This paper reports on a proof of concept project funded by the UK National Council for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), with the aim of developing an in vitro model to recapitulate the human osteoarthritic joint, based on a multiple human cell type co-culture system, for research and drug development in OA. The targets were: (i) the development of a cell culture platform that could produce a mixed stable cell culture of cell types that represent the key components of the human joint: synoviocytes – type I and type II; osteoblasts; osteoclasts; chondrocytes/cartilage or cartilage-like matrix; adipocytes; and immune cells. (ii) demonstration of cell phenotype stability and viability for at least 72 hours. In order to establish the cell culture platform we have developed an eight-channel cell printer, capable of accurately and reliably printing the required cell types to create osteochondral and synovial cell types within a transwell system. Two different sets of cells have been developed and processed using the cell printer: a set based on using an immortalised hTERT MSC line to create osteoblasts, chondrocytes and adipocytes, with commercial cells lines providing the other cell types, and a set obtained from tissue excised during orthopaedic surgery. This gives both a repeatable set of cells with which to undertake mode of action studies, and a bank of cell sets which will be representative of different stages of osteoarthritis. The co-cultures have been immunohistochemically assessed in order to demonstrate maintenance of phenotype.

A subgroup of patients that undergo TKR surgery have evidence of neuropathic pain and central sensitization that may predispose to severe postoperative pain. This study assesses the correlation of MRI detected bone marrow lesions (BMLs) and synovitis with markers of neuropathic pain and central sensitization in patients undergoing TKR surgery and healthy volunteers.

31 patients awaiting TKR and 5 healthy volunteers were recruited. Each subject underwent a 3-T knee MRI scan that was graded for BMLs (0–45) and synovitis (0–3) using subsets of the MRI Osteoarthritis Knee Score (MOAKS). All subjects were asked to complete the PainDetect questionnaire to identify nociceptive pain (< 13), unclear pain (13–18) and neuropathic pain (>18). Correlation between BMLs and PainDetect score was the primary outcome measure. Secondary outcomes included the correlation of synovitis to PainDetect and temporal summation (TS) a measure of central sensitization to the PainDetect score. TS was determined using a monofilament to evoke pain. Pilot histological analysis of the prevalence of osteoclasts (TRAP⁺) within BMLs versus normal subchondral bone was performed, implying a role in BML pathology.

Increasing BML MOAKS score correlated with neuropathic pain (painDetect), r_s = 0.38, p=0.013 (one-tailed). There was a positive correlation between synovitis and PainDetect score, τ =0.23, p= 0.031 (one-tailed). TS was greater in the neuropathic pain than in nociceptive pain patients, U = 18.0, p=0.003 (one-tailed). TRAP staining identified more osteoclasts within BMLs than contralateral condyle lesion free subchondral bone, z = −2.232, p = 0.026 (Wilcoxon Signed Rank Test, one-tailed).

BMLs and synovitis are more prevalent in neuropathic pain and central sensitization in knee OA. Higher osteoclast prevalence was seen within BMLs which may help explain the association with BMLs and pain in OA.

Painful OA is linked to CNS changes in pain processing. Temporal summation of pain (TSP) is a measure of one such CNS change, central sensitization. TSP is defined using a series (≥0.33Hz) of painful stimuli and is a predictor of postoperative pain, experienced by 20% of patients after total knee replacement (TKR) surgery. This study has developed a protocol to use functional MRI to assess CNS changes in OA pain processing.

This pilot includes 3 participants with chronic knee OA pain awaiting TKR (62 ± 4.4) and 5 healthy volunteers (50 ± 13.6). 3-Tesla BOLD fMRI brain scans were recorded during short series of one second painful stimuli, applied using an automated inflatable cuff to the calf muscle of the leg with the affected knee or left side in healthy volunteers. The pain intensity at onset and during the 10 painful stimuli were recorded using a numerical rating scale. The pattern of brain activation was averaged across noxious stimuli, and the differential activation compared the 1st vs. 10th (last) stimulus. Bone marrow lesions (BMLs), synovitis and effusion size were scored from 3-Tesla knee MRI's using MOAKS scoring.

TSP was raised in OA patients compared to control group (p=0.023). TSP brain activity in the chronic OA patients displayed higher signal within the subgenual anterior cingulate (sgACC) compared to healthy volunteers. Knee MRI identified OA patient's exhibited higher BML scores (p=0.038) and more knee effusion (p=0.018), but the lack of synovitis did not differ from control group (p=0.107).

Enhanced TSP in chronic knee OA pain may be linked with augmented responses in emotional circuitry. BMLs and effusion size appear to contribute more with pain than synovitis. These results may help understand sensitization to improve outcomes for patients with knee OA undergoing TKR surgery.

Background

Bioresorbable materials offer the potential of developing fracture fixation plates with similar properties to bone thereby minimising the “stress shielding” associated with metal plates and obviating the need for implant removal. Phosphate glass fibre reinforced (PGF)-polylactic acid (PLA) composites are bioresorbable and have demonstrated sufficient retention of mechanical properties to enable load bearing applications.

The type, duration and intensity of exercise required to induce mechanical hypoalgesia is poorly defined. We are interested in identifying the exercise parameters required to induce raised pressure pain thresholds. This pilot study investigates the effect of indoor rowing on pressure pain threshold (PPT) in high performance rowers. Our ultimate aim is to investigate the potential of utilising exercise in the treatment of chronic pain and specifically in relation to the management of knee osteoarthritis. 20 high performance rowers (13M:7F; Mean Age 20.8 years; SD 1.74) were recruited from the University of Nottingham and Nottingham Boat Club high performance rowing teams under a research protocol approved by the University of Nottingham Ethics Committee. PPT measurements were made in triplicate using an algometer (SOMEDIC, Sweden) at the medial knee joint line, anterior tibia and sternum, pre- and post-exercise. Anthropomorphic and rowing ergometer power output data were also recorded. There was significant increase in PPT values at all sites following exercise (Medial joint line: 127.6Nm-2, 26%, p=0.001; Tibia: 110.8Nm-2, 24.7%, p<0.001; Sternum: 48.9Nm-2, 11.7%, p=0.005 – Wilcoxon Signed Rank) statistical power was 97.1%, 100% and 88.1%, respectively. PPT was greater at baseline at the medial joint line compared to other sites, reaching highly significant relative to the sternum (p<0.001). We determined that ten minutes of high intensity indoor rowing induced hypoalgesia in high performance rowers. Further research is required to investigate the detailed interplay between exercise and hypoalgesia, including its duration post exercise, to identify suitability for use in pain management strategies.

Background

Charcot neuropathic osteoarthropathy is a rare, destructive process affecting the bones and joints of feet in patients with diabetic peripheral neuropathy. The aetiology of Charcot remains unknown, although it has been suggested that it is triggered by the occurrence of inflammation in the foot of a susceptible individual, and that the inflammation results in increased osteoclastic activity.

Objective

To determine the reliability, reproducibility, variability and validity of the Osteoarthritis Research Society International (OARSI) Osteoarthritis Cartilage Histopathology (OACH) system and Mankin Histopathology – Histochemical Grading System (HHGS) when applied to the characterisation of the osteoarthritic human knee.