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Scientific Articles   |    
In Vivo Oxidation in Remelted Highly Cross-Linked Retrievals
B.H. Currier, MChE1; D.W. Van Citters, PhD1; J.H. Currier, MS1; J.P. Collier, DE1
1 Thayer School of Engineering, Dartmouth College, 8000 Cummings Hall, Hanover, NH 03755. E-mail address for B.H. Currier: barbara.h.currier@dartmouth.edu
View Disclosures and Other Information
Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from DePuy, a Johnson & Johnson company, and the National Institute of Standards and Technology (NIST). In addition, one or more of the authors or a member of his or her immediate family received, in any one year, payments or other benefits in excess of $10,000 or a commitment or agreement to provide such benefits from a commercial entity (DePuy, a Johnson & Johnson company).

A commentary by Victor M. Goldberg, MD, and Jevan Furmanski, PhD, is available at www.jbjs.org/commentary and as supplemental material to the online version of this article.
Investigation performed at the Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire

Copyright © 2010 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2010 Oct 20;92(14):2409-2418. doi: 10.2106/JBJS.I.01006
A commentary by Victor M. Goldberg, MD, is available here
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Abstract

Background: 

Elimination of free radicals to prevent oxidation has played a major role in the development and product differentiation of the latest generation of highly cross-linked ultra-high molecular weight polyethylene bearing materials. In the current study, we (1) examined oxidation in a series of retrieved remelted highly cross-linked ultra-high molecular weight polyethylene bearings from a number of device manufacturers and (2) compared the retrieval results with findings for shelf-stored control specimens. The hypothesis was that radiation-cross-linked remelted ultra-high molecular weight polyethylene would maintain oxidative stability in vivo comparable with the stability during shelf storage and in published laboratory aging tests.

Methods: 

Fifty remelted highly cross-linked ultra-high molecular weight polyethylene acetabular liners and nineteen remelted highly cross-linked ultra-high molecular weight polyethylene tibial inserts were received after retrieval from twenty-one surgeons from across the U.S. Thirty-two of the retrievals had been in vivo for two years or more. Each was measured for oxidation with use of Fourier transform infrared spectroscopy. A control series of remelted highly cross-linked ultra-high molecular weight polyethylene acetabular liners from three manufacturers was analyzed with electron paramagnetic resonance spectroscopy to measure free radical content and with Fourier transform infrared spectroscopy to measure oxidation initially and after eight to nine years of shelf storage in air.

Results: 

The never-implanted, shelf-aged controls had no measurable free-radical content initially or after eight to nine years of shelf storage. The never-implanted controls showed no increase in oxidation during shelf storage. Oxidation measurements showed measurable oxidation in 22% of the retrieved remelted highly cross-linked liners and inserts after an average of two years in vivo.

Conclusions: 

Because never-implanted remelted highly cross-linked ultra-high molecular weight polyethylene materials had no measurable free-radical concentration and no increase in oxidation during shelf storage, these materials were expected to be oxidation-resistant in vivo. However, some remelted highly cross-linked ultra-high molecular weight polyethylene retrievals showed measurable oxidation after an average of more than two years in vivo. This apparent departure from widely expected behavior requires continued study of the process of in vivo oxidation of ultra-high molecular weight polyethylene materials.

Clinical Relevance: 

Remelted highly cross-linked ultra-high molecular weight polyethylene acetabular and tibial retrievals showed unexpected oxidation.

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    References

    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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    B.H. Currier, MChE
    Posted on March 19, 2011
    Ms. Currier and colleagues respond to Dr. Morrison and Mr. Jani
    Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire

    The purpose of our publication was to present the unexpected findings of subsurface oxidation in remelted highly cross-linked UHMWPE. By all previously published evaluations including our own, there is no measurable free radical concentration and no shelf oxidation of never-implanted remelted highly cross-linked bearings. Therefore, our expectation was that remelted highly cross-linked UHMWPE would be oxidatively stable in vivo.

    However, a small percentage of the remelted highly cross-linked retrievals that were analyzed in our recent study showed a distinct ketone oxidation maximum below the articular surface, similar to that seen in oxidized gamma-sterilized UHMWPE. This finding was so surprising that bringing it to the attention of the orthopaedic community was deemed of high importance, with the goal of encouraging the analysis of retrieved remelted highly cross-linked UHMWPE bearings.

    The characteristics of this oxidation are very different from explant shelf oxidation reported by Muratoglu, et al. (1). Explant shelf oxidation is highest at the surface of the polyethylene bearing and decreases with distance from the articular surface (1). In contrast, the oxidation of concern in this paper appeared as a definitive subsurface peak. Figure 1 compares retrievals that were in vivo for similar time, but were analyzed after different explant shelf time. The oxidation profiles are quite different. Explant shelf time of more than one year resulted in oxidation that was maximum at the articular surface and decreased with depth into the bearing. In contrast, the retrieval with an explant shelf time of 0.3 years showed no oxidation at the articular surface, but rather oxidation that was highest subsurface.


    Fig. 1

    Figure 1: Oxidation data from two acetabular liners, retrieved after similar in vivo time. Both retrievals were hexane extracted before FTIR analysis. Explant shelf time of >1 year resulted in oxidation that was maximum at the articular surface of the liner. In contrast, no oxidation remained at the articular surface of the liner with only 0.3-year post-retrieval shelf time. The oxidation in this liner is maximum subsurface.

    The dataset for this initial study was small and was a combination of all remelted highly cross-linked retrievals received by our laboratory: hips, knees, gamma cross-linked, e-beam cross-linked, short or long in vivo time, short or long explant shelf time. While the subsurface character of the oxidation makes it distinct and notable, the statistics relating peak oxidation level to other implant parameters were, as the Letter to the Editor correctly points out, quite weak in this small data set. Now, 18 months after the initial submission, we have double the original number of remelted highly cross-linked retrievals and are beginning to be able to identify variables that increase the likelihood of the occurrence of subsurface oxidation.

    The principal focus of our paper was that remelted highly cross-linked bearings that have been in vivo exhibit oxidation that cannot be ascribed to the generally accepted concept that oxidation results from free radicals existing in the polyethylene. Recognition that the in vivo environment can cause changes in the oxidation potential of remelted highly-cross-linked polyethylene is critical, in that it requires the orthopaedic community to understand a new oxidation mechanism.

    Reference

    1. Muratoglu OK, Wannomae KK, Rowell SL, Micheli BR, Malchau H. Ex vivo stability loss of irradiated and melted ultra-high molecular weight polyethylene. J Bone Joint Surg Am. 2010;92:2809-16.

    Mark L. Morrison, PhD
    Posted on March 19, 2011
    Critique of Article by Currier et al.
    Smith & Nephew Orthopaedics

    Editor's Note: Dr. Morrison is a Lead Research Engineer and Mr. Jani is a Principle Research Engineer at Smith & Nephew Orthopaedics.

    To the Editor:

    We read with interest the recent publication by Currier et al. on the measurement of oxidation in highly crosslinked, remelted retrievals ("In Vivo Oxidation in Remelted Highly Cross-Linked Retrievals", 2010;92:2409). We would like to commend the authors and the editors for publishing the raw data from this study on the JBJS-A website for public scrutiny. Because of their openness, we were able to perform our own analyses of their data. Upon detailed analyses we find the published data set does not support some of the assertions and conclusions reached in this paper, as discussed below.

    Of particular concern is the assertion that measurable oxidation occurs during use in vivo in remelted highly crosslinked UHMWPE. The remelting step after radiation crosslinking is designed to reduce free radical concentrations to levels below the capability of common measuring techniques, thereby rendering greater oxidative stability to the material. Currier et al. measure oxidation in 22% of retrieved materials, albeit at relatively low levels. The key question is when did this oxidation occur. Theoretically, we know that oxidation could have occurred at any of the three stages in the life of a UHMWPE implant:

    1. on the shelf prior to implantation

    2. during use in vivo

    3. on the shelf after retrieval

    Regarding the first stage, there is abundant evidence (including the present paper) that this does not occur for highly crosslinked, remelted UHMWPE (1,2). Therefore, the effect of this stage need not be examined further.

    The only way to determine if oxidation is occurring in the second stage during use in vivo is to examine the implants immediately upon retrieval surgery. Alternatively the implants can be stored in a non-oxidizing environment immediately upon retrieval for future evaluation. We acknowledge that these strategies are not easy. Nonetheless, several studies (3,4) have utilized the latter approach and reported no measurable oxidation in highly crosslinked, remelted acetabular liners.

    Multiple studies (4-6) have documented that measurable levels of oxidation can occur in the third stage after the implants are retrieved and routinely stored (i.e., shelf aged in air). These same studies have concluded that oxidation was not occurring in vivo through either direct measurement (4) or correlation analyses (5,6).

    All of the components analyzed in this study experienced all three of these stages, including documented times after retrieval. Therein lies the difficulty; how much of the measured oxidation occurred during use in vivo, and how much occurred after retrieval? The authors suggest in the title and body of the paper that oxidation occurred during use in vivo. Based on the published data in this paper, we do not believe that this assertion is conclusive.

    Because the individual effects of in-vivo and shelf-aging times on oxidation can not be separated in this study, it is prudent to examine the relationships between the lengths of time spent in each stage (i.e. predictor variables) and the measured oxidation indices (OIs) to evaluate which predictor variables are most influential on the measured oxidation (i.e. when oxidation is occurring). We performed the same Spearman's rank correlation employed by the authors and found that the strongest predictor of oxidation index was shelf-aging time (Table 1). This crucial correlation was not included by the authors. Although all of these predictor variables were found to exhibit significant correlations with oxidation index, time in vivo was, in fact, the weakest predictor of oxidation (i.e. the lowest correlation coefficient).

    Table 1: Full Data Set
    Summary of the Spearman's rank correlation coefficients (ρ) and levels of significance (p) between the predictor variables and oxidation indices
    VariableSpearman's ρp
    Time in vivo0.2280.030
    Shelf-aging time0.3600.002
    Total time since implantation0.3510.002

    We also created a scatter plot of the reported data (Figure 1) and used linear regression to estimate the rates of oxidation associated with each of these predictor variables. We acknowledge that linear regression may not be the best model for oxidation, but for illustrative purposes it is good for first order approximation. This graph shows that the rate of real oxidation on the shelf is much greater than the rate of alleged oxidation in vivo, which means that even short shelf-aging times after retrieval can measurably influence the measured oxidation indices.


    Fig. 1

    As noted by the authors, only 15 of the 69 components (22%) exhibited measurable oxidation, defined as OI > 0.10 in the paper. In other words, a full 78% of the oxidation data used by the authors for their correlations is below the detection limit and can legitimately be regarded as "measurement noise." If we remove this measurement noise by reducing these data points to oxidation indices of zero and calculate the correlation coefficients based upon confidently measurable OIs, the only statistically significant correlations with OI are with shelf aging time and total time since implantation (Table 2). In this case, time in vivo is not significantly correlated with oxidation and remains the weakest predictor variable. This further underscores the importance of shelf-aging time after retrieval and its potential for overwhelming low levels of oxidation that may have occurred in vivo, if any.

    Table 2: Modified Data Set
    Summary of the Spearman's rank correlation coefficients (ρ) and levels of significance (p) between the predictor variables and oxidation indices
    VariableSpearman's ρp
    Time in vivo0.1870.126
    Shelf-aging time0.415<0.001
    Total time since implantation0.3450.004

    A scatter plot of these measurable oxidation indices as a function of the predictor variables (Figure 2) visually illustrates these correlations and rates of oxidation.


    Fig. 2

    If we now focus only on implants that have relatively short shelf-aging times of less than 6 months, we are left with four implants (6% of full data set) with oxidation indices greater than 0.10. Those implants had oxidation indices in the range of 0.11 to 0.14 with shelf-aging times of 1.8 to 4.4 months (Figure 2). Could this measurable oxidation have occurred in vivo? At best we can say "perhaps."

    We attempted to utilize the oxidation rate on the shelf (Figure 1) to predict the OI of a component at the time of retrieval (i.e. shelf-aging time = 0.0). Through this method, regression analysis indicated that the OI would be 0.03 ± 0.12 (±95% prediction intervals). Based upon the large prediction interval, it is apparent that the scatter in the data is too high or the number of replicates too low to accurately predict the presence of oxidation at the time of retrieval through this method. It should, however, be noted that the predicted OI at time zero (0.03) is below the detection limit — essentially zero.

    In summary, this study showed the following:

    1. Oxidation in 15 out of 69 (22%) crosslinked, remelted UHMWPE implants after retrieval. The remaining 78% showed no measurable extent of oxidation.

    2. Eleven of the 15 oxidized implants experienced shelf lives after retrieval of greater than six months. Therefore, the oxidation in these implants cannot be definitively attributed to in vivo use. The data shows that the oxidation rate on the shelf after retrieval is high enough to mask the presence of oxidation upon retrieval.

    3. Four of the oxidized implants (6% of total) were on the shelf less than six months and had a mean OI of 0.13 ± 0.01 (±SD). The oxidation in these implants can not singularly be attributed to have occurred in vivo. Nonetheless, neither can the possibility that oxidation occurred in vivo be eliminated. Further studies, with greater numbers of well-controlled retrievals will help understanding of this behavior. Wannomae et al. (3) and Rowell et al. (4) did conduct studies of well-controlled retrievals and showed no evidence of in-vivo oxidation.

    It is possible that mild levels oxidation of highly crosslinked, remelted components may be occurring in vivo, but the data presented in this paper does not show that conclusively. We agree with the authors that vigilance in the monitoring of oxidative behavior of crosslinked UHMWPE is warranted.

    Acknowledgement: We would like to thank the authors of this paper for numerous private communications, the salient points of which are included in this letter. We appreciate their willingness to discuss the paper with candor.

    References

    1. Muratoglu OK, Merrill EW, Bragdon CR, O'Connor D, Hoeffel D, Burroughs B, Jasty M, Harris WH. Effect of radiation, heat, and aging on in vitro wear resistance of polyethylene. Clin Orthop Relat Res. 2003;417:253-62.

    2. Laurent MP, Johnson TS, Crowninshield RD, Blanchard CR, Bhambri SK, Yao JQ. Characterization of a highly cross-linked ultrahigh molecular-weight polyethylene in clinical use in total hip arthroplasty. J Arthroplasty. 2008;23:751-61.

    3. Wannomae KK, Bhattacharyya S, Freiberg A, Estok D, Harris WH, Muratoglu O. In vivo oxidation of retrieved cross-linked ultra-high-molecular-weight polyethylene acetabular components with residual free radicals. J Arthroplasty. 2006;21:1005-11.

    4. Rowell SL, Engh CA, Hopper RH, Muratoglu OK. In vivo lipid absorption in highly cross-linked UHMWPE acetabular liners. Orthopaedic Research Society 2011 Annual Meeting; 2011 Jan 13-16; Long Beach, CA. Paper no 0374.

    5. Rowell SL, Wannomae KK, Micheli BR, Muratoglu OK. Ex vivo stability loss of irradiated and melted UHMWPE. Orthopadic Research Society 2010 Annual Meeting; 2010 Mar 6-9; New Orleans, LA. Paper no 2304.

    6. Muratoglu OK, Wannomae KK, Rowell SL, Micheli BR, Malchau H. Ex vivo stability loss of irradiated and melted ultra-high molecular weight polyethylene. J Bone Joint Surg Am. 2010;92:2809-16.

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