How lymphocyte-mediated metal sensitivity affects orthopaedic implant performance remains poorly understood. Do patients with implants exhibit elevated lymphocyte reactivity to metals and is this reactivity more generalized or more implant-alloy specific? We investigated these questions by measuring lymphocyte responses to implant metals (Cr", Cof7, Ni+' at 0.1 mM, and Ti+4 at 0.001 mM) in six subject groups: Group la = young controls, Group 1 b = age matched controls, Group 2a = subjects with osteoarthritis (OA) and no history of metal sensitivity, Group 2b = OA subjects with history of metal sensitivity, Group 3a = total hip arthroplasty (THA) subjects with no to mild radiographic osteolysis, and Group 3b = THA subjects with moderate osteolysis. Lymphocyte proliferation, using Lymphocyte Transformation Testing (LTT), and cytokine release provided quantitative reactivity measurement, where a stimulation index of >2 indicated metal sensitivity. OA subjects with a history of metal sensitivity (Group 2b) were more metal reactive to Ni than any other group, as expected (66%) incidence and Stimulation Index >20). However, THA subjects (Groups 3a & b) were >3 fold more reactive to Cr (p < 0.04), than were controls (Groups la & b) or OA subjects (Groups 2a & b). THA subjects with moderate vs mild osteolysis (Group 3b vs 3a) were more reactive to Co (43% vs 0% incidence). Only osteolytic THA subjects demonstrated increased cytokine responses with >two-fold (p < 0.05) increases in soluble interferon-y (IFN-y) and interleukin-2 (IL-2) levels in response to Cr challenge. This elevated incidence and averaged level of lymphocyte reactivity supports a metal-specific adaptive immune response and suggests involvement in the pathogenesis of poor implant performance, e.g. aseptic osteolysis.

Despite reports associating tissue necrosis with implant failure, the degree to which processes, such as metal toxicity, negatively impact implant performance is unknown. We evaluated representative human peri-implant cells (i.e., osteoblasts, fibroblasts, and lymphocytes) when challenged by Al+3, Co+2, Cr+3, Fe+3, Mo+5, Ni+2, and V+3 chloride solutions (and Na+2 as a control) over a wide range of concentrations (0.01-10.0 mM). Cell responses were measured using proliferation assays, viability assays, and microscopic cell morphology assessments. Differential effects were found to be less a function of the cell type than of the composition and concentration of metal challenge. No preferential immunosuppression was demonstrated. Below 0.01 mM, no metal was toxic. The most toxic metals (i.e., Co, Ni, and V) reduced proliferation (IC50), and viability (LC50) and cell morphology of osteoblasts, fibroblasts, and lymphocytes by <50% at challenge concentrations <1 mM. All other metals tested required >5 mM to exact the same responses. Below 1 mM, these toxic metals also induced alterations in all cell morphology consisting of loss of filopodia or lamellipodia or changes in cell shape. Metals that were toxic at clinically relevant concentrations (less than previously reported values in peri-implant tissues/fluids) include Co (0.6 mM), Ni (0.8 mM), V (0.5 mM) for lymphocytes and Co (0.8 mM), V (0.3 mM), Al (1-5 mM), Fe (1-5 mM) for fibroblasts, and Co (0.8 mM), Ni (0.7 mM), V (0.1 mM) for osteoblasts. Only Co and V were toxic in vitro at concentrations below that detected in vivo in synovial fluid (V at 0.1 mM and Co at 0.8 mM for fibroblasts, and V at 0.4 mM and Co at 0.8 mM on osteoblasts). Thus, soluble Co and V released from Co- and Ti-based alloys, respectively, could be implicated as the most likely to mediate cell toxicity in the periprosthetic milieu.

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Implant debris remains the major factor limiting the longevity of total joint replacements. Whether soluble implant debris of Zr and Nb containing implant alloys constitute a greater risk than other implant metals remains unknown. We evaluated the relative effects of soluble forms of Zr+4 and Nb+5 (0.001–10.0 mM) relative to Cr+3, Mo+5, Al+3, Co+2, Ni+2, Fe+3, Cu+2, Mn+2, Mg+2, Na+2, and V+3 chloride solutions on human peri-implant cells (i.e., osteoblast-like MG-63 cells, fibroblasts, and lymphocytes). Metals were ranked using a 50% decrease in proliferation and viability to determine toxic concentrations. Lymphocytes, fibroblasts, and osteoblasts were, generally, similarly affected by metals where the most toxic metals, Co, Ni, Nb, and V required &lt;1.0 mM to induce toxicity. Less toxic metals Al, Cr, Fe, Mo, and Zr generally required &gt;1.0 mM challenge to produce toxicity. Overall, Co and V were the most toxic metals tested, thus Zr and Nb containing implant alloys would not likely be more toxic than traditional implant alloys. Below concentrations of 0.1 mM, neither Zr nor Nb reduced osteoblast, lymphocyte, or fibroblast proliferation. Zr was generally an order of magnitude less toxic than Nb to lymphocytes, fibroblasts, and osteoblasts. Our results indicated that soluble Zr and Nb resulting from implant degradation likely act in a metal- and concentration-specific manner capable of producing adverse local and remote tissue responses to the same degree as metals from traditional implant alloys, e.g., Ti-6Al-4V (ASTM F 138) and Co-Cr-Mo alloys (ASTM F 75).