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Hyaluronic acid in Joint, Skin & Eye Health
By Yousry Naguib, Ph.D.
Nutrition Industry Executive magazine, March 2004

Hyaluronic acid, also referred to as hyaluronan, is a ubiquitous polysaccharide present at high concentrations in cornea, skin, and joints. Hyaluronic acid (HA) was first isolated by Meyer and Palmer in 1934 from the vitreous of bovine eyes [1], which was later identified as a high molecular weight (600,000-10,000,000 daltons) glycosaminoglycan- polysaccharide formed by repeating disaccharide units consisting of N-acetylglucosamine and glucuronic acid. HA is synthesized by chondrocyte cells in the cartilage and by keratinocytes in the skin epidermis.
HA possesses two major molecular characteristics that contribute to its physiological functions: its unique ability to retain water, and its instructive effects on cell signaling and behavior (adhesion, migration and proliferation). HA has been widely used for osteoarthritis, ophthalmology, and cosmetics for skin care.
HA comes from three principle sources, human umbilical cords, rooster combs, and certain bacterial cultures, such as those of streptococci groups A and C.

HA in the Skin
Skin is the largest organ in the body, both by weight and surface area. In adults, the weight of skin accounts for about 10 percent of the total bodyweight. Skin serves numerous functions; the most obvious one is the protective or barrier function. The skin protects the body from physical and chemical injuries, feels the environment through various sensory cells, and helps regulate body temperature through sweat glands. The skin is also an important part of our appearance. The skin needs both external and internal care, including nourishing the structure and function of the skin from within.
Skin consists of a thin outer layer called the epidermis, which is responsible for protecting the body from the outside world, and a much thicker inner layer called the dermis. The epidermis consists of several layers, the top one is called stratum corneum, which is composed of lipids, and keratin (a protein that provides some rigidity to the skin). Below the epidermis lies the dermis, which contains the extra cellular matrix ECM.
ECM is composed primarily of type I collagen (natural protein that forms the connective tissues), which is responsible for the strength and structural integrity of the skin. The space between the cells in the ECM is filled with hyaluronic acid (HA), which plays an essential role in cellular hydration, allows for the proper transfer of nutrients, facilitates intracellular communication, and improves elasticity of the skin [2].
The largest amount (approximately 50%) of HA in our body resides in skin tissue, where it is synthesized primarily by dermal fibroblasts and by epidermal keratinocytes. When the amounts of HA in the skin tissues decrease due to aging, the water retention and resilience of skin will be lost, thereby causing rough skin, and fine wrinkles.
To help compensate for the decline in HA with aging, HA containing dietary supplement products from natural sources such as rooster combs and certain bacterial cultures have been developed. Natural HA molecules have comparatively large molecular weight and are not easily absorbed in the body.
Recently, Soft Gel Technologies introduced a low molecular weight (50,000 daltons to 200,000 datlons) HA, called “Injuv®”, which contains 9% HA for oral consumption. Injuv® has been demonstrated to make the skin feel soft due to its ability to retain moisture in the ECM in the skin. In a clinical study conducted at Ostuma University in Japan, 96 women, aged 22 to 65 years, were given 6 capsules; each contains 70 mg Injuv® standardized to 9% HA, for 45 days. Each subject was instructed to complete a subjective questionnaire at the end of the study. Eighty subjects reported improvement in skin moisture and smoothness.
Another natural source of HA is collagen II. There are several types of collagen; the main ones are designated Type-I, Type-II and Type-III. Type-II collagen is found predominantly in articular cartilage and is sold as dietary supplements, such as Biocell Collagen-II (hydrolyzed sternum chicken collagen type II protein) from BioCell Technologies, and the InterHealth product UC-II (undenatured sternum chicken collagen type II). BioCell Collagen II contains 10% HA.
Research has shown HA to be associated with reduced scarring in fetal wound healing. HA content in fetal wounds remains high for longer periods than in adult wounds, leading to the suggestion that HA may reduce collagen deposition and therefore lead to reduced scarring [3].
The beneficial effects of exogenous HA in wound healing have been demonstrated in animal experiments. Topical application of HA has been shown to accelerate skin wound healing in rats [4].
In addition to stimulating wound healing, HA has also been proposed to protect against oxygen free radical damage. A topical application of low molecular weight HA preparation has been shown to accelerate wound healing in rats under oxidative stress.  Rats with excision and incision wounds were given xenobiotics, to produce oxygen free radicals, or placebo. Wound healing was significantly slower in the xenobiotic group than in the placebo. When the wounds of the xenobiotic group were treated topically with low molecular weight HA (0.2%) cream, the wound healing was significantly increased [5].
HA in a gel form is frequently used as injection fillers for the correction of facial lines and soft tissue enhancement [6,7]. However, a recent study warned against the potential complications when treating facial lines with HA gel [8].

Arthritis is a prevalent and debilitating disease that affects articulating joints. The joint is where bones connect with each other, such as the knee, hip or elbow. The most common forms of arthritis are osteoarthritis, which occurs as a result of wear and tear of the joints as we age, and rheumatoid arthritis (autoimmune disease).
Osteoarthritis (OA) accounts for more than half of all arthritis cases in the United States. About 20 million Americans, mostly women over the age 45, suffer from osteoarthritis, and with baby boomers aging, that number is on the rise.
OA develops when the linings of joints degenerate, leading to pain and decreased mobility. The onset of OA is gradual and results from progressive loss of cartilage proteoglycans (cartilage breakdown). Normally, cartilage provides a cushion to help bones glide over one another and to absorb shock from physical movement, such as running. When the cartilage breaks down and wears away, the bones rub together causing pain and swelling. The typical clinical symptoms are pain, followed by inflammation, swelling, and stiffness as the disorder progresses making it difficult to walk up and down stairs or using hands, thus altering the patient’s quality of life.
In cartilage, HA forms the backbone in the complex proteoglycan network that is responsible for the structural as well as mechanical characteristics of the cartilage tissue [9]. HA is an important component of the body’s natural building blocks of the proteoglycans of cartilage. It is found in the soft connective tissue, and the synovial joint fluid (the fluid secreted by the lining of the joint to nourish and lubricate the joint).
In OA, the concentration of HA is decreased in both the cartilage and synovial fluid. A large body of literature supports the clinical efficacy and safety of HA for the treatment of osteoarthritis. In 1997, FDA approved intra-articular injection (also refers to as vasco-supplementation) of HA to relieve pain and improve function in patients with knee OA [10].
Although the exact mechanism of intra-articular injection of HA for the treatment of pain associated with knee osteoarthritis (OA) is unknown, research suggests that HA can increase viscoelasticity of the synovial fluid, enhance proteoglycan synthesis, and alter the behavior of immune cells.
Clinical studies of HA products are inconclusive but seem to indicate beneficial effects with minimal adverse reactions in a significant number of patients with OA. In one study, the effectiveness of intra-articular injection of HA was compared with a placebo or a non-steroidal anti-inflammatory medication. The HA injections had a relatively long-term favorable effect (compared with corticosteroid injections) on pain, and function [11].
Another study, involving one hundred patients, also demonstrated that five weekly intra-articular injections of sodium hyaluronate were superior to placebo and well tolerated in patients with mild to moderate osteoarthritis of the knee with a symptomatic benefit which persisted for 6 months [12].
A recent meta-analysis study of 22 trials concluded that intra-articular HA has a small effect when compared with an intra-articular placebo. Compared with lower molecular weight HA, the highest HA may be more efficacious in treating knee OA, but the evidence is inconclusive [13].
HA represents a substantive addition to the therapeutic armamentarium in osteoarthritis.

One of the first therapeutic uses of HA was as a replacement for the liquid vitreous of the human eye to aid in ophthalmic surgery, especially in the treatment of retinal detachment. HA is also used as a viscoelastic tool in ophthalmologic surgery
Because of its unique physiological and chemical properties, Hyaluronic acid has been successfully used in a number of medical disciplines, including ophthalmology, osteoarthritis, and in wound healing.


[1] Meyer K, Palmer JW. The polysaccharide of the vitreous humor.J Biol Chem 1934; 107:629
[2] Journal of Investigative Dermatology 2000; 114:1184
[3] Longaker MT et al. Studies in fetal wound healing. A prolonged presence of Hyaluronic acid characterizes fetal wound fluid. Ann Surg 1991; 213:292
[4] Abatangelo G et al. Healing of Hyaluronic acid-enriched wounds: histological observations. J Surg Res1983; 35:410
[5] Trabucchi E et al. Low molecular weight Hyaluronic acid prevents oxygen radical damage to granulation tissue during wound healing. Int J Tissue React 2002; 24:65
[6] Jordan DR. Soft-tissue fillers for wrinkles, folds and volume augmentation. Can J Ophthalmol 2003; 38:285
[7] Narins RS et al. A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg. 2003; 29:588
[8] Honig JF et al. Severe granulomatous allergic tissue reaction after hyaluronic acid injection in the treatment of facial lines and its surgical correction. J Craniofac Surg. 2003; 14:197
[9] Fosang AJ, Hardingham TE. Matrix proteoglycans. In: Comper WD, editor. Extracellular matrix, volume II. Molecular components and interactions. The Netherlands: Harwood Academic Publishers, 1996:200-229
[10] Altman RD et al. Intra-articular sodium hyaluronate in the treatment of patients with OA of the knee. J Rheumatol 1998; 25:2203
[11] Intra-articular HA injections have few side effects. Altman RD. Intra-articular sodium hyaluronate in osteoarthritis of the knee. Semin Arthritis Rheum 2000; 30(2 Suppl 1):11
[12] Huskisson EC, Donnelly S. Hyaluronic acid in the treatment of osteoarthritis of the knee. Rheumatology (Oxford) 1999; 38:602
[13] Lo GH et al. Intra-articular Hyaluronic acid in treatment of knee osteoarthritis: a meta-analysis. JAMA 2003; 290