Isabelle Catelas

New insights into wear and biological effects of metal-on-metal bearings.

BACKGROUND Despite the renewed interest in metal-on-metal implants in the past two decades, the underlying wear mechanisms and biological effects are still not fully understood. METHODS This paper first reviews the tribology of metal-on-metal bearings, bringing new insights into the interaction of wear and corrosion, and putting the characteristics and the potential origin of wear particles in perspective with the proposed wear mechanisms. It then summarizes the current knowledge on the biological effects of particles and metal ions in relation to these wear mechanisms. RESULTS Tribochemical reactions play an important role in the wear of metal-on-metal joints. The generated tribomaterial, which progressively forms by mechanical mixing of the uppermost nanocrystalline zone of the metal surface with proteins from the synovial fluid, governs the wear rate and influences the corrosive behavior of the bearing. Nanometer-sized wear particles may initially originate from the passivation layer covering the implant surface and then detach from this tribolayer. The inflammatory response observed surrounding metal-on-metal implants appears to be lower than that around metal-on-polyethylene implants. However, metallic byproducts, which can complex with proteins, may lead to a T lymphocyte-mediated hypersensitivity response. CONCLUSIONS The tribolayer appears to have beneficial effects on the wear rate. Much information has been gained on wear particle characteristics, but the exact mechanisms of particle detachment remain to be further elucidated. Excessive wear along with a hypersensitivity response may be at the origin of the early adverse tissue reactions that have been recently reported in some patients with metal-on-metal implants.

Polyethylene and metal wear particles: characteristics and biological effects

This paper first presents a brief overview about the mechanism of wear particle formation as well as wear particle characteristics in metal-on-polyethylene and metal-on-metal artificial hip joints. The biological effects of such particles are then described, focusing on the inflammatory response induced by each type of particles as well as on how metal wear products may be the source of a T lymphocyte-mediated specific immune response, early adverse tissue responses, and genotoxicity. Finally, some of the current in vivo models used for the analysis of tissue response to various wear particles are presented.

In vitro macrophage response to nanometer-size chromium oxide particles

An increasing number of studies have reported adverse tissue reactions around metal-on-metal (MM) hip implants. However, the origin and mechanisms of these reactions remain unclear. Moreover, the biological effects of nanometer-size chromium oxide particles, the predominant type of wear particles produced by MM implants, remain mostly unknown. The purpose of this study was to analyze the cytotoxic effects of clinically relevant nanometer-size chromium oxide particles on macrophage response in vitro. J774.A1 macrophages were cultured with either 60 nm or 700 nm commercially available Cr2 O3 particles at different concentrations. Two different particle sizes were analyzed to evaluate potential volume effects. Cell mortality was analyzed by light microscopy, flow cytometry (annexin V-fluorescein isothiocyanate and propidium iodide assay), and using a cell death detection enzyme-linked immunosorbant assay (ELISA). Tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1 alpha (MIP-1α) release was measured by ELISA, and gene expression was analyzed by quantitative real-time PCR. Results showed that, at high concentrations, Cr2 O3 particles of both sizes can be cytotoxic, inducing significant decreases in total cell numbers and increases in necrosis. Results also suggested that these effects were dependent on particle volume. However, TNF-α, MCP-1, and MIP-1α cytokine release and gene expression remained low. Overall, this study demonstrates that nanometer-size particles of Cr2 O3 , a stable form of chromium oxide ceramic, have rather low cytotoxic effects on macrophages. Therefore, these particles may not be the main culprit in the initiation of the inflammatory reaction in MM periprosthetic tissues. However, other parameters (e.g., potential intracellular damage) remain to be investigated.

Implant wear and aseptic loosening. An overview

ZusammenfassungDer Verschleiß von Gelenkimplantaten unterliegt multifaktoriellen Einflussgrößen, die in Ihrem Zusammenspiel auch bei nominell identischen Gleitpaarungen höchst unterschiedliche Partikelmengen und -formen generieren können. Die biologische Reaktion und damit letztendlich der klinische Erfolg des Implantats wird dabei von den speziellen Partikeleigenschaften beeinflusst. Eine dauerhafte Implantatversorgung bedingt einen optimierten Kompromiss zwischen Material, Design, Operationsmethode und patientenspezifischen Faktoren.AbstractWear of total joint implants is multifactorial in nature. Even for identical materials and geometries, the interaction of those parameters can generate different numbers of particles as well as different particle sizes and shapes. These different wear-particle characteristics will directly influence the biological response to an implant and thereby its clinical success. The long-term success of a total joint replacement requires an optimized compromise among implant material, design, surgical procedure, and biological performance.Wear of total joint implants is multifactorial in nature. Even for identical materials and geometries, the interaction of those parameters can generate different numbers of particles as well as different particle sizes and shapes. These different wear-particle characteristics will directly influence the biological response to an implant and thereby its clinical success. The long-term success of a total joint replacement requires an optimized compromise among implant material, design, surgical procedure, and biological performance.

Verschleiß und aseptische Prothesenlockerung

ZusammenfassungDer Verschleiß von Gelenkimplantaten unterliegt multifaktoriellen Einflussgrößen, die in Ihrem Zusammenspiel auch bei nominell identischen Gleitpaarungen höchst unterschiedliche Partikelmengen und -formen generieren können. Die biologische Reaktion und damit letztendlich der klinische Erfolg des Implantats wird dabei von den speziellen Partikeleigenschaften beeinflusst. Eine dauerhafte Implantatversorgung bedingt einen optimierten Kompromiss zwischen Material, Design, Operationsmethode und patientenspezifischen Faktoren.AbstractWear of total joint implants is multifactorial in nature. Even for identical materials and geometries, the interaction of those parameters can generate different numbers of particles as well as different particle sizes and shapes. These different wear-particle characteristics will directly influence the biological response to an implant and thereby its clinical success. The long-term success of a total joint replacement requires an optimized compromise among implant material, design, surgical procedure, and biological performance.Wear of total joint implants is multifactorial in nature. Even for identical materials and geometries, the interaction of those parameters can generate different numbers of particles as well as different particle sizes and shapes. These different wear-particle characteristics will directly influence the biological response to an implant and thereby its clinical success. The long-term success of a total joint replacement requires an optimized compromise among implant material, design, surgical procedure, and biological performance.

Effects of hip implant modular neck material and assembly method on fatigue life and distraction force

Hip implant neck fractures and adverse tissue reactions associated with fretting‐corrosion damage at modular interfaces are a major source of concern. Therefore, there is an urgent clinical need to develop accurate in vitro test procedures to better understand, predict and prevent in vivo implant failures. This study aimed to simulate in vivo fatigue fracture and distraction of modular necks in an in vitro setting, and to assess the effects of neck material (Ti6Al4V vs. CoCrMo) and assembly method (hand vs. impact) on the fatigue life and distraction of the necks. Fatigue tests were performed on the cementless PROFEMUR® Total Hip Modular Neck System under two different loads and number of cycles: 2.3 kN for 5 million cycles, and 7.0 kN for 1.3 million cycles. The developed in vitro simulation setup successfully reproduced in vivo modular neck fracture mode and location. Neck failure occurred at the neck–stem taper and the fracture ran from the distal lateral neck surface to the proximal medial entry point of the neck into the stem. None of the necks failed under the 2.3 kN load. However, all hand‐assembled Ti6Al4V necks failed under the 7.0 kN load. In contrast, none of the hand‐assembled CoCrMo necks and impact‐assembled necks (Ti6Al4V or CoCrMo) failed under this higher load. In conclusion, Ti6Al4V necks were more susceptible to fatigue failure than CoCrMo necks. In addition, impact assembly substantially improved the fatigue life of Ti6Al4V necks and also led to overall higher distraction forces for both neck materials. Overall, this study shows that the material and assembly method can affect the fatigue strength of modular necks. Finally, improper implant assembly during surgery may result in diminished modular neck survivability and increased failure rates.

Effects of cobalt and chromium ions on lymphocyte migration

A T cell‐mediated hypersensitivity reaction has been reported in some patients with CoCrMo‐based implants. However, the role of cobalt and chromium ions in this reaction remains unclear. The objective of the present study was to analyze the effects of Co2+ and Cr3+ in culture medium, as well as the effects of culture supernatants of macrophages exposed to Co2+ or Cr3+, on the migration of lymphocytes. The release of cytokines/chemokines by macrophages exposed to Co2+ and Cr3+ was also analyzed. The migration of murine lymphocytes was quantified using the Boyden chamber assay and flow cytometry, while cytokine/chemokine release by J774A.1 macrophages was measured by ELISA. Results showed an ion concentration‐dependent increase in TNF‐α and MIP‐1α release and a decrease in MCP‐1 and RANTES release. Migration analysis showed that the presence of Co2+ (8 ppm) and Cr3+ (100 ppm) in culture medium increased the migration of T lymphocytes, while it had little or no effect on the migration of B lymphocytes, suggesting that Co2+ and Cr3+ can stimulate the migration of T but not B lymphocytes. Levels of T lymphocyte migration in culture medium containing Co2+ or Cr3+ were not statistically different from those in culture supernatants of macrophages exposed to Co2+ or Cr3+, suggesting that the effects of the ions and chemokines were not additive, possibly because of ion interference with the chemokines and/or their cognate receptors. Overall, results suggest that Co2+ and Cr3+ are capable of stimulating the migration of T (but not B) lymphocytes in the absence of cytokines/chemokines, and could thereby contribute to the accumulation of more T than B lymphocytes in periprosthetic tissues of some patients with CoCrMo‐based implants.

Differential proteomic analysis of synovial fluid from hip arthroplasty patients with a pseudotumor vs. Periprosthetic osteolysis : PROTEOMICS OF HIP SYNOVIAL FLUID

Adverse tissue reactions to metal implants, including pseudotumors, can compromise implant functionality and survivorship. The identification of specific proteins in the synovial fluid (SF) of hip arthroplasty patients with a pseudotumor may lead to a better understanding of the underlying pathomechanisms. The objective of the present study was to compare the protein content of SF from patients with a short‐term metal‐on‐metal hip implant associated with a pseudotumor and patients with a long‐term metal‐on‐polyethylene hip implant associated with periprosthetic osteolysis. Discovery proteomics was used to identify differentially abundant proteins in albumin‐depleted SF. In toto, 452 distinct proteins (present in at least half of the patients in one or both groups) were identified. Thirty of these 452 proteins were differentially abundant between the two groups, including two potential biomarkers: 6‐phosphogluconate dehydrogenase (which plays a major protective role against oxidative stress) for the pseudotumor group, and scavenger receptor cysteine‐rich type 1 protein M130 (which is involved in low‐grade inflammation) for the periprosthetic osteolysis group. Other differentially abundant proteins identified suggest the presence of an adaptive immune response (particularly a type‐IV hypersensitivity reaction), necrosis, and greater oxidative stress in patients with a pseudotumor. They also suggest the presence of an innate immune response, oxidative stress, tissue remodeling, and apoptosis in both patient groups, although differences in the specific proteins identified in each group point to differences in the pathomechanisms. Overall, results provide insights into the molecular mechanisms underlying metal‐related pseudotumors and periprosthetic osteolysis, and may ultimately help elucidate pseudotumor etiology and assess the risk that asymptomatic pseudotumors will develop into an aggressive lesion.

Effects of cobalt and chromium ions on oxidative stress and energy metabolism in macrophages in vitro: OXIDATIVE STRESS AND ENERGY METABOLISM IN MACROPHAGES

Cobalt and chromium ions released from cobalt‐chromium‐molybdenum (CoCrMo)‐based implants are a potential health concern, especially since both ions have been shown to induce oxidative stress in macrophages, the predominant immune cells in periprosthetic tissues. Ions of other transition metals (Cd, Ni) have been reported to inhibit the activity of mitochondrial enzymes in the electron transport chain. However, the effects of Co and Cr ions on the energy metabolism of macrophages remain largely unknown. The objective of the present study was to analyze the effects of Co2+ and Cr3+ on oxidative stress and energy metabolism in macrophages in vitro. RAW 264.7 murine macrophages were exposed to 6–18 ppm Co2+ or 50–150 ppm Cr3+. Results showed a significant increase in two markers of oxidative stress, reactive oxygen species level and protein carbonyl content, with increasing concentrations of Co2+, but not with Cr3+. In addition, oxygen consumption rates (OCR; measured using an extracellular flux analyzer) showed significant decreases in both mitochondrial respiration and non‐mitochondrial oxygen consumption with increasing concentrations of Co2+, but not with Cr3+. OCR results further showed that Co2+, but not Cr3+, induced mitochondrial dysfunction, including a decrease in oxidative phosphorylation capacity. Overall, this study suggests that mitochondrial dysfunction may contribute to Co2+‐induced oxidative stress in macrophages, and thereby to the inflammatory response observed in periprosthetic tissues.

The quest for mechanically and biologically functional soft biomaterials via soft network composites

&NA; Developing multifunctional soft biomaterials capable of addressing all the requirements of the complex tissue regeneration process is a multifaceted problem. In order to tackle the current challenges, recent research efforts are increasingly being directed towards biomimetic design concepts that can be translated into soft biomaterials via advanced manufacturing technologies. Among those, soft network composites consisting of a continuous hydrogel matrix and a reinforcing fibrous network closely resemble native soft biological materials in terms of design and composition as well as physicochemical properties. This article reviews soft network composite systems with a particular emphasis on the design, biomaterial and fabrication aspects within the context of soft tissue engineering and drug delivery applications.