Cobalt ions stimulate a fibrotic response through matrix remodelling, fibroblast contraction and release of pro-fibrotic signals from macrophages

摘要

Many studies report the adverse responses to metal-on-metal (MoM) hip prostheses, with tissues surrounding failed MoM hip prostheses revealing abundant tissue necrosis and fibrosis. These local effects appear to be initiated by metal ions released from the prosthesis causing the secretion of inflammatory mediators. However, little is known about the effect of the metal ions on tissue remodelling and pseudotumor formation, which are also associated with the failure of MoM hip prostheses. The peri-prosthetic soft tissue masses can lead to pain, swelling, limited range of joint movement and extensive tissue lesion. To elucidate this cellular response, a multidisciplinary approach using both two- and three-dimensional (2D and 3D) in vitro culture systems was employed to study the effects of Co2+ and Cr3+ on human fibroblast activation and mechanobiology. Co2+ induced a fibrotic response, characterised by cytoskeletal remodelling and enhanced collagen matrix contraction. This was associated with increased cell stiffness and contractile forces as measured by atomic force microscopy and traction force microscopy, respectively. These effects were triggered by the generation of reactive oxygen species (ROS). Moreover, this fibrotic response was enhanced in the presence of macrophages, which increased the prevalence of a-smooth muscle actin (a-SMA)-positive fibroblasts and collagen synthesis. Cr3+ did not show any significant effect on fibroblast activation. Co2+ promoted matrix remodelling by fibroblasts that was further enhanced by macrophage signalling. Use of alternative implant materials or manipulation of this fibrotic response could provide an opportunity for enhancing the success of prostheses utilising CoCr alloys.