**2. Biological reactions**

#### **2.1 Metal ion release**

All metal implants in human bodies corrode which results in metal ion release. This represents for most patients no problem. However, if a critical metal ion concentration is exceeded, local or rarely systemic problems can occur. The released metal particles may accumulate in and around affected joints as well as in body fluids, lymph nodes, bone marrow and internal organs. As a result, both local and systemic reactions are possible. Local tissue reactions to metal particles around joint arthroplasties have been described in the past by the generic term "metallosis". Natu et al. [5] introduced the term "adverse reactions to metal debris" (ARMD) which is the most widely used description for local tissue reactions.

Potential systemic adverse effects of metal particles include toxicity-related organ damage, mutagenic effects (carcinogenesis) and teratogenicity. Discussions have primarily focused on the potential damage of cobalt and chromium. While chromium particles may be significant in terms of their mutagenic potential, cobalt has been described to cause organ toxicity. In a review, Leyssens et al. [6] described the potential damage from cobalt exposure with special reference to different routes of exposure (including metallic bearings). The highest concentrations of cobalt in the body were seen in oral uptake and failed metal implants. The clinically possible sequelae of cobalt intoxication include mainly neurological effects (particularly impaired hearing and eyesight) as well as cardiovascular and endocrine effects. In general, it is assumed that such cobalt-related effects on organs require concentrations higher than 300 μg/l, which have not been described in patients with standard knee arthroplasty implants [7, 8].

Another potential effect of metal ions may be chromosomal aberrations. Therefore, the potential carcinogenic effects of metal implants have been discussed. However, in two extensive meta-analysis, no evidence of an increase in systemic tumor incidence was found. Considering the available clinical data including large registry studies, there is no evidence that metal-containing arthroplasty implants increase the risk of cancer or mortality in patient [9]. The same applies to potential teratogenic effects, which have not been reported.

Both, local and systemic effects are mostly a problem of metal-on-metal (MoM) hip arthroplasties or dual taper modular hip stems [10–14] but rarely seen in knee arthroplasties. Only large knee arthroplasty implants (tumor implants, hinged TKA, MoM) have the potential to cause relevant metal ion release and therefore local or systemic effects [15]. In standard TKA implants, this is not a matter of concern. Several studies have investigated metal ion concentrations in standard and coated TKA [16]. Although a relevant reduction of metal ion release has been reported in-vitro [17], there have been no relevant differences in-vivo. However, there are reports about the relevant increase in large hinged TKA which is a matter of concern [15] and needs to be observed.
