**4. Intraarticular delivery of hyaluronic acid**

 Hyaluronic acid or hyaluronan (HA) is a component of ECM and the body fluids, including the synovial fluid that organizes proteoglycans and other proteins on the cell membrane surface through noncovalent unions; in the fluids, it is responsible for their rheological properties. Structurally, HA is a glycosaminoglycan polymer formed by repeated sequence of D-glycuronic acid and N-acetyl-Dglycosamine linked by means of alternant β-1, β-1, 4, and 3 glycoside links. HA plays a key role in the physiology of diarthrosis especially in the articular cartilage as well as in the maintenance of synovial fluid viscosity, thus in viscoelasticity and lubrication. It is synthesized by the synoviocytes and has a molecular weight of about 6000–7000 kDa.

Most of the inflammatory and degenerative joint diseases course with increased local concentrations of pro-inflammatory molecules and proteases that degrade HA originating from small HA-fragments with a low-molecular weight. Consequently, in those diseases, there is a reduction in the viscosity and lubrication properties of the synovial fluid and a dramatic change in the biological receptor-mediated effects of HA. Moreover, the resulting small fragments acting through different membrane receptors can stimulate the inflammatory responses in the synovial membrane and the lesions in the articular cartilage [42, 43]. Therefore, one of the therapeutic strategies for the treatment of some joint diseases is to restore the rheological properties of the synovial fluid [44] and the joint homeostasis [45] throughout the intraarticular delivery of HA.

HA plays a key role in the pathogenesis of the degenerative and traumatic joint diseases acting as a pro-inflammatory or anti-inflammatory molecule, stimulating or inhibiting cellular migration, division, and differentiation [46]. The final effects depend both on the state of the tissue (expression of HA receptors, phase of the cell cycle, and signaling pathways) [47] and the characteristics of the HA (tridimensional structure and the size of the HA molecule) [48–50].

The intraarticular administration of exogenous HA is called "viscosupplementation," and it is focused to restore the rheological properties of the synovial fluid and to block the generative processes. Until now, the effectiveness of intraarticular administration of HA offers discordant results [51, 52]. Nevertheless, the meta-analysis of treatments that used intraarticular HA and the European Society for Clinical and Economic Aspects of Osteoarthritis recommends the use of intraarticular injections

of HA in absence of response to conventional anti-inflammatory drugs, since it improves the functionality of the joint and diminishes pain [53, 54].

 The beneficial effects of viscosupplementation with HA in TMD have not been probed satisfactory and are not more effective that of corticosteroids and NSAIDs [35, 55, 56]. Also, although there was no significant difference between the effectiveness HA and corticoids intraarticular injections, there was some evidence that HA was better than placebo [57]. However, most studies report a decrease in pain levels independently by the TMD [58]. On the other hand, it seems that HA regulates various inflammatory mediators in osteoarthritis in the TMJ [59]. In any case, at present, there is insufficient, consistent evidence to either support or refute the use of HA for treating patients with TMD.
