**3. Wear debris and aseptic loosening of total hip arthroplasty**

Osteolysis and subsequent loosening remain the most frequent complication after THA and the main cause for its failure. Wear-induced particle debris and the associated host response

Evidence Linking Elevated Oxidative Stress and Aseptic Loosening of Hip Arthroplasty 301

Oxidative stress is a condition when the balance of formation of oxidants exceeds the rate of metabolism and the ability of antioxidant systems to remove ROS. High levels of ROS can

Alternatively, oxidative stress can trigger activation of specific physiologic signaling pathways (Rached et al., 2010). In several studies, reactive oxygen species have been demonstrated as one of the key factors in inflammation (Kamikawa et al., 2001, Wang et al., 2002, Tsaryk, 2009). Because of the inflammatory nature of aseptic loosening of total hip replacement, arthroplasty, it is likely that free radicals play a major role in this condition as well. In the periprosthetic tissues, detection of reactive oxygen species provides evidence for the formation and activity of free radicals (Windhager et al., 1998, Kinov et al., 2006). Under physiological conditions, ROS are part of normal regulatory circuits, and the cellular redox state is tightly controlled by antioxidants. However, increased concentrations of ROS and loss of cellular redox homeostasis following extensive particulate challenge can lead to up-

The interface between implant and bone is rich of transitional metals from the alloy of the implant. Transition elements like vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), molybdenum (Mo), so-called d-block elements, show variable valence, which allow them to undergo changes in oxidation state involving one electron. If free radicals have a causative role in aseptic loosening than transition metals would have a strong promotional effect (Windhager et al., 1998). Via the Fenton reaction they would greatly stimulate inflammation and loosening. Iron i.e., exerts its toxicity through a series of reactions with reactive oxygen species called modified Haber-Weiss or Fenton reaction (Fe2+ + H2O2 → Fe3+ [H2O2-] → .OH + -OH), generating the highly toxic hydroxyl radical (.OH) (Lubec, 1996). The generation of hydroxyl radicals via Fenton chemistry represents one of the most important mechanisms in various pathologic conditions. Hydroxyl radicals can lead to DNA and protein damage and impairment of normal DNA and protein synthesis and cell proliferation and thus has been thought to be casually involved in the multistep process of loosening (Wang et al., 2002). Furthermore, ferrous/ferric ion has a decisive function in lipid peroxidation process by direct reaction with unsaturated fatty acids or reaction with preformed lipid hydroperoxides to form chain-carrying alkoxyl and peroxyl radicals, leading to severe damage of cellular

The effects of the metal wear particles on oxidative stress are not augmented by polyethylene and cement wear debris, originating from materials used for implant fixation. In an in vitro study, Petit et al. compared the effects of different wear products from hip prostheses on the nitration of proteins (an evidence for oxidative damage) in macrophages (Petit et al., 2005). The effect of both Co(2+) and Cr(3+) ions was inhibited by glutathione monoethyl-ester that provides protection against oxidative stress. However, ultra-high molecular weight-polyethylene and alumina ceramic particles had no significant effect on

Because of their excellent mechanical properties, titanium and titanium alloys are widely used in orthopedic implants. Moreover, superb corrosion resistance and biocompatibility are characteristic for titanium and are the main reasons for its wide use in various biomaterials. However, as a result of wear and corrosion, titanium ions are released in the periprosthetic tissues and can be found in systemic circulation. Titanium may be directly involved in ROS production interacting with H2O2 leading to formation of hydroxyl radicals

damage proteins, lipids, and DNA, and eventually cause cell death.

regulation of inflammatory processes in the interface membrane.

integrity (Lin & Girotti, 1993, Minotti & Aust, 1992, Schaich, 1992).

**4. Oxidative stress** 

the nitration of proteins.

is principle factor in this process. Abundant evidence show that the macrophages play a key role in wear debris induced periprosthetic osteolysis (Brooks et al., 2002, Park et al., 2005, Purdue et al., 2006, Sabokbar et al., 1997, Wang et al., 2002). Phagocytosis of wear particles induces secretion of various proinflammatory cytokines such as tumor necrosis factor alpha (TNF-), IL-1 and PGE2 (Goldring, Lam et al., 2000, Yao et al., 2008). This inflammatory response is modulated by various factors including chemical composition, size, shape, and volume of the particles (Sieber et al., 1999, Yang et al., 2002). The prostheses-bone interface could be also influenced by other factors such as endotoxins (Kido et al., 2004), matrix metaloproreinases secreted from activated macrophages that directly resorb bone (Brooks et al., 2002), and mechanical factors such as high fluid pressure (Aspenberg & Van der Vis, 1998, Van der Vis et al., 1998). Although the inflammatory response to wear debris is central to the process of aseptic loosening, the detailed nature of the local response may vary based upon several parameters, including prosthetic type and material, patterns of wear, and patient-related factors (Purdue et al., 2006).

Similar to polyethylene debris, metallic debris migrate in the periprosthetic tissues, and because of its smaller size is easily phagocytosed by histiocytes (Doorn et al., 1999). Metal ions can be involved in various cellular, local and systemic biological reactions. However, the mechanism of metal toxicity is not fully understood today. It is well known fact that metals are involved in production of reactive oxygen species (ROS), such as superoxide ions (O2**·–**), hydrogen peroxide (H2O2), hydroxyl radical (OH**·**), and nitrogen oxide (NO**·**) via Fenton/Haber-Weiss chemistry (Sawyer, 1990). Free radicals may damage purine and pyrimidine bases of DNA (Valko et al., 2006). Moreover, direct binding of Cr to DNA is reported (Wolf et al., 1989) that may inhibit the process of DNA repair (Witkiewicz-Kucharczyk & Bal, 2006). These gene modifications and eventual mutations can lead to carcinogenesis. Metal ions have been also associated with a delayed immune reaction (hypersensitivity) (Hallab et al., 2001). It was suggested that a vicious circle of particle phagocytosis, cellular lysis and subsequent release of particles by the involved cells may play role in delayed hypersensitivity reaction mediated by T-lymphocytes (Hallab et al., 2005). In addition to systemic and cellular reactions various local adverse reactions such as extensive necrosis (Ollivere et al., 2009), periprosthetic osteolysis (Amstutz et al., 2011) and pseudotumour reactions (either cystic or solid) (De Haan et al., 2008, Wynn-Jones et al., 2011) have been reported with MoM bearings. Perivascular accumulation of activated macrophages and T-lymphocytes has also been associated with periprosthetic osteolysis (Park et al., 2005). In addition, direct toxicity may also be involved in bone loss (Fleury et al., 2006, McKay et al., 1996).

Cells in synovial membrane of the artificial hip joint generate synovial fluid that is called pseudosynovial fluid and secrete the mediators of inflammation into it. Schmalzried et al. hypothesized that wear debris is dispersed into the joint fluid (Schmalzried et al., 1992). Access to the joint fluid for the wear particles is dependent on the contact between implant and bone. Wear debris activates macrophages, which activate osteoclasts or become osteoclasts themselves and initiate bone resorption (Sabokbar et al., 1997). The resulting bone loss will enlarge the interface and ease the flow of joint fluid, resulting in higher transportation capacity of the debris and gradual loosening of the implant. This concept is in concordance with the high pressure theory that was suggested by Aspenberg and Van der Vis (Aspenberg & Van der Vis, 1998).
