Investigating the translational value of Periprosthetic Joint Infection (PJI) models to determine the risk and severity of Staphylococcal biofilms.

With the advent of antibiotic-eluting polymeric materials for targeting recalcitrant infections, using preclinical models to study biofilm is crucial for improving the treatment efficacy in periprosthetic joint infections. The stratification of risk and severity of infections is needed to develop an effective clinical dosing framework with better outcomes. Here, using in-vivo and in-vitro implant-associated infection models, we demonstrate that methicillin-sensitive and resistant Staphylococcus aureus (MSSA and MRSA) have model-dependent distinct implant and peri-implant tissue colonization patterns. The maturity of biofilms and the location (implant vs tissue) were found to influence the antibiotic susceptibility evolution profiles of MSSA and MRSA and the models were able to capture the differing host-microbe interactions in vivo. Gene expression studies revealed the molecular heterogeneity of colonizing bacterial populations. The comparison and stratification of the risk and severity of infection across different preclinical models provided in this study can aid in guiding clinical dosing to effectively prevent or treat PJI.

Di-cumyl peroxide cross-linked UHMWPE/vitamin-E blend for total joint arthroplasty implants.

Majority of ultrahigh molecular weight polyethylene (UHMWPE) medical devices used in total joint arthroplasty are cross-linked using gamma radiation to improve wear resistance. Alternative methods of cross-linking are urgently needed to replace gamma radiation due to rapid decline in its supply. Peroxide cross-linking is a candidate method with widespread industrial applications. Oxidative stability and biocompatibility, which are critical requirements for medical device applications, can be achieved using vitamin-E as an additive and by removing peroxide by-products through high-temperature melting, respectively. We investigated compression molded UHMWPE/vitamin-E/di-cumyl peroxide blends followed by high-temperature melting in inert gas as a material candidate for tibial knee inserts. Wear resistance increased and mechanical properties remained largely unchanged. Oxidation induction time was higher than most of the other clinically available formulations. The material passed the local-end point biocompatibility tests per ISO 10993. Compounds found in exhaustive extraction were of no concern with margin-of-safety values well above the accepted level, indicating a desirable toxicological risk profile. Statement of Clinical Significance: Peroxide cross-linked, vitamin-E stabilized, and high-temperature melted UHMWPE has recently been cleared for clinical use in tibial knee inserts. With all the salient characteristics needed in a material that can provide superior long-term performance in total joint patients, peroxide cross-linking can replace the gamma radiation cross-linking of UHMWPE.

Antibiotic-Loaded Ultrahigh Molecular Weight Polyethylenes.

The occurrence of periprosthetic joint infections (PJI) after total joint replacement constitutes a great burden for the patients and the healthcare system. Antibiotic-loaded polymethylmethacrylate (PMMA) bone cement is often used in temporary spacers during antibiotic treatment. PMMA is not a load-bearing solution and needs to be replaced by a functional implant. Elution from the ultrahigh molecular weight polyethylene (UHMWPE) bearing surface for drug delivery can combine functionality with the release of clinically relevant doses of antibiotics. In this study, the feasibility of incorporating a range of antibiotics into UHMWPE is investigated. Drug stability is assessed by thermo-gravimetric analysis and nuclear magnetic resonance spectroscopy. Drug-loaded UHMWPEs are prepared by compression molding, using eight antibiotics at different loading. The predicted intra-articular concentrations of drugs eluted from UHMWPE are above minimum inhibitory concentration for at least 3 weeks against Staphylococci, which are the major causative bacteria for PJI. The antibacterial efficacy is confirmed for samples covering 2% of a representative knee implant in vitro over 72 h, showing that a small fraction of the implant surface loaded with antibiotics may be sufficient against Staphylococci.

Addressing prosthetic joint infections via gentamicin-eluting UHMWPE spacer.

AIMS: We propose a state-of-the-art temporary spacer, consisting of a cobalt-chrome (CoCr) femoral component and a gentamicin-eluting ultra-high molecular weight polyethylene (UHMWPE) tibial insert, which can provide therapeutic delivery of gentamicin, while retaining excellent mechanical properties. The proposed implant is designed to replace conventional spacers made from bone cement. METHODS: Gentamicin-loaded UHMWPE was prepared using phase-separated compression moulding, and its drug elution kinetics, antibacterial, mechanical, and wear properties were compared with those of conventional gentamicin-loaded bone cement. RESULTS: Gentamicin-loaded UHMWPE tibial components not only eradicated planktonic Staphylococcus aureus, but also prevented colonization of both femoral and tibial components. The proposed spacer possesses far superior mechanical and wear properties when compared with conventional bone cement spacers. CONCLUSION: The proposed gentamicin-eluting UHMWPE spacer can provide antibacterial efficacy comparable with currently used bone cement spacers, while overcoming their drawbacks. The novel spacer proposed here has the potential to drastically reduce complications associated with currently used bone cement spacers and substantially improve patients' quality of life during the treatment. Cite this article: Bone Joint J 2020;102-B(6 Supple A):151-157.

Chemically Cross-Linked UHMWPE With Superior Toughness.

Radiation cross-linked ultra-high-molecular-weight polyethylenes (UHMWPEs) are clinically used extensively in total joint arthroplasty due to their high wear resistance. Peroxide cross-linking of UHMWPE has been proposed to achieve this high level of wear resistance by simultaneously consolidating and cross-linking in the melt state. High temperature melting of uncross-linked and cross-linked UHMWPEs have further shown to improve the toughness. Here, we report on the wear and mechanical properties of a peroxide cross-linked and high-temperature melted UHMWPE as a function of vitamin E concentration for oxidative stabilization, peroxide concentration for cross-linking and high temperature melting temperature for toughness improvement. This method, combining consolidation and cross-linking in one step, presents an opportunity to manufacture highly wear and oxidation-resistant joint implant-bearing surfaces with much improved toughness. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2182-2188, 2019.

An antioxidant stabilized, chemically cross-linked UHMWPE with superior toughness.

Chemical cross-linking of ultrahigh molecular weight polyethylene (UHMWPE) using an organic peroxide followed by high temperature melting results in a large increase in toughness accompanied by a decrease in cross-link density, which, surprisingly does not compromise the wear resistance. We compared the mechanical properties and wear behavior of a vitamin E blended, chemically cross-linked and high temperature melted UHMWPE produced by ram extrusion (PRX HTM) to those measured with the clinically available 100-kGy irradiated and melted UHMWPE (CISM 100). We also assessed the local biocompatibility of PRX-HTM in rabbit subcutaneous pouch and osteochondral defect models. The ultimate tensile strength and pin-on-disc wear rate were similar to CISM 100; whereas the elongation-at-break and impact toughness were much higher with PRX-HTM. The stress intensity factor range at crack inception was also higher with PRX-HTM. Accelerated aging did not result in any measurable oxidation or changes in mechanical properties. Hip simulator wear rate of acetabular liners made with PRX-HTM was 0.3 ± 0.4 mg/million-cycle, similar to that reported for CISM 100 liners. The wear particles were largely spherical with a number-averaged particle size of 0.95 µm with ~75% of particles below 1 µm. The subcutaneous and osteochondral rabbit implantations showed no histological differences between PRX-HTM and the control CISM 100. Pre-clinical wear, mechanical, and biocompatibility testing of PRX HTM showed feasibility for the use of this material as a total joint arthroplasty implant bearing surface. This process has the potential of eliminating the additional step of radiation cross-linking by combining consolidation and cross-linking while improving toughness. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1945-1952, 2019.

Increased oxidative protection by high active vitamin E content and partial radiation crosslinking of UHMWPE.

Vitamin E stabilization successfully improved long-term oxidation resistance of wear-resistant ultra-high-molecular-weight polyethylene (UHMWPE) used for joint implants. Stabilization can be achieved by blending an antioxidant into the UHMWPE resin powder before consolidation and irradiation. Balancing the wear resistance and vitamin E content in the blend is the current challenge with this approach, because vitamin E hinders crosslinking of UHMWPE during irradiation, which decreases wear resistance. The vitamin E concentration in the blend is generally limited to less than 0.3 wt%. Wear- and oxidation-resistant UHMWPE has been obtained previously by consolidating blends of pre-irradiated UHMWPE powders (XPE) into an unmodified polyethylene matrix (PE), where the improvement in wear rate depended on the radiation dose and fraction of XPE. We hypothesized that increasing the vitamin E content in the unirradiated matrix would not compromise wear and would further improve the oxidative stability of XPE/PE blends. Pin-on-disk wear testing showed that the XPE/PE blends containing 0.1-1.0 wt% vitamin E in the matrix had comparable wear rates. We used an aggressive accelerated aging test in the presence of the pro-oxidant squalene and oxidation induction time (OIT) test and found that higher amounts of vitamin E resulted in stronger oxidation resistance for XPE/PE blends. The mechanical strength and toughness of the blends were not affected by changing the vitamin E content in the matrix. Stabilizing UHMWPE with higher vitamin E content may extend the service life of UHMWPE implants. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1860-1867, 2018.

Knee simulator wear of vitamin E stabilized irradiated ultrahigh molecular weight polyethylene.

Wear and damage of ultrahigh molecular weight polyethylene (UHMWPE) tibial inserts used in total knee arthroplasty are accelerated by oxidation. Radiation crosslinking reduces wear but produces residual free radicals adversely affecting stability. One alternative to stabilize radiation-crosslinked UHMWPE is to infuse the material with vitamin E (vit E). We investigated the properties of 100-kGy e-beam-irradiated UHMWPE that was subsequently doped with vitamin E in comparison with conventional UHMWPE. Both polymers were sterilized with gamma irradiation in vacuum packaging. Vitamin E-doped UHMWPE showed lower wear before and after aging (2.4 ± 0.5 and 2.5 ± 0.8 mg/million cycle, respectively, vs 26.9 ± 3.5 and 40.8 ± 3.0 mg/million cycle for conventional UHMWPE). Conventional UHMWPE showed oxidation after accelerated aging, and its mechanical properties were adversely affected, whereas vit E-doped UHMWPE showed no oxidation or changes in its mechanical properties. Vitamin E stabilization of radiation-crosslinked UHMWPE resulted in low wear and high oxidation resistance; it is an alternative load-bearing material for total knee applications.

Ex vivo stability loss of irradiated and melted ultra-high molecular weight polyethylene.

BACKGROUND: Radiation crosslinking reduces wear of ultra-high molecular weight polyethylene (UHMWPE), and subsequent annealing or melting increases oxidative stability. Little is known about the oxidative stability of polyethylene total joint components after in vivo service and subsequent shelf storage in air. METHODS: We analyzed thirty-four surgically retrieved, radiation crosslinked acetabular liners to determine their oxidative stability after in vivo service (range, 0.5 to 84.0 months). Oxidation was determined at the time of explantation. After shelf storage in air (range, 7.0 to 72.0 months), oxidation, crosslink density, and thermal properties were determined. Oxidation of one control liner that was shelf-aged in air (for eighty-four months) was also determined. RESULTS: At the time of explantation, all components showed minimal oxidation; however, oxidation levels increased during shelf storage, with a concomitant decrease in crosslink density and increase in crystallinity. Increasing oxidation, increasing crystallinity, and decreasing crosslink density correlated with the duration of ex vivo storage. The shelf-aged control liner showed no detectable oxidation. CONCLUSIONS: The oxidation and loss of crosslink density of the irradiated and melted UHMWPE was surprising. Two potential mechanisms that might alter the oxidative stability of UHMWPE in vivo are cyclic loading and absorption of lipids. Both of these mechanisms can generate new free radicals in UHMWPE and can initiate and propagate its oxidation.

Delamination and adhesive wear behavior of alpha-tocopherol-stabilized irradiated ultrahigh-molecular-weight polyethylene.

Wear and delamination of conventional ultrahigh-molecular-weight polyethylene (UHMWPE) components used in total knee arthroplasty can compromise long-term performance. Radiation cross-linking and melt-annealing reduced wear and increased delamination resistance of UHMWPE. An alternative material is the alpha-tocopherol-stabilized irradiated UHMWPE (alphaTPE), with improved mechanical and fatigue properties vs irradiated and melted UHMWPE. We studied the wear and delamination resistance of alphaTPE and conventional UHMWPE (direct compression molded GUR 1050 and Himont 1900) under reciprocating unidirectional motion. Wear resistance was improved, and no delamination was observed in alphaTPE. Accelerated aging did not alter the wear and delamination behavior of alphaTPE. The GUR 1050 UHMWPE showed delamination and pitting when subjected to unidirectional reciprocating motion after accelerated aging. Himont 1900 UHMWPE showed no delamination when subjected to unidirectional reciprocating motion after accelerated aging. alpha-Tocopherol-stabilized irradiated UHMWPE is advanced for use in total knee arthroplasty due to its high resistance to wear, delamination, and oxidation.

Fracture of a cross-linked polyethylene liner due to impingement.

We report a case of fracture at 2 years after implantation of a 50-kGy moderately cross-linked ultrahigh molecular weight polyethylene liner with an extended lip (Marathon, DePuy, Warsaw, IN). The extended lip section had fractured. The liner showed no oxidation. The articular surface was grossly deformed, likely due to wear, creep, and/or plastic deformation, and the liner showed no recovery of machining marks upon melting, indicating that some wear had occurred. Electron microscopy revealed fatigue striations on the fracture surface. The likely cause of failure was femoral neck impingement-induced wear and fatigue on the liner.

Highly cross-linked ultrahigh molecular weight polyethylene with improved fatigue resistance for total joint arthroplasty: recipient of the 2006 Hap Paul Award.

Eliminating postirradiation melting and stabilizing the residual free radicals of radiation cross-linked ultrahigh molecular weight polyethylene (UHMWPE) with vitamin E resulted in improved fatigue crack propagation resistance without compromising wear resistance. We designed a cantilever postbending test to determine the bending fatigue resistance of alpha-tocopherol-doped, irradiated UHMWPE (alpha-TPE) in comparison to conventional UHMWPE. The bending fatigue behavior of alpha-TPE was comparable to conventional UHMWPE. Upon accelerated aging, the fatigue resistance of alpha-TPE was substantially better than that of conventional UHMWPE. alpha-TPE has shown improved wear and oxidation resistance, migration stability of vitamin E, and improved mechanical properties. The use of this material may be beneficial in total knee arthroplasty where its improved fatigue properties may be an advantage under high stresses.

Diffusion of vitamin E in ultra-high molecular weight polyethylene.

Vitamin E-doped, radiation crosslinked ultra-high molecular weight polyethylene (UHMWPE) is developed as an alternate oxidation and wear resistant bearing surface in joint arthroplasty. We analyzed the diffusion behavior of vitamin E through UHMWPE and predicted penetration depth following doping with vitamin E and subsequent homogenization in inert gas used to penetrate implant components with vitamin E. Crosslinked UHMWPE (65- and 100-kGy irradiation) had higher activation energy and lower diffusion coefficients than uncrosslinked UHMWPE, but there were only slight differences in vitamin E profiles and penetration depth between the two doses. By using homogenization in inert gas below the melting point of the polymer following doping in pure vitamin E, the surface concentration of vitamin E was decreased and vitamin E stabilization was achieved throughout a desired thickness. We developed an analytical model based on Fickian theory that closely predicted vitamin E concentration as a function of depth following doping and homogenization.

In vivo oxidation of retrieved cross-linked ultra-high-molecular-weight polyethylene acetabular components with residual free radicals.

Wear of ultra-high-molecular-weight polyethylene (UHMWPE) contributes to debris that can lead to periprosthetic osteolysis in total hip arthroplasty. Irradiation not only decreases wear of UHMWPE but also generates residual free radicals that can oxidize the UHMWPE in the long term. Melting or annealing is used to quench the free radicals. Melting is more effective than annealing. We hypothesized that the postirradiation annealed UHMWPE components would oxidize in vivo and that postirradiation melted ones would not. We analyzed surgical explants of UHMWPE acetabular liners. The irradiated and annealed explants showed embrittlement, oxidation, and an increase in crystallinity. The irradiated and melted UHMWPE explants showed no oxidation, no increase in crystallinity, and no embrittlement. To prevent long-term chemical changes in highly cross-linked UHMWPE components, the residual free radicals must be stabilized after irradiation, preferably by melting and not annealing.

In vitro comparison of frictional torque and torsional resistance of aged conventional gamma-in-nitrogen sterilized polyethylene versus aged highly crosslinked polyethylene articulating against head sizes larger than 32 mm.

BACKGROUND: The advent of highly crosslinked polyethylene has allowed the re-evaluation of the use of femoral heads larger than 32 mm for metal-on-polyethylene total hip arthroplasties. However, the effect of larger heads on the frictional torque of highly crosslinked polyethylene is unknown. METHODS: We performed an in vitro examination of the effect of larger chrome cobalt femoral heads (40 mm diameter) on the frictional torque and torsional resistance of hip articulations on aged liners of polyethylene that were sterilized by gamma rays while in nitrogen, and aged highly crosslinked polyethylene. The frictional torque at the femoral head articulation was usually higher for the highly crosslinked polyethylene than for the conventional polyethylene. The aged conventional liners oxidized considerably, which led to gross failure of the polyethylene at the anti-rotation portion of the rim. The aged crosslinked polyethylene showed no such failures despite the higher frictional torque. INTERPRETATION: Our findings suggest that in terms of torsional resistance to fatigue when studied as a device, rather than as an isolated material, under these conditions, aged highly crosslinked polyethylene is preferable to aged conventional polyethylene.

Wear resistance and mechanical properties of highly cross-linked, ultrahigh-molecular weight polyethylene doped with vitamin E.

Our hypothesis was that cross-linked, ultrahigh-molecular weight polyethylene (UHMWPE) stabilized with vitamin E (alpha-tocopherol) would be wear-resistant and fatigue-resistant. Acetabular liners were radiation cross-linked, doped with vitamin E, and gamma-sterilized. Hip simulator wear rate of vitamin E-stabilized UHMWPE was approximately 1 and 6 mg/million-cycles in clean serum and in serum with third-body particles, respectively, a 4-fold to 10-fold decrease from that of conventional UHMWPE. The ultimate strength, yield strength, elongation at break, and fatigue resistance of vitamin E-stabilized UHMWPE were significantly higher than that of 100 kGy-irradiated and melted UHMWPE, and were unaffected by accelerated aging. Rim impingement testing with 3.7-mm-thick acetabular liners up to 2 million-cycles showed no significant damage of the cross-linked liners compared with conventional, gamma-sterilized in inert UHMWPE, vitamin E-stabilized liners. The data indicate good in vitro wear properties and improved mechanical and fatigue properties for vitamin E-stabilized, cross-linked UHMWPE.

Migration stability of alpha-tocopherol in irradiated UHMWPE.

The oxidation resistance of irradiated ultra-high molecular weight polyethylene (UHMWPE) components used in total joint arthroplasty can be improved by adding alpha-tocopherol (vitamin E) through diffusion. To ensure long-term oxidative stability, a minimum alpha-tocopherol concentration needs to be maintained throughout these components. Migration of alpha-tocopherol out of the components is one mechanism that could compromise long-term oxidative stability. We hypothesized that alpha-tocopherol could elute out during standard implant fabrication steps such as cleaning as well as during in vivo use. We doped 85 kGy irradiated UHMWPE with alpha-tocopherol at 120 degrees C and homogenized at 120 degrees C. We determined the extent of elution of alpha-tocopherol or its effect on oxidative stability following cleaning in isopropyl alcohol (IPA) and following 5 million cycles (MC) of simulated normal gait in bovine serum. There was no significant elution of alpha-tocopherol in repeated and prolonged cleaning in IPA as measured by average surface and bulk alpha-tocopherol concentrations. There was no change in the oxidative stability following 5 MC of hip simulator testing, indicating minimal elution during simulated normal gait.

The effect of real-time aging on the oxidation and wear of highly cross-linked UHMWPE acetabular liners.

Irradiation decreases the wear of ultra-high molecular weight polyethylene (UHMWPE) but generates residual free radicals, precursors to long-term oxidation. Melting or annealing is used in quenching free radicals. We hypothesized that irradiated and once-annealed UHMWPE would oxidize while irradiated and melted UHMWPE would not, and that the oxidation in the former would increase wear. Acetabular liners were real-time aged by immersion in an aqueous environment that closely mimicked the temperature and oxygen concentration of synovial fluid. After 95 weeks of real-time aging, once-annealed components were oxidized; the melted components were not. The wear rate of the real-time aged irradiated and once-annealed components was higher than the literature reported values of other contemporary highly cross-linked UHMWPEs. Single annealing after irradiation used with terminal gamma sterilization may adversely affect the long-term oxidative stability of UHMWPE components.

Alpha-tocopherol-doped irradiated UHMWPE for high fatigue resistance and low wear.

Longevity of total joints has been compromised by wear and fatigue of ultrahigh molecular weight polyethylene (UHMWPE) components. Crosslinking reduces UHMWPE wear, but combined with postirradiation melting, also reduces its fatigue strength, therefore limiting its use in high-stress applications. We hypothesized that a lipophilic antioxidant (alpha-tocopherol, alpha-T) can protect UHMWPE against oxidation eliminating the need for postirradiation melting of crosslinked UHMWPE and improve its fatigue strength. To test these hypotheses, 65- and 100-kGy irradiated, alpha-T-doped and subsequently gamma-sterilized UHMWPE were used. (I) alpha-T-doped irradiated UHMWPEs showed significantly lower oxidation levels (0.48+/-0.25 and 0.44+/-0.06) compared to 100-kGy irradiated UHMWPE (3.74+/-0.16) after 5 weeks of accelerated aging at 80 degrees C in air. (II) Wear rate of alpha-T-doped irradiated UHMWPE (1.9+/-0.5, and 0.9+/-0.1mg/million cycles (MC) for 65- and 100-kGy irradiated UHMWPE, respectively) were comparable to that of 100-kGy irradiated/melted UHMWPE (1.1+/-0.7mg/million cycles). (III) The stress intensity factor at crack inception ( DeltaKi) of 100-kGy irradiated UHMWPE increased significantly upon doping with alpha-T from 0.74 to 0.87MPam(1/2) ( p<0.01 ). The DeltaKi for the 100-kGy irradiated and melted UHMWPE, currently in clinical use, was 0.55MPam(1/2). Doping with alpha-T eliminated the need for postirradiation melting to protect irradiated UHMWPE against long-term oxidation. The fatigue strength was improved by 58% for alpha-T-doped 100-kGy irradiated UHMWPE compared to irradiated and melted UHMWPE. The increase in oxidative stability of alpha-T-doped UHMWPE is attributed to the ability of alpha-T to react with peroxy free radicals on lipid chains and arrest the oxidation reactions. The improved fatigue strength is attributed to the increase in plasticity of UHMWPE due to the lipophilic nature of alpha-T.