The Crosslinked Ultra-high Molecular Weight Polyethylene

The Crosslinked Ultra-high Molecular Weight Polyethylene Fu-Wen Shen Ph.D. and Harry McKellop, Ph.D. The J Vernon Luck Orthop Research Center, Orthopaedic Hospital/University of California Los Angeles, Correspondence addresses: Dr. Fu-Wen Shen The J Vernon Luck Orthop Research Center, Orthopaedic Hospital/University of California Los Angeles, 2400 South Flower Street, Los Angeles, CA 90007 USA FSHEN@laoh.ucla.edu

INTRODUCTION The majority of total hip prostheses implanted in the past three decades have included an acetabular cup of ultrahigh molecular weight polyethylene (UHMWPE) articulating against a femoral ball of cobalt-chromium alloy. Wear of the polyethylene bearing surfaces of prosthetic hip joints produces billions of sub-micron wear particles annually [1], often causing a foreign body response that may lead to bone resorption (osteolysis) and loosening of the components, and thereby limiting the life expectancy of hip prostheses. This is of particular concern for young and/or active patients, who may face one or more revisions, with cumulative bone loss, in their lifetime. Thus, improving the wear resistance of the polyethylene can substantially extend the clinical life span of total hip prostheses. During the past three decades, the majority of polyethylene components were sterilized by gamma irradiation in air at doses between 2.5 and 4 Mrads. However, oxygen that was present in the polyethylene when it was irradiated, or that diffused into the polyethylene during shelf storage and/or in vivo, could react with the free radicals that were generated by the radiation, causing oxidative degradation that lowered the molecular weight, increased the density, stiffness and brittleness, and reduced the fracture strength and elongation to failure [2-3]. Any of these changes could adversely affect the wear resistance of the polyethylene [4-6]. In contrast, if little oxygen was present, the free radicals generated during radiation sterilization could form carbon-carbon crosslinks between adjacent polyethylene molecules [7], and crosslinking has been shown to markedly improve the wear resistance of polyethylene acetabular cups in laboratory wear simulators [8-20] and in clinical studies [21-25]. In order to retain the potential benefits of gamma-induced crosslinking and to minimize the detrimental effects of oxidation during sterilization and subsequent shelf storage, several manufacturers began gamma-sterilizing polyethylene components in a lowoxygen atmosphere. However, free radicals remained in the polyethylene that could lead to in vivo oxidation. Other manufacturers have chosen to sterilize without irradiation, using ethylene oxide or gas plasma. Although sterilization without radiation avoids the problem of oxidation of the free radicals, it also eliminates any improvement of the wear resistance that might be conferred by radiation-induced crosslinking. Consequently, orthopaedic researches were directed to the development of an UHMWPE implant that has the resistance to oxidation of the non-irradiation sterilized polyethylene while possesses optimum level of crosslinking to improve its wear resistance. 73

CLINICAL STUDIES OF POLYETHYLENES WITH ELEVATED CROSSLINKING Polyethylene cups that were intentionally crosslinked at levels much higher than occurs with radiation sterilization (2.5 4 Mrads) were used in three clinical studies. Grobbelaar and colleagues [21,22] crosslinked finished polyethylene cups with 10 Mrads of gamma radiation. By irradiating the cups in the presence of acetylene gas, crosslinking in the surface layer (~300 microns) was substantially increased above what would normally occur at 10 Mrads. No post-irradiation thermal treatment was done to reduce residual free radicals. In a 14-to-20-year follow-up based on radiographs, Grobbelaar and colleagues [22] reported a lack of measurable wear in 56 out of 64 cases and only two revisions due to osteolytic loosening. Oonishi and colleagues [23,24] crosslinked finished polyethylene cups with 100 Mrads of gamma radiation in ambient atmosphere. As with Grobbelaar s method, no post-irradiation thermal treatment was done to reduce residual free radicals. In an early clinical follow-up, Oonishi and colleagues [23] reported steady-state wear rates of 0.247 and 0.098 mm/yr for noncrosslinked polyethylene cups bearing against CoCr and alumina heads, respectively, and 0.076 and 0.072 mm/yr for 100-Mrad crosslinked polyethylene cups bearing against CoCr and alumina heads, respectively. Recently, in the mean follow up of 17.3 years, Oonishi and colleagues [24] reported that against CoCr femoral heads, the steady-state wear rates averaged 0.29 and 0.06 mm/yr for the noncrosslinked and 100-Mrad crosslinked polyethylene cups, respectively. Wroblewski and colleagues chemically crosslinked polyethylene cups with silane [25]. In a 10- year follow-up, Wroblewski and colleagues reported that after an initial bedding-in period (2 years), the average steady-state wear rate of crosslinked polyethylene against alumina ceramic head was only 0.02 mm/yr. While this wear rate was well below the clinical range for gamma-air cups, it was not clear how much of the advantages was due to the head material rather than crosslinking. Nevertheless, the results of the three clinical studies were encouraging in that, despite any reduction in material strength caused by elevated crosslinking and the lack of thermal treatment to reduce residual free radicals in the gamma-crosslinked polyethylenes, none of the investigators reported fracture or other mechanical failures from the crosslinked polyethylene cups. 74

INTENTIONALLY CROSSLINKED, THERMALLY STABILIZED UHMW POLYETHYLENES In the past few years, a number of laboratory wear simulations have demonstrated that the wear rate of UHMWPE cups decreases markedly with an increasing level of crosslinking [10,12,17]. As shown in Figure 1 [14], the greatest wear reduction per Mrad occurred as the dose increased from zero to about 5 Mrads, with progressively less improvement at higher doses and no additional benefit after 10 to 15 Mrads. Although the baseline wear rate differed among various wear simulators due to systematic differences in the load, sliding distance per cycles and other factors, the dose-wear curve was essentially consistent among different laboratories and with different crosslinking techniques. While the dose-wear relationship was the basis for the recent development of various intentionally-crosslinked UHMW polyethylenes, orthopaedic manufacturers have arrived at different opinions on the optimum dose and processing parameters for optimizing the clinical performance of a crosslinked UHMWPE implant. The fabrication and characteristics of the new, intentionally-crosslinked thermally-stabilized UHMW polyethylenes are summarized in Table [14]. Marathon Gamma-Crosslinked and Remelted Polyethylene In the Marathon process, extruded bars of UHMWPE are crosslinked with 5 Mrads of gamma radiation. The crosslinked bars are then heated to 155 C (above melting temperature) for 24 hours, followed by annealing at 120 C for 24 hours and then slow cooling to room temperature. Because the residual free radicals generated by irradiation are primarily trapped in the crystalline region, heating above the melting temperature enables them to combine each other, forming additional crosslinks and minimizing the potential for long-term oxidation [10,11]. The acetabular cup is then machined from the central portion of the crosslinked-remelted bar, thereby removing the oxidized surface layer, and is sterilized using gas plasma to avoid re-introducing free radicals or increasing the level of crosslinking. Under clean test condition, the Marathon polyethylene has shown about 85% reduction in wear compared with non-crosslinked polyethylene, while against severely roughened femoral balls, Marathon still shows substantially better wear resistance than noncrosslinked polyethylene [11]. XLPE Gamma-Crosslinked and Remelted Polyethylene XLPE is fabricated in similar manner as Marathon, except that the crosslinking dose is 10 Mrads and the final sterilization is done with ethylene oxide. 75

Longevity Electron Beam-Crosslinked and Remelted Polyethylene In the Longevity process, compression molded sheets of UHMWPE are crosslinked at room temperature with a 10 MeV electron beam to a total of 10 Mrads. The crosslinked polyethylene is heated above the melting temperature to extinguish the residual free radicals and machined into acetabular cups and sterilized with gas plasma [26]. Durasul Electron Beam-Crosslinked and Remelted Polyethylene In the Durasul process, the polyethylene is machined into short segments or pucks that are preheated to about 125 C and crosslinked from both sides with a 10 MeV electron beam to a total of 9.5 Mrads. The crosslinked polyethylene is then heated above the melting temperature to extinguish free radicals and machined into cups and sterilized with ethylene oxide [13]. Comparative tests indicated that electron beam crosslinking at warm temperature provided less reduction in elongation to break than that at room temperature [13]. Crossfire Gamma-Crosslinked and Annealed Polyethylene Different from the Marathon process, in which the crosslinked polyethylene is heated above melting temperature to extinguish residual free radicals, in the Crossfire process, extruded bars of UHMWPE are crosslinked with 7.5 Mrads of gamma radiation and then the crosslinked bars are annealed just below the melting temperature for a proprietary duration. Cups are machined out of the crosslinked-annealed bars, packaged in nitrogen atmosphere, and sterilized by exposure to an additional 2.5 to 3.5 Mrads of gamma radiation. After the final gamma sterilization, no thermal treatment is applied to extinguish residual free radicals. Developers of the Crossfire process prefer annealing to remelting of polyethylene on the bases that annealing induces less change in material morphology and properties [27]. Because the residual free radicals are primarily trapped in the crystalline regions that remain in the polyethylene unless it is heated above the melting temperature, annealing (i.e., heating below the melting temperature) is not as effective as remelting (heating above the melt temperature) in extinguishing the residual free radicals. For example, in one study [28], Crossfire polyethylene that was artificially aged at 80 C in air for 3 weeks exhibited substantial oxidative degradation of its strength and wear resistance. In contrast, artificial aging had negligible effect on the wear and mechanical properties of crosslinkedremelted polyethylenes [11]. 76

Aeonian Gamma-Crosslinked and Annealed Polyethylene Except for lower crosslinking dose and annealing temperature, the rationale and processing of Aeonian are similar to those for crossfire. The substantial improvement of wear resistance with the crosslinked UHMWPE (between 5 and 10 Mrads, Fig. 1) would provide a substantial clinical benefit. One clinical review has indicated that significant osteolysis is rare in patients whose polyethylene acetabular cups are wearing linearly less than 0.1 mm per year [5]. In contrast, if the linear wear rate exceeds 0.3 mm per year, osteolysis becomes more common. Thus, if the wear rates in the clinical use of these new crosslinked polyethylenes is as low as in the laboratory tests, the rate of accumulation of polyethylene wear particles should be well below the level that is necessary to initiate osteolysis. However, increasing the level of crosslinking can reduce the strength and toughness [10,30,31] of the UHMWPE below that necessary to avoid fracture in vivo (Fig. 2). In determining an amount of crosslinking that will retain safe values of strength and toughness, it should be recalled that the vast majority of polyethylene cups that were implanted during the past three decades were crosslinked to a moderate level with 2.5 to 4 Mrads of gamma radiation used for sterilization. Despite this, fracture in vivo has been rare, and the components that have fractured were typically found to be highly oxidized [32]. The implication of this historical track record is that the strength and toughness of a polyethylene component that has a moderate amount of intentional crosslinking and that has been rendered immune to post-irradiation oxidative degradation by the application of a suitable thermal treatment to eliminate free radicals (Fig. 3), should be more than sufficient even for high-stress clinical applications such as knee prostheses. Thus, the optimal crosslinking dose will provide an UHMWPE with sufficient wear resistance to avoid osteolysis in even the most active patients, while retaining the strength and toughness well above that required for a lifetime of clinical use. A close monitoring of the clinical performance of each of the new crosslinked polyethylenes is required. 77

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Table. Comparison Among New Crosslinked Thermally-Stabilized Polyethylenes (The processing parameters shown in this table were compiled from various publications, and information provided by the manufacturers is subject to ongoing modification.) Name and Manufacturer Radiation Type and Dose Thermal Stabilization Final Sterilization Total Crosslinking Dose and Type Marathon γ radiation to 5 Remelted at Gas plasma 5 Mrads gamma DePuy, Inc. Mrads at room temperature 155ºC for 24 hours followed by annealing at 120ºC for 24 h. XLPE γ radiation to 10 Remelted at Ethylene 10 Mrads gamma Smith & Nephew Richards, Inc. Mrads at room temperature 150ºC for two hours oxide Longevity Electron beam radiation to 10 Remelted at 150ºC for about six Gas plasma 10 Mrads electron beam Zimmer, Inc. Mrads at room temperature hours Durasul Sulzer, Inc. Electron beam radiation to 9.5 Remelted at 150ºC for about Ethylene oxide 9.5 Mrads electron beam Mrads at 125 ºC two hours Crossfire Strykerγ radiation to 7.5 Mrads at room Annealed at about 120ºC for a Gamma at 2.5 to 3.5 *10 to 11 Mrads of gamma Osteonics- Howmedica, Inc. temperature proprietary duration Mrads while packaged in nitrogen Aeonian Kyocera, γ radiation to 3.5 Mrads at room Annealed at 110ºC for 10 hours Gamma at 2.5 to 4 Mrads *6 to 7.5 Mrads of gamma Inc. temperature while packaged in nitrogen *For Crossfire and Aeonian, the total crosslinking dose will depend on how much irradiation is used for terminal sterilization. The allowable range is 2.5 to 4 Mrads. 81

1 Normalized Wear Rate 0.8 0.6 0.4 Electron beam radiation at 25 C + remelting Electron beam radiation at 125 C + remelting Gamma radiation + annealing Gamma radiation + remelting 0.2 0 0 5 10 15 20 Radiation Dose (Mrad) Figure 1: Reduction in wear with increased level of crosslinking. The curves for the two gamma-radiation crosslinked polyethylenes were produced on hip simulators in two different laboratories [10,17]. The curves for the two electron beam crosslinked polyethylenes were produced on a bi-directional pin-on-disk machine in a third laboratory [12]. Because two wear machines may produce different wear magnitudes for the same materials due to differences in the applied load and/or the sliding distance per cycle, the original data were normalized by dividing by the wear rate for noncrosslinked polyethylene obtained in each test. 82

400 Dose range for conventional sterilization 350 300 ASTM Type 1 & 2 Elongation at Break (%) 250 200 150 ASTM Type 3 100 Non-irradiated Non-remelted Remelted 50 0 0 5 10 15 20 25 Radiation Dose (Mrad) Figure 2: Effect of radiation crosslinking on the elongation of UHMWPE [10]. The specimens were machined from extruded bars that were crosslinked with varying radiation doses, with or without remelting to extinguish residual free radicals. The bracket indicates the dose range (2.5 to 4.0 Mrad) that has been used for the radiation-sterilization of UHMWPE components in clinical use over the past three decades. 83

Ratio Ratio Yield Strength Ultimate Strength Elongation 5 Atm O 2 70 deg. C 2 weeks 1 ASTM Minimums Aged Brittle Fracture Aged Non-Sterilized UHMWPE 3.3 Mrad Gamma-Air 3.3 Mrad Gamma-Air 5 Mrads Remelted 5 Mrads Remelted Figure 3. Typical values of the tensile properties of non-crosslinked and crosslinked UHMW polyethylenes [10,11]. Left to right: a) conventional, non-irradiated (non-crosslinked) polyethylene, b) polyethylene that has been sterilized by gamma irradiation in air (as was used industrially for the past three decades), prior to aging, c) air-irradiated polyethylene after aging for 5 years or more in vivo, and d) the crosslinked and remelted polyethylene of the present study. Due to the removal of the free radicals by remelting, there was little or no additional in mechanical properties after extensive artificial aging (14 days at 70 C under 5 atm oxygen). Thus, implant components fabricated from gamma crosslinked and remelted polyethylene should not experience the progressive degradation of their mechanical properties during clinical use that has been typical of air-irradiated components in the past. 84