Biological Response of Osteoblasts and Osteoprogenitors to Orthopaedic Wear Debris

Total joint replacements are one of the most commonly performed orthopaedic procedures worldwide, with over 700,000 surgeries performed annually in the US to treat arthritic conditions of the hip and knee. One of the major complications of total joint replacement is implant wear and osteolysis, a process that involves continuous shedding of micronand submicron-sized particles from implant components. Implant particles elicit cascades of inflammatory, osteolytic, and granulomatous reactions from macrophages, osteoclasts, and fibroblasts, causing the prosthesis to become unstable. Since the mid 1990s, in vitro studies have shown that wear debris particles inhibit the osteogenic function of osteoblasts and osteoprogenitor cells of human and rodent species. Osteolysis and implant loosening involve not only increased bone resorption by osteoclasts and inflammatory cells, but also reduced bone formation by osteoblasts and their progenitors. This disruption of proliferation, differentiation, function, and survival of osteoblasts prevents the implant from properly integrating with surrounding bone. The inhibitory effects of implant wear debris on osteoblasts and osteoprogenitors have been demonstrated using particles of metallic (titanium, cobalt chrome), polymeric (polyethylene, PMMA), and ceramic (alumina, zirconia) implants. Human and rodent primary osteoblasts and osteoblast cell lines, such as MG-63 cells, treated with titanium and polyethylene particles in culture, uniformly show reduced type I collagen synthesis with evidence of particle phagocytosis and morphological changes consistent with cell injury and cytoskeletal disorganization on microscopy. Selected studies also show that particles impair osteoblast viability, proliferation, adhesion, extracellular matrix production, and osteogenic protein expression (e.g., alkaline phosphatase). Implant particles uniformly stimulate expression of NF-κB and IL-6, IL-8, PGE2, RANKL, M-CSF, and MCP-1, pro-inflammatory factors known to recruit monocyte-macrophages or induce osteoclast differentiation and activity. These studies also indicate that the effect of particles on osteoblasts depends on particle size and composition and the maturational state of the cell. Metal implants such as cobalt chromium and titanium alloys pose an additional risk of metal ion toxicity. Wear debris particles also inhibit the osteogenic activity of osteoprogenitors and marrow stromal cells (MSCs). Human bone marrow-derived MSCs exposed to titanium particles exhibit reduced proliferation, type I collagen expression, viability, and matrix mineralization with evidence of particle phagocytosis and structural and biochemical changes indicative of