The Journal of Arthroplasty 30 (2015) 1828–1834
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In Vivo Oxidative Stability Changes of Highly Cross-Linked Polyethylene Bearings: An Ex Vivo Investigation Shannon L. Rowell, BS a, Christopher R. Reyes, BS a, Henrik Malchau, MD, PhD a,b,c, Orhun K. Muratoglu, PhD a,c a b c
Harris Orthopaedic Laboratory, Massachusetts General Hospital, Boston, Massachusetts Sahlgrenska University Hospital, Mölndal, Sweden Harvard Medical School, Cambridge, Massachusetts
a r t i c l e
i n f o
Article history: Received 27 October 2014 Accepted 5 May 2015 Keywords: polyethylene (UHWMPE) oxidation accelerated aging total joint arthroplasty retrievals
a b s t r a c t The development of highly cross-linked UHMWPEs focused on stabilizing radiation-induced free radicals as the sole precursor to oxidative degradation. However, secondary in vivo oxidation mechanisms have been discovered. After a preliminary post-operative analysis, we subjected highly cross-linked retrievals with 1–4 years in vivo durations and never-implanted controls to accelerated aging to predict the extent to which their oxidative stability was compromised in vivo. Lipid absorption, oxidation, and hydroperoxides were measured using infrared spectroscopy. Gravimetric swelling was used to measure cross-link density. After aging, all retrievals, except vitamin E-stabilized components, regardless of initial lipid levels or oxidation, showed significant oxidative degradation, demonstrated by subsurface oxidative peaks, increased hydroperoxides and decreased cross-link density, compared to their post-operative material properties and never-implanted counterparts, confirming oxidative stability changes. © 2015 Elsevier Inc. All rights reserved.
Highly cross-linked polyethylene has become the standard bearing in total hip and knee arthroplasty [1]. Several clinical follow-up studies in total hip patients have documented substantially increased wear resistance with highly cross-linked polyethylene [2–4]. The use of this material also markedly decreased the occurrence of peri-prosthetic osteolysis [3,5]. Cross-linking of UHMWPE is typically achieved by ionizing radiation, which also creates residual free radicals compromising the oxidative stability of the polymer. First and second generation highly cross-linked polyethylenes are stabilized using methods such as post-irradiation melting to maximize the quenching of free radicals, post-irradiation annealing below the melt temperature to reduce the free radical content, or incorporation of an antioxidant to maintain mechanical properties and actively stabilize free radicals generated during irradiation or subsequently during in vivo service. Melting has been very effective in improving the oxidation resistance of irradiated UHMWPE; while post-irradiation annealing resulted in early and rapid in vivo oxidation [6–8], which is a concern for the recent use of these materials in total knees. Oxidation promotes and accelerates failure in the form of delamination and fracture, mostly in tibial inserts and patellar components [9].
More recently, an investigation by our group reported on the in vivo compromise of oxidation resistance of highly cross-linked UHMWPE implants. In that study, we found that irradiated and melted UHMWPE implants were oxidizing on the shelf after surgical removal from patients. We hypothesized that in vivo lipid absorption and cyclic loading causes this in vivo change in oxidative stability. Recent in vitro studies have identified the highly oxidative effect of lipids, specifically squalene, on polyethylene [10]. Squalene is present in synovial fluid and is absorbed into the UHMWPE components among a number of other esterified fatty acids [11]. Mechanically-induced oxidation has also been shown to result in increased oxidation under the articular surfaces of tibial knee inserts in vivo [12]. Traditional in vitro aging tests used for pre-clinical evaluation of oxidative resistance were limited in their scope and did not incorporate the possible detrimental effects of lipids and/or cyclic loading. In this study, we propose to address those accelerated aging challenges by using samples made from surgically retrieved components, thereby testing materials that have been effectively “pre-conditioned” by their in vivo service. After a preliminary post-operative analysis, we subjected retrievals to ex vivo accelerated aging tests to predict the extent to in vivo service compromised their oxidative stability. Methods
No author associated with this paper has disclosed any potential or pertinent conflicts which may be perceived to have impending conflict with this work. For full disclosure statements refer to http://dx.doi.org/10.1016/j.arth.2015.05.006. Reprint requests: Orhun K. Muratoglu, PhD, Harris Orthopaedic Laboratory, Massachusetts General Hospital, 55 Fruit Street, GRJ-1229, Boston, MA 02114. http://dx.doi.org/10.1016/j.arth.2015.05.006 0883-5403/© 2015 Elsevier Inc. All rights reserved.
Materials We examined four types of highly cross-linked UHMWPE bearings in this study (Table 1). These included two first generation, irradiated and
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Table 1 Highly Cross-Linked UHMWPE Material Types and In Vivo Durations of Retrievals. In Vivo Duration (months) Material Longevity Prolong X3 E1
Irradiation + Free Radical Stabilization
Sterilization
100 kGy e-beam irradiation, followed by melting at N135 °C 65 kGy e-beam irradiation, followed by melting at N135 °C 3 cycles of 30 kGy gamma irradiation followed by 8 hours of 130 °C annealing 100 kGy gamma-irradiation, followed by vitamin E diffusion and annealing at 130 °C
Gas plasma Gas plasma Gas plasma 30 kGy gamma in argon
melted UHMWPEs (Longevity acetabular liners and Prolong tibial bearings, Zimmer Inc., Warsaw, IN) and two second generation highly cross-linked UHMWPEs, sequentially irradiated and annealed UHMWPE (X3 acetabular liners and tibial bearings, Stryker Inc., Mahwah, NJ) and irradiated and vitamin E-diffused UHMWPE (E1 acetabular liners and tibial bearings, Biomet Inc., Warsaw, IN). The criteria for selection of retrievals included components with in vivo durations between 1 year and 4 years for each material type. Reasons for revision are described in Appendix I. Each set contained six retrievals, except E1, of which we examined nine retrievals. E1 retrievals were the newest bearing material, introduced in 2008, and therefore their longest in vivo duration was 36.6 months. Retrievals were vacuum-sealed and stored at −20 °C while not undergoing analysis in order to inhibit ex vivo changes that occur on the shelf at room temperature in air [9]. As controls, we analyzed never-implanted bearings of each material both before and after accelerated aging. Accelerated Aging Post-operative material analysis was performed directly after revision surgery to examine initial oxidation levels and material characteristics, including lipid absorption, in vivo oxidation, hydroperoxides for oxidation potential and cross-link density. Material analysis was performed across the thickness of each bearing as a function of depth, at both the region of highest load in the articular surface and at the unloaded rim of acetabular liners or eminence of tibial inserts. After post-operative analysis, remaining component segments were subjected to accelerated aging for two weeks in a vessel pressurized with pure oxygen to 5 atm and heated to 70 °C [13]. Antioxidant-containing retrievals and conventional highly cross-linked retrievals were aged in separate pressure vessels to avoid cross-contamination. We repeated the material analysis after accelerated aging. Material Analysis Fourier transform infrared microscopy (FTIR; Bio-Rad FTS2000, Natick, MA) was used to determine lipid absorption, oxidation and hydroperoxide levels. Thin cross-sections (500 μm) were cut with a microtome from the articular surface and non-load bearing surface of each component. Infrared absorbance spectra were collected as a function of depth from each surface. Lipid absorption and oxidation were derived from carbonyl absorbance peaks centered around 1740 cm − 1 (1680 cm −1–1780 cm −1), both before and after hexane extraction (Ref ASTM F2102). The area under the spectral peak was normalized to the area below 1395 cm−1 (1330 cm − 1–1390 cm − 1) after subtracting the corresponding baselines. Absorbed species from the joint were extracted from thin sections over 16 hours in boiling hexanes, followed by a vacuum drying period of 24 hours. Lipid absorption (CIlipid) was calculated by subtracting posthexane carbonyl levels (CIpost-hexane or OI, considered to be solely derived from the polymer oxidation products) from the pre-hexane carbonyl level (CIpre-hexane) which presumably was due to both the absorbed species and oxidation; Eq. (1)).
CIlipid ¼ CI pre‐hexane −CIpost‐hexane
ð1Þ
Average 22.7 30.8 20.5 20.0
± ± ± ±
11.8 16.0 13.0 9.7
Median 20.5 31.0 14.8 15.0
Range 12.0–44.0 9.0–47.0 10.0–45.0 11.0–36.6
Oxidation indices above 0.1 signal detectable oxidation. Historically in conventional UHMWPEs, an OI less than 1.0 is considered low oxidation without substantial effects on mechanical behavior [14,15]. Regions with an OI greater than 3.0 demonstrated substantial loss of mechanical properties that could compromise clinical performance [15,16]. Hydroperoxides are intermediary byproducts of the oxidation cycle and increases seen in these levels are considered to be indicative of potential future oxidation [17,18] and an acceleration of the oxidative chain reaction. Hydroperoxides were measured by reacting hexane extracted thin sections with nitric oxide for 16 hours in an inert environment to form nitrates measurable with FTIR. Nitrate levels, or hydroperoxide index (HI), were then calculated from the height of the nitrate absorbance at 1630 cm −1 (1607 cm −1–1680 cm − 1) and normalized against the height of the absorbance at 1895 cm − 1 (1850 cm−1–1985 cm−1), after subtracting the corresponding baselines. Cross-link density was calculated using gravimetric swelling analysis [19]. Three cubes (3 mm to each side) were cut from the articular surface, non-load-bearing surface, and the bulk thickness below the articular surface for each component. Cubes were weighed before and after 2-hour immersion in boiling xylenes (130 °C) to calculate the swell ratio and subsequent cross-link density at each region of interest in the components. The Wilcoxon signed rank test, a nonparametric, paired difference test, was used to compare oxidation and material properties between individual retrievals before and after aging. Statistical significance was assigned where P b 0.05. Results Post-operative Analysis Retrievals included in this study had in vivo durations spanning one to four years, but did not necessarily show equal post-operative oxidation levels across the subgroups nor could a correlation with in vivo duration be established for any subgroup (Figs. 1A and 2A). All retrievals (n = 27) contained absorbed lipids, which penetrated below both loaded and unloaded surfaces with penetration depths of 1.3 ± 0.5 mm and 0.6 ± 0.2 mm, respectively. The post-operative carbonyl absorbance measured after hexane extraction, and mostly attributed to oxidation, varied between a maximum OI of 0.01 and 0.94 (Fig. 2A). Neverimplanted controls were used to establish baseline material properties for each component type (Table 2). After Ex Vivo Accelerated Aging After ex vivo accelerated aging, the average carbonyl indices of the neverimplanted controls were around an OI of 0.1 (Table 2). Crosslink density in all controls remained unchanged (P N 0.05). Hydroperoxide levels decreased in the irradiated and melted acetabular control and vitamin E-stabilized control, but increased in the irradiated and melted tibial insert and sequentially irradiated and annealed control by 78% and 38%, respectively. Vitamin E-stabilized retrievals maintained low oxidation, while no significant material property changes were measured after accelerated aging (Figs. 1–4; Appendix II for P-values). Maximum oxidation values ranged between an OI of 0.12 and 0.24 after accelerated aging, which was similar to the increase seen in the never-implanted liner (from
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Fig. 1. Box plots showing the distribution of (A) maximum in vivo oxidation and (B) maximum oxidation after accelerated aging in highly cross-linked retrievals.
0.06 before aging to 0.20 after aging; Table 2). Cross-link density showed no decrease after aging (P = 0.678; Fig. 4). Hydroperoxide levels remained constant, averaging a 5% decrease overall, compared to the post-operative level (P = 0.374; Fig. 3). Conversely, an increase in oxidation was seen in all of the sequentially irradiated and annealed and warm-irradiated and melted retrieved tibial bearings along with half of the retrieved irradiated and melted acetabular liners (P b 0.028; Figs. 1 and 2; Appendix II). In these three groups, all retrievals with measurable in vivo oxidation, showed postaging maximum oxidation indices greater than 0.5 at the articular surface. Accelerated aging resulted in a three-to five-fold increase in hydroperoxides in subsurface regions where oxidation was found (Fig. 3),
accompanied with a 34% to 90% decrease in cross-link density (Fig. 4). Regardless of lipid absorption levels or the extent of in vivo oxidation present, maximum oxidation values after accelerated aging were detectable and increased to a range of 0.30 to 2.63 across all three subgroups. In retrievals with measurable post-operative oxidation indices, aging-induced oxidation occurred primarily below the articular surface in conjunction with their in vivo oxidation peaks (Fig. 5). Even retrievals without measurable in vivo oxidation showed oxidation after ex vivo accelerated aging. This oxidation took the form of subsurface peaks in the articular surface region, while oxidation was located at the surface of unloaded regions. Post-aging oxidation profiles in the unloaded region paralleled lipid diffusion profiles. Unlike
Fig. 2. Maximum oxidation values for retrievals showed significant increase from (A) post-operative values in the irradiated/melted and sequentially irradiated/annealed explants after accelerated aging (B) regardless of in vivo oxidation levels.
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Table 2 Before and After Accelerated Aged Never-Implanted Highly Cross-Linked Material Properties. Maximum Oxidation (MOI)
Average Oxidation (OI) Material Longevity Prolong X3 E1
Before 0.009 0.000 0.027 0.007
± ± ± ±
0.003 0.002 0.004 0.006
After 0.015 0.028 0.035 0.102
± ± ± ±
0.002 0.012 0.003 0.030
Before
After
0.024 0.012 0.142 0.060
0.069 0.052 0.050 0.196
irradiated and melted retrievals, sequentially irradiated and annealed retrievals for both hip and knee showed uniform increases in bulk oxidation after aging as well (0.35 ± 0.16) compared to post-operative averages (0.08 ± 0.05). When comparing the oxidative behavior of sequentially irradiated and annealed tibial bearings with irradiated and melted tibial bearings, there was also a key difference in regional oxidation. The former tibial bearings featured oxidative degradation in both the loaded and unloaded regions, while the latter tibial bearings showed no substantial increase in oxidation in the unloaded eminence with a range of 0.06 to 0.18 and no detectable concomitant material changes (Figs. 5 and 6). Discussion We assessed the changes that occurred in vivo on the oxidative stability of various types of highly cross-linked UHMWPE components through an investigation of surgically-retrieved components using accelerated aging. We found that in vivo service compromised the oxidative stability of highly cross-linked UHMWPE load bearing components fabricated using either post-irradiation melting or sequential irradiation and annealing. The vitamin E-stabilized components showed no change in their oxidative stability with up to three years of in in vivo service. Historically, high temperature, high oxygen accelerated aging tests were used in preclinical testing of new materials to compare and predict long-term oxidation behavior [13]. Previous accelerated aging studies reported excellent oxidation resistance in irradiated and melted [20]
Average Hydroperoxide Level (HI) Before 0.950 0.724 0.600 0.598
± ± ± ±
0.036 0.038 0.013 0.030
After 0.751 1.290 0.828 0.533
± ± ± ±
0.028 0.099 0.006 0.005
Crosslink Density (mol/dm3) Before 0.301 0.205 0.262 0.269
± ± ± ±
0.006 0.004 0.009 0.007
After 0.319 0.205 0.248 0.292
± ± ± ±
0.007 0.005 0.002 0.010
and sequentially irradiated and annealed UHMWPE [21]. In this study, the never-implanted components showed low to no detectable oxidation after accelerated aging, which was comparable to the previously published accelerated aging results. However, with material property changes being reported in vivo [12,22] and ex vivo [9], subjecting fresh bearings to traditional aging protocols may not be clinically relevant in predicting long-term performance. The oxidation of short in vivo duration retrievals reported here after accelerated aging supports the hypothesis that even a short exposure to the in vivo environment could have a detrimental effect on oxidative stability. In addition, retrievals with no detectable oxidation immediately after revision surgery still appeared to be oxidatively compromised as early as one year after implantation. Retrievals with sub-articular surface oxidation after in vivo service showed increased values with accelerated aging, demonstrating that the oxidative chain reaction initiated in vivo continued to progress during ex vivo accelerated aging. When present, postaccelerated aging oxidation maxima in the unloaded regions were predominantly at the surface as opposed to the subsurface, likely the consequence of absorbed lipids. Oxidation behavior differed between sequentially irradiated and annealed retrievals and their irradiated and melted counterparts in both extent and location, with the former showing more advanced oxidation and oxidation located in both loaded and unloaded regions. The most likely cause of the more advanced oxidative degradation in sequentially irradiated and annealed components is the presence of free radicals [23,24]. Sequentially irradiated and annealed components
Fig. 3. Hydroperoxide levels increased an average of 2× during 1–4 years in vivo service for thermally treated retrievals, and then again after accelerated aging. Conversely, vitamin E stabilized retrievals showed no change in oxidation potential during in vivo service and accelerated aging.
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Fig. 4. Cross-link density decreased in all sequentially irradiated/annealed and irradiated/melted retrievals likely because of chain scissioning during accelerated aging; while vitamin Estabilized retrievals showed no significant change from post-operative values.
undergo gas plasma-sterilization and are subsequently stored in airpermeable packaging [21,25]. If oxidative stability were compromised during shelf storage, this material could be more adversely affected by prolonged exposure to in vivo conditions. The combination of shelf oxidation and residual free radicals could also explain why sequentially irradiated and annealed UHMWPE appeared more susceptible to oxidation than materials without free radicals [23,24]. However, preimplantation shelf storage durations were not available for retrievals in this study, limiting our ability to investigate the effects of shelf storage on the results.
The substantially lower oxidation level in the vitamin E-diffused retrievals both before and after accelerated aging, demonstrated the antioxidant potency of vitamin E. This material is radiation cross-linked before the incorporation of vitamin E. Therefore, the dissolved oxygen reacts with free radicals formed during irradiation and results in the formation of some hydroperoxides. The low levels of oxidation seen in vitamin E diffused components are likely due to the thermal dissociation of these hydroperoxides. From this study, we have determined that even without detectable oxidation at the time of revision, both irradiated and melted and sequentially irradiated and annealed materials had undergone
Fig. 5. Average maximum oxidation values at both loaded and unloaded regions after accelerated aging for all four types of highly cross-linked retrievals.
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Fig. 6. Oxidation profiles at the articular surface of (A) 2 year 65 kGy warm irradiated and melted retrieved tibial bearing and (B) 2 year sequentially irradiated retrieved tibial bearing, both showing detectable subsurface in vivo oxidation peaks in the loaded region. Backside oxidation occurred after aging even without post-operative oxidation present.
[26–28]. These findings also suggest that the presence of an antioxidant may be able to stabilize in vivo mechanisms compromising long-term oxidative stability and increase the longevity of highly cross-linked UHMWPE materials.
changes in oxidative stability during in vivo service. Sequentially irradiated and annealed components appeared to be more prone to both in vivo oxidation and overall destabilizing effects of in vivo factors, consistent with historic materials containing residual free radicals
Appendix I. Reasons for revision for each material type of retrieved highly cross-linked UHMWPE.
Table 1 Patient Demographics for Each Material Type of Retrieved Highly Cross-Linked UHMWPE. Reason for Revision Infection Loosening components Instability Pain Malpositioning, liner fracture Dislocation Patellar maltracking Sepsis due to lupus Unknown
Longevity
Prolong
X3
E1
Total
2 2 1 0 0 1 0 0 1
2 2 1 1 0 0 0 0 0
2 1 2 0 0 0 1 0 0
3 1 0 1 2 0 0 1 0
9 6 4 2 2 1 1 1 1
Appendix II. Maximum oxidation, oxidation potential, as measured by hydroperoxide levels, and cross-link density before and after accelerated aging of retrieved highly cross-linked UHMWPE.
All statistical analyses were performed using the Wilcoxon signed rank test, chosen to compare paired sets of data with non-normal distributions and unequal variances.
Table 1 Average Maximum Oxidation Index, Before and After Accelerated Aging and Statistical Significance Calculated Using the Wilcoxon Paired Rank Test. Average Maximum Oxidation (MOI) at Rim Material
Before Aging
After Aging
Longevity Prolong X3 E1
0.03 0.03 0.17 0.10
0.32 0.11 0.80 0.14
± ± ± ±
0.01 0.03 0.16 0.04
± ± ± ±
0.34 0.04 0.62 0.05
Average Maximum Oxidation (MOI) at Articular Surface P 0.028 0.046 0.028 0.038
Before Aging
After Aging
0.08 0.39 0.37 0.12
0.78 1.30 1.48 0.19
± ± ± ±
0.08 0.23 0.32 0.04
± ± ± ±
0.65 0.82 0.75 0.04
P 0.028 0.028 0.028 0.011
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Table 2 Average Hydroperoxide Index, Before and After Accelerated Aging and Statistical Significance Calculated Using the Wilcoxon Paired Rank Test. Average Hydroperoxides at Rim Material
Before Aging
After Aging
Longevity Prolong X3 E1
0.85 0.85 1.16 0.65
3.34 1.19 3.20 0.61
± ± ± ±
0.13 0.06 0.64 0.04
± ± ± ±
3.10 0.36 1.81 0.05
Average Hydroperoxides at Articular Surface P 0.028 0.116 0.028 0.110
Before Aging
After Aging
1.14 1.37 1.02 0.63
4.49 6.54 5.12 0.61
± ± ± ±
0.79 0.56 0.30 0.03
± ± ± ±
3.12 1.55 1.33 0.05
P 0.028 0.028 0.028 0.374
Average Hydroperoxides at Bulk Before Aging
After Aging
0.95 0.92 1.00 0.60
2.76 2.80 4.69 0.57
± ± ± ±
0.35 0.20 0.31 0.04
± ± ± ±
1.53 1.04 1.16 0.05
P 0.028 0.028 0.028 0.314
Table 3 Average Cross-link Density, Before and After Accelerated Aging and Statistical Significance Calculated Using the Wilcoxon Paired Rank Test. Average Cross-link Density at Rim Material Longevity Prolong X3 E1
Before Aging 0.288 0.228 0.200 0.280
± ± ± ±
0.012 0.009 0.048 0.033
After Aging 0.203 0.155 0.133 0.290
± ± ± ±
0.076 0.081 0.063 0.028
Average Cross-link Density at Articular Surface P 0.046 0.046 0.028 0.176
Before Aging 0.298 0.224 0.218 0.285
± ± ± ±
0.028 0.008 0.029 0.038
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After Aging 0.196 0.105 0.099 0.291
± ± ± ±
0.083 0.041 0.043 0.029
P 0.075 0.028 0.028 0.678
Average Cross-link Density at Bulk Before Aging 0.298 0.226 0.219 0.278
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0.068 0.061 0.044 0.027
P 0.028 0.028 0.028 0.066
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In Vivo Oxidative Stability Changes of Highly Cross-Linked Polyethylene Bearings: An Ex Vivo Investigation Shannon L. Rowell, BS a, Christopher R. Reyes, BS a, Henrik Malchau, MD, PhD a,b,c, Orhun K. Muratoglu, PhD a,c a b c
Harris Orthopaedic Laboratory, Massachusetts General Hospital, Boston, Massachusetts Sahlgrenska University Hospital, Mölndal, Sweden Harvard Medical School, Cambridge, Massachusetts
a r t i c l e
i n f o
Article history: Received 27 October 2014 Accepted 5 May 2015 Keywords: polyethylene (UHWMPE) oxidation accelerated aging total joint arthroplasty retrievals
a b s t r a c t The development of highly cross-linked UHMWPEs focused on stabilizing radiation-induced free radicals as the sole precursor to oxidative degradation. However, secondary in vivo oxidation mechanisms have been discovered. After a preliminary post-operative analysis, we subjected highly cross-linked retrievals with 1–4 years in vivo durations and never-implanted controls to accelerated aging to predict the extent to which their oxidative stability was compromised in vivo. Lipid absorption, oxidation, and hydroperoxides were measured using infrared spectroscopy. Gravimetric swelling was used to measure cross-link density. After aging, all retrievals, except vitamin E-stabilized components, regardless of initial lipid levels or oxidation, showed significant oxidative degradation, demonstrated by subsurface oxidative peaks, increased hydroperoxides and decreased cross-link density, compared to their post-operative material properties and never-implanted counterparts, confirming oxidative stability changes. © 2015 Elsevier Inc. All rights reserved.
Highly cross-linked polyethylene has become the standard bearing in total hip and knee arthroplasty [1]. Several clinical follow-up studies in total hip patients have documented substantially increased wear resistance with highly cross-linked polyethylene [2–4]. The use of this material also markedly decreased the occurrence of peri-prosthetic osteolysis [3,5]. Cross-linking of UHMWPE is typically achieved by ionizing radiation, which also creates residual free radicals compromising the oxidative stability of the polymer. First and second generation highly cross-linked polyethylenes are stabilized using methods such as post-irradiation melting to maximize the quenching of free radicals, post-irradiation annealing below the melt temperature to reduce the free radical content, or incorporation of an antioxidant to maintain mechanical properties and actively stabilize free radicals generated during irradiation or subsequently during in vivo service. Melting has been very effective in improving the oxidation resistance of irradiated UHMWPE; while post-irradiation annealing resulted in early and rapid in vivo oxidation [6–8], which is a concern for the recent use of these materials in total knees. Oxidation promotes and accelerates failure in the form of delamination and fracture, mostly in tibial inserts and patellar components [9].
More recently, an investigation by our group reported on the in vivo compromise of oxidation resistance of highly cross-linked UHMWPE implants. In that study, we found that irradiated and melted UHMWPE implants were oxidizing on the shelf after surgical removal from patients. We hypothesized that in vivo lipid absorption and cyclic loading causes this in vivo change in oxidative stability. Recent in vitro studies have identified the highly oxidative effect of lipids, specifically squalene, on polyethylene [10]. Squalene is present in synovial fluid and is absorbed into the UHMWPE components among a number of other esterified fatty acids [11]. Mechanically-induced oxidation has also been shown to result in increased oxidation under the articular surfaces of tibial knee inserts in vivo [12]. Traditional in vitro aging tests used for pre-clinical evaluation of oxidative resistance were limited in their scope and did not incorporate the possible detrimental effects of lipids and/or cyclic loading. In this study, we propose to address those accelerated aging challenges by using samples made from surgically retrieved components, thereby testing materials that have been effectively “pre-conditioned” by their in vivo service. After a preliminary post-operative analysis, we subjected retrievals to ex vivo accelerated aging tests to predict the extent to in vivo service compromised their oxidative stability. Methods
No author associated with this paper has disclosed any potential or pertinent conflicts which may be perceived to have impending conflict with this work. For full disclosure statements refer to http://dx.doi.org/10.1016/j.arth.2015.05.006. Reprint requests: Orhun K. Muratoglu, PhD, Harris Orthopaedic Laboratory, Massachusetts General Hospital, 55 Fruit Street, GRJ-1229, Boston, MA 02114. http://dx.doi.org/10.1016/j.arth.2015.05.006 0883-5403/© 2015 Elsevier Inc. All rights reserved.
Materials We examined four types of highly cross-linked UHMWPE bearings in this study (Table 1). These included two first generation, irradiated and
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Table 1 Highly Cross-Linked UHMWPE Material Types and In Vivo Durations of Retrievals. In Vivo Duration (months) Material Longevity Prolong X3 E1
Irradiation + Free Radical Stabilization
Sterilization
100 kGy e-beam irradiation, followed by melting at N135 °C 65 kGy e-beam irradiation, followed by melting at N135 °C 3 cycles of 30 kGy gamma irradiation followed by 8 hours of 130 °C annealing 100 kGy gamma-irradiation, followed by vitamin E diffusion and annealing at 130 °C
Gas plasma Gas plasma Gas plasma 30 kGy gamma in argon
melted UHMWPEs (Longevity acetabular liners and Prolong tibial bearings, Zimmer Inc., Warsaw, IN) and two second generation highly cross-linked UHMWPEs, sequentially irradiated and annealed UHMWPE (X3 acetabular liners and tibial bearings, Stryker Inc., Mahwah, NJ) and irradiated and vitamin E-diffused UHMWPE (E1 acetabular liners and tibial bearings, Biomet Inc., Warsaw, IN). The criteria for selection of retrievals included components with in vivo durations between 1 year and 4 years for each material type. Reasons for revision are described in Appendix I. Each set contained six retrievals, except E1, of which we examined nine retrievals. E1 retrievals were the newest bearing material, introduced in 2008, and therefore their longest in vivo duration was 36.6 months. Retrievals were vacuum-sealed and stored at −20 °C while not undergoing analysis in order to inhibit ex vivo changes that occur on the shelf at room temperature in air [9]. As controls, we analyzed never-implanted bearings of each material both before and after accelerated aging. Accelerated Aging Post-operative material analysis was performed directly after revision surgery to examine initial oxidation levels and material characteristics, including lipid absorption, in vivo oxidation, hydroperoxides for oxidation potential and cross-link density. Material analysis was performed across the thickness of each bearing as a function of depth, at both the region of highest load in the articular surface and at the unloaded rim of acetabular liners or eminence of tibial inserts. After post-operative analysis, remaining component segments were subjected to accelerated aging for two weeks in a vessel pressurized with pure oxygen to 5 atm and heated to 70 °C [13]. Antioxidant-containing retrievals and conventional highly cross-linked retrievals were aged in separate pressure vessels to avoid cross-contamination. We repeated the material analysis after accelerated aging. Material Analysis Fourier transform infrared microscopy (FTIR; Bio-Rad FTS2000, Natick, MA) was used to determine lipid absorption, oxidation and hydroperoxide levels. Thin cross-sections (500 μm) were cut with a microtome from the articular surface and non-load bearing surface of each component. Infrared absorbance spectra were collected as a function of depth from each surface. Lipid absorption and oxidation were derived from carbonyl absorbance peaks centered around 1740 cm − 1 (1680 cm −1–1780 cm −1), both before and after hexane extraction (Ref ASTM F2102). The area under the spectral peak was normalized to the area below 1395 cm−1 (1330 cm − 1–1390 cm − 1) after subtracting the corresponding baselines. Absorbed species from the joint were extracted from thin sections over 16 hours in boiling hexanes, followed by a vacuum drying period of 24 hours. Lipid absorption (CIlipid) was calculated by subtracting posthexane carbonyl levels (CIpost-hexane or OI, considered to be solely derived from the polymer oxidation products) from the pre-hexane carbonyl level (CIpre-hexane) which presumably was due to both the absorbed species and oxidation; Eq. (1)).
CIlipid ¼ CI pre‐hexane −CIpost‐hexane
ð1Þ
Average 22.7 30.8 20.5 20.0
± ± ± ±
11.8 16.0 13.0 9.7
Median 20.5 31.0 14.8 15.0
Range 12.0–44.0 9.0–47.0 10.0–45.0 11.0–36.6
Oxidation indices above 0.1 signal detectable oxidation. Historically in conventional UHMWPEs, an OI less than 1.0 is considered low oxidation without substantial effects on mechanical behavior [14,15]. Regions with an OI greater than 3.0 demonstrated substantial loss of mechanical properties that could compromise clinical performance [15,16]. Hydroperoxides are intermediary byproducts of the oxidation cycle and increases seen in these levels are considered to be indicative of potential future oxidation [17,18] and an acceleration of the oxidative chain reaction. Hydroperoxides were measured by reacting hexane extracted thin sections with nitric oxide for 16 hours in an inert environment to form nitrates measurable with FTIR. Nitrate levels, or hydroperoxide index (HI), were then calculated from the height of the nitrate absorbance at 1630 cm −1 (1607 cm −1–1680 cm − 1) and normalized against the height of the absorbance at 1895 cm − 1 (1850 cm−1–1985 cm−1), after subtracting the corresponding baselines. Cross-link density was calculated using gravimetric swelling analysis [19]. Three cubes (3 mm to each side) were cut from the articular surface, non-load-bearing surface, and the bulk thickness below the articular surface for each component. Cubes were weighed before and after 2-hour immersion in boiling xylenes (130 °C) to calculate the swell ratio and subsequent cross-link density at each region of interest in the components. The Wilcoxon signed rank test, a nonparametric, paired difference test, was used to compare oxidation and material properties between individual retrievals before and after aging. Statistical significance was assigned where P b 0.05. Results Post-operative Analysis Retrievals included in this study had in vivo durations spanning one to four years, but did not necessarily show equal post-operative oxidation levels across the subgroups nor could a correlation with in vivo duration be established for any subgroup (Figs. 1A and 2A). All retrievals (n = 27) contained absorbed lipids, which penetrated below both loaded and unloaded surfaces with penetration depths of 1.3 ± 0.5 mm and 0.6 ± 0.2 mm, respectively. The post-operative carbonyl absorbance measured after hexane extraction, and mostly attributed to oxidation, varied between a maximum OI of 0.01 and 0.94 (Fig. 2A). Neverimplanted controls were used to establish baseline material properties for each component type (Table 2). After Ex Vivo Accelerated Aging After ex vivo accelerated aging, the average carbonyl indices of the neverimplanted controls were around an OI of 0.1 (Table 2). Crosslink density in all controls remained unchanged (P N 0.05). Hydroperoxide levels decreased in the irradiated and melted acetabular control and vitamin E-stabilized control, but increased in the irradiated and melted tibial insert and sequentially irradiated and annealed control by 78% and 38%, respectively. Vitamin E-stabilized retrievals maintained low oxidation, while no significant material property changes were measured after accelerated aging (Figs. 1–4; Appendix II for P-values). Maximum oxidation values ranged between an OI of 0.12 and 0.24 after accelerated aging, which was similar to the increase seen in the never-implanted liner (from
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Fig. 1. Box plots showing the distribution of (A) maximum in vivo oxidation and (B) maximum oxidation after accelerated aging in highly cross-linked retrievals.
0.06 before aging to 0.20 after aging; Table 2). Cross-link density showed no decrease after aging (P = 0.678; Fig. 4). Hydroperoxide levels remained constant, averaging a 5% decrease overall, compared to the post-operative level (P = 0.374; Fig. 3). Conversely, an increase in oxidation was seen in all of the sequentially irradiated and annealed and warm-irradiated and melted retrieved tibial bearings along with half of the retrieved irradiated and melted acetabular liners (P b 0.028; Figs. 1 and 2; Appendix II). In these three groups, all retrievals with measurable in vivo oxidation, showed postaging maximum oxidation indices greater than 0.5 at the articular surface. Accelerated aging resulted in a three-to five-fold increase in hydroperoxides in subsurface regions where oxidation was found (Fig. 3),
accompanied with a 34% to 90% decrease in cross-link density (Fig. 4). Regardless of lipid absorption levels or the extent of in vivo oxidation present, maximum oxidation values after accelerated aging were detectable and increased to a range of 0.30 to 2.63 across all three subgroups. In retrievals with measurable post-operative oxidation indices, aging-induced oxidation occurred primarily below the articular surface in conjunction with their in vivo oxidation peaks (Fig. 5). Even retrievals without measurable in vivo oxidation showed oxidation after ex vivo accelerated aging. This oxidation took the form of subsurface peaks in the articular surface region, while oxidation was located at the surface of unloaded regions. Post-aging oxidation profiles in the unloaded region paralleled lipid diffusion profiles. Unlike
Fig. 2. Maximum oxidation values for retrievals showed significant increase from (A) post-operative values in the irradiated/melted and sequentially irradiated/annealed explants after accelerated aging (B) regardless of in vivo oxidation levels.
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Table 2 Before and After Accelerated Aged Never-Implanted Highly Cross-Linked Material Properties. Maximum Oxidation (MOI)
Average Oxidation (OI) Material Longevity Prolong X3 E1
Before 0.009 0.000 0.027 0.007
± ± ± ±
0.003 0.002 0.004 0.006
After 0.015 0.028 0.035 0.102
± ± ± ±
0.002 0.012 0.003 0.030
Before
After
0.024 0.012 0.142 0.060
0.069 0.052 0.050 0.196
irradiated and melted retrievals, sequentially irradiated and annealed retrievals for both hip and knee showed uniform increases in bulk oxidation after aging as well (0.35 ± 0.16) compared to post-operative averages (0.08 ± 0.05). When comparing the oxidative behavior of sequentially irradiated and annealed tibial bearings with irradiated and melted tibial bearings, there was also a key difference in regional oxidation. The former tibial bearings featured oxidative degradation in both the loaded and unloaded regions, while the latter tibial bearings showed no substantial increase in oxidation in the unloaded eminence with a range of 0.06 to 0.18 and no detectable concomitant material changes (Figs. 5 and 6). Discussion We assessed the changes that occurred in vivo on the oxidative stability of various types of highly cross-linked UHMWPE components through an investigation of surgically-retrieved components using accelerated aging. We found that in vivo service compromised the oxidative stability of highly cross-linked UHMWPE load bearing components fabricated using either post-irradiation melting or sequential irradiation and annealing. The vitamin E-stabilized components showed no change in their oxidative stability with up to three years of in in vivo service. Historically, high temperature, high oxygen accelerated aging tests were used in preclinical testing of new materials to compare and predict long-term oxidation behavior [13]. Previous accelerated aging studies reported excellent oxidation resistance in irradiated and melted [20]
Average Hydroperoxide Level (HI) Before 0.950 0.724 0.600 0.598
± ± ± ±
0.036 0.038 0.013 0.030
After 0.751 1.290 0.828 0.533
± ± ± ±
0.028 0.099 0.006 0.005
Crosslink Density (mol/dm3) Before 0.301 0.205 0.262 0.269
± ± ± ±
0.006 0.004 0.009 0.007
After 0.319 0.205 0.248 0.292
± ± ± ±
0.007 0.005 0.002 0.010
and sequentially irradiated and annealed UHMWPE [21]. In this study, the never-implanted components showed low to no detectable oxidation after accelerated aging, which was comparable to the previously published accelerated aging results. However, with material property changes being reported in vivo [12,22] and ex vivo [9], subjecting fresh bearings to traditional aging protocols may not be clinically relevant in predicting long-term performance. The oxidation of short in vivo duration retrievals reported here after accelerated aging supports the hypothesis that even a short exposure to the in vivo environment could have a detrimental effect on oxidative stability. In addition, retrievals with no detectable oxidation immediately after revision surgery still appeared to be oxidatively compromised as early as one year after implantation. Retrievals with sub-articular surface oxidation after in vivo service showed increased values with accelerated aging, demonstrating that the oxidative chain reaction initiated in vivo continued to progress during ex vivo accelerated aging. When present, postaccelerated aging oxidation maxima in the unloaded regions were predominantly at the surface as opposed to the subsurface, likely the consequence of absorbed lipids. Oxidation behavior differed between sequentially irradiated and annealed retrievals and their irradiated and melted counterparts in both extent and location, with the former showing more advanced oxidation and oxidation located in both loaded and unloaded regions. The most likely cause of the more advanced oxidative degradation in sequentially irradiated and annealed components is the presence of free radicals [23,24]. Sequentially irradiated and annealed components
Fig. 3. Hydroperoxide levels increased an average of 2× during 1–4 years in vivo service for thermally treated retrievals, and then again after accelerated aging. Conversely, vitamin E stabilized retrievals showed no change in oxidation potential during in vivo service and accelerated aging.
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Fig. 4. Cross-link density decreased in all sequentially irradiated/annealed and irradiated/melted retrievals likely because of chain scissioning during accelerated aging; while vitamin Estabilized retrievals showed no significant change from post-operative values.
undergo gas plasma-sterilization and are subsequently stored in airpermeable packaging [21,25]. If oxidative stability were compromised during shelf storage, this material could be more adversely affected by prolonged exposure to in vivo conditions. The combination of shelf oxidation and residual free radicals could also explain why sequentially irradiated and annealed UHMWPE appeared more susceptible to oxidation than materials without free radicals [23,24]. However, preimplantation shelf storage durations were not available for retrievals in this study, limiting our ability to investigate the effects of shelf storage on the results.
The substantially lower oxidation level in the vitamin E-diffused retrievals both before and after accelerated aging, demonstrated the antioxidant potency of vitamin E. This material is radiation cross-linked before the incorporation of vitamin E. Therefore, the dissolved oxygen reacts with free radicals formed during irradiation and results in the formation of some hydroperoxides. The low levels of oxidation seen in vitamin E diffused components are likely due to the thermal dissociation of these hydroperoxides. From this study, we have determined that even without detectable oxidation at the time of revision, both irradiated and melted and sequentially irradiated and annealed materials had undergone
Fig. 5. Average maximum oxidation values at both loaded and unloaded regions after accelerated aging for all four types of highly cross-linked retrievals.
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Fig. 6. Oxidation profiles at the articular surface of (A) 2 year 65 kGy warm irradiated and melted retrieved tibial bearing and (B) 2 year sequentially irradiated retrieved tibial bearing, both showing detectable subsurface in vivo oxidation peaks in the loaded region. Backside oxidation occurred after aging even without post-operative oxidation present.
[26–28]. These findings also suggest that the presence of an antioxidant may be able to stabilize in vivo mechanisms compromising long-term oxidative stability and increase the longevity of highly cross-linked UHMWPE materials.
changes in oxidative stability during in vivo service. Sequentially irradiated and annealed components appeared to be more prone to both in vivo oxidation and overall destabilizing effects of in vivo factors, consistent with historic materials containing residual free radicals
Appendix I. Reasons for revision for each material type of retrieved highly cross-linked UHMWPE.
Table 1 Patient Demographics for Each Material Type of Retrieved Highly Cross-Linked UHMWPE. Reason for Revision Infection Loosening components Instability Pain Malpositioning, liner fracture Dislocation Patellar maltracking Sepsis due to lupus Unknown
Longevity
Prolong
X3
E1
Total
2 2 1 0 0 1 0 0 1
2 2 1 1 0 0 0 0 0
2 1 2 0 0 0 1 0 0
3 1 0 1 2 0 0 1 0
9 6 4 2 2 1 1 1 1
Appendix II. Maximum oxidation, oxidation potential, as measured by hydroperoxide levels, and cross-link density before and after accelerated aging of retrieved highly cross-linked UHMWPE.
All statistical analyses were performed using the Wilcoxon signed rank test, chosen to compare paired sets of data with non-normal distributions and unequal variances.
Table 1 Average Maximum Oxidation Index, Before and After Accelerated Aging and Statistical Significance Calculated Using the Wilcoxon Paired Rank Test. Average Maximum Oxidation (MOI) at Rim Material
Before Aging
After Aging
Longevity Prolong X3 E1
0.03 0.03 0.17 0.10
0.32 0.11 0.80 0.14
± ± ± ±
0.01 0.03 0.16 0.04
± ± ± ±
0.34 0.04 0.62 0.05
Average Maximum Oxidation (MOI) at Articular Surface P 0.028 0.046 0.028 0.038
Before Aging
After Aging
0.08 0.39 0.37 0.12
0.78 1.30 1.48 0.19
± ± ± ±
0.08 0.23 0.32 0.04
± ± ± ±
0.65 0.82 0.75 0.04
P 0.028 0.028 0.028 0.011
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Table 2 Average Hydroperoxide Index, Before and After Accelerated Aging and Statistical Significance Calculated Using the Wilcoxon Paired Rank Test. Average Hydroperoxides at Rim Material
Before Aging
After Aging
Longevity Prolong X3 E1
0.85 0.85 1.16 0.65
3.34 1.19 3.20 0.61
± ± ± ±
0.13 0.06 0.64 0.04
± ± ± ±
3.10 0.36 1.81 0.05
Average Hydroperoxides at Articular Surface P 0.028 0.116 0.028 0.110
Before Aging
After Aging
1.14 1.37 1.02 0.63
4.49 6.54 5.12 0.61
± ± ± ±
0.79 0.56 0.30 0.03
± ± ± ±
3.12 1.55 1.33 0.05
P 0.028 0.028 0.028 0.374
Average Hydroperoxides at Bulk Before Aging
After Aging
0.95 0.92 1.00 0.60
2.76 2.80 4.69 0.57
± ± ± ±
0.35 0.20 0.31 0.04
± ± ± ±
1.53 1.04 1.16 0.05
P 0.028 0.028 0.028 0.314
Table 3 Average Cross-link Density, Before and After Accelerated Aging and Statistical Significance Calculated Using the Wilcoxon Paired Rank Test. Average Cross-link Density at Rim Material Longevity Prolong X3 E1
Before Aging 0.288 0.228 0.200 0.280
± ± ± ±
0.012 0.009 0.048 0.033
After Aging 0.203 0.155 0.133 0.290
± ± ± ±
0.076 0.081 0.063 0.028
Average Cross-link Density at Articular Surface P 0.046 0.046 0.028 0.176
Before Aging 0.298 0.224 0.218 0.285
± ± ± ±
0.028 0.008 0.029 0.038
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After Aging 0.196 0.105 0.099 0.291
± ± ± ±
0.083 0.041 0.043 0.029
P 0.075 0.028 0.028 0.678
Average Cross-link Density at Bulk Before Aging 0.298 0.226 0.219 0.278
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0.025 0.010 0.021 0.033
After Aging 0.218 0.163 0.102 0.287
± ± ± ±
0.068 0.061 0.044 0.027
P 0.028 0.028 0.028 0.066
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