Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms.

BACKGROUND: While antibiotics remain our primary tools against microbial infection, increasing antibiotic resistance (inherent and acquired) is a major detriment to their efficacy. A practical approach to maintaining or reversing the efficacy of antibiotics is the use of other commonly used therapeutics, which show synergistic antibacterial action with antibiotics. Here, we investigated the extent of antibacterial synergy between the antibiotic gentamicin and the anti-inflammatory ketorolac regarding the dynamics of biofilm growth, the rate of acquired resistance, and the possible mechanism of synergy. METHODS: Control (ATCC 12600, ATCC 35984) and clinical strains (L1101, L1116) of Staphylococcus aureus and Staphylococcus epidermidis with varying antibiotic susceptibility profiles were used in this study to simulate implant-material associated low-risk and high-risk biofilms in vitro. The synergistic action of gentamicin sulfate (GS) and ketorolac tromethamine (KT), against planktonic staphylococcal strains were determined using the fractional inhibitory concentration measurement assay. Nascent (6 h) and established (24 h) biofilms were grown on 316L stainless steel plates and the synergistic biofilm eradication activity was determined and characterized using adherent bacteria count, minimum biofilm eradication concentration (MBEC) measurement for GS, visualization by live/dead imaging, scanning electron microscopy, gene expression of biofilm-associated genes, and bacterial membrane fluidity assessment. RESULTS: Gentamicin-ketorolac (GS-KT) combination demonstrated synergistic antibacterial action against planktonic Staphylococci. Control and clinical strains showed distinct biofilm growth dynamics and an increase in biofilm maturity was shown to confer further resistance to gentamicin for both 'low-risk' and 'high-risk' biofilms. The addition of ketorolac enhanced the antibiofilm activity of gentamicin against acquired resistance in staphylococcal biofilms. Mechanistic studies revealed that the synergistic action of gentamicin-ketorolac interferes with biofilm morphology and subverts bacterial stress response altering bacterial physiology, membrane dynamics, and biofilm properties. CONCLUSION: The results of this study have a significant impact on the local administration of antibiotics and other therapeutic agents commonly used in the prevention and treatment of orthopaedic infections. Further, these results warrant the study of synergy for the concurrent or sequential administration of non-antibiotic drugs for antimicrobial effect.

Irradiation Behavior of Analgesic and Nonsteroidal Anti-Inflammatory Drug-Loaded UHMWPE for Joint Replacement.

Local delivery of pain medication can be a beneficial strategy to address pain management after joint replacement, as it can decrease systemic opioid usage, leading to less side and long-term effects. In this study, we used ultrahigh molecular weight polyethylene (UHMWPE), commonly employed as a bearing material for joint implants, to deliver a wide set of analgesics and the nonsteroidal anti-inflammatory drug tolfenamic acid. We blended the drugs with UHMWPE and processed the blend by compression molding and sterilization by low-dose gamma irradiation. We studied the chemical stability of the eluted drugs, drug elution, tensile properties, and wear resistance of the polymer blends before and after sterilization. The incorporation of bupivacaine hydrochloride and tolfenamic acid in UHMWPE resulted in either single- or dual-drug loaded materials that can be sterilized by gamma irradiation. These compositions were found to be promising for the development of clinically relevant drug-eluting implants for joint replacement.

A longitudinal rat model for assessing postoperative recovery and bone healing following tibial osteotomy and plate fixation.

BACKGROUND: Rodent models are commonly employed to validate preclinical disease models through the evaluation of postoperative behavior and allodynia. Our study investigates the dynamic interplay between pain and functional recovery in the context of traumatic osteotomy and surgical repair. Specifically, we established a rat model of tibial osteotomy, followed by internal fixation using a 5-hole Y-plate with 4 screws, to explore the hypothesis that histological bone healing is closely associated with functional recovery. OBJECTIVE: Our primary objective was to assess the correlation between bone healing and functional outcomes in a rat model of tibial osteotomy and plate fixation. METHODS: Seventeen male Sprague-Dawley rats underwent a metaphyseal transverse osteotomy of the proximal tibia, simulating a fracture-like injury. The resultant bone defect was meticulously repaired by realigning and stabilizing the bone surfaces with the Y-plate. To comprehensively assess recovery and healing, we performed quantitative and qualitative evaluations at 2, 4, 6, and 8 weeks post-surgery. Evaluation methods included micro-CT imaging, X-ray analysis, and histological examination to monitor bone defect healing. Concurrently, we employed video recording and gait analysis to evaluate functional recovery, encompassing parameters such as temporal symmetry, hindlimb duty factor imbalance, phase dispersion, and toe spread. RESULTS: Our findings revealed complete healing of the bone defect at 8 weeks, as confirmed by micro-CT and histological assessments. Specifically, micro-CT data showed a decline in fracture volume over time, indicating progressive healing. Histological examination demonstrated the formation of new trabecular bone and the resolution of inflammation. Importantly, specific gait analysis parameters exhibited longitudinal changes consistent with bone healing. Hindlimb duty factor imbalance, hindlimb temporal symmetry, and phase dispersion correlated strongly with the healing process, emphasizing the direct link between bone healing and functional outcomes. CONCLUSIONS: The establishment of this tibia osteotomy model underscores the association between bone healing and functional outcomes, emphasizing the feasibility of monitoring postoperative recovery using endpoint measurements. Our overarching objective is to employ this model for assessing the local efficacy of drug delivery devices in ameliorating post-surgical pain and enhancing functional recovery.

Residual Byproducts of Peroxide Crosslinked Vitamin E-Blended Ultrahigh Molecular Weight Polyethylene.

BACKGROUND: Wear resistance of ultrahigh molecular weight polyethylene (UHMWPE) is improved via ionizing radiation crosslinking and subsequent high temperature melting for improved toughness. Our group has previously reported that crosslinking can also be achieved chemically using organic peroxides. However, volatile peroxide byproducts are generated during consolidation. The purpose of this study was to quantify elution of volatile peroxide byproducts from UHMWPE before and after in vivo implantation, and to determine their effects on local tissues. METHODS: We prepared crosslinked UHMWPE samples with 5 times the nominal concentration of peroxide needed for improved wear resistance. Control samples (not crosslinked), crosslinked samples, and crosslinked high temperature melting samples were implanted subcutaneously in New Zealand white rabbits for 28 days. Fourier-transform infrared spectroscopy (FTIR) was used to quantify elution of residual peroxide byproducts, and biocompatibility was determined via histological analysis of periprosthetic tissues. RESULTS: Fourier-transform infrared spectroscopy demonstrated elution of residual peroxide byproducts in vivo. No histological differences were observed between tissues in contact with any of the 3 groups of implants; tissues were characterized by fibrosis and a synovial-like lining for all groups. CONCLUSION: UHMWPE chemically crosslinked with very high concentration of organic peroxide did not show any detrimental changes to surrounding subcutaneous tissues, further demonstrating feasibility of crosslinking UHMWPE with a peroxide, rather than irradiation, for the potential use of the material as a bearing surface for joint arthroplasty.

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.

The efficacy of antibiotic-eluting material in a two-stage model of periprosthetic joint infection.

Periprosthetic joint infections occur in about 2% of patients who undergo primary total joint arthroplasty, a procedure performed over 1 million times in the United States. The gold standard of treatment is a two-stage revision. This study aimed to establish a two-stage procedure in a preclinical small animal model (rat) to test and compare the efficacy of an antibiotic-eluting material in managing infection. Joint replacement was simulated by transchondylarly implanting a polyethylene (PE) plug into the distal femur and a titanium screw in the proximal tibia. Methicillin-sensitive Staphylococcus aureus (MSSA) 108 CFU/mL was injected into the tibial canal and the joint space before wound closure. The control groups were killed on postoperative day (POD) 18 (n = 12) and on POD 42 (n = 4) to assess both early and later-stage outcomes in the control group. The test group underwent revision surgery on POD 18 for treatment using gentamicin-eluting polyethylene (GPE, n = 4) and was observed until POD 42 to evaluate the efficacy of treatment. Our results showed that the bone loss for the treatment group receiving GPE was significantly less than that of the control (p < 0.05), which was supported by the histology images and an AI-tool assisted infection rate evaluation. Gait metrics duty factor imbalance and hindlimb temporal symmetry were significantly different between the treatment and control groups on Day 42. This animal model was feasible for evaluating treatments for peri-prosthetic joint infections (PJI) with a revision surgery and specifically that revision surgery and local antibiotic treatment largely hindered the peri-prosthetic bone loss. Statement of clinical significance: This revision model of peri-prosthetic infection has the potential of comparatively evaluating prophylaxis and treatment strategies and devices. Antibiotic-eluting UHMWPE is devised as at tool in treating PJI while providing weight bearing and joint space preservation.

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.

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 could 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 guide clinical dosing to effectively prevent or treat PJI.

Diffusion doping of analgesics into UHMWPE for prophylactic pain management.

Pain management after total joint arthroplasty is often addressed by systemic delivery of opioids. Local delivery of non-opioid analgesic drugs directly in the joint space from the UHMWPE component of the prosthesis would be highly beneficial to increase the efficacy of the drugs, decreasing the overall side effects and the risk of opioid addiction. It has been shown that effective concentrations of local analgesics can be achieved by eluting from analgesic-blended UHMWPE; however, this approach is limited by the decrease in mechanical properties resulting from the extent of phase separation of the blended drugs from the polymeric matrix. Here we hypothesized that mechanical properties could be maintained by incorporating analgesics into solid form UHMWPE by diffusion as an alternative method. Lidocaine or bupivacaine were diffused in solid form UHMWPE with or without radiation crosslinking. The loaded drug content, the spatial distribution of the drugs and their chemical stability after doping were characterized by FTIR and NMR spectroscopy, respectively. Drug release kinetics, tensile mechanical properties and wear rates were assessed. The results showed that diffusion doping could be used as a promising method to obtain a therapeutic implant material without compromising its mechanical and structural integrity.

The efficacy of vitamin E in preventing arthrofibrosis after joint replacement.

BACKGROUND: Arthrofibrosis is a joint disorder characterized by excessive scar formation in the joint tissues. Vitamin E is an antioxidant with potential anti-fibroblastic effect. The aim of this study was to establish an arthrofibrosis rat model after joint replacement and assess the effects of vitamin E supplementation on joint fibrosis. METHODS: We simulated knee replacement in 16 male Sprague-Dawley rats. We immobilized the surgical leg with a suture in full flexion. The control groups were killed at 2 and 12 weeks (n = 5 per group), and the test group was supplemented daily with vitamin E (0.2 mg/mL) in their drinking water for 12 weeks (n = 6). We performed histological staining to investigate the presence and severity of arthrofibrosis. Immunofluorescent staining and α2-macroglobulin (α2M) enzyme-linked immunosorbent assay (ELISA) were used to assess local and systemic inflammation. Static weight bearing (total internal reflection) and range of motion (ROM) were collected for functional assessment. RESULTS: The ROM and weight-bearing symmetry decreased after the procedure and recovered slowly with still significant deficit at the end of the study for both groups. Histological analysis confirmed fibrosis in both lateral and posterior periarticular tissue. Vitamin E supplementation showed a moderate anti-inflammatory effect on the local and systemic levels. The vitamin E group exhibited significant improvement in ROM and weight-bearing symmetry at day 84 compared to the control group. CONCLUSIONS: This model is viable for simulating arthrofibrosis after joint replacement. Vitamin E may benefit postsurgical arthrofibrosis, and further studies are needed for dosing requirements.

The 2023 Orthopedic Research Society's international consensus meeting on musculoskeletal infection: Summary from the in vitro section.

Antimicrobial strategies for musculoskeletal infections are typically first developed with in vitro models. The In Vitro Section of the 2023 Orthopedic Research Society Musculoskeletal Infection international consensus meeting (ICM) probed our state of knowledge of in vitro systems with respect to bacteria and biofilm phenotype, standards, in vitro activity, and the ability to predict in vivo efficacy. A subset of ICM delegates performed systematic reviews on 15 questions and made recommendations and assessment of the level of evidence that were then voted on by 72 ICM delegates. Here, we report recommendations and rationale from the reviews and the results of the internet vote. Only two questions received a ≥90% consensus vote, emphasizing the disparate approaches and lack of established consensus for in vitro modeling and interpretation of results. Comments on knowledge gaps and the need for further research on these critical MSKI questions are included.

A Novel Method to Determine the Longitudinal Antibacterial Activity of Drug-Eluting Materials.

Ultrahigh molecular weight polyethylene (UHMWPE) is widely used in total joint arthroplasties as a load-bearing surface. Periprosthetic joint infections, the majority of which occur shortly after joint replacement, constitute almost 25% of total knee revision surgeries, and the complete eradication of bacterial infection poses a major challenge. A promising way to tackle this problem is to ensure the local sustained delivery of antibiotic concentrations sufficient to inhibit the bacteria to support routine systemic antibiotic prophylaxis. There is increased research into the development of efficient local drug delivery devices. Although established antibacterial testing methods for drugs can be used to test the antibacterial efficacy of drug-eluting materials, they are lacking in terms of providing real-time and longitudinal antibacterial efficacy data that can be correlated to the elution profiles of antibiotics from these devices. Here, we report a direct and versatile methodology to determine the antibacterial efficacy of antibiotic-eluting UHMWPE implants. This methodology can be used as a platform to avoid bacterial culture at each time point of a lengthy experiment and can also be adapted to other local drug delivery devices.

Dual-analgesic loaded UHMWPE exhibits synergistic antibacterial effects against Staphylococci.

Total joint arthroplasty is one of the most common surgeries in the United States, with almost a million procedures performed annually. Periprosthetic joint infections (PJI) remain the most devastating complications associated with total joint replacement. Effective antibacterial prophylaxis after primary arthroplasty could substantially reduce incidence rate of PJI. In the present study we propose to provide post-arthroplasty prophylaxis via dual-analgesic loaded ultra-high molecular weight polyethylene (UHMWPE). Our approach is based on previous studies that showed pronounced antibacterial activity of analgesic- and NSAID-loaded UHMWPE against Staphylococci. Here, we prepared bupivacaine/tolfenamic acid-loaded UHMWPE and assessed its antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis. Dual-drug loaded UHMWPE yielded an additional 1-2 log reduction of bacteria, when compared with single-drug loaded UHMWPE. Analysis of the drug elution kinetics suggested that the observed increase in antibacterial activity is due to the increased tolfenamic acid elution from dual-drug loaded UHMWPE. We showed that the increased fractal dimension of the drug domains in UHMWPE could be associated with increased drug elution, leading to higher antibacterial activity. Dual-analgesic loaded UHMWPE proposed here can be used as part of multi-modal antibacterial prophylaxis and promises substantial reduction in post-arthroplasty mortality and morbidity.

Hydrogel device for analgesic drugs with in-situ loading and polymerization.

The high prevalence of opioid addiction and the shortcomings of systemic opioids has increased the pace of the search for alternative methods of pain management. The local delivery of pain medications has started to be used as a tool for pain management and to decrease the use of systemic opioids for these patients. Here, we explored an in-situ polymerizable hydrogel system for the local delivery of analgesics and nonsteroid anti-inflammatory drugs (NSAID) for orthopaedic applications. We synthesized a series of methacrylated oligomeric polyethylene glycol-co-lactic acid polymer using microwave radiation for the delivery of bupivacaine hydrochloride as an analgesic and ketorolac tromethamine as an NSAID. We determined drug elution and gel degradation profiles in vitro. Biocompatibility was assessed against osteoblasts in vitro and by histological analysis after subcutaneous implantation for 4 weeks in vivo. Intra-articular and systemic concentrations and pharmacokinetic parameters were estimated using a two-compartment pharmacodynamic model based on in-vitro elution profiles. This type of in-situ applicable hydrogels is promising for extending the local efficacy of pain medication and further reducing the need for opioids.

Clinical course and outcome of Covid-19 in patients with myasthenia gravis.

OBJECTIVES: To analyze the prognosis and outcomes of COVID-19 in patients with MG and to determine factors associated with COVID-19 severity in patients with MG. METHODS: Information concerning COVID-19 occurrence in patients with MG was collected in this single-center observational study. Univariate and multivariate analyses were used to identify factors associated with severe Covid-19. RESULTS: Two hundred seventy-five of the 386 records of MG were included in this study. Eighty-two (29.8%) patients had concurrent COVID-19 . The patients' mean age was 50.3 ± 1.6 years, and the mean duration of MG was 6.7 ± 5.4 years. MG was diagnosed after COVID-19 in five cases. Covid-19 was mild in 45 patients (54.9%), moderate in 23 (28.1%), and severe in 14 (17.07%), while mortality occurred in four of the severe cases (4.9%). Three of the exitus patients were receiving rituximab therapy. Pre-Covid MG Activity of Daily Living (MG-ADL) severity scores were significantly high in severe cases. A history of myasthenic crisis was also higher in severe cases. Similarly, univariate and multivariate analyses revealed an association between severe COVID-19 and myasthenic crisis history and high pre-Covid MG-ADL. The type of MG treatment had no independent effect on COVID-19 severity. CONCLUSION: The vast majority of the MG patients made a good recovery from Covid-19. The risk of severe COVID-19 is high in patients with high MG-ADL severity scores and a history of myasthenic crisis.

Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms.

Background: While antibiotics remain our primary tools against microbial infection, increasing antibiotic resistance (inherent and acquired) is a major detriment to their efficacy. A practical approach to maintaining or reversing the efficacy of antibiotics is the use of other commonly used therapeutics, which show synergistic antibacterial action with antibiotics. Here, we investigated the extent of antibacterial synergy between the antibiotic gentamicin and the anti-inflammatory ketorolac regarding the dynamics of biofilm growth, the rate of acquired resistance, and the possible mechanism of synergy. Methods: Control (ATCC 12600, ATCC 35984) and clinical strains (L1101, L1116) of S. aureus and S. epidermidis with varying antibiotic susceptibility profiles were used in this study to simulate implant-material associated low-risk and high-risk biofilms in vitro. The synergistic action of gentamicin sulfate (GS) and ketorolac tromethamine (KT), against planktonic staphylococcal strains were determined using the fractional inhibitory concentration measurement assay. Nascent (6hr) and established (24hr) biofilms were grown on 316 stainless steel plates and the synergistic biofilm eradication activity was determined and characterized using adherent bacteria count, MBEC measurement for GS, gene expression of biofilm-associated genes, visualization by live/dead imaging, scanning electron microscopy, and bacterial membrane fluidity assessment. Results: Gentamicin-ketorolac combination demonstrated synergistic antibacterial action against planktonic Staphylococci. Control and clinical strains showed distinct biofilm growth dynamics and an increase in biofilm maturity was shown to confer further resistance to gentamicin for both 'low-risk' and 'high-risk' biofilms. The addition of ketorolac enhanced the antibiofilm activity of gentamicin against acquired resistance in staphylococcal biofilms. Mechanistic studies revealed that the synergistic action of gentamicin-ketorolac interferes with biofilm morphology and subverts bacterial stress response altering bacterial physiology, membrane dynamics, and biofilm properties. Conclusion: The results of this study have a significant impact on the local administration of antibiotics and other therapeutic agents commonly used in the prevention and treatment of orthopaedic infections. Further, these results warrant the study of synergy for the concurrent or sequential administration of non-antibiotic drugs for antimicrobial effect.

Vitamin E-stabilized UHMWPE for total joint implants: a review.

BACKGROUND: Osteolysis due to wear of UHMWPE limits the longevity of joint arthroplasty. Oxidative degradation of UHMWPE gamma-sterilized in air increases its wear while decreasing mechanical strength. Vitamin E stabilization of UHMWPE was proposed to improve oxidation resistance while maintaining wear resistance and fatigue strength. QUESTIONS/PURPOSES: We reviewed the preclinical research on the development and testing of vitamin E-stabilized UHMWPE with the following questions in mind: (1) What is the rationale behind protecting irradiated UHMWPE against oxidation by vitamin E? (2) What are the effects of vitamin E on the microstructure, tribologic, and mechanical properties of irradiated UHMWPE? (3) Is vitamin E expected to affect the periprosthetic tissue negatively? METHODS: We performed searches in PubMed, Scopus, and Science Citation Index to review the development of vitamin E-stabilized UHMWPEs and their feasibility as clinical implants. RESULTS: The rationale for using vitamin E in UHMWPE was twofold: improving oxidation resistance of irradiated UHMWPEs and fatigue strength of irradiated UHMWPEs with an alternative to postirradiation melting. Vitamin E-stabilized UHMWPE showed oxidation resistance superior to that of irradiated UHMWPEs with detectable residual free radicals. It showed equivalent wear and improved mechanical strength compared to irradiated and melted UHMWPE. The biocompatibility was confirmed by simulating elution, if any, of the antioxidant from implants. CONCLUSIONS: Vitamin E-stabilized UHMWPE offers a joint arthroplasty technology with good mechanical, wear, and oxidation properties. CLINICAL RELEVANCE: Vitamin E-stabilized, irradiated UHMWPEs were recently introduced clinically. The rationale behind using vitamin E and in vitro tests comparing its performance to older materials are of great interest for improving longevity of joint arthroplasties.

Vitamin E diffused, highly crosslinked UHMWPE: a review.

Highly crosslinked UHMWPE has become the bearing surface of choice in total hip arthroplasty. First generation crosslinked UHMWPEs, clinically introduced in the 1990s, show significant improvements compared to gamma sterilised, conventional UHMWPE in decreasing wear and osteolysis. These crosslinked UHMWPEs were thermally treated (annealed or melted) after irradiation to improve their oxidation resistance. While annealing resulted in the retention of some oxidation potential, post-irradiation melted UHMWPEs had reduced fatigue strength due to the crystallinity loss during melting. Thus, the stabilisation of radiation crosslinked UHMWPEs by the diffusion of the antioxidant vitamin E was developed to obtain oxidation resistance with improved fatigue strength by avoiding post-irradiation melting. A two-step process was developed to incorporate vitamin E into irradiated UHMWPE by diffusion to obtain a uniform concentration profile. Against accelerated and real-time aging in vitro, this material showed superior oxidation resistance to UHMWPEs with residual free radicals. The fatigue strength was improved compared to irradiated and melted UHMWPEs crosslinked using the same irradiation dose. Several adverse testing schemes simulating impingement showed satisfactory behaviour. Peri-prosthetic tissue reaction to vitamin E was evaluated in rabbits and any effects of vitamin E on device fixation were evaluated in a canine model, both of which showed no detrimental effects of the inclusion of vitamin E in crosslinked UHMWPE. Irradiated, vitamin E-diffused, and gamma sterilised UHMWPEs have been in clinical use in hips since 2007 and in knees since 2008. The clinical outcome of this material will be apparent from the results of prospective, randomised clinical studies.

The role of Vitamin E in hip implant-related corrosion and toxicity: Initial outcome.

In orthopedic healthcare, Total Hip Replacement (THR) is a common and effective solution to hip-related bone and joint diseases/fracture; however, corrosion of the hip implant and the release of degradation metal ions/particles can lead to early implant failure and pose potential toxicity risk for the surrounding tissues. The main objective of this work was to investigate the potential role of Vitamin E to minimize corrosion-related concerns from CoCrMo hip implants. The study focused on two questions (i) Can Vitamin E inhibit CoCrMo corrosion? and (ii) Does Vitamin E moderate the toxicity associated with the CoCrMo implant particles? In the study (i) the electrochemical experiments (ASTM G61) with different concentrations of Vitamin E (1, 2, 3 mg/ml against the control) were performed using normal saline and simulated synovial fluid (Bovine calf serum-BCS, 30 g/L protein, pH 7.4) as electrolytes. The polished CoCrMo disc (Ra 50 nm) was the working electrode. The findings suggested that both Vitamin E-Saline (45 ± 0.9%) and Vitamin E-BCS (91 ± 3%) solutions protected against implant corrosion at a Vitamin E concentration of 3 mg/ml, but Vitamin E-BCS showed protection at all Vitamin E (1-3 mg/ml) concentration levels. These results suggested that the Vitamin E and the protein present in the BCS imparted additive effects towards the electrochemical inhibition. In the study (ii) the role of Vitamin E in cytotoxicity inhibition was studied using a mouse neuroblastoma cell line (N2a) for CoCrMo particles and Cr ions separately. The CoCrMo particles were generated from a custom-built hip simulator. The alamarBlue assay results suggested that Vitamin E provides significant protection (85% and 75% proliferation) to N2a cells against CoCrMo particles and Cr ions, respectively at 1 µg/ml concentration, as compared to the control group. However, the results obtained from ROS expression and DNA fiber staining suggest that Vitamin E is only effective against CoCrMo degradation particles and not against Cr ions. In summary, the findings show that Vitamin E can minimize the corrosion processes and play a role in minimizing the potential toxicity associated with implants.

Radioprotection and cross-linking of allograft bone in the presence of vitamin E.

Bone allografts are the preferred method for bone augmentation in over 500,000 orthopedic surgical procedures in the US. Sterilization by ionizing radiation is the most effective method of minimizing the bioburden of bone allografts; however, radiation causes chain scission of collagen, resulting in the reduction of the allografts' mechanical strength. In this study, we doped bone allografts with vitamin E as radioprotectant using a novel two-step process to protect the collagen architecture against radiation damage and to preserve the mechanical strength of the construct. In addition, combining the radioprotectant with a cross-linking agent further minimized collagen degradation and further preserved the mechanical strength of the allografts. Both vitamin E and combined vitamin E/genipin-treated allograft were less cytotoxic to both osteoblasts and osteoclasts when compared to irradiated-only allografts. Host bone-allograft unionization was faster in a rat calvaria defect model with vitamin E-treated and combined vitamin E and genipin-treated allograft when compare to irradiated-only allografts. This method can enable the efficient and uniform radioprotective treatment of bone allograft of desired shapes for sterilization with improved mechanical strength and biointegration.