ABSTRACT: Hyaluronic acid is a naturallyoccurring polysaccharide possessing unique properties, such as high viscosity and water retention, tunable molecular weight, and lack of immunogenicity and toxicity, that allow for its usage in biomedical, pharmaceutical, food, and cosmetic industries. Two primary production methods exist for hyaluronic acid: extraction from animal tissues and biological fermentation. Each production method has advantages and disadvantages, but neither are sustainable. Trends in the age, weight, and beauty standards of the world population are causing increased demand for hyaluronic acidbased treatments, such as dry eye lubricating drops, osteoarthritis viscosupplements, and dermal fillers. The market and demand for hyaluronic acid keeps growing, so challenges to the industry are explored.
Hyaluronic acid is a naturallyoccurring polymer of disaccharides found in humans, animal, and bacteria. Nearly a century of research has been dedicated to hyaluronic acid after its discovery in 1934. The FDA has approved the use of hyaluronic acid for multiple applications, such as dermal fillers, and osteoarthritis and dry eye treatment. Biological production using fermentation is most common, but extraction from animal tissues is still used. As an important component in many medical, pharmaceutical, and beauty products, hyaluronic acid has performed remarkably in the global market. Increasing geriatric and obese populations in advanced countries are causing growth in hyaluronic acid’s use as a therapeutic treatment to common eye and joint ailments.
In the 1880’s, French scientist Portes first observed vitreous mucin that behaved differently than other mucinoids. He called the vitreous mucin “hyalomucine”.1 In 1934, Meyer and Palmer performed the first isolation of hyaluronic acid by mixing the vitreous humor of 100 cattle eyes with acetone. The mixture was extracted using various methods, each leading to small amounts of a polysaccharide with a high molecular weight. Meyer and Palmer identified the components of the polysaccharide as “uronic acid, an amino sugar, and possibly a pentose.”2 (The pentose hypothesis was proven incorrect by Meyer and Weissman in 1954.3) They named the compound “hyaluronic acid” from hyaloid (meaning glassy appearance) and uronic acid. Meyer and Palmer mentioned a connection between glaucoma and hyaluronic acid in their closing statements2, which would eventually lead to the development of hyaluronic acidbased ophthalmic treatments.
Hyaluronic acid is a naturally occurring, unbranched polymer of glucuronic acid and Nacetylglucosamine, found in humans, animals, and bacteria. Fungi, insects, and plants do not produce hyaluronic acid. About half of the hyaluronic acid in humans is found in the skin, and the remainder is in joints, eyes, and cartilage. The chemical structure of a hyaluronic acid repeat unit is shown in Figure 1.
Figure 1. Chemical structure of hyaluronic acid monomer1. The full polysaccharide can consist of over 10,000 repeat units.
The structure of hyaluronic acid contains multiple hydrophilic functional groups on each repeat unit that allow for extremely high water retention. Many skincare companies state it can hold over 1,000 times its weight in water46 when explaining their product’s moisturizing abilities. The polysaccharide chains become tangled at concentrations as low as 0.1%, resulting in an extremely high, sheardependent viscosity7, which is appropriate for lubricating applications. Hyaluronic acid notably lacks immunogenicity and toxicity, finding applications in cosmetic, biomedical, and food industries.7 The molecular weight of the molecule is customizable, and applications depend highly on the molecular weight. Synthetic modifications are often made to crosslink or conjugate hyaluronic acid chains for customized applications.1 Conjugated hyaluronic acid chains can accommodate active molecules, while crosslinked chains have reduced degradation rates and improved physical properties.1
Because hyaluronic acid is naturally found in the human body, many marketed products focus on replacing the hyaluronic acid in the skin and joints that diminishes with age. When the amount of hyaluronic acid in the skin decreases, wrinkles start to form. Dermal fillers, such as Juvederm® by Allergan, are injected into the skin to replace lost hyaluronic acid and fill out imperfections, such as wrinkles and scars. Hyaluronic acid based fillers have the advantage of a longer shelf life than collagen fillers.7 Many skincare products also include hyaluronic acid with claims of skin hydration, elasticity restoration, and wrinkle prevention, but scientific proof for wrinkle prevention through topical application is not available.1 If high concentrations of hyaluronic acid are applied topically, the hygroscopic property may extract the skin’s moisture, resulting in the opposite of the product’s intended purpose. Hyaluronic acid can also protect skin from ultraviolet radiation.8
Hyaluronic acid losses in joints lead to more serious problems than visible imperfections. Hyaluronic acid degrades more quickly in people affected by osteoarthritis, causing joint pain and stiffness because of the lack of lubrication. Hyaluronic acid viscosupplementation was approved by the FDA for treatment of knee osteoarthritis in 1997. The treatments, such as SynViscOne® by Genzyme, are injected into the knee’s synovial fluid to provide lubrication and relief.
After the first isolation by Meyer and Palmer, hyaluronic acid began to be isolated from human umbilical cords, rooster comb, and bacteria.1,7,9 In 1942, Endre Balazs applied for a patent to use hyaluronic acid as a commercial egg white substitute.10 In the 1950s, research towards producing hyaluronic acid using pathogenic bacteria was conducted. By the end of the 1970s, animal tissue-based extraction was optimized, and bacterial fermentation had been initiated. In 1979, Balazs developed and patented an efficient method to produce high purity hyaluronic acid from rooster comb, which set the basis for industrial production of hyaluronic acid.1 Balazs and his company, Biotrics, developed a surgical aid in ophthalmic surgery called Healon®, the first patented hyaluronic acid product. From the 1990s to the 2000s, a revival of bacterial fermentation research occurred.
Hyaluronic acid can be produced by either biological or synthetic (in vitro) production, but only biological production is used industrially. The two main biological production methods are extraction from animal tissues, primarily rooster comb, and largescale bacterial fermentation. Extraction from animal tissues was more prevalent before the development and optimization of bacterial fermentation but is now surpassed by bacterial fermentation. During the extraction process, animal proteins may remain bound to the animalderived hyaluronic acid and can cause an immune response or transmit diseases.11 The extraction process uses dangerous organic solvents, and is also costly, time consuming, and labor intensive, so alternative methods, such as bacterial fermentation, are preferred.11
Largescale bacterial fermentation was initially developed using Streptococci, which produced numerous toxins.11 Bacillus, E. coli, and Lactococcus were genetically engineered to produce hyaluronic acid.7,11 Bacterial fermentation has lower production costs and produces less environmental pollution than extraction from animal tissues.7 New research is leading to improvements in the fermentation medium.12 The rise in cost of raw materials for cell fermentation weakens competitiveness7, so using byproducts from other processes, such as cashew apple juice12, as a growth medium can reduce production cost by up to 30%.7
Increased demand and limitations to the mass production of hyaluronic acid using animal and bacteria sources drive developments of synthetic production methods. Synthetic (in vitro) production technology is still being developed and often has low yields. Using a cellfree enzyme system, it is possible to produce high molecular weight hyaluronic acid with low polydispersity, but the yields remain very low.11 This process uses enzymes to convert a feed of glucose and glucosamine into hyaluronic acid following the same biological pathway as animal cells.11
The hyaluronic acid market was worth 7.2B USD in 2016 and is expected to reach 15.4B USD by 2025.13 As the geriatric segment of the population grow larger, the ophthalmic applications market is expected to grow the fastest because of increasing rates of glaucoma, cataracts, dry eyes, and other agerelated eye degenerations.13 Increased rates of obesity also influence the hyaluronic acid market, causing increases in hyaluronic acid treatment injections for osteoarthritis and joint pain. Dermal fillers had 8% growth in 2014.13 Western beauty standards emphasize voluminous features and smooth, youthful skin, leading to a 131% increase in dermal filler procedures in the US from 2013 to 2014.13
The global distribution of hyaluronic acid revenue in 2015 is provided in Figure 2. Currently North America
Figure 2. Hyaluronic acid market share by country in 2015.13 North America holds more than 40% of the revenue. MEA stands for Middle East and Africa.
dominates the hyaluronic acid market, but the Asia Pacific market is expected to be the fastest-growing region.13 The growth of Asia Pacific region’s market is likely because of China and Japan’s rapidly-growing geriatric population and need for agerelated treatments, such as osteoarthritis and glaucoma treatment. Because Asian beauty standards are highly influenced by western beauty standards, an increase is expected in the Asian dermal filler market also.
The hyaluronic acid industry is also expanding geographically and introducing new technology because of large company mergers in recent years. SanofiAventis produces the FDAapproved products Synvisc® and Hyalgan®, which are both injection viscosupplements used for osteoarthritis treatment. In 2011, SanofiAventis acquired Genzyme for 20.1B USD.14 Allergan dominates the dermal filler market with 45% of the global market share12 with a sizeable portion coming from Juvederm® production. In 2015, Actavis acquired Allergan for 70.5B USD, creating one of the world’s top ten pharmaceutical companies.15 These deals are expected to cause other company mergers and acquisitions.13
Other noteworthy companies involved in different segments of the global hyaluronic market are Contipro, Hyaltech, and Ricerfarma. Contipro is a Czechbased company that conducts specialized research and manufactures a wide range of hyaluronic acid products for consumerspecific applications. In the United Kingdom, Hyaltech produces medical-grade hyaluronic acid using biological fermentation. Ricerfarma is the first company to use hyaluronic acid for dental applications, specifically gum reconstruction, and made 18M Euro (20M USD) in 2016.
One major challenge to the hyaluronic acid industry is unsustainable production methods combined with rapidly increasing demand. Limitations to the biological production pathways result in a need for alternative production pathways. Improvements to decrease polydispersity and increase molecular weight need to be made to biological fermentation. Opportunities for improving yield and efficiency in synthetic production methods could revolutionize hyaluronic acid production and allow for improved production to sustain an older, growing population.