Hyaluronan - Basic Science

L Funk, 2003

Hyaluronan is the general term designating the linear repeating disaccharide, (beta-D-glucuronyl-beta-D-N-acetyl-glucosamine) of very high molecular mass (upwards of 10x10⁶ Daltons).
The molecular weight of Hyaluronan varies between different tissues and species. It may also vary depending on the condition of the tissue. For example, the molecular weight of Hyaluronan in synovial fluid (normally 4-5 million Daltons) is often reduced in joint disorders.
There are on average around 2500 repeating disaccharide units in endogenous Hyaluronan and the mean molecular weight is approximately 400 Daltons. However, the number of repeating disaccharides in a Hyaluronan molecule can reach 10,000 or more, with a molecular weight of around 4 million Daltons.)

The term “hyaluronic acid” was adopted when the biopolymer was first isolated from the vitreous of bovine eyes in 1934. However, under physiological conditions, hyaluronan is not present in the acid form, therefore this term is redundant. The term “sodium hyaluronate” mostly designates the highly purified, narrow molecular weight range hyaluronan used as a therapeutic agent. These different terms specify only the natural, non-chemically modified biopolymer which is present in most of the body tissues.

Hyaluronan is nearly ubiquitous in its distribution being present in the interstitial spaces of most animal tissues.

Its principal role is as a structural element but functions may differ depending on its location in the body.

Hyaluronan can also:

• - Play a significant role in the body during repair process, mediating cell adhesion, differentiation, motility and blood vessel growth;
• - Retain large quantities of water and therefore control tissue hydration;
• - Protect tissue against overuse and shocks by its viscoelastic properties.

The human joint lined by the synovial membrane and is filled with a viscous fluid called the synovial fluid (SF), which can be regarded as a modified extra-cellular fluid. Like other extra-cellular fluids, the SF acts as a transport medium supplying the articular cartilage with nutrients and oxygen and carrying away the waste products of metabolism. The main component of the SF is hyaluronan. The SF contains a complex solution of proteins, electrolytes, uric acid and glucose, in concentrations similar to blood plasma. Hyaluronan is constantly produced by the synoviocytes present in the synovial membrane and then extruded in the synovial space. There is a strict balance between its production and degradation.

The SF has principally protective functions in the joint, acting as a lubricant, shock absorber and ‘filter’, and plays a key role in the maintenance of joint homeostasis. An important point of hyaluronan is that the meshworks it forms are ordered. The shapes of the hyaluronan secondary structures determine the shapes of the aggregates, and each branch in the meshwork carries with it two intrinsic directions, up or down, established by the hyaluronan chains. This ordered meshwork is of importance depending on the situation the hyaluronan solution is placed. (Balazs et al. 1993)

Hyaluronan solutions, and as such the synovial fluid, are viscoelastic. This means that the solution presents viscous and elastic characteristics at the same time. The viscosity is important providing lubrication when the solution is subjected to gradual shear stress. Hyaluronan solutions present non-Newtonian behaviour. This means that the viscosity decreases when the shear stress increases thus increasing lubrication. Example: the synovial fluid lubricates the joint when walking.

The elasticity is important when a sudden loading force is applied to hyaluronan solutions. In that case, hyaluronan chains first absorb the loading force and then release it in a proper manner (shock absorbing properties). Example: absorption of shocks between boneheads when running.

Due to its properties in solution hyaluronan forms meshworks that restrict the free movement of cells and large molecules through the joint, acting as a sort of filter. In fact the hyaluronan meshwork forms ‘pores’ which allow the free passage of small molecules, such as nutrients, but effectively block the passage of larger molecules, such as inflammatory cells or proteins. The hyaluronan chains are constantly moving in the solution, and the effective “pores” in the network continuously change in size. Statistically, all sizes of pores can exist, but with different probabilities. This means that in principle, all molecules can pass through a hyaluronan network, but with different degrees of retardation depending on their hydrodynamic volumes. This is very important as the hyaluronan in the synovial fluid can help to modulate the inflammatory response.

The hyaluronan contained in the SF also helps to form a coating layer over the entire inner surface of the joint. This layer is formed mainly from hyaluronan, in association with proteins, and is approximately 2um thick. It plays several important roles in the protection of the articular cartilage including lubrication and a ‘barrier function’. The hyaluronan layer is constantly degraded and renewed.

The SF constantly supplies the hyaluronan layer with new molecules. In the healthy joint, this constant process is very important in the maintenance of joint homeostasis. Hyaluronan is present at different levels in the joint (Abatangelo et al. 1995). At each level, hyaluronan will play a different role: In the synovial tissues thus forming a protective barrier: this barrier protects the synovium against inflammatory mediators and shields pain receptors from pain mediators thus modulating pain perception; ß (fibroblast-like) cells of the synovium and is secreted into the synovial fluid.