Characterisation of wear debris from UHMWPE on zirconia ceramic, metal-on-metal and alumina ceramic-on-ceramic hip prostheses generated in a physiological anatomical hip joint simulator

Wear 250 (2001) 120–128

Characterisation of wear debris from UHMWPE on zirconia ceramic, metal-on-metal and alumina ceramic-on-ceramic hip prostheses generated in a physiological anatomical hip joint simulator J.L. Tipper a,∗ , P.J. Firkins b , A.A. Besong b , P.S.M. Barbour b , J. Nevelos b , M.H. Stone c , E. Ingham a , J. Fisher b,1 b

a Medical and Biological Engineering (MBE), Division of Microbiology, University of Leeds, Leeds LS2 9JT, UK Medical and Biological Engineering (MBE), School of Mechanical Engineering, University of Leeds, Leeds LS2 9JT, UK c Department of Orthopaedic Surgery, Leeds General Infirmary, Leeds LS1 3EX, UK

Abstract There is currently much interest in the characterisation of wear debris from different types of artificial hip joints. There have been numerous studies on the wear of UHMWPE in hip joint simulators, but relatively few studies on the wear of alternative materials such as metal-on-metal (MOM) and ceramic-on-ceramic (COC). The aim of this study was to compare the wear volumes and wear debris generated from zirconia ceramic-on-UHMWPE, MOM and COC hip joints under identical conditions in the same hip joint simulator. All prostheses showed an initial higher ‘bedding in’ wear rate, which was followed by a lower steady state wear rate. The zirconia ceramic-on UHMWPE prostheses showed the highest wear rates (31 ± 4.0 mm3 /million cycles), followed by the MOM (1.23 ± 0.5 mm/million cycles), with the COC prostheses showing significantly (P < 0.01) lower wear rates at 0.05 ± 0.02 mm3 /million cycles. The mode (±95% confidence limits) of the size distribution of the UHMWPE wear debris was 300 ± 200, 30 ± 2.25 nm for the metal particles, and 9 ± 0.5 nm for the ceramic wear particles. The UHMWPE particles were significantly larger (P < 0.05) than the metal and ceramic wear particles, and the metal particles were significantly larger (P < 0.05) than the ceramic wear particles. A variety of morphologies and sizes were observed for the UHMWPE wear particles, including submicrometer granules and large flakes in excess of 50 ␮m. However, the wear particles generated in both the MOM and COC articulations were very uniform in size and oval or round in shape. This investigation has demonstrated substantial differences in volumetric wear. The in vitro wear rates for the zirconia-on-UHMWPE and MOM are comparable with clinical studies and the UHMWPE and metal wear particles were similar to the wear debris isolated from retrieved tissues. However, the alumina/alumina wear rate was lower than some clinical retrieval studies, and the severe wear patterns and micrometer-sized particles described in vivo were not reproduced here. This study revealed significant differences in the wear volumes and particle sizes from the three different prostheses. In addition, this study has shown that the alternative bearing materials such as MOM and COC may offer a considerable advantage over the more traditional articulations which utilise UHMWPE as a bearing material, both in terms of wear volume and osteolytic potential. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Wear; Wear debris; Hip prostheses; Simulation

1. Introduction Aseptic loosening is the primary cause of failure of total hip replacements (THRs), and accounts for almost three-quarters of all revision operations [1]. Aseptic loosening has been strongly linked with ultra high molecular weight polyethylene (UHMWPE) wear debris-induced osteolysis [2–6], and since the occurrence and severity of ∗ Corresponding author. Tel.: +44-113-2335-611; fax: +44-113-2335-638. E-mail addresses: [email protected] (J.L. Tipper), [email protected] (J. Fisher). 1 Tel.: +44-113-2332128; fax: +44-113-2424611.

osteolysis appears to be related to the size and volume concentration of wear particles [7], it follows that reducing the quantity and generation rate of wear particles should reduce the occurrence of long-term aseptic loosening. The majority of THRs implanted at the present time comprise a metal femoral head manufactured from either cobalt chrome or stainless steel, which articulates on an UHMWPE acetabular cup. Scratch damage to metal femoral heads has been shown to significantly increase the wear rate of UHMWPE, in both in vitro testing and in vivo [8,9]. Therefore, it is believed that the use of scratch-resistant ceramic femoral heads would reduce the wear rate of UHMWPE and have a beneficial effect on osteolysis. Prostheses using alumina and

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zirconia femoral heads articulating on UHMWPE acetabular cups have been used clinically since 1975, and in vivo wear rates of UHMWPE have been shown to be reduced by 50% compared to UHMWPE-on-metal articulations [10]. It has also been shown that alunima femoral heads produce less UHMWPE wear and are more resistant to scratching in vitro [11]. Another approach to the problem caused by UHMWPE wear particles has been to use alternative bearing surfaces, such as metal-on-metal (MOM) and ceramic-on-ceramic (COC). Some of the first-generation McKee–Farrar MOM hip prostheses were clinically successful for 20 years or more [12]. In addition, second-generation MOM hip prostheses have demonstrated low wear rates when compared to metal-on-polyethylene in in vitro testing [13]. Short-term clinical performance of these second-generation MOM prostheses has been encouraging, with reports of mean wear rates as low as 0.3 mm3 per year [14–18]. The wear rate of first-generation MOM hip prostheses was reported to be 1–6 mm3 per year, compared to 30–100 mm3 for traditional metal on polyethylene hips [19–21]. Amstutz and Grigoris [22] also reported wear volumes, which were 40–100 times lower with MOM prostheses, compared to metal-on-polyethylene hip prostheses. However, a low wear volume in itself is not the only important factor governing the long-term clinical outcome of a THR. The size, morphology and biological response to any wear particles released are also important. Recent studies have shown that the wear particles generated in MOM prostheses are in the nanometer size range [23–25]. Consequently, the number of particles produced in a MOM articulation may exceed the number of UHMWPE particles, despite the low wear volumes. Doorn et al. [23] isolated and characterised metal wear particles from the periprosthetic tissues from first and second-generation MOM hip prostheses. The particles were in the size range 51–116 nm, and were mainly round in shape. These authors estimated that between 6.7 × 1012 to 2.5 × 1014 particles would be produced per year, 13–500 times more particles than the 5 × 1011 UHMWPE particles produced per year in a typical metal-on-polyethylene prosthesis [23]. The small size of the particles gives rise to large numbers of particles, even for wear volumes as low as 1 mm3 per year. In addition, there exists considerable discussion over the possible distribution of these small particles in the body, and their biological effects on cells and tissues. Metal particles have been shown to be disseminated throughout the body and have been found in the lymph nodes, liver, spleen, and bone marrow [26–29]. Little is known about their long-term systemic effects. It is still not clear whether osteolysis occurs around MOM prostheses. The new generation MOM prostheses have not been associated with osteolysis [17]; however, the results of long-term implantation are at this time unknown. Schmalzried et al. [30] studied a series of McKee–Farrar hips, some of which had been implanted for 30 years, and found the incidence of osteolysis to be 4% for the whole series. This compared

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favourably to metal-on-polyethylene hips, but indicated that MOM prostheses may not eliminate osteolysis in the longer term. In general, histological studies of periprosthetic tissues have not shown an inflammatory reaction to metal wear particles, but areas of tissue necrosis have been associated with small amounts of visible metal particles [17,23,31]. There have been many studies on the effect of micrometer sized metal wear particles on cells in vitro [32–35], however, the effect of nanometer sized particles has not been studied, and the relevance of the studies using the larger particles is debatable. Nevertheless, the current MOM bearings are showing considerable potential as an osteolysis-free solution for younger patients. Ceramic-on-ceramic hip prostheses have been used clinically for a number of years. The wear rates of retrieved prostheses are generally much lower than for polyethylene bearings, and of the order of 1 mm3 per year [36]. However, occasional cases of higher, more severe wear have been reported. Under ideal conditions in the laboratory extremely low wear rates of 0.01–0.1 mm3 /million cycles have been reported [37,38]. Attention is now focused on understanding the difference between laboratory and ex vivo wear rates, and attempting to investigate the causes of more severe wear in isolated cases in vivo. Ceramic wear particles have been reported to be in the nanometer size range, however, larger particles up to 1 ␮m have also been found in ex vivo specimens [39]. There is a limited amount of data available in the literature on the biological responses to ceramic wear particles. In its bulk form alumina is chemically inert, and this was one of the factors that influenced its selection as a bearing material. Recently, evidence of wear debris-induced osteolysis has been reported in a series of COC Mittelmeier hip prostheses [40]. Histological examination of the periprosthetic tissues from around revised Mittelmeier hip prostheses revealed abundant ceramic wear debris with a mean size of 0.71 ␮m (range 0.13–7.2 ␮m). In addition, Hatton et al. [41] reported that alumina particles with a mean size of 0.5 ± 0.19 ␮m (±S.D.) induced the production of TNF-␣ from peripheral blood mononuclear cells in vitro. To date, the biological activity of the nanometer sized wear particles has not been determined. Nevertheless, with in vivo wear rates of approximately 1 mm3 per year, COC couples offer considerable potential as an osteolysis-free solution for young patients. There have been a number of studies of polyethylene wear in hip joint simulators [42–49], however, different designs of simulator together with the application of different loads and motions means that results are often difficult to compare directly. In addition, relatively few studies on the wear of alternative materials such as MOM and COC prostheses have been performed. To date no direct comparison of the wear debris generated from these three different materials has been reported. The aim of this study was to compare the wear volumes and wear debris generated from three different types of hip prosthesis under identical conditions in a hip joint simulator.

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2. Materials and methods Three types of hip prosthesis were studied: (1) zirconia ceramic femoral heads on UHMWPE GUR 1120 acetabular cups (␥ irradiated with 2.5 Mrads in air); (2) low carbon (0.07%) wrought cobalt chrome alloy (ASTM F1537) femoral heads on high carbon (0.2%) wrought cobalt chrome alloy (ASTM F1537) acetabular cups, as described previously by Firkins et al. [50]; medical grade HIPed ‘BIOLOX Forte’ alumina ceramic femoral heads (CeramTec AG; ISO 6474) on medical grade HIPed ‘Biolox Forte’ alumina ceramic (CeramTec AG; ISO 6474) acetabular cups. All prostheses had 28 ␮m diameter heads and three prostheses of each type were tested. A physiological hip joint simulator was used with the cup in the superior position to the head and inclined in the anatomical position between 45 and 60◦ to the vertical axis. A single axis twin peak Paul type loading curve [51] was applied through the vertical axis of the cup. Two directions of motion were applied, flexion-extension (+30 and −15◦ ) and internal–external rotation (±10◦ ). The motions were 90◦ out of phase such that an open elliptical wear track was generated between the components. These conditions have previously been shown to reproduce similar wear rates and features as when three independently controlled loads and motions were applied to UHMWPE cups [52]. All simulator tests were performed at a frequency of 1 Hz in 25% (v/v) bovine serum (Harlan Sera-Lab Ltd., UK) plus 0.1% (w/v) sodium azide, which was added to retard bacterial growth. For the MOM and COC prostheses, wear volumes were determined gravimetrically every million cycles to 5 million cycles. Prior to weighing, the femoral heads and acetabular cups were cleaned with a mild detergent, followed by ultrasonic cleaning with isopropanol, to allow accurate measurement of wear and surface topography. The first million cycles represented ‘bedding in’ wear, as has been described previously for hard-on-hard bearings [53,54]. For the UHMWPE-on-zirconia ceramic prostheses, changes in shape and volume of the acetabular cups were determined using a three-dimensional co-ordinate measurement machine (CMM; Kemco, UK). The volume changes due to both creep and wear were monitored every half million cycles up to 5 million [55]. The surface roughness of the femoral heads was measured before and after testing using contacting Form Talysurf (Taylor Hobson Ltd., Leicester, UK) or non-contacting surface profilometry (UBM Messtechnik GMBH, Ettlinggen, Germany). The initial surface roughness (Ra ) was between 0.005 and 0.008 ␮m for all femoral heads, regardless of material. The diametral clearances of the MOM components were between 58 and 62 ␮m, and between 40 and 60 ␮m for the COC prostheses. In addition, the bearing surfaces of the alumina COC prostheses were analysed using a WYKO NT2000 white light interferometer after 2 and 5 million cycles. UHMWPE wear debris was isolated from the serum using a method described previously by Besong et al. [56].

Briefly, an aliquot of serum was digested with 12 M potassium hydroxide for 48 h at 60◦ C. Contaminating proteins and lipids were removed by the addition of an equal volume of chloroform:methanol (2:1) followed by centrifugation at 2000 × g for 10 min at room temperature. Any remaining proteins were removed by precipitation with ice-cold absolute ethanol followed by centrifugation at 2000 ×g for 2 h at 4◦ C. Polyethylene wear debris was recovered by sequential filtration on to 10 and 0.1 ␮m cyclopore membranes (Whatman International, UK). A section of each filter was sputter coated with gold and observed using scanning electron microscopy (SEM; Hitachi S700). Representative photographs were taken at magnifications of 200–20,000 times. Metallic and ceramic wear particles were characterised by transmission electron microscopy (TEM). An appropriate volume of serum (60–100 ml) was centrifuged (12000 × g, 10 min) to pellet the wear particles and the supernatant was discarded. The pellet was fixed in 2.5% (v/v) glutaraldehyde in 0.1 M phosphate buffered saline (PBS) at pH 7.4 for 2 h at 4◦ C. The samples were then washed three times in 0.1 M PBS for 2 h at 4◦ C, and fixed in 1% (w/v) osmium tetraoxide for 1–2 h at 4◦ C. The samples were washed in 0.1 M PBS for 15 min and dehydrated through graded ethanol (70, 90 and 100% (v/v)) at room temperature for 10–20 min. The samples were polymerised in araldite resin for 20–24 h at 70◦ C and 100 nm sections were cut using an LKB ultramicrotome fitted with a diamond knife. The sections were transferred to copper grids for staining with lead nitrate and sodium citrate for 1–2 min. The samples were double stained with 15% (v/v) uranyl acetate. The sections were observed using a Jeol 1200 EX transmission electron microscope and representative photographs of the wear debris were taken at magnifications of 25–75 K times. All wear debris was characterised using digital image analysis (Image Pro Plus, Media Cybernetics, USA) using mean maximum diameter or length measurements. A minimum of 100 particles per sample were measured by image analysis. Statistical analysis of the results was carried out using single classification analysis of variance (ANOVA).

3. Results The wear scars on the heads and cups for the zirconia-onUHMWPE and MOM were located in the superior quadrant, as found clinically. The majority of the wear for the MOM articulations occurred on the low carbon cobalt chrome heads (3:1). Some deep scratches (>1 ␮m) were observed on the low carbon heads, possibly caused by carbides which were present in the high carbon cups. A thin layer of calcium phosphate deposit was observed on all components from the MOM pairings, which made accurate surface analysis by contacting profilometry very difficult. No change in surface roughness was detected for the alumina ceramic components and very few wear features were observed using three-dimensional contacting profilometry. However, when

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Table 1 Volumetric wear rates of the three prosthesis types tested Material combination

UHMWPE/zirconia (n = 3) Cobalt chrome/cobalt chrome (n = 3) Alumina/alumina (n = 3)

Wear rate (mm3 /million cycles) ± 95% confidence limits Initial

Steady state

53 3.1 0.12

31 ± 4.0 1.23 ± 0.5 0.05 ± 0.02

Fig. 1. Scanning electron micrographs of UHMWPE wear particles generated from the zirconia ceramic-on-UHMWPE prostheses in the hip simulator. Sections of filter membrane were sputter coated with gold and observed at 20 kV. (a) Submicrometer granules of UHMWPE isolated on a 0.1 ␮m filter membrane, bar 0.5 ␮m. (b) A large flake-like particle isolated on the 10 ␮m filter membrane, bar 50 ␮m.

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Fig. 2. Transmission electron micrograph showing nanometer-sized metal wear particles generated from the MOM articulations in the hip joint simulator, bar 100 nm, voltage 80 kV.

the wear surfaces were subjected to closer inspection using a WYKO NT2000 white light interferometer, small scale pitting and short curved scratches were visible in the contact areas of both heads and cups The pitting may have been caused by small scale grain removal, and the scratches by third body wear. Polishing marks from manufacture were also visible on the surfaces. The zirconia ceramic heads also remained undamaged after testing. SEM of the worn surfaces of the UHMWPE cups revealed areas of localised adhesive wear and fatigue damage. The volumetric wear rates for the three materials are shown in Table 1. The initial ‘bedding in’ wear was always higher than the steady state wear for each type of prosthesis. For the UHMWPE cups the initial ‘bedding in’ wear also included creep deformation. The

zirconia ceramic-on-UHMWPE had the highest wear rate at 31 mm3 /million cycles, and the alumina COC the lowest at 0.05 mm3 /million cycles. There was at least one order of magnitude difference in the wear rates of each prosthesis type, which was highly significant (P < 0.01). Wear particles above 100 nm for the UHMWPE and above 2 nm for the MOM and COC were successfully characterised. The mode (±95% confidence limits) of the size distribution for the UHMWPE debris was 300 ± 200, 30 ± 2.25 nm for the metal particles, and 9 ± 0.5 nm for the ceramic wear particles. The UHMWPE particles were significantly larger (P < 0.05) than the metal and ceramic particles, and the metal particles were significantly larger than the ceramic particles (P < 0.05). The UHMWPE

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Fig. 3. Transmission electron micrograph showing nanometer-sized ceramic wear particles generated from the COC articulations in the hip joint simulator, bar 100 nm, voltage 80 kV.

particles generated in the zirconia ceramic-on-UHMWPE articulations and characterised by SEM are shown in Fig. 1. Metal and ceramic particles characterised by TEM are shown in Figs. 2 and 3, respectively. One of the most striking differences between the wear particles generated in the different prostheses was that the UHMWPE wear particles ranged in size from 100 to 50,000 nm. UHMWPE particles were not detected below 100 nm, however, particles in this size range may exist, even though the techniques currently employed in the isolation of UHMWPE wear particles from serum and tissues do not allow isolation of particles smaller than 100 nm. A variety of particle morphologies were observed from submicrometer granules (Fig. 1a) to large flakes or shards in excess of 50 ␮m (Fig. 1b). In contrast, the wear particles generated in both the MOM and COC couples were very uniform in both size and morphology. The metal particles were 30 ± 5 nm (range 9–66 nm) in size, and the majority of the metal particles shown in Fig. 2 were oval to round in shape and appeared as electron dense aggregates or clumps of particles. The particles generated in the COC

Fig. 4. Frequency distribution (mean ± S.E.) of the UHMWPE particles generated in the zirconia ceramic-on-UHMWPE articulations in the hip joint simulator. Less than 0.1% of the particles were >10 ␮m in length, and therefore were not included.

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Fig. 5. Mass distribution (mean ± S.E.) of the UHMWPE particles as a function of size generated in the zirconia ceramic-on-UHMWPE articulations in the hip joint simulator.

couples were even smaller at 9 ± 0.5 nm (range 2–27.5 nm) and were also oval to round in appearance. These particles also appeared as electron dense aggregates when viewed using TEM (Fig. 3). The wear particles from the UHMWPE-on-zirconia ceramic were also quantitatively analysed. The mode of the frequency distribution of particle size was in the 0.1–0.5 ␮m size range (Fig. 4). The mass distribution with respect to size is shown in Fig. 5. The majority of the mass, 73 ± 2.42% (mean ± S.E.) was composed of particles that were smaller than 10 ␮m in size.

4. Discussion and conclusions This investigation of the wear of three different prostheses under identical conditions in the same simulator has demonstrated substantial differences in volumetric wear. The in vitro wear rates for the zirconia-on-UHMWPE and MOM are in agreement with clinical studies [10] and the UHMWPE and metal wear particles were similar to the wear debris isolated from retrieved tissues [9,23]. The alumina/alumina wear rate was lower than some clinical retrieval studies, and the severe wear patterns found in vivo [36] were not reproduced here. The alumina material used in this study was hot isostatically pressed (HIPped), which has a smaller grain size, lower porosity and higher density than previous materials. When this material was introduced clinically in 1995, the manufacturers claimed that this material wore less than earlier materials. At present there is little clinical experience with retrieved HIPped ceramic couples to compare with this simulator data, and therefore, comparisons are made with the higher wearing non-HIPped ceramic materials. Ceramic wear particles as large as 1000 nm have been identified in vivo [39], whereas the ceramic particles generated in vitro from the HIPped material were closer to 10 nm. It has been suggested that the wear mechanisms of the two materials may differ [57], with the older non-HIPped material experiencing grain boundary

fracture and grain pull-out as the main wear mechanisms, which may be responsible for the larger particles seen clinically [39]. However, it is more likely that the causes of the differences between in vivo and in vitro wear rates and wear debris, are due to the different biomechanical conditions that can occur in vivo, in particular micro-separation of the head and cup that can lead to rim contact and head damage. Further studies from our group, which introduced micro-separation into in vitro simulations, have reproduced the higher clinical wear rates and head damage [58]. The biological effects of UHMWPE wear debris have been well documented [2–6], and although the use of zirconia femoral heads produced lower wear volumes of UHMWPE than metal femoral heads, both in vitro (31 mm3 /million cycles compared to 35–45 mm3 /million cycles) [52] and clinically [10], the volumetric particle load is still considerable. The majority of the UHMWPE wear debris isolated in this study was shown to be in the biologically active size range, with 73% of particles (by mass) in the 0.1–10 ␮m size range. Previous studies have shown that particles in the 0.2–10 ␮m size range were most biologically active, and stimulated macrophages to produce high levels of the pro-inflammatory cytokine TNF-␣ [59]. The wear particles generated in the MOM and COC articulations in this study were in the nanometer size range. Consequently, the number of particles produced in a MOM or COC articulation may exceed the number of UHMWPE particles, despite the low wear volumes, and although the number of particles is an important factor, it is more likely that the volumetric concentration of wear particles will be more important. As a result, the significantly lower wear volumes of the MOM and COC articulations may confer a significant advantage over the more traditional articulations, which utilise UHMWPE as a bearing surface. There is evidence to suggest that particles in the nanometer size range are not taken up by phagocytosis, but by pinocytosis, a mechanism which fails to activate the inflammatory reaction linked to UHMWPE wear debris uptake [60]. Metal particles in the nanometer size range may produce necrosis of the tissues if sufficient volume is generated and accumulated in the periprosthetic tissues [60]. Clinical studies indicate that this is likely to be associated with volumetric wear rates greater than 1 mm3 as recorded in this study. The biological effect of nanometer-sized alumina ceramic particles is unclear. Hatton et al. [41] showed that commercially produced alumina ceramic particles 0.5 ␮m in size stimulated the production of TNF-␣ from peripheral blood mononuclear cells, all be it at a reduced level compared to that observed with UHMWPE particles of the same size and volumetric concentration. More recently it has been shown that when a mixed population of nanometer and micrometer-sized alumina wear particles were co-cultured with primary human mononuclear cells, the level of TNF-␣ produced was lower than with the commercially produced alumina [61]. This indicated that ceramic wear particles were less biologically active than UHMWPE wear particles, and moreover, as

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wear volumes produced in COC prostheses can be up to 4000-fold lower, the volume of ceramic particles in vivo may not reach sufficiently high enough levels to elicit an inflammatory response. Hence the incidence of osteolysis and loosening of the ceramic implants may well be considerably lower. However, in the severe wear cases seen in vivo [40] the alumina particle load may reach the necessary threshold to cause osteolysis and loosening. This study has revealed significant differences in the wear volumes and particle sizes from the three different prostheses, however, there is a need to determine the biological activities of these wear particles at functional concentrations to allow prediction of the relative functional biocompatibilty and osteolytic potential of these different types of bearing surfaces. From theses studies it is postulated that the UHMWPE wear particles will have the highest biological activity, as the majority of the particles produced were smaller than 10 ␮m in size, and these particles produced high levels of TNF-␣ release from primary human mononuclear cells. Clinically relevant alumina ceramic wear particles have been shown to be less biologically active than polyethylene particles, and this coupled with dramatically reduced wear volumes means that the osteolytic potential of COC hip prostheses is much lower than ceramic-on polyethylene or metal hip prostheses. As yet the nature of the biological activity of the nanometer-sized metal wear particles is unclear, however, preliminary data from our laboratory suggests that these particles are toxic to human macrophages and fibroblasts at elevated concentrations in vitro, and therefore may produce tissue necrosis when wear is high. However, the osteolytic potential of MOM hip prostheses is believed to be far lower than the traditional metal-on-polyethylene hip prostheses. This study has shown that the alternative bearing materials such as MOM and COC may offer a considerable advantage over the more traditional articulations which utilise UHMWPE as a bearing material, both in terms of wear volume and osteolytic potential.

Acknowledgements The work reported in this paper was performed in independent studies supported by Depuy International, a Johnson and Johnson Company, the EPSRC, the Arthritis Research Campaign and Stryker International Research and Development.

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