# Viscosupplementation in the Therapy for Osteoarthritic Knee
## 3 Cross-Linked Hyaluronic Acid
### Cross Linked HA Administration Method (Frequency, Dose)  
In the initial paper announcing the efficacy of CL HA, CL HA was administered once a week for 3 weeks, just like natural HA [74, 96, 109]. However, in the case of CL HA, most papers have reported a similar effect to natural HA administered multiple times with one use [110, 111]. In a paper, Hylan G-F 20, a CL HA, was administered at various doses and frequencies. It was found that a single administration of 6 mL of the drug was as effective as administration of 2 mL three times [112]. Although CL HA has been used clinically for a shorter period than HA, the basic structure of the two drugs is the same, and research results are continuously reported that even one administration of CL HA shows similar  
\begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**Publication Year** & **Study Design** & **Comparison Agent** & **Patients Number (Treat/Control)** & **Injection Times** & **Result** \\ \hline
2005 [95] & RCT & Orthovisc & 184(92/92) & 3 &
\begin{tabular}{c} VAS, WOMAC improved during 52 weeks: \\ no significant differences in outcome between two group \\ \end{tabular} \\ \hline
2007 [96] & RCT & \
\begin{tabular}{c} MMW HA, \\ LMW HA \\ \end{tabular} & 660(220/220/220) & 3 &
\begin{tabular}{c} WOMAC improved: \\ no significant differences in outcome between 3 group \\ \end{tabular} \\ \hline
2010 [97] & RCT & saline & 232(115/117) & 1 &
\begin{tabular}{c} WOMAC and VAS were improved; \\ Hylan G-F 20 statistically significantly greater \\ improvements \\ \end{tabular} \\ \hline
2012 [98] & RCT & saline & 379(251/128) & 1 &
\begin{tabular}{c} WOMAC and VAS were improved; \\ GEL-200 statistically significantly greater improvements \\ \end{tabular} \\ \hline
2013 [99] & RCT & DCF, CN & 61(20/21/20) & 1 &
\begin{tabular}{c} WOMAC improved: \\ no significant differences in outcome between 3 group \\ \end{tabular} \\ \hline
2014 [100] & RCT & saline & 218(108/110) & 1 &
\begin{tabular}{c} no significant differences in outcome; \\ statistically significant improvement in pain relief at 6 \\ weeks among patients without clinical effusion at baseline \\ \end{tabular} \\ \hline
2015 [101] & RCT & Artz & 349(175/174) & 1 &
\begin{tabular}{c} Durolane 1 time vs. Artz 5 times \\ WOMAC improved in both group; \\ single injection of Durolane is non-inferior to 5 injections of \\ Artz over 18 and 26 weeks for pain, physical function, \\ global self-assessment, and knee stiffness \\ \end{tabular} \\ \hline
2018 [102] & RCT & \
\begin{tabular}{c} Hylan G-F 20 \\ (ADH) \\ \end{tabular} & 258(129/129) & 1 &
\begin{tabular}{c} CCH vs. ADH \\ VAS, WOMAC, Lequiese improved; CCH injection was \\ superior to ADH injection. \\ \end{tabular} \\ \hline
2019 [103] & \
\begin{tabular}{c} Open label, \\ RCT \\ \end{tabular} & Usual care & 156(77/79) & 3 &
\begin{tabular}{c} KOOS, VAS improved in both group; \\ IA HMW-HA added to usual care is effective for knee OA \\ in patients in the working age. \\ \end{tabular} \\ \hline
2019 [104] & RCT & saline & 311(152/159) & 1 &
\begin{tabular}{c} WOMAC, VAS, stiffness improved; \\ GEL-200 statistically significantly greater improvements \\ \end{tabular} \\ \hline
2019 [105] & \
\begin{tabular}{c} Open label, \\ prospective \\ \end{tabular} & non & 46 & 2 &
\begin{tabular}{c} decrease of cartilage catabolism, MRI cartilage volume and \\ thickness increased \\ \end{tabular} \\ \hline
2019 [106] & RCT & saline & 369(185/184) & 1 &
\begin{tabular}{c} WOMAC, VAS improved; \\ Monovisc statistically significantly greater improvements \\ \end{tabular} \\ \hline
2020 [85] & RCT & Hyalgan & 90(45/45) & 3 &
\begin{tabular}{c} WOMAC, VAS, LI improved in both group; \\ Athromac statistically significantly greater improvements \\ at WOMAC stiffness. \\ \end{tabular} \\ \hline \hline \end{tabular}
\end{table}
Table 3: \(Cont.\)effects to multiple administrations of HA. Therefore, it is recommended to consider the use of CL HA as well as HA in patients with OA of the knee.