Chemistry and physicochemical properties
HA is a non-sulphated GAG and is composed of repeating polymeric disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine linked by a glucuronidic β (1→3) bond.17,18 In aqueous solutions HA forms specific stable tertiary structures.19 Despite the simplicity in its composition, without variations in its sugar composition or without branching points, HA has a variety of physicochemical properties. HA polymers occur in a vast number of configurations and shapes, depending on their size, salt concentration, pH, and associated cations.20 Unlike other GAG, HA is not covalently attached to a protein core, but it may form aggregates with proteoglycans.21 HA encompasses a large volume of water giving solutions high viscosity, even at low concentrations.13

Tissue and cell distribution of HA
HA is widely distributed, from prokaryotic,22,23 to eukaryotic cells.24 In humans, HA is most abundant in the skin,25-29 accounting for 50% of the total body HA,30 the vitreous of the eye,31 the umbilical cord,17 and synovial fluid,32,33 but it is also present in all tissues and fluids of the body, such as skeletal tissues,27 heart valves,34 the lung,35-39 the aorta,40 the prostate,41 tunica albuginea, corpora cavernosa and corpus spongiosum of the penis.42 HA is produced primarily by mesenchymal cells but also by other cell types.34-38,43

Biological function of HA
Over the past 2 decades there was considerable evidence presented that unraveled the functional role of HA in molecular mechanisms and indicated the potential role of HA for the development of novel therapeutic strategies for many diseases.

Functions of HA include the following: hydration, lubrication of joints, a space filling capacity, and the framework through which cells migrate.34 The synthesis of HA increases during tissue injury and wound healing25,44,45 and HA regulates several aspects of tissue repair, including activation of inflammatory cells to enhance immune response46-48 and the response to injury of fibroblasts49,50 and epithelial cells.51-55 HA also provides the framework for blood vessel formation7,45 and fibroblast migration,56,57 that may be involved in tumor progression.58 The correlation of HA levels on the cell surface of cancer cells with the aggressiveness of tumors has also been reported.59

The size of HA appears to be of critical importance for its various functions described above. HA of high molecular size, usually in excess of 1,000 kDa, is present in intact tissues and is antiangiogenic and immunosuppressive, whereas smaller polymers of HA are distress signals and potent inducers of inflammation and angiogenesis