AOX™ ANTIOXIDANT POLYETHYLENEsynthes.vo.llnwd.net/o16/LLNWMB8/US Mobile/Synthes North America/Product Support...containing polyethylene involves mixing the antioxidant into the polyethylene

AOX™ ANTIOXIDANT POLYETHYLENE

DePuy Synthes Joint Reconstruction*, a leader in producing high quality polyethylene, proudly offers AOX™ Antioxidant Polyethylene for the ATTUNE® Knee System.

Fourth generation polyethylenes build upon the learnings from the evolution in polyethylene materials. Extensive studies have been conducted on irradiated ultra high molecular weight polyethylene (UHMWPE) to understand its vulnerability to oxidation in an environment that contains oxygen.1,2 Stabilization by post-irradiation re-melting has accomplished an improvement over second generation polyethylenes that are now established as susceptible to in-vivo oxidative degradation.3,4 These third generation polyethylenes, which involve a high degree of crosslinking by high energy irradiation followed by thermal stabilization, are the current state of the art for commercial orthopaedic devices.

Incorporation of additives that promote oxidative stability, while common practice in the engineering industry, has not been applied to the orthopaedic grade of polyethylene until recently. This approach has yielded the fourth generation of polyethylenes.

Our implant systems are evolving. With our advanced blend of polyethylene resin and the unique COVERNOX™ Antioxidant, DePuy Synthes Joint Reconstruction has created a new polyethylene material that has extraordinary efficiency in trapping free radicals and scavenging oxygen. This first of its kind combination is designed to deliver optimal wear resistance and long term oxidative stability.

By eliminating the annealing or remelting process, AOX Polyethylene delivers outstanding oxidative stability and optimum wear resistance without compromising the mechanical properties of polyethylene.5, 6

NEXT GENERATIONWELCOME TO THE

Oxidative Stability

Wear Resistance

Mechanical Strength

Mechanical Toughness

AOX Polyethylene 3x Annealed 10 Mrad Remelted Vitamin E Doped

3 7

3 3

3 7 3

7

3

7

3

3

7

3

3

3

2 DePuy Synthes Joint Reconstruction ATTUNE® Knee System AOX™ Antioxidant Polyethylene

The third generation polyethylenes, particularly the highly crosslinked and remelted polyethylenes, have demonstrated very good performance characteristics, including optimal wear properties, and are designed to deliver long term oxidative stability. This raises the question why there is need for the next generation polyethylene.

While remelting provides enhanced performance characteristics, there is a reduction in the crystallinity of the resulting polymer as the polymer solidifies from the molten state after irradiation. This is because the high degree of crosslinking severely restricts the mobility in the polymer chains and inhibits the ability for the chains to order themselves and pack into crystalline lamellar structures to the same extent as non-irradiated polyethylene. The consequence of the loss in crystallinity is a modest loss in mechanical strength and fatigue resistance.

Stabilization by thermal annealing also has limitations. Free radical elimination by quenching due to remelting is very effective because, in the molten state, the polyethylene chains are mobile and this allows free radicals to find each other and react and get neutralized. Since annealing takes place below the melt temperature, the mobility of the chains is much more restricted and the efficiency of free radical quench is rather poor. This is confirmed by the high free radical concentration measured in thermally annealed samples by Electron Spin Resonance.7 The remaining free radicals can have serious implications regarding the in vivo oxidative stability of annealed products.

The evolution of fourth generation polyethylenes is therefore driven by the need to retain the crystalline properties of polyethylene while preserving the oxidative stability of the molecular chains upon irradiation. The incorporation of antioxidants into polyethylene has been well established in other industrial applications and proven to be very successful in providing high oxidative stability. The antioxidants used in such industrial polymers scavenge free radicals resulting from exposure of polyethylene to environmental radiation (sunlights and other sources). It is therefore easy to envisage the relevance to the orthopaedic applications where Gamma (γ) irradiation is employed for crosslinking and sterilization, thus producing free radicals that are the primary cause for oxidation in polyethylene.

The addition of free radical scavengers into polyethylene stabilizes the polymer by neutralizing the free radicals without the need for remelting, thereby preserving crystallinity in the polyethylene. This is the primary reason for the development of fourth generation polyethylenes.

WHAT IS THE RATIONALE FOR THE DEVELOPMENT OF FOURTH GENERATION POLYETHYLENES?


OH

O

O

O

O O

O

O O

OH

OH OH

WHAT ARE THE CHOICE ANTIOXIDANTS REPORTED FOR FOURTH GENERATION POLYETHYLENES?

Hindered phenolic antioxidants are a widely used chemical class of antioxidants. One such antioxidant that has been introduced recently for use in orthopaedic devices is the synthetic version of Vitamin E, also known as alpha (α)-Tocopherol.8 It has the following chemical structure.

α-Tocopherol is a liquid at room temperature (melting point = 2.4 ~ 3.5 ºC). α-Tocopherol stabilized polyethylene for orthopaedic applications has been commercialized by Biomet® as E1™ and by Zimmer® as Vivacit-E®.

While α-Tocopherol demonstrates adequate stabilization against oxidation, it is not one of the well established stabilizers for UHMWPE. There are other proven antioxidants that have confirmed excellent performance history in a number of applications wherein polyethylene is exposed to severe ionizing radiation and oxidizing environments. Hindered phenols with proven capability include, but are not limited to, the chemical species shown to the right.

OH

H3C

H3C

CH3

O

H3C CH3

H3C H3CCH3

Vitamin E (α-tocopherol)

Chemical Formula: C73H108O12 Molecular Weight: 1177.63

Pentaerythritol tetrakis ([3,5-di tertiary butyl-4-phenoxy] propionate). DePuy Synthes Joint Reconstruction COVERNOX™ Antioxidant

Benzenepropanoic acid, 3,5-bis (1,1-dimethyl ethyl-4-hydroxy octadecyl ester)

(CH2)2 C O

O

HO C18H37


These additives are available commercially under the brand names of Irganox® 1076 and Irganox® 1010 respectively from Ciba Specialties. Extensive research at DePuy Synthes Joint Reconstruction has been conducted on the use of these two antioxidants in UHMWPE. These hindered phenols were deemed as potential candidates for antioxidant polyethylene due to the following reasons:

1. Irganox® 1076 has been used previously in a limited number of DePuy Synthes Joint Reconstruction’s OGEE™ Cup Implants* that were chemically crosslinked.

2. Irganox® 1076 was employed as an antioxidant stabilizer in the high density polyethylene (HDPE) OGEE Cup Flange* that was injection molded.

Food Packaging

Medical Supplies

* Flange made from hindered phenol (Irganox® 1076) antioxidant-stabilized and chemically crosslinked high density polyethylene

Clinical outcome: Over 20 year implantation with no adverse effects noted due to use of antioxidant material.9

3. Antioxidants in this family have been used in food grade packaging plastics and medical supplies.


HOW ARE ANTIOXIDANT STABILIZED POLYETHYLENES MADE?

Antioxidant stabilized polyethylenes have been developed using both GUR 1020 and GUR 1050 UHMWPE. There are two methodologies that may be employed in the incorporation of an antioxidant additive into UHMWPE.

Antioxidant Infusion Process

The first method, which has been adopted for the manufacture of E1™, involves the infusion of an antioxidant (α-tocopherol in the case of E1™) into consolidated UHMWPE. The basic steps of this process are described as follows. Irradiated and cross-linked UHMWPE (for example, an irradiation dose of 10 Mrads for E1™) is immersed in liquid form α-tocopherol at elevated temperatures (approximately 120 ºC) and subjected to isostatic pressure based on the method reported by Oral et. al.10 The diffusive process generates a gradient in the concentration of α-tocopherol in the UHMWPE as a function of depth. Typical gradients that have been reported are shown below:10

Commercial manufacture using this diffusive process for use in orthopaedics infuses the UHMWPE material with an excess of α-tocopherol.11 A specified outer section, where the concentration of antioxidant is the highest (up to tenfold to that in the central portion of the consolidated polymer) is then removed and discarded. Subsequent to the infusion process, the α-tocopherol-soaked UHMWPE is subjected to homogenization to redistribute the α-tocopherol more uniformly throughout the bulk, consolidated UHMWPE material. The homogenization is carried out in an argon atmosphere for 24 hours at 120 °C. This necessitates recurring verification of the uniformity of the distribution of α-tocopherol within the compounded polymer. Hip and knee implants are then machined from the compounded UHMWPE, cleaned, packaged and sterilized. E1™ based devices are sterilized with a Gamma radiation dose of 3–3.5 Mrads.12 While the presence of α-tocopherol reduces the crosslinking efficiency somewhat, there is additional crosslinking imparted by the radiation sterilization that causes further loss of toughness.

The typical flowchart for the manufacture of α-tocopherol-stabilized UHMWPE by the infusion process is shown below.

0.30

0.25

0.20

0.15

0.10

0.05

0.000 1 2 3 4 5 6 7 8 9 10

α-to

cop

her

ol I

nd

ex (

A.U

.)

Depth

α-to

cop

her

ol I

nd

ex (

A.U

.)

Depth

0.30

0.25

0.20

0.15

0.10

0.05

0.000 1 2 3 4 5

Representative α-tocopherol concentration profiles in (a) 4.9 mm thick and (b) 10 mm thick 85 kGy irradiated, α-tocopherol doped and homogenized UHMWPE.

a b

1020/1050 POLYETHYLENE BAR STOCK

MACHINE COMPONENT

IRRADIATION CROSS LINK AT 10 MRADS

INFUSION OF α-TOCOPHEROL AT 120C

HOMOGENIZATION AT 120C

TERMINAL STERILIZATION AT 3.5 MRADS


Antioxidant: Powder Mixing Process

The second process that is used to produce antioxidant containing polyethylene involves mixing the antioxidant into the polyethylene powder prior to consolidation. This is the method used for AOX Polyethylene.

AOX Polyethylene is the fourth generation UHMWPE resulting from research at DePuy Synthes Joint Reconstruction and is manufactured using GUR 1020 (Ticona) stabilized by the hindered phenol antioxidant, Pentaerythritol tetrakis ([3,5-di tertiary butyl-4-phenoxy] propionate). The antioxidant, henceforth denoted by its trade name, COVERNOX Antioxidant, is custom-synthesized and is manufactured to pharmaceutical grade purity.13

The process of generating AOX Polyethylene involves dispersion of the COVERNOX Antioxidant into GUR 1020 powder. The compounded powder is then consolidated into either compression moulded sheets or ram extruded bars. The consolidated AOX Polyethylene is then machined, vacuum-foil packaged and the final components are irradiated.

ANTIOXIDANT

ANTIOXIDANT SOLUTIONUHMWPE POWDER

COMPOUNDED ANTIOXIDANT/UHMWPE POWDER

CONSOLIDATED BAR STOCK OR SHEET

MACHINE COMPONENT

PACKAGE COMPONENT

GAMMA CROSSLINKING + STERILIZATION

The flowchart for the manufacture of AOX Polyethylene devices is shown below.


With enhanced molecular functionality compared with Vitamin E, COVERNOX Antioxidant is extremely efficient at trapping free radicals and preventing oxidation.

The COVERNOX™ Antioxidant is custom manufactured and exclusively available to DePuy Synthes Joint Reconstruction.

Stabilizes free radicals

Post irradiation, COVERNOX Antioxidant combines with remaining free radicals.

Protects against oxidation

The COVERNOX Antioxidant molecule bonds with free radicals and prevents oxidation, maintaining mechanical integrity and oxidative stability.

Free R

adica

l

Hydro

gen/

Carbo

n

COVERNOX A

ntiox

idant

Oxyge

n

COVERNOX™ ANTIOXIDANT

Under aggressive conditions sufficient to oxidize non-irradiated polyethylene, AOX Polyethylene is completely unaffected and retains its mechanical properties. AOX Polyethylene bonds with free radicals which eliminates the potential for oxidation. Annealed polyethylenes do not eliminate oxidative potential.5,14,15

Introducing COVERNOX Antioxidant into the base resin before the polyethylene is consolidated enables the antioxidant to be uniformly dispersed throughout the material and remain blended, thus eliminating the risk of outward migration. The process provides an oxidatively stable polyethylene formulation.

0 20 40 60

14

12

10

8

6

4

2

0

Time Of Aging (Days)

Non-Irridated GUR 1020

AOX Polyethylene

Oxi

dat

ion

Ind

ex (

Max

)5

0 2 4 6

3.0

2.5

2.0

1.5

1.0

0.5

0

Accelerated Aging (Weeks)

3x Anneal

AOX Polyethylene

Oxi

dat

ion

Ind

ex 5,

14


Maintaining mechanical properties is important as high patient loads have the potential to deform and break down polyethylene over time. By utilizing GUR 1020 resin, with its better inherent mechanical properties and lower molecular weight compared with GUR 1050,16,17 AOX Polyethylene maintains high material strength when compared to most other commercially available polyethylene options.

Tensile testing, measuring how polyethylene reacts under pull or stretch load, shows that AOX Polyethylene loses none of its ability to resist deformation or breakage.

Unlike remelting, this approach to providing oxidative stability does not cause a decline of mechanical strength.18

30

25

20

15

10

5

0

60

50

40

30

20

10

0

3x Annealed15AOX Polyethylene5 10 Mrad Remelted19 Vitamin E Doped20

Yie

ld S

tren

gth

(M

Pa)

Ult

imat

e Te

nsi

le S

tren

gth

(M

Pa)

Strength of Materials

MAINTAINING HIGH MATERIAL

STRENGTH


Normal patient loads can impose high contact stresses on polyethylene knee components so mechanical toughness, or resistance to surface crack initiation and subsequent propagation leading to shear induced delamination, is critical. It is especially important in a posterior stabilized design, which is subjected to repeated high stress loading on the insert spine.

Fatigue crack resistance, measured as ∆K inception, provides evidence of the material toughness. Relative toughness can also be measured by a ‘double notched’ Izod test that shows resistance to fracture when encountering sudden or catastrophic impact. While the chart shows that AOX Polyethylene exhibits lower toughness than that of non-irradiated “standard” polyethylene, it is superior to other competitive products.5,20

TOUGHNESS

Toughness of Materials

1.6

1.4

1.2

1

0.8

0.6

0.4

0.2

0

120

100

80

60

40

20

0

AOX Polyethylene5

3x Annealed7

10 Mrad Remelted7

Non-irradiated GUR 102015

AOX Polyethylene21

3x Annealed- No data available

10 Mrad Remelted20

Vitamin E Doped20

Do

ub

le N

otc

hed

Izo

d T

ou

gh

nes

s (k

J/m

2)

∆K

Ince

pti

on

1.6

1.4

1.2

1

0.8

0.6

0.4

0.2

0

120

100

80

60

40

20

0

AOX Polyethylene5

3x Annealed7

10 Mrad Remelted7

Non-irradiated GUR 102015

AOX Polyethylene21

3x Annealed- No data available

10 Mrad Remelted20

Vitamin E Doped20

Do

ub

le N

otc

hed

Izo

d T

ou

gh

nes

s (k

J/m

2)

∆K

Ince

pti

on

EXCELLENT MECHANICAL


AOX Polyethylene is exposed to a nominal dose of 8 Mrad Gamma radiation to deliver optimum wear properties via crosslinking of the polymer without compromising material strength. The ATTUNE Fixed Bearing Knee design exhibits reduced wear benefits in comparison to existing designs due to the optimized kinematics of the component design and the material change.22

Polyethylene Wear22

SIGMA® CR FB Knee with XLK Polyethylene

ATTUNE® CR FB Knee withAOX™ Polyethylene

Millions of Cycles

Wei

gh

t Lo

ss (

mg

)

543210

40

30

20

10

0

MAXIMIZING

WEAR RESISTANCE


A two-part study was conducted to evaluate the effects of the antioxidant content, radiation dose, accelerated aging, and physical form on the biocompatibility of AOX Polyethylene. These tests indicated that increased levels of the antioxidant, an increased dose of irradiation, accelerated-aged AOX Polyethylene, and irradiated powder which simulates wear debris do not induce any adverse biological response. The comprehensive biocompatibility analyses on the AOX Polyethylene formulation also demonstrated no evidence of any adverse effects.23

The AOX Polyethylene manufacturing process is designed to provide a uniform distribution of antioxidant within the final component. A spectroscopic analysis was conducted to verify the concentration and uniformity of the COVERNOX Antioxidant both in powder and moulded forms. This study validated that the antioxidant is uniformly distributed throughout AOX Polyethylene in both forms.24

The molecular structure of the COVERNOX Antioxidant and its solid state at room temperature are characteristics that contribute to its inability to migrate from the material. To confirm this low extractability, aggressive extraction conditions of refluxing hexane for an extended duration were employed. Both ester and ketone index profiles for AOX Polyethylene show relatively constant levels of the COVERNOX Antioxidant regardless of exposure to the hexane extraction or accelerated aging.25

Testing and researched areas include:

• Mechanical Integrity and Fatigue Resistance

• Uniformity of AO Concentration and Distribution

• Oxidative Stability

• Wear Resistance

• Extraction Resistance of COVERNOX Antioxidant

• Biocompatibility

• Biological and Toxicological Risk Assessments

• By-products of Irradiation Analysis

• Osteolytic Potential

• Antioxidant Migration Potential

Extensive testing was completed during the research and development process of AOX Polyethylene both internally and with external research institutions.

TESTED UNLIKE ANY OTHER


ATTUNE PS FB KneeATTUNE CR FB Knee ATTUNE Medialized Dome Patella

ATTUNE Medialized Anatomic Patella

ATTUNE CR RP Knee ATTUNE PS RP Knee

Antioxidant stabilized UHMWPE technology provides oxidative stability to an already well

established orthopaedic implant material, to enhance long-term performance. Patients expect

to continue their active lifestyles post-surgery, so today’s knee implants need to meet these demands.

NEXT GENERATIONWELCOME TO THE

AOX Polyethylene is available with the ATTUNE Knee System


DePuy Orthopaedics, Inc.700 Orthopaedic DriveWarsaw, IN 46582T. +1 (800) 366-8143

www.depuysynthes.com

Limited Warranty and Disclaimer: DePuy Synthes Joint Reconstruction products are sold with a limited warranty to the original purchaser against defects in workmanship and materials. Any other express or implied warranties, including warranties of merchantability or fitness, are hereby disclaimed.

WARNING: In the USA, this product has labeling limitations. See package insert for complete information.

CAUTION: USA Law restricts these devices to sale by or on the order of a physician.

Not all products are currently available in all markets.

References:

1. Rinmac, C.M., Klein, R.W., Betts, F., Wright, T.M. (1994). J. Bone Joint Surg., 76A:

1052-1056.

2. Premnath, V., Harris, W.H., Jasty, M., Merrill, E.W. (1996). Biomaterials, 17: 1741-

1753.

3. McKellop, H., Shen, F-W., Lu, B., Campbell, P., Salovery, R. (1999). J. Orth. Res, 17:

157-167.

4. Muratoglu, O.K., Bragdon, C.R., O’Connor, D.O., Jasty, M., Harris, W.H. (2001).

Journal of Athroplasty, 16(2): 179-160.

5. Data on File at DePuy Synthes Joint Reconstruction WR070300.


7. Morrison, M.L., Jani, S. (2009). Evaluation of sequentially crosslinked ultra-high

molecular weight polyethylene. Journal of Biomedical Materials Research Part B:

Applied Biomaterials 90B(1): 87-100.

8. Oral, E., Wannomae, K.K., Hawkins, N., Harris, W.H., Muratoglu, O.K. (2004).

Biomaterials, 25: 5515-5522.

9. Williams, S., Isaac, G., Porter, N., Fisher, J., Older, J. (2008). Clin Orthop Rel

Research., 466:366-372.

10. Oral, E., Wannomae, K.K., Rowell, S.L., Muratoglu, O.K. (2006). Biomaterial, 27:

2434-2439.

11. Biomet Commercial Literature for E1™HXLPEhttp://www.biomet.com/orthopedics/

productDetail.cfm? Category+1& product+235.

12. Lachiewicz, P.F., Geyer, M.R. (2011). Journal of the American Academy of

Orthopedic Surgeons,19(3): 143-151.

13. DePuy Material Specification MS 70014107.

14. Muratoglu, O.K. (2007). Grand Rounds Presentation at the Dartmouth Hitchcock

Medical Center on May 16. http://www.dnslides.org/ortho/ortho0515607/msh.htm.

15. Greer, K.W., Sharpe, M.S. (2007). Comparison of Cross-Linked UHMQPE Stabilized

by Sequential Annealing or by Remelting. 53rd Annual Meeting of the Orthopaedic

Research Society. February; Poster #1784.



18. Kurtz, S.M., UHMWPE Biomaterials Handbook (2nd ed.):73-74.

19. Malhi, A.S., Wannomae, K.K., Christensen, S.D., Godleski, C., Muratoglu, O.K. A

Novel Processing Methodology for Improvement of Mechanical Properties in Highly

Cross-Linked Polyethylene. 52nd Annual Meeting of the Orthopaedic Research

Society. March; Poster #0657.

20. Muratoglu, O.K., Burrough, B.R., Malhi, A.S., Christensen, S.D., Wannomac,

K., Oral, E., Spielgelberg, S., Harris., W.H. Two Second Generation Cross-linked

UHMWPES Show Improves Mechanical Properties and Fatigue Strength. 51st

Annual Meeting of the Orthopaedic Research Society. Poster #1661.


22. Dressler, M.R., Swope, S., Tikka, J., Hardaker, C., Heldreth, M., Render, T. (2012).

Wear of a Total Knee Replacement with Antioxidant UHMWPE and Gradually

Varying Sagittal Curvature. ORS Annual Meeting. February; Poster #0959.

23. King, R., Arscott, E., Narayan, V. (2010). Biocompatibility Study OF GAMMA-

IRRADIATED UHMWPE STABILIZED WITH A HINDERED PHENOL ANTIOXIDANT. ORS

Annual Meeting. March; Poster #2285.

24. Senyurt, A.F., Sharp, M., Warner, D., Narayan, V. (2010). DETERMINATION OF

ANTIOXIDANT DISTRIBUTION IN POWDER AND MOLDED UHMWPE MATERIALS.

ORS Annual Meeting. Poster # 2293.

25. King, R., Sharp, M., Narayan, V. (2010). Hexane Extraction Study of Gamma-

Irradiated UHMWPE Stabilized with a Hindered-Phenol Antioxidant. ORS Annual

Meeting. Poster #2286.

© DePuy Synthes Joint Reconstruction, a division of DOI 2014. All rights reserved. DSUS/JRC/0714/0314 0914

DePuy (Ireland)Loughbeg, RingaskiddyCo. Cork, IrelandT. +353 21 491 4000

The third party trademarks used herein are the trademarks of their respective owners.*DePuy Synthes Joint Reconstruction, a division of DePuy Orthopaedics, Inc.

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AOX™ ANTIOXIDANT POLYETHYLENEsynthes.vo.llnwd.net/o16/LLNWMB8/US Mobile/Synthes North America/Product Support...containing polyethylene involves mixing the antioxidant into the polyethylene