Viscoelasticity

When combined with water, hyaluronan forms a viscoelastic solution. Viscoelasticity is the term applied to liquids that combine the viscous properties of a liquid with the elastic properties of a solid. High molecular weight hyaluronan is predominantly elastic at low shear rates while low molecular weight hyaluronan behaves in a predominantly viscous manner.

The viscosity of a solution of hyaluronan is dependent on the shear rate (called non-Newtonian viscosity) and decreases as the shear force increases: a behaviour called pseudoplasticity. High pseudoplasticity means that viscosity drops rapidly (offering less 'resistance') as shear rate increases. Low pseudoplasticity means that viscosity drops slowly as the shear rate increases. Of all the viscoelastic substances, hyaluronan solutions possess the highest degree of pseudoplasticity. The pseudoplasticity of a hyaluronan solution can be illustrated using the blinking process as an example:

  • Between blinks (i.e. at low shear rate), the hyaluronan solution is at rest and the molecules assume a randomly coiled structure that offers protective elastic properties



Hyaluronan molecules at rest (between blinks)...

  • However, as the eye blinks, the shear rate increases. The molecules of hyaluronan become less tangled and tend to align so that they can move freely past one another. The solution thus becomes less viscous, allowing the eyelids to move easily over the surface of the eye.



...and under shear stress (during blinks)

 


Pseudoplasticity of hyaluronan

The pseudoplasticity of a solution of hyaluronan has great significance in the eye, as it is the same as that displayed by the mucus layer of the tear film. This means that solutions of hyaluronan can mimic the properties of this layer (mucomimesis). In addition, the drop in viscosity that occurs in response to the increase in shear rate prevents the hyaluronan from being cleared from the eye during blinking. This allows the solution to stay in the eye much longer. Also, because the viscosity of a hyaluronan solution decreases during blinking, it is more comfortable in the eye than a purely viscous (Newtonian) fluid such as HPMC, which can cause a dragging sensation as the eyelids open and close during the blinking process.

Elasticity of hyaluronan

If compressed quickly, a solution of hyaluronan will rebound quickly; however, if compressed slowly, the rebound occurs slowly. This is because the elasticity of the hyaluronan gel is provided by two separate mechanisms:

  • The coiled structure of the hyaluronan molecule gives it elasticity of the sort shown by a spring. This means that the molecule can deform rapidly in response to a sudden force, and return immediately to its former shape once the force is removed.

  • However, when force is exerted more slowly, the molecule responds by releasing some of the water molecules bound within it, thus reducing the molecule's overall volume. At the same time, loss of water from within the molecule raises the osmotic
    pressure, so that when the compressive force is removed, water is drawn back into the hyaluronan, restoring the gel to its original volume.


Elastic properties of hyaluronan

The elastic properties of a hyaluronan solution are important during the blinking process. During blinking, the hyaluronan molecules are under stress and become compressed. However, between blinking the stress is removed and the molecules return
to their former shape. This process helps the hyaluronan solution to stay and spread over the surface of the eye during the blinking process without hampering it. In other words, the hyaluronan molecules adapt to follow the movement of the lids during blinking.

     The elasticity of hyaluronan is complementary to, but      
independent of its pseudoplastic behaviour.

 

 

Water retention ability

The coiled structure of the hyaluronan molecule results in large hydrophilic domains that bind to water through a weak hydrogen bond. These domains are highly effective at taking up and retaining water.

During blinking (compression), hyaluronan acts like a sponge and releases water into its surrounding environment. When the compressive force is removed, osmotic pressure draws water back into the structure. At rest, the weak interactions with water mean that hyaluronan is able to retain water within its domains. These properties mean that evaporation of water from hyaluronan solutions is slow; thus when used as an eye drop, it allows longer lubrication of the eye.
 

Mucoadhesiveness

Solutions of hyaluronan adhere well to the mucin layer of the precorneal tear film. As a result, such solutions cover the cornea well to form an effective, long-lasting protective coating that is slow to evaporate. The coating ability of hyaluronan is dependent
on the correct balance of molecular weight and its concentration in solution.



Mucomimesis

The precorneal tear film has very specific physical properties, which are determined largely by the mucus it contains. These properties are mimicked closely by hyaluronan solutions. The physical similarity between the tear film and hyaluronan solutions is
believed to contribute to the efficacy and tolerability of these solutions when they are used as lubricant eye drops.

Wound healing properties

Hyaluronan has also been shown to have wound healing properties. The stable protective coating that hyaluronan forms over the cornea prevents further damage and allows natural healing to take place more rapidly.

Free radical scavenging properties

Free radicals are molecules that contain one or more unpaired electrons (a free electron). This makes them highly reactive and as a result, they can cause damage to cell membranes, DNA and other cellular structures through oxidative chain reactions. For example, certain free radicals can damage the phospholipid membrane (in a process called lipid peroxidation) and thus harm the integrity of the healthy cells.


Scavenging action of hyaluronan 

Some free radicals are produced naturally in the body and others derive from environmental hazards such as tobacco smoke, radiation and excess alcohol. In the eye, free radicals are also produced when the eyes aren't adequately lubricated (leading to KCS), in response to the use of preservatives in artificial tears, and when the eye is hypertonic. Free radicals in the eye can contribute to diseases such as cataract formation in the lens.


Antioxidants such as selenium and vitamins A, C and E are known to protect cells by neutralising free radicals, thus negating their deleterious effects. The chemical structure of hyaluronan, combined with the meshwork structure it forms in solution, means that it also has a scavenging effect, an added benefit that can be important in the eye. However, the scavenging effect of hyaluronan leads to a breakdown in the structure of the molecule, resulting in a decrease in molecular weight.

SUMMARY

  • Hyaluronan exists naturally in all living organisms (not plants) and is a universal component of the extracellular space

  • Hyaluronan is a polyanionic glycosaminoglycan (GAG) polysaccharide

  • Hyaluronan forms an expanded random coil structure in physiological solutions and occupies a very large 3D domain
    - Hyaluronan has the properties of a highly hydrophilic material, but also possesses hydrophobic patches characteristic of lipids
    - The domain structure of hyaluronan has the property of slowing the diffusion of large molecules proportionate to their size

  • Many of the physiological functions of hyaluronan can be attributed to its waterbinding ability
    - The evaporation of water from hyaluronan solutions is slow, allowing longer lubrication of the eye

  • The viscosity of hyaluronan displays a non-Newtonian behaviour, it means it decreases as shear forces increase
    - The pseudoplasticity of a hyaluronan solution can mimic the properties of the mucus layer of the tear film
    - The drop in viscosity prevents the hyaluronan from being cleared from the eye during blinking

  • The elasticity of hyaluronan helps the solution to stay and spread over the surface of the eye during the blinking process without hampering it

  • The chemical structure of hyaluronan, combined with the meshwork structure it forms in solution has a scavenging effect on free radicals

  • Hyaluronan is known to have wound healing properties
    - By coating the cornea, it prevents further damage and allows natural healing to occur more rapidly

  • Hyaluronan can be produced commercially from bacterial sources
    - Hyaluronan produced in this way has the advantage that it is easy to grow, has a more uniform size, can be produced on a large scale and does not give rise to allergic, inflammatory or other types of adverse reactions

 

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