**6.4.2 Malondialdehyde determination in pseudosynovial fluid**

Determination of oxidative stress assessed by level of lipid peroxidation product MDA in pseudojoint fluid showed higher oxidative stress in revision cases. The mean MDA value of the 18 patients with loose hip prostheses was 27.5 nmol/L (±17.6 SD, range 13.5 to 82.9). MDA level in the pseudojoint fluid from controls was significantly lower – 14.9 nmol/L (±4.5 SD, range 10.7 to 28.9) (p=0.001). Figure 6 shows the comparison between patients and controls in graphical form. Although not significantly, MDA level correlated moderately with linear polyethylene wear and grade of femoral osteolysis (Spearman's rho=0.321 and rho=0.315, respectively). Oxidative stress measured by MDA level in pseudosynovial fluid did not correlate with pelvic osteolysis or time elapsed from previous surgery.

Evidence Linking Elevated Oxidative Stress and Aseptic Loosening of Hip Arthroplasty 309

In the 40 hips, levels of MDA correlated with levels of GSH and GSSG (rho=0.509, p<0.0001, and rho=0.421, p<0.001, respectively). Because oxidative stress is a significant contributor to tissue fibrosis, a second set of correlations was calculated that measured the correlation between oxidative stress and hydroxyproline content. There was a correlation between GSH, GSSG, as well as MDA levels and periprosthetic collagen content. GSH/GSSG ratio and MDA level correlated with degree of osteolysis (rho=0.337, p=0.007, and rho=0.374, p=0.017, respectively). GSSG and MDA levels were higher in hips with greater annual wear

Three different mechanisms are mainly responsible for osteolysis and loosening: exacerbated inflammation caused by ROS production in the periprosthetic tissue; cascade of cellular and molecular interactions ultimately resulting in osteoclasts activation; and, compromised bone formation resulting from increased cytotoxicity on mesenchymal

Wear debris such as polyethylene, PMMA and metal particles, metal degradation products and ions may be exposed to the ROS produced by the inflammatory cells in the periprosthetic tissues. Mediators such as H2O2, NO and ONOO− are released by the macrophages and the inflammatory cells. Metal debris and metal degradation products could react with the free radicals resulting in elevation of oxidative stress. H2O2 in the cells can also undergo the Fenton reaction in the presence of metal ions with subsequent formation of highly toxic hydroxyl radical (Lubec, 1996, Sawyer, 1990). Various studies have reported that ROS are connected with tissue damage and fibrosis (Park et al., 2001, Riedle & Kerjaschki, 1997, Wang et al., 2002, Windhager et al., 1998). On the other hand, the effect of submicron wear debris on macrophage production of reactive oxygen species is largely unexplored. Thus, these facts led to the hypothesis that ROS play a role in aseptic loosening and formation of fibrous pseudocapsule around hip implants. Our results demonstrated in vivo elevated oxidative stress in periprosthetic tissues and pseudosynovial fluid from loose hip prostheses and hip implants with high rate of wear. This added further insight into the

When the cells are exposed to a large amount of oxidants, the capacity of the regulatory mechanisms of cellular response to oxidative stress may be exceeded by the rate of ROS production, resulting in a condition of "oxidative stress". In the present study, we found increased levels of markers of oxidative stress in periprosthetic tissues and pseudosynovial fluid from loose THAs. Our results are difficult to compare as the available studies on the possible role of oxidative stress in aseptic loosening of THA are in vitro experiments. We believe that, in the early stage of aseptic loosening, the exposure to wear debris could be responsible for the increase in the values of markers of oxidative stress in total hip arthroplasties with high rate of wear and osteolysis. Moreover, free radicals may be involved in sustaining the foreign-body reaction to wear debris. Later on, chronic exposure would result in a triggering of compensatory mechanisms leading to progressive increase in antioxidants and low oxidative stress as observed in the beginning of loosening (Table 1). This is consistent with the conception of oxidative stress regulation. However, other

**7. Rationale of oxidative stress and aseptic loosening** 

mechanism of aseptic loosening of hip arthroplasty.

mechanisms may play role, too.

**6.7 Correlations** 

of the polyethylene.

osteoprogenitors.
