Immune reactivity to metal implants

Erwin Pai Hsiung Chan

    Research output: ThesisDoctoral Thesis

    266 Downloads (Pure)


    The use of metals like titanium (Ti) and vanadium (V) are common in many medical implants for orthopaedic and orthodontic purposes. The most frequent cause of implant failure is aseptic loosening, resulting from an inflammatory reaction and increased osteolysis at the bone-metal interface. Currently, the pathophysiological mechanism of aseptic loosening remains poorly understood. One hypothesis suggests the reactivity of immune cells (metal hypersensitivity) towards metal ions released through the biocorrosion of metal implants. This thesis examines the effects of titanium and vanadium ions on various immune cells like monocytes, dendritic cells (DCs) and T-lymphocytes. Thereby investigating the role and mechanism which titanium and vanadium plays in aseptic loosening. Through energy filtered transmission electron microscopy, the accumulation of titanium ions was visualized in human monocyte-derived DCs and T-lymphocytes after 24 hours exposure. Titanium was seen to co-localise with phosphorous-rich regions, like the cell membrane, organelles and nucleus of these cells. Flow cytometry measured changes in the cell surface marker expression of monocytes, osteoclasts, DCs and T-lymphocytes treated with the metals. Monocytes exposed to titanium (IV) showed an increase of Tartate-Resistant Acid Phosphatase (TRAP), important for osteolysis and indicative of differentiation towards an osteoclast-like phenotype. DCs treated with Ti(IV) and vanadium (III) had reduced antigen presenting MHC class II expression, but not a reduced capacity to proliferate non-adherent peripheral blood monocytic cells (naPBMCs). Under the influence of Ti(IV), T-lymphocytes, DCs and monocytes expressed elevated levels of the chemokine receptor, CCR4. This would allow for the migration of CCR4+ cells towards the bone and skin regions. Functional changes were measured with BrdU incorporation proliferation assays, cytokine assays (CBA Kits) and the successful generation of titanium-specific T-lymphocytes from Ti(IV) treated DCs. Ti(IV) specific T-lymphocytes conceptually shows the possible formation of an antigenic titanium-protein complex, which can be recognized by the immune system. DCs treated with Ti(IV) and V(III) were able to cause the proliferation of naPBMCs, even with a reduced antigen presenting capability. However, there was no additional influence of V(III) on the immune response through DCs. Cytokines released by DCs and T-lymphocytes after Ti(IV) treatments showed a skew towards an inflammatory Th1-type response through the release of TGF-! and IL-12p70. Activated T-lymphocytes exposed to Ti(IV) also released RANK-L, which drives osteoclastogenesis and subsequently increased osteolysis. The research supports and suggests an interaction between immune and bone cells where titanium-induced inflammation drives an osteolytic cycle that prevents the integration of metal implants into the bone. Hence, suggesting a mechanism for implant failure through aseptic loosening in patients with titanium-vanadium implants.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Publication statusUnpublished - 2009


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