# Viscosupplementation in the Therapy for Osteoarthritic Knee
## 3 Cross-Linked Hyaluronic Acid  
Cross-linked hyaluronic acid (CL HA) is a high MW HA made by chemically crosslinking natural HA. Not all high MW HAs are cross-linked, but most are cross-linked HAs. The structure of CL HA is as follows (Figure 2) [7]. Many papers have reported that high MW CL HA is more effective than low MW HA. It has been reported that one administration of high MW HA has a similar effect to three administrations of low MW [85; 86]. However, due to the specificity of crosslinking, pathological development of granulomatous inflammation, a pseudoseptic response, is also known [75]. Although the number of cases reported for adverse events is higher with CL HA, such adverse events are not severe enough to require medical intervention [86].  
Many studies have reported that CL HA is good for pain and knee function compared to the control group (saline). There are also papers on the effect and frequency of administration with general HA. Papers on how CL HA differs from regular HA are listed in Table 3. Table 3 summarizes 21 well-designed RCT papers among a total of 25 papers searched for IA CL HA. Seven papers have shown that it is effective for pain caused by OA of the knee compared to the saline group. There were two papers each comparing IA Steroid and oral administration of NSAIDs, and there was no significant difference in efficacy or better results. Another paper compared non-crosslinked HA and reported that a single administration of IA CL HA produced similar results to multiple administrations of IA HA.  
\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
1995 [87] & RCT & NSAID & 102(34/31/37) & 3 &
\begin{tabular}{c} Hylan G-F 20 was better than continuous NSAID therapy for VAS, joint function except activity restriction at \\ 26 weeks \\ \end{tabular} \\ \hline
1998 [88] & RCT & saline & 117(57/60) & 3 &
\begin{tabular}{c} VAS, pain during weight-bearing, resting, painful \\ movement-dramatic improvement during 24 weeks \\ \end{tabular} \\ \hline
1999 [89] & RCT & LMW HA & 70(38/32) & 3 &
\begin{tabular}{c} VAS, pain during weight-bearing, painful movement: \\ Hylan G-F 20 patients significantly better results compare \\ with LMW HA patients \\ \end{tabular} \\ \hline
2002 [90] & RCT & \
\begin{tabular}{c} Artzal \\ saline \\ \end{tabular} & 210(70/70/70) & 3 &
\begin{tabular}{c} WOMAC, weight-bearing pain, resting pain, maximum \\ pain: \\ \end{tabular} \\ \hline
2002 [90] & RCT & \
\begin{tabular}{c} Artzal \\ saline \\ \end{tabular} & 210(70/70/70) & 3 &
\begin{tabular}{c} no significant differences in outcome between any of the \\ three study groups during the first 26 weeks \\ Significantly longer duration of clinical benefit for \\ hyaluron treatment than for placebo. \\ \end{tabular} \\ \hline
2003 [91] & RCT & betamethasone & 100(50/50) & 3 &
\begin{tabular}{c} VAS, WOMAC improved: \\ no significant differences in outcome between two group \\ \end{tabular} \\ \hline
2004 [92] & RCT & saline & 346(172/174) & 1 &
\begin{tabular}{c} WOMAC and quality of life were improved in both; \\ greater response to NASH than placebo was observed at \\ week 6 \\ \end{tabular} \\ \hline
2004 [93] & RCT & TA & 215(113/102) & 3 &
\begin{tabular}{c} WOMAC and VAS were improved in both; \\ Hylan G-F 20 resulted in a longer duration of effect than TA \\ \end{tabular} \\ \hline
2005 [94] & RCT & HA & 40(20/20) & 3 &
\begin{tabular}{c} Joint fluid aspiration: \\ NO levels were reduced in both groups \\ VAS, WOMAC improved: \\ no significant differences in outcome between two group \\ \end{tabular} \\ \hline \hline \end{tabular}
\end{table}
Table 3: Clinical studies evaluating the efficacy of intra-articular cross-linked hyaluronic acid (CL HA) in knee osteoarthritis.  
Figure 2: Traditional cross-linked transformation of HA with 1,4-butanediol diglycidyl ether (BDDE) [7].