Control of the Hyaluronidase Activity Towards Hyaluronan by Formation of Electrostatic Complexes: Fundamental and Application Relevance - Natural Polymers, Biopolymers, Biomaterials, and Their Composites, Blends, and IPNs - page 126

formation of such aggregates involves link proteins (Day and Prestwich, 2002; Yang
et al., 1994). These laters belong to a family of proteins termed hyaladherins because
of their ability to specifically bind HA. Hyaladherins also include membrane receptors
such as CD44 (cluster of differentiation 44) and RHAMM (receptor for hyaluronan-
mediated motility) (Day and Prestwich, 2002; Yang et al., 1994). Binding of HA to
such receptors can activate intracellular signaling pathways. Thus, hyaladherins play
an important role in the involvement of HA in cell proliferation, differentiation, adhe-
sion, and migration (Evanko et al, 1999; Knudson and Knudson, 1993).
As one may have expected, the viscosity of HA solutions strongly increases as
the HA chain length is increased (Cowman and Matsuoka, 2005). Interestingly, it was
shown that the ability of HA to bind hyaladherins as well as the stability of the result-
ing complexes also depends on the HA chain length (Courel et al., 2002; Deschrevel et al.,
2008b). In other words, the biological functions of HA strongly vary according to its
chain length (Stern et al., 2006). From the general point of view, HA of high molar
mass is believed to play a homeostatic role, whereas, HA chains of low molar masses
act as endogenous danger signals (Scheibner et al., 2006; Stern et al., 2006). For ex-
ample, it is established that high molar mass HA is anti-angiogenic, anti-inflammatory,
and immunosuppressive, while HA chains of low molar masses (below 2.5 × 10 5 g
mol -1 ) are pro-inflammatory and activate the innate immune system, and HA oligo-
saccharides (4-25 disaccharides units) are angiogenic (Delmage et al., 1986; Gately
et al., 1984; Hogde-Dufour et al., 1997; Liu et al., 1996; McKee et al., 1996, 1997;
Takahashi et al., 2005; Taylor et al., 2004; Termeer et al., 2002; Trochon et al., 1997;
West and Kumar, 1989).
The many biological functions of HA make it plays important roles under nor-
mal conditions but also under pathological conditions since HA is involved, for
example, in immune response (Delmage et al., 1986; Gately et al., 1984; Scheibner
et al., 2006), wound healing (David-Raoudi et al., 2008) and tumor proliferation and
invasion (Stern, 2008). Moreover, the absence of immunogenicity of HA, its biocom-
patibility, biophysicochemical properties, and biological functions have led to its use
in an increasing number of medical and aesthetic applications. However, for several
of these applications, HA have two major drawbacks: a high rate of in vivo degrada-
tion and poor mechanical properties. In order to overcome these drawbacks and to
extend the application range of HA, the latter has been the subject of various chemi-
cal modifications (Deschrevel, in press). In the medical field, HA or its derivates are
used in ophtalmology, osteoarthritis, laryngology, urology, embryo implantation, ad-
hesion prevention, wound healing, tissue engineering, and drug delivery engineering
(Deschrevel, in press). Molar mass of HA has always been taken into account with
respect to the various applications. However, as the knowledge about the influence of
the chain length of HA on its biological functions has increased, molar mass of HA has
become a crucial parameter and the demand of HA fragments of well-defined size has
increased (Deschrevel, in press).
The knowledge of the pathways of HA synthesis and catabolism (Deschrevel, in
press) strongly suggests that HA molar mass distribution is most probably regulated
through the catabolic pathway. In addition, according to Mio and Stern (2002), such