The History of Hyaluronic Acid

Dr Patrick Treacy details the discovery and development of the popular dermal filler component.

 

Many different hyaluronic acid (HA) injectable fillers are available on the market and differ in terms of concentration, particle size, cross-linking density, requisite needle size, duration, stiffness, hydration, presence of lidocaine, type of cross-linking technology and cost. HA soft-tissue fillers include a range of products (some include the Juvéderm, Restylane and Belotero ranges) that are used commonly for facial rejuvenation and enhancement of facial features. 

 

Although these products are similar in many ways, they are not interchangeable and have unique characteristics that need to be considered. HA is a natural component of many soft tissues and is identical across species, minimising immunogenicity. 

 

In 1934, while Nazi Germany and Poland were signing a 10-year non-aggression treaty, Germans Karl Meyer and John Palmer wrote in the Journal of Biological Chemistry about an unusual polysaccharide with an extremely high molecular weight, isolated from the vitreous of bovine eyes. 

 

Meyer was born in the village of Karpen, Germany, near Cologne. In 1917, he was drafted into the German army and served in the last year of World War I. After the war, he entered medical school at the University of Cologne and received an MD degree in 1924. He then went to Berlin for a year of study in medical chemistry and met several promising young biochemists, including Fritz Lippman, Hans Krebs and Ernst Chain.

 

Sir Hans Krebs was born at Hildesheim, Germany. In June 1933, the National Socialist Government terminated his appointment, and he went to the School of Biochemistry, Cambridge, where he researched the complex chemical processes that provide living organisms with high-energy phosphate, by way of what is known as the Krebs or citric acid cycle. The Nobel Prize in Physiology or Medicine in 1953 was divided equally between Krebs ‘for his discovery of the citric acid cycle’ and Lipmann ‘for his discovery of co-enzyme A and its importance for intermediary metabolism’. Ernest Chain was another German-born British biochemist, who became a 1945 co-recipient of the Nobel Prize for Physiology or Medicine for his work on penicillin.

 

Meanwhile, Meyer decided, no doubt in part because of the rising anti-semitism in Europe and the increasing probability of war, to go back to the US. He received a position as assistant professor in the Department of Ophthalmology at the College of Physicians and Surgeons. Meyer began to study the lysozyme present in tears and undertook to identify a physiological substrate for the enzyme.

 

Examination of the viscous vitreous humour of the eye as a plausible source of substrate quickly led to the discovery of hyaluronan, which is reported in the Journal of Biological Chemistry. While there, Meyer and his assistant, John Palmer, isolated a novel, high molecular weight polysaccharide and reported that it was composed of ‘a uronic acid and an amino sugar’.

 

Being the first to mention it, they gave the new substance the name hyaluronic acid (HA, the modern name ‘hyaluronan’) derived from ‘hyaloid’ (glass-like in appearance) and ‘uronic acid’. Nearly 25 years of work was required to establish the structure of the repeating disaccharide that is the basic unit of the hyaluronan polymer, namely, glucuronate-β-1,3-N- acetylglucosamine-β1,4-.

 

In 1958, while the US launched its first satellite, Explorer I, and NASA was established, Meyer chaired the annual meeting of the American Society of Biological Chemists and stated in his opening remark:

 

 

How wrong he was. Like the Beatles and computers being originally turned down, HA was to become one of the most important chemicals in the world.

 

While Meyer and Palmer are generally considered to have discovered hyaluronic acid, it is fair to mention that as far back as 1918, just as World War I ended, P.A. Levene and J. Lopez-Suarez had isolated a new polysaccharide from the vitreous body and cord blood that they called ‘mucoitin-sulfuric acid’. 

 

It consisted of glucosamine, glucuronic acid, and a small amount of sulphate ions. It is now clear that this substance was HA, extracted together with a mixture of sulphated glycosaminoglycans. At the time of the discovery of hyaluronan, the polysaccharides, which represent a major part of the organic material on our planet, were already quite well known. 

 

Several so-called mucopolysaccharides, currently known as glycosaminoglycans, had already been discovered. HA is known to belong to this class as well. Mucopolysaccharides were isolated from mucus, to which they give viscous lubricating properties. These properties, in turn, are related to glycosaminoglycan’s ability to bind to a significant amount of water.

 

Over the next decade, Meyer, and others, isolated HA from various animal organs. It was found to exist in joint fluid, the umbilical cord and, recently, it has become possible to extract HA from almost all vertebrate tissues. 

 

In 1937, as the Golden Gate Bridge opened to pedestrian traffic, F. Kendall was busy isolating HA from the capsules of streptococci groups A and C. I believe this was the biggest breakthrough for HA fillers, as even today, streptococci groups are the most economical and reliable source for the industrial production of HA. 

 

Finding a use for HA in medicinal practice did not actually occur until 1943, during the Second World War. The start of World War II (WWII) led to the deployment of combat troops in several continents, and fatalities and casualties among both the military and civilians became an inevitable consequence. A large amount of injured people needed life-saving treatment and a speedy return to duty. The Soviet Union, its allies and its opponents had no specialised medical units for patients with burn injuries in military or civilian hospitals when the WWII began. 

 

Intensive studies of the specific issues of diagnosis and treatment of thermal and frostbite injury were conducted in the Soviet Union before the war. The first special units for patients with burn injuries were created, and the first specialists received their first clinical experience.

 

The contributions of famous Soviet scientists in the development of the treatment of burns and frostbite in WWII is well documented. N.F. Gamaleya (Н.Ф. Гамалея) created a new type of bandage to treat the frostbitten soldiers. The main component of the bandage was an extract from the umbilical cord, which he called a ‘factor of regeneration’. 

 

The method was later approved by the USSR Ministry of Health and the drug received the name ‘Regenerator’. It is apparent that HA was a major contributor towards the positive effect of the treatment, given that the human umbilical cord contains a significant amount of HA. Several practical ventures that explored HA’s medical applications followed. Research into finding practical applications to match the physical-chemical properties of HA is considered to have begun in 1951 with the publication of a series of five volumes under the title, Hyaluronan: From Basic Science to Clinical Application, by E.A. Balazs et al. It was the same year that the North Korean offensive pushed beyond the 38th parallel as truce negotiations failed.

 

In the 1950s, Balazs initiated experiments with HA to investigate its potential as a prosthesis for the treatment of retinal detachment. In 1953, Roseman and co-workers published an article in which they describe the precipitation of HA from the cultural liquid (CL) of Group A streptococcus. They reported the yield 200-300 mg from 4 l of CL. Later, Warren and Gray found the semi-synthetic media for the cultivation of the HA producers. In 1970, hyaluronan was first injected into the joints of racehorses that suffered from arthritis with a clear and positive outcome observed. It was the same year that the Beatles broke up and US President Richard Nixon ordered an invasion of Cambodia, widening the war in Vietnam.

 

In 1982, R. Miller started to use HA in implanted intraocular lenses. It was the same year that the first CD player was sold in Japan. Since these ground-breaking cases, hyaluronan has become one of the most important components in ophthalmology and has found extremely wide application in aesthetic medicine. 

 

In 1996, while Mad Cow Disease hit Britain, causing the mass slaughter of herds of cattle and new laws to stop beef being sold on the bone, a Swedish company called Q-Med released to the world NASHA technology (Non-Animal Stabilised Hyaluronic Acid). For the first time, HA gel particles within a viscoelastic medium, subjected to a physiological salt solution, could be used as a soft-tissue augmentation facial implant.

 

The process was invented by Bengt Ågerup, who was born in Uppsala (1943) and studied renal physiology at a university there. He had previously worked for many years as a researcher at Pharmacia. In March 2011, he sold his shares in Q-Med to Galderma SA, a French-Swiss pharmaceutical company. 

 

In 2018, a new breakthrough skin treatment called Profhilo® was developed by IBSA, which introduced a new category to the injectables market – bio remodelling. It is an injectable, stabilised HA-based product, produced without the use of chemical cross-linking agents (BDDE) according to a patented technology (NAHYCO), designed to remodel multi-layer skin tissue.

 

It will be interesting to see how HA’s journey will continue to develop and benefit people around the world.