Metal particles and ions are liberated from the articular interface of metal-metal (MM) total hip arthroplasties. To better understand their cellular effect, we analyzed the internalization of these metal particles and ions by macrophages in vitro. Macrophages were exposed to metal particles isolated from MM prostheses cycled in a hip simulator and to metal ions. Cells were processed for transmission electron microscopy analysis. Results reveal the internalization of metal particles and Cr³⁺ ions in specifically localized cytoplasmic areas. This study is the first to reveal that metal particles of clinically relevant size and Cr³⁺ ions are internalized by an apparently active process.

In order to minimize articular interface wear, metal-metal (MM) hip implants have been considered as an alternative to conventional metal-polyethylene bearings. While the local histological effects of the metallic particles and ions appear to be similar to that seen with metal-polyethylene hip replacements (i.e., a foreign-body macrophage response), little is known about the cellular effects of these metal particles and ions.

The purpose of this study was to better understand the cellular effect of metal particles and ions, we analyzed their internalization by macrophages in vitro.

J774 mouse macrophages were exposed to metal particles isolated from serum of MM prostheses cycled in a hip simulator and to Cr³⁺ (CrCl₃) and Co²⁺ (CoCl₂) ions. Cells were then processed for transmission electron microscopy analysis.

Micrographs revealed the internalization of metal particles and Cr³⁺ ions in specifically localized cytoplasmic areas, suggesting that they are phagocytosed via an active pathway. Energy disperse X-ray analysis spectra of macrophages incubated with Cr³⁺ revealed a chromium phosphate composition. The same structure and composition were also observed when Cr³⁺ ions were incubated in culture medium without cells, suggesting that they were formed outside the cells. Co²⁺ ions did not form visibly agglomerated structures.

This study is the first to reveal that metal particles of clinically relevant size are internalized by an apparently active process and that Cr³⁺ ions can be internalized by macrophages after binding to phosphorus or phosphoproteins. Kinetic studies are now necessary to better understand the mechanism of phagocytosis and the ultimate outcome of these particles and ions in macrophages.

In December 2000, the Inter-Op acetabular component (Sulzer Orthopedics Inc., TX) was recalled. Contamination by an oil-based residue that was inadvertently left in the porous coating following a change in manufacturing processes was suspected to have resulted in lack of fixation. The aim of this study was to characterize the histopathology of the these failures for consistency with this hypothesis.

Materials and methods: Four hundred and fifty cups were submitted for gross and histopathological examination. H& E stained paraffin sections of tissue taken from the socket, membranes and/or capsules from the first 100 cases were reviewed histologically using a new rating scheme which accounts for the presence and extent of inflammatory cells, wear particles, and uncharacteristic tissue features. Immunohistochemical staining was performed on paraffin sections for IL1b, IL6 and TNFa (N=10) and for lymphocytes (CD3, CD4, CD20; N=8), and lipid stains were applied to selected frozen sections.

Results: Cases were revised after ave. 6 months for pain and lack of fixation. Grossly the components had minimal attached tissue, if any. Histologically, the most common finding was extensive chronic inflammation (mostly lymphocytic), although many also had abundant acute inflammation (neutrophils and early granulation tissue). Lymphocytes were mostly common T and helper T cells. Eosinophils (cells associated with intense allergic reactions) were rare. Other uncharacteristic findings included histiocyte-rich granulomas, peculiar metal-like dust associated with silicate-like structures, vacuolated cells and unusual tissue spaces (20 – 50 mm in diameter) some of which were positive with lipid stains. Tissues stained strongly positive for IL-1b and IL-6 but only weakly for TNFa. A similar inflammatory response was noted to have spread into the capsular tissues.

Conclusion: Given the absence of conclusive bacterial cultures in the majority of cases, the histopathology seems consistent with an oil-based contaminant mixed with debris generated from the machines used at the manufacturing plant.

A recent study of tissues from 14 modern metal-on-metal (MM) total hips reported an intense diffuse and perivascular (p.v.) lymphocytic infiltrate, suggestive of hypersensitivity (Willert et al. Osteologie 2000; 9:2–16). This study evaluated the histopathology of tissues from modern MMs using cases obtained at revision or autopsy.

Materials and methods: 35 MM THRs or surface replacements (SRs) that failed due to dislocation, aseptic loosening, and pain or obtained at autopsy (n = 4) were used. H& E stained sections were rated semiquantitatively. Selected cases were studied by immunohistochemistry for macrophage (CD68) and lymphocyte markers (CD3, 4, 20). Wear was measured with a coordinate measuring machine.

Results: Generally, the THRs without metallosis showed minimal visible wear particles, consistent with their low measured wear (av. total wear depth was 8.25 ± 6.7 um at av. 30 mos). Although SRs had an av. linear wear depth of 46 ± 48 microns at av. 23 mos, the metal rating was also low (av. 0.8), except in 1 case with HA 3rd body induced high wear and subsequent osteolysis. Lymphocytic aggregates were not a common feature but B type cells were extensive in 1 case (THR revised for pain after 36 months) moderate in 1 autopsy SR (with CoCr metallosis due to run-in wear of an out of round component) and minimal in 4 of the SRs.

Discussion and conclusions: Extensive diffuse or p.v. lymphocytes were not a consistent finding in these 35 cases. These features were not seen in well-functioning autopsy retrieved cases with low wear rates, nor in the SR with osteolysis and the highest amount of component wear. Until the long-term local and systemic effects of metal wear products, including hypersensitivity are better understood, continued histopathological assessment of periprosthetic tissues from MM total hips is recommended.

Although the response of macrophages to polyethylene debris has been widely studied, it has never been compared with the cellular response to ceramic debris. Our aim was to investigate the cytotoxicity of ceramic particles (Al₂O₃ and ZrO₂) and to analyse their ability to stimulate the release of inflammatory mediators compared with that of high-density polyethylene particles (HDP). We analysed the effects of particle size, concentration and composition using an in vitro model. The J774 mouse macrophage cell line was exposed to commercial particles in the phagocytosable range (up to 4.5 μm). Al₂O₃ was compared with ZrO₂ at 0.6 μm and with HDP at 4.5 μm. Cytotoxicity tests were performed using flow cytometry and macrophage cytokine release was measured by ELISA.

Cell mortality increased with the size and concentration of Al₂O₃ particles. When comparing Al₂O₃ and ZrO₂ at 0.6 μm, we did not detect any significant difference at the concentrations analysed (up to 2500 particles per macrophage), and mortality remained very low (less than 10%). Release of TNF-α also increased with the size and concentration of Al₂O₃ particles, reaching 195% of control (165 pg/ml v 84 pg/ml) at 2.4 μm and 350 particles per cell (p < 0.05). Release of TNF-α was higher with HDP than with Al₂O₃ particles at 4.5 μm. However, we did not detect any significant difference in the release of TNF-α between Al₂O₃ and ZrO₂ at 0.6 μm (p > 0.05). We saw no evidence of release of interleukin-1α or interleukin-1ß after exposure to ceramic or HDP particles.