Abstract
Titanium is used in a wide variety of materials ranging from medical devices to materials used in everyday life. Adverse biological reactions that could occur in patients, consumers, and workers should be monitored and prevented. There is a lack of available agents to test and predict titanium-related hypersensitivity. The aim of this study was to develop two bioavailable titanium substances in ionic and nanoparticulate form to serve as antigens for hypersensitivity testing in vitro. Peripheral blood mononuclear cells from 20 test subjects were stimulated with the antigens and secretion of monocytic and lymphatic cytokines and chemokines were measured by a multiplex bead assay. Lymphocyte stimulation indices were also determined in a subset of test subjects by measuring CD69 and HLA-DR expression by flow cytometry. Cytokine profiling revealed that both antigens increased production of typical monocyte and macrophage secreted cytokines after 24 h, with significant increases in IL-1β, IL-7, IL-10, IL-12, IL-2R, IL-6, GM-CSF, TNF-α, IL-1RA, MIP-1α, MIP-1β, IFN-α, and IL-15. Lymphatic cytokines and chemokines were not significantly induced by activation. After seven days of stimulation, ionic-Ti (2.5 μg/mL) caused proliferation (stimulation index > 2) of CD4+ cells and CD8+ cells in all persons tested (N = 6), while titanium dioxide nanoparticles (50 μg/mL) only caused significant proliferation of CD4+ cells. Our preliminary results show that the experimental titanium antigens, especially the ionic form, induce a general inflammatory response in vitro. A relevant cohort of test subjects is required to further elucidate their potential for predictive hypersensitivity testing.
Highlights
Titanium and its oxides are utilized broadly for the creation of materials, and it is estimated that 1.45 million metric tons were produced in the United States in 2007 [1]
Human serum albumin (HSA) was found to be the reagent that contributed to the endotoxin level in the Ti-antigens, but HSA alone did not stimulate cytokine release
We have shown that both nanoparticulate and ionic titanium antigens initiate immune responses in vitro
Summary
Titanium and its oxides are utilized broadly for the creation of materials, and it is estimated that 1.45 million metric tons were produced in the United States in 2007 [1]. The unique material properties of titanium dioxide (TiO2), such as its high strength and ease of machinability, explain its extensive use for creation of materials including paint, cosmetics, sunscreen, toothpaste, plastics, paper, textiles, food packaging, and medical devices [2,3]. Exposure to titanium nanoparticles and titanium materials is broad and affects consumers, patients, and people with occupational exposure [4,5,6]. Titanium materials were historically considered bio-inert, since metallic titanium is highly resistant to corrosion. In 2006, the International Agency for Research on Cancer classified TiO2 as possibly carcinogenic to humans [7]
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