Summary Statement. The chemistry, amount, morphology, and size distribution of wear debris from silicon nitride coatings generated in the bearing surface can potentially reduce the negative biological response and increase the longevity compared to conventional materials in joint replacements. Introduction. Total hip implants have a high success rate at 15 years of implantation, but few survive over 25 years. At present, revisions are mostly due to aseptic loosening, believed to mainly be caused by the biological response to wear debris generated in the joint bearing. For the polymer liners the size of the wear debris determines the biological response, while for metal bearing surfaces a limitation is the metal ion release. When ceramics are used, the wear debris is in general small and mechanical factors may be the main cause for failure. A more recent, experimental alternative is to let the well-known metallic substrate serve as the soft, tough bulk, and additionally apply a hard and smooth ceramic coating. In this way a lower wear rate and reduced metal ion release could be obtained. Furthermore, the chosen composition, silicon nitride (SixNy), contains no detrimental ions, and silicon nitride debris has been shown to slowly dissolve in aqueous medium. Altogether, it can potentially increase the longevity of the implant. However, the debris from SixNy coatings has not yet been characterised. In this study, a wear model test was performed to generate wear debris from SixNy coatings. The debris was characterised using scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) in combination with computational calculations. Methods. Silicon nitride coatings deposited on flat cobalt chromium alloy (ASTM F75) were worn in a reciprocating ball on disc setup in a 25% serum solution at 37°C against an alumina ball with a load of 1.5 N. Wear debris was separated using serum digestion with hydrochloric acid (ISO 17853:2011) and examined in SEM in combination with EDS. As reference polyethylene (PE) was used to verify that relevant particles sizes were achieved. The SEM images were processed using a modified MATLAB-script originating from Cervera Gontard et al. [1], identifying the particles and calculating their size. Results. Particles generated from SixNy coatings (n=62) a size distribution D50 [D10-D90] of 0.29 µm [0.16–0.69] and were round to oval in shape. The PE particles (n=70) had a size distribution of 0.29 µm [0.13–1.3], shaped similar to the SixNy particles or with a more elongated shape. Discussion and conclusions. PE wear debris has been reported to lie in the size range of nm up to several μm in vivo, with a large proportion within the critical size for macrophage activation (0.2 to 0.8 μm). The model test reports relevant sizes and shape of PE debris, confirming the validity of the method. Particles generated from the SixNy coatings showed a smaller size range than PE, however most particles were within the critical size range for biological activation. In conclusion, this model test could be used to generate what we believe are relevant sizes and shapes of PE and SixNy wear debris and to learn more at an early stage of prediction of wear debris. Further dissolution studies as well as studies on the in vitro and in vivo cell response to these types of particles will be performed. The authors thank the Swedish Foundation for Strategic Research (SSF) through MS2E and FP7 NMP project LifeLongJoints for financial support, as well as Linköping University for the coating facilities and expertise

Wear debris was extracted from 21 worn hip and knee replacements. Its mutagenic effects were tested on human cells in tissue culture using the micronucleus assay and fluorescent in situ hybridisation. The extracted wear debris increased the level of micronuclei in a linear dose-dependent manner but with a tenfold difference between samples. The concentration of titanium +/− vanadium and aluminium within the wear debris was linearly related both to the level of centromere-positive micronuclei in tissue culture, indicating an aneuploid event, and to the level of aneuploidy in vivo in peripheral blood lymphocytes. The concentration of cobalt and chromium +/− nickel and molybdenum in the wear debris correlated with the total index of micronuclei in tissue culture, both centromere-positive and centromere-negative i.e. both chromosomal breakage and aneuploidy events. The results show that wear debris can damage chromosomes in a dose-dependent manner which is specific to the type of metal. The results from studies in vitro correlate with those in vivo and suggest that the wear debris from a worn implant is at least partly responsible for the chromosomal damage which is seen in vivo

We compared wear particles from two different designs of total hip arthroplasty with polycrystalline alumina-ceramic bearings of different production periods (group 1, before ISO 6474: group 2, according to ISO 6474). The neocapsules and interfacial connective tissue membranes were retrieved after mean implantation times of 131 months and 38 months, respectively. Specimen blocks were freed from embedding media, either methylmethacrylate or paraffin and digested in concentrated nitric acid. Particles were then counted and their sizes and composition determined by SEM and energy-dispersive x-ray analysis (EDXA).

The mean numbers and sizes of most alumina wear particles did not differ for both production periods, but the larger sizes of particle in group 1 point to more severe surface destruction. The increased metal wear in group 2 was apparently due to alumina-induced abrasion of the stems. In this study the concentrations of particles in the periprosthetic tissues were 2 to 22 times lower than those observed previously with polyethylene and alumina/polyethylene wear couples.

Ultra-high-molecular-weight polyethylene (UHMWPE) components for total joint replacement generate wear particles which cause adverse biological tissue reactions leading to osteolysis and loosening. Sterilisation of UHMWPE components by gamma irradiation in air causes chain scissions which initiate a long-term oxidative process that degrades the chemical and mechanical properties of the polyethylene. Using a tri-pin-on-disc tribometer we studied the effect of ageing for ten years after gamma irradiation in air on the volumetric wear, particle size distribution and the number of particles produced by UHMWPE when sliding against a stainless-steel counterface.

The aged and irradiated material produced six times more volumetric wear and 34 times more wear particles per unit load per unit sliding distance than non-sterilised UHMWPE. Our findings indicate that oxidative degradation of polyethylene after gamma irradiation in air with ageing produces more wear.

Wear debris from implant interfaces is the major factor leading to periprosthetic osteolysis. Fibroblast-like synoviocytes (FLSs) populate the intimal lining of the synovium and are in direct contact with wear debris. This study aimed to elucidate the effect of Ti particles as wear debris on human FLSs and the mechanism by which they might participate in the bone remodeling process during periprosthetic osteolysis. FLSs were isolated from synovial tissue from patients, and the condition medium (CM) was collected after treating FLSs with sterilized Ti particles. The effect of CM was analyzed for the induction of osteoclastogenesis or any effect on osteogenesis and signaling pathways. The results demonstrated that Ti particles could induce activation of the NFκB signaling pathway and induction of COX-2 and inflammatory cytokines in FLSs. The amount of RANL in the conditioned medium collected from Ti particle-stimulated FLSs (Ti CM) showed the ability to stimulate osteoclast formation. The Ti CM also suppressed the osteogenic initial and terminal differentiation markers for osteoprogenitors, such as alkaline phosphate activity, matrix mineralization, collagen synthesis, and expression levels of Osterix, Runx2, collagen 1α, and bone sialoprotein. Inhibition of the WNT and BMP signaling pathways was observed in osteoprogenitors after the treatment with the Ti CM. In the presence of the Ti CM, exogenous stimulation by WNT and BMP signaling pathways failed to stimulate osteogenic activity in osteoprogenitors. Induced expression of sclerostin (SOST: an antagonist of WNT and BMP signaling) in Ti particletreated FLSs and secretion of SOST in the Ti CM were detected. Neutralization of SOST in the Ti CM partially restored the suppressed WNT and BMP signaling activity as well as the osteogenic activity in osteoprogenitors. Our results reveal that wear debris-stimulated FLSs might affect bone loss by not only stimulating osteoclastogenesis but also suppressing the bone-forming ability of osteoprogenitors. In the clinical setting, targeting FLSs for the secretion of antagonists like SOST might be a novel therapeutic approach for preventing bone loss during inflammatory osteolysis

Introduction and Objective. Total joint replacement (TJR) is indicated for patients with end-stage osteoarthritis (OA) where conservative treatment has failed. Approximately 1.3 million primary hip replacement surgeries have been recorded in the United Kingdom since 2003 and this number is set to rise due to an increase in obesity as well as an ageing population. Total hip replacement (THR) has a survival rate of 85% at 20 years; the most common reason for failure is aseptic loosening which often occurs secondary to osteolysis caused by immune-mediated inflammation responses to wear debris generated from the materials used in the THR implant. Therefore, by understanding the biological steps by which biomaterials cause immune-mediated reactions it should be possible to prevent them in the future thereby reducing the number of costly revision surgeries required. Materials and Methods. The human osteoblast-like cell line (MG-63) was seeded at a density of 100,000 cell per well of a 6-well plate and treated with and increasing doses (0.5, 5, and 50mm. 3. per cell) of cobalt-chromium (CoCr) particles generated on a six-station pin-on-plate wear generator or commercially available ceramic oxide nanopowders (Al. 2. O. 3. and ZrO. 2. ) for 24 hours. TNF-alpha was used as a positive control and untreated cells as a negative control. Cells were then analysed by transmission electron microscopy (TEM) to determine whether the osteoblasts were capable of phagocytosing these biomaterials. MG-63 cells were used in conjunction with trypan blue and the XTT Cell Proliferation II Kit to assess cytotoxicity of the biomaterials investigated. Cells supernatants were also collected and analysed by enzyme-linked immunosorbant assay (ELISA) to investigate changes in pro-inflammatory protein secretion. Protein extracted from lysed cells was used for western blotting analysis to investigate RANKL protein expression to determine changes to osteolytic activation. Lysed cells were also used for RNA extraction and subsequent cDNA synthesis for real-time quantitative polymerase chain reaction (RT-qPCR) in order to assess changes to pro-inflammatory gene expression. Results. There was no significant change to cellular viability or proliferation in the osteoblasts treated with CoCr, Al. 2. O. 3. or ZrO. 2. when compared to the untreated negative control. TEM images showed clear and distinct intracellular vesicles within the cell cytoplasm which contained CoCr, Al. 2. O. 3. and ZrO. 2. RANKL expression increased at 5 and 50mm. 3. per cell CoCr and 50mm. 3. per cell Al. 2. O. 3. and ZrO. 2. Pro-inflammatory protein secretion of CXCL10, IL-8, and IL-6 all significantly increased at 50mm. 3. per cell CoCr, Al. 2. O. 3. , and ZrO. 2. Similarly to the protein secretion, CXCL10, IL-8, and IL-6 gene expression was significantly upregulated at 50mm. 3. per cell CoCr, Al. 2. O. 3. , and ZrO. 2. Conclusions. Increased in vitro RANKL expression in response to CoCr, Al. 2. O. 3. , and ZrO. 2. may result in disruption of bone metabolism and lead to osteolysis which can contribute to aseptic loosening in vivo. Significant increases in IL-6 are particularly important because as well as being a pro-inflammatory cytokine, IL-6 is also secreted by osteoblasts in order to stimulate mature osteoclast formation to mediate bone breakdown. CXCL10 and IL-8 are chemotactic cytokines and increased secretion in response to implant biomaterials can contribute to ongoing pro-inflammatory responses through the recruitment of monocytes and neutrophils respectively. This is interesting as in vivo data demonstrates increased cellular infiltrate in patients experiencing responses to implant materials. Overall, these findings show clear immune activation as well as altered metabolism of MG-63 osteoblast cells in response to implant wear debris which is in agreement with in vivo clinical reports

The biological significance of cobalt-chromium wear particles from metal-on-metal hip replacements may be different to the effects of the constituent metal ions in solution. Bacteria may be able to discriminate between particulate and ionic forms of these metals because of a transmembrane nickel/cobalt-permease. It is not known whether wear particles are bacteriocidal. We compared the doubling time of coagulase negative staphylococcus, Staphylococcus aureus and methicillin resistant S. aureus when cultured in either wear particles from a metal-on-metal hip simulator, wear particles from a metal-on-polyethylene hip simulator, metal ions in solution or a control. Doubling time halved in metal-on-metal (p = 0.003) and metal-on-polyethylene (p = 0.131) particulate debris compared with the control. Bacterial nickel/cobalt-transporters allow metal ions but not wear particles to cross bacterial membranes. This may be useful for testing the biological characteristics of different wear debris. This experiment also shows that metal-on-metal hip wear debris is not bacteriocidal

Summary Statement. CXCR4 gene and protein expression is regulated in a dose and time-dependent manner by metallic wear debris but not polyethylene wear debris in vitro and in vivo. Introduction. Progressive osteolysis leading to aseptic loosening among metal-on-metal (MoM) total hip arthroplasties (THA's), and adverse reactions to metallic debris (ARMD) are increasing causes for concern among existing patients who have been implanted with MoM hip replacements. Close surveillance of these patients is necessary and difficulties lie in early detection as well as differentiating low-grade infection from ARMD in the early stages. Several inflammatory markers have been investigated in this context, but to date, none is specific with regards to the offending material. In earlier studies, it has been shown that osteoblastic phenotypes and differentiation are regulated by different types of wear particles. Methods. In vitro experiments were performed using MG63 and SaOs-2 osteoblast-like cells co-cultured with increasing concentrations of metallic (Co-35Ni-20Cr-10Mo and Co-28Cr-6Mo) and polyethylene (UHMWPE-GUR1020) particles simulating periprosthetic wear debris. Real-time Polymerase Chain Reaction (RT-PCR) and Western Blotting were used to quantify gene and protein expression of CXCR4. The expression of TNF-a and the effects of AMD3100 on both CXCR4 and TNF-a expression among these cells was also investigated. Immunohistochemical techniques were used to investigate the in-vivo expression of CXCR4 in retrieval tissues obtained from 2 cohorts of failed metal-on-metal and ceramic-on-polyethylene THA's. Results. In-vitro RT-PCR and experiments demonstrated a dose-dependent increase in CXCR4 mRNA (7.5 fold for MG63 and 4.0 fold for SaOs-2 cells) among cells co-cultured with metal alloy particles. Western blotting also showed a time-dependent increase in protein expression of CXCR4. No regulatory effects on CXCR4 gene expression were seen among cells co-cultured with UHMWPE particles. The attempted blockade of CXCR4 by it's known competitive receptor agonist AMD3100 (bicyclam) led to a significant inhibition of metal particle induced TNF-a mRNA expression. In-vivo immunohistochemical data from the 2 cohorts of patients with failed THA's showed CXCR4 positivity among 83% of patients with metal-on-metal hip replacements but none among ceramic-on-polyethylene hip replacements. Discussion/Conclusion. CXCR4, the chemokine receptor for the chemokine SDF-1 (stromal cell derived factor-1), has been shown to play a pivotal role in bone metastasis, inflammatory and autoimmune conditions but has not been investigated in the context of periprosthetic osteolysis in failed joint replacements. Our in-vivo and in-vitro findings collectively suggest that the CXCR4 chemokine is specifically upregulated in a dose and time-dependent manner in the presence of metallic (cobalt-chrome) wear debris but not by polyethylene wear debris. The CXCR4 chemokine receptor may be a selective and specific biomarker for progressive osteolysis seen in failed MoM hip replacements and this phenomenon could potentially have a translational effect on the practice of orthopaedic surgery. Further research is needed to evaluate the interactions of CXCR4 with osteoclast activation and signalling pathways

Wear products of metal implants are known to induce biological events which may have profound consequences for the microcirculation of skeletal muscle. Using the skinfold chamber model and intravital microscopy we assessed microcirculatory parameters in skeletal muscle after confrontation with titanium and stainless-steel wear debris, comparing the results with those of bulk materials. Implantation of stainless-steel bulk and debris led to a distinct activation of leukocytes combined with a disruption of the microvascular endothelial integrity and massive leukocyte extravasation. While animals with bulk stainless steel showed a tendency to recuperation, stainless-steel wear debris induced such severe inflammation and massive oedema that the microcirculation broke down within 24 hours after implantation. Titanium bulk caused only a transient increase in leukocyte-endothelial cell interaction within the first 120 minutes and no significant change in macromolecular leakage, leukocyte extravasation or venular diameter. Titanium wear debris produced a markedly lower inflammatory reaction than stainless-steel bulk, indicating that a general benefit of bulk versus debris could not be claimed. Depending on its constituents, wear debris is capable of eliciting acute inflammation which may result in endothelial damage and subsequent failure of microperfusion. Our results indicate that not only the bulk properties of orthopaedic implants but also the microcirculatory implications of inevitable wear debris play a pivotal role in determining the biocompatibility of an implant

Introduction and Objective. Total joint replacement is indicated for osteoarthritis where conservative treatment has failed, and in the UK the number of patients requiring hip and knee replacements is set to increase with an ageing population. Survival of total hip replacements is around 85% at 20 years with the most common reason for revision being aseptic loosening of the implant secondary to osteolysis, which is caused by immune-mediated reactions to implant debris. These debris can also cause pseudotumour formation. As revision surgery is associated with higher morbidity, mortality, infection rates, venous thromboembolism, resource demand and poorer subsequent function it is important to understand the mechanisms underlying the pro-inflammatory process to improve implant survival. Toll-like receptor 4 (TLR4), an innate immune receptor, has been demonstrated to mediate deleterious immune responses by the Tyson-Capper research group, including inflammatory cytokine interleukin-8 (IL-8) secretion. Statin use in epidemiological studies has been associated with reduced overall risk of revision surgery after hip replacement. In-vitro studies have demonstrated the potential for statins to reduce orthopaedic debris-induced immune responses which can lead to osteolysis and pseudotumour formation. As literature from cardiological investigations demonstrate that statins can reduce the expression and responsiveness of TLR4, this could be an exciting mechanism to exploit to reduce the host immune response to orthopaedic wear debris, thereby improving implant survival by reducing immune mediated osteolysis. This ongoing study investigates simvastatin's effect on cobalt ion-mediated changes in gene and protein expression of interleukin-8 and soluble-ICAM-1 (sICAM-1) which is an angiogenic factor implicated in pseudotumour formation. Materials and Methods. TLR4-expressing human monocyte/macrophage THP-1 cells were pre-incubated with 50μM simvastatin for 2-hours or a vehicle control, before being exposed to exposed to 0.75mM cobalt chloride, in addition to a further 24-hour co-incubation with 50μM simvastatin or vehicle control. IL-8 protein and sICAM-1 secretion was measured by enzyme-linked immunosorbent assay (ELISA). Gene expression changes were quantified by TaqMan-based real time polymerase chain reaction. Results. Pre-treatment with simvastatin significantly reduced cobalt-mediated IL-8 protein secretion (n=3) and sICAM-1 protein secretion (n=2) in THP-1 cells (p-value<0.0001). Work will be undertaken to determine changes in gene expression, the role of TLR4 in these responses and the effect of simvastatin on additional inflammatory markers. Conclusions. Simvastatin significantly reduces cobalt-ion mediated IL-8 and sICAM-1 protein secretion in THP-1 cells. This in-vitro finding demonstrates the potential for simvastatin to reduce recruitment of leukocytes which mediate the deleterious inflammatory processes driving aseptic loosening and pseudotumour formation

Summary Statement. To evaluate carbon-fiber-reinforced PEEK as alternative biomaterial for total disc arthroplasty a closed loop between biotribology (in vitro), application of sterile particle suspensions in the epidural space of rabbits and biological response in vivo was established. Introduction. To prevent adjacent level degeneration in the cervical spine, total disc arthroplasty (TDA-C) remains an interesting surgical procedure for degenerative disc disease. Short- or midterm complications are migration, impaired post-operative neurological assessment due to artefacts in x-ray and MRI diagnosis and substantial rates of heterotopic ossification. The idea was to create a TDA-C design based on a polymer-on-polymer articulation to overcome these limitations of the clinically established metal-on-polyethylene designs. The objective of our study was to characterise the biotribological behaviour of an experimental cervical disc replacement made out of carbon-fiber-reinforced (CFR) PEEK and evaluate the biological response of particulate wear debris in the epidural space in vivo. Materials & Methods. In vitro wear simulation acc. to ISO 18192-1 was performed for 10 million cycles on a clinically established TDA-C device (Aesculap, Tuttlingen) made of cobalt-chromium-on-polyethylene in a direct comparison to an experimental disc prototype made of CFR-PEEK. An estimation of particle size and morphology was done acc. to Affatato et al. [5] and sterile suspensions of comparable particles (size 90% < 1 µm) in phospate buffered saline (PBS) were produced [6] for the application in the epidural space of 36 white new zealand rabbits. The particle concentration was 1 mg/ml with a volume of 0.2 ml injected percutaneously using fluoroscopic guidance and the inflammatory response was assessed 3 and 6 months post-operatively in a direct comparison between the groups PBS (control), UHMWPE and CFR-PEEK. Results. The gravimetric wear rate was for the cobalt-chromium-on-polyethylene TDA-C device as a clinical reference 1.0 ± 0.1 mg/ million cycles, compared to 0.02 ± 0.02 mg/ million cycles for the experimental CFR-PEEK articulation (p < 0.001), whereas the cumulative amount of wear of the CFR-PEEK TDA-C prototypes (0.5 ± 0.23 mg/ million cycles) was decreased by an order of a magnitude compared to cobalt-chromium-on-polyethylene (12.1 ± 1.46 mg/ million cycles) (p < 0.001). For CFR-PEEK and UHMWPE most of the particles were observed in a submicron size range and the morphology was comparable. Histopathological examination demonstrated wear debris in the vertebral canal of injection sites surrounded by inflammatory cells. The inflammation was limited to the epidural space around the particles and polymer particles were associated by a low grade foreign body reaction comprising macrophages and multi-nucleated giant cells. CFR-PEEK particulate wear debris showed at least similar histopathological reactions than UHMWPE in the cervical epidural space. Conclusion. A closed loop between biotribology (in vitro), application of sterile particle suspensions in the epidural space of rabbits and biological response in vivo was established to evaluate carbon-fiber-reinforced PEEK as alternative biomaterial for total disc arthroplasty

Objectives. Third-body wear is believed to be one trigger for adverse results with metal-on-metal (MOM) bearings. Impingement and subluxation may release metal particles from MOM replacements. We therefore challenged MOM bearings with relevant debris types of cobalt–chrome alloy (CoCr), titanium alloy (Ti6Al4V) and polymethylmethacrylate bone cement (PMMA). Methods. Cement flakes (PMMA), CoCr and Ti6Al4V particles (size range 5 µm to 400 µm) were run in a MOM wear simulation. Debris allotments (5 mg) were inserted at ten intervals during the five million cycle (5 Mc) test. . Results. In a clean test phase (0 Mc to 0.8 Mc), lubricants retained their yellow colour. Addition of metal particles at 0.8 Mc turned lubricants black within the first hour of the test and remained so for the duration, while PMMA particles did not change the colour of the lubricant. Rates of wear with PMMA, CoCr and Ti6Al4V debris averaged 0.3 mm. 3. /Mc, 4.1Â mm. 3. /Mc and 6.4 mm. 3. /Mc, respectively. . Conclusions. Metal particles turned simulator lubricants black with rates of wear of MOM bearings an order of magnitude higher than with control PMMA particles. This appeared to model the findings of black, periarticular joint tissues and high CoCr wear in failed MOM replacements. The amount of wear debris produced during a 500 000-cycle interval of gait was 30 to 50 times greater than the weight of triggering particle allotment, indicating that MOM bearings were extremely sensitive to third-body wear. Cite this article: Bone Joint Res 2015;4:29–37

Wear particles produced by alumina ceramic-on-ceramic (CoC) bearings cause a minimal immunological response with low cytotoxicity and inflammatory potential. 1, 2. However, more comprehensive immunological studies are yet to be completed for the composite CoC (zirconia-toughened, platelet reinforced alumina) hip replacements due to difficulties in isolating the very low volume of clinically relevant wear debris generated by such materials in vitro. The aim of this study was to compare the cytotoxic effects of clinically relevant cobalt chromium (CoCr) nano-particles with commercial composite ceramic particles. Composite ceramic particles (commercial BIOLOX® delta powder) were obtained from CeramTec, Germany and clinically relevant CoCr wear particles were generated using a six station pin-on-plate wear simulator. L929 fibroblast cells were cultured with 50µm. 3. of CoCr wear debris or composite ceramic particles at low to high volumes ranging from 500µm. 3. –0.5µm. 3. per cell and the cyctotoxic effects of the particles were assessed over a period of 6 days using the ATP-Lite™ cell viability assay. The composite ceramic particles were bimodal in size (0.1–2µm & 30–100nm) and showed mild cytotoxic effects when compared with equivalent particle volumes (50µm. 3. ) of clinically relevant CoCr nano-particles (10–120nm). The CoCr nano-particles had significant cytotoxic effects from day 1, whereas the composite ceramic particles only showed cytotoxic effects at particle concentrations of 50 and 500µm. 3. after 6 days. The increased cytotoxicity of the clinically relevant CoCr nano-particles may have been attributed to the release of Co and Cr ions. This study demonstrated the potential cytotoxic effects of model ceramic particles at very high volume concentrations, but it is unlikely that such high particle volumes will be experienced routinely in vivo in such low wearing bearing materials. Future work will investigate the longer-term effects on genotoxicity and oxidative stress of low volumes of clinically-relevant generated BIOLOX® delta ceramic wear particles

Metal on metal hip replacements have been one of worst failures in recent years in terms of orthopaedic implants. Some of these devices have had catastrophic failure rates, with reports of 48% failure at 6 years. The failure of these devices has led to considerable suffering, pain and reduction in quality of life; consequently, they have given rise to high costs and multi-million-dollar legal cases. This talk will describe the history of the current metal on metal failure and discuss some of the reasons why might have occurred. It will also consider the reasons that wear debris arising from the trunnion is worse in terms of biological activity then that arising from the bearing surfaces

Summary Statement. Novel radiopaque UHMWPE sublaminar cables may be a promising alternative to gliding pedicle screws or titanium sublaminar cables within a growth-guidance system for the surgical treatment of early onset scoliosis. Introduction. Growth-guidance or self-lengthening rod systems are an alternative to subcutaneous growing rods and the vertical expandable prosthetic titanium rib for the treatment of early onset scoliosis. Their main perceived advantage over growing rods is the marked decrease in subsequent operative procedures. The Shilla growth-guidance system and a modern Luque trolley are examples of such systems; both depend on gliding pedicle screws and/or sliding titanium sublaminar wires. However, the unknown consequences of metal-on-metal wear debris are reason for concern especially in young patients. In this study, instrumentation stability, residual growth in the operated segment after surgery and biocompatibility of the novel radiopaque UHMWPE cables as an alternative to gliding pedicles screws or titanium sublaminar wires were assessed in an immature sheep model. Materials and methods. Twelve immature sheep were treated with segmental sublaminar spinal instrumentation: dual CoCr rods were held in place by pedicle screws at the most caudal instrumented level (L5) and novel radiopaque UHMWPE (Bi. 2. O. 3. additive) woven cables were placed at 5 thoracolumbar levels. Lateral radiographs were taken at 4-week intervals to evaluate growth of the instrumented segment. Four age-matched, unoperated animals served as radiographic control. After 24 weeks follow-up, the animals were sacrificed and the spines were harvested for histological evaluation and CT analysis. Results. No neurological deficits and no complications occurred during the initial postoperative period. One animal died during follow-up due to unknown cause. At sacrifice, none of the cables had loosened and the instrumentation remained stable. Substantial growth occurred in the instrumented segment (L5-T13) in the intervention group. No significant difference in growth of the operated segment was found between the intervention and control groups. Histological analysis showed fibrous encapsulation of the novel radiopaque UHMWPE sublaminar cable in the epidural space, with no evidence of chronic inflammation. Discussion. Novel radiopaque UHMWPE cables may be a promising alternative to gliding pedicle screws or titanium sublaminar cables within a growth-guidance system. UHMWPE cables may improve growth results due to the smooth surface properties of the UHMWPE cable and address concerns regarding the consequences of metal-on-metal wear debris

Aseptic loosening of orthopaedic implants is usually attributed to the action of wear debris from the prosthesis. Recent studies, however, have also implicated physical pressures in the joint as a further cause of loosening. We have examined the role of both wear debris and pressure on the secretion of two chemokines, MIP-1α and MCP-1, together with M-CSF and PGE2, by human macrophages in vitro. The results show that pressure alone stimulated the secretion of more M-CSF and PGE. 2. when compared with control cultures. Particles alone stimulated the secretion of M-CSF and PGE. 2. , when compared with unstimulated control cultures, but did not stimulate the secretion of the two chemokines. Exposure of macrophages to both stimuli simultaneously had no synergistic effect on the secretion of the chemokines, but both M-CSF and PGE. 2. were increased in a synergistic manner. Our findings suggest that pressure may be an initiating factor for the recruitment of cells into the periprosthetic tissue

Metal-on-metal (MOM) hip resurfacings release chromium and cobalt wear debris into the surrounding joint. The hip tissue taken from failed MOM hips shows specific histological features including a subsurface band-like infiltrate of macrophages with particulate inclusions, perivascular lymphocytic infiltrate and fibrin exudation. This tissue response has been called Aseptic Lymphocytic Vasculitis Associated Lesion (ALVAL). There is a recognised carcinogenic potential associated with hexavalent chromium and epidemiological data from first generation MOM arthroplasties may suggest an increased incidence of haematological malignancy. The ALVAL type reaction includes a marked proliferation of lymphocytes in the perivascular space and thorough investigation of this lymphocytic response is warranted. This study aims to further characterise the lymphocytic infiltrate using immunohistochemistry and to test clonality using polymerase chain reaction (PCR). Tissues from revised all cause failed MOM hip arthroplasties (n=77) were collected and analysed initially using routine H&E staining. Those that met the diagnostic criteria of ALVAL described above (n=34) were further stained with a panel of immunohistochemical markers (CD3, CD4, CD8 (T-cell markers) and CD20 (B-cell marker)). 10 representative ALVAL cases were selected and sent for gene rearrangement studies using PCR to determine whether the lymphocytes were polyclonal or monoclonal in nature. The analysis of the lymphocytic aggregates in ALVAL, showed a mixed population of B and T cells. Within the aggregates, there was a predominance of B cells (CD20) over T cells (CD3). Of the 10 cases which were analysed by PCR, 7 were suitable for interpretation. None of these cases showed evidence of monoclonal lymphocyte proliferation. The carcinogenic potential of wear debris from MOM hips, particularly affecting the haematopoietic system should be investigated. This study has shown a predominantly B-lymphocyte response in tissues surrounding MOM hips which is polyclonal. Although the numbers are small, the study suggests an immune mediated response in MOM hip tissue and excludes a neoplastic proliferation. However, long term follow up of patients with MOM hips may be prudent

Particulate wear debris can induce the release of bone-resorbing cytokines from cultured macrophages and fibroblasts in vitro, and these mediators are believed to be the cause of the periprosthetic bone resorption which leads to aseptic loosening in vivo. Much less is known about the effects of particulate debris on the growth and metabolism of osteoblastic cells. We exposed two human osteoblast-like cell lines (SaOS-2 and MG-63) to particulate cobalt, chromium and cobalt-chromium alloy at concentrations of 0, 0.01, 0.1 and 1.0 mg/ml. Cobalt was toxic to both cell lines and inhibited the production of type-I collagen, osteocalcin and alkaline phosphatase. Chromium and cobalt-chromium were well tolerated by both cell lines, producing no cytotoxicity and no inhibition of type-I collagen synthesis. At the highest concentration tested (1.0 mg/ml), however, chromium inhibited alkaline phosphatase activity, and both chromium and cobalt-chromium alloy inhibited osteocalcin expression. Our results clearly show that particulate metal debris can modulate the growth and metabolism of osteoblastic cells in vitro. Reduced osteoblastic activity at the bone-implant interface may be an important mechanism by which particulate wear debris influences the pathogenesis of aseptic loosening in vivo

Summary. Particulate wear debris with different chemical composition induced similar periprosthetic tissue reactions in patients with loosened uncemented and cemented titanium hip implants, which suggests that osteolysis can develop independent of particle composition. Introduction. Periprosthetic osteolysis is a serious long-term complication in total hip replacements (THR). Wear debris-induced inflammation is thought to be the main cause for periprosthetic bone loss and implant loosening. The aim of the present study was to compare the tissue reactions and wear debris characteristics in periprosthetic tissues from patients with failed uncemented (UC) and cemented (C) titanium alloy hip prostheses. We hypothesised that implant wear products around two different hip designs induced periprosthetic inflammation leading to osteolysis. Patients & Methods. Thirty THR-patients undergoing revision surgery were included: Fifteen patients had loose cemented titanium stems (Titan. ®. , DePuy) and 15 had well-fixed uncemented titanium stems (Profile, DePuy), but loose or worn uncemented metal-backed cups with conventional UHMWPE liners (Gemini, Tropic and Tri-Lock Plus, DePuy; Harris/Galante and Trilogy, Zimmer). A semi-quantitative histological evaluation was performed in 59 sections of periprosthetic tissues using light microscopy. Wear particles were counted by polarised light and high resolution dark-field microscopy. Additionally, particle composition was determined by SEM-EDXA following particle isolation using an enzymatic digestion method. Blood metal ions were determined with high resolution-ICP-MS. Results. The implants in the uncemented group were revised after a median of 15.7 years (range: 7.25–19.3) due to osteolysis and high wear of the polyethylene liner and metal backing resulting in gross metallosis, and/or cup loosening. The average lifetime of implants in the cemented group was only 6.5 years (range: 1.5–11.75) due to early stem loosening with large osteolysis pockets in the femur close to the cement mantle. Tissue examination revealed similar results for both groups: numerous mononuclear histiocytes and chronic inflammatory cells, a few neutrophils and multinucleated giant cells, and to some extent necrosis. The amount of metal particles per histiocyte positively correlated with the tissue reactions in the cemented, but not in the uncemented group. A higher particle load (medians: C: 14727 vs. UC: 1382 particles/mm. 2. , p<0.0001) was found in tissues adjacent to cemented stems, which contained mainly submicron ZrO. 2. particles. Particles containing pure Ti or Ti alloy elements (size range: 0.21 to 6.46 µm) were most abundant in tissues from the uncemented group. Here, also PE was more frequent, but accounted only for a small portion of total particles (2.8 PE/mm. 2. ). The blood concentrations of titanium (range: 3.8–138.5 microgram/L) and zirconium (cemented cases, range: 0.6–3.5 microgram/L) were highly elevated in cases with high abrasive wear and metallosis. Discussion/Conclusion. Phagocytosis of different wear particles by histiocytes induced a similar chronic inflammatory reaction in the periprosthetic tissues in both groups. ZrO. 2. particles, originating from bone cement degradation, dominated in the cemented group, while in the uncemented group the high abundance of pure Ti and Ti alloy particles of various sizes indicates wear of the metal-backed cups. The low density of polyethylene particles in the tissues suggests that they are not solely responsible for the tissue reactions and accompanying osteolysis. Our findings suggest that the chemical composition of wear particles plays a minor role in the mechanism of osteolysis. Particle size, load and ionic exposure might be more important

Summary Statement. Vitamin E-UHMWPE particles have a reduced osteolysis potential in vivo when compared to virgin, highly cross-linked UHMWPE in a murine calvarial bone model. Introduction. Ultra high-molecular weight polyethylene (UHMWPE) particle-induced osteolysis is one of the major causes of arthroplasty revisions. The lack of particle clearance from the joint inevitably leads to the upregulation of the inflammatory cascade, resulting in bone resorption and implant loosening. Recent in vitro findings (Bladed CL et al. ORS 2011 and J Biomed Mater Res B Appl Biomater, 2012) have suggested that UHMWPE wear particles containing vitamin-E (VE) may have reduced functional biologic activity and decreased potential to cause osteolysis. This is of significant importance since VE-stabilised cross-linked UHMWPEs were recently introduced for clinical use, and there is no in vivo data determining the effects of wear debris from this new generation of implants. In this study we hypothesised that particles from VE-stabilised, radiation cross-linked UHMWPE (VE-UHMWPE) would cause reduced levels of osteolysis in a murine calvarial bone model when compared to virgin gamma irradiated cross-linked UHMWPE. Methods. Study groups were the following: 1) Radiation cross-linked VE-UHMWPE, approximately 0.8% by weight, diffused after 100 kGy; 2). Radiation cross-linked virgin UHMWPE (virgin UHMWPE); 3). Shams. Particle generation and implantation: UHMWPE was sent to Bioengineering Solutions (Oak Park, IL) for particle generation. After IACUC approval, C57BL/6 mice (n=12 for each group) received equal amount of particulate debris (3mg) overlying the calvarium and were euthanised after 10 days. Micro-CT scans: High resolution micro-CT scans were performed using an X-Tek HMX ST 225 with a set voltage of 70 kV and current of 70 µA. Topographical Grading Scale: Each calvarial bone (interparietal, right and left parietal, right and left frontal) was blindly scored using the following scale: 0=No osteolysis, defined as intact bone; 1=Minimal osteolysis, affecting 1/3 or less of the bone area; 2=Moderate osteolysis, affecting at least 2/3 of the bone area; 3=Severe osteolysis, defined as completely osteolytic bone. Histological Analysis: H&E and TRAP staining was performed on tissue to confirm the micro-CT findings and to quantify osteoclasts. Statistical Analysis: Inter-rater analysis was performed using Cohen's kappa analysis. An inter-rater coefficient >0.65 was considered as high inter-rater agreement. Comparison between groups was made using one-way ANOVA with post hoc Bonferroni correction for multiple comparisons. Correlations are reported as Spearman's rho. A p-value<0.05 was considered statistically significant. Results. More than 83% of the VE-UHMWPE and more than 85% of the virgin UHMWPE particles measured less than 1 µm in mean particle size. The mean particle size for VE-UHMWPE was 1.12 µm (range 0.28 to 79.08 µm), while virgin UHMWPE particles measured 1.22 µm (range 0.28 to 82.04 µm). There was a statistically significant greater level of osteolysis visualized on the topographical grading scale in calvaria implanted with virgin UHMWPE wear particles. The micro-CT findings were confirmed histologically. A greater amount of inflammatory tissue overlaying the calvaria was observed in the virgin UHMWPE group when compared to both shams and VE-UHMWPE groups. Post hoc analysis revealed significant difference between VE-UHMWPE and virgin UHMWPE for the topographical osteolysis grading score (p = 0.002) but no difference in osteoclast count (p = 0.293). Discussion/Conclusion. This is the first in vivo study reporting the effects of clinically-relevant UHMWPE particles generated from a VE-UHMWPE implant that is in current clinical use. These results suggest that VE-UHMWPE particles have reduced osteolysis potential in vivo when compared to virgin, highly cross-linked UHMWPE in a murine calvarial bone model. Arthroplasty procedures using VE-UHMWPE might be less susceptible to peri-prosthetic loosening caused by wear debris