Biologic Responses to Metal Debris and Metal Ions

Historical Background

The late Professor Hans Willert proposed a biologic mechanism of aseptic loosening, that continuous release of large volumes of biomaterial particles of any kind eventually overwhelms the joint clearance mechanisms, with the accumulated particles inducing a foreign-body reaction. According to his proposed mechanism, the particles are ingested by macrophages, which trigger the production of inflammatory cytokines, leading to bone resorption and implant loosening. Bone cement was initially thought to be the main source of debris, but the introduction of cementless devices did not solve the problem of aseptic loosening or osteolysis.

Retrieval analysis of hip resurfacing components with osteolysis of the femoral neck and the resurfaced head contributed to the understanding that PE rather than cement or titanium (Ti) was the main culprit, although those materials can also contribute to osteolysis. In contrast to stemmed prostheses that generally are removed from the bone and any osteolytic membranes at the time of revision, hip resurfacings retain the bone-membrane interfaces and facilitate their histologic evaluation. By using a special lipid stain that showed intracellular aggregates of PE particles that otherwise were invisible at the light microscope level, the extensive distribution of PE particles was demonstrated even in the presence of Ti metallosis.

Polyethylene Wear and Osteolysis

It is useful to discuss metallic wear debris reactivity from the context of what has been learned from studies of debris from PE materials that were subject to oxidative degradation and prone to high wear. Debate is ongoing as to which factor is most important for the cellular response to wear particles. But it is generally accepted that for PE particles, their abundance in the submicron to micron size, the nondegradable nature of the polymer, and the high volumes that are typically produced are the characteristics that, when combined, lead to an aggressive local inflammatory response that results in bone resorption and implant loosening. The more subtle particle characteristics, such as aspect ratio, surface roughness, and the composition of absorbed proteins, may also determine bioreactivity. While the biologic mechanisms involved in reactions to metallic particles appear to be more complex compared to PE particles, partly owing to their formation of metal ions and corrosion products, we are beginning to understand these complex biologic reactions as explained in the following sections.

Cellular Mechanisms of Osteolysis

Several excellent reviews document the molecular details of the processes involved in macrophage phagocytosis, cytokine production, and osteoclast activation. The characteristic periprosthetic tissue response to particulate PE can be summarized as follows:

• 1.

  The response involves a nonspecific innate foreign-body reaction reminiscent of a granulomatous response (i.e., where the nondegradable material is sequestered by macrophages, giant cells, and fibrous tissue) that does not require active participation of T lymphocytes and generally does not lead to tissue necrosis except where abundant particulate debris exists.

• 2.

  The biologic reaction is strongly determined by the concentration, size, material, and form of the wear particles. While individual variability in the extent of osteolysis has been noted, a threshold amount of wear related to the risk for osteolysis has been established (0.3 mm/yr), although some researchers have concluded that a continuous dose response can be demonstrated.

It appears that both similarities and differences exist in how cells react to PE and metallic debris; nanometer-sized PE particles can behave similarly to nanometer-sized metallic particles. Conversely, metallic particles can form larger, micron-sized agglomerates. Size, concentration, and shape of these particles in both PE and metal alloys appear to affect the type of cellular response. However, the difference and complexity of understanding biologic responses to metallic particles comes from the production of ions (that, in turn, form complexes with proteins) and corrosion products. For example, cobalt (Co) ions are reported to affect endothelial transmigration of leukocytes to a much greater extent than chromium (Cr) ions.

Recent studies investigated in vitro responses to particulate metallic wear debris. Posada et al. tested the effects of Co-Cr metallic wear debris generated from simulator-produced MOM resurfacing implants on human monocyte-like cells. They found an increase in tumor necrosis factor-α (TNF-α) secretion by resting U937 cells, which could contribute to osteolysis, and an increase in interferon-γ (IFN-γ), which could represent cellular protection against tissue damage.

Overall, the incidence and degree of osteolysis observed with MOM implants are typically less compared to conventional PE. This finding suggests that the biologic response leading to osteolysis is influenced more by the size and other features of the particles and not simply the total amount of debris.

PE is not the only material responsible for osteolysis. Polymethylmethacrylate (PMMA) cement in the presence of radiopaque additives causes bone resorption in mouse monocytes; monocytes and macrophages reacting to bone cement particles are capable of differentiating into osteoclasts. Cement debris may be generated from abrasion or fatigue fracture, third-body wear, or from incomplete mixing of the cement monomer and polymer. The debris can result in inflammatory and foreign-body reactions. As discussed later, solid corrosion products generated at modular junctions may also contribute to the local particle burden and stimulate adverse cellular responses, leading to necrosis or hypersensitivity-like reactions.

How Cobalt-Chromium Wear Products Are Formed

Examination of particles produced under the ideal bearing conditions found in a hip simulator reveals that Co-Cr alloy particles are both globular and needle shaped. Electron microscopic studies suggest that globular wear particles result from torn-off nanocrystals, while needle-shaped particles are generated by fractured ε-martensite structures within the outermost layers of the implant. Wear particles comprise both the alloy material and oxides from the articulating surface, particularly Cr-rich oxides of the outer passivation layer and organometallic phosphates, which are deposited from the synovial fluid. Wimmer and colleagues described a tribolayer less than 200 nm thick that consisted of a nanocrystalline mixture of metal and organic material.

Particle isolation and scanning electron examination techniques have shown that metallic wear particles are predominantly nanometer sized, and recent studies demonstrated that their size is affected by the specific wear mechanism responsible for their production. Kovochich et al. found significant differences in particles that were produced under normal conditions compared to edge-loading conditions. The latter produced particles that were larger and more numerous. Particles from normal wear were mostly Cr compared to Co-Cr alloy particles produced under edge loading, which suggests that the passivation layer composed of chromium oxide is disturbed under edge loading. Particles produced under normal conditions were also more round to oval compared to elongated particles produced during edge loading. These factors can influence the biologic response to metal wear; particles created during normal wear (small, round, and mostly Cr) are thought to be cleared readily from the local joint, while particles created under edge loading (larger, irregular shaped, and mostly Co) may lead to a greater inflammatory response. In well-functioning hips with low wear rates, the majority of wear debris consists of oxidized Cr nanoparticles with minimal to no Co content. Conversely, in malpositioned hips, larger particles with higher concentrations of Co are produced. These results are consistent with observations from several studies that showed that MOM wear rates are increased under edge-loading conditions in vitro and in vivo .

Although most of the particles entering the joint are produced from the bearing, nonarticulating surfaces can contribute to the particle burden. For example, the taper connections of modular total joint replacements can be an important source of metal wear and corrosion products.