Hyaluronan lubricity

Viscosupplementation is a clinical procedure that is being used increasingly in the treatment of osteoarthritis. This technique uses a substance known as hyaluronan to restore the lubricating properties of synovial fluid in osteoarthritic joints.6,41 Hyaluronan is a polysaccharide that can be injected into an arthritic joint to help restore the normal viscosity of the synovial fluid.6 This treatment helps reduce joint stresses, thus limiting the progression of articular destruction seen in osteoarthritis.106 Viscosupplementation has therefore been shown to reduce pain and improve function in osteoarthritis.1,95... 

Hyaluronan, despite the simplicity of its structure, has a surprisingly wide range of functions. In high concentrations, as found in the ECM of the dermis, it regulates water balance, osmotic pressure, functions as an ion exchange resin, and regulates ion flow. It functions as a sieve, to exclude certain molecules, to enhance the extracellular domain of cell surfaces, particularly the luminal surface of endothelial cells.28 It can also function as a lubricant and as a shock absorber. Hyaluronan can also act as a structural molecule, as in the vitreous of the eye, in joint fluid, and in Wharton s jelly. 

After my return to Boston, I extended my work on hyaluronan from the vitreus and the rooster comb to the synovial fluid. The physical properties, such as viscosity and elasticity, of synovial fluid were poorly understood, especially in human joints. I started to investigate the physical properties of cattle synovial fluid. As I had done 20 years earlier in Budapest, I went to the slaughterhouses of the Boston area and collected joint fluids. This time I was interested in how aging affects the physical properties and hyaluronan content of the joint fluid. The physical properties or, in more scientific terms, the rheology of the fluid is important because its role is to protect and lubricate the tissues of the joint. I traveled to Iowa to collect synovial fluids from cattle herds fed various diets that contained hormones. I hoped to discover a hormonal control of hyaluronan synthesis, similar to the one Szirmai and I had found that controlled hyaluronan synthesis in the rooster comb. 

Many drugs that have an anti-inflammatory action may also have other mechanisms of action. Corticosteroids are one of the most commonly administered classes of intraarticular medication in equine medicine. Hyaluronan (sodium hyaluronate, HA) is a natural component of the joint and its intraarticular use has anti-inflammatory actions and may have lubricating effects. Similarly dimethyl sulfoxide is used for both its anti-inflammatory and its antimicrobial actions. 

Hyaluronan is continuously synthesized and secreted by fibroblasts, keratino-cytes, chondrocytes and other specialized cells in the extracellular matrix (ECMs) throughout the body. It is synthesized by HA synthase (see also Chapter 9) at the inner face of the plasma membrane [98]. The level of HA synthesis is very high in skin and cartilage [99]. Hyaluronic acid is not one of the major components of the ECMs of the connective tissues, but it is found in various locations such as synovial fluid, vitreous humor, and umbilical cords [100]. Its biological functions include the maintenance of mechanical properties such as swelling in connective tissues and control of tissue hydration, providing lubricating properties in synovial fluid and heart valves. 

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... 

Investigating the adsorption of synovial fluid components onto artificial surfaces is of great importance in understanding the lubrication mechanisms occurring in artificial hip implants 6-8. However, the extreme complexity of synovial fluid, characterized by large concentrations of hyaluronan and the presence of many different proteins, most of which are derived from plasma, is often not accounted for in such adsorption studies 9. ... 

The natural lubricant present after arthroplasty is a complex mixture containing proteins, lipids and hyaluronan. However, the literature on natural lubrication has focused on single-component studies rather than on synovial fluid, mostly for reasons of... 

Fraser et al (1972) showed 25 years ago that addition of various serum proteins to hyaluronan substantially increased the viscosity and this has received a renewed interest in view of recently discovered hyaladherins (see above). The TSG-6 and inter-a-trypsin inhibitor and other acute phase reactants such as haptoglobin are concentrated to arthritic synovial fluid [52], It is not known to what extent these are affecting the rheology and lubricating properties. 

At the time of the discovery of hyaluronan, the polysaccharides, which represent the major part of the organic material on our planet, were already quite well known. A number of so-called mucopolysaccharides, currently known as glycosaminoglycans, had already been discovered. Hyaluronic acid is known to belong to this class as well. Mucopolysaccharides were isolated from mucus, to which they give viscous lubricating properties. These properties, in turn, are related to glycosaminoglycan s ability to bind to a significant amount of water. 

The major component of the synovial fluid, that is, hyaluronan, has two main functions namely lubricant and shock impulse damping [25]. Furthermore, hyaluronic acid is a major component of the extracellular matrix of the connective tissue. This kind of polymer should exhibit viscoelastic properties that directly depend on its microstructure and external parameters such as shear rate, stress and temperature. Knowledge of dependence of model synovial fluid viscosity on the shear rate, stress and temperature is very useful for biomedical applications, for example, in treatment of joint diseases. 

In a departure from historical approaches to introducing fillers in UHMWPE, researchers from Colorado State University have developed a novel UHMWPE-hyaluronan microcomposite [50, 51]. This microcomposite is detailed in Chapter 18. Hyaluronan is a natural lubricant in articular cartilage. By incorporating this biomolecule into UHMWPE, researchers theorized that wear could be reduced. Because hyaluronan is hydrophilic and UHMWPE is hydrophobic, fabrication of an UHMWPE-hyaluronan microcomposite is by no means a straightforward proposition and is accomplished via a complex and elegant multistep procedure. The process, which is described in greater detail in Chapter 18, begins with the production of a porous UHMWPE substrate, which constitutes the matrix of the microcomposite. The hyaluronan is complexed with quaternary ammonium cations (CTA-I-) and silylated [52]. A solution of silyl hyaluronan-CTA is then diffused into the open celled porous UHMWPE matrix, chemically crosslinked in situ, and then hydrolyzed... 

UHMWPE/hyaluronan biomaterials, on the other hand, were designed to exploit the high strength and durability of UHMWPE and the hydrophihc synovial lubricating ability of hyaluronan (HA). A composite approach avoids the weak attachments of plasma surface grafting and the inferior mechanical properties of hydrogel and cushion materials. 

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