The formation of titanium (Ti)-wear particles during the lifetime of an implant is believed to be a major component of loosening due to debris-induced changes in bone cell function. Radiographic evidence indicates a loss of fixation at the implant-bone interface, and we believe that the accumulation of Ti particles may act on the bone-remodeling process and impact both long-and short-term implant-fixation strengths. To determine the effects of various sizes of the Ti particles on osteoblast function in vivo, we measured the loss of integration strength around Ti-pin implants inserted into a rat tibia in conjunction with Ti particles from one of four size-groups. Implant integration is mediated primarily by osteoblast adhesion͞focal contact pattern, viability, proliferation and differentiation, and osteoclast recruitment at the implant site in vivo. This study demonstrates the significant attenuation of osteoblast function concurrent with increased expression of receptor activator of nuclear factor B ligand (RANKL), a dominant signal for osteoclast recruitment, which is regulated differentially, depending on the size of the Ti particle. Zymography studies have also demonstrated increased activities of matrix metalloproteinases (MMP) 2 and 9 in cells exposed to larger Ti particles. In summary, all particles have adverse effects on osteoblast function, resulting in decreased bone formation and integration, but different mechanisms are elicited by particles of different sizes.implant stability ͉ focal contact ͉ integration strength ͉ receptor activator of nuclear factor B ligand ͉ matrix metalloproteinase A septic loosening is emerging as the most common cause of failure for total joint replacements (1, 2). The condition is characterized by an area of osteolysis found at the bone-prosthesis interface and can be identified radiographically as the presence of radiolucent zones at the bone-implant interface (3-6). Previously, aseptic loosening was thought to be a purely mechanical event resulting from the instability of the prosthesis (7-9). However, a biological mechanism of aseptic loosening has recently been proposed that focuses on the bone-prosthesis interface (10, 11). To gain insight into the mechanisms by which particular wear debris induces osteolysis, a number of investigators have studied tissue from revision-surgery patients who have developed aseptic loosening (12-14). Willert and coworkers (15) have reported that the release of wear debris into the bone-implant bed leads to the development of a foreign-body reaction. This reaction is often made worse by repetitive exposure to the foreign substance.In conjunction with the recent literature (16) describing the evidence of abrasion and burnishing in failed cementless implants, the particles generated from micromotion between bone and implant in the femoral bone bed at the bone-implant interface are believed to be the major cause of numerous osteoblast functional changes that eventually result in improper participation of bone-bed formation and remodeling (16...