Hyaluronan products

Differences have been reported in the chemical purity of the five hyaluronan products (40). The clinical importance of their differences is not clear, but it continues to be evaluated in RCTs. 

Upon first glance, it may appear this chapter is oversaturated with technological details that would be of interest only to technologists working in hyaluronan production. However, the material is presented in this way intentionally in order to properly elucidate the difficulties of hyaluronic acid production and the potential problems caused by the technological impurities in the final product when intended for medical application. 

Hyaluronan Production from Animal Sources General Methods... 

Biotechnological methods of hyaluronan production from bacterial strains involve cultivation in selected conditions where the polysaccharide capsule is formed during the stage of logarithmic growth on the surface of the bacterial cells. But at the stationary growing stage, HA can move into the cultural liquid and a capsule could become thin or disappears completely [30]. At the end of the process, up to 1-6 g of the desirable product could accumulate in 11 of the cultural liquid. HA accumulation could be controlled by the measurements of the viscosity of the cultural liquid. 

We realize that the description of the overall reactivity and chanical modifications of hyaluronan is a dense subject that could fill a separate monograph. However, this chapter will focus mainly on the chemical modifications of hyaluronan that lead to cross-linking. Such modifications play an important role for the creation of hyaluronic acid with valuable chemical and physical properties necessary for biological application of hyaluronan products. 

Glucosamine (Table 6.3) and hyaluronan products (Table 6.4) belong to the category of structure-modifying compounds that, contrary to non-steroidal anti-inflammatory drugs, not only stop the pain syndrome but also help to recover cartilage tissue. 

Medical Applications of Hyaluronan 171 Table 6.3 Hyaluronan products for treatment of osteoarthrosis... 

The hyaluronan polymer isolated from animals or bacteria is identical, and since bacterial hyaluronan is not immunogenic, it is an excellent source for medical grade hyaluronan. Extracting hyaluronan from microbial fermentation broth is a relatively simple process with high yields. An additional and important advantage of microbial hyaluronan production is that microbial cells can be physiologically and/or metabolically adapted to produce hyaluronan of high MW. 

Therefore, microbial hyaluronan production using either pathogenic streptococci or safe recombinant hosts, containing the necessary hyalnronan synthase, is nowadays more and more preferred [6]. 

Targeting to SECs should be directed at specific receptors present on this ceU type. A wide range of proteins and other molecules can be taken up by SECs through receptor-mediated endocytosis. For example, SECs play an important role in the uptake of degradation prodncts of the extracellular matrix. For this purpose they have hyaluronan [6], (pro)coUagen, and fi-bronectin receptors [7]. The first two receptors are nniqnely located on SECs. Elevated levels of serum hyaluronan and fibronectin, that are often fonnd in Uver disease [8], are nsnally the result of dysfunction of the clearance capacity of SECs combined with an increased production by HSCs [9]. 

Such enzymatic catalyzed polycondensations have allowed the synthesis of a number of natural polysaccharides, but has also allowed the production of nonnatural polysaccharides such as cellulose-xylan hybrids and functionalized hyaluronan, chondroitin sulfate, and chondroitin. Such work illustrates the ever-narrowing bridge between natural and synthetic polymers and polymer syntheses. 

Noble, P.W., Hyaluronan and its catabolic products in tissue injury and repair. Matrix Biol., 21, 25,... 

Bollet et al. [11] demonstrated the presence of hyaluronidase activity in various mammalian tissues. They showed that this type of hyaluronidase differed from the testicular type concerning pH optimum and pH range of activity. Subsequent studies revealed that the enzyme was present in the lysosomal fraction of the tissues [12]. The liver is an especially rich source [13]. Degradation of hyaluronan leads to the same end products as testicular hyaluronidase [11]. Lysosomal hyaluronidase from rat liver degrades chondroitin-4- and -6-sulfate, but not dermatan sulfate, desulfated dermatan sulfate, heparan sulfate, keratan sulfate, or heparin [14], Lysosomal hyaluronidase has an acid pH optimum and a narrow pH range of activity [14]. This difference in pH profile of activity has commonly been used to differentiate between testicular and lysosomal hyaluronidase. A similar acid-active hyaluronidase is present in human serum [15]. 

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