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Objectives Evaluate test-retest repeatability, ability to discriminate between osteoarthritic and healthy participants, and sensitivity to change over 6 months, of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) biomarkers in knee OA. Methods Fourteen individuals aged 40–60 with mild-moderate knee OA and 6 age-matched healthy volunteers (HV) underwent DCE-MRI at 3 T at baseline, 1 month and 6 months. Voxelwise pharmacokinetic modelling of dynamic data was used to calculate DCE-MRI biomarkers including Ktrans and IAUC60. Median DCE-MRI biomarker values were extracted for each participant at each study visit. Synovial segmentation was performed using both manual and semiautomatic methods with calculation of an additional biomarker, the volume of enhancing pannus (VEP). Test-retest repeatability was assessed using intraclass correlation coefficients (ICC). Smallest detectable differences (SDDs) were calculated from test-retest data. Discrimination between OA and HV was assessed via calculation of between-group standardised mean differences (SMD). Responsiveness was assessed via the number of OA participants with changes greater than the SDD at 6 months. Results Ktrans demonstrated the best test-retest repeatability (Ktrans/IAUC60/VEP ICCs 0.90/0.84/0.40, SDDs as % of OA mean 33/71/76%), discrimination between OA and HV (SMDs 0.94/0.54/0.50) and responsiveness (5/1/1 out of 12 OA participants with 6-month change > SDD) when compared to IAUC60 and VEP. Biomarkers derived from semiautomatic segmentation outperformed those derived from manual segmentation across all domains. Conclusions Ktrans demonstrated the best repeatability, discrimination and sensitivity to change suggesting that it is the optimal DCE-MRI biomarker for use in experimental medicine studies. Key Points • Dynamic contrast-enhanced MRI (DCE-MRI) provides quantitative measures of synovitis in knee osteoarthritis which may permit early assessment of efficacy in experimental medicine studies. • This prospective observational study compared DCE-MRI biomarkers across domains relevant to experimental medicine: test-retest repeatability, discriminative validity and sensitivity to change. • The DCE-MRI biomarker Ktransdemonstrated the best performance across all three domains, suggesting that it is the optimal biomarker for use in future interventional studies.

Osteoarthritis (OA) is a common disease characterized by cartilage degeneration and joint remodeling. The underlying molecular changes underpinning disease progression are incompletely understood. We investigated genes and pathways that mark OA progression in isolated primary chondrocytes taken from paired intact versus degraded articular cartilage samples across 38 patients undergoing joint replacement surgery (discovery cohort: 12 knee OA, replication cohorts: 17 knee OA, 9 hip OA patients). We combined genome-wide DNA methylation, RNA sequencing, and quantitative proteomics data. We identified 49 genes differentially regulated between intact and degraded cartilage in at least two –omics levels, 16 of which have not previously been implicated in OA progression. Integrated pathway analysis implicated the involvement of extracellular matrix degradation, collagen catabolism and angiogenesis in disease progression. Using independent replication datasets, we showed that the direction of change is consistent for over 90% of differentially expressed genes and differentially methylated CpG probes. AQP1, COL1A1 and CLEC3B were significantly differentially regulated across all three –omics levels, confirming their differential expression in human disease. Through integration of genome-wide methylation, gene and protein expression data in human primary chondrocytes, we identified consistent molecular players in OA progression that replicated across independent datasets and that have translational potential.

Poor knee extension function after total knee arthroplasty (TKA) is associated with factors including articular geometry and alignment. Femoral trochlear geometry has evolved from symmetrical to become more prominent proximal–laterally, with the groove aligned proximal–lateral to distal–medial. This study in vitro tested the hypothesis that a modern asymmetrical prosthesis would restore patellar tracking and stability to more natural behaviour than an older symmetrical prosthesis. Six knees had their patellar tracking measured optically during active knee extension. Medial–lateral force versus displacement stability was measured at fixed angles of knee flexion. The measurements were repeated after inserting each of the symmetrical and asymmetrical TKAs. Significant differences of patellar lateral displacement stability, compared to normal, were not found at any angle of knee flexion. The patella tracked medial–laterally within 2.5 mm of the natural path with both TKAs. However, for both TKAs near knee extension, the patella was tilted laterally by approximately 6° and was also flexed approximately 8° more than in the natural knee. The hypothesis was not supported: The more anatomical component design did not provide more anatomical patellar kinematics and stability.

A biomimetic hip joint simulator that can be used to evaluate the outcome of the cemented total hip replacement has been designed, manufactured and evaluated. The simulator produces motion in the extension/flexion plane, with a socket to rotate internal/externally. At the same time a dynamic loading cycle is applied. A validation test was performed on a cemented femoral stem within a novel composite femur. The bone quality has a strong effect on the stem migration and on the integrity of the interfaces. The migration of the stem is a combination of 3-D translation and rotation of the stem. Under the same loading conditions, weak bone allows more stem migration than strong bone. There is a great decrease in the strength of the stem-cement interface after the dynamic test, and the weak bone composite exhibited a greater reduction in interfacial strength than the strong bone composite. The decrease of the interfacial strength indicates that the primary bonding between the stem and the cement mantle had deteriorated and the integrity of stem-cement interface was damaged. The study demonstrates the value of using a hip joint simulator to investigate stem migration and interface integrity within the cemented hip replacement, suggesting that method can be used for in vitro evaluation of the biomaterials used in the cemented hip replacements.

Currently, polymethylmethacrylate (PMMA) or acrylic bone cement is the most commonly used adhesive material in total hip replacement (THR) surgery [1, 2]. The mechanical properties of acrylic bone cement are very influential in determining successful long-term performance of THR [3‐7]. A large number of commercial formulations are available, differing in chemical composition and physical properties of both powder and monomer constituents. Studies on the mechanical properties of commercial available bone cements revealed that the different cements behave differently [8‐11]. Harper and Bonfield [12] investigated ten commercial bone cements under the same test regimes, and found that handling characteristics of each bone cement varied, and significant differences in both static and dynamic behaviors between the various bone cements. The reasons for the differences obtained in mechanical properties can be attributed to variations in both compositions of polymer and monomer, particle size, morphology, and molecular weight of powder, strength of polymer bead-matrix interface, and powder-to-liquid ratios. A large number of studies reporting the mechanical properties of bone cement and the factors that affect these properties have been reported in the literature [1, 13‐16].

Bone cement creep behavior was studied using commercial available clinical bone cement. Creep deformation was measured using a micrometer with a resolution of 1 μm. It was demonstrated that the restraint has a very strong effect on the creep of bone cement, half-restrained specimens creep more than that of fully restrained specimens. The creep of the investigated bone cement increased with the dynamic loading cycles, and two creep stages, a high initial creep rate followed by a steady creep stage, can be identified. The relationship between the creep deformation and the loading cycles was expressed by a single logarithmic model.

Background The interfacial molecular mechanisms that regulate mammalian cell growth and differentiation have important implications for biotechnology (production of cells and cell products) and medicine (tissue engineering, prosthetic implants, cancer and developmental biology). We demonstrate here that engineered protein motifs can be robustly displayed to mammalian cells in vitro in a highly controlled manner using a soluble protein scaffold designed to self assemble on a gold surface. Results A protein was engineered to contain a C-terminal cysteine that would allow chemisorption to gold, followed by 12 amino acids that form a water soluble coil that could switch to a hydrophobic helix in the presence of alkane thiols. Bioactive motifs from either bone morphogenetic protein-2 or osteopontin were added to this scaffold protein and when assembled on a gold surface assessed for their ability to influence cell function. Data demonstrate that osteoblast adhesion and short-term responsiveness to bone morphogenetic protein-2 is dependent on the surface density of a cell adhesive motif derived from osteopontin. Furthermore an immobilised cell interaction motif from bone morphogenetic protein supported bone formation in vitro over 28 days (in the complete absence of other osteogenic supplements). In addition, two-dimensional patterning of this ligand using a soft lithography approach resulted in the spatial control of osteogenesis. Conclusion These data describe an approach that allows the influence of immobilised protein ligands on cell behaviour to be dissected at the molecular level. This approach presents a durable surface that allows both short (hours or days) and long term (weeks) effects on cell activity to be assessed. This widely applicable approach can provide mechanistic insight into the contribution of immobilised ligands in the control of cell activity.

Streptococcus bovis is a very rare cause of infection of joint arthroplasty. Infections with S. bovis have been reported to be associated with various gastrointestinal conditions. We present a case of total knee arthroplasty infected with S. bovis 40 months after a successful knee replacement. The diagnosis was established on joint fluid as well as blood cultures. Early diagnosis, arthroscopic wash out and appropriate antibiotics helped salvage the prosthesis. Early colonoscopy revealed carcinoma of the sigmoid colon that was surgically resected.