# Viscosupplementation in the Therapy for Osteoarthritic Knee
## 2 Hyaluronic Acid
### Hyaluronic Acid Physiology  
The clinical benefit of IA HA for knee OA is from two perspectives: mechanical viscous replenishment in the joint cavity and re-establishment of intra-articular HA homeostasis by inducing the production of endogenous HA [60; 61]. As mentioned above, hyaluronic acid is a substance present in cartilage and synovial fluid with molecular weights ranging \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Publication Year [Ref.]** & **Study Design** & **Pro/Cons** & **Result** \\ \hline
2021 [6] & Systemic review & pro & The use of IA HA is suggested for refractory patients who do not respond to treatment with drugs such as NSAIDsIDs and acetaminophen. \\ \hline
2021 [49] & Systemic review & pro & Even when not supported by high evidence consensus, intra-articular CS and HA injections have gained precise indications for symptomatic relief and clinical improvement in OA. \\ \hline
2021 [50] & Meta-analysis & pro & Hylan G-F 20 at both frequencies (either as single or 1–3 weekly injections) are efficacious and generally well tolerated for long-term use. \\ \hline
2021 [51] & Systemic review & pro & HA reported good outcomes both for pain reduction and functional improvement. \\ \hline
2021 [52] & Meta-analysis & pro & In the meta-analysis, support the appropriate use of steroids and HAs for patients with Knee OA. \\  & & & For pain relief and AE, steroids are most likely the best treatment, followed by HA \\ \hline
2012 [53] & Systemic review & cons & IA HA has fewer benefits and increases the risk of serious side effects. \\ \hline
2016 [54] & Meta-analysis & cons & IA HA vs. physical therapy; \\  & & & Physical therapy agents seemed to have greater effects than IA HA on disability and pain. \\ \hline
2017 [55] & Meta-analysis & cons & IA-saline injection yields a statistically and clinically meaningful improvement up to 6 months after the injection in patients with knee OA. \\  & & & placebo effect for IA saline injections affects outcomes during comparative studies for the IA HA group \\ \hline
2019 [56] & Systemic review & cons & IA HA and IA CS can provide meaningful benefits to an appreciable number of patients, emerging evidence indicates that the apparent effectiveness of these treatments is largely a result of placebo effect. \\ \hline \hline \end{tabular}
\begin{tabular}{c c} \hline \hline CS, corticosteroid; ESCEO, The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases; OARSI, Osteoarthritis Research Society International; AE, adverse effect. \\ \end{tabular}
\end{table} 
Table 2: Cont. from 6500 to 10,900 kDa [62]. During arthritis, endogenous HA present in cartilage and synovial fluid is broken down into substances of high molecular weight and low molecular weight (depolymerization). Consequently, viscoelastic properties of the synovial fluid are reduced. Therefore, when HA is injected from the outside, it acts as a lubricant instead of an endogenous HA with a lower molecular weight. In addition, it induces the relief of pain caused by degenerative arthritis through various mechanisms [63]. There is also a report showing that exogenous HA can affect joints by slowing the degradation rate of type II collagen in the joint cavity [64]. After administering HA and methylprednisolone acetate (MPA) three times, the cartilage was biopsied 6 months later and examined for articular surface morphology, territorial matrix, chondrocyte number, and ultrastructure. It has been reported that the HA group has a higher chondrocyte density than the MPA group with improved appearance of the regional matrix, reconstitution of the superficial layer, and catabolism of chondrocytes [65]. Mechanistically, HA is known to attenuate phagocytosis and decrease cyclic adenosine monophosphate, fibronectin, and prostaglandin associated with inflammatory responses [66]. [PERSON] et al. have reported that HA has disease-modifying activity in OA patients through these actions [67].