**1. Introduction**

294 Recent Advances in Arthroplasty

[91] Mesko, J. W., D'Antonio, J. A., Capello, W. N., Bierbaum, B. E. & Naughton, M.

[92] Yoon, TR, Rowe SM, Jung ST, Seon KJ, Maloney WJ. Osteolysis in association with a

[93] Nam KW, Yoo JJ, Lae Kim Y, Kim YM, Lee MH, Kim HJ. Alumina-debris-induced

[94] Jarrett, C. A. *et al.* The squeaking hip: a phenomenon of ceramic-on-ceramic total hip

[95] Fowles, J., Bunker, J. P. & Schurman, D. J. Hip surgery data yield quality indicators.

[96] Espehaug, B., Havelin, L. I., Engesaeter, L. B. & Vollset, S. E. The effect of hospital-type

[97] McKellop HA, D'Lima Darryl. How have wear testing and joint simulator studies

[98] Bragdon CR, Jasty M, Greene M, Rubash HE, Harris WH. Biologic fixation of total hip

[99] Bechtold JE, Kubic V, Soballe K. Bone ingrowth in the presence of particulate

[101] Mulroy RD, Harris WH. The effect of inproved cementing techniques on component

[102] Stauffer RN. Ten year results of second generation femoral cementing in total hip

[103] Stauffer RN. Ten year follow up study of total hip replacement. J Bone Joint Surg Am

[104] Barrack RL, Mulroy RD, Harris WH. Improved cementing techniques and femoral

[105] Davies JP, Jasty M, O'Connor DO, Burke DW, Harrigan TP, Harris WH. The effect of

centrifuging bone cement. J Bone Joint Surg Br 1989; 71: 39-42.

periprosthetic tissue response. J Bone Joint Surg Br 2002; 84: 915-919. [100] Herberts P, Malchau H. Long-term registration has improved the quality of hip

report. J Bone Joint Surg Am 2007; 89: 2499-2503.

1988-1996. *Acta Orthop Scand* 70, 12-18 (1999).

j.arth.2010.04.029 (2011).

JBJS.F.00970 (2009).

*Bus Health* 4, 44-46 (1987).

2008; 16 (suppl 1): S111-S119.

2004; 86 (suppl 2): 105-117.

Orthop Scand 2009; 71: 111-121.

Total Hip Surgery. Cambridge, MA, Oct, 1991.

Surg Br 1990; 72: 757-760.

1982; 7: 983-990.

1992; 74: 385-389.

1459-1468.

Ceramic-on-ceramic hip outcome at a 5- to 10-year interval: has it lived up to its expectations? *J Arthroplasty* 26, 172-177, doi:S0883-5403(10)00261-5 [pii]10.1016/

total hip arthroplasty with ceramic bearing surfaces. J Bone Joint Surg Am 1998; 80:

osteolysis in contemporary alumina-on-alumina total hip arthroplasty. A case

arthroplasty. *J Bone Joint Surg Am* 91, 1344-1349, doi:91/6/1344 [pii] 10.2106/

and operating volume on the survival of hip replacements. A review of 39,505 primary total hip replacements reported to the Norwegian Arthroplasty Register,

helped to discriminate among materials and designs? J AM Acad Orthop Surg

implants: Insights gained from a series of canine studies. J Bone Joint Surg Am

polyethylene: Synergy between interface motion and particulate polyethylene in

replacement. A review of the Swedish THR Register comparing 160,000 case. Acta

loosening in total hip replacement: An 11-year radiographic rebiew. J Bone Joint

replacement surgery. Read at the Harvard Medical School Postgraduate Course on

component loosening in young patients with hip arthroplasty. J Bone Joint Surg

Aseptic loosening is still the most common late complication after total hip arthroplasty (THA) and one of the main reasons for its failure. Artificial joints are made of metallic, polymeric and ceramic components. In the process of prosthesis functioning in the recipient's body implant materials are subject to wear and fretting as well as of influence of aggressive biological fluids. Wear debris particles, corrosion products and metal ions from the bearing and contact surfaces of the implant are released in the periprosthetic tissues. As a result of the processes taking part at the implant-bone interface osteolysis develops with subsequent loosening of the implant.

Today, the most widely used bearing surface is a metal femoral head made of cobalt chromium molybdenum alloy coupled with a polymeric inlay fabricated from ultra-high molecular weight polyethylene (UHMWPE). For decades in clinical use, metal on polyethylene (MoPE) bearings in total hip arthroplasty provided consistent results. Despite the widespread use of UHMWPE as a bearing surface its wear is the main obstacle restricting the longevity of the artificial joint. With an average rate of polyethylene (PE) wear of 0.1mm per year, 100 million UHMWPE particles (assumed diameter of 1 μm) are liberated into the joint space on a daily basis (Muratoglu & Kurtz, 2002). It is now well established that cyclic mechanical loading, production of wear particles, and the ensuing cascade of adverse tissue response are all significant contributors to local osteolysis at the prosthesis–bone interface and in certain cases loosening of the prosthesis (Aspenberg & Herbertsson, 1996, Goldring et al., 1986, Schmalzried et al., 1992, Willert & Semtlitsch, 1977). Deterioration of clinical results with time and eventually revision of the arthroplasty were a very strong impetus for the search for the "ideal bearing" (Muratoglu & Kurtz, 2002). Improving longevity of the total hip arthroplasty by engineering of new bearing couples with improved biomechanical characteristics and lower rate of wear has been the main line of ongoing research in the orthopedic community. Today, orthopedic surgeons have a wide choice of implants and bearing couples for a particular patient. The new generation of joint bearings provides significantly lower wear rates and is anticipated to diminish the incidence of osteolysis and subsequent revisions.

Evidence Linking Elevated Oxidative Stress and Aseptic Loosening of Hip Arthroplasty 297

Materials are very important for the long-term success of THA. Since the introduction of low friction arthroplasty (LFA) by Sir John Charnley in the 1960's, much has been learned about the durability and biocompatibility of materials used in joint replacement. Concerns about higher rates of aseptic loosening and subsequent prosthesis revision among young and active patients have lead to the development of new implant designs and alternative bearings (Muratoglu & Kurtz, 2002). Strength and endurance, friction and wear properties, inertness and biocompatibility of the materials should be optimized in order to eliminate or

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

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

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

diminish to a negligible extent the reaction of the organism to wear debris.

**2. Materials for bearings of hip prostheses** 

**2.1 Brief historical remarks** 

polyethylene and metal debris.

& Kurtz, 2002).

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 implant as long as wear particles are produced.

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

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 loosening of THA are still to be elucidated.

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