**2.1 Brief historical remarks**

296 Recent Advances in Arthroplasty

Next to development of new bearing surfaces, the second line of research focuses on understanding of the underlying mechanisms of the process aseptic loosening of THA. Aseptic loosening is characterized with osteolysis and formation of thick membrane around the prostheses that eventually leads to its loosening. Currently, it is well established fact that loosening is a result of host response to wear debris and corrosion products of implant materials. Particles can readily be detected in the periprosthetic tissues as well as at remote locations such as lymph nodes, liver, spleen or bone marrow. Wear debris induce inflammation in the periprosthetic tissues that is sustained through the functioning of the

Metal wear debris, degradation and corrosion products, such as ions and reactive oxygen species (ROS), has been considered to be crucial factors in the process of loosening leading to the failure of metal implants (Tsaryk, 2009). Metal debris could induce inflammatory responses mediated by neutrophils, macrophages, fibroblasts and other cells. Metal ions and corrosion products are potentially toxic, can cause allergic reactions of hypersensitivity,

Elevated oxidative stress has been proposed to be a causative factor in many inflammatory and degenerative disorders with tissue damage and fibrosis in different organs and systems (Hogg, 1998, Park et al., 2001). In addition, recent in vitro studies showed the combined effect of particles and macrophage and osteoclast activation on the increase of oxidative stress (Fleury et al., 2006, Petit et al., 2005, Wei et al., 2009). This suggests involvement of reactive oxygen species (ROS) in the mechanism of aseptic loosening of hip arthroplasty. The chronic inflammation state with the elevated oxidative stress results in extensive formation of granulation tissue and fibrous capsule, periprosthetic bone resorption due to osteoclast activation by inflammatory stimuli and finally aseptic loosening of the implant (Tsaryk, 2009). In support of this hypothesis we proved the involvement of ROS in excessive fibrosis around loose hip prostheses (Kinov et al., 2006). This suggests involvement of reactive oxygen species in the mechanism of aseptic loosening of hip arthroplasty leading to formation of the fibrous pseudocapsule that typically consists of a combination of fibrous tissue and macrophages. However, the mechanisms of involvement of ROS in aseptic

Some researchers further implicated that free radicals may be involved in the induction and maintenance of chronic inflammation with resulting periprosthetic bone resorption. In support of this hypothesis, recent studies on osteoporosis (Hamel et al., 2008, Li et al., 2009) show that elevated oxidative stress is involved in inhibiting osteoblastic differentiation and stimulating osteoclastogenesis. In addition, in vitro study showed the combined effect of particles and macrophage and osteoclast activation on release of reactive oxygen and nitrogen species (Wang et al., 2002). Different studies investigate the mechanisms of action of oxidative stress on bone formation (Bai et al., 2004, 2005, Chen et al., 2010, Kim et al., 2010, Mazière et al., 2010, Rached et al., 2010). However, the exact mechanism and actions of ROS on inhibition of osteoblasts are still largely unknown. Considering the fact that elevated oxidative stress induces bone loss in postmenopausal osteoporosis (Lean et al., 2005) whereas antioxidants suppress osteoclast activity and enhance differentiation of osteoblasts (Aitken et al., 2004, Mody et al., 2001) it is possible that ROS are involved in aseptic loosening of total hip arthroplasty. In support of this, in two previous studies, we have shown direct evidence for involvement of elevated oxidative stress in aseptic loosening of

chromosomal aberrations, and eventually malignancy (Keegan et al., 2007).

implant as long as wear particles are produced.

loosening of THA are still to be elucidated.

THA (Kinov et al., 2006, 2010).

Aseptic loosening has been observed since the beginning of hip replacement. Metal bearings were first introduced by Wiles in the 1930s (Wiles, 1957), but they received wider application in the 1950s and 1960s with the pioneer works of McKee-Farrar and Ring (McKee & Watson-Farrar, 1966, Ring, 1967). The earlier prototypes were manufactured of stainless steel and fracture of the prostheses was a frequent complication (McKee & Watson-Farrar, 1966, Ring, 1967). To solve this problem the cobalt chromium molybdenum (CoCrMo/CoCrMo) articulation was developed. However, the metal-on-metal (MoM) bearing was eventually abandoned in the 1970's in favor of the Charnley's low friction arthroplasty. Next to biomechanical factors associated with the joint center and surgical implementation technique, two main reasons for shift from MoM bearing were manufacturing problems and long-term concerns associated with metal toxicity (Muratoglu & Kurtz, 2002).

In 1958, Charnley introduced the "low friction arthroplasty" in which the initial bearing material was polytetrafluoroethylene (Charnley, 1979). Because of high rate of wear and "intense foreign-body reaction", in 1962, polytetrafluoroethylene was replaced with ultrahigh molecular weight polyethylene. After use of UHMWPE the rate of wear and the need for revision decreased tremendously. In the cases that required revision the implant-bone interface was surrounded by granulomatous tissue rich of inflammatory cells. Charnley believed that those findings were a result of infection (Charnley et al., 1968). A benign, noninflammatory adverse tissue response was suggested (Harris et al., 1976). Willert and Semlitsch proposed that aseptic loosening resulted from reaction to wear debris ingested by the macrophages in the periprosthetic tissue (Willert & Semlitsch, 1977). Their findings were supported by Mirra et al. (Mirra et al., 1976), and Goldring et al. demonstrated that the periprosthetic membranes were capable of producing collagenase and prostaglandin E2, a powerful stimulator of bone resorption in vivo (Goldring et al., 1986). Polymethylmethacylate (PMMA) was proposed as a cause for osteolysis and loosening and the term "cement disease" was introduced (Jones & Hungerford, 1987). However, the problems of osteolysis and aseptic loosening persisted after the implementation of improved cementing techniques and cementless implants. This led researchers and clinicians to propose other causes for osteolysis and subsequent loosening such as polyethylene and metal debris.

The first ceramic-on-ceramic (CoC) total hip arthroplasty was developed by Boutin in 1970 (Boutin, 1971, Boutin & Blanquaert, 1981). The main advantages of ceramics are its superior wear characteristics and biocompatibility, along with better corrosion resistance compared to metallic alloys. Initially, application of ceramics in total hip arthroplasty

Evidence Linking Elevated Oxidative Stress and Aseptic Loosening of Hip Arthroplasty 299

100 times more wear debris particles than CoCr/UHMWPE bearings (Doorn et al., 1999, Firkins et al., 2001). As a result of increased biological activity of the smaller metal particles different problems from those of MoPE bearings emerged. Adverse reactions to metal debris have been reported to be a cause of pain in metal-on-metal hip arthroplasty (Wynn-Jones et al., 2011) and potential carcinogenesis raised concerns (Keegan et al., 2007). Two important features determine the survivorship of each type of metal implant: metallurgy and implant design. They are interrelated and determine the biological response to an implant and the survivorship of THA. The properties of the bearing surface are dependent on the manufacturing process. This will result in different wear pattern and metal ion release

Large femoral heads used with MoM bearing have certain advantages: allow accelerated rehabilitation, good range of motion, lesser possibility for impingement, greater intrinsic stability. However, MoM bearing is very sensitive to improper surgical technique. Suboptimal or improper positioning of the components of the arthroplasty leads to impingement, edge loading, reduced clearance that subsequently results in elevated

After the drawback of implant fracture in the 1970's and early 1980's, the very low wear rate of ceramic materials renewed interest in developing new designs of CoC bearings for clinical use in the 1990's. Ceramics are brittle, polycrystalline hard bodies, characterized with high hardness and friction endurance. Particles produced by CoC articulations are considered biologically inert and could reduce the rate of osteolysis observed with conventional PE bearings. Despite their brittleness, ceramic materials have several tribological properties, including hardness, which contribute to wear and scratch resistance (Kurtz, 2004). There are three types of ceramics that are of interest in THA, including alumina, zirconia, and alumina matrix composites (Kurtz, 2004). The strength of the ceramics depends on the size of the alumina or zirconia powder grains and the distribution of internal defects, as well as on its composition (i.e., percentage of alumina versus zirconia). Advances in technology with diminishing of grain size have resulted in improved strength. However, the survival of the CoC hip arthroplasty is highly dependent on surgical implantation technique. This articulation is less forgiving than conventional UHMWPE bearing to improper positioning of the components with a subsequent risk of fracture. Although fracture risk is low, it continues to be an issue of debate among orthopedic surgeons. Another potential problem is chipping of the liner that occurs with impingement

Biomechanical studies show excellent wear resistance of ceramic bearings. However, clinical studies do not show significant advantage of ceramics compared to polyethylene. In two randomized studies, an alumina-on-alumina bearing was compared with cobalt-chrome-onpolyethylene bearing (Bierbaum et al., 2002, Capello et al., 2005). There was no significant

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

(Catelas et al., 2003).

production of metal wear debris.

**2.4 Ceramics in hip arthroplasty** 

or during insertion with improper placement.

difference in clinical outcome between CoC and MoPE bearings.

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

exclusively included use of alumina (Al2O3) (Boutin & Blanquaert, 1981). In the late 1980s, alumina was replaced with zirconia (ZrO2) due to its superior strength and toughness as compared with alumina (Willmann, 1998). Drawback of ceramic materials used for bearing couples is their inherently lower strength and toughness under tension and bending. Fracture of the ceramic bearing component is the main mode of failure that occurs even with modern ceramic composites.
