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Clinical findings support this hypothesis: bacterial biofilms exist on many implants from patients with aseptic loosening and antibiotics in bone cement reduce the rate of aseptic loosening. Three approaches were used to demonstrate that adherent endotoxin increases bioactivity of titanium particles. These experiments measured cytokine production and osteoclast differentiation <jats:italic>in vitro<\/jats:italic> and murine calvarial osteolysis <jats:italic>in vivo<\/jats:italic>. First, removal of &gt;99.9% of the adherent endotoxin from titanium particles significantly ablates their biological activity. Second, adding lipopolysaccharide back to these \u201cendotoxin\u2010free\u201d particles restores their biological activity. Third, cells or mice that are genetically hyporesponsive to endotoxin are significantly less responsive to titanium particles than are wild\u2010type controls. Other investigators have confirmed and extended these results to include virtually all orthopedically relevant types of particles, including authentic titanium alloy particles retrieved from patients with loosening. Our recent studies suggest that adherent endotoxin on orthopedic implants may also inhibit initial osseointegration of the implants. Taken together, these studies suggest that bacterial endotoxin may have a significant role in induction of aseptic loosening. \u00a9 2004 Wiley Periodicals, Inc. 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