The Pathology of Orthopedic Implant Failure Is Mediated by Innate Immune System Cytokines

Abstract

All of the over 1 million total joint replacements implanted in the US each year are expected to eventually fail after 15–25 years of use, due to slow progressive subtle inflammation at the bone implant interface. This inflammatory disease state is caused by implant debris acting, primarily, on innate immune cells, that is, macrophages. This slow progressive pathological bone loss or “aseptic loosening” is a potentially life-threatening condition due to the serious complications in older people (>75 yrs) of total joint replacement revision surgery. In some people implant debris (particles and ions from metals) can influence the adaptive immune system as well, giving rise to the concept of metal sensitivity. However, a consensus of studies agrees that the dominant form of this response is due to innate reactivity by macrophages to implant debris where both danger (DAMP) and pathogen (PAMP) signalling elicit cytokine-based inflammatory responses. This paper discusses implant debris induced release of the cytokines and chemokines due to activation of the innate (and the adaptive) immune system and the subsequent formation of osteolysis. Different mechanisms of implant-debris reactivity related to the innate immune system are detailed, for example, danger signalling (e.g., IL-1β, IL-18, IL-33, etc.), toll-like receptor activation (e.g., IL-6, TNF-α, etc.), apoptosis (e.g., caspases 3–9), bone catabolism (e.g., TRAP5b), and hypoxia responses (Hif1-α). Cytokine-based clinical and basic science studies are in progress to provide diagnosis and therapeutic intervention strategies.

Exposure of the murine RAW 264.7 macrophage cell line to dicalcium silicate coating: assessment of cytotoxicity and pro-inflammatory effects

“…Furthermore, wear-debris particles from implants use TLR4 signaling to stimulate macrophages [49]. Toll-like receptor activation, such as that caused by TNF-a and IL-6, is involved in the response to implant debris or coating ions that cause progressive pathological bone loss or ''aseptic loosening'' [50]. Previous studies have demonstrated that surface topography (in particular, that of surfaces that have been subjected to sandblasting and acid etching) modulates the expression of pro-inflammatory cytokines and chemokines by macrophages in a time-dependent manner.…”

Macrophage responses to implants: prospects for personalized medicine

“…In the United States alone, there are .1 million such surgical operations performed each year [34]. Some of these patients need to undergo a revision surgery, usually related to aseptic loosening associated with periarticular osteopenia, focal osteolysis, and infection [35].…”

“…Host cells, primarily resident macrophages and fibroblasts, upon recognition of the wear particles, start to produce a wide range of proinflammatory cytokines and growth factors, such as TNF-a, IL-1a, IL-1b, IL-6, IL-8, IL-11, IL-15, TGF-a, GM-CSF, M-CSF, PDGF, and epidermal growth factor [37,38]. These inflammatory factors are able to induce osteoclast formation through the RANKL/RANK/OPG pathway, which stimulates osteolysis, as well as recruits inflammatory macrophages and lymphocytes [34,36,39,40]; these cells produce additional proinflammatory and pro-osteoclastogenic factors, thus enhancing the reaction. On the other hand, wear particles inhibit the differentiation of mesenchymal stem cells into osteoblasts and induce apoptosis.…”

Review: the potential impact of surface crystalline states of titanium for biomedical applications

“…Still a portion of implants fails due to the development of chronic inflammation at the implant-tissue interface (Landgraeber et al, 2014). Prolonged friction between articulating surfaces as well as high mechanical stress result in the release of microscopic wear particles.…”