skin hydration

Yes, size really matters…Hyaluronic Acid

Posted on Posted in Ingredients

Here is a great post shared by our pals at BFT, Hyaluronic Acid – Yes, Size Does Matter, it will help you understand the real difference between Low and High molecular weight Hyaluronic Acid.
Enjoy!

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.

low Hyaluronic acid

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).

hyaluronic acid and collagenThe 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 micro-needling.

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.

Click here to order our Serum with HA

References

  • Jiang D1, Liang J, Noble PW. Hyaluronan as an immune regulator in human diseases. Physiol Rev. 2011 Jan;91(1):221-64. PMID: 21248167.
  • Zgheib C1, Xu J1, Liechty KW1. Targeting Inflammatory Cytokines and Extracellular Matrix Composition to Promote Wound Regeneration. Adv Wound Care (New Rochelle). 2014 Apr 1;3(4):344-355. PMID: 24757589.
  • Voelcker V1, Gebhardt C, Averbeck M, Saalbach A, Wolf V, Weih F, Sleeman J, Anderegg U, Simon J. Hyaluronan fragments induce cytokine and metalloprotease upregulation in human melanoma cells in part by signalling via TLR4. Exp Dermatol. 2008 Feb;17(2):100-7. PMID: 18031543.
  • Esser PR1, Wölfle U, Dürr C, von Loewenich FD, Schempp CM, Freudenberg MA, Jakob T, Martin SF. Contact sensitizers induce skin inflammation via ROS production and hyaluronic acid degradation. PLoS One. 2012;7(7):e41340. PMID: 22848468.
  • Black KE1, Collins SL, Hagan RS, Hamblin MJ, Chan-Li Y, Hallowell RW, Powell JD, Horton MR. Hyaluronan fragments induce IFNβ via a novel TLR4-TRIF-TBK1-IRF3-dependent pathway. J Inflamm (Lond). 2013 May 30;10(1):23. PMID: 23721397.
  • Horton MR1, McKee CM, Bao C, Liao F, Farber JM, Hodge-DuFour J, Puré E, Oliver BL, Wright TM, Noble PW. Hyaluronan fragments synergize with interferon-gamma to induce the C-X-C chemokines mig and interferon-inducible protein-10 in mouse macrophages. J Biol Chem. 1998 Dec 25;273(52):35088-94. PMID: 9857043.
  • Hodge-Dufour J1, Noble PW, Horton MR, Bao C, Wysoka M, Burdick MD, Strieter RM, Trinchieri G, Puré E. Induction of IL-12 and chemokines by hyaluronan requires adhesion-dependent priming of resident but not elicited macrophages. J Immunol. 1997 Sep 1;159(5):2492-500. PMID: 9278343.
  • McKee CM1, Lowenstein CJ, Horton MR, Wu J, Bao C, Chin BY, Choi AM, Noble PW. Hyaluronan fragments induce nitric-oxide synthase in murine macrophages through a nuclear factor kappaB-dependent mechanism. J Biol Chem. 1997 Mar 21;272(12):8013-8. PMID: 9065473.
  • McKee CM1, Penno MB, Cowman M, Burdick MD, Strieter RM, Bao C, Noble PW. Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44. J Clin Invest. 1996 Nov 15;98(10):2403-13. PMID: 8941660.
  • Ghosh S1, Hoselton SA2, Wanjara SB2, Carlson J3, McCarthy JB4, Dorsam GP2, Schuh JM2. Hyaluronan stimulates ex vivo B lymphocyte chemotaxis and cytokine production in a murine model of fungal allergic asthma. Immunobiology. 2015 Feb 7. PMID: 25698348.
  • Ghosh S1, Samarasinghe AE, Hoselton SA, Dorsam GP, Schuh JM. Hyaluronan deposition and co-localization with inflammatory cells and collagen in a murine model of fungal allergic asthma. Inflamm Res. 2014 Jun;63(6):475-84. PMID: 24519432.
  • Nikitovic D1, Berdiaki A2, Galbiati V3, Kavasi RM2, Papale A3, Tsatsakis A4, Tzanakakis GN2, Corsini E3. Hyaluronan regulates chemical allergen-induced IL-18 production in human keratinocytes. Toxicol Lett. 2014 Oct 1;232(1):89-97. PMID: 25280773.
  • Fieber C1, Baumann P, Vallon R, Termeer C, Simon JC, Hofmann M, Angel P, Herrlich P, Sleeman JP. Hyaluronan-oligosaccharide-induced transcription of metalloproteases. J Cell Sci. 2004 Jan 15;117(Pt 2):359-67. PMID: 14657275.
  • Campo GM1, Avenoso A, D’Ascola A, Scuruchi M, Prestipino V, Nastasi G, Calatroni A, Campo S. The inhibition of hyaluronan degradation reduced pro-inflammatory cytokines in mouse synovial fibroblasts subjected to collagen-induced arthritis. J Cell Biochem. 2012 Jun;113(6):1852-67. PMID: 22234777.
  • Campo GM1, Avenoso A, D’Ascola A, Prestipino V, Scuruchi M, Nastasi G, Calatroni A, Campo S. 4-mer hyaluronan oligosaccharides stimulate inflammation response in synovial fibroblasts in part via TAK-1 and in part via p38-MAPK. Curr Med Chem. 2013;20(9):1162-72. PMID: 23298137.
  • Liang J1, Jiang D, Jung Y, Xie T, Ingram J, Church T, Degan S, Leonard M, Kraft M, Noble PW. Role of hyaluronan and hyaluronan-binding proteins in human asthma. J Allergy Clin Immunol. 2011 Aug;128(2):403-411. PMID: 21570715.

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