We evaluated histologically samples of synovial tissue from the knees of 50 patients with rheumatoid arthritis (RA). The samples were taken during revision for aseptic loosening. The findings were compared with those in 64 knees with osteoarthritis (OA) and aseptic loosening and in 18 knees with RA without loosening. The last group had been revised because of failure of the inlay or the coupling system of a constrained prosthesis. All the patients had had a total ventral synovectomy before implantation of the primary prosthesis. In all three groups a foreign-body reaction and lymphocellular infiltration were seen in more than 80% of the tissue samples. Deposits of fibrin were observed in about one-third to one-half of the knees in all groups. Typical signs of the reactivation of RA such as rheumatoid necrosis and/or proliferation of synovial stromal cells were found in 26% of knees with RA and loosening, but not in those with OA and loosening and in those with RA without loosening. Our findings show that reactivation of rheumatoid synovitis occurs after total knee replacement and may be a cofactor in aseptic loosening in patients with RA

We collected 16 samples of the membrane which surrounds loose hip prostheses from patients undergoing revision operations for aseptic loosening. To serve as the control group, samples of the synovial tissue and the fibrous capsular tissue were collected from 11 patients undergoing primary hip arthroplasties. Analyses of the expression levels of inducible nitric oxide synthase (iNOS), tumour necrosis factor-α (TNF-α), and cytosolic phospholipase A. 2. (cPLA. 2. ) mRNAs were performed by a reverse transcription polymerase chain reaction, and the content of nitrite was measured by the Griess reaction using sodium nitrite as the standard. The expression levels of iNOS, TNF-α, and cPLA. 2. mRNAs in the membranes were significantly higher than those in the control samples (p < 0.05). The expression levels of iNOS mRNA and the nitrite content in the membranes significantly correlated with those of TNF-α and cPLA. 2. mRNAs, respectively. In addition, the expression levels of iNOS, TNF-α, and cPLA. 2. mRNAs were significantly higher in membranes from cementless than in those from cemented implants (p < 0.05). Our results suggest that the expression levels of iNOS, TNF-α, and cPLA. 2. mRNAs in the membranes are regulated by closely-related mechanisms and that these have a significant role in aseptic loosening

Our aim was to determine if the serum levels of bone-resorbing cytokines (IL-1β, TNF-α, IL-6, GM-CSF) are altered in patients with aseptic loosening of a total hip prosthesis, and if such levels are influenced by the type of implant. We determined cytokine levels in sera from 35 patients before revision for failed total hip arthroplasty and compared them with those in 25 healthy donors. We also assessed the soluble receptor of interleukin-2 (sIL-2r) in serum as an indication of a specific immune reaction against the implant. Our findings showed that the sIL-2r and TNF-α serum level did not change. The IL-6 level was not significantly altered, but was higher in patients with TiAlV prostheses than in those with a CrCoMo implant and in patients with cemented prostheses. The IL-1β level was found to be higher in those with a TiAlV cemented prosthesis than in the control group (p = 0.0001) and other groups of patients (p = 0.003 v uncemented TiAlV, p = 0.01 v cemented CrCoMo, p = 0.001 v uncemented CrCoMo). The GM-CSF level significantly increased in patients compared with healthy subjects (p = 0.008), and it was higher in those with cemented than with uncemented implants (p = 0.01). Only patients with cementless CrCoMo prostheses had levels of GM-CSF similar to those of the control group. The highest GM-CSF concentrations were observed in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs) in the last months before revision (p = 0.04). In addition, when massive osteolysis was observed, the level of GM-CSF tended to decrease to that of the control group

We compared and quantified the modes of failure and patterns of wear of 11 Mittelmeier and 11 Ceraver-Ostal retrieved alumina-alumina hip prostheses with reference to the corresponding clinical and radiological histories.

Macroscopic wear was assessed using a three-dimensional co-ordinate measuring machine. Talysurf contacting profilometry was used to measure surface roughness on a microscopic scale and SEM to determine mechanisms of wear at the submicron level.

The components were classified into one of three categories of wear: low (no visible/measurable wear), stripe (elliptical wear stripe on the heads and larger worn areas on the cups) and severe (macroscopic wear, large volumes of material lost). Overall, the volumetric wear of the alumina-alumina prostheses was substantially less than the widely used metal and ceramic-on-polyethylene combinations. By identifying and eliminating the factors which accelerate wear, it is expected that the lifetime of these devices can be further increased.

Post-mortem retrieval of canine, cemented femoral components was analysed to assess the performance of these implants in the dog as a model for human total hip replacement (THR). Mechanical testing and radiological analysis were performed to determine the stability of the implant and the quality of the cement. Thirty-eight implants from 29 dogs were retrieved after time intervals ranging from 0.67 to 11.67 years. The incidence of aseptic loosening was 63.2%, much higher than in human patients (6% in post-mortem studies). Failure of the femoral implants began with debonding at the cement-metal interface, similar to that in implants in man. The incidence of aseptic loosening was much lower in bilateral than in unilateral implants. Significant differences were observed for three different designs of implant. While the dog remains the animal model of choice for THR, results from this study provide insight into interspecies differences in the performance of implants. For example, the performance of THR in dogs should be compared with that in young rather than in elderly human patients

Matrix metalloproteinases (MMPs) may have a role in the process of aseptic loosening. Doxycycline has been shown to inhibit MMPs. Our aim was to investigate the potential pharmacological effect of doxycycline on aseptic loosening. We used radiolabelled mouse calvariae cultured with human interface membrane cells from aseptically loosened hips. Bone resorption was confirmed in this model. The effect of doxycycline was assessed by culturing dead radiolabelled bone discs with cells from the interface membrane with doxycycline. The control group consisted of the same culture system without doxycycline. Supernatant . 45. calcium and the total . 45. calcium remaining in the bone discs at the completion of the culture were used to measure osteolysis. We found that doxycycline can inhibit osteolysis at the interface membrane of aseptically loosened hips. This may have therapeutic implications for the treatment of patients with aseptic loosening of total joint replacements

A foreign-body-type host response can contribute to the induction and release of collagenolytic tissue-destructive enzymes of pathogenetic significance. Our aim was to analyse collagenase-3 in two conditions with putative involvement of foreign-body reactions. Synovial membrane-like tissue samples were obtained from cases of aseptic loosening of a total hip replacement (THR) and osteoarthritis (OA). The reverse transcription polymerase chain reaction (RT-PCR) disclosed that all the samples from patients contained collagenase-3 mRNA compared with only three out of ten control samples. The identity of the RT-PCR amplification product was confirmed by nucleotide sequencing. Immunohistochemical staining showed that collagenase-3 was present in endothelial cells, macrophages and fibroblasts, including those found in the synovial lining. This finding was confirmed by avidin-biotin-peroxidase complex-alkaline phosphatase-anti-alkaline phosphatase double staining and the specificity of the staining by antigen preabsorption using recombinant human collagenase-3. Collagenase-3 was released into the extracellular space and thus found in the synovial fluid in all patient samples as shown by Western blotting. The similar extent of collagenase-3 expression in aseptic loosening and OA compared with the low expression in control synovial membrane suggests involvement of a similar, foreign-body-based pathogenetic component in both. Comparative analysis of collagenase-3 and of foreign particles indicates that paracrine factors rather than phagocytosis per se are responsible for the induction of collagenase-3. We suggest that due to its localisation and substrate specificity, collagenase-3 may play a significant pathogenetic role in accelerating tissue destruction in OA and in aseptic loosening of a THR

We measured the levels of cobalt and chromium in the serum in three groups of patients after uncemented porous-coated arthroplasty. Group 1 consisted of 14 consecutive patients undergoing revision for aseptic loosening. Group 2 comprised 14 matched patients in whom the arthroplasty was stable and group 3 was 14 similarly matched patients with arthritis awaiting hip replacement. Specimens were analysed using atomic absorption spectrophotometry. Aseptic loosening of a component resulted in a significant elevation of serum cobalt (p < 0.05), but not of serum chromium. The relative risk of a component being loose, if the patient had a serum cobalt greater than 9.0 nmol/l, was 2.8

Periprosthetic bone loss after total joint arthroplasty is a major clinical problem resulting in aseptic loosening of the implant. Among many cell types, osteoblasts play a crucial role in the development of peri-implant osteolysis. In this study, we tested the effects of calcitriol (1α,25-dihydroxy-vitamin-D. 3. ) and the bisphosphonate pamidronate on titanium-particle- and TNF-α-induced release of interleukin-6 and suppression of osteoblast-specific gene expressions in bone-marrow-derived stromal cells with an osteoblastic phenotype. We monitored the expression of procollagen α1[1], osteocalcin, osteonectin and alkaline phosphatase mRNAs by Northern blots and real-time reverse transcription and polymerase chain reaction analyses. The release of various cytokines was also analysed by ELISA. We found that calcitriol or pamidronate could only partially recover the altered functions of osteoblasts when added alone. Only a combination of these compounds restored all the tested functions of osteoblasts. The local delivery of these drugs may have therapeutic potential to prevent or to treat periprosthetic osteolysis and aseptic loosening of implants

We performed 83 consecutive cemented revision total hip arthroplasties in 77 patients between 1977 and 1983 using improved cementing techniques. One patient (two hips) was lost to follow-up. The remaining 76 patients (81 hips) had an average age at revision of 63.7 years (23 to 89). At the final follow-up 18 hips (22%) had had a reoperation, two (2.5%) for sepsis, three (4%) for dislocation and 13 (16%) for aseptic loosening. The incidence of rerevision for aseptic femoral loosening was 5.4% and for aseptic acetabular loosening 16%. These results confirm that cemented femoral revision is a durable option in revision hip surgery when improved cementing techniques are used, but that cemented acetabular revision is unsatisfactory

We studied the presence of sensory nerves by immunohistochemistry in the interface membranes of hip prostheses after aseptic loosening. Substance P (SP), neurokinin A (NKA) and calcitonin gene-related peptide (CGRP) were analysed as was protein gene product (PGP) 9.5, a general marker for nerve fibres. We identified nerve fibres in all samples but differences in their density were found. SP- and NKA-positive fibres were predominantly non-vascular, forming varicose nerve terminals. CGRP-immunoreactive nerve fibres with varicose terminals were seen mostly close to blood vessels, but also as free nerve endings. Sensory neuropeptides participate not only in nociception but also stimulate immune cells to release cytokines. The presence of sensory nerves in the interface membrane may reflect a pathophysiological response contributing to the aseptic loosening of hip prostheses

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

Wear of polyethylene is associated with aseptic loosening of orthopaedic implants and has been observed in hip and knee prostheses and anatomical implants for the shoulder. The reversed shoulder prostheses have not been assessed as yet. We investigated the volumetric polyethylene wear of the reversed and anatomical Aequalis shoulder prostheses using a mathematical musculoskeletal model. Movement and joint stability were achieved by EMG-controlled activation of the muscles. A non-constant wear factor was considered. Simulated activities of daily living were estimated from in vivo recorded data. After one year of use, the volumetric wear was 8.4 mm. 3. for the anatomical prosthesis, but 44.6 mm. 3. for the reversed version. For the anatomical prosthesis the predictions for contact pressure and wear were consistent with biomechanical and clinical data. The abrasive wear of the polyethylene in reversed prostheses should not be underestimated, and further analysis, both experimental and clinical, is required

Aseptic loosening is a major cause of failure of total hip arthroplasty. The adverse tissue response to prosthetic wear particles, with activation of cytokine and prostanoid production, contributes to bone loss around the implants. We have investigated the possibility that inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) are expressed in macrophages in the pseudomembrane at the bone-implant interface, thereby contributing to the periprosthetic bone resorption. We also assessed whether peroxynitrite, a nitric oxide (NO)-derived oxidant associated with cellular injury, is generated in the membrane. Enzymatic activity of iNOS was measured using the arginine-citrulline assay technique and prostaglandin E. 2. (PGE. 2. ), as an indicator of COX-2 activity, was measured using an enzyme immunoassay. Cellular immunoreactivity for iNOS, nitrotyrosine (a marker of peroxynitrite-induced cellular injury) and COX-2 was assessed by quantitative peroxidase immunocytochemistry while immunofluorescence methods were used for subsequent co-localisation studies with CD68. +. macrophages. The presence of calcium-independent iNOS activity and PGE. 2. production was confirmed in the homogenized interface membrane. Immunocytochemistry showed that periprosthetic CD68. +. wear-debris-laden macrophages were the most prominent cell type immunoreactive for iNOS, nitrotyrosine and COX-2. Other periprosthetic inflammatory and resident cell types were also found to immunolocalise nitrotyrosine thereby suggesting peroxynitrite-induced protein nitrosylation and cellular damage not only in NO-producing CD68. +. macrophages, but also in their neighbouring cells. These data indicate that both iNOS and COX-2 are expressed by CD68. +. macrophages in the interface membrane and peroxynitrite-induced cellular damage is evident in such tissue. If high-output NO and peroxynitrite generation were to cause macrophage cell death, this would result in the release of phagocytosed wear debris into the extracellular matrix. A detrimental cycle of events would then be established with further phagocytosis by newly-recruited inflammatory cells and subsequent NO, peroxynitrite and prostanoid synthesis. Since both NO and have been implicated in the induction and PGE. 2. maintenance of chronic inflammation with resulting loss of bone, and peroxynitrite in the pathogenesis of disease states, they may be central to the pathogenesis of aseptic loosening

There are many methods for analysing wear volume in failed polyethylene acetabular components. We compared a radiological technique with three recognised ex vivo methods of measurement. We tested 18 ultra-high-molecular-weight polyethylene acetabular components revised for wear and aseptic loosening, of which 13 had pre-revision radiographs, from which the wear volume was calculated based upon the linear wear. We used a shadowgraph technique on silicone casts of all of the retrievals and a coordinate measuring method on the components directly. For these techniques, the wear vector was calculated for each component and the wear volume extrapolated using mathematical equations. The volumetric wear was also measured directly using a fluid-displacement method. The results of each technique were compared. The series had high wear volumes (mean 1385 mm. 3. ; 730 to 1850) and high wear rates (mean 205 mm. 3. /year; 92 to 363). There were wide variations in the measurements of wear volume between the radiological and the other techniques. Radiograph-derived wear volume correlated poorly with that of the fluid-displacement method, co-ordinate measuring method and shadowgraph methods, becoming less accurate as the wear increased. The mean overestimation in radiological wear volume was 47.7% of the fluid-displacement method wear volume. Fluid-displacement method, coordinate measuring method and shadowgraph determinations of wear volume were all better than that of the radiograph-derived linear measurements since they took into account the direction of wear. However, only radiological techniques can be used in vivo and remain useful for monitoring linear wear in the clinical setting. Interpretation of radiological measurements of acetabular wear must be done judiciously in the clinical setting. In vitro laboratory techniques, in particular the fluid-displacement method, remain the most accurate and reliable methods of assessing the wear of acetabular polyethylene

Aspiration arthrography using an iodinated contrast medium is a useful tool for the investigation of septic or aseptic loosening of arthroplasties and of septic arthritis. Previously, the contrast media have been thought to cause false negative results in cultures when present in aspirated samples of synovial fluid, probably because free iodine is bactericidal, but reports have been inconclusive. We examined the influence of the older, high osmolar contrast agents and the low osmolar media used currently on the growth of ten different micro-organisms capable of causing deep infection around a prosthesis. Five media were tested, using a disc diffusion technique and a time-killing curve method in which high and low inocula of micro-organisms were incubated in undiluted media. The only bactericidal effects were found with low inocula of Escherichia coli and Pseudomonas aeruginosa in ioxithalamate, one of the older ionic media. The low and iso-osmolar iodinated contrast media used currently do not impede culture. Future study must assess other causes of false negative cultures of synovial fluid and new developments in enhancing microbial recovery from aspirated samples

Our aim was to analyse the influence of the size, shape and number of particles on the pathogenesis of osteolysis. We obtained peri-implant tissues from 18 patients having revision surgery for aseptically loosened Freeman total knee replacements (10), Charnley total hip replacements (3) and Imperial College/London Hospital double-cup surface hip replacements (5). The size and shape of the polyethylene particles were characterised using SEM and their concentration was calculated. The results were analysed with reference to the presence of radiological osteolysis. The concentration of polyethylene particles in 6 areas with osteolysis was significantly higher than that in 12 areas without osteolysis. There were no significant differences between the size and shape of the particles in these two groups. We conclude that the most critical factor in the pathogenesis of osteolysis is the concentration of polyethylene particles accumulated in the tissue

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

We made a semiquantitative study of the comparative histology of pseudomembranes from 12 loose cemented ceramic-ceramic and 18 metal-polyethylene total hip replacements. We found no significant difference in cellular reaction between the two groups, but there was a major difference in the origin of the particulate debris. In the metal-polyethylene group, polyethylene of articular origin was predominant, while in the ceramic-ceramic group the cellular reaction appeared to be a response to zirconia ceramic particles used to opacify cement used for fixation. Isolation and characterisation of the debris showed that the zirconia particles formed the greatest proportion (76%) in ceramic-ceramic hips, while alumina debris of articular origin formed only 12%. Our study has indicated that aseptic loosening of ceramic cups is not due to a response to debris generated at the articular interface, but to mechanical factors which lead to fragmentation of the cement

Sterilisation by gamma irradiation in the presence of air causes free radicals generated in polyethylene (PE) to react with oxygen, which could lead to loss of physical properties and reduction in fatigue strength. Tissue retrieved from failed total hip replacements often has large quantities of particulate PE and most particles associated with peri-implant osteolysis are oxidised. Consequently, an understanding of the cellular responses of oxidised PE particles may lead to clarification of the pathogenesis of osteolysis and aseptic loosening. We have used the agarose system to demonstrate the differential effects of oxidised and non-oxidised PE particles on the release of proinflammatory products such as interleukin-1β (IL-1β), IL-6, and tumour necrosis factor-α (TNF-α) from monocytes/ macrophages (M/M). Oxidised PE particles were shown to stimulate human M/M to phagocytose and to release cytokines. Oxidation may alter the surface chemistry of the particles and enhance the response to specific membrane receptors on macrophages, such as scavenger-type receptors