® All metals in contact with biological systems undergo corrosion. This electrochemical process leads to the formation of metal ions, which may activate the immune system by forming complexes with endogenous proteins. ® Implant degradation products have been shown to be associated with dermatitis, urticaria, and vasculitis. If cutaneous signs of an allergic response appear after implantation of a metal device, metal sensitivity should be considered. Currently, there is no generally accepted

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... for the clinical determination of metal hypersensitivity to implanted devices. ® The prevalence of dermal sensitivity in patients with a joint replacement device, particularly those with a failed implant, is substantially higher than that in the general population. ® Until the roles of delayed hypersensitivity and humoral immune responses to metallic orthopaedic implants are more clearly defined, the risk to patients may be considered minimal. ® It is currently unclear whether metal sensitivity is a contributing factor to implant failure. mplant-related metal sensitivity has been well documented in case and group studies; however, overall it remains a relatively unpredictable and poorly understood phenomenon in the context of orthopaedic implant materials 1-3 . Dermal hypersensitivity to metal is common, affecting about 10% to 15% of the population 1,2,4,5 . Dermal contact with and ingestion of metals have been reported to cause immune reactions, which most typically manifest as hives, eczema, redness, and itching 1,6,7 . Historically, the ability of implant materials to demonstrate appropriate host and material responses has resulted in the elimination of candidate materials based on observation of adverse host responses. However, some adverse responses are difficult to characterize in preclinical and clinical settings because of their infrequent or subtle nature. In vivo metal hypersensitivity or hypersensitivity-like reactivity to metallic biomaterials is one such response. Although little is known about the short and long-term pharmacodynamics and bioavailability of circulating metal degradation products in vivo 5,8-10 , there have been many reports of sensitivity responses temporally associated with implantation of metal components. Degradation products of metallic biomaterials include particulate wear debris, colloidal organometallic complexes (specifically or nonspecifically bound), free metallic ions, inorganic metal salts or oxides, and precipitated organometallic storage forms. All metals in contact with biological systems corrode 11,12 , and the released ions, while not sensitizers on their own, can activate the immune system by forming complexes with native proteins 5,13,14 . These metal-protein complexes are considered to be candidate antigens (or, more loosely termed, allergens) for eliciting hypersensitivity responses. Nonbiodegradable polymeric biomaterials used for load-bearing in total joint arthroplasty are not easily chemically degraded in vivo and have not been intensely investigated or implicated in case or group studies as sources of hypersensitivity-type immune responses. This is presumably due to the relatively large size of the degradation products associated with the mechanical wear of polymers in vivo; these products may be large enough to prevent the formation of polymer-protein haptenic complexes with human antibodies. The biological response in this situation is a response to particles. However, immunogenic reactions associated with polymethylmethacrylate have been reported, albeit less frequently 15 , and may be due to a still-present unreacted monomer that serves in a hapten-like manner. Metals known as sensitizers (haptenic moieties in antigens) are beryllium 16 , nickel 4,6,7,16 , cobalt 16 , and chromium 16 ; in addition, occasional responses to tantalum 17 , titanium 18,19 , and vanadium 17 have been reported. Nickel is the most common metal sensitizer in humans, followed by cobalt and chromium 1,4,6,7 . The prevalence of metal sensitivity among the general population is approximately 10% to 15% (Fig. 1) , with nickel sensitivity having the highest prevalence (approximately 14%) 1 . Cross-reactivity between nickel and cobalt is most common 1,5 . The amounts of these metals found in medical-grade alloys are shown in Table I . Although the specifics associated with metal-protein binding and the biological mechanisms by which these com-I