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Health News Archive 547 - Hyaluronic Acid
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Hyaluronic Acid Stimulates Collagen Production

Injections with “dermal fillers” containing hyaluronic acid appear to stimulate production of collagen, a primary protein in the skin, and may partially restore the structure of sun-damaged skin, according to an article in the February 2007 issue of Archives of Dermatology, one of the JAMA/Archives journals.

Injectable skin fillers have become increasingly popular for correcting the lines and wrinkles associated with aging, as well as acne scars and other skin conditions, according to background information in the article. Hyaluronic acid, a compound that occurs naturally in the skin and connective tissue, is among the most widely used fillers in the United States. Its molecules bind to water in the skin, hydrating and firming its structure, and the loss of hyaluronic acid with aging is associated with skin dehydration and wrinkling. Because hyaluronic acid degrades rapidly in the skin, the commercially available version is cross-linked, or bound to itself chemically to increase stabilization.

Frank Wang, M.D., and colleagues at the University of Michigan Medical School, Ann Arbor, injected non-animal stabilized hyaluronic acid (NASHA), one of the most commonly used forms, into the forearms of 11 healthy volunteers (average age of 74 years). All participants were fair-skinned, and eight had moderate sun damage—visible as brown spots, drooping skin, wrinkles or uneven pigmentation—while three had mild to moderate damage. They received three injections of .7 milliliters of stabilized hyaluronic acid 2 to 5 centimeters apart in one forearm, and three injections of saline solution at the same volume and spacing in the other arm. Skin biopsy samples approximately 4 millimeters in diameter were taken from the site of the injection four and 13 weeks later.

It is commonly assumed that fillers achieve their effects by filling space in the skin; through examining the skin samples under an electron microscope, the researchers found that this appeared to be the case with stabilized hylauronic acid. “To further investigate potential mechanisms for this filler’s long-lasting cosmetic benefits, we assessed the biological response of skin to NASHA,” the authors write. “We found that NASHA injections induce type 1 collagen production in photo-damaged forearm skin.” Because there is currently no evidence that skin on different parts of the body behave differently, it is likely that hyaluronic acid has the same effect on facial skin.

“Overall, our findings indicate that NASHA injections induce robust collagen production through several potential mechanisms, including the mechanical stretching of fibroblasts [cells that secrete collagen proteins], stimulation of growth factors and inhibition of collagen breakdown,” the authors write. “Of these, mechanical stretching may be the most important.” This physical stretching of the cells encourages them to produce compounds that both support collagen growth and suppress chemicals that break down cells’ structures.

These findings suggest that, in addition to its cosmetic benefits, hyaluronic acid may be beneficial in skin-wasting diseases that involve collagen deficiencies, such as those associated with HIV or steroid use.

Frank Wang, MD; Luis A. Garza, MD, PhD; Sewon Kang, MD; James Varani, PhD; Jeffrey S. Orringer, MD; Gary J. Fisher, PhD; John J. Voorhees, MD; In Vivo Stimulation of De Novo Collagen Production Caused by Cross-linked Hyaluronic Acid Dermal Filler Injections in Photodamaged Human Skin. Arch Dermatol. 2007;143:155-163.


Objective To determine whether endogenous synthesis of new extracellular matrix may contribute to the degree and duration of clinical benefits derived from cross-linked hyaluronic acid dermal filler injections.

Design In vivo biochemical analyses after filler injections.

Setting Academic referral center.

Participants Eleven healthy volunteers (mean age, 74 years) with photodamaged forearm skin.

Interventions Filler and vehicle (isotonic sodium chloride) injected into forearm skin and skin biopsy specimens taken 4 and 13 weeks later.

Main Outcome Measures De novo synthesis of collagen, the major structural protein of dermal extracellular matrix, was assessed using immunohistochemical analysis, quantitative polymerase chain reaction, and electron microscopy.

Results Compared with controls, immunostaining in skin receiving cross-linked hyaluronic acid injections revealed increased collagen deposition around the filler. Staining for prolyl-4-hydroxylase and the C-terminal and N-terminal epitopes of type I procollagen was enhanced at 4 and 13 weeks after treatment (P<.05). Gene expression for types I and III procollagen as well as several profibrotic growth factors was also up-regulated at 4 and 13 weeks compared with controls (P<.05). Fibroblasts in filler-injected skin demonstrated a mechanically stretched appearance and a biosynthetic phenotype. In vitro, fibroblasts did not bind the filler, suggesting that cross-linked hyaluronic acid is not directly stimulatory.

Conclusions Injection of cross-linked hyaluronic acid stimulates collagen synthesis, partially restoring dermal matrix components that are lost in photodamaged skin. We hypothesize that this stimulatory effect may be induced by mechanical stretching of the dermis, which in turn leads to stretching and activation of dermal fibroblasts. These findings imply that cross-linked hyaluronic acid may be useful for stimulating collagen production therapeutically, particularly in the setting of atrophic skin conditions.

Author Affiliations: Departments of Dermatology (Drs Wang, Garza, Kang, Orringer, Fisher, and Voorhees) and Pathology (Dr Varani), University of Michigan Medical School, Ann Arbor. Dr Garza is now with the Department of Dermatology, University of Pennsylvania, Philadelphia.

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