Viscosupplementation A Hyaluronan in the Joint

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The rheological properties of synovial fluid and purified hyaluronan were first systematically studied by the author and his co-workers in the 1960s using both healthy and arthritic human and equine synovial fluids and purified hyaluronan (94-96). Fig. 5 demonstrates the rheological properties of two pooled human synovial fluid samples obtained from healthy knee joints and one from osteoarthritic joints (95). The synovial fluids of healthy young (27-34 years) and old (52-78 years) subjects, when exposed in dynamic experiments to shear stress at low frequencies (< 0.1 Hz), behaved as viscous fluids, but when the frequency increased (> 0.1 Hz), the fluids became more and more elastic. At a given point of frequency ('cross-over point'), values of the elastic modulus (G0)

Image Elastic Modulus

Frequency, Hertz

Figure 5 The dependence of dynamic moduli (G0 and G00 in Pa) of three human synovial fluid samples on frequency (in Hz). The concentration and limiting viscosity number, are given in parentheses. The two vertical dotted lines indicate the transfer of energy (at various frequencies) that the cartilage surfaces and the synovial tissue experience in running, walking or jumping (from Ref. 95).

Frequency, Hertz

Figure 5 The dependence of dynamic moduli (G0 and G00 in Pa) of three human synovial fluid samples on frequency (in Hz). The concentration and limiting viscosity number, are given in parentheses. The two vertical dotted lines indicate the transfer of energy (at various frequencies) that the cartilage surfaces and the synovial tissue experience in running, walking or jumping (from Ref. 95).

and the viscous modulus (G") became equal. This is where the transition from the viscous fluid to elastic body occurs. It is especially obvious at higher frequencies when the viscous modulus was found to be much lower in fluids from young than from old persons. Note also that the fluid from the young donor at all frequencies showed greater elasticity than that of the old (2,94). It was also discovered in these studies (see Fig. 5) that arthritic human synovial fluids lose some or all of their elastic properties at all frequencies because the cross-over point shifts to higher frequencies and it never occurs in the measured frequency range. This is due to the lower concentration, lower average molecular weight or changes in the conformation of the hyaluronan molecules in arthritic joint fluids. Thus the ratio of energy stored elastically to the energy dissipated as viscous flow decreases with aging and, even more significantly, with osteoarthritis. This is particularly true at high frequencies, corresponding to vigorous movement like running or jumping.

These studies also found that the rigidity of the fluids, which is a complex of the two moduli, is extremely dependent on the concentration and molecular weight of the hyaluronan molecule. The logarithm of the rigidity, thus also the elasticity at higher frequencies, is linearly dependent on the product of molecular weight (or intrinsic viscosity) and concentration. A 10-fold increase in the coil-overlap parameter (the product of molecular weight and concentration) results in approximately a 100-fold increase in the rigidity or elasticity of the fluid (2). Most importantly, the protective effect of hyaluronan in healthy joints dramatically increases as the frequency reaches the range that the joint experiences during running and jumping. The gap between the two cartilage surfaces closes faster and faster, resulting in a rapid transfer of mechanical energy from one cartilage surface to the other. The importance of the synovial fluid is to absorb this mechanical energy by its rigidity and elasticity. This loss of rigidity and elastic properties with aging and arthritis was interpreted as a loss in the protective properties of the fluid in between cartilage surfaces and in the soft tissues of the joint. This protection of the joint tissues by the rigidity and elasticity of the synovial fluid is the first of two cardinal principles in explaining the role of hyaluronan in the joint. The second cardinal principle is the elastic protection of the mechanosensitive apparatus of pain receptors (nociceptors) in the synovial tissue.

The discovery of the analgesic effect of intra-articularly injected elastoviscous hyaluronan solutions (NIF-NaHA) in the 1960s in arthritic dogs and racehorses was one of the most important events that led to viscosupple-mentation as a new therapeutic paradigm. It was also noted that the analgesic effect lasted longer than the residence time of the injected hyaluronan in the joint. It was also an early observation in horses that, parallel with the long-lasting analgesia, the abnormally low rheological properties of the hyaluronan in the affected joints returned to normal (97). This meant that the broad polydispersity and the low concentration of hyaluronan reverted to normal levels parallel with the long-lasting analgesia. The first comprehensive hypothesis on the mode of action of viscosupplementation was based on this observation: the restoration of the homeostasis of the overall metabolism of the joint. This chain reaction is triggered by pain relief, which permits the regular movement of the joint and is essential to restore the normal flow of the synovial fluid. This is the 'sine qua non' for the maintenance of the normal metabolism of joint tissues as well as that of the hyaluronan. The turnkey in this hypothesis is the restoration of joint motion due to the analgesia caused by viscosupplementation (98).

The first behavioral studies on racehorses and dogs were confirmed later by Japanese researchers' work using peritoneal and joint pain models in rats. These studies revealed that the analgesia is related to the concentration and average molecular weight of hyaluronan used (5). The pioneering electrophysiological studies of Belmonte and Schmidt and their co-workers in the 1990s confirmed the analgesic effect discovered in behavioral animal models. Using healthy joints and an acute intra-articular inflammation model in cats and rats, their studies established that the analgesic effect of hyaluronan solution depends on the elastoviscosity of the hyaluronan solution used. They found that only the most elastoviscous hyaluronan (hylan G-F 20) reduced the nerve impulse activity in sensory fibers evoked by movements within or outside the working range of both normal and inflamed joints. This analgesic effect is observable in the animal model only for a few hours after the intra-articular injection of the hyaluronan preparation because, after that time, the model is not maintainable. Therefore, this experiment explains the analgesic effect of viscosupplementation in the short term only. But it establishes that the stretch-activated channels of the nociceptive nerve terminals, the mechanosensory transduction apparatus that detects deflections on the cell membranes and is coupled to the cytoskeleton, are highly sensitive to the elastoviscous environment, in this case, created by hyaluronan solution injected into the joint (6). This interpretation of the mechanosensitive apparatus of the cell membranes to elastoviscous fluids to which it is exposed was confirmed by these authors using the frog oocyte model. In this in vitro cellular model the stretch-activated ion channels both on the inside and the outside surface of the cell membranes were exposed to various elastoviscous hyaluronan and DNA solutions. The mechanical stretch of the cell membrane caused deformation and openings of the ion channels, which were recorded by electrical activity that is proportional to the number of channels opened. Only elastoviscous solutions, both hyaluronan and DNA, adjacent to the channels could desensitize them (5,99). For further details on the electrophysiological work using cat, rat and frog oocyte models in evaluating the sensitivity of the mechanosensitive apparatus of nociceptive nerve endings and ion channels of cell membranes to elastoviscous hyaluronan and hylan preparations, see quoted references (5,99,100).

Parallel to the development of the use of hyaluronan in the vitreus the same preparations were used for the first time in the knee joint to eliminate pain (105). Preclinical studies on dogs, monkeys and horses showed that articular pain after traumatic arthritis could be alleviated by intra-articular injection of elastoviscous solutions of hyaluronan (80). Non-elastoviscous solutions of the same concentration of hyaluronan were not effective. The pain-relieving (analgesic)

effect of viscoelastic hyaluronan solutions was later studied in rats using behavioral pain models (101,102). It was found that the analgesic effect depends on concentration and average molecular weight, confirming that the elastoviscosity of the solution, which is the product of concentration times average molecular weight, is the active analgesic principle (for review see Ref. 5). The hypothesis, that in arthritis in horses and humans the elastoviscosity of the synovial fluid was always lower than in the healthy joint, was supported by the earlier findings. This is due to the decrease of the concentration of hyaluronan and its average molecular weight in this pathological condition (97).

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