct type and quality?

    Thanks so much

    • drgeorge says:

      Thanks for your questions, Kim. In eczema, the anti-inflammatory effect of high molecular weight as opposed to other size molecules makes it a preferable choice. Inflammation is the major component In fact, I just ran across an article where HA has shown anti-inflammatory benefit in gingival (gum) treatment for periodontal disease. Worth a try for sure.

      As far as its use in arthritis is concerned, oral radioactive tagged high molecular weight HA was fed to rats and dogs. Most (86.7 to 95.6%) was excreted in urine and feces, almost all in the feces. There was, however, evidence that radioactive uptake was present in skin, bone, and joint tissue at 24 hours. A different study in rats with oral and injected radioactive tagged HA showed up to 90% was absorbed from the digestive tract and used as an energy source or a structural constituent of tissues. The tissue that showed the majority of deposition was the skin, not the joints.

      The above makes BFT extremely skeptical of the efficacy of HA in arthritis. I am certain the marketing materials used to sell such products would have a completely different message. If you have access to what scientific claims they make, and the studies used to substantiate those claims, we would love you to share. Our bottom line at this juncture, save your money until the science is clear and convincing – to you and to us.

      While there is well documented proof of efficacy of intra-articular injected HA in osteoarthritis, the lack of

  31. Stephen says:


    Regarding HMW Hyaluronic acid what molecular weight in kDa would you recommend using?

    The following articles suggest that 50kDa has the benefit of topical absorption without the pro-inflammatory effects. Do you agree with this? Thank you.


    Farwick M, Gauglitz G, Pavicic T, Köhler T, Wegmann M, Schwach-Abdellaoui K, et al. Fifty-kDa hyaluronic acid upregulates some epidermal genes without changing TNF-α expression in reconstituted epidermis. Skin pharmacology and physiology. 2011;24[4]:210-7.

    Farwick M, Lersch P, Strutz G. Low molecular weight hyaluronic acid: its effects on epidermal gene expression & skin ageing. SÖFW Journal. 2008;134[11]:17.

    • drjohn says:

      Hi Stephen, this article makes conclusions from its own data that I disagree with. It states “no pro-inflammatory effects” and yet TNF-alpha (a very inflammatory cytokine) is elevated both at 20kDa and 50 kDa HA sizes. Here is the graph from that paper:

    • drjohn says:

      Stephen, the article makes conclusions that are in conflict with the data they themselves present. Look at this graph:


      Clearly TNF-alpha is elevated to at least twice normal at both the 20kDa and 50 kDa HA sizes. TNF-alpha is a highly inflammatory cytokine. Only when you get to 360kDa (LMW) do you see it return to baseline. The gene expression itself looks “defensive” – the skin is trying to create a barrier against a stress or invader. They should have measured matrix synthetic genes.

  32. Candice says:

    Hello Hi Dr John/George,

    Can you tell me what you think of Paula’s Choice Resist Hyaluronic Acid Booster? She uses Sodium Hyaluronate and Hyaluronic Acid in the HA Booster. Not sure if the HA in the product is LMW HA. http://www.paulaschoice.com/shop/skin-care-categories/targeted-treatments/_/Resist-Hyaluronic-Acid-Booster

    Also, can you tell me if the problem with the Hylamide Booster Low-Molecular HA is the inclusion of Hydrolyzed Sodium Hyaluronate, not the Sodium Hyaluronate Crosspolymer? http://hylamide.com/product/booster-low-molecular-ha-30ml

    And why do companies that seem to be innovative like Hylamide/NIOD contain LMW HA in their products if it is problematic?


    • drjohn says:

      I think Paula’s in the good stuff (HMW). The problem with any lysed HA is the signaling nature of the fragments which turn down your own collagen synthesis. To cross link a LMW HA is silly in the first place, since the supposed reason for making in LMW is to allow it to absorb, while cross linking does the opposite and assures it will not be absorbed.

  33. Matt says:

    Interesting article, yet it seems that LMW-HA is considered safe to use in other quarters, which makes me a little confused.

    What is your opinion on this study that showed a number of beneficial effects of LMW-HA?


    • drjohn says:

      Matt, this paper doesn’t seem to be a bout LMW-HA, but since it never mentions MW at all, only size of molecules (nano) we can’t be sure. But since it explicitly states they “reduce the size of HA molecules without disturbing their constituent subunit structure” we will assume that no hydrolysis or fragmentation takes place. Sounds more like a new de novo synthesis in the lab. Since all molecules are nano anyway, it makes even less sense. Lost in translation?

  34. kelly says:

    Are any of the ingredients used in the Ante Age products considered “hormones”? I stay away from hormones because I develop melasma easily on my face.

  35. G says:

    Regarding the Paula’s Choice product above, it does contain low molecular weight HA (as do other products of hers). This info is given under the FAQ section for that product, under the question “What is the difference between sodium hyaluronate and hyaluronic acid?”.

    Many companies use LMW HA but call it sodium hyaluronate in the ingredients list. I always ask companies what version of HA they use, and most of the time they say LMW. Very annoying.

    • drjohn says:

      Sodium hyaluronate is the sodium salt of HA. Making a salt form has nothing to do with MW per se, it is more a way to “clean up” the native molecule which tends to bind lots of stuff like lipids, proteins, etc. But it is still native HA -as opposed to fragmented HA (LMW) which happens when you add a digestive enzyme (hyaluronidase). Paula (well really her hirelings – she just reads what they write) seems to think sodium hyaluronate will penetrate skin, but this is incorrect. It is still a huge molecule. But that’s OK because its benefit happens right there anyway – on top of skin – proving a natural barrier.

      • aliha says:

        Hello, Thanks for the really informative article. Regarding HMW Hyaluronic acid what molecular weight in kDa would you recommend using? I have found one at Amazon.com from bulk supplements. It is described as pure Hyaluronic acid-(Na Hyaluronate) (verified in lab) and although the moelcular weight is not mentioned, when contacted they described it as 0.8 MilliThe powder does convert into thin gel like sonsistency when dissolved in cold atrer (in contrast to LMW HA which does not form gel when mixed in water). Any help would be really appreciated. Thanks

  36. Tess says:

    Wow! I came across this article because I had read about the ‘Asian beauty regimen’ and how HA is important in the use of pne having dry skin.
    I’ve never read your blog or anything else: so for a 37 yo female with some sensitivity and dry skin and just having started to research what I need to do face-wise/age-wise – can you tell me about skinmedica aha/bha and HA products? Yay or nay? I’m also ingesting 1000mg of vitamin C and 2300mg of evening primrose oil which the oil seems to have really helped ‘plump’ my skin? Any info is greatly appreciated – here’s the links to the skinmedica products: http://ha5.skinmedica.com and https://www.skinmedica.com/aha-bha-cream.html If these are not recommended, I saw in one of the threads you recommended a ‘pure HA for $5 per oz on Amazon – can you please give the name? And what recommendations on BHA /AHA (any combo pairing for me is questionable) can you comment on what would be better? I’ve been reading on Paula’s choice and she’s not a fan of the BHA /AHA at all – would love to hear your thoughts ??

    • drjohn says:

      Tess, I’m also not a fan of HA/AHA (irrational combo) and while I respect SkinMedica’s roots and good science of the past, I find the HA5 product to be reflective of new people being in charge at SkinMedica. We are now seeing a trend to form over substance, and marketing over science. Sad indeed. See review of GA5 in response to Martha’s question, above.

  37. Tess says:

    Also – what do you make of the Danne montague King line- cannot find a decent review on it due to it being deemed ‘paramedical’ – and I’ve also been using it for years and getting the cinnamon facial and the alkaline facial – thank you!

    • drjohn says:

      Tess, quacky sounding enzyme stuff, to be sure. Enzymes chew stuff up – our bodies internal garbage disposals. One does not “dissolve” scars with enzymes – you might deepen them! Enzymes (luckily) are short lived on skin, as they are neutralized by the skins production of its primary defense system – endogenous enzymes called proteases which rapidly dispose enzymes and other proteins that land on our skin.

      • M says:

        Interesting take on scar tissue and inflammatory response. What do you think about this possibly being a trigger for fibrosis disorders like Dupuytren’s Contracture? I fear this triggered or could worsen it for me as I now have this condition.

        • drgeorge says:

          Dupuytren’s disease is a fibroproliferative disease that involves collagen deposition and ultimately affects hand mobility and grip strength. The first reference to this pathology dates back to 1614. There is a difference between Dupuytren’s disease and contracture. The first is a general nomenclature, including both asymptomatic patients with only minor soft-tissue changes that do not limit function and those with severe disease and contracture. Contracture, on the other hand, defines only those patients with affected function. It is more common among Northern European men and rare in blacks and Asians. Its prevalence in 12% at age 55, rising to 29% at age 75.

          The cause of Dupuytren’s disease is poorly understood but may be related to microtrauma. In the early stages of the disease, the common type 1 collagen usually found in hand tissues is replaced by type 3 collagen, which is a main component of reticular fibrous tissue. It develops following an inflammatory response. It appears to have an autosomal dominant inheritance pattern. Diabetes mellitus also seems to be a risk factor with a 3 fold greater risk. Smoking and alcohol intake have also been related to its development with both smoking and alcohol having a dose-response association with the disease. Workers who use vibratory tools have a higher risk. It most commonly affects the pinkie and ring fingers of the hand but can affect all digits.
          It evolves through a variety of stages. The first one, called proliferative, is characterized by the development of nodules. When these nodules start to contract, the disease enters the involutional stage, when collagen production increases and myofibroblasts become the predominant cell type. Nodule-cord units develop. In the last phase of the disease, the residual phase, myofibroblasts decrease resulting in hypocellular nodules and cords formed predominately by types I and III collagen. The classification varies from a stage 0, in which a nodule or cord without contracture is present, to stage IV. Every stage from I to IV corresponds to an increase in 45º of overall extension loss.
          The main objective of treatment is to improve digit extension and hand function. Therefore, treatment is usually proposed before hand function is severely affected, that is, before long-dated severe finger contractures which might cause joint stiffness, as relatively newly developed contractures carry a higher probability of success.
          Both steroids and vitamin E have been tested in the treatment of Dupuytren’s disease. However, studies are still lacking to prove the benefit of these agents. Physical therapy seems to improve digital extension, hand span and grip strength. However, the evidence is still not conclusive. Radiotherapy allegedly reduces the development of myofibroblasts and it is claimed to have indications in early disease. However, toxicity might preclude its use. Collagenase is an FDA-approved alternative to surgery which is still the standard of care for Dupuytren’s disease.
          Dupuytren’s disease: history, diagnosis, and treatment. EFORT Open Rev. 2019 Feb; 4(2) 63-69

  38. Kelly says:

    My Ante-Age duo is on its way!

    What should my AM and PM skin routine be then? (Currently–AM: cleanser, vit C serum, moisturizer, Tizo sunblock.
    PM: cleanser, Obagi 5 blender with Refissa)
    Thank you

  39. G says:

    Paula’s product also contains fragmented HA though – it has both HMW and LMW HA.

    As you said above, sodium hyaluronate contains native (HMW) HA. But some companies list ‘sodium hyaluronate’ in the ingredients list when they have in fact used fragmented (LMW) HA. I know this because I have emailed some companies to clarify what their ‘sodium hyaluronate’ refers to. Are these companies mislabelling their products, or am I misunderstanding something?

    • drjohn says:

      They are misleading, because they they themselves are mislead. So many “formulators” in this industry have no training whatsoever in biologic sciences, skin physiology, or biochemistry. More art than science. We have provided more than ample evidence of the untoward effects of HA fragments, so-called LMW-HA, especially when you get down below 150kD. Published studies abounds. Does nobody read, or understand, the scientific literature?

  40. tariq says:

    does anyone know where i can by very high weight HA for oral use?

  41. Zen says:

    Hello and thank you for the wonderful article!
    I may have missed it, but what is considered a high weight and what is considered a low weight? For example, I purchased a “mix” of weights, but with nothing to compare it to, I’m not really sure what is considered a “high” weight and what is considered a “low” weight, generally speaking .
    200k – Penetrates deep into the skin, healing and hydrating (this almost frightens me in light of your post)
    500k – Penetrates into the top layers of skin to promote elasticity and hydration.
    800k – Works with the top layer of skin to create a protective, hydrating layer; holding in moisture, balancing pH, and maintaining elasticity.
    Thank you so much for your wonderful blog. I’m already hooked!

    • drjohn says:

      See answer to Ritu below. By “k” I believe you mean kDa (daltons, or kiloDaltons to be precise). For proteins, 50 daltons is considered too big. So even 200kD would be huge. (this ignores all sorts of tricks available to cloak molecules so they get through the barrier – not used here – subject of a post in the future).

  42. Ritu says:

    Hello, Thanks for the really informative article. Regarding HMW Hyaluronic acid what molecular weight in kDa would you recommend using? I have found one at Amazon.com from bulk supplements. It is described as pure Hyaluronic acid-(Na Hyaluronate) (verified in lab) and although the moelcular weight is not mentioned, when contacted they described it as 0.8 MilliThe powder does convert into thin gel like sonsistency when dissolved in cold atrer (in contrast to LMW HA which does not form gel when mixed in water). Any help would be really appreciated. Thanks

    • drjohn says:

      High molecular weight (HMW) HA is always >1,000 kDa. Anything lower than that (10-1000 kDa) should be considered LMW. The powder granule size tells you nothing about MW. The bulk Supplements products is HMW in the sodium salt form.

      • Ingrid says:


        I do understand that this article is a few years old, but, I do have a question regarding Hyaluronic acid, sodium hyalorunate and the different molecular weights I really hope you can help me with, due to health situation and sensivity.

        I started use HA for the first time just s couple of weeks ago. First in form of a serum with sodium hyaluronate, and then in form of a cream, where they say to have formulated with both high and low molecular weights. Or as they say «sodium hyaluronate in two different molecular weights, providing deep hydration from the most inner layer to the outer layer of the skin».
        But, they say «sodium hyaluronate in two different molecular weights». First of all, can also sodium hyaluronate be hydrolized in to smaller molecular weights?
        And, if they not, what does this mean?

        Secondly, my skin have been severaly dehydrated due to longterm illness and stress put on my body, so when started use, (first the serum and secondly the cream, not together but seperately), my skin plumped extremely up with only two applications. It of course feels much better, – does not feel dehydrated in the inner layers anymore, and looks better.

        But, is it quite normal that the skin will plump up that rapidly if the hyaluronic acid used is not hydrolized? (Although my skin has been extremely thirsty) Does this mean that the molecular weights in both the serum and cream are too low?

        Should add that the cream consists of 3% hyaluronic acid both low molecular weight and the high from what they say. But, the information is a little bit confusing, and did first get the percentage info after emailing the company.

        Thank you, and really hoping I can get clearence and help regarding this, due to my health situation, as well as having thinner and sensitized skin below my eyes due to recently severe eczema/inflammation flare, and wanting to take care and strengthen the skin.
        Both the companies is supposed to be targeted towards sensitive and eczema prone skin. And, especially the company with the cream. But, still I an unsure due to the confusing information regarding «sodium hyaluronate in different molecular weights».

        • drjohn says:

          Ingrid, yes, HA can be hydrolysed (broken into smaller, low molecular weight fragments. That’s generally how these manufacturers are making the LMW version.
          HA is a great moisturizer, as it repairs the skin barrier to hold moisture in, and is quite natural. Yes, you can feel it on the first application.
          You don’t need it to penetrate! it works mainly on the skin surface.
          3% HA is a bit think, as it turns to a jello like consistency once you get above 2.5%. But all you need to do is add a little water of your own to make it just right.

          At any rate – I continue to recommend that you avoid anything with LMN – HA, no matter what the concentration.
          There is an increasing body of evidence about its inflammatory signaling nature, and the penetration story is nonsense since its benefits do not even depend on penetration.
          More skin care industry hocus-pocus.

  43. Jocelyn says:

    I know I’m late to the party here, but after reading this post last night I contacted Paula’s Choice because I’m another reader who has relied on PC to provide well formulated products based on science rather than industry hype. I have been using the PC hyaluronic acid booster for some time now (and it is fairly expensive so I want to know it’s doing some good). Here is their response to my inquiry:
    “Thank you for reaching out to us! I would be more than happy to help. Our RESIST Hyaluronic Acid Booster uses a combination of low molecular weight hyaluronic acid, high molecular weight hyaluronic acid and sodium hyaluronate for a cocktail approach to skin-identical ingredient and NMF (natural moisturizing factor). None of these ingredients is inflammatory when used topically and responsibly.
    Low molecular weight hyaluronic acid is capable of penetrating below skin’s surface, but not much deeper than that. Ingredients like antioxidants and skin-identical ingredients need to stay in skin’s upper layers to yield their intended benefits, including defense against environmental free-radical damage (which hits the skin’s surface first).”

    So, yes, I’m disappointed that she does in fact use LMW HA in her product(s). What percentage of the HA used is LMW is unknown, of course. I have a freshly new bottle I’ve just begun using and I’m now on the fence as to whether I should continue using it. At $45 for just 0.67oz I’m inclined to finish it up before moving on to the Timeless serum suggested above. What to do! At any rate, I’m just a lay person who likes to stay informed and spend my limited resources on things that work well, and very much appreciate the solid info shared here. Cheers!

    • drjohn says:

      I understand PC has a staff of “researchers” but not actual PhD or MD level scientists. I think they have the best of intentions, but don’t always get it right in the deeper aspects of the science. We respect them for their adherence to quality standards, nonetheless. Why don’t you send them a list of the key reference we provide here, and ask them for a response? Maybe you will tickle their interest to read further on the subject.

  44. Martha Landon says:

    I’ve really enjoyed reading your site and have learned so much. Have you all taken a look at the new-ish Skinmedica HA5 product? After seeing that you felt like the The Original Hyaluronic Acid Serum 100% Pure 2 oz. from Timeless Skin Care on Amazon for $9.98 was a great deal and works well. The SkinMedica HA5 is $178.00 on their website. Wondering what theirs has to offer that the Timeless version is lacking? Thank you for any thoughts.

    • drjohn says:

      I find HA5 to be both confusing and disturbing. It’s marketing message is that it contains 5 different forms of HA. 1. cross-linked HA, 2. non cross-linked HA 3. sodium HA 4. time release HA, and 5. nano HA. The latter sounds like HA hydrolyzed into LMW fragments, since intact HA molecular size is more than 3,000 nm.

      You can read here and look up all the references as to why we think LMNW HA has major problems in causing inflammation and inhibiting healthy, non-scarring matrix production. As to #4, why would time release HA be of value (other than a marketing gimmick?) Released from what? There is much confusion out there about the difference between sodium hyaluronate and HA. This just adds to it. The sodium salt is the exact same HA molecule, but in order to create the salt the native form may become purified of other tagalong molecules that like to attach to HA. Those might be lipids, or even growth factors. Of course with synthetic HA you start with a pure salt of some sort anyway (could be K+ or whatever). The notion that it is smaller and therefore penetrates skin better is not accurate. Even the Na+ salt is a huge molecule and not likely to gain entry in any meaningful numbers.

      Now we like topical cross-linked HA for several reasons, most especially because it forms a stable framework in which we can embed some of our favorite growth factors and anti-inflammatory cytokines. But there is no attempt here to take advantage of this. Instead, they add some non-science (quackish) ingredients like plant stem cell extract. Any company that does that is showing its true colors – short on science, the marketers have taken over, there is a sucker born every minute, etc. Sad, because a few years ago SkinMedica was a thought leader and did good quality science. I hope for the sake of the consumer they get back to their medical roots.

  45. Clementine says:

    Hi drjohn,
    Wow, I can’t believe I found you! You appear to be the HA guru and then some!
    At any rate, thanks for all the well researched data and advice. The following quote from you last year reads this:
    “Getting them all and using them will break the bank and eat up half your day, so look for products that contain multiple actives. Your BFT hosts, drjohn and drgeorge, developed one you may want to consider that we think is best in breed. Email us if you want to learn more about it.”
    Yes, I would like to know more about this. Is it available yet?

    Also, in another reply to a reader you said this: “….. put together a product combining HA with KGF for vaginal rejuvenation (also for vulva). We call if RejuVV, currently in clinical testing.”

    Is RejuVV available yet and in its absence do you still recommend Hyalofemme on Amazon?

    Finally and in relation to VA do you recommend the High Molecular Weight oral capsules and if so, any brand in particular you would recommend?

    Many thanks for your insights and time and sharing your knowledge with we laypeople.

    • drjohn says:

      Not so sure about oral HA for VA. No evidence I know of. Once HA gets to the gut it gets digested, hydrolysed, broken down to peptides and amino acids. Then it takes a first pass through the liver where it gets shunted into all sorts of pathways. best way to get some surface action going intra-V would be more direct application. Hyalofemme fits the bill. Wish it were free of other chemicals though. You could buy HA in bulk and make your own (until we get RejuVV out there).

  46. David Archer says:

    Hello Doctor,

    So I recently had an eye exam and it turns out I have a little dermatitis around my eyelids. My Optometrist recommended a HA-based eyelid soothing cream called ilast, which is 0.5% Sodium Hyaluronate. Do you have any thoughts on the ilast product line? There is ilast clean and ilast care. Both are HA-based, but the clean is 0.2% Sodium Hyaluronate, and the care is 0.5% Sodium Hyaluronate. This is the HMW HA correct?

  47. Lily says:

    Hi Doctor,

    How do you feel about the Ordinay’s hyaluronic acid + B5 serum based off the ingredient list? The description states it contains LMW HA. Should I discontinue use of the serum?


    Here are the ingredient provided:
    Aqua (Water), Sodium Hyaluronate, Sodium Hyaluronate Crosspolymer, Panthenol, Ahnfeltia Concinna Extract, Glycerin, Pentylene Glycol, Propanediol, Polyacrylate Crosspolymer-6, PPG-26-Buteth-26, PEG-40 Hydrogenated Castor Oil, Trisodium Ethylenediamine Disuccinate, Citric Acid, Ethoxydiglycol, Caprylyl Glycol, Hexylene Glycol, Ethylhexylglycerin, Phenoxyethanol, Chlorphenesin.

    • drjohn says:

      Lily, looks like another product where the “formulators” (or maybe just marketers) ignore the compelling published, peer-reviewed medical evidence base – how expedient. Web site rather telling -products about fashion, not about science.

  48. JAS says:

    what are your thoughts of a product based on both HMW & LMW-HA in an ratio favouring HMW-HA, so to give the potential benefits of both types?

    • drjohn says:

      Makes no sense since there is no clinical benefit to LMW-HA, as indeed many studies show that small fragments down regulate regenerative process and act as inflammatory stimuli.

  49. C says:

    Oh how I have enjoyed reading this! Thank you so much!

    May I ask one thing, which remained unclear to me – does HMW HA prevent certain active ingredients from penetrating deeper into the skin? If it acts as a barrier to lock moisture in, does it lock other things out?

    I am wondering about vitamins and the like applied in form of an oil on top of an HA serum.

    Looking forward to your answer, will be highly appreciated.

    • drjohn says:

      Good question! There are a group of proteins that bind to HA (hyaladherins). Some of this are cytokine/GF signaling molecules which can be active ingredients (e.g. present as constituents of conditioned media of stem cells). This does not, however, mean that HA locks these actives out – in fact it may provide them with a safe harbor so that they can be released by diffusion and amplify an effect, or prolongs its action. We think of HA sometimes as being a molecular chaperone. Especially in the context of microneedling, where the skin barrier is penetrated. For other (non-hyaladherin) actives, providing an HA protective layer helps prevent degradation of e.g. delicate proteins by keeping them moist and in contact with stratum corneum. It makes more sense then to use HA as the top layer. As a glycoprotein, mixing oil in confuses the picture.

  50. Leuca says:

    I kept reading about this LMW HA craze so I simply googled it and yours was the first page that came up. Based on how companies tend to label their products vs what ingredient manufacturers are telling them, is there really a safe way for people to decipher ingredient lists anymore, at least when it comes to ingredients such as HA? I see companies like Paula’s Choice/Drunk Elephant stick to HA/SH/SHCP on their ingredient lists; what is the chance that said ingredients could actually be hydrolized and there is a miscommunication?

    After a recent bout of contact dermatitis from a bunch of bug bites, and as somebody who tries to be up-to-date in taking care of my skin in general, I’m scared that I could be inadvertently purchasing a product that could be not only slowing my recovery, but hurting my skin’s long-term health/appearance in the process.

    • drjohn says:

      Leuca, we appreciate your concerns. Because the use of LMW HA is scientifically unsound and therefore mostly used as a marketing trick (“our HA is better than their HA”) then I would suspect that if they are employing it they are also putting it on the label and advertising it as such. And because it takes an extra step to make it LMW, it adds a bit to the cost. So I wouldn’t worry about that. But you are very wise to look into these things, because so much of what is marketed is so completely whacky and just as likely to do harm than good.

  51. Shelly says:

    Hello Doctor – Thanks so much for your wealth of information and sharing it with us!
    Could you let me know the best order of applying products for am/pm facial care. For am – wash, tone, serums (vit.C, Coenzyme Q10, etc…) HA serum, moisturizer and then sunscreen. For pm – wash, tone, retin A, HA serum, moisturizer. I question when to apply the HA serum. Thanks again!

    • drjohn says:

      HA stays on the surface, doesn’t normally penetrate intact skin, and helps construct the natural defense barrier against the ravages of the world. HA should be the topcoat.

  52. MishyMash says:

    Great article – the information and humor are greatly appreciated! I reserve the ULMW HA (5k daltons or less) for formulations containing actives, such as LAA and peptides, due to the clinical findings available via https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970829/. Junk science. clever marketing, or both????

  53. Rita says:

    Hi, I am looking into purchasing Pure Bulk Hyaluronic Acid (Bovine Sourced). It says it is long chain. I know you mentioned in your post that long chain is HMW HA. So, with that being said, do I just trust that this product HMW HA is high enough, and that it is not a MMW HA. I want to be 100% sure of what I am putting on my skin, so that I do not cause any harm to my body. The website does state that it is 1.29 x 10 da. I’ve tried to figure this out on my own, but I’m at a loss and would really appreciate your help if you don’t mind. Thank you

    • drjohn says:

      Looks like the HMW stuff to me. What concentration, and how will you use it?

      • Rita says:

        I would be mixing a 1% solution (HA and water) for my face.
        My mom is considering taking it internally due to the fact that her optometrist told her that the gel behind her eye was diminishing and that is why she is seeing “cob webs”. I know in your post you stated that most of the HA, taken internally, is excreted through the urine. Is it safe to put HA directly into the eye if it is diluted in a solution? And if so, do you have any recommendations on a solution that I could mix for her?

        • drgeorge says:

          Rita, we don’t understand. Are you asking whether a solution of HA placed directly onto the eyeball will be of benefit? If so, it seems very unlikely insofar as the HA withing the vitreous humor of the eye is there as a result of physiologic cellular processes that manufacture it locally within the posterior chamber of the eye. We are not ophthalmologists but the concept of placing HUGE molecules (HA is polymerized in solution with lots of water) topically on the globe of the eye and expecting it to migrate into the interior of the eye just makes no physiologic sense. I would suspect that natural tear formation will eventually wash the HA out of the eye. The result of what you are describing sounds similar to “artificial tears”.

  54. Diane says:


    After going through your article and comments, I think I need to stop using a product called Collagen Replenish Powder with HA & Vit. C by Reserveage Nutrition. I have been faithfully using this product since February of this year, once per day, a scoop of 2.6 grams, which is their recommended serving. (It’s in a powder form and I put it in my tea.) I contacted the company yesterday to ask which form of HA they use and this is copied and pasted from their reply back to me.

    “In regards to your question on Collagen Replenish- We use low molecular weight sodium Hyaluronate for Hyaluronic Acid.”

    I apologize if you have to repeat yourself, but is this junk and should I stop taking the product immediately and toss it in the trash? You may not be able to or can not answer the next two questions and I understand if you can’t. How long do you think it will take to get out of my system and do you think I caused any inflammatory damage in the meantime? I have been feeling ok really no different since I have been taking it.

    Thank you very much for publishing this article. How I came to investigating the form of HA is another story but your article is an eye-opener, just another reason to do the research first before ingesting any kind of supplement.

    Thanks again.

    • drjohn says:

      Yes, it is fragmented HA and thus should be avoided. LMW HA acts as an inflammatory biosignal. Opposite of what you want to hydrate, nourish, or replenish skin.

  55. Kim says:

    Hello doctors,

    This is a follow up comment to one I left a couple of months back re: the Timeless Skin Care HA prep you endorsed in an earlier comment. Did you see it? I had written to this company and asked them about the molecular weight of their HA; they replied that they currently used a medium weight, I believe I also cut and pasted some of their email in my comment. I think it wise to keep your readership informed of things like this, so they might buy wisely.

  56. Veronika says:

    Hello, I too have reached out to Timeless and they told me that they use medium weight HA in their serums and LMW in their sprays.
    I am considering purchasing the Hydraplenish Hyaluronic Acid Serum from Nature’s Way. They specifically list HMW HA on their ingredients list and Amazon reviews of this products are rated as high quality (by the fakespot.com website).

  57. Geraldine says:

    Thanks so much for providing this wealth of information- greatly appreciated

    I make my own HA serum using HMW-HA. I have been applying it morning and night on my damp skin then I’ll mix a few drops of therapeutic grade essential oils (frankincense & geranium) to some Rose (or Jojoba oil) and moisturise my face/neck with that.
    Is it ok in that order or should I use the HA last?

    Lastly my recipe for the serum is very basic: distilled water, HA and glycerin and this is meant to last 2 weeks if kept refrigerated. Does that sound about right to you? Thanks in advance

  58. Ellie says:

    So in simple terms HMW good LMW bad? I recently purchased 100% Pure HA from Jaba Labs and after reading this article I went back and checked. It is Low. I have used it on 2 clients for Micro Needling. Should I be worried for them? I also sent some home with them to use for the rest of the day. Is there anything I can do with this product or should I just throw it out. I also purchased for myself their HA with Collagen and Vit C. Should I stop using it?
    On Amazon I have seen Pure Hyaluronic Acid Serum Powder (High Molecular Weight Sodium Hyaluronate). Cosmetic Grade,… Is this something I can just mix with water and use in my micro needle treatments. Thank you so much for all your help. 🙂

    • drjohn says:

      LMW is only good if you actually want inflammation. Let’s say you are trying to treat an open leg ulcer on a diabetic, or maybe grow hair. But for purposes of facial skin rejuvenation for aesthetic purposes, it makes no sense to add in an inflammatory agent which is counter to what you are trying to achieve. So yes, use HMW HA. As far as microneedling goes, follow the rule of “nothing other than native human molecules” at the time of needling, and for at least 4 hours afterward, to prevent foreign body or allergic reactions. So you have to read the label of any product. Even vitamin C has been associated with allergic granulomas. If you mix your own HA, make sure it is pure and comes from a reliable source. Use purified water, best to use sterile containers and utensils. You can greatly boost the effects of HA by adding native human biosignals such as growth factors. But these are not DIY molecules – they are highly specialized, so obtain through reliable channels.

  59. Ellie says:

    I am having trouble finding HMW HA. Do yo know where I can buy it?

    • drjohn says:

      I have made several recommendations only to find out later that they are products with problems. How about if Cellese just creates a simple, pure HMW-HA solution?

  60. imraan says:

    Hi Dr Jon
    I just wish to say that generally don’t reply to any sites but the information, the humour and the clarity of your explanations are fantastic. .take a bow!!!As a general practitioner it’s not my field but I do have an interest in aesthetics. I see a lot of patients in my clinic with Arv viz stavudine induced lipodystrophy of the face and was wondering if HA would help.this led me to doing some searching and I was lost till I came across this site.Really well written and you took the time to answer each question posed comprehensively.
    I hAve read above that it will FORM a barrier on the skin and HmwHa will not penetrative. My question is can it be injected and will that have any benefit at all.if so is the effect lasting or will it it succumb to enzymatic degradation at some point…I’m just shooting in the dark here as I am new to this.
    Again ,many thanks for all the detailed answers you have provided..it was really well worth the read
    Dr imraan essa

  61. Alex tosas says:

    Dr.john … Yes have cellese make the hmw ha please👍

  62. SandraP says:

    I came across this article a few days ago when doing some research on HA… thinking of mixing my own lil serum at home has turned into an unending list of questions (bovine or vegan, long chain or short chain, low molecular weight or high molecular weight, trusted or non trusted manufacturer). It’s taken me three days to come back to this article because one click led to another which led to another and on this site, every link is more interesting and informative than the last! I’ve only just breached the tip of the informational iceberg on your site and I can’t wait to read more. Thank you for putting out real, scientific opinions.

    My question references something that come up early on in this thread – you commented that you’re working on a HA mask… I’ve tried looking up Cellese and a mask, but see nothing. I also read above more recently that you’re realizing maybe you should offer a good grade HA for home use.

    Any more info on this mythical HA mask?! Any info would be greatly appreciated.

  63. Kika bjorkman says:

    What about Barbara Sturm hyluronic with long chain and short chain??
    Is this really that good?
    Thank you

    • drjohn says:

      Short chain HA is never good (unless for some reason you want to induce inflammation and suppress protein production).

  64. Kika says:

    Thank you for making it more clear. I suppose companies use short/long chain verbiage now to attract buyers, as it sounds like it packs more of an Antaging punch!

    • drjohn says:

      Yes Kika, sounds good … but the science says it is anything but good. There is a lot of creative “marketing” by folks who actually haven’t a clue what they are talking about.

  65. Ali says:

    Hello Dr John,

    Im looking for a HMW HA serum to use as the lubricant/glide during Microneedling. What is the minimum amount of HA Daltons to be safest for use during Microneedling. There is a company that sells a HA serum that they consider LMW and theirs is made from HA powder that is 8,000 Daltons, is this high enough? I would also have the option to make my own serum with HA powder of 1.0-1.5 million Daltons, is this High Molecular Weight not necessary, or would it be ideal?

    Thank you for your input and suggestions.

    • drjohn says:

      Ali – you should make your own HMW-HA. Millions is better! Also by making your own you can make it fresh and keep it in the refrigerator for a short while. That way no preservatives either.

  66. Gene Stewart says:

    What KDa range do you consider to be HMW-HA?
    And can you comment in general about Dr. Mototsugu Fukaya research as published in
    Journal of Cosmetics, Dermatological Sciences and Applications, 2014, 4, 150-155
    Published Online June 2014 in SciRes. http://www.scirp.org/journal/jcdsa

    Thanks much,

    • drjohn says:

      Hi Gene, we tend to like our HA to be polymerized to >1M. The research you point to is highly flawed. In vitro test of 3 biochemical intermediates, after two weeks of LMW-HA, two of which are known to be involved with the cellular stress responses. In particular, intracellular glucocorticoid utilization (leading to insulin resistance, etc). Why this would be in any way be argued to be a benefit I don’t get.

  67. Gene Stewart says:

    Thanks for this. The challenge is to optimally penetrate to aid with hydration while doing no harm. Any ref.(s) you can point to showing absorbtion/penetration levels/rates and effectiveness on skin hydration for HMW-HA? And or associated dermatitis issues with various MW HA’s (animal tests or clinical)?

    • drjohn says:

      This is a misconception. You say HA needs to penetrate, but the truth is that it does not. Think of HA as a protective topcoat. It does its main job by creating an interlinked network of molecules on top of the skin, creating a barrier until the skin builds its own, or a supplemental barrier. This barrier function of the skin is a key factor in skin health. It holds in moisture but at the same time “breathes”. It is friendly to healthful microbes, and unfriendly to pathogenic ones. It traps key nutrients, growth factors, anti-inflammatories and holds on to them (special spicules) and holds them in close proximity to the skin surface. It also leeches into follicles where it provides scaffolding and is a carrier for additional physiologic GF’s to promote regeneration. HMW-HA is a natural anti-inflammatory. Hydrolyzed, fragmented or LMW-HA acts as a biosignal in the opposite direction (see references scattered throughout this topic thread). Things that penetrate that can help the skin to build its own barrier molecules include certain ceramides, glycoproteins, and physiologic lipids in the right ratios.

  68. Elizabeth Thomas says:

    I have been on the website of Cellese AnteAGE and find the lack of scientific information regarding the product a bit annoying. There is so little information. I find that surprising because I am aware that you are both published scientists in biomedical sciences. The discussion on this thread is great for examining issues in the pharmacology of active agents on skin regeneration and factors that inhibit or promote healthy skin. Any thoughts on using one’s own blood platelets as injected into the dermal layer, or applied topically? I understand this is now a procedure used in dermatology clinics under medical supervision. How do you you think this stacks up against other non-invasive treatments for specific concerns of skin health and ageing?

    • drgeorge says:

      Hi, Elizabeth. Thank you for checking out the AnteAGE website. There is literally gobs of scientific information still in place on our old website that we will be migrating over to our new one – let’s call it our “legacy” repository. I’m sure you will find it quite impressive. We lit up our new website just a few weeks ago so a lot of content from the old one still needs to be uploaded. There will be obvious ways to “drill down” to access it. Expect it in January.

      As to your question about using one’s own platelets (PRP or platelet rich plasma), there is good evidence that PRP has true benefits in many circumstances. PDGF (platelet derived growth factor) was one of the earliest ones used to help heal indolent ulcers of the feet and legs; it was first used where I practiced in the early 1990’s. PRP is useful in promoting bone growth, tendon and ligament repair, and is also being used as an adjunct to hair regrowth by injecting into the scalp (mixed results on that score.) The so-called “Vampire Facial” and “Vampire Facelift”, trademarked by an enterprising physician you have to pay royalties to if you use the names, involves microneedling with PRP (facial) or injecting it in conjunction with fat transfers (facelift). With microneedling, we don’t see a great need for PRP since the trauma itself will activate platelets within the dermis and PRP’s net profile is predominantly pro-inflammatory since the alpha granules in platelets are chock full of TNF-alpha, IL-1 and IL-6, all very pro-inflammatory. With fat transfers, the PRP may help stimulate angiogenesis (new blood vessel formation) which helps the fat cells obtain oxygen and nutrients to stay alive and thrive. (There are indeed growth factors and cytokines in PRP that provide benefit.) When it comes to skin recovery following microneedling or other types of intentional trauma (laser, RF microneedling, etc.), we still recommend a combination of growth factors and cytokines that promotes healing while reducing inflammation, something that our endogenous yet migratory bone marrow mesenchymal stem cells do naturally, which is why we focused on them long ago. Having been in the business quite a few years now, we are true believers in minimally invasive or non-invasive approaches to skin rejuvenation and anti-aging.

  69. jess says:

    I have 2 questions. I mix my own vit c serum (pure ascorbic acid and
    distilled water) in small batches once a week (to prevent spoilage.) I
    recently have incorporated HMW-HA into my serum. Since you mentioned
    that HMW-HA doesn’t actually penetrate the skin but rather sits on top
    of it, would that mean that the HMW-HA is preventing the vit c from
    penetrating the skin as well? should I mix two separate serums and apply
    at different times throughout the day to prevent this?

    My second question is related to dermarolling. is it reccommended to use
    HMW-HA mixed with water while dermarolling? I have been dermarolling for
    a couple years now and the thought of rolling on anything but clean dry
    skin seems foreign to me. Thanks so much! Love your articles!!!

    • drgeorge says:

      High molecular weight hyaluronic acid does not penetrate the skin – the molecular weight is very high, greater than 800 thousand daltons, which are large molecules indeed. Vitamin C, however, has a molecular weight of only 176 daltons, which is quite small and capable of easy penetration. Although the Vitamin C will be applied in the HA polymer matrix, it is small enough to diffuse through the matrix and still gain access to the skin. It should work fine to mix the two.

      Home dermarolling on clean dry skin is fine since the needles are short (typically 0.2 to 0.25 mm) and the rolling function makes tissue “drag” and friction not an issue. The same goes for dermal stamping – no friction or drag. That is not the case with most medical needling devices which use rapidly oscillating multi-needle tips within a protective sheath. These devices typically slide across the skin while in constant contact. In that instance, lubrication is appropriate so the instrument can “glide” easily. These needle lengths are longer, 0.5 mm up to two or three mm if treating deep scars. Practitioners use sterile saline, solutions containing hyaluronic acid, or products specially formulated for microneedling. Our own products for this purpose do contain HA, along with synthetic growth factors or conditioned media from laboratory culture of human bone marrow stem cells.

  70. Pam Crouch says:

    I looked up the Bulk Hyaluronic acid using the one on amazon “BulkSupplements Pure Hyaluronic Acid (Na Hyaluronate) Powder (10 grams) “they Stated it was plant sourced. One reviewer stated she asked the company from what plant and they replied to her “Hyaluronic acid is fermented from Corn Glucose. ” Also, it is formulated in China. Is this good ?

    • drjohn says:

      HA is not all that complicated to make. The usual sources are rooster combs and fermentation (in bacteria). Either way want to make sure it is pure. We source a lot of high purity, quality chemicals these days from China, so country of origin not the issue. For the true skin care nerds out there, feast on this … Production Methods for Hyaluronan

  71. Katia says:

    I have eczema and fairly reactive skin on the whole, while still developing occasional acne. I just started using The Ordinary’s Hyalornic acid 2%. What I read on their website was that the molecule size of their HA carries between small, medium, and large. Would varying molecule sizes make it more or less dangerous when considering inflammation and scarring?

    • drjohn says:

      Hi Katia, Since small means “low molecular weight” (LMW) than it is a problem. LMS -HA is inflammatory. That’s the last thing you want if you are dealing with eczema or acne or scarring. All are inflammation related. You would be better off finding a native high molecular weight” HA.

    • drgeorge says:

      A very interesting question and one that demonstrates the conundrum that hyaluronic acid poses for women hoping to increase skin hydration. No one wants to increase hydration at the expense of initiating increased inflammation, which is what happens when low molecular weight HA is applied. It is inflammatory. The following quote is taken from an article in the journal Wounds in the March 2016 edition: “Studies have revealed that most HA properties depend on its molecular size. High molecular weight HA displays anti-inflammatory and immunosuppressive properties, whereas low molecular weight HA is a potent proinflammatory molecule.” https://www.ncbi.nlm.nih.gov/pubmed/26978861

      You mentioned that you are using Ordinary’s Hyaluronic Acid 2%, which is described on their website thus: “Hyaluronic Acid (HA) can attract up to 1,000 times its weight in water. The molecular size of HA determines its depth of delivery in the skin. This formulation combines low-, medium- and high-molecular weight HA, as well as a next-generation HA crosspolymer at a combined concentration of 2% for multi-depth hydration.” http://theordinary.com/product/rdn-hyaluronic-acid-2pct-b5-30ml

      The caution that BFT wants readers to consider is based on studies that show that the penetration of HA into the skin is indeed inversely proportional to molecular weight i.e. smaller molecules penetrate more deeply. An article entitled “Human skin penetration of hyaluronic acid of different molecular weights as probed by Raman spectroscopy” confirms. Quoting from the article – “Our results show a difference of skin permeation of the three HA. Indeed, HA with low molecular weight (20-300 kDa) passes through the stratum corneum in contrast of the impermeability of high molecular weight HA (1000-1400 kDa).” https://www.researchgate.net/publication/275053701_Human_skin_penetration_of_hyaluronic_acid_of_different_molecular_weights_as_probed_by_Raman_spectroscopy [accessed Jan 09 2018].

      These two articles, when combined, lead to an obvious inference (conclusion?): applying low molecular weight may be to be a fool’s errand. Why apply low molecular weight HA to the skin, which the evidence shows will successfully penetrate into the skin more deeply than high molecular weight HA, when the result is inciting inflammation within the skin? Does that sound like a rationale strategy when we all agree inflammation is pro-aging and not something to be deliberately created, especially when it is part of one’s daily skincare regimen?

  72. Rima says:

    Dr John, hoping You can get your chaps on the MD team to provide some training/webinar type sessions for those of us using, pitching and believing in the BM MSC. There is so much BS floating around, it would be MOST useful to be able to ask some questions at regular intervals so we are better equipped. This page is clear evidence that you and Dr G are clearly committed to educating us. Just want to be even better able to push back on the crap that I’m asked on a regular basis. BTW, the other day I purposely (sort of) over peeled my neck with several layers of AHA peels. I slathered my neck with AnteageMD step 1 (totally backed off step 2) and quite literally two days later I was 90% healed. What should reasonably have taken a week to heal took 48 hours. I did use a ZO skin barrier repair cream also but that was it. The AnteAgeMD stuff is bloody good but there is much more I feel we could learn from you in order to really get it out there…love this website but it’s pretty difficult to follow responses, etc

    • drjohn says:

      Hi Rima, yes we see that rapid healing ( aloing with better aesthetic results) every day in our research clinic, and in the feedback we get from users. We do have a series of webinars for professionals. You should contact customer support (info@anteage.com) about that. DrGeorge and i are startying a book and video project which should help (once we finish). Thanks for you very articulate support!

  73. Kim says:

    Out of fear of “inflam’AGING”, over the past year I have done extensive research about hyaluronic acid skincare products. As Drjohn suggests, I wanted a product with high molecular weight since low molecular weight HA causes inflammation, and it also tends to penetrate more deeply into the skin making it even more problematic as an anti-aging ingredient.

    I wanted to write to triumphantly (and finally!) report that I have (or at least I think I have) found a purveyor of high molecular weight hyaluronic acid. The company is NOW Foods Products, and they responded to my emailed inquiry about molecular weight:

    “Our HA is 1 million Daltons which is considered high MW. This avoids issues with impurities and varying molecular sizes that can be associated with animal sourcing of this compound.”

    NOW offers two moisturizers, and an HA firming serum for what I think are pretty reasonable prices (especially in contrast to what other companies charge for medium and low weight HA). Now Foods is also organic, which is a bonus.

    I hope this info is helpful to the folks who visit barefacedtruth. You can see the NOW Foods products at https://www.nowfoods.com/

    The website does not discuss molecular weights but the company will respond to inquiries.

  74. diana says:

    Thanks for all the information on hyaluronic acid. I am thinking about giving HA supplements to my dog for joint issues. Is there any benefit? Thanks from me and Maffy.

    • drgeorge says:

      Hyaluronic acid taken by mouth has been proven to be absorbed and to find its way into tissues throughout the body. Viscous HA preparations are well proven to be of benefit when injected into arthritic joints. It does appear that there is benefit when HA is taken orally as well. The Journal of Nutrition published a review article that looked at 13 randomized, double-blind, placebo controlled trials testing whether or not oral HA improved joint pain, effusions (“water on the knee”), inflammation, and strength. Their conclusion: “HA is a safe raw material and the efficacy of oral HA in relieving knee pain was demonstrated in several clinical trials. HA as a dietary supplement exhibits mild efficacy and no side effects. By utilizing these characteristics, HA dietary supplements provide at least some possibility for the treatment and prevention of serious conditions in patients with osteoarthritis exhibiting mild knee pain. This review may improve the understanding of HA dietary supplements and it is expected that HA will emerge as a modality for treating knee pain that can be safely used by patients.”

      It looks like it might be worth a try. If Moffy appears to be in less pain, there’s your answer. The “placebo effect” in dogs is not in play.

      Oral hyaluronan relieves knee pain: a review
      Journal of Nutrition; Jan 27 2016

  75. Cako says:

    Hi, I ordered 10 grams of low molecular weight HA powder to make my own DIY serum to use during and after microneedling. But I read the article before it even arrived.

    Now that i know size does matter, I won’t use it, but I don’t have the option for a refund. Can I use this LMW HA in any other situation or should I dispose of it?


    • drgeorge says:

      Low molecular weight hyaluronic acid is well-known to promote inflammation, AND also to penetrate more deeply into the skin – both not good. Sorry, can’t suggest you use your product on your skin.

      The chemical formula of HA contains the following atoms: 28 carbon, 42 hydrogen, 2 nitrogen, 2 sodium, and 23 oxygen, giving it a molecular weight just shy of 821 daltons. However, it never exists as single molecules but rather in the form of polymers which are many molecules linked together. The number of molecules in the polymer is what gives rise to the low, medium, and high molecular weights. Low molecular weight HA is < 5,000 daltons; medium 60 to 800 thousand daltons; high > 800 thousand daltons. (a dalton = one atomic mass unit, defined as the atomic weight of a hydrogen atom, or 1/12 the mass of a carbon atom.)

      There is a Japanese study of oral HA being of value in alleviating knee pain when taken in capsule form for 12 months. In that study, there is a summary table of 13 other studies that collectively showed improvement in joint pain and junction with oral HA. The molecular weights studied included low and medium HA with some 900 thousand daltons. Maybe you can put your low molecular weight HA to work, just not on your skin.

      Oral Administration of Polymer Hyaluronic Acid Alleviates Symptoms of Knee Osteoarthritis: A Double-Blind, Placebo-Controlled Study over a 12-Month Period ScientificWorldJournal. 2012; 2012: 167928

  76. Nancy Cooney says:

    I recently found your website….wonderful information. You indicated you could recommend a product that would contain good HA and perhaps also sunscreen. It is so difficult to filter though all the hype. I have normal 65 year old skin and want to protect it as long as I can.

    Thank you for any recommendations/products you may have and please continue supplying truthful, researched information…..so sadly needed!

    • drgeorge says:

      Can’t say what the molecular weight of hyaluronic acid is in these products, but ones that contain HA and sunscreen include: Olay Age Defying Advanced with Hyaluronic Adid Hydrating Moisturizer with Sunscreen Broad Spectrum SPF 15; La Roche-Posay Hydraphase Intense UV 24-Hour Face Moisturizer Broad Spectrum SPF20; Aveeno Positively Radiant Daily Mosisturizer SPF 15. There are likely others.

  77. Jaycie says:

    The back of the La Roche-Posay box says it has Hyaluronic Acid fragments, so I’d guess it is LMW. I’d have never known about this issue without stumbling upon BFT in my research. Thank you for providing the information, even though some of it is a bit over my head!

  78. Yang says:

    This is a very interesting post. However, the references you are citing are all done in cell culture models with only one report done in a keratinocyte cell line. These reports are not sufficient to support your conclusion that topical application of low HA could be harmful. I would be very interested in seeing any results from keratinocyte organotypical culture or human skin graft results.

    • drjohn says:

      See relevant papers referenced by this recent review.

      Food and Chemical Toxicology
      Volume 101, March 2017, Pages 128-138
      Food and Chemical Toxicology
      Review: HA metabolism in skin homeostasis and inflammatory disease


    • drjohn says:

      Cell Death Dis. 2017 Jun 1;8(6):e2857. doi: 10.1038/cddis.2017.249.
      Inflammatory mediator ultra-low-molecular-weight hyaluronan triggers necrosis of B-precursor leukemia cells with high surface CD44 expression.
      Kasai S1, Furuichi Y1, Ando N1, Kagami K1, Abe M1, Nakane T1, Goi K1, Inukai T1, Saitoh S2, Ohno S2, Okazaki S3, Nagano O3, Saya H3, Sugita K1.

  79. Sandra says:

    I’ve read all of your comments and replies as I find this really interesting! I just wanted to make sure I understand this right – Sodium hyaluronate, unless stated it’s the LMW-HA, is generally safe??
    I noticed it’s in my ‘hydrating’ eye drops and I certainly don’t want to put anything in my eyes that could cause inflammation etc. (I’ve repeated your reply,that I’m basing this on, below)

    APRIL 7, 2015 AT 3:58 PM · REPLY
    Sodium hyaluronate generally is HMW-HA (the good stuff) which is the natural form. If HA has been processed (enzymatically degraded) to produce LMW fragments (extra steps taken in the lab, at extra cost), the company selling it should say so. They use it as a marketing ploy, so it makes no sense for them to put in something that costs more if they aren’t going to advertise it as such. Pure unadulterated sodium hyaluronate or HA is natural, physiologic, so no worries, we like it a lot and use it in our own microneedling solution.”

    • drjohn says:

      Generally true, yes. Unless it says LMW-HA then it most likely is the native stuff, which is HMW-HA. You would have to add a hyaluronidase enzyme to break down the large chains to shorter versions.

  80. Lisa says:

    I’m wondering how this applies to the Juvederm injectable technologies, with their latest product line touting a vycross technology linking short and long chain hylauronic acid, vs their older product line of long chain linkages “hylacross”. Do short and long correlate with small and large size? Don’t want to put the wrong thing in my body!!

    • drjohn says:

      It makes even less sense to use fragmented (short chain) HA and then cross link it. Now you lose any advantage of smaller size, and as cross linking gradually deteriorates it preferentially adds inflammatory HA fragments. May as well just put proteases (hyaluronidase) in there as well. If small chain fragments elustion is the goal, that’s a quick way to get an inflammatory boost. Again the question is why? And don’t these product guys read the literature on HA biosignaling?

  81. s says:

    Does this mean a product like Fillerina is bad for the skin? I was very interested in trying it as it seemed like it could be helpful, but now I’m unsure.

    • drjohn says:

      These low molecular weight HA’s are contrary to known science of hyaluronic fragments. If you desire temporary plumping or filling from inflammation-induced edema, go for it. But every time you use it you add more inflammatory stimulus. As is well established, inflammation leads to accelerated aging. Tissue fibrosis, disorganized & de-elasticized matrix.

  82. ken osborn says:

    I have been reading about 4-methylumbelliferone [4MU], a promising nontoxic agent for the prevention and treatment of advanced prostate cancer, according to a JNCI article. 4MU inhibits HA synthesis. [ref: Journal of the National Cancer Institute, Volume 107, Issue 7, 1 July 2015] My questions: if HA synthesis is inhibited, then would that eventually result in the depletion of high molecular weight HA with significant negative side effects?

    • drjohn says:

      Ken, you touch on a complex topic – that of carcinogenesis and how tumors can co-opt natural processes (such as hyaluron synthesis) for their evil purposes. When we discover molecules that interfere with such normal synthetic pathways, scientists will try to fins ways to exploit those inhibitors in growing tumors. The problem is that they have systemic side effects. 4MU has a whole host of problems it creates, skin thinning being one of them. Classical two edged sword issue.

  83. Eddie says:

    Dear Doctors,

    In comments, you explained that inflammation is associated with low molecular weights of HA itself, and not concerned with sodium. So, hydrolyzed/LMW HA is harmful. But, what about Hydrolyzed/LMW Sodium Hyaluronate?

    Deciem brand’s NIOD Multi-Molecular Hyaluronic Complex claims to offer a combination of “15 forms of hyaluronic compounds, hyaluronic precursors, and a hyaluronic support technology” at Low, Mid, and High molecular levels. At a glance of its ingredients list, however, its HA ingredients are mostly different molecular weights of sodium hyaluronate: Hyaluronic Acid, Sodium Hyaluronate, Sodium Butyroyl Hyaluronate, Sodium Hyaluronate Crosspolymer, Hydrolyzed Sodium Hyaluronate

    Since, the LMW hyaluronic compounds it uses are sodium forms, and not of hyaluronic acid, are they safe?

    Here is the full ingredient list and the link:
    Aqua (Water), Hydrolyzed Yeast Extract, Glycerin, Hyaluronic Acid, Sodium Hyaluronate, Sodium Butyroyl Hyaluronate, Sodium Hyaluronate Crosspolymer, Hydrolyzed Sodium Hyaluronate, Disodium Acetyl Glucosamine Phosphate, Tetradecyl Aminobutyroylvalylaminobutyric Urea Trifluoroacetate, Pseudoalteromonas Exopolysaccharides, Tamarindus Indica Seed Gum, Tremella Fuciformis Sporocarp Extract, Ceratonia Siliqua Gum, Myristoyl Nonapeptide-3, Plantago Lanceolata Leaf Extract, Salvia Sclarea Extract, Arginine, Aspartic Acid, Glycine, Alanine, Serine, Valine, Isoleucine, Proline, Threonine, Histidine, Phenylalanine, PCA, Sodium PCA, Betaine, Sodium Lactate, Epigallocatechin Gallatyl Glucoside, Gallyl Glucoside, Algae Extract, Sodium Salicylate, Lecithin, Polyglucuronic Acid, Xanthan Gum, Trisodium Ethylenediamine Disuccinate, Sclerotium Gum, Pullulan, Cetyl Hydroxyethylcellulose, Propanediol, Pentylene Glycol, Dimethyl Isosorbide, Citric Acid, Magnesium Chloride, Silica, Polysorbate 20, Ethoxydiglycol, Propyl Gallate, Dehydroacetic Acid, Benzyl Alcohol, Potassium Sorbate, Sodium Benzoate, Ethylhexylglycerin, 1,2-Hexanediol, Caprylyl Glycol, Phenoxyethanol (https://niod.com/product/multi-molecular-hyaluronic-complex-15ml?redir=1)

    • drjohn says:

      Eddie, the chemical form doesn’t matter. These will diffuse in tissues anyway. The inflammatory stimulus is the presence of short chain HA (or fragments of HA chains) and has nothing to so with sodium which forms an HA salt on any sized HA.

  84. Eddie says:

    Recently I reached out to Deciem for the molecular weight/size of their hyaluronic acid compounds and asked why their products low-molecular-weight and even “very” low-molecular-weight hyaluronic acids despite there being overwhelming scientific findings of its inflammatory nature. Their answer is really interesting. I would love to know what you think, Doctor John:

    “The molecular weight range of HA used in MMHC2 is from 10,000 daltons to 1,800,000+ daltons.

    HA under the skin (and in the body) serves as a lubricant and cushion. A large portion of it is in the dermis. HA that has been used in beauty products has been presented as a hydrator though HA has no “hydration” role within the skin. It’s a cushion underneath and a lubricant within the body. But the larger sizes of HA cannot penetrate the skin so they literally form a film on the surface that makes you look smooth right away and as HA attracts water, the film can even draw water out of the top layer of the skin so that you develop an addiction to HA products (becoming more dry when washing off).

    As soon as you start targeting below the skin surface, everything becomes more interesting because chemistry and biology are very different- and more specifically, the specific size of HA will make a very dramatic difference in not only its chemical function (say feeling of hydration) but also its biological trigger (how the body reacts to the molecule). This in effect means that various molecules with very different physiological effects will have the same INCI designation on the ingredient listing and this phenomenon is actually most apparent when it comes to HA and HA-like compounds.

    LMHA induces an inflammatory reaction while HMHA induces an anti-inflammatory reaction. This very point is actually what makes LMHA much more than just a hydrator. Its competition with HMHA (both of which are in the skin) actually leads to a state of balance called homeostasis- basically, the inflammatory and anti-inflammatory responses compete, creating balance. The conclusion the article makes would only be valid if there was only LMHA present and no HMHA, in which case our bodies would have naturally been in an inflammatory state from birth as both forms are in the body.

    We take the supplementation of different grades of HA to a new level by also including precursors of HMHA. Since we cannot physically get HMHA in but we can get LMHA in, supplementing HMHA wouldn’t help. The precursors actually work to cause your own production of HMHA to then further encourage this state of homeostasis, in addition to multi-layer hydration within various depths of the skin. This very reason is why NIOD and Hyalmide actually target many signs of aging and is not really just a “hydration serum”. Basically, the precursors (1 in Hylamide, 5 in NIOD) trigger HMHA production while we supplement LMHA topically to encourage this state of “peace” and to hydrate at multiple depths. Also, in all of our products that use LMHA, we also include medium-molecular weights as well which additionally (but partially) support the above position. “

    • drjohn says:

      Eddie – it’s a good story, but needs to be filed under fiction. Postulating that somehow inflammatory is good because it is balanced by anti-inflammatory. By this same logic everything bad for us is good because we have defenses for it. Oxidants are good because we make antioxidants. Toxins are good because we make antitoxins. Pollens and viruses are good because we make antibodies. This is nonsense. He’s making this up. Sounds more like like yin-yang philosophy than valid biochemistry. And HMW HA is not really anti-inflammatory anyway. It’s non-inflammatory (neutral). You should write back to him and ask him for published studies that prove his point. The rest is mumbo jumbo too. These purported precursors are not precursors at all. Things like fruit HA and mushroom HA “equivalents”. Yeah, right. Because mushroom skin is just so irresistible. This is a bunch of pseudoscience and sleight of hand market speak. Buyer beware, folks.

  85. Samantha says:

    Do you guys know of any supplement that would help the body increase its own production of hyaluronic acid?

    • drgeorge says:

      Interesting question and one best answered by providing some of the research that supports the use of oral HA supplements for skin health and appearance. The named products are in bold within the abstracts.

      Be aware that articles naming products are often the results of studies financed by the companies making those products.

      Clin Cosmet Investig Dermatol. 2017 Jul 18;10:267-273.
      Oral hyaluronan relieves wrinkles: a double-blinded, placebo-controlled study over a 12-week period.
      Hyaluronan (HA) has critical moisturizing property and high-water retention capacity especially for human skin. This study aimed to evaluate the effect of oral intake of HA.
      During the study period, the HA groups showed better level of the whole sulcus volume ratio, wrinkle area ratio, and wrinkle volume ratio than the placebo group. After 8 weeks of ingestion, the HA 300 k group showed significantly diminished wrinkles compared with the placebo group. Skin luster and suppleness significantly improved after 12 weeks in all groups compared with the baseline.
      The results suggest that oral HA (both HA 2 k and HA 300 k) inhibits skin wrinkles and improves skin condition.

      J Photochem Photobiol B. 2015 Mar;144:94-103.
      A dietary supplement improves facial photoaging and skin sebum, hydration and tonicity modulating serum fibronectin, neutrophil elastase 2, hyaluronic acid and carbonylated proteins.

      Excessive exposure to the sun can cause severe photoaging as early as the second decade of life resulting in a loss of physiological elastic fiber functions. We designed a first study to assess differences in facial skin pH, sebum, elasticity, hydration and tonicity and serum levels of fibronectin, elastin, neutrophil elastase 2, hyaluronic acid and carbonylated proteins between patients affected by facial photoaging and healthy controls. In a second study we tested the hypothesis that a dietary supplement would improve facial photoaging, also promoting changes in the above-mentioned skin and serum parameters.
      We found significantly increased serum levels of neutrophil elastase 2, elastin and carbonylated proteins and decreased levels of hyaluronic acid and fibronectin in patients affected by facial photoaging, if compared with healthy controls. These findings coupled with a significant decrease in skin hydration, tonicity and elasticity and increased skin pH and sebum. Treatment with the dietary supplement VISCODERM Pearls significantly improved VAS photoaging score and skin hydration, sebum and tonicity 2 weeks after the end of a 4-week treatment period in patients affected by moderate to severe facial photoaging. These findings coupled with a significant increase in serum fibronectin and hyaluronic acid and a decrease in serum carbonylated proteins and neutrophil elastase 2 in the active treatment group, if compared with placebo. Our findings suggest that VISCODERM Pearls is effective for treatment of facial photoaging but further studies in larger cohorts of patients are required.

      J Evid Based Complementary Altern Med. 2017 Oct;22(4):816-823.
      Ingestion of an Oral Hyaluronan Solution Improves Skin Hydration, Wrinkle Reduction, Elasticity, and Skin Roughness: Results of a Clinical Study.
      Intake of oral supplements with the aim of a cutaneous antiaging effect are increasingly common. Hyaluronic acid (HA) is a promising candidate, as it is the key factor for preserving tissue hydration. In our practice study, we evaluated the effect of an oral HA preparation diluted in a cascade-fermented organic whole food concentrate supplemented with biotin, vitamin C, copper, and zinc (Regulatpro Hyaluron) on skin moisture content, elasticity, skin roughness, and wrinkle depths. Twenty female subjects with healthy skin in the age group of 45 to 60 years took the product once daily for 40 days. Different skin parameters were objectively assessed before the first intake, after 20 and after 40 days. Intake of the HA solution led to a significant increase in skin elasticity, skin hydration, and to a significant decrease in skin roughness and wrinkle depths. The supplement was well tolerated; no side effects were noted throughout the study.

  86. Mary says:

    Is Sodium Hyaluronate Crosspolymer HMW or LMW?

    • drgeorge says:

      Sodium Hyaluronate Crosspolymer is a modified form of skin-replenishing hyaluronic acid attached to a polymer structure that keeps it within skin’s uppermost layers longer, allowing for enhanced hydration. By virtue of being a polyer, it us going to have a higher total molecular weight. LMW HA is produced when HA molecules are hydrolyzed into shorter chain fragments.

  87. Steph says:

    Thank you for an informative post. Would Sodium Hyroulanate Crosspolymer be considered high or low molecular weight?

    • drjohn says:

      Crosspolymerization means linking together HA molecules to make XL-HA an even bigger polymer complex. So higher molecular weight. But whether that is is useful on the skin surface depends on the context. Its main use is as a filler, for injection, to create volume to mask wrinkles. It breaks down very slowly, as it is less subject to proteases, and thus lasts much longer than native HA. That may be good if you want to create a membrane-like surface film (good in some situations). The best way to polymerize is to first apply HMW-HA then spray the cross linker molecule in a spray. Sort of like a mask. But in general use, say in a daily moisturizing product, you may find it peels and shreds as it is worn away by movement and touch.

  88. Leslie says:

    I just had lip augmentation and the surgeon mistakenly injected Volbella when I requested a different product that was a larger molecule. I didn’t know until I went to check out. He said he can inject something to break it down and get rid of it. I don’t want to bother with this route, but I am worried about the carcinogenic effects and I don’t know if the 0.5 cc volume he used is worth it to have it broken down – or if that actually makes it worse? Do you have thoughts on the best case of action at this point? Help! I’m freaking out!

    • drgeorge says:

      No need to freak out. The family of Juvéderm fillers, including Juvéderm Volbella, are hyaluronic acid products that vary in molecular weight, formulation particle size, viscosity and duration of effect, depending on their intended use. Hyaluronic acid is a totally natural molecule, found in many tissues of the body. BFT sees little reason to worry about cancer and are unaware of any such complication having been reported. To the contrary, if there was a connection, the FDA would have prohibited their use long, long ago.

      Notice in the description of the Juvéderm fillers below, Volbella is indeed intended for use in lip augmentation. Because of smaller particle size, it is less likely to “overfill” resulting in a “softer” more natural look. If you like what you see with Volbella, there is no reason to inject hyaluronidase, the enzyme that “dissolves” these types of fillers. You would then just be injecting another formulation of hyaluronic acid, and not one specifically intended for use in lip enhancement.

      The descripton of Juvéderm fillers below is taken from the company website:

      JUVÉDERM® Injectable Gel Fillers Indications and Important Safety Information
      JUVÉDERM VOLUMA® XC injectable gel is for deep injection in the cheek area to correct age-related volume loss in adults over 21. JUVÉDERM VOLLURE™ XC injectable gel is for injection into the facial tissue for the correction of moderate to severe facial wrinkles and folds (such as nasolabial folds) in adults over 21. JUVÉDERM® XC injectable gel is for injection into the facial tissue for the correction of moderate to severe facial wrinkles and folds (such as nasolabial folds). JUVÉDERM® Ultra XC is for injection into the lips and perioral area for lip augmentation in adults over the age of 21. JUVÉDERM VOLBELLA® XC injectable gel is for injection into the lips for lip augmentation and for correction of perioral lines in adults over the age of 21.

      For a additional information you may find helpful, look at the reference below. It was written prior to the launch of Volbella but the gist of the article should be informative.

      Arch Dermatol Res. 2010 Dec; 302(10): 757–762.
      Duration of wrinkle correction following repeat treatment with Juvéderm hyaluronic acid fillers

  89. Ashley says:

    Hey Dr. John,

    I had a microneedling session about 2 months ago. They recommended using HA post-treatment. I already had The Ordinary’s Hyaluronic Acid 2% + B5, so I used that. I didn’t pick at my face, I didn’t go into direct sunlight, I moisturized, drank tons of water, even adjusted my diet for optimal healing. I have a couple weird “hole”-ish scars on my face. I came across the research that notes lower-molecular weight HA is associated with scarring (which is what The Ordinary’s HA contains, it has mixed molecular weights) I’m worried that’s what caused it, since there seems to be no other reason as to what would. And my face is my living. I work in fashion + entertainment.


    • drjohn says:

      As we have emphasized often in these pages, at the time of microneedling and in the period of 4-12 hours thereafter, only native human molecules should be applied to skin whose natural defense barrier has been purposely compromised. While such natural biosignals can create superior aesthetic results from microneedling, anything foreign to humans (not made by us) has potential for becoming a troublemaker. The Ordinary HA product contains: AQUA (WATER), SODIUM HYALURONATE, SODIUM HYALURONATE CROSSPOLYMER, PANTHENOL, AHNFELTIA CONCINNA EXTRACT, GLYCERIN, PENTYLENE GLYCOL, PROPANEDIOL, POLYACRYLATE CROSSPOLYMER-6, PPG-26-BUTETH-26, PEG-40 HYDROGENATED CASTOR OIL, TRISODIUM ETHYLENEDIAMINE DISUCCINATE, CITRIC ACID, ETHOXYDIGLYCOL, CAPRYLYL GLYCOL, HEXYLENE GLYCOL, ETHYLHEXYLGLYCERIN, PHENOXYETHANOL, CHLORPHENESIN. Lots of molecules not native to human biochemistry. last I looked we as humans do not manufacture our own PEG or PG or buteth-26. Not part of our DNA. This is clearly not a product designed to be used with microneedling. HA crosspolymer is a marketing trick and does nothing to make a better HA. From what you describe, you may be suffering hypotrophic scarring, or it may just be edema from inflammation that will resolve on its own. I would suggest you find a dermatologist on your area who can evaluate. What city?

  90. Yaz says:


    Very interesting read! I have just recently become interested in hyaluronic acid and have started (orally) taking a LMW ha powder. I read that for oral ingestion, only LMW are useful as they can be absorbed. Is this right? The powder I am currently taking is only 50kda. Now that I’ve been reading your blog, I am worried I am only causing damage and am thoroughly confused. Is LMW safe to take orally? Do HMW even work when taken orally?

    I look forward to your response.


    • drjohn says:

      LMW-HA is poorly absorbed from the intestine. Most of it is broken down to constituent amino acids and sugars. Some reaches the colon and is fermented, and some absorbed. All things absorbed through the gut goes first to the liver. Any absorbed HA is enzymatically disposed. If it gets past the liver, it can be excreted in breath. Only a small fraction reaches other tissues, including skin. You can help absorption of HA by combining with phospholipids into nanoparticles. So claiming that oral LMW-HA gets into and helps skin is a bit of a stretch – and why bother since HMW-HA largely gets broken down to LMW-HA in the gut anyway. Sounds like a marketing ploy designed to empty your wallet, not plump up your skin. Don’t worry about toxicity – not enough gets in the be concerned anyway.

  91. Luke says:

    The following is the reply I got from timeless:
    The Hyaluronic Acid 100% Pure Serum is the base for most of our serums.
    We use a high molecular weight Hyaluronic Acid (sodium hyaluronate) except for our Hyaluronic Acid Spray which we use a lower molecular weight. It is the lower molecular weight Hyaluronic Acid that absorbs easily into the skin than a higher molecular weight. Both are wonderful to use but the lower molecular weight is best used in products that are not as viscous. We use a 1% concentration of Hyaluronic Acid. Any percentage higher would actually gel up and there would be no permeability. The contents are 1% sodium hyaluronate, which equates to 100% hyaluronic acid. Any solutions higher than 1% sodium hyaluronate will dry out the skin since it is a humectant that attracts water.

    • drjohn says:

      I’m just sad that there are so many purveyors of LMW-HA out there not reading the medical literature. Why make a spray that is inflammatory??? Just because you can? Please stop it!

  92. shelly says:

    What kind of HA does Neutrogena use in their hydro boost products? HMW or LMW HA? If not HMW, what are some products/brands that do carry this option? I’ve been trying to find a HMW only and can’t seem to find a product that specifies this anywhere. Thank you.

    • drjohn says:

      We get asked this question so often. HMW-HA is the natural form, and is easy to make. I’ve recommended several, only to find out later that the manufacturer did hydrolyze into smaller HA’s, so I stopped recommending. I’m tempted to just make up a giant batch and make it available on Amazon for the cost of packaging and shipping.

      I keep HA in my wine cooler at home. I’m thinking that it may even get better with age, weird as that sounds. If you treat it right, it becomes more stable over time, while retaining its functionality. I now have vintages from various batches.

  93. Carmen Dichiera says:

    Dear Dr John
    I am very grateful for all the shared information. I am about to make my own 1 % HMW-HA serum.

    My questions:
    >. I do micro needling once every four weeks with a 1.5 (upgrading slowly to 2mm) roller.
    Should I apply my HMW-HA serum during or after the procedure?

    > I would like to add something else that will work well with anti ageing during and after micro needling.
    I already take orally hydrolysed collagen peptides, vitamin C, MSM and many other skin supplements.

    This is what I want to apply after Micro Needling:

    First 4 Hours:
    1. HMW-HA
    2. Vitamin C 25% serum (make my own every week fresh)

    After 4 Hours
    3. Organic Aloe Vera – alcohol-free
    3. Squalene Oil/Vitamin E/Q-10/Gamma Linoleic Acid/

    What are your thoughts on this?

    Kund regards
    Carmen ♥

    • drjohn says:

      Carmen – HMW-HA can be applied during and after. If you make your own you need to be sure it is bug free (I’m assuming you don’t use a preservative – if so you cannot store very long). I never recommend non-native molecules being applied during or soon after microneedling. By native I mean native human – not plants. Even Vitamin C (two of the cases of granuloma from microneedling in the JAMA paper used Vitamin C products). After 4 hours you are probably safe although some have argued that your skin remains vulnerable for up to 12 hours.

  94. Dpending on the outcome says:

    Any foods rich in HA ?

    • drgeorge says:

      Sure, some food are better sources of HA than others. Meat products have more than vegetables and fruits with the skin of poultry and fish and liver being especially good sources. No surprise there (for skin, at least) since connective tissue has the highest concentration and there’s lots of connective tissue in skin. Some botanical sources are higher than others: potatoes, sweet potatoes and bananas rank high. Some references below.

      Nutr J. 2014 Jul 11;13:70.
      Ingested hyaluronan moisturizes dry skin.

      ScientificWorldJournal. 2014;2014:378024.
      Dietary hyaluronic acid migrates into the skin of rats.


  95. Janine says:

    Hi Docs, are you familiar with crosspolymer hyaluronic acid? I have been researching it but I can’t find much information on it. I see this being used a lot in the Ordinary Line. I don’t know if it is considered a HMW HA? Any enlightenment would be greatly appreciated. Thank you, Janine.

    • drjohn says:

      Crosspolymer HA is HMW-HA that is then cross-linked to bind together the long HA polymeric threads (1M+ Daltons) into a mesh-like skin barrier (~1B+ daltons?). I guess you could call it supersized (S-HMW-HA). Its the same process as is used to create the injectable HA fillers popular in aesthetic medicine these days. There was one study touting its topical superiority over native HMW-HA but it was seriously flawed in that it did not use HMW-HA as the control, but rather compared it to no treatment on skin explants. I wish they had chosen a better design. In theory it has the advantage of a more cohesive barrier to water loss, but that would actually depend a lot on the “pore size” of such a mesh which to my knowledge has not been established and would likely depend on which crosslinker molecule is used, in what measure, under what conditions. Polymers are just tricky that way. More studies would be helpful. There is no reason to be concerned about safety from LMW-HA – it should remain intact and not penetrate skin. I do question how such a film applied daily affects the skin microbiome. As we know, many pathogenic bacteria wreak havoc by creating their own biofilms that in some ways look a lot like these polymer mesh biofilms. These are just theoretical concerns and I have no knowledge of problems being reported.

  96. Miroslava says:

    Hi Doctor George and John,

    Great article and what a source of useful information.

    After reading about HA and it’s absorbtion orally – it is actually absorb poorly. Isn’t taking gelatin a better source for HA, especially when taken orally?

  97. Cristina says:

    I have a full bottle of The Ordinary’s HA which, as it has been commented already, contains LMHA (as well as HMHA). So I will not be using it on my face as it is prone to inflammation.
    Rather than throw it away, I was thinking of using it on the dry skin on the soles of my feet.
    Somehow, I have made a connection about your statement early on:
    ”there is new research out that furthers the argument we make about the inflammatory nature of LMW-HA, and the mechanism of action includes the activation of macrophages (tissue eating white cells)”
    and those flesh-eating fish that became popular for feet pedicures in shopping centres some years ago.
    Genius or crazy idea?

    • drjohn says:

      Pure genius. There is another product I recommend for dry, thick, cracked soles of feet (or hands – some occupations at risk) … Hoofmaker. It’s a product made for horses hooves, but it is inexpensive and works quite well for the worst cases of dry cracked feet such as occurs in folks suffering from obesity (pressure and friction on feet from excess weight or from from footwear that rubs can cause hyperkeratinization). You can buy Hoofmaker on Amazon for ~$4.50 for 6 oz. Bargain of the century.

  98. Shawn OBrien says:

    I’d like to know what you think of the scientific study in the link below. Based on their results, they concluded, “We found that an LMW HA of approximately 50 kDa penetrates the skin better than larger sized HA and, accordingly, influences the expression of many genes including those contributing to keratinocyte differentiation and formation of intercellular tight junction
    complexes which are reported to be reduced in aged and photodamaged skin. This can be utilized without running the risk of increased proinflammatory activity.” Here’s the link:

    • drjohn says:

      Hi Shawn, glad to respond.

      The main flaw with this study is that it incorrectly relies on a lack of stimulation of tumor necrosis factor (TNF) alpha as a sign that the 50 kD HA fragments they were using did not cause inflammation. This is not reality. There are many more markers of inflammation than this one protein. Now read the whole paper and see what particular proteins were over expressed when skin is exposed to the 50 kD HA. It includes E-cahedrin, β-catenin, and some claudins. Let’s look at these. E-cadherin is consistently found to be expressed in inflammatory breast cancer (IBC) as well as inflammatory bowel disease. The What about β-catenin? Wnt/β-catenin signaling in one of the best known inflammation signaling pathways involved in cancer and all manner of inflammatory conditions. How about claudin-2? In intestinal inflammation (Crohn’s disease, ulcerative colitis), immune-mediated diseases (celiac disease), and infections (HIV enteropathy), claudin-2 is upregulated and contributes to diarrhea via a leak flux mechanism. So clearly the authors ignored a lot of extant science to make their bizarre conclusions. In truth – the 50kD HA IS INFLAMMATORY! by their own measures.

      So that you can be a better scientist than these guys, you should read up on gene study heat maps that help you to know what gene products are associated with inflammation (early, late, and chronic) and which are not. Here is a good publication: Wound healing and inflammation genes revealed by array analysis of ‘macrophageless’ PU.1 null mice as a starting point. Look at Figure 6 heat maps – there are a significant number of genes associated with inflammation in various conditions & stages. This one is about wound healing.

      • Lauren says:

        Is there some way you could make your products available to me? I’m desperate to find a suitable microneedling serum to be used during and after rolling. I have deep scarring which makes me very self conscious. The potential detrimental ingredients in online products worries me.

        • drgeorge says:

          We can recommend AnteAGE and AnteAGE MD microneedling products without reservation. These are the brands we developed and market. (The formulation is also marketed by others under private label agreement.) Several hundred thousand unit doses have been used by consumers and by aesthetic professionals, both estheticians and medical practitioners, over the past several years. We are unaware of serious adverse events. You can visit anteage.com if you care to learn more and order.

  99. Adrianna says:

    I have rosacea and stubborn perioral dermatitis under my nose. I bought Osea Hyaluronic Serum after reading that HA can improve rosacea but now I wonder if I’m making things worse! The ingredients list “3 molecular weights of Hyaluronic Acid.” If I am understanding this article correctly, and there is low molecular weight HA in the product, are you saying this product will increase inflammation, not improve it? Also, have you heard of tremellus mushroom? I’m considering using that on my face instead of HA to improve moisturization.

    • drgeorge says:

      Hyaluronic acid (HA) exists in a continuum of molecular weights, from very low to very high and everything in between. As expected, skin penetration of very low HA is the highest but also associated with the greatest inflammatory response. It’s hard to know what type of HA a particular product contains. Manufacturing techniques are not always precise so an HA ingredient may have a slew of molecular weights including very low HA. We admit the literature is confusing. The first article below speaks to the benefits of low molecular weight HA in treatment of seborrheic dermatitis, the second the the lack of difference in immunostimulatory effect on rodent skin when low, medium and high molecular weight HA is applied.

      J Clin Aesthet Dermatol. 2014 May;7(5):15-8.
      Efficacy and safety of a low molecular weight hyaluronic Acid topical gel in the treatment of facial seborrheic dermatitis final report.

      Int J Biol Macromol. 2018 Feb;107(Pt A):1-8. doi: 10.1016/j.ijbiomac.2017.08.131. Epub 2017 Aug 30.
      Absence of differences among low, middle, and high molecular weight hyaluronan in activating murine immune cells in vitro.

      For a given product, you could consider conducting a “N of One” study on yourself. It’s quite simple: apply the product to your dermatitis to see if the inflammation of your dermatitis improves and then discontinue the product and see if the dermatitis worsens. You’ll have your own personal answer in short order. This is a valid study technique as described in the article below.

      Per Med. 2011 Mar; 8(2): 161–173. ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118090/ )
      The n-of-1 clinical trial: the ultimate strategy for individualizing medicine?

      The tremella mushroom, specifically Tremella fuciformis, also called Silver Ear or Snow Mushroom, is in common use in Asia, including as a topical skin treatment. It reportedly has hydrating as well as melanin inhibiting effect. We have no experience with it but admit it sound interesting. If you give it a try, please let us know what you think.

  100. A says:

    I contacted one of the doctors from the studies you cited. Here was his response:

    Much of the data around low-molecular weight hyaluronan has been called into question by this paper: https://www.nature.com/articles/srep36928. That work suggests that most of our old preparations of low molecular weight hyaluronan were likely to have been contaminated by small amounts of bacterial products that may have been responsible for the pro-inflammatory effects. The publication of this work has made us in the field revisit much of the old literature around low molecular weight hyaluronan.

    While that uncertainty is unfortunate, this is how science actually progresses. We get data that challenges our assumptions and need to revisit our past work. That takes time. It can be intellectually messy. In the meantime, all I can say is that it’s not clear to me at least what hylauronan size means from an inflammatory perspective.

    That said, I’m unaware of any data suggesting that hyaluronan of any size causes cancer. Hyaluronan is certainly something tumors produce to manipulate the tissue environment around them. But that is different from causing the cancer. There are also many years of safety data from humans who received these products and from animal models. The hyaluronan in your skin care products is very unlikely to cause cancer.

    • drjohn says:

      You fail to consider the well established link between chronic inflammation and cancer. It’s in all the pathology textbooks- so must be true 🙂
      Further, you need to read some more recently published studies that reference that 2016 study but take us well down the path of understanding how hyaluronic MW might operate to either favor or promote a tumor forming environment.

      Start with this one: Differing Roles of Hyaluronan Molecular Weight on Cancer Cell Behavior and Chemotherapy Resistance tDiffering Roles of Hyaluronan Molecular Weight on Cancer Cell Behavior and Chemotherapy Resistance

      Hyaluronan (HA), a glycosaminoglycan located in the extracellular matrix, is important in embryo development, inflammation, wound healing and cancer. There is an extensive body of research demonstrating the role of HA in all stages of cancer, from initiation to relapse and therapy resistance. HA interacts with multiple cell surface receptors, including CD44, receptor for hyaluronan mediated motility (RHAMM) and intracellular signaling pathways, including receptor tyrosine kinase pathways, to promote the survival and proliferation of cancer cells. Additionally, HA promotes the formation of cancer stem cell (CSC) populations, which are hypothesized to be responsible for the initiation of tumors and therapy resistance. Recent studies have identified that the molecular weight of HA plays differing roles on both normal and cancer cell behavior. This review explores the role of HA in cancer progression and therapy resistance and how its molecular weight is important in regulating CSC populations, epithelial to mesenchymal transition (EMT), ATP binding cassette (ABC) transporter expression and receptor tyrosine kinase pathways.

      And then there is the fascinating finding of cancer resistance in some species whose HA has a very high molecular weight

      A Trickster in Disguise: Hyaluronan’s Ambivalent Roles in the Matrix.

      The molecular weight of HA varies and has great impact on its physiological functions and activities (27). Above 1,000 kDa HA is defined as high molecular weight HA (HMW-HA). HMW-HA possesses anti-inflammatory, anti-proliferative, and anti-angiogenic properties and is, furthermore, involved in wound healing processes (5, 27, 28). In homeostasis, HA is found in its HMW form in almost all human tissues. However, pathological circumstances, such as inflammation, show evidence for an elevated HA fragmentation resulting in a higher level of HA polymers with a lower molecular weight (29). Therefore, the effects of HA in the pathological context are often associated with the variable mass of the polymer (5).

      A comparison of human and naked mole rat HA is of interest because recent findings provide evidence for a link between the naked mole rat’s cancer resistance and its extremely HMW-HA.

      The evidence is piling up. Where HA is concerned, the high the MW the better.

  101. Elle says:

    Are you saying using LMWHA is going to make me look older and give me cancer? Isn’t there a difference between the HA your body produces and the HA that is put into it? My body will just assume that some random plant based HA is something I made and react the same way to it? If this was actually a danger wouldn’t the FDA forbid its usage in beauty products?

    • drjohn says:

      We are saying read the scientific literature, or a summary of it, and decide for yourself whether something inflammatory applied to skin for long periods of time a good thing. LMWHA is a biosignal for inflammation. That seems pretty much established by reams of evidence.
      There is a lie going around about HA coming from plants. HA is either derived from animal tissues (human or other) OR is synthesized in a production laboratory by bacterial or fungal fermentation. Plants make some nice polysaccharides, but not HA.
      There is a myth going around that the FDA will forbid ingredients in beauty products because they are actually inflammatory or toxins. Probably not unless people start dying suddenly. We can create create along list of nasties present in so called skin care being vended today.. You can read about a few of them here on BFT. The FDA cosmetics division seems more concerned about what is said about a product than what is actually in it.

      • Elle says:

        Whatever its origins, my body will react to it the same way it would react to my own HA? It can’t tell the difference?

        Since LMWHA is risky to apply, what are some better products that can help reduce the appearance of fine lines?

        • drjohn says:

          Again, we want to be careful in what we are talking about. HA is native to humans, that means we make it. It is also native to other animals. Plants, not unless genetically modified.
          Better products for fine lines? Of course we might be tempted to mention our own (http://anteage.com).

  102. Dorothy says:

    Dear DrJohn,
    In your post on Sept 21s you provided some new studies on the effect of HMW-HA on cancer cells. I am recently recovering from an advanced breast cancer and had also basal cell carcinomas removed from my face. Do you believe that HMW-HA topically applied is safe? I understand that the LMW-HA is inflammatory and could be detrimental for cancer patients. I am planning to buy: BulkSupplements Hyaluronic Acid (Na Hyaluronate) Powder (10 Grams) based on your recommendation in your earlier post. I will make small batched of 1% HMW-HA solution with ascorbic acid to be kept in the fridge. Is this safe for cancer patients? I am no longer in chemo and radiation. Thank you in advance.

    • drjohn says:

      Yes Dorothy, HMW-HA should be perfectly safe. If you want some premixed rather that do it yourself, AnteAGE now makes one. Google on AnteAGE®️ High Molecular Weight Hyaluronic Acid Gliding Solution. Best of health to you, DrJohn

  103. Dorothy says:

    Thank you DrJohn.

  104. Ingrid says:

    Hi dr. John,

    Thank you for your reply to me some comments above

    I have read a couple of your comments above, where you’re stating that it is especially below 130kda, If I’m remembering right, that inflammation occurs, and that only when the kda measures is at 360 the graph calms down again. – Referring to the study you replied to a comment above about.
    Does this mean that all above 360kda really is safe although companies naming it LMW?

    After having the bad reaction to the cream containing 3% HA in two molecular sizes, which unfortunately gave me nerve pain and numbness in the face, – having nerve issues related to longterm illness, and being made aware of this information, I did send a few emails to several skincare companies regarding their use of HA, and it seems as those who are willing to share the information on percentage and molecular weight have the consensus of 800-1200kda being high molecular weight – is this right, and are those products then safe to use?
    It seems the kda scale of HA is measured in bulks like this, – One of the companies says to use sodium hyaluronate in 400-600kda for instance as LMW.

    I am getting confused as to what is safe to use, and in what percentages – since I did have that bad reaction to the cream containing 3%, but not at all the same to two serums containing LMW, but with much lower percentage.

    What I’m Really asking is if the 800-1200kda is safe and really considered HMW, as well as if the LMW at 400-600kda is not safe at all, although it’s above 360kda?

    I’m lastly wondering what you would considering the upper tolerance limit in percentage for someone with sensitive nerves perhaps would be regardless of Molecular size? (Or also with high molecular size) ?

    Thank you very much for your help

    • drjohn says:

      In answer to Ingrid’s questions … 800-1200kda is the standard definition of HMW and is safe. As to whether any of these other average molecular sizes is still healthy i am going to say NO. Now the reason I say that is not because 400-600 is inherently unhealthy, but because any company that uses hydrolized HA is going to get a mixture. So let’s say you start with natural, unprocessed HA (800-1200 kda sized polymer chains) and do some chemical disruptions to arrive at 400-600. That may be the average, but in truth you are stripping off the fragments in random sized chunks. So you end up with a mix of sizes, including LMW “scraps”. Now theoretically you could do filtrations to get rid of smaller, but its actually hard (it is easier to filter out larger, not smaller, sized polymer fragments). Also – It turns out to be expensive. I frankly do not trust these companies to be doing that kind of molecular sorting at a commercial scale. So my recommendation is to stay away from anything other than the HA that nature makes so elegantly (the HMW variety). If a company monkeys with that at all it means they don’t really understand the science. There is no benefit to their HA manipulation, and there is potential for harm. They do it out of ignorance. Ask them who their medical scientists or medical directors are. Chances are they will say “we don’t need no stinking physician-scientists”. Dorry to be cynical, but we have been doing this a long time, and we have many examples.

      BTW Ingrid you might consider a product with nerve growth factors. We have had successes treating nerve hyper- and hypo- sensitivities through small nerve trophic factors (embedded in HMW-HA, a native human molecule that makes a wonderful storage and delivery vehicle for native human GF’s).

  105. Ingrid says:

    Hi dr. John,

    Thank you for your reply.
    I did a couple of days ago read in this article : https://www.nayaglow.com/2019/04/30/hyaluronic-acid-explained/ that high molecular weight is from 1500kda and up, and low molecular weight is 400-1000 – confusing, but, is this misleading?

    Also wondering – will the high molecular HA still give the plumping effect, just by holding on to water, and then not in the form of the «edema» like effect?

    And lastly, regarding the hyaluronic acid – what do you think about the indian senna seed extract as a botanical alternative to hyaluronic acid? It is supposed to be penetrating the skin’s surface and is found to work as a substitute for hyaluronic acid, and, then have a low molecular weight in nature as my mind have understood it. I do not know if for this reason it will also give a nerve-reaction, But, will it not be the same question in regards to molecular weight of this plant extract’s polysaccharides as with true hyaluronic acid, as this really is not hyaluronic acid?

    And, could I ask – I am wondering what your best recommendations for ingredients and type of skincare-products is for restoring and repairing DNA and cells (in the skin), as well as the best anti-inflammatory ingredients to use, after years of illness and stress to the body?
    I am 28 years old, and want to restore the skin’s hydration levels, elasticity, youth-fullness and smoothness.

    Thank you – where may I find products containing nerve growth factors, and how do they work topically? Thank you so much for your help!

    Kind regards, Ingrid

    • drjohn says:

      Anything above 1,000 kDa HA is defined as high molecular weight HA (HMW-HA). HMW-HA possesses anti-inflammatory, anti-proliferative, and anti-angiogenic properties and is, furthermore, involved in wound healing processes.

  106. Hi DrJohn
    Due to corticosteroid use for a GI condition, I have fragile forearm skin, where subcutaneous bleeding occurs with only slight mechanical trauma. There is a study in Pubmed (https://www.ncbi.nlm.nih.gov/pubmed/22499444) indicating that intermediate size HA fragments–50–400kDa- in conjunction with retinaldehyde may improve this condition and skin quality. Do you know a source for intermediate size HA fragments? Thank you.

  107. Ingrid says:

    Hi Drjohn,

    I thought I had been answering you last reply a few weeks ago, but, it appears I had not.

    Thank you for your help.
    I did read an article stating that high molecular hyaluronic acid in it’s Natural and unadulterated form is 1800kda and above : https://www.nayaglow.com/2019/04/30/hyaluronic-acid-explained/
    – Is this wrong?

    Thank you for your recommendation on the nerve growth factors – where may I find skincare with these? Tried googling, but coul not find any products, only articles.
    I am wondering if you have any suggestions on skincare to really aid in deeply rehydrating dehydrated skin and lowering redness and inflammation, for someone highly immune-compromised and sensitive due to longterm illness – highly reactive and sensitive skin and body, – not tolerating much? (In both the chemical and botanical world)

    Hoping, and Thank you for your help!
    It is really appreciated when not having seen many people/doctors/skin estheticians able to help.

    Kind regards, Ingrid

    • drjohn says:

      Ingrid, 1800 kda (1,800,000) is HMW. You will find nerve growth factors in products derived from BM-MSC (stem cells) such as AnteAGE. They are also coming out with a line of biosignals products with individual GF’s including NGF & BDGF.

  108. H M says:

    Is https://www.makingcosmetics.com/ a trustworthy site in your opinion to purchase from? I have recently bought Ceramides and Hyaluronic Acid from them. Thanks so much for your valuable time.

  109. Carin says:

    Dear Dr. John
    Bos Essentials (from Amazon) makes a hyaluronic acid powder that is 800 kDa – 1,500 kDa. Is this considered high molecular weight (or do I need to aim for over 1000 kDa, as I’ve occasionally read?)
    It only lists “hyaluronic acid powder” in the ingredient list. Is this specific enough?
    Would this be a good product to buy to make my own hyaluronic serum?

  110. Zoe says:

    Please comment on this article:
    Vegan Hyaluronic Acid – made using genetically manipulated Bacillus

    Some excerpts:

    If you believed all the hype on the internet, you’d think Hyaluronic Acid was a miracle moisturiser.

    In reality, the opposite is true – and to a startling degree.

    Founder David Lyons sees beyond the hype because more than 30 years of clinical experience tells him Hyaluronic Acid will not give lasting results.

    Hyaluronic Acid is a marvellous thing. It can hold up to 1000 times its weight in water, promote collagen production and give skin that delightful plumpness we all associate with youth.

    But, sadly, once naturally occurring HA is lost through ageing, it is gone for ever.
    Whatever its source, Hyaluronic Acid can’t help.

    Using products that contain Hyaluronic Acid, no matter how this is sourced, in the hope it will draw moisture to the skin, or replenish our natural stores, is wishful thinking. This applies just as much to Hyaluronic Acid supplements as to Hyaluronic Acid skin care.

    ..So, the irony is that, as it sits on the surface of the skin, Hyaluronic Acid – with its great affinity for water – actually draws moisture out of the epidermis where it is most needed.
    Hyaluronic Acid will deplete your skin

    Yes, despite claims to the contrary, Hyaluronic Acid will actually dehydrate your skin over time.

    Not only that, but Hyaluronic Acid has been shown to promote the build-up of keratin cells. These are the cells responsible for the flakiness you see on sun-damaged skin. So even if you think you see some improvement initially, it will soon be all downhill from there.

    Also, in comments: The darkness under the eyes is likely due to your over-response/sensitivity to the HA (Hyaluronic Acid/Sodium Hyaluronate). The effect of HA in the thin skin under the eyes may, in some people, even at low doses, produce loosening of the cellular bonds in the tissues.

    • drjohn says:

      More amateur science:

      ..So, the irony is that, as it sits on the surface of the skin, Hyaluronic Acid – with its great affinity for water – actually draws moisture out of the epidermis where it is most needed. Hyaluronic Acid will deplete your skin. Yes, despite claims to the contrary, Hyaluronic Acid will actually dehydrate your skin over time.

      It is true the molecule by itself (dehydrated) draws water to itself. But in topically applied skin care products it is fully hydrated, not dry. If your skin is thirsty HA will yield some of that moisture to your skin. It the borrows from the atmosphere to replenish its own supply.

      Not only that, but Hyaluronic Acid has been shown to promote the build-up of keratin cells.
      HA we make ourselves in skin itself turns over rapidly (less than a day). Very dynamic. It does not increase keratin or slow turnover.

      Also, in comments: The darkness under the eyes is likely due to your over-response/sensitivity to the HA (Hyaluronic Acid/Sodium Hyaluronate). The effect of HA in the thin skin under the eyes may, in some people, even at low doses, produce loosening of the cellular bonds in the tissues.
      Nonsense, show me the published evidence for that!

  111. LARRY GLASS says:

    I am wondering whether you can venture an opinion as to whether a topical application of middle weight, 500-730 kDa hyaluronic acid, to the area of an achilles tendinopathy would be a beneficial treatment. I had a 30-40% tear of the left achilles tendon, recently treated with amniotic fluid injections that appear to have reduced the tearing to 15-20% (but without visible improvement of tendon enlargement). Among the ingredients in the amniotic fluid are different molecular weights of HA. At least one double-blind study shows that injections of middle weight HA improves achilles tendinopathies. Another study shows that 20-300 kDa HA will penetrate the skin, but heavy weight HA does not. Do you think that middle weight HA, topically applied, would penetrate the skin and also enter the achilles tendon. Is it worth a try? Is there any risk? What are your thoughts?

    • drjohn says:

      As far as injections go, it makes sense that amniotic fluid (AF, which contains exosomes) would be healing. While there is some natural human HA in AF (made by mom & baby), it is predominantly HMW. Fragments (LMW) occur if there are proteases about, but proteases are about only under stressful conditions. That could occur with disease, or a very stressful birth event, but not a healthy amnion, especially cesarean birth. Forget the LMW HA unless you need an inflammatory boost. If it were my tendon I would be thinking about exosomes (e.g. cord stem cell derived) which are the best characterized in terms of tendon and ligament healing.

  112. russell says:

    Hello, i hope you’re well

    What is your view of the HA powder from lotion crafter?


    “Our Hyaluronic Acid is made by the bacterial fermentation of plant matter (generally using a ferment culture which may include wheat peptones, and yeast, as well as glucose derived from corn). The Hyaluronic Acid will not contain any plant-derived DNA. It is considered vegan and non-GMO.

    Im looking at the “Hyaluronic Acid LMW 0.8 – 1.0 Million Daltons”, which Lotion Crafter have labeled as LWM, but your comment to Ingrid on NOVEMBER 9, 2019 AT 4:58 PM suggests it is HMW? I’m confused by Lotion Crafters LMW labeling. What are your thoughts?

    Thank you in advance for the answer and thanks for the amazing site

    • drjohn says:

      Simple rule: If it says LMW then stay away. There are plenty of other sources who keep the molecule in its natural HMW state.

    • drjohn says:

      Somebody over there is math-impaired. 0.8m – 1.0mm (800,000 to 1,000,000) is high molecular weight HA. Just to make things interesting – Wheat Peptone is produced by the enzymatic hydrolysis of wheat gluten. I hope it does not claim “gluten free”… also has corn sugar.

  113. Tracey says:

    Hi Dr John

    I recently read about a ingredients called Micronized 11KDA Hyaluronic Acid. Can i know what is the different between this and normal HA or even fragmented HA? Is 11KDA HA good for the skin?



    • drjohn says:

      11kDa is very small. Yes, tiny fragments of HA which are proven in abundant studies to be inflammatory. Not good for the skin.

  114. Nat says:

    What are your thoughts on microneedling with regular HA? I always thought it was a good thing, but then I read this article that claims microneedling depletes your bodies ability to produce collagen, harms DNA, and ultimately causes premature skin aging, and higher skin cancer risks.


    • drjohn says:

      Nat, Sadly, this person makes all sorts of embarrassingly stupid and nonsensical statements about skin physiology, and regularly misreads the biology literature. She claims her MS in biology somehow gives her special powers that actual scientists don’t have. I won’t go into detail. I will point you to Lab Muffin, an insightful PhD in chemistry (PhD outranks MS), and her review of the vitamin C nonsense espoused by this self-annointed skin care expert. The microneedling stuff is total crappola. Go read Dr Setterfield’s book if you want to understand how microneedling induces collagen formation, not breaks it down. Tons of actual studies in peer-reviewed journals studies to prove this. You will find many of them referenced here on BFT.

  115. LARRY GLASS says:

    HI–I sent you a comment about hyaluronic acid and possible topical application of 500-730 kDa for achilles tendinopathy about a week or two ago. Haven’t heard back. Please reply.

    • drjohn says:

      500-730 is in the low to middle size range. That means it is not very inflammatory (the lower the molecular weight the more inflammatory). Also not high, so not anti-inflammatory. This paper shows the macrophage responses of different molecular weights of HA . “…results indicate that hyaluronic acid has molecular weight dependent effects on modulating macrophage phenotype. In solution, the high molecular weight form of the polymer promotes alternative (anti-inflammatory) macrophage activation, even when macrophages are challenged with a classical (inflammatory) activating stimulus. Conversely, macrophages exposed to low molecular weight HAs are encouraged to produce pro-inflammatory mediators associated with the classically activated state. The most pronounced effects are seen with the lowest and highest molecular weight forms of the polymer.”

      So the question becomes tendinopathy – does the tendon benefit from a short inflammatory kick (e.g.a diabetic with poor wound healing) or is it sore and rather inflamed already, in which case pushing away inflammation is better? But medium weight HA kinda begs the question. if you want inflammation why not go LMW (50kD)? Keep in mind that topical HMW or even medium is not really going to get much to the joint or tendon sheath unkess other modality used to encourage absorption (chemical absorption enhancer, ultrasound, etc).

  116. Kate says:

    Hi, when hyaluronic acid/sodium hyaluronate is produced by fermentation is there a risk of any kind of contamination or it is 100% safe?

    • drgeorge says:

      Hyaluronic acid is found in many human tissues and is particularly abundant in the eyeball, joint fluids, and soft connective tissue. HA has a decades-long history of safe and successful use when injected into painful joints like knees and ankles. That form of HA was typically obtained from rooster combs, the red fleshy tissue on the head of male chickens. Now it is primarily produced from the fermentation of group A streptococcus bacteria. The manufacturing and purification process completely eliminates the bacteria and bacterial fragments. It would finish that process as a sterile product. In the manufacturing of HA products for cosmetics, the last step before release into the market is microorganism testing to confirm it does not contain bacteria or mold. If that test is not passed, it is not released.

  117. Hülya says:

    Greetings from Turkey. We’re a few friends here following your blog and find what you say very fascinating. I’ve just started using Tretinoin. I don’t want to further irritate my skin, I want to make a topical HA serum at home. I found a product that claims that it’s 1.6 million to 2 million Dalton molecular weight with 99% in polymer form. Is this appropriate so I don’t inflame my skin with low molecular HA?

    • drgeorge says:

      High molecular weight HA is >800,000 daltons in molecular weight. Your choice falls well above that threshold. Let us know how it goes.

  118. Poon, Helen says:

    About the scientific publications you mentioned in this article, can you provide the reference? ? I would like to take a look

    • drjohn says:

      Hi Helen, if you look through all the comments and discussion, you will find many references to published data.

  119. Natalia Hancock says:

    Thank you very much for the information. I wonder what would be the most bio-compatible dermal filler?

    • drgeorge says:

      Dermal fillers are most commonly a formulation primarily containing hyaluronic acid polymers, although other compounds are used including polyacrylamide gel, polymethyl methacrylate, calcium hydroxyapatite and poly-L-lactic acid.

      Calcium hydroxyapatite is a mineral-like compound naturally found in human bones. Poly-L-lactic acid is a synthetic filler that helps to stimulate collage production which means that volume increases occur slowly, over a period of several months. Polymethyl methacrylate is semi-permanent but has been known to cause lumps that are visible under the skin. The same compound, albeit in a different polymer configuration, is used as bone cement for joint implants like knees and hips.

      That said, biocompatibility is well tested for all approved fillers – although there is the occasional localized hypersensitivity reaction in some patients. Most adverse events, which are infrequent, have more to do with injection technique, proper location of injection, good sterile technique, avoidance of important local vascular structures and judicious judgement as to the amount to inject to avoid local pressure necrosis from inadequate blood flow.

  120. Nadia says:

    Hi, I’m Nadia. I have read several studies about this and have been amazed. I sent a message to the manufacturer of an HA serum that I use and asked him about the safety of LMW-HA and this is what he replied:
    “Hello Nadia, they are low molecular 50 kDa, which is best to prevent wrinkles without inflammation. Research shows molecular below 20 kDa might cause inflammation”
    Is this true?

    • drjohn says:

      Nadia,yes it is true that LMW-HA causes inflammation. Yes it is true that 20kDa is low (we actually term that VLMW-HA = “very low). So is he claiming that they create HA that is >20kDa but <50kDa? That is actually exceptionally hard to do, and expensive. Involves tangential flow filtration and ultracentrifugation of hydrolyzed HA to separation out all fragments <20 and >50. Thats a very tiny range chemically speaking. *the reaction itself cannot be controlled to only produce 20-50 kDa HA. That’s one problem. The other problem is the body of literature pointing to inflammation at any level below 1,000. So this conclusion “best to prevent wrinkles without inflammation” is at odds with the larger body of research.

      Tell you what, tell this manufacturer to contact us and let’s see what they have to say. We encourage all scientific debate. We will be nice!

  121. Nadia says:

    Thanks for answering. This is incredible!!! I will copy your answer and send the link to them. (Joyal Beauty)
    Ohh and I’m going to switch to a HMW-HA serum. Also, there are now supplements that can help produce a little more HA, among other wonderful benefits for health and skin. Hugs!!

  122. Susan Benson says:

    If I have medical depth microneedling, can the high molecular weight hyaluronic acid (used for glide and immediately after) penetrate the micro-channels created in the skin? I have read its a large molecule that normally can’t be absorbed but I wondered if the channels from microneedling are big enough to allow it to penetrate into the epidermis or dermis? I ask because I have read HA can stimulate collagen in the skin when used in fillers and I wondered if entry into the skin during microneedling can do the same.

    Also is there any difference between a pure high weight molecular HA serum you can buy in a store and a high weight non-cross linked HA filler used for mesotherapy or short term filler (ie. injectable moisturizer) that a professional would use in treatment? I am thinking the latter must somehow last longer in the skin.

    • drgeorge says:

      On the basis of relative size, the channel created by microneedling are HUGE compared to the molecular size of even very high molecular weight hyalruonic acid. HA can easily gain access while the channels are open. Realize, however, that the channels progressively close during the first few hours after treatment, which will impede penetration so it should be applied during or immediately after treatment.

      Mesotherapy performed by a professional consists of shallow injections which requires absolute sterility of products to ensure infection from the product does not occur. I would not want store-bought products used for that purpose. As to molecular weight, the professional preparations are semi-viscous polymers. Can’t say what kind of HA in the products you buy at the store.

  123. JTania says:

    I prefer the Laluset pharmacy-grade hyaluronic acid cream, which I believe, is made of 0.2% sodium hyaluronate over all the HAs I have tried.
    It seems to keep my skin plumped nicely for a few hours and softens any lines.
    Is this a good product in your estimation?

    • drgeorge says:

      You made a consumer choice and like the results. That’s what matters most. In looking at the product, there’s nothing that jumps out to indicate it has any great advantages over other topical HA products. If the price is reasonable, you like the product and the results it provides, that’s a good product.

  124. Susan Benson says:

    I read that hyaluronic acid injected into the skin can stimulate fibroblasts, so dermal fillers can have a side effect of creating collagen.

    Theoretically, if non-cross-linked hyaluronic acid serum (around 1000 kda so not LW) was used during and after a medical microneedling treatment, could it reach the dermis via the many channels and stimulate fibroblasts? (The serum would be a sterile mesotherapy product). Do you have any thoughts on this. I am not sure if the few weeks it would last in the skin would be enough time to have some stimulatory effects.

    • drgeorge says:

      Microneedling does provide temporary channels that enable penetration of topically applied substances into the dermal layer, providing the needling is of “medical” depth i.e. results in bleeding. Typically, this would be 0.5 mm and deeper. The amount of HA that would reach the dermis, however, would be very modest compared to other kinds of HA skin treatments, such as dermal fillers and mesotherapy, which do have evidence of fibroblast stimulation and collagen production. (references below). Repeated treatments may be effective but recall that microneedling is also known as collagen induction treatments, as it is known to stimulate fibroblast activity with or without application of topical substances. A search of PubMed, the global “library” of medical literature does not return published studies that address your specific question.

      Science of Hyaluronic Acid Beyond Filling: Fibroblasts and Their Response to the Extracellular Matrix
      Plast Reconstr Surg. 2015 Nov;136(5 Suppl):188S-195S.

      “Loss of viscoelasticity is one of the primarily signs of skin aging, followed by appearance of visible wrinkles. Hyaluronic acid (HA)-based fillers are widely used to fill wrinkles and compensate for volume loss. Recent clinical observations demonstrate persistence of the filling effect longer than the biological availability of the filler. Stimulation of new collagen by cross-linked HA and up-regulation of elastin have been suggested as possible explanation to this observation and have been supported experimentally. Cross-linked HA substitutes for fragmented collagen in restoring extracellular matrix required for normal activity of fibroblasts, such as collagen and elastin production. To restore extracellular matrix efficiently, serial monthly treatments are required. Boosting of facial and nonfacial skin through fibroblast activation is a new indication for HA-based products. Injectable HA has also been recently registered in Europe as agents specific for the improvement of skin quality (Restylane Skinboosters). Further explanation of the possible mechanisms supported by long-term clinical examples is presented herein.”

      In vitro study of RRS HA injectable mesotherapy/biorevitalization product on human skin fibroblasts and its clinical utilization
      Clin Cosmet Investig Dermatol. 2016; 9: 41–53.

      “This study demonstrated that RRS HA injectable promotes human skin fibroblast viability and enhances the expression of type I collagen and elastin genes in vitro.”

      Efficacy of mesotherapy in facial rejuvenation: a histological and immunohistochemical evaluation
      Int J Dermatol. 2012 Aug; 51(8): 913–919.

      Six women, Fitzpatrick skin types III and IV, three-month course of mesotherapy at two-week intervals. “The present study indicates that mesotherapy for skin rejuvenation does not result in statistically significant histological changes or clinical improvement.”

      The Efficacy and Safety of Hyaluronic Acid Microinjection for Skin Rejuvenation in Vietnam Open Access Maced J Med Sci. 2019 Jan 30; 7(2): 234–236.

      “In conclusion, this study objectively demonstrated the efficacy and safety of HA microinjection for skin rejuvenation. In particular, we showed that intradermal HA mesotherapy might be of value to decrease the wrinkles and increase the suppleness of ageing skin when conducted by a trained physician.”
      A New Minimally Invasive Mesotherapy Technique for Facial Rejuvenation
      Dermatol Ther (Heidelb). 2013 Jun; 3(1): 83–93.

      “The new minimally invasive mesotherapy technique described can improve the clinical appearance of the skin in different age groups.”

  125. SUSAN says:

    I am interested in taking Hyaluronic acid orally for joint pain but because of my finances, it must be affordable so I would want to use bulk powder. The cosmetic grade in bulk is cheaper than the oral “supplements”. Can I take this orally mixed with almond milk. You mentioned a bulk grade supplement from amazon.com in a past post. Is this a good product in your opinion?

  126. Mira says:

    I moderate a FB group for a master esthetician (she’s a big fan of Dr. Setterfield so it’s awesome seeing you two mention him btw and we’ve got lots of AnteAge fans) and we have a lot of members interested in microneedling. We’ve been given conflicting info on what constitutes low, medium, and high molecular weight hyaluronic acid. Can you clarify this so we have accurate information to share?

    • drgeorge says:

      Confusion on this topic is widespread so let’s use a published study that examined the impact of molecular weight on activation of macrophage (a type of cell involved in inflammation and tissue repair (citation below.) The authors defined it thusly: “Herein, we have explored the effect of different hyaluronic acid molecular weights, low (≤ 5 kDa), intermediate (60-800 kDa), and high (> 800 kDa), on macrophage activation.” This translates: Low ≤ 5000 Daltons, Intermediate 60,000 to 800,000 Daltons, High > 800,000 Daltons

      ACS Biomater Sci Eng. 2015 Jul 13; 1(7): 481–493.
      High and low molecular weight hyaluronic acid differentially influence macrophage activation

  127. Mich says:

    Are you aware of whether The Skincare Company Hyaluronic B5 serum contains LMW or HMW HA? Also, does the AnteAGE serum/accelerator contain HA?

    • drgeorge says:

      We find no information describing the specifics of the HA in Skincare Company’s B5 Serum. The AnteAGE duo Accelerator contains sodium hyaluronate, which is a purified derivative “salt” of HA.

  128. Ali says:

    I have found some hyaluronic acid powder on amazon, and I was wondering if it would be safe for me to try to make my own serums with this! I really don’t like some of the ingredients in bought serums, and my budget is too tight to afford “organic stuff”.

    • drgeorge says:

      There is no way to opine as to the “safety” of making your own serums from HA purchased on Amazon.com. As written elsewhere on BFT, we are wary of low molecular weight HA in topical products based on the recognized potential to initiate an inflammatory response, not something desirable or beneficial. Is there any sort of certificate of analysis for the product you purchase? That might be informative. We have no comment beyond that.

  129. Brenda says:

    I recently bought some vegan 30 mg “Fluid HA Proprietary Blend LMW HA Sodium Hyaluronic” prior to finding your website. Rather than throwing it out would it be beneficial to apply to the scalp for increased hair growth?

    • drgeorge says:

      We are not familiar with topical hyaluronic acid being useful in initiating hair regrowth. Google Scholar and PubMed searches produced no encouraging results. We do find HA being of some benefit as a vehicle for applying topical pigment (dye) to hair and also as a “hanging drop” medium in which to grow dermal papilla cells. We see no reason to NOT apply to the scalp but anticipate no positive results. Maybe it will enhance sheen and shine, who knows?

      Kalabusheva E, Terskikh V, Vorotelyak E
      Hair Germ Model In Vitro via Human Postnatal Keratinocyte-Dermal Papilla Interactions: Impact of Hyaluronic Acid. Stem Cells Int. 2017 Oct 10

  130. Patrik says:

    I have seen products with 5000 Daltons, LMW-HA. But isn´t that nanotechnology?

    • drgeorge says:

      Nanotechnology is generally understood to mean technology conducted at the nanoscale, which is about 1 to 100 nanometers. A nanometer is one billionth of a meter or 10 to the minus ninth power. For reference, a sheet of newspaper is about 100,000 nanometers thick. An online calculator places 5000 Daltons (assuming a globular shape) to be slightly less than one nanometer in diameter. At about .66 nanometer, 5000 Daltons is therefore just shy of the lower threshold of the nanotechnology scale.

  131. Alexandra L says:

    I am interested in adding HA to a skin cream I make that contains ozonated olive oil as well as several other oils. Would it provide additional benefit to add HA powder to this formula or would it be better to apply pure hydrated HA first and then the oil? I also wonder whether HWW-HA may actually create a barrier and prevent the oils from penetrating? I would appreciate your thoughts. BTW, I am so glad to have found your site. I appreciate and thank you for all of your generosity!

    • drgeorge says:

      Adding HA powder to the oil is not a good idea. HA is extremely hydrophylic, meaning it “loves” to mix and hydrate with water and does so at a ratio of about 1000:1 meaning a little powder goes a long way. Powder added to oils will never mix and hydrate. At most, it will create a paste and a mess. As far as how to use your homemade HA and oil concoctions, you can try a little trial and error as to which to apply first, or alternate the time of day you apply each mixture. HA is great at hydrating upper layers of the skin; oil products are better at actually penetrating the stratum corneum. Our two-part system has an aqueous phase predominant component (Serum) and one that is more lipid-based (Accelerator). We recommend applying them in that order. Let us know how it goes.

      • Ava Billy-Jackman says:

        I have seen what would be called high performance serums with hyaluronic acid and squalane. If HA powder, or hydrated HA do not mix with oil, then how do they create those products? And just to be clear, I use my oils first, then use the HA? Thanks for your response and your kind spirit.

        • drgeorge says:

          Products that contain both water-compatible and oil-compatible ingredients abound in the market. Mixing hydrophilic and hydrophobic ingredients in a manner is which they do not separate into layers is called emulsification. Easy to do. If you want the effect of HA in hydrating the skin surface, it should be applied first. Lipids, common in moisturizer products, can be placed as last layer to “seal” the surface to prevent water loss. These are not hard and fast rules. You can try your products in varying application schemes and see what you prefer.

  132. Aimee says:

    After doing a lot of research, I found an article on low molecular HA and its topical effects. Most scientific studies concluded LMHA as beneficial and showed a significant increase in hydration, collagen production and helped those with dermatitis without many adverse effects. There are also articles that contradict this so it’s a bit confusing.

    I think the concern is that LMHA is pro-inflammatory or takes part in an inflammatory response but my understanding is that not all inflammation is bad. Some inflammation could be healing or a healing response. Is that possible with LMHA?

  133. DrGeorge says:

    The pro-inflammatory / anti-inflammatory controversy concerning LMHA does have contradictory information available, certainly less so for HMWHA. We opt for the more conservative approach and utilize and recommend HMWHA which avoids the issue. All HA is very hydrophilic meaning it loves to absorb and retain water molecules within its structure. It will always have a role in keeping skin plump and hydrated. Inflammation is a more complicated topic.

    All trauma and skin diseases have an inflammatory component and it is indeed part of our natural healing cascade. Brief episodes can be helpful in mounting a healing response. Chronic inflammation, however, is always bad leading to fibrosis and pigment abnormalities in the skin over time. It is for that reason that we feel strongly that topical products intended for chronic use should NOT incite inflammation, but rather, do the opposite. Our products contain conditioned media from mesenchymal stem cells from bone marrow which are by nature prolific producers of anti-inflammatory biosignals i.e. cytokines and growth factors.

  134. Alex L says:

    I am considering purchasing pure mulberry silk pillowcases infused with HA. I don’t know if they contain HMW or LMW HA. Since HA is hydrophilic and pure Mulberry silk is a hydrophobic natural fiber, would you consider this useful, useless, or somewhere in between in terms of helping keep skin hydrated. Or, is it potentially counterproductive because it would absorb water from the skin.

  135. drgeorge says:

    It never ceases to amaze us how marketers connive and confuse the public to get their money for nonsensical products. We see no valid reason why this combination would provide any benefit except cover a nice comfortable pillow to promote a good night’s sleep. Unless you can find a valid scientific study that confirms there is any value whatsoever in such a contrived product, we would recommend steering clear. Spend your money on something with proven value. To us, this pillowcase doesn’t meet that criterion.

  136. Em says:

    First of all, I would really like to express appreciation for the great info on your site. Thank you. It is wonderful to have a knowledgeable source that weeds out the nonsense and marketing that consumers have to wade through.

    While I would like to purchase nearly ALL the products on your site- our low CDN dollar dictates I stick to a budget. Therefore, I will only be able to try your home microneedling serum for my once-a-month deeper 1.5 mm microneedling sessions. For my ongoing twice weekly use, I was planning to make a DIY HMW HA serum for use with my sonophoresis/iontophoresis device. Wondering if you know of any reliable sources that one might look to for HMW HA powder (I am getting hung up on whether it should be pharmaceutical grade, medical grade, or food grade etc – as I don’t want to end up with a whole bunch of heavy metals or whatnot that I did not bargain for along with the HA)!!!

  137. drgeorge says:

    This question has come up several times before. Certainly, if you are microneedling with HA, the purer the formulation the better. We have used some form of HA in our products since their initial launch many years ago. Our HA is synthesized and comes with certificates of analysis which indicate the HA component as 100% i.e. no other substances, including heavy metals. As your home formulation will likely be smallish in volume, we don’t have a vendor to recommend as we have never researched them. Even so, you should inquire about a certificate of analysis. Your question is a reasonable one to ask although the issue, due to the small amount of topical product actually penetrating the skin, may be not one worth losing sleep about.

  138. Toni Apatira says:

    Thank you for taking the time to respond to the comments on the blog posts. I love reading through all the comments.

    The general consensus is that LMWHA is pro-inflammatory and HMWHA is anti-inflammatory. The study below appears to indicate there is a benefit to the presence of LMWHA as it facilities the clearance of debris and infectious agents. Low-level inflammation is generally considered to be negative but is there any benefit for the use of LMWHA as described in the study on a short-term basis?


  139. DrGeorge says:

    We love our readers! Your questions are challenging and show our efforts to teach and inform have taken solid root over the years.

    A major thesis of our work in stem cell science, skin physiology and esthetics has been inflammation has an essential and necessary role in healing (Mother Nature knows best), but stimulating inflammation on a chronic basis, especially with skincare ingredients applied daily, is counterproductive. Because HA is such a ubiquitous ingredient in skincare products, the question of whether or not it stimulates inflammation is an important one. Why slather pro-inflammatory ingredients, especially ones with lower molecular weight that can penetrate skin more easily? LMWHA fits both of these descriptors although in physiology and wound healing, it may have a role to play. Your article addresses some of these considerations but only in part. HA breaks down into smaller fragments during tissue injury and fibroblast-like cells, called fibrocytes, arise from circulating progenitor cells that infiltrate the site of wounds. The article you cite states that “cells appear to be able to sense the difference between HMWHA, LMWHA and oligo-HA [….] LMWHA but not HMWHA stimulates macrophages to secrete inflammatory cytokines such as IL-8…” “LMWHA binds to specialized receptors (called toll-like receptors) to elicit pro-inflammatory action, while HMWHA dampens inflammation by inhibiting this signaling.”

    We therefore stick to our guns: HMWHA is preferred over LMWHA as an ingredient for topical products applied to the skin on a chronic / daily basis.

  140. Toni Apatira says:

    Thank you so much for the response! I agree that sustained inflammation is the basis for a significant amount of illnesses and medical issues so it makes perfect sense that the skin would not be any different. It’s alarming that LMWHA appears to be in everything these days!

  141. Cathie Ferguson says:

    Which HA would you recommend using along with a hand sanitizer to combat the drying effects of the alcohol? I see you compare low and high-weight HA and I’m wondering about the benefits of combining them along with medium-weight HA which I see on manufacturers’ sites.

    • drgeorge says:

      For this purpose, we don’t see a distinct advantage among the HA molecular weight choices. HA applied to intact skin is essentially staying in place until the next handwashing washes it away. If you should happen to try several molecular weight HAs, let us know if there is a difference. We doubt you will see one but always are open to new evidence that may make us change our opinion.

  142. Tara says:

    Hi, I’m really confused as to how I can tell if a product is using LMHA. If it’s not stated in the product description, is there a way to tell? Is it listed a certain way in the ingredients?

    • drgeorge says:

      Molecular weight is not something one can ascertain through “feel” except, perhaps, when one is dealing with HA-only formulations of extreme molecular weight, high and low. In that case, one may feel a difference in viscosity and flow. Even so, because cross-linking between HA molecules is also a consideration in how formulations are created, these cross-links will also influence viscosity and flow. Consider, HA fillers which vary in “thickness.” From our experience, manufacturers do not typically indicate molecular weights in their formulations.

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