Production Methods for Hyaluronan

Abstract

Hyaluronan is a polysaccharide with multiple functions in the human body being involved in creating flexible and protective layers in tissues and in many signalling pathways during embryonic development, wound healing, inflammation, and cancer. Hyaluronan is an important component of active pharmaceutical ingredients for treatment of, for example, arthritis and osteoarthritis, and its commercial value far exceeds that of other microbial extracellular polysaccharides. Traditionally hyaluronan is extracted from animal waste which is a well-established process now. However, biotechnological synthesis of biopolymers provides a wealth of new possibilities. Therefore, genetic/metabolic engineering has been applied in the area of tailor-made hyaluronan synthesis. Another approach is the controlled artificial (in vitro) synthesis of hyaluronan by enzymes. Advantage of using microbial and enzymatic synthesis for hyaluronan production is the simpler downstream processing and a reduced risk of viral contamination. In this paper an overview of the different methods used to produce hyaluronan is presented. Emphasis is on the advancements made in the field of the synthesis of bioengineered hyaluronan.

Reed-Sternberg cell–derived lymphotoxin-α activates endothelial cells to enhance T-cell recruitment in classical Hodgkin lymphoma

“…The differing functions of hyaluronan, whether proinflammatory, immune stimulatory, or immunosuppressive, are known to be dependent on molecular weight. 59 Both NF-kB and AP-1 are constitutively active in HRS cells. 12,60 Increased activity of COX2 enzyme in HRS cells has also been reported.…”

Hyaluronic Acid in the 3^rd Millennium

“…Despite the extraction protocols were improved over the years, this methodology was always hampered by several technical limitations which led to the production of highly polydispersed HA (MW ≥ 10 6 Da) with low yield [1,46]. This was due to the polymer intrinsic polydispersity, its low concentration in the tissues, and its uncontrolled degradation caused by the endogenous HYAL and the harsh isolation conditions [46,49].…”

“…Microorganisms-derived HA is biocompatible with human body because HA structure is highly conserved among the different species [1,49]. Streptococci strains A and C have been the first bacteria used for HA production, and, nowadays, many commercial products are derived from Streptococcus equi (such as Restylane® by Q-med AB and Juvederm® by Allergan).…”

“…Optimum bacterial culture conditions to obtain HMW HA (3.5-3.9 x 10 6 Da) have been determined at 37°C, pH 7, in presence of lactose or sucrose [125,126]. Hyaluronan yield has been optimized up to 6-7 g/L, which is the upper technical limit of the process due to mass transfer limitation caused by the high viscosity of the fermentation broth [1]. As Streptococci genus includes several human pathogens, an accurate and expensive purification of the produced HA is necessary [46,49].…”

“…Indeed, the first study that can be referred to HA dates from 1880: the French scientist Portes observed that mucin from vitreous body was different from other mucoids in cornea and cartilage, and called it "hyalomucine" [1]. Nevertheless, only in 1934, Meyer and Palmer isolated from bovine vitreous humor a new polysaccharide containing an aminosugar and an uronic acid, and named it HAfrom "hyaloid" (vitreous) and "uronic acid" [2].…”