Cobalt chrome alloy is commonly used in joint replacement surgery. However, it is recognised that some patients develop lymphocyte mediated delayed type hypersensitivity (DTH) responses to this material, which may result in extensive bone and soft tissue destruction. Phase 1. United Kingdom: From an existing database, we identified extreme phenotype patient groups following metal on metal (MoM) hip resurfacing or THR: ALVAL with low wearing prostheses; ALVAL with high wear; no ALVAL with high wear; and asymptomatic patients with implants in situ for longer than ten years. Class I and II HLA genotype frequency distributions were compared between these patients’ groups, and in silico peptide binding studies were carried out using validated methodology. Phase 2. United Kingdom: We expanded the study to include more patients, including those with intermediary phenotypes to test whether an algorithm could be developed incorporating “risk genotypes”, patient age, sex and metal exposure. This model was trained in phase 3. Phase 3. United Kingdom, Australia, United States. Patients from other centres were invited to give DNA samples. The data set was split in two. 70% was used to develop machine learning models to predict failure secondary to DTH. The predictions were tested using the remaining blinded 30% of data, using time-dependent AUROCs, and integrated calibration index performance statistics. A total of 606 DNA samples, from 397 males and 209 female patients, were typed. This included 176 from patients with failed prostheses, and 430 from asymptomatic patients at a mean of >10 years follow up. C-index and ROC(t) scores suggested a high degree of discrimination, whilst the IBS indicated good calibration and further backed up the indication of high discriminatory ability. At ten years, the weighted mean survival probability error was < 4%. At present, there are no tests in widespread clinical use which use a patient's genetic profile to guide implant selection or inform post-operative management. The algorithm described herein may address this issue and we suggest that the application may not be restricted to the field of MoM hip arthroplasty

Aims. Aseptic loosening is a leading cause of uncemented arthroplasty failure, often accompanied by fibrotic tissue at the bone-implant interface. A biological target, neutrophil extracellular traps (NETs), was investigated as a crucial connection between the innate immune system’s response to injury, fibrotic tissue development, and proper bone healing. Prevalence of NETs in peri-implant fibrotic tissue from aseptic loosening patients was assessed. A murine model of osseointegration failure was used to test the hypothesis that inhibition (through Pad4-/- mice that display defects in peptidyl arginine deiminase 4 (PAD4), an essential protein required for NETs) or resolution (via DNase 1 treatment, an enzyme that degrades the cytotoxic DNA matrix) of NETs can prevent osseointegration failure and formation of peri-implant fibrotic tissue. Methods. Patient peri-implant fibrotic tissue was analyzed for NETs biomarkers. To enhance osseointegration in loose implant conditions, an innate immune system pathway (NETs) was either inhibited (Pad4-/- mice) or resolved with a pharmacological agent (DNase 1) in a murine model of osseointegration failure. Results. NETs biomarkers were identified in peri-implant fibrotic tissue collected from aseptic loosening patients and at the bone-implant interface in a murine model of osseointegration failure. Inhibition (Pad4-/-) or resolution (DNase 1) of NETs improved osseointegration and reduced fibrotic tissue despite loose implant conditions in mice. Conclusion. This study identifies a biological target (NETs) for potential noninvasive treatments of aseptic loosening by discovering a novel connection between the innate immune system and post-injury bone remodelling caused by implant loosening. By inhibiting or resolving NETs in an osseointegration failure murine model, fibrotic tissue encapsulation around an implant is reduced and osseointegration is enhanced, despite loose implant conditions. Cite this article: Bone Joint J 2021;103-B(7 Supple B):135–144

Introduction. We aimed to identify genes associated with the development of ALVAL at relatively low levels of wear. Methods. At our unit all patients undergoing revision of a MoM hip prosthesis have periprosthetic tissue samples graded for ALVAL. Explants undergo volumetric wear testing of the bearing and taper surfaces. We identified patients with moderate/severe ALVAL who had been exposed to lower than the median wear rate of all recorded patients who had developed ALVAL (<3mm. 3. /year). This was termed the “ALVAL” group. We then identified all patients whose tissues had shown no signs of ALVAL. The patients in the two groups were sent buccal DNA collection kits. DNA was examined using next generation sequencing. Alleleic frequencies in the two groups were compared using Fisher's test and compared to a background UK population group (n=8514). We then conducted binary logistic regression with patient age, sex, primary source of debris (taper/bearing) and HLA genotype as the predictors. With the hypothesis that a cobalt/albumin metalloprotein acts as the epitope, we used validated binding prediction software to determine the relative affinities of the binding grooves created by different DQA1/DQB1 genetic combinations for albumin derived peptides. Given the protection that male sex and younger age appears to confer against ALVAL, we hypothesized that testosterone peptides may compete for these binding sites. Results. 28 ALVAL and 37 non ALVAL patients returned their samples for testing. The frequencies of DQA1∗05:05 and DQB1∗03:01 were significantly greater in the ALVAL groups(p=0.018). The variables positively associated with ALVAL were female sex(0.021), increasing age(0.003) and DQA1/DQB1 combinations with greater binding affinity for albumin fragments(0.03). Greater binding affinities for testosterone peptides were inversely related to ALVAL(0.05). Discussion. Common immune genotypes are associated with a greater risk of ALVAL. Conclusion. The evidence base on which MoM follow up protocols are based should be re-evaluated in light of these findings and future studies designed accordingly

Aims

Hip resurfacing remains a potentially valuable surgical procedure for appropriately-selected patients with optimised implant choices. However, concern regarding high early failure rates continues to undermine confidence in use. A large contributor to failure is adverse local tissue reactions around metal-on-metal (MoM) bearing surfaces. Such phenomena have been well-explored around MoM total hip arthroplasties, but comparable data in equivalent hip resurfacing procedures is lacking. In order to define genetic predisposition, we performed a case-control study investigating the role of human leucocyte antigen (HLA) genotype in the development of pseudotumours around MoM hip resurfacings.

Next-generation sequencing (NGS) is a well-established technique for amplification and sequencing of DNA and has recently gained much attention in many fields of medicine. Our aim was to evaluate the ability of NGS in identifying the causative organism(s) in patients with periprosthetic joint infection (PJI). In this prospective study samples were collected from 78 revision total hip arthroplasties. Synovial fluid, deep tissue and swabs were obtained at the time of surgery and shipped to the laboratory for NGS analysis. Deep tissue specimens were also sent to the institutional lab for culture. PJI was diagnosed using the Musculoskeletal infection society (MSIS) definition of PJI. Thirty-four revisions were considered infected; culture was positive in 25 of these (25/34, 73.5%), while NGS was positive in 26 (26/34, 76.4%). Among the positive cultures, complete concordance between NGS and culture in 21 cases (21/25, 84.0%). 4 cases were discordant. Among these cases, 3 cases were culture-positive and NGS-negative, while 1 was both positive on NGS and culture for disparate organisms. Among the 9 cases of culture-negative PJI(CN-PJI), NGS was able to identify an organism in 4 cases (4/9, 44.4%). The remaining 5 cases were negative on both NGS and culture (5/9, 55.6%). Forty-four revisions were considered to be aseptic; NGS exclusively identified microbes in 7 of 44 “aseptic” revisions (15.9%) and culture exclusively isolated an organism in 3 of 44 cases (6.8%). Both NGS and culture were positive in 1 of case however the result was discordant. The remaining cases (33/44, 75.0%) were both NGS and culture negative. NGS detected several organisms in most positive samples, with a greater number of organisms detected in aseptic compared to septic cases (7 vs. 3.7, respectively). NGS may be a promising technique for identifying the infecting organism in PJI. Our findings suggest that some cases of PJI may be polymicrobial that escape detection using conventional culture

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Developmental dysplasia of the hip (DDH) is a complex musculoskeletal disease that occurs mostly in children. This study aimed to investigate the molecular changes in the hip joint capsule of patients with DDH.

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Interleukin (IL)-1β is one of the major pathogenic regulators during the pathological development of intervertebral disc degeneration (IDD). However, effective treatment options for IDD are limited. Suramin is used to treat African sleeping sickness. This study aimed to investigate the pharmacological effects of suramin on mitigating IDD and to characterize the underlying mechanism.

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To evaluate the effect of ultrasound-targeted simvastatin-loaded microbubble destruction (UTMD_SV) for alleviation of the progression of osteoarthritis (OA) in rabbits through modulation of the peroxisome proliferator-activated receptor (PPARγ).

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We have previously demonstrated raised cobalt and chromium levels in patients with larger diameter femoral heads, following metal-on-polyethylene uncemented total hip arthroplasty. Further data have been collected, to see whether these associations have altered with time and to determine the long-term implications for these patients and our practice.

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Many case reports and small studies have suggested that cobalt ions are a potential cause of cardiac complications, specifically cardiomyopathy, after metal-on-metal (MoM) total hip arthroplasty (THA). The impact of metal ions on the incidence of cardiac disease after MoM THA has not been evaluated in large studies. The aim of this study was to compare the rate of onset of new cardiac symptoms in patients who have undergone MoM THA with those who have undergone metal-on-polyethylene (MoP) THA.

The long term biological effects of wear products following total hip arthroplasty (THA) are unclear. However, the indications for THA are expanding, with increasingly younger patients undergoing the procedure.

This prospective, randomised study compared two groups of patients undergoing THA after being randomised to receive one of two different bearing surfaces: metal-on-polyethylene (MoP) n = 22 and metal-on-metal (MoM) n = 23. We investigated the relationship between three variables: bearing surface (MoP vs MoM), whole blood levels of chromium (Cr) and cobalt (Co) and chromosomal aberrations in peripheral lymphocyte pre-operatively and at one, two and five years post-surgery.

Our results demonstrated significantly higher mean cobalt and chromium (Co and Cr) blood levels in the MoM group at all follow-up points following surgery (p < 0.01), but there were no significant differences in the chromosomal aberration indices between MoM and MoP at two or five years (two years: p = 0.56, p = 0.08, p = 0.91, p = 0.51 and five years: p = 0.086, p = 0.73, p = 0.06, p = 0.34) for translocations, breaks, loss and gain of chromosomes respectively. Regression analysis showed a strong linear relationship between Cr levels and the total chromosomal aberration indices in the MoM group (R² = 0.90016), but this was not as strong for Co (R² = 0.68991). In the MoP group, the analysis revealed a poor relationship between Cr levels and the total chromosomal aberration indices (R² = 0.23908) but a slightly stronger relationship for Co (R² = 0.64292). Across both groups, Spearman’s correlation detected no overall association between Co and Cr levels and each of the studied chromosomal aberrations. There remains no clear indication which THA bearing couple is the most biocompatible, especially in young active patients. While THA continues to be very successful at alleviating pain and restoring function, the long-term biological implications of the procedure still require further scrutiny.

Cite this article: Bone Joint J 2015;97-B:1183–91.

In this study of 41 patients, we used proteomic, Western blot and immunohistochemical analyses to show that several reactive oxygen species scavenging enzymes are expressed differentially in patients with primary osteoarthritis and those with non-loosening and aseptic loosening after total hip replacement (THR). The patients were grouped as A (n = 16, primary THR), B (n = 10, fixed THR but requiring revision for polyethylene wear) and C (n = 15, requiring revision due to aseptic loosening) to verify the involvement of the identified targets in aseptic loosening. When compared with Groups A and B, Group C patients exhibited significant up-regulation of transthyretin and superoxide dismutase 3, but down-regulation of glutathione peroxidase 2 in their hip synovial fluids. Also, higher levels of superoxide dismutase 2 and peroxiredoxin 2, but not superoxide dismutase 1, catalase and glutathione perioxidase 1, were consistently detected in the hip capsules of Group C patients.

We propose that dysregulated reactive oxygen species-related enzymes may play an important role in the pathogenesis and progression of aseptic loosening after THR.

Lately, concerns have arisen following the use of large metal-on-metal bearings in hip replacements owing to reports of catastrophic soft-tissue reactions resulting in implant failure and associated complications. This review examines the literature and contemporary presentations on current clinical dilemmas in metal-on-metal hip replacement.

Metal-on-metal bearings are being increasingly used in young patients. The potential adverse effects of systemic metal ion elevation are the subject of ongoing investigation. The purpose of this study was to investigate whether cobalt and chromium ions cross the placenta of pregnant women with a metal-on-metal hip resurfacing and reach the developing fetus. Whole blood levels were estimated using high-resolution inductively-coupled plasma mass spectrometry.

Our findings showed that cobalt and chromium are able to cross the placenta in the study patients with metal-on-metal hip resurfacings and in control subjects without any metal implants. In the study group the mean concentrations of cobalt and chromium in the maternal blood were 1.39 μg/l (0.55 to 2.55) and 1.28 μg/l (0.52 to 2.39), respectively. The mean umbilical cord blood concentrations of cobalt and chromium were comparatively lower, at 0.839 μg/l (0.42 to 1.75) and 0.378 μg/l (0.14 to 1.03), respectively, and this difference was significant with respect to chromium (p < 0.05).

In the control group, the mean concentrations of cobalt and chromium in the maternal blood were 0.341 μg/l (0.18 to 0.54) and 0.199 μg/l (0.12 to 0.33), and in the umbilical cord blood they were 0.336 μg/l (0.17 to 0.5) and 0.194 μg/l (0.11 to 0.56), respectively. The differences between the maternal and umbilical cord blood levels in the controls were marginal, and not statistically significant (p > 0.05). The mean cord blood level of cobalt in the study patients was significantly greater than that in the control group (p < 0.01). Although the mean umbilical cord blood chromium level was nearly twice as high in the study patients (0.378 μg/l) as in the controls (0.1934 μg/l), this difference was not statistically significant. (p > 0.05)

The transplacental transfer rate was in excess of 95% in the controls for both metals, but only 29% for chromium and 60% for cobalt in study patients, suggesting that the placenta exerts a modulatory effect on the rate of metal ion transfer.

We have studied the relationship between metal ion levels and lymphocyte counts in patients with metal-on-metal hip resurfacings. Peripheral blood samples were analysed for lymphocyte subtypes and whole blood cobalt and chromium ion levels in 68 patients (34 with metal-on-metal hip resurfacings and 34 with standard metal-on-polyethylene total hip replacements). All hip components were radiologically well-fixed and the patients were asymptomatic. Cobalt and chromium levels were significantly elevated in the patients with metal-on-metal hip resurfacings, compared with the patients with standard metal-on-polyethylene designs (p < 0.0001). There was a statistically significant decrease in the level of CD8⁺ cells (T-cytotoxic/suppressor) (p = 0.005) in the metal-on-metal hip resurfacing group. A threshold level of blood cobalt and chromium ions was associated with reduced CD8⁺ T-cell counts. We have no evidence that our patients suffered as a result of this reduced level of CD8⁺ T-cells.

This is a longitudinal study of the daily urinary output and the concentrations in whole blood of cobalt and chromium in patients with metal-on-metal resurfacings over a period of four years.

Twelve-hour urine collections and whole blood specimens were collected before and periodically after a Birmingham hip resurfacing in 26 patients. All ion analyses were carried out using a high-resolution inductively-coupled plasma mass spectrometer. Clinical and radiological assessment, hip function scoring and activity level assessment revealed excellent hip function.

There was a significant early increase in urinary metal output, reaching a peak at six months for cobalt and one year for chromium post-operatively. There was thereafter a steady decrease in the median urinary output of cobalt over the following three years, although the differences are not statistically significant. The mean whole blood levels of cobalt and chromium also showed a significant increase between the pre-operative and one-year post-operative periods. The blood levels then decreased to a lower level at four years, compared with the one-year levels. This late reduction was statistically significant for chromium but not for cobalt.

The effects of systemic metal ion exposure in patients with metal-on-metal resurfacing arthroplasties continue to be a matter of concern. The levels in this study provide a baseline against which the in vivo wear performance of newer bearings can be compared.