Radiation impacts on toxicity of cobalt-chromium (CoCr) implant debris.

Particulate and soluble debris are generated by mechanical and non-mechanical degradation of implanted medical devices. Debris containing cobalt and chromium (CoCr) is known to cause adverse biological reactions. Implant-related complications are often diagnosed using radiography, which results in more frequent patient exposure to ionizing radiation. The aim of this study was to evaluate the potential for increased toxicity due to combined radiation and CoCr exposure. This was investigated using a controlled in vitro model consisting of commercially available CoCr debris that was generated from components of hip replacements and human cell lines relevant to the joint environment: endothelial HMEC-1 and synovial SW982. Particle sizes and shapes were heterogenous. Cells tended to internalize smaller particles, as observed by electron microscopy. Indicators of toxicity were measured after short (24 h after radiation) or extended (12-14 d after radiation) exposure timelines. In the short-term, CoCr reduced cell viability, increased apoptosis, and increased oxidative stress. The effects of radiation were not apparent until the timeline was extended. CoCr and radiation reduced cell survival, with both additive and synergistic effects. Mechanisms for reduced survival included rapid cell death caused by CoCr and senescence caused by radiation. In conclusion, results showed combined toxicological effects of CoCr and radiation at the doses and timelines used for this in vitro model. These observations warrant further investigation using other experimental models to determine translational impact.

Toxicity evaluation of particles formed during 3D-printing: Cytotoxic, genotoxic, and inflammatory response in lung and macrophage models.

Additive manufacturing (AM) or "3D-printing" is a ground-breaking technology that enables the production of complex 3D parts. Its rapid growth calls for immediate toxicological investigations of possible human exposures in order to estimate occupational health risks. Several laser-based powder bed fusion AM techniques are available of which many use metal powder in the micrometer range as feedstock. Large energy input from the laser on metal powders generates several by-products, like spatter and condensate particles. Due to often altered physicochemical properties and composition, spatter and condensate particles can result in different toxicological responses compared to the original powder particles. The toxicity of such particles has, however, not yet been investigated. The aim of the present study was to investigate the toxicity of condensate/spatter particles formed and collected upon selective laser melting (SLM) printing of metal alloy powders, including a nickel-chromium-based superalloy (IN939), a nickel-based alloy (Hastelloy X, HX), a high-strength maraging steel (18Ni300), a stainless steel (316L), and a titanium alloy (Ti6Al4V). Toxicological endpoints investigated included cytotoxicity, generation of reactive oxygen species (ROS), genotoxicity (comet and micronucleus formation), and inflammatory response (cytokine/chemokine profiling) following exposure of human bronchial epithelial cells (HBEC) or monocytes/macrophages (THP-1). The results showed no or minor cytotoxicity in the doses tested (10-100 µg/mL). Furthermore, no ROS generation or formation of micronucleus was observed in the HBEC cells. However, an increase in DNA strand breaks (detected by comet assay) was noted in cells exposed to HX, IN939, and Ti6Al4V, whereas no evident release of pro-inflammatory cytokine was observed from macrophages. Particle and surface characterization showed agglomeration in solution and different surface oxide compositions compared to the nominal bulk content. The extent of released nickel was small and related to the nickel content of the surface oxides, which was largely different from the bulk content. This may explain the limited toxicity found despite the high Ni bulk content of several powders. Taken together, this study suggests relatively low acute toxicity of condensates/spatter particles formed during SLM-printing using IN939, HX, 18Ni300, 316L, and Ti6Al4V as original metal powders.

COMPARATIVE EVALUATION OF HISTOTOXICITY INDICATORS OF METAL ALLOYS FOR THE MANUFACTURE OF METAL CERAMIC DENTAL CONSTRUCTIONS.

OBJECTIVE: The aim: To carry out a comparative assessment of metal alloys for the manufacture of metal-ceramic constructions of dentures by determining the indicator of their histotoxicity. PATIENTS AND METHODS: Materials and methods: To identify the effect of metal alloys on cobalt and nickel bases on the tissue of organism, we carried out an experimental-morphological study of standard samples of metal alloys "Shot-alloy", "Remanium-2000", "Cerium", "Dent-NCB", "Cellite-N". RESULTS: Results: A careful histological analysis of the capsules formed around the metal alloy samples during two periods of the experiment showed that the healing time of the subcutaneous tissue was not the same. The most complete healing, that is, the formation of mature fibrous connective tissue, occurred during the implantation of the cobaltbased alloy "Remanium-2000" and the capsule formed at the end of the experiment around the implanted sample from the "Shot-alloy" alloy, and during the implantation of the "Cerium" alloy, healing the wound surface and the formation of a connective tissue capsule occurs fully than in previous cases. CONCLUSION: Conclusions: The analysis of the performed experiment testifies in favor of the point of view that the speed and quality of healing of damaged subcutaneous tissue upon the introduction of implanted research alloys depend largely on the individual chemical components that make up the alloys, or on their combination.

Are Metal Ions That Make up Orthodontic Alloys Cytotoxic, and Do They Induce Oxidative Stress in a Yeast Cell Model?

Compositions of stainless steel, nickel-titanium, cobalt-chromium and ß-titanium orthodontic alloys were simulated with mixtures of Fe, Ni, Cr, Co, Ti and Mo metal ions as potential oxidative stress-triggering agents. Wild-type yeast Saccharomyces cerevisiae and two mutants ΔSod1 and ΔCtt1 were used as model organisms to assess the cytotoxicity and oxidative stress occurrence. Metal mixtures at concentrations of 1, 10, 100 and 1000 µM were prepared out of metal chlorides and used to treat yeast cells for 24 h. Every simulated orthodontic alloy at 1000 µM was cytotoxic, and, in the case of cobalt-chromium alloy, even 100 µM was cytotoxic. Reactive oxygen species and oxidative damage were detected for stainless steel and both cobalt-chromium alloys at 1000 µM in wild-type yeast and 100 µM in the ΔSod1 and ΔCtt1 mutants. Simulated nickel-titanium and ß-titanium alloy did not induce oxidative stress in any of the tested strains.

A comparative study on the physicochemical characteristics of nanoparticles released in vivo from CoCrMo tapers and cement-stem interfaces of total hip replacements.

The good biocompatibility and corrosion resistance of the bulk CoCrMo alloy has resulted in it being used in the manufacture of implants and load bearing medical devices. These devices, however, can release wear and corrosion products which differ from the composition of the bulk CoCrMo alloy. The physicochemical characteristics of the particles and the associated in vivo reactivity are dictated by the wear mechanisms and electrochemical conditions at the sites of material loss. Debris released from CoCrMo hip bearings, taper junctions, or cement-stem interfaces can, therefore, have different chemical and morphological characteristics, which provide them with different in vivo toxicities. Here, we propose to assess and compare the characteristics of the particles released in vivo from CoCrMo tapers and cement-stem interfaces which have received less attention compared to debris originating from the hip bearings. The study uses state-of-art characterization techniques to provide a detailed understanding of the size, morphology, composition, and chemistry of the particles liberated from the wear and corrosion flakes from revised hip replacements, with an enzymatic treatment. The phase analyses identified Cr2 O3 nanoparticles released from tapers and cement-stem interfaces, whose composition did not vary with origin or particle morphology. The size distributions showed significantly smaller particles were released from the stems, compared to the particles originating from the corresponding tapers. The investigation demonstrates that the tribocorrosive processes occurring at the taper and stem interfaces both result in Cr2 O3 nanoparticle formation.

Removal of dental alloys and titanium attenuates trace metals and biological effects on liver and kidney.

To determine whether the potential effects on liver and kidney caused by dental alloys could be reduced or terminated by the removal of nickel-chromium (Ni-Cr) alloy, cobalt-chromium (Co-Cr) alloy, and commercially pure titanium (CP-Ti), they were placed in the cheek pouches of Syrian hamsters according to ISO 10993-10. Then, the peak/plateau and end times of trace metals in the blood were determined with or without the removal of the dental alloys. Based on these time points, the trace metals and their effects on liver and kidney were examined. We found that trace metals released from these dental alloys and titanium were accumulated transiently in the blood, liver, and kidney but had no effect on the histopathology of the liver or kidney. Although the functions of the liver and kidney were compromised, the function of these tissues seemed to be clinically acceptable compared to those in control Syrian hamsters. In addition, the apoptotic effect on renal cells was terminated by removing the Ni-Cr and Co-Cr alloys, and that on hepatocytes was also eliminated by removing the Ni-Cr alloy. In contrast, the effect of the Co-Cr alloy on hepatocytes was temporary and recovered by itself. Taken together, Ni- and Co-based dental alloys and titanium have no effect on the histopathology or function of liver and kidney. Moreover, Ni-Cr and Co-Cr alloys induce transient trace metal accumulation and apoptotic effects in liver and kidney, which can be reduced or terminated by the removal of the alloys, while CP-Ti shows favorable biocompatibility.

Particulate and ion forms of cobalt-chromium challenged preosteoblasts promote osteoclastogenesis and osteolysis in a murine model of prosthesis failure.

This study investigated the interactive behavior of the particulate and ion forms of cobalt-chromium (Co-Cr) alloy challenged preosteoblasts during the process of prosthetic implant loosening. Preosteoblasts were challenged with Co-Cr particles or Co(II) ions for 72 h, followed by the proliferation and PCR assays. For in vivo test, a titanium pin was implanted into proximal tibia of SCID mice to mimic knee replacement. Co-Cr particles or Co(II) ion challenged preosteoblasts (5 × 105 ) were intra-articularly injected into the implanted knee. The animals were sacrificed 5 weeks post-op, and the prosthetic knees were harvested for biomechanical pin-pullout testing, histological evaluations, and microCT assessment. In vitro study suggested that Co-Cr particles and Co(II) ions significantly suppressed the proliferation of preosteoblasts in a dose-dependent manner. RT-PCR data on the challenged cells indicated overexpression of receptor activator of nuclear factor kappa-B ligand (RANKL) and inhibited osteoprotegerin (OPG) gene expression. Introduction of the differently challenged preosteoblasts to the pin-implant mouse model resulted in reduced implant interfacial shear strength, thicker peri-implant soft-tissue formation, more TRAP+ cells, lower bone mineral density, and bone volume fraction. In conclusion, both Co-Cr particles and Co(II) ions interfered with the growth, maturation, and functions of preosteoblasts, and provides evidence that the metal ions as well play an important role in effecting preosteoblasts in the pathogenesis of aseptic loosening. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 187-194, 2019.

Resultados a medio plazo de la artroplastia total de cadera metal-metal con cabeza de gran tamaño Magnum / Midterm results of Magnum large head metal-on-metal total hip arthroplasty

Objetivos: A raíz de las alertas sanitarias surgidas por la alta incidencia de recambios en la artroplastia de cadera metal-metal, se presentan los resultados obtenidos del seguimiento prospectivo de la serie de nuestro centro con cabezas de gran tamaño. Material y métodos: Se incluyeron todos los pacientes tratados con el cotilo Recap-M2a-Magnum, Biomet de 2008 a 2011. Se revisaron prospectivamente todos los pacientes registrando Harris Hip Score y síntomas de intoxicación por cromo-cobalto y se solicitaron niveles séricos de estos iones, radiografía y ecografía. Se solicitó resonancia magnética en caso de ecografía positiva. Resultados: Se incluyeron 26 varones de 48,54 años de edad media [32-62, DE: 7,18]. Se utilizó un abordaje anterolateral y vástagos Bimetric (7) o F40 (19). La moda de los diámetros cefálicos fue 46 [42-52]. La inclinación media del cotilo fue 39,35° [21-59°, DE: 9,78]. Durante el seguimiento (7,3 años [5,9-9,4 años, DE: 0,78]), 3 pacientes (11,5%) precisaron revisión (2 por movilización aséptica, un pseudotumor). El tiempo medio hasta la revisión fue 5,4 años [3,1-8,0, DE: 2,48]. La probabilidad acumulada de supervivencia fue del 88,5% (IC95% 76,3-100%). El Harris Hip Score fue de 94,47 [66,5-100, DE: 8,94] y los pacientes no mostraron ningún síntoma de intoxicación metálica, con niveles de cromo 1,88 mcg/dl [0,6-3,9] y cobalto 1,74 mcg/dl [0,5-5,6]. Se encontró un pseudotumor en un paciente asintomático y pequeñas cantidades de líquido periprotésico en 5 pacientes (19,2%). Discusión y conclusiones: Seguimos encontrando altas tasas de revisión al extender el seguimiento de los pacientes debido a la movilización aséptica y la formación de pseudotumores. La resonancia nuclear magnética no parece la prueba más adecuada para el estudio de las complicaciones de este tipo de prótesis

Objectives: We present the results of the prospective follow up of a sample of large head metal-metal total hip arthroplasty obtained after the safety alert regarding a higher incidence of revision of these implants. Material and methods: All patients implanted with the Recap-M2a-Magnum cup between 2008 and 2011 were included. They were prospectively reviewed recording Harris Hip Score, clinical symptoms of chromium or cobalt intoxication. Serum levels of these ions were requested as well as X-Rays and ultrasonography. An MRI was performed in the cases of positive ultrasonography. Results: Twenty-six males with a mean age of 48.54 years [32-62, SD: 7.18] were included. An anterolateral approach and Bi-Metric (7) and F-40 (19) stems were used. Cephalic diameters ranged 42-52 (mode: 46) and the mean cup inclination was 39.35° [21-59°, SD: 9.78]. During follow-up (7.3 years [5.9-9.4; SD: .78]), 3 patients (11.5%) underwent revision (2 cases aseptic loosening, 1 pseudotumour). Mean time until revision was 5.4 years [3.1-8.0; SD: 2.48]. The accumulated survival probability was 88.5% (95% CI 76.3-100%). Harris Hip Score was 94.47 [66.5-100; SD: 8.94] and the patients showed no metallic intoxication symptoms. The levels of chromium were 1.88 mcg/dl [0.6-3.9] and cobalt 1,74 mcg/dl [0.5-5,6]. One pseudotumour was found in an asymptomatic patient, and small amounts of periarticular liquid were found in 5 patients (19.2%) Discussion and conclusions: High revision rates are still found when follow up is extended due to aseptic loosening and pseudotumour formation. MRI might not be the most adequate test to study the complications of these prostheses

Biological Impact of Silicon Nitride for Orthopaedic Applications: Role of Particle Size, Surface Composition and Donor Variation.

The adverse biological impact of orthopaedic wear debris currently limits the long-term safety of human joint replacement devices. We investigated the role of particle size, surface composition and donor variation in influencing the biological impact of silicon nitride as a bioceramic for orthopaedic applications. Silicon nitride particles were compared to the other commonly used orthopaedic biomaterials (e.g. cobalt-chromium and Ti-6Al-4V alloys). A novel biological evaluation platform was developed to simultaneously evaluate cytotoxicity, inflammatory cytokine release, oxidative stress, and genotoxicity potential of particles using peripheral blood mononuclear cells (PBMNCs) from individual human donors. Irrespective of the particle size, silicon nitride did not cause any adverse responses whereas cobalt-chromium wear particles caused donor-dependent cytotoxicity, TNF-α cytokine release, oxidative stress, and DNA damage in PBMNCs after 24 h. Despite being similar in size and morphology, silicon dioxide nanoparticles caused the release of significantly higher levels of TNF-α compared to silicon nitride nanoparticles, suggesting that surface composition influences the inflammatory response in PBMNCs. Ti-6Al-4V wear particles also released significantly elevated levels of TNF-α cytokine in one of the donors. This study demonstrated that silicon nitride is an attractive orthopaedic biomaterial due to its minimal biological impact on human PBMNCs.

Articulation of Native Cartilage Against Different Femoral Component Materials. Oxidized Zirconium Damages Cartilage Less Than Cobalt-Chrome.

BACKGROUND: Oxidized zirconium (OxZr) is produced by thermally driven oxidization creating an oxidized surface with the properties of a ceramic at the top of the Zr metal substrate. OxZr is much harder and has a lower coefficient of friction than cobalt-chrome (CoCr), both leading to better wear characteristics. We evaluated and compared damage to the cartilage of porcine patella plugs, articulating against OxZr vs CoCr. Our hypothesis was that, owing to its better wear properties, OxZr would damage cartilage less than CoCr. If this is true, OxZr might be a better material for the femoral component during total knee arthroplasty if the patella is not resurfaced. METHODS: Twenty-one plugs from porcine patellae were prepared and tested in a reciprocating pin-on-disk machine while lubricated with bovine serum and under a constant load. Three different configurations were tested: cartilage-cartilage as the control group, cartilage-OxZr, and cartilage-CoCr. Macroscopic appearance, cartilage thickness, and the modified Mankin score were evaluated after 400,000 wear cycles. RESULTS: The control group showed statistically significant less damage than plugs articulating against both other materials. Cartilage plugs articulating against OxZr were statistically significantly less damaged than those articulating against CoCr. CONCLUSION: Although replacing cartilage by an implant always leads to deterioration of the cartilage counterface, OxZr results in less damage than CoCr. The use of OxZr might thus be preferable to CoCr in case of total knee arthroplasty without patella resurfacing.

Co-Cr dental alloys induces cytotoxicity and inflammatory responses via activation of Nrf2/antioxidant signaling pathways in human gingival fibroblasts and osteoblasts.

OBJECTIVE: Although cobalt-chromium (Co-Cr) dental alloys are routinely used in prosthodontics, the biocompatibility of Co-Cr alloys is controversial. The aims of the present study were to investigate the effects of Co-Cr alloys on human gingival fibroblasts (HGF) and osteoblasts in an in vitro model as well as their potential molecular mechanisms, focusing on NF-E2-related factor 2 (Nrf2) pathways. METHODS: Cells were directly seeded on prepared Co-Cr alloy discs (15.0mm diameter, 1.0mm thickness) or indirectly treated with Co-Cr alloy located at the bottom of an insert well and incubated for 3 days. Cytotoxicity and reactive oxygen species (ROS) production was evaluated by MTS assay and flow cytometry, respectively. Protein and mRNA levels were determined by Western blotting and RT-PCR analysis, respectively. RESULTS: Cell viability and flow cytometric assay demonstrated that the Co-Cr alloy was cytotoxic to HGFs and osteoblasts, and significantly increased ROS production. In addition, the Co-Cr alloys upregulated pro-inflamamtory cytokines (TNF-α, IL-1ß, IL-6, and IL-8) and increased levels of various inflammatory mediators (iNOS derived nitrite oxide, and COX-2-derived PGE2) in both cells. A mechanistic study showed that Co-Cr alloys activates the NRF2 pathway and up-regulate antioxidant enzymes including heme oxygenase-1 (HO-1). Co-Cr alloys activated JAK2/STAT3, p38/ERK/JNK MAPKs and NF-κB signaling pathways. Furthermore, antioxidants (resveratrol and NAC) and HO-1 inhibitor (SnPP) significantly inhibited the production of ROS and inflammatory mediators, as well as the activation of NF-κB signaling in Co-Cr alloy stimulated HGFs and osteoblasts. SIGNIFICANCE: This study is the first to show that Co-Cr alloys exert cytotoxic and inflammatory effects via activation of Nrf2/ARE signaling and up-regulation of downstream HO-1, which could represent candidate targets for the regulation of inflammatory responses to Co-Cr alloys.

Surface passivity largely governs the bioaccessibility of nickel-based powder particles at human exposure conditions.

The European chemical framework REACH requires that hazards and risks posed by chemicals, including alloys and metals, are identified and proven safe for humans and the environment. Therefore, differences in bioaccessibility in terms of released metals in synthetic biological fluids (different pH (1.5-7.4) and composition) that are relevant for different human exposure routes (inhalation, ingestion, and dermal contact) have been assessed for powder particles of an alloy containing high levels of nickel (Inconel 718, 57 wt% nickel). This powder is compared with the bioaccessibility of two nickel-containing stainless steel powders (AISI 316L, 10-12% nickel) and with powders representing their main pure alloy constituents: two nickel metal powders (100% nickel), two iron metal powders and two chromium metal powders. X-ray photoelectron spectroscopy, microscopy, light scattering, and nitrogen absorption were employed for the particle and surface oxide characterization. Atomic absorption spectroscopy was used to quantify released amounts of metals in solution. Cytotoxicity (Alamar blue assay) and DNA damage (comet assay) of the Inconel powder were assessed following exposure of the human lung cell line A549, as well as its ability to generate reactive oxygen species (DCFH-DA assay). Despite its high nickel content, the Inconel alloy powder did not release any significant amounts of metals and did not induce any toxic response. It is concluded, that this is related to the high surface passivity of the Inconel powder governed by its chromium-rich surface oxide. Read-across from the pure metal constituents is hence not recommended either for this or any other passive alloy.

Fatal cobalt toxicity after total hip arthroplasty revision for fractured ceramic components.

CONTEXT: Post-arthroplasty metallosis, which refers to metallic corrosion and deposition of metallic debris in the periprosthetic soft tissues of the body, is an uncommon complication. Systemic cobalt toxicity post-arthroplasty is extremely rare. The few known fatal cases of cobalt toxicity appear to be a result of replacing shattered ceramic heads with metal-on-metal or metal-on-polyethylene implants. Friction between residual shards of ceramic and cobalt-chromium implants allows release of cobalt into the synovial fluid and bloodstream, resulting in elevated whole blood cobalt levels and potential toxicity. CASE DETAILS: This is a single patient chart review of a 60-year-old woman with prior ceramic-on-ceramic right total hip arthroplasty complicated by fractured ceramic components and metallosis of the joint. She underwent synovectomy and revision to a metal-on-polyethylene articulation. Ten months post-revision, she presented to the emergency department (ED) with right hip pain, dyspnea, worsening hearing loss, metallic dysgeusia, and weight loss. Chest CTA revealed bilateral pulmonary emboli (PE), and echocardiogram revealed new cardiomyopathy with global left ventricular hypokinesis with an ejection fraction (EF) of 35-40% inconsistent with heart strain from PE. Whole blood cobalt level obtained two days into her admission was 424.3 mcg/L and 24-h urine cobalt level was 4830.5 mcg/L. Although the patient initially clinically improved with regard to her PE and was discharged to home on hospital day 5, she returned 10 days later with a right hip dislocation and underwent closed reduction of the hip. The patient subsequently decompensated, developing cardiogenic shock, and respiratory failure. She went into pulseless electrical activity (PEA) and expired. Autopsy revealed an extensive metallic effusion surrounding the right hip prosthesis that tested positive for cobalt (41,000 mcg/L). There was also cobalt in the heart muscle tissue (2.5 mcg/g). A whole blood cobalt level obtained two days before she expired was 641.6 mcg/L. DISCUSSION: This is a case of fatal cobalt-induced cardiomyopathy in a patient whose ceramic components of a total hip arthroplasty fractured causing metallosis with worsening cobalt toxicity. We recommend that when a fractured device is revised with a prosthesis with cobalt-chromium components, whole blood and urine cobalt measurements should be obtained and periodically monitored to evaluate for rising concentrations. Providers should be aware of clinical signs and symptoms of cobalt toxicity in patients who have prostheses with cobalt-chromium components. If suspected, toxicology and orthopedics should be involved for possible chelation and removal of the prosthesis.

The effect of recasting on biological properties of Ni-Cr dental alloy.

Introduction: Increases in market prices of gold over the last 20 years have led to expansion of basic dental alloys, which, primarily due to their good mechanical properties and acceptable prices, have found their place in everyday dental practice. However, within the procedure of making dental prosthetic restorations, the alloys are melted and cast, which leads to changes in their physical, mechanical and biological properties. Objective: The objective of the study was to test biocompatibility of a Ni-Cr dental alloy (WIRON 99) depending on the number of melting and casting processes. Methods: The working method included the testing of cytotoxicity of the alloy obtained by casting after one, after four, and after eight successive processes of melting. Cytotoxicity of samples was tested by means of a 24-hour and a three-day cytotoxicity test, done on L929 fibroblasts. Results: A repeatedly melted and cast alloy shows a reduced biocompatibility and causes specific responses of the tissues in the surrounding area. Since the cytotoxic effect is more significant in the extended contact with the culture cells, a three-day cytotoxicity test showed discrete changes which were the indicator of cell growth inhibition in the cell culture. Conclusion: The obtained results confirm the working hypothesis that repeated alloy melting and casting will decrease biocompatibility of dental alloys and will lead to specific responses of the tissue in the surrounding area.

Toxicology of wear particles of cobalt-chromium alloy metal-on-metal hip implants Part II: Importance of physicochemical properties and dose in animal and in vitro studies as a basis for risk assessment.

The objective of the Part II analysis was to evaluate animal and in vitro toxicology studies of CoCr particles with respect to their physicochemistry and dose relevance to metal-on-metal (MoM) implant patients as derived from Part I. In the various toxicology studies, physicochemical characteristics were infrequently considered and administered doses were orders of magnitude higher than what occurs in patients. Co was consistently shown to rapidly release from CoCr particles for distribution and elimination from the body. CoCr micron sized particles appear more biopersistent in vivo resulting in inflammatory responses that are not seen with similar mass concentrations of nanoparticles. We conclude, that in an attempt to obtain data for a complete risk assessment, future studies need to focus on physicochemical characteristics of nano and micron sized particles and on doses and dose metrics relevant to those generated in patients or in properly conducted hip simulator studies.

Toxicology of wear particles of cobalt-chromium alloy metal-on-metal hip implants Part I: physicochemical properties in patient and simulator studies.

The objective of Part I of this analysis was to identify the relevant physicochemical characteristics of wear particles from cobalt-chromium alloy (CoCr) metal-on-metal (MoM) hip implant patients and simulator systems. For well-functioning MoM hip implants, the volumetric wear rate is low (<1mm(3) per million cycles or per year) and the majority of the wear debris is composed of oxidized Cr nanoparticles (<100nm) with minimal or no Co content. For implants with surgical malpositioning, the volumetric wear rate is as high as 100mm(3) per million cycles or per year and the size distribution of wear debris can be skewed to larger sizes (up to 1000nm) and contain higher concentrations of Co. In order to obtain data suitable for a risk assessment of wear debris in MoM hip implant patients, future studies need to focus on particle characteristics relevant to those generated in patients or in properly conducted simulator studies. FROM THE CLINICAL EDITOR: Metallic implants are very common in the field of orthopedics. Nonetheless, concerns have been raised about the implications of nano-sized particles generated from the wear of these implants. In this two-part review, the authors first attempted to identify and critically evaluate the relevant physicochemical characteristics of CoCr wear particles from hip implant patients and simulator systems. Then they evaluated in vitro and animal toxicology studies with respect to the physicochemistry and dose-relevance to metal-on-metal implant patients.

Toxicity of cobalt-chromium nanoparticles released from a resurfacing hip implant and cobalt ions on primary human lymphocytes in vitro.

Adverse tissue responses to prostheses wear particles and released ions are important contributors to hip implant failure. In implant-related adverse reactions T-lymphocytes play a prominent role in sustaining the chronic inflammatory response. To further understand the involvement of lymphocytes in metal-on-metal (MoM) implant failure, primary human lymphocytes were isolated and treated with cobalt-chromium (Co-Cr) wear debris and Co ions, individually, and in combination, for 24, 48 and 120 h. There was a significant increase in cell number where debris was present, as measured by the Neutral Red assay. Interleukin-6 (IL-6), interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α) secretion levels significantly decreased in the presence of metal particles, as measured by ELISA. Interleukin-2 (IL-2) secretion levels were significantly decreased by both debris and Co ions. Flow cytometry analysis showed that the metal nanoparticles induced a significant increase in apoptosis after 48-h exposure. This investigation showed that prolonged exposure (120 h) to metal debris induces lymphocyte proliferation, suggesting that activation of resting lymphocytes may have occurred. Although cytokine production was affected mainly by metal debris, cobalt toxicity may also modulate IL-2 secretion, and even Co ion concentrations below the MHRA guideline levels (7 ppb) may contribute to the impairment of immune regulation in vivo in patients with MoM implants.

Effects of CoCr metal wear debris generated from metal-on-metal hip implants and Co ions on human monocyte-like U937 cells.

Hip resurfacing with cobalt-chromium (CoCr) alloy was developed as a surgical alternative to total hip replacement. However, the biological effects of nanoparticles generated by wear at the metal-on-metal articulating surfaces has limited the success of such implants. The aim of this study was to investigate the effects of the combined exposure to CoCr nanoparticles and cobalt ions released from a resurfacing implant on monocytes (U937 cells) and whether these resulted in morphology changes, proliferation alterations, toxicity and cytokine release. The interaction between prior exposure to Co ions and the cellular response to nanoparticulate debris was determined to simulate the situation in patients with metal-on-metal implants receiving a second implant. Effects on U937 cells were mainly seen after 120h of treatment. Prior exposure to Co ions increased the toxic effects induced by the debris, and by Co ions themselves, suggesting the potential for interaction in vivo. Increased TNF-α secretion by resting cells exposed to nanoparticles could contribute to osteolysis processes in vivo, while increased IFN-γ production by activated cells could represent cellular protection against tissue damage. Data suggest that interactions between Co ions and CoCr nanoparticles would occur in vivo, and could threaten the survival of a CoCr metal implant.

Co(II)-mediated effects of plain and plasma immersion ion implanted cobalt-chromium alloys on the osteogenic differentiation of human mesenchymal stem cells.

Medical CoCr is one of the main alloys used for metal-on-metal prosthesis in patients with total hip arthroplasty. CoCr surfaces modified by nitrogen plasma immersion ion implantation (PIII) are characterized by improved wear resistance but also showed increased Co(II) ion release under in vitro conditions. For the first time, CoCr modified by nitrogen PIII was evaluated with regard to its effect on the osteogenic differentiation of MSC. The activity of alkaline phosphatase, the expression of the osteogenic genes Runt-related transcription factor 2, osteopontin as well as integrin-binding bone sialoprotein and the production of osteocalcin and hydroxyapatite were determined. The results of our study demonstrate that Co(II) ions released from the alloy affected the osteogenic differentiation of MSC. Distinct differences in differentiation markers were found between pristine and modified alloys for osteocalcin but not for integrin-binding sialoprotein and hydroxyapatite. Interestingly, osteopontin was upregulated in naive and differentiated MSC by Co(II) ions and modified CoCr, likely through the induction of a cellular hypoxic response. The findings of this study contribute to a better understanding of possible risk factors with regard to a clinical applicability of surface modified CoCr implant materials.