High molecular weight hyaluronan

For several years I tried to convince Pharmacia to work with me to develop new derivatives of hyaluronan and test them on a broad spectrum of medical therapeutic applications. But Pharmacia was not even ready to market my high molecular weight, non-inflammatory fraction of hyaluronan for the treatment of human arthritis, despite the fact that they had many successful clinical trials and that they were selling the material worldwide for treatment of arthritis in animals. I believe that this was because they were not ready to invest in a substantially larger manufacturing facility for hyaluronan. They were, however, ready to support me financially in my research and development effort to develop new hyaluronan derivatives. 

The function of hyaluronic acid was initially confined to the maintenance and sta-bihty of the ECM (96). However, the action of hyaluronic acid varies with its size, which determines its function in a cell-type specific manner (97-101). Hyaluronic acid represents more than 50% of the ECM in the skin. High molecular weight hyaluronic acid (>1,000 kDa) controls tissue water content, ECM lubrication, structural integrity, free oxygen radicals, and distribution of plasma proteins (96,100,101). The synthesis of hyaluronic acid is achieved by hyaluronan synthase-1 to -3 (102,103). The stability of hyaluronic acid varies with its microenvironment, as its half-life is less than 10 min in blood, up to 12 h in the skin, and extends to months in the vitreous gel of the eye (100,101). Hyaluronic acid is the only GAG with a function of its breakdown molecules, as small hyaluronic acid molecules and fragments stimulated the maturation of dentritic cells and the synthesis of proinflammatory IL-lp, IL-12, and TNF-a (103-105). The latter effect seems to be restricted to an interaction of hyaluronic acid fragments with the Toll-like receptor 4 (104,105). The observation that bacterial spreading in the... 

ICamppiah KSIC Sundararajan S, Xu ZH, Li XD. The effect of protein adsorption on die friction behavior of ultra-high molecular weight polyediylfflie. Tribol Lett 2006 22 181-188. IQtano T, Ateshian GA, Mow VC, Kadoya Y, Yamano Y. Constituents and pH changes in protein ridi hyaluronan solution affect the biotribological properties of artiticial articular joints. J Biomech 2001 34 1031-1037. 

Oxidation stress is unbalanced between prooxidants and natural antioxidants in body that lead to several diseases such as rheumatoid. Hyaluronic acid (HA), is a high molecular weight biopolysacharide, is found in the extracellular matrix of soft connective tissues and is particularly concentrated in synovial fluid (SF). Half-live time of Hyaluronan in SF is approximately 12 hrs in normal conditions. This process is accelerated under normal oxidation stress that generates troubles in human joints. 

It is believed that HA is the earliest evolutional form of glycosaminoglycans. Contrary to HA, other glycosaminoglycans are synthesized in the Golgi apparatus. They covalently bond with proteins to form the proteoglycans, which further transfer into the extracellular matrix by the exocytosis mechanism [41]. Three forms of hyaluronan synthase (HASj, HAS, HAS3) are found in human and vertebrate bodies. The enzyme HAS performs slow synthesis of high molecular weight HA, the enzyme... 

DeAngelis, P.L., Weigel, P.H. (1994) Immunochemical confirmation of the primary structure of streptococcal hyaluronan synthase and synthesis of high molecular weight by the recombinant ensime. Biochemistry, 33, 9033-9039. 

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