The determination of biocompatibility has been dominated historically by the characterization of candidate materials based upon the observation of adverse host responses. However, some adverse responses are subtle in clinical settings and continue to foster debate and investigation. One of these responses is "metal allergy" or hypersensitivity to metallic biomaterials. Current methods used to diagnose hypersensitivity reactions, such as dermal patch testing and migration inhibition assays, are not well accepted in orthopedic practice as a means for the characterization of hypersensitivity to metallic joint-replacement components. An increasing need to resolve whether metal sensitivity may be a significant and/or predisposing factor for eliciting an over-aggressive immune response in patients with metallic implant components requires improved and standardized widespread study. Here we present three in vitro methodologies: (1) a proliferation assay, (2) cytokine analysis using ELISA, and (3) a migration inhibition assay. When in conjunction with one another, these assays may be used to more comprehensively quantify metal-induced hypersensitivity responses. Therefore, these methodologies are detailed with the intent of facilitating multi-center large-scale studies. In the following cases, a multi-assay approach for measuring the prevalence of delayed-type hypersensitivity in orthopedic patients shows the propensity to yield a more comprehensive and, therefore, more conclusive determination than currently employed patch testing or single assay techniques.

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