Mechanism and Prevention of Titanium Particle-Induced Inflammation and Osteolysis

Abstract

The worldwide number of dental implants and orthopedic prostheses is steadily increasing. Orthopedic implant loosening, in the absence of infection, is mostly attributable to the generation of wear debris. Dental peri-implantitis is characterized by a multifactorial etiology and is the main cause of implant failure. It consists of a peri-implant inflammatory lesion that often results in loss of supporting bone. Disease management includes cleaning the surrounding flora by hand instruments, ultrasonic tips, lasers, or chemical agents. We recently published a paper indicating that US scaling of titanium (Ti) implants releases particles that provoke an inflammatory response and osteolysis. Here we show that a strong inflammatory response occurs; however, very few of the titanium particles are phagocytosed by the macrophages. We then measured a dramatic Ti particle-induced stimulation of IL1β, IL6, and TNFα secretion by these macrophages using multiplex immunoassay. The particle-induced expression profile, examined by FACS, also indicated an M1 macrophage polarization. To assess how the secreted cytokines contributed to the paracrine exacerbation of the inflammatory response and to osteoclastogenesis, we treated macrophage/preosteoclast cultures with neutralizing antibodies against IL1β, IL6, or TNFα. We found that anti-TNFα antibodies attenuated the overall expression of both the inflammatory cytokines and osteoclastogenesis. On the other hand, anti-IL1β antibodies affected osteoclastogenesis but not the paracrine expression of inflammatory cytokines, whereas anti-IL6 antibodies did the opposite. We then tested these neutralizing antibodies in vivo using our mouse calvarial model of Ti particle-induced osteolysis and microCT analysis. Here, all neutralizing antibodies, administered by intraperitoneal injection, completely abrogated the particle-induced osteolysis. This suggests that blockage of paracrine inflammatory stimulation and osteoclastogenesis are similarly effective in preventing bone resorption induced by Ti particles. Blocking both the inflammation and osteoclastogenesis by anti-TNFα antibodies, incorporated locally into a slow-release membrane, also significantly prevented osteolysis. The osteolytic inflammatory response, fueled by ultrasonic scaling of Ti implants, results from an inflammatory positive feedback loop and osteoclastogenic stimulation. Our findings suggest that blocking IL1β, IL6, and/or TNFα systemically or locally around titanium implants is a promising therapeutic approach for the clinical management of peri-implant bone loss.

Tussilagone Inhibits Osteoclastogenesis and Periprosthetic Osteolysis by Suppressing the NF-κB and P38 MAPK Signaling Pathways

“…Second, Ti particle-induced calvarial osteolysis model, as we used, under-represents the wear-debris-induced osteolysis model used in the emulation of aseptic prosthetic loosening pathogenesis. Different types of wear particles found in the bone-graft interface of patients with different implant materials such as Ti (Eger et al, 2018), cobalt-chromium-molybdenum (CoCrMo) , ceramics (Gibon et al, 2017), tricalcium phosphate (Lv et al, 2016), polyether-ether-ketone (Du et al, 2018), highly cross-linked polyethylene, and ultrahigh-molecular-weight polyethylene (Ormsby et al, 2019) demonstrate various traits in osteolysis. In addition, the limitations that 30 mg Ti particles was locally administrated at one time to produce calvarial osteolysis model was discussed by Liu et al (Liu et al, 2014) in one of his study.…”

Curcumin has immunomodulatory effects on RANKL‐stimulated osteoclastogenesis in vitro and titanium nanoparticle‐induced bone loss in vivo

“…24 A large number of studies have reported that M1-type macrophages were stimulated and induced by wear debris, which is generated from the surface of an implant prosthesis, and released proinflammatory cytokines, creating a proinflammatory microenvironment. 10,43,44 This proinflammatory microenvironment further activates the osteoclastic signalling pathways and promotes the recruitment and differentiation of osteoclast precursor cells. 8 In our study, following TiPs stimulation, the M1-specific marker CCR7 was significantly increased, Second, although the proinflammatory cytokines mainly released by macrophages and the consequent immune responses change the local immune status, various cells, including osteoblasts, fibroblasts and mesenchymal cells, may also release proinflammatory cytokines and participate in the process of wear particle-mediated osteolysis.…”

“…Li et al reported that deacylcynaropicrin inhibited RANKL-mediated osteoclast fusion by promoting M2-type macrophage polarization 24. A large number of studies have reported that M1-type macrophages were stimulated and induced by wear debris, which is generated from the surface of an implant prosthesis, and released proinflammatory cytokines, creating a proinflammatory microenvironment 10,43,44. This proinflammatory microenvironment further activates the osteoclastic signalling pathways and promotes the recruitment and differentiation of osteoclast precursor cells 8.…”

Nanosized Alumina Particle and Proteasome Inhibitor Bortezomib Prevented inflammation and Osteolysis Induced by Titanium Particle via Autophagy and NF-κB Signaling

“…As a result of rapid advances of the biomaterials science, reliable implants were considered to be most widely accepted operative procedure for treating damaged skeleton and diseased organs, such as various skeletal defects, tooth deficiency, joints replacements and et al Due to the routine use of implants, wear particles or debris can be observed from surfaces in relative friction between implants and physiological environment, surfaces between different component of implant, scaffolds for tissue engineering, or materials for drug delivering [1][2][3][4] . In particle disease, peri-implant osteolysis which is caused by wear particles remains the main complication for implant failure after the surgical [5][6][7][8] .…”

“…In the last 20 years, titanium (Ti) has evolved into one of the most widely used material for implant, tissue engineering, material for drug delivery and composite biomaterials, considered its outstanding mechanical properties 1,[13][14][15][16][17] . Nevertheless, Ti implants have some inherent disadvantages.…”