Hyaluronic Acid

Topical hyaluronic acid has long been used as a moisturizer and to repair injured skin, but recent studies show that it also has the potential to improve wrinkles and restore skin elasticity.

Effects


Grade Level of Evidence
A Multiple double-blind, controlled clinical trials.
B 1 double-blind, controlled clinical trial.
C At least 1 controlled or comparative clinical trial.
D Uncontrolled, observational, animal or in-vitro studies only.
Grade Effect Size of Effect Comments

A

Healing

Strong

Speeds up wound closure by promoting re-epithelization.

C

Increased skin hydration

Strong

Can bind up to 1000 times its weight of water, and is thus very effective in hydrating the skin.

C

Increased skin elasticity

Strong

Low molecular weight hyaluronic acid is especially effective in restoring skin elasticity.

C

Dermatitis treatment

Strong

Improves all clinical signs and symptoms of atopic dermatitis, and is also effective in treating facial seborrheic dermatitis.

C

Wrinkle treatment

Moderate

Improves both wrinkle depth and roughness, possibly via its ability to bind water and reduce UV-induced skin inflammation.

D

Rosacea treatment

Moderate

Reduces papules, erythema, burning/stinging and dryness in rosacea patients.

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Scientific Research


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Table of contents:

1. Sources

Hyaluronic acid is a major component of the extracellular matrix of most connective tissue.[1] It is especially abundant in the skin, where it has a protective, structure-stabilizing and shock-absorbing role.[2] The body of an adult human has about 15g of hyaluronic acid, of which approximately half is located in the skin.[3][4]

Hyaluronic acid is present in both the epidermis and the dermis. In fact, it is the main substance found in the dermis due to its viscoelastic properties.[1][5]

Interestingly, while the dermis consists largely of extracellular matrix, the reverse is true for the epidermis, which is comprised almost entirely of keratinocytes. Hence, the actual concentration of hyaluronic acid in the matrix around the cells in the epidermis, is actually an order of magnitude higher than in the dermis.[2]

2. Bioavailability

Structurally, hyaluronic acid is a glycosaminoglycan, a long, unbranched polysaccharide comprising repeated units of disaccharides, D-glucuronic acid and N-acetyl-D-glucosamine. Its molecular weight is proportional to the number of disaccharide repeats.[3]

Hyaluronic acid is largely ionized at the pH prevailing on the skin, and is therefore strongly hydrophilic. This and its high molecular weight should hinder its penetration of the strateum corneum, but experiments have shown that hyaluronic acid is able to penetrate mouse, rabbit and human skin.[6][7]

It turns out that hyaluronic acid in the hydrated state forms internal hydrogen bonds along its saccharide chain, creating a twisting ribbon structure where the axial hydrogen atoms form a non-polar, relatively hydrophobic face.[2][8] This hydrophobic face can increase its permeation through the stratum corneum.[9]

Moreover, hyaluronic acid has a considerable capacity to bind water, which is thought to enhance the absorption of hyaluronic acid as increased hydration of the skin surface is known to influence its permeability.[2]

A new carrier system making use of a skin-penetrating peptide has recently been shown to further enhance the penetration of topical hyaluronic acid in human skin.[10]

3. Effects on the skin

3.1 Increased hydration

A negatively charged polyanionic polymer at physiological pH, hyaluronic acid has a strong affinity for water, a characteristic that explains its great hydration capacity -- 1g of hyaluronic acid can bind up to 6 litres of water.[11] As a result, hyaluronic acid is often used as a moisturizing agent in cosmetic formulations.[12]

Low molecular weight (130 kDa) hyaluronic acid is the most effective in moisturizing the skin, increasing the hydration level of the skin by 13.8% after 2 months of treatment, compared to an increase of 2.9% for a formulation with high molecular weight (2000 kDa) hyaluronic acid.[12] Similarly, nano-sized hyaluronic acid formulated as a cream, serum and lotion (Hyalogy) improved skin hydration by up to 96% when used in conjunction for 8 weeks.[13]

3.2 Wound healing

Hyaluronic acid performs many pivotal functions in skin repair following injury.[14] In the inflammatory phase of wound healing, it accumulates in the wound bed, modulating the activities of inflammatory cells and dermal fibroblasts. In the proliferative phase, its synthesis by fibroblasts and keratinocytes is elevated, and it binds to CD44, a receptor localised in lipid raft domains. This interaction induces cell migration and proliferation, promoting wound closure.[15]

In clinical trials, wounds including burns, acute radioepithelitis, venous leg ulcers and diabetic foot lesions have been shown to respond to topical treatment with hyaluronic acid.[16][17] Moreover, the association of hyaluronic acid with silver sulfadiazine, the gold standard for topical burn therapy, accelerates the re-epithelization of second-degree burns, significantly reducing the time to heal.[18][19]

3.3 Anti-wrinkle effect

Low molecular weight hyaluronic acid-based creams have been demonstrated to markedly improve wrinkle depth and skin roughness compared to placebo cream in a controlled study.[12] A product range containing nano-hyaluronic acid (Hyalogy) has also been shown to decrease the depth of wrinkles by up to 40% after 8 weeks of treatment.[13]

Furthermore, intermediate-size hyaluronic acid fragments seem to synergize with retinal in treating photoaged skin. 3 months of application of an anti-wrinkle cream (Avène Eluage Cream) and anti-wrinkle concentrate (Avène Anti-wrinkle Concentrate) containing 0.5% to 1% retinal/hyaluronic acid fragments significantly improved forehead wrinkles, nasolabial folds, crow's feet and wrinkles around the mouth.[20]

It has been hypothesized that hyaluronic acid's anti-wrinkle effect may be explained by its potent water-binding properties, and its action as an anti-inflammatory agent.[12] UV-induced skin inflammation is thought to trigger downstream signal transduction cascades that activate matrix metalloproteinases, which degrade extracellular matrix proteins such as collagen and hence play a role in wrinkle formation.[21]

3.4 Improved elasticity

The molecular weight of hyaluronic acid used in cream formulations seems to play a role in its efficacy in restoring skin elasticity. 1 month's treatment with a 130 kDa hyaluronic acid cream increased the overall elasticity of the skin by 20%, whereas improvements ranging from 6.1% to 14.5% were seen for formulations with other molecular weights of hyaluronic acid.[12] Formulation of nano-hyaluronic acid as a cream, serum and lotion also enhanced skin firmness and elasticity by up to 55% in 8 weeks.[13]

In a third study, products containing retinal and intermediate-size hyaluronic acid fragments (Avène Eluage Cream and Avène Anti-wrinkle Concentrate) improved skin elasticity by 33% over 90 days when used in combination.[20]

3.5 Dermatitis treatment

Hyaluronic acid has been used to treat atopic dermatitis, one of the most common skin disorders among children.[22][23] A prescription ceramide-hyaluronic acid emollient foam (Hylatopic Plus) has been shown to improve all clinical signs and symptoms of atopic dermatitis with no associated adverse events.[23][24][25] This makes it preferable to topical corticosteriods, the prolonged use of which causes skin atrophy, telangiectasia, striae, steroid-induced dermatoses, rosacea and acne exacerbation.[25]

A gel containing 0.2% of the sodium salt of hyaluronic acid (Bionect Hydrogel) was also effective in treating facial seborrheic dermatitis,[26] a disorder usually found on sebum-rich areas of the body such as the face, scalp or trunk.[27]

3.6 Rosacea treatment

Hyaluronic acid appears to be useful in treating facial rosacea. In a small, unblinded observational study, 0.2% hyaluronic acid sodium salt cream (Bionect Cream) improved papules, erythema, burning/stinging and dryness after 4 weeks, and the improvements persisted for a month after the treatment was stopped.[28]

4. Side Effects

Hyaluronic acid, sodium hyaluronate and potassium hyaluronate are considered safe for use in cosmetics[29] as hyaluronic acid was not toxic in a wide range of acute animal toxicity studies, was not immunogenic, not a sensitizer, not a reproductive or developmental toxicant and not genotoxic.[29]

Topical hyaluronic acid is also considered to have excellent tolerabilty -- none of the human studies conducted so far have reported any side effects or adverse events associated with its use in creams, gels or foams.[25][26][28]

Scientific References


  1. Monheit GD, Coleman KM. Hyaluronic acid fillers. Dermatol Ther. (2006)
  2. Brown MB, Jones SA. Hyaluronic acid: a unique topical vehicle for the localized delivery of drugs to the skin. J Eur Acad Dermatol Venereol. (2005)
  3. Kablik J, et. al. Comparative physical properties of hyaluronic acid dermal fillers. Dermatol Surg. (2009)
  4. Edsman K, et. al. Gel properties of hyaluronic acid dermal fillers. Dermatol Surg. (2012)
  5. Mercer SE, et. al. Histopathologic identification of dermal filler agents. J Drugs Dermatol. (2010)
  6. Brown TJ, Alcorn D, Fraser JR. Absorption of hyaluronan applied to the surface of intact skin. J Invest Dermatol. (1999)
  7. Birkenfeld B, et. al. The penetration of topically applied ointment containing hyaluronic acid in rabbit tissues. Pol J Vet Sci. (2011)
  8. Necas J, et. al. Hyaluronic acid (hyaluronan): a review Veterinarni Medicina. (2008)
  9. Yang JA, et. al. Transdermal delivery of hyaluronic acid -- human growth hormone conjugate. Biomaterials. (2012)
  10. Chen M, et. al. Topical delivery of hyaluronic acid into skin using SPACE-peptide carriers. J Control Release. (2014)
  11. Ramos-E-Silva M, et. al. STYLAGE®: a range of hyaluronic acid dermal fillers containing mannitol. Physical properties and review of the literature. Clin Cosmet Investig Dermatol. (2013)
  12. Pavicic T, et. al. Efficacy of cream-based novel formulations of hyaluronic acid of different molecular weights in anti-wrinkle treatment. J Drugs Dermatol. (2011)
  13. Jegasothy SM, Zabolotniaia V, Bielfeldt S. Efficacy of a New Topical Nano-hyaluronic Acid in Humans. J Clin Aesthet Dermatol. (2014)
  14. Chen WY, Abatangelo G. Functions of hyaluronan in wound repair. Wound Repair Regen. (1999)
  15. Ghazi K, et. al. Hyaluronan fragments improve wound healing on in vitro cutaneous model through P2X7 purinoreceptor basal activation: role of molecular weight. PLoS One. (2012)
  16. Weindl G, et. al. Hyaluronic acid in the treatment and prevention of skin diseases: molecular biological, pharmaceutical and clinical aspects. Skin Pharmacol Physiol. (2004)
  17. Voigt J, Driver VR. Hyaluronic acid derivatives and their healing effect on burns, epithelial surgical wounds, and chronic wounds: a systematic review and meta-analysis of randomized controlled trials. Wound Repair Regen. (2012)
  18. Koller J. Topical treatment of partial thickness burns by silver sulfadiazine plus hyaluronic acid compared to silver sulfadiazine alone: a double-blind, clinical study. Drugs Exp Clin Res. (2004)
  19. Costagliola M, Agrosì M. Second-degree burns: a comparative, multicenter, randomized trial of hyaluronic acid plus silver sulfadiazine vs. silver sulfadiazine alone. Curr Med Res Opin. (2005)
  20. Cordero A, et. al. Retinaldehyde/hyaluronic acid fragments: a synergistic association for the management of skin aging. J Cosmet Dermatol. (2011)
  21. Fisher GJ, Voorhees JJ. Molecular mechanisms of photoaging and its prevention by retinoic acid: ultraviolet irradiation induces MAP kinase signal transduction cascades that induce Ap-1-regulated matrix metalloproteinases that degrade human skin in vivo. J Investig Dermatol Symp Proc. (1998)
  22. DaVeiga SP. Epidemiology of atopic dermatitis: a review. Allergy Asthma Proc. (2012)
  23. Pacha O, Hebert AA. Treating atopic dermatitis: safety, efficacy, and patient acceptability of a ceramide hyaluronic acid emollient foam. Clin Cosmet Investig Dermatol. (2012)
  24. Draelos ZD. A clinical evaluation of the comparable efficacy of hyaluronic acid-based foam and ceramide-containing emulsion cream in the treatment of mild-to-moderate atopic dermatitis. J Cosmet Dermatol. (2011)
  25. Frankel A, et. al. Bilateral comparison study of pimecrolimus cream 1% and a ceramide-hyaluronic acid emollient foam in the treatment of patients with atopic dermatitis. J Drugs Dermatol. (2011)
  26. Schlesinger T, Rowland Powell C. Efficacy and safety of a low-molecular weight hyaluronic Acid topical gel in the treatment of facial seborrheic dermatitis. J Clin Aesthet Dermatol. (2012)
  27. Cicek D, et. al. Pimecrolimus 1% cream, methylprednisolone aceponate 0.1% cream and metronidazole 0.75% gel in the treatment of seborrhoeic dermatitis: a randomized clinical study. J Dermatolog Treat. (2009)
  28. Schlesinger TE, Powell CR. Efficacy and tolerability of low molecular weight hyaluronic acid sodium salt 0.2% cream in rosacea. J Drugs Dermatol. (2013)
  29. Becker LC, et. al. Final report of the safety assessment of hyaluronic acid, potassium hyaluronate, and sodium hyaluronate. Int J Toxicol. (2009)