CORR Insights®: No Reduction in Revision Risk Associated With Highly Cross-linked Polyethylene With or Without Antioxidants Over Conventional Polyethylene in TKA: An Analysis From the American Joint Replacement Registry

Where Are We Now?

Before the 1990s, most polyethylene components used in prosthetic joints had been packaged in air, sterilized with 2.5 to 4 mrads of gamma radiation, and shelf-stored for various durations before implantation. The gamma radiation generated a moderate amount of cross-linking, which was found to reduce the rate of wear in laboratory tests [9] and subsequently in clinical use [6]. However, the radiation also formed residual free radicals in the polyethylene that during shelf storage in air and subsequent use in vivo could lead to substantial oxidation of the polyethylene [3]. This oxidation, in turn, markedly reduced the resistance of the polyethylene to fatigue crack propagation, delamination, and gross fracture, especially in knee prostheses, which are typically subject to more complex loading than hips [2].

To improve the resistance of implants to oxidation, several manufacturers began sealing them in a low-oxygen package before irradiation [10]. But although this could minimize oxidation during shelf storage, the implants still were subject to substantial oxidation during use in vivo [4]. A different approach was to avoid the generation of residual free radicals (and, therefore, oxidation) by sterilizing them with ethylene oxide or gas plasma, but this also eliminated the moderate amount of cross-linking that occurred during gamma sterilization, leading to an increase in wear [6].

Researchers also realized that polyethylene is more susceptible to wear when subjected to a “crossing-path” motion [14], in which the motion of the opposing bearing surface against a given point on the surface of the polyethylene changes direction during the wear cycle, rather than always being in the same direction, or back and forth in the same direction. A crossing-path motion typically occurs to a greater extent in hip prostheses than in knees [7]. Consequently, it was reasonable to predict that hip prostheses would benefit more from the reduction in wear afforded by the increased cross-linking in highly cross-linked polyethylene (HXLPE) than knee implants would, while knees would benefit preferentially from the improved resistance to oxidation afforded by the thermal treatments or antioxidants. But did this prediction prove to be true?

Since their introduction in the late 1990s, HXLPEs have demonstrated excellent clinical performance in hip prostheses [1, 11], with millions of implants in use and nearly no reports of clinically important osteolysis. HXLPEs have been in clinical use in knee arthroplasty since the early 2000s. As Kendall et al. [8] acknowledge, the evidence regarding the performance of HXLPEs in knees is mixed. For example, a recent meta-analysis of 10 studies that comprised 963,467 patients with TKAs found no substantial difference in the overall rate of revision for any reason with conventional or HXLPE components, while in a subset of 411,543 patients, the rate of revision for aseptic loosening was substantially lower with HXLPEs [5].

In the current study, Kendall et al. [8] compared the risk of revision for any cause and for aseptic loosening among three populations of patients who underwent TKA: those using conventional polyethylene, those with HXLPE that had been stabilized against long-term oxidation using thermal treatments, and those treated with an antioxidant (so-called antioxidant doping). The thermal treatments included remelting or annealing (heating above or below the melt temperature, respectively), and the antioxidant was mixed with the polyethylene at the time of consolidation or diffused into the implant after it was fabricated. The authors found no difference in the risk of revision among the three groups.

The authors compiled data on the incidence of revision for any reason and revision for aseptic loosening. But it is important to recognize that although extensive osteolysis can undermine the fixation of an implant, leading to aseptic loosening, the two are not synonymous. Osteolysis can occur in the absence of loosening and vice versa [12]. This is particularly true of knee prostheses, where loosening in the absence of substantial osteolysis can result from inadequate initial fixation, combined with instability caused by malalignment. Indeed, if poor fixation and/or instability were the dominant causes of aseptic loosening in the authors’ [14] database, any advantage of cross-linking and oxidative stability in preventing osteolysis-induced loosening might not yet be numerically apparent. The authors concluded that “As the less time-tested and more costly alternative, HXLPE polyethylene, with or without an antioxidant, should not be widely adopted in TKA until or unless it is shown to be superior to conventional polyethylene.” As will be discussed here, however, given the limitations of their study, it is reasonable to recommend that HXLPEs that have been stabilized against oxidation be the preferred choice for TKAs until there are substantial data establishing that their clinical performance is worse than that of conventional polyethylene.

Where Do We Need To Go?

Although the authors [8] do not state the nature of the conventional polyethylene used in their study, because the components were implanted from 2012 to 2019, it is likely they were packed and stored in a low-oxygen atmosphere. If so, they may eventually show a greater susceptibility to oxidation in vivo than the stabilized HXLPE implants. Further studies with longer follow-up should determine whether that is the case.

In their study, Kendall et al. [8] cited the commonly expressed concern that because cross-linking can reduce the mechanical strength of polyethylene, the potential for fracture of the components in vivo might be increased. Although it is correct that cross-linking followed by remelting reduces the crystallinity, and therefore the fracture toughness relative to raw polyethylene, remelting also quenches the free radicals that are generated by the cross-linking radiation. This results in greater resistance to long-term oxidative degradation than that of conventional gamma-sterilized polyethylene that has not been stabilized against post-irradiation oxidation [13], and such oxidation markedly reduces the fracture toughness [4]. Also, annealing is far less effective in quenching free radicals, and some cross-linked–annealed components have shown long-term oxidation that is somewhat greater than that of conventional polyethylene, although this has not yet been manifested in terms of more-frequent revisions. Thus, HXLPEs that were stabilized against oxidation might not have experienced an increased rate of fracture compared with conventional polyethylene. This prediction has been sustained based on clinical use spanning more than 20 years for hips and knees.

In their study [8], the authors compiled clinical data only for patients 65 years or older with 3 to 10 years of follow-up. Future studies should focus on assessing whether the HXLPEs provide a substantial clinical advantage in those patients who are the most likely to benefit.

How Do We Get There?

Data should be compiled separately for younger, more active patients; for revisions because of fatigue fracture of the polyethylene that might have resulted from oxidative degradation; and for longer-term follow-up. In addition, separate datasets should be compiled for the major categories of polyethylenes in clinical use: gamma-sterilized in a low-oxygen atmosphere (conventional), highly cross-linked and remelted, highly cross-linked and annealed, mixed with an antioxidant and highly cross-linked, and highly cross-linked and diffusion-doped with an antioxidant. Each of these may provide different levels of clinical performance, especially in long-term use in active patients. Finally, revisions for extensive osteolysis should be evaluated separately from those for aseptic loosening in the absence of substantial osteolysis, to identify any benefit of improved resistance to wear.