CoCrMo-Nanoparticles induced peri-implant osteolysis by promoting osteoblast ferroptosis via regulating Nrf2-ARE signalling pathway.

OBJECTIVES: Aseptic loosening (AL) is the most common reason of total hip arthroplasty (THA) failure and revision surgery. Osteolysis, caused by wear particles released from implant surfaces, has a vital role in AL. Although previous studies suggest that wear particles always lead to osteoblast programmed death in the process of AL, the specific mechanism remains incompletely understood and osteoblast ferroptosis maybe a new mechanism of AL. MATERIALS AND METHODS: CoCrMo nanoparticles (CoNPs) were prepared to investigate the influence of ferroptosis in osteoblasts and calvaria resorption animal models. Periprosthetic osteolytic bone tissue was collected from patients who underwent AL after THA to verify osteoblast ferroptosis. RESULTS: Our study demonstrated that CoNPs induced significant ferroptosis in osteoblasts and particles induced osteolysis (PIO) animal models. Blocking ferroptosis with specific inhibitor Ferrostatin-1 dramatically reduced particle-induced ferroptosis in vitro. Moreover, in osteoblasts, CoNPs significantly downregulated the expression of Nrf2 (nuclear factor erythroid 2-related factor 2), a core element in the antioxidant response. The overexpression of Nrf2 by siKeap1 or Nrf2 activator Oltipraz obviously upregulated antioxidant response elements (AREs) and suppressed ferroptosis in osteoblasts. Furthermore, in PIO animal models, the combined utilization of Ferrostatin-1 and Oltipraz dramatically ameliorated ferroptosis and the severity of osteolysis. CONCLUSIONS: These results indicate that CoNPs promote osteoblast ferroptosis by regulating the Nrf2-ARE signalling pathway, which suggests a new mechanism underlying PIO and represents a potential therapeutic approach for AL.

Breakage of metal hip arthroplasty components: Retrieval and structural analysis.

BACKGROUND: Breakage of joint arthroplasty components are rare, yet during an implant retrieval program we found several cases. OBJECTIVE: In this study we examined the components to determine the causes and mechanisms of breakage of these implants. METHODS: From our collection of 849 retrievals we selected 682 cases with metal parts (503 hip, 79 knee arthroplasties) and identified fractured components: seven hip resurfacing implants, five total hip replacement stems, one monopolar femoral head, and one modular revision femoral stem from. Implants were examined using optical and scanning electron microscopy; metallographic sections were prepared and samples of periprosthetic tissues underwent microscopic examination. RESULTS: In the resurfacing components breakage occurred in small stems placed in the femoral neck due to necrosis of femoral heads, with no metal flaws detected. Fatigue breakage of femoral stems was caused by presence of material flaws in the CoCrMo alloy, and corrosion. The monopolar head failed in fatigue fracture mechanism, breakage was initiated in an undercut near the taper connection for femoral component. The modular stem from Ti alloy sustained fatigue fracture induced by corrosion caused by debris from previously revised stem; no material flaws were detected in this sample. In most cases periprosthetic tissues had a morphology typical for aseptic loosening. CONCLUSIONS: In our series failure was caused by material flaws, presence of stress raisers and localized corrosion. Our findings indicate that sharp edges and other features which can act as stress raisers should be avoided in newly designed implants. Corrosion induced fracture of the modular Ti stem indicates the need for a detailed debridement of periprosthetic tissues during revision arthroplasties.

The effects of cobalt-chromium-molybdenum wear debris in vitro on serum cytokine profiles and T cell repertoire.

Cobalt-chromium-molybdenum (CoCrMo) alloy-based metal-on-metal prostheses have been the implant of choice for total hip replacement in younger patients. However 6.2% of patients require revision of their CoCrMo total hip replacement (THR) implant within five years of surgery and their use was restricted in 2013. We aimed to determine if there were individual differences in the immune response to wear debris that might indicate a poor outcome with a CoCrMo prosthesis. Blood from 22 donors was incubated with CoCrMo particles (>99.9% less than 10 µm diameter) generated by a wear simulator for 24 h. T cell phenotype was assessed by immunostaining and secretion of 8 different pro- and anti-inflammatory cytokines was measured using multiplex technology. Clear differences were seen between individuals in the induction of Th17 and Th1 responses, with some donors showing pro-inflammatory responses (increased IL17 or IFNγ) and others showing anti-inflammatory responses (decreased IL17 or IFNγ). The only differences seen for gender and age related to increased IL-10 expression from T cells in females (p = 0.008) and a trend towards decreased IL-6 expression systemically for older donors (p = 0.058). We conclude that individuals show differential responses to CoCrMo wear debris and that these responses could give early indications of the suitability of the patient for a metal-on-metal prosthesis.

The fibroblast expression of RANKL in CoCrMo-particle-induced osteolysis is mediated by ER stress and XBP1s.

Particle-induced osteolysis is a major cause of aseptic loosening, which is the most common reason for total hip arthroplasty (THA) failure and revision surgery. Although existing studies suggest that synovial fibroblasts present in the interfacial membrane are important targets of wear particles during bone resorption, the interaction mechanisms between the particles and fibroblasts remains elusive. In the present study, we investigated the effect of ER stress induced by CoCrMo particles (CoPs) in fibroblasts, calvarial resorption animal models and aseptic loosening clinical samples and its role in the stimulation of the RANKL expression. Our study further demonstrated that CoPs could induce significant ER stress in fibroblasts. Blocking ER stress with a specific inhibitor dramatically reduced the particle-induced expression of RANKL in vitro and in vivo. Furthermore, in fibroblasts, downregulation of the expression of XBP1s, a signaling molecule of ER stress, significantly reduced the expression of RANKL induced by wear particles. Moreover, inhibition of ER stress or XBP1s both ameliorated the CoPs-induced osteolysis in animal models. Collectively, these results suggested that in particle-induced osteolysis, CoPs could stimulate fibroblasts to secret RANKL through ER stress and the signaling molecule XBP1s. Therefore, downregulating ER stress or the signaling molecule XBP1s of fibroblasts represents a potential therapeutic approach for treating particle-induced peri-implant osteolysis. STATEMENT OF SIGNIFICANCE: For the first time, our study demonstrated that ER stress mediated the induction of RANKL expression by CoPs in fibroblasts and promoted particle-induced osteolysis. Furthermore, the upregulation of RANKL by CoPs in fibroblasts was mediated by the ER stress signaling molecule XBP1s. Both blocking ER stress and inhibiting the protein XBP1s by specific inhibitors resulted in downregulation of the expression of RANKL and amelioration of osteolysis induced by the implanted particles. Collectively, these findings suggest a possible mechanism underlying the RANKL expression induced by wear particles in fibroblasts, and downregulating ER stress and the XBP1s expression of fibroblasts represents a potential therapeutic approach for treating aseptic loosening.

Adverse reactions to metal debris in metal-on-polyethylene total hip arthroplasty using a titanium-molybdenum-zirconium-iron alloy stem.

We report a series of three patients who underwent uncemented total hip arthroplasty with a modular titanium-molybdenum-zirconium-iron stem and a cobalt-chrome-molybdenum head on an ultra-high molecular weight highly cross-linked polyethylene liner bearing. All three cases subsequently developed pain and adverse reaction to metal debris, leading to revision of the implants within thirty-six months. They were subsequently found to have hypersensitivity to cobalt or chromium. However where tested, blood metal ion levels were within MHRA guideline limits. Corrosion was noted at the taper-trunnion junction. It is possible, that the multi alloy head-neck combination may lead to corrosion. Hypersensitivity to metal ions may result to ARMD at lower metal ion levels. The use of ceramic heads may help avoid this risk.

Systemic hypersensitivity reaction (without cutaneous manifestations) to an implantable cardioverter-defibrillator.

Implantable cardiac devices play a significant role in decreasing the morbidity and mortality in patients with cardiovascular disease. Tissue-device interactions leading to systemic hypersensitivity are rarely reported or are perhaps misdiagnosed as infectious in origin. We report the case of a 51-year-old female who underwent placement of an implantable cardiac defibrillator (ICD) and a biventricular pacemaker and who immediately postoperatively experienced sepsislike symptoms without any identifiable causative pathogens and without any dermatitis. Patch testing revealed an extreme reaction to cobalt confirmed as present in the defibrillator. Removal of the ICD led to the complete resolution of her symptoms. Patch testing helped guide the construction of a gold-coated ICD, which was implanted in the patient. The patient has remained symptom free after implantation of this gilded ICD.

Failed metal-on-metal total hip arthroplasty presenting as painful groin mass with associated weight loss and night sweats.

We report an unusual case of a failed metal-on-metal total hip arthroplasty presenting as a groin mass with associated weight loss, night sweats, and raised inflammatory markers. After a malignant process was ruled out, the patient was found to have a loose acetabular component. Histopathologic results revealed features of an aseptic lymphocytic vasculitic associated lesion. All symptoms resolved completely after the metal-on-metal bearing was revised to metal-on-polyethylene.

Co-Cr-Mo alloy particles induce tumor necrosis factor alpha production in MLO-Y4 osteocytes: a role for osteocytes in particle-induced inflammation.

Wear debris-induced osteolysis is purportedly the limiting problem affecting the long term results of joint arthroplasty. Pathogenic effects of wear debris in peri-implant cells such as macrophages, osteoblasts and osteoclasts have been well studied. In contrast, the effects of wear debris on osteocytes, which make up over 90% of all bone cells, remain unknown. We hypothesized that metal implant debris can induce the pro-inflammatory response in osteocytes. This study demonstrated the effects of cobalt-chromium-molybdenum alloy (Co-Cr-Mo) particles on a well-characterized MLO-Y4 osteocyte cell line. Co-Cr-Mo alloy particle treatment significantly (p<0.05) up-regulated tumor necrosis factor alpha (TNFalpha) gene expression after 3 and 6 h and TNFalpha protein production after 24 h, but down-regulated interleukin-6 (IL-6) gene expression after 6 h. Co-Cr-Mo alloy particle treatment also induced osteocyte apoptosis after 24 h. This apoptotic effect was partially (40%) dependent on TNFalpha. Therefore, our results suggest that osteocytes play a role in particle-induced inflammation and bone resorption following total joint arthroplasty by inducing pro-inflammatory cytokines and inducing osteocyte apoptosis.

An analysis of the in vivo deterioration of Co-Cr-Mo implants through wear and corrosion.

The degradation of Co-Cr-Mo ASTM F75-92 hip implants after a harvesting period of 81 months in sheep was investigated. Hip prostheses and tissue samples were obtained from a medical study involving total hip arthroplasty of the cemented type in 12 sheep. Upon euthanasia, the explants were retrieved for analyses of the surfaces and evidence of degradation, while tissue samples from the interface regions were harvested for chemical analysis and evidence of Co, Cr, and Mo contents. Clear evidence of wear and corrosion was detected. Results also indicated that the modes of metal transport through the poly(methyl methacrylate) bone cement play an important role as the surface degradation mechanisms of the metal. The results are being discussed in terms of electrochemical and triboelectrochemical behaviour of the Co-Cr-Mo alloy.

Metallosis after contemporary metal-on-metal total hip arthroplasty. Five to nine-year follow-up.

BACKGROUND: Authors of recent studies have reported early periprosthetic osteolysis in patients who have been treated with a contemporary metal-on-metal total hip arthroplasty and have suggested that metal hypersensitivity associated with an immunologic response to metal may be of etiologic importance. We evaluated the results and histologic findings in patients who had undergone revision of a failed contemporary metal-on-metal total hip arthroplasty. METHODS: Two hundred and seventeen total hip arthroplasties (SL-Plus stem and Bicon-Plus cup) with a Sikomet metal-on-metal articulation were implanted in 194 consecutive patients, and the results were retrospectively reviewed at a mean of seventy-seven months postoperatively. Clinical follow-up with the Harris hip score and plain radiographic evaluation were performed. Periprosthetic tissues from fourteen hips that had undergone revision arthroplasty were subjected to histologic analysis. RESULTS: The mean Harris hip score improved from 45 points preoperatively to 88 points at the final evaluation. Fourteen hips (6.5%) were revised: nine because of aseptic loosening, two because of technical failure, and three because of septic failure. Histologic examination of the retrieved periprosthetic tissues from the eleven patients who had undergone revision because of aseptic loosening or technical failure showed metallosis and extensive lymphocytic and plasma-cell infiltration around the metal debris. With removal of the component because of aseptic loosening as the end point, survivorship was 93% for the stem and 98% for the cup. CONCLUSIONS: Our findings are in agreement with those in recent publications and support the possibility that periprosthetic osteolysis and aseptic loosening in hips with a metal-on-metal articulation are possibly associated with hypersensitivity to metal debris. Prospective, comparative, randomized long-term studies are necessary to determine the cause(s) of loosening of prostheses with this particular articulation.

Release of elements from retrieved maxillofacial plates and screws.

Vitallium appliances and surrounding tissues were investigated to evaluate the release and accumulation of elements. Four microplates, sixteen screws and surrounding tissues were removed from three patients presenting inflammation 4 to 6 years after surgery and were submitted to SEM and X-ray microprobe analysis. Histology was performed on paraffin or PMMA sections of tissues.A continuous release of elements from metallic appliances into soft tissues was observed. Cobalt, chromium, and nickel were detected in soft and boney tissues in close proximity to the appliance. Aluminium, as a component of screw coatings, accumulated in soft tissues, and a remarkable amount of aluminium was detected in the dense lamella of lamellar bone. The results suggest that coatings containing aluminium should be avoided and the time these appliances are allowed to remain in patients should be shortened. Further studies on element release and the fate of aluminium in bone are warranted.

[Metallurgical differentiation of cobalt-chromium alloys for implants]. / Metallkundliche Differenzierung von Kobalt-Chrom-Legierungen für Implantate.

BACKGROUND: Cobalt Chromium alloys are used in cemented total hip or knee arthroplasty as well as in metal-on-metal bearings in total hip arthroplasty. An increasing number of publications report about (allergic) reactions to wear particles of Cobalt Chromium alloys. Reactions to nickel are more frequent in comparison to Cobalt or Chromium particles. It is well known that different kinds of Cobalt Chromium alloys contain different amounts of alloying elements; nevertheless. The aim of the current work was to compare the different Cobalt Chromium alloys according to ASTM F or ISO standards in respect to the different alloying elements. MATERIAL AND METHODS: Co28Cr6Mo casting alloys according to ASTM F 75 or ISO 5832-4 as well as forging alloy types according to ASTM F 799 and ISO 5832 such as Co20Cr15W10Ni, Co35Ni20Cr, Fe40Co20Cr10Ni, Co20Cr20Ni, and Co28Cr6Mo were analyzed in respect to their element content of Co, Cr, Ni, Mo, Fe, W, and Mn. RESULTS: In 1935 the Cobalt based alloy "Vitallium" Co30Cr5Mo basically used in the aircraft industry was introduced into medicine. The chemical composition of this alloy based on Cobalt showed 30 wt.% Chromium and 5 wt.% Molybdenum. The differentiation using alloy names showed no Nickel information in single alloy names. CONCLUSION: The information given about different alloys can lead to an unprecise evaluation of histopathological findings in respect to alloys or alloying constituents. Therefore, implant manufacturers should give the exact information about the alloys used and adhere to European law, Euronorm 93/42/EWG.

[Detection of metals in human tissues by spectrum analysis]. / Opredelenie metallov v tkaniakh cheloveka s pomoshch'iu spektral'nykh metodov issledovaniia.

Potentialities of spectrography experts were demonstrated to be helpful to the employees of patient-care facilities (expertise and research institutions) in solving a variety of burning issues by joint effort. Tissue samplings, hairs and daily urine were comparatively analyzed, by the example of using the low-friction hip arthroplasty by comochrome friction Protasu-21WF, for the content of microelements (ME) belonging to the hip endoprosthesis. We found that MEs (Co, Cr, Mo) are mostly discharged during the first year of endoprosthesis utilization, after which, a regular reduction of concentrations was noted. No exceeding norms were registered in any cases, which denotes a minimal wear of the friction pair.

[Hip metallosis caused by wear of a TT-1 stem on a ceramic modular head hip prosthesis --case report]. / Metaloza biodra wskutek zuzycia metalowego stozka trzpienia protezy TT-1 przez ceramiczna glowe--opis przypadku.

The author presents a case of metal stem cone wear caused by a ceramic head. During revision hip arthroplasty procedure a new modular ceramic head was implanted in combination with a stable cemented TT-1 stem. 13 months after surgery the hip became symptomatic and 20 months after the procedure total loosening of the cup was observed. Wear of the stem cone was visible. During the next revision procedure all hip prosthesis elements were removed, soft tissue debridement was performed and a new cemented prosthesis was implanted. One year post-op the hip is pain free.