NIHRDataInsights/HRCSData huggingface dataset:
Title: Developing, Testing and Fitting the Next Generation of Prosthetic Limbs
Funder: Royal Academy of Engineering

Abstract: Limb loss presents a high socioeconomic cost to tens of thousands of people in the UK. Worldwide, the WHO estimates that 100 million people need prosthetic or orthotic devices, but 80-90 per cent do not have access to P&O services because of a shortage of personnel, service units and health rehabilitation infrastructures.Even the most advanced prosthetic limb will be ineffective if its user-specific socket (the interface with the user’s residual limb) is not comfortable. Prosthetists agree that their profession needs to employ a more evidence-based approach, to take advantage of the skill and experience they spend years developing. However, they are cautious about technologies which might interfere with their application of these skills.My research is addressing this at several levels. We are developing computer models to predict how socket design influences the human-prosthesis load transfer, and ways to present these models to clinicians for use without advanced training, software or powerful computers. To inform these models, we are collecting population datasets matching socket design to outcome measures, and biophysical data to understand what load the residual limb’s tissues can sustain safely. Finally, we are working with psychologists and business modellers to establish what people really need from their prosthetics, and how this differs between children and adults, and across very different cultural backgrounds in lower and middle income countries. These tools should reduce the costs of prosthetic limb provision, enable healthcare providers to make informed decisions about the limb components they fund, and help amputees around the world to make a faster return to an active life.


Research activity codes: 5.3 MEDICAL DEVICES;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: MUSCULOSKELETAL
Title: Development of an Automated Software Model for Measurement of Paediatric Skeletal Age using Small Bore Extremity Magnetic Resonance Imaging
Funder: Royal College of Radiologists

Abstract: To develop an automated software model (using features such as physis width and volume, metaphyseal and physeal texture, and epiphyseal volume) for measurement of paediatric skeletal age using small bore extremity magnetic resonance imaging. To calculate agreement between X-ray and MRI skeletal age estimates.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: MUSCULOSKELETAL
Title: Early diagnosis and intervention of osteoporosis using nanovibrational stimulation
Funder: Science and Technology Facilities Council

Abstract: Osteoporosis is a disease of the bone which affects 3M people in the UK, is associated with 300,000 fractures per year, and costs the NHS £1.9B/yr (figures provided by the National Osteoporosis Society, 2015). Current medical practice is to diagnose osteoporosis and provide pharmacological treatment only after a fragility fracture has occurred. This project seeks to revolutionise treatment through a drug-free, proactive management, through use of precision nanovibrational stimulation applied via bone conduction (similar to bone conduction headphones). Nanovibrational stimulation has recently been shown to produce osteoblasts (bone building cells) in the lab from mesenchymal stem cells (MSCs - adult stem cells found in the bone and elsewhere in the human body). This was the first time that osteogenesis (promotion of bone) has been observed in MSCs without the requirement for drugs and/or complex engineered scaffolds. Since osteoporosis has been linked to insufficient osteogenesis in MSCs, nanovibrational stimulation could provide a breakthrough route to decrease the onset, or perhaps even reverse the effects, of osteoporosis. In order to evaluate this in a timely manner, this project will study disuse-related osteoporosis (due to spinal injury) since this provides a time-accelerated model for testing interventions. The academic team will work alongside the clinicians within the Scottish Centre for Innovation in Spinal Cord Injury (SCISCI) in the Queen Elizabeth National Spinal Injuries Unit and conduct the first trials in nanovibrational stimulation for proactive treatment of osteoporosis.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Performance, regulation and competition in medical devices: a case-study on hip prostheses
Funder: Versus Arthritis

Abstract: An ageing population alongside continuous advances in medical technology places emphasis on the regulation and reimbursement of the prostheses used for Total Hip Replacement surgery. Access to and provision of these prostheses by the manufacturers is essential to individuals with musculoskeletal disease. There are a large number of prostheses on the market with little evidence of their cost-effectiveness.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: MUSCULOSKELETAL
Title: Mapping phenotypic to genetic variability in the High Bone Mass Study
Funder: Versus Arthritis

Abstract: Osteoporosis, characterised by low bone mineral density(BMD), is common and causes fractures with high morbidity. Currently less than 5% of the variance in BMD is explained, so-called 'missing heritability’. Understanding the genetic causes of the rare extreme phenotype of High Bone Mass(HBM) is a novel approach. We have collected a unique UK-based population of cases with unexplained HBM (lacking LRP5, LRP4, SOST mutations) with BMD>3 standard deviations above normal and a mild skeletal dysplasia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: PROMOTE: A pragmatic, double-blind, randomised, placebo-controlled trial of methotrexate to treat painful knee osteoarthritis
Funder: Versus Arthritis

Abstract: Osteoarthritis (OA) is a significant and growing problem in our ageing population; 10% of people over the age of 55 have disabling knee pain, rising to almost 50% aged 80 and over. Current treatment options for knee OA are limited by both efficacy and toxicity; barring surgery there are no safe long-term treatment options for the growing number of people with painful knee OA. The identification of alternative treatment options, which will give good analgesic effect, is therefore critical to enable optimal management of people with knee OA. Recent imaging studies suggest inflammation as a likely source of pain in OA. Methotrexate is the commonest drug used to treat synovitis in RA; current evidence suggests it is the most effective DMARD and safe in long-term use. We have performed a 30 patient pilot study of methotrexate in knee OA. At 24 weeks 50% of patients had at least a 20% pain reduction, 37% had at least a 40% pain reduction. Four patients withdrew due to side-effects and two due to inefficacy. In light of this positive pilot data, this study aims to definitely examine the analgesic effectiveness of methotrexate for treating knee OA in a large, placebo-controlled, double-blind, randomised trial.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Lessening the burden of osteoarthritis: elucidating the pathogenic role of the PAR-2 pathway
Funder: Versus Arthritis

Abstract: Osteoarthritis (OA) is a global musculoskeletal disease, identified as high priority in the strategic aims of Arthritis Research UK. There are no disease-modifying OA drugs (DMOADs), leaving only analgesia and ultimately surgery to reduce pain and disability. We have compelling evidence that proteinase-activated receptor-2 (PAR-2), activated by the serine proteinase matriptase, is a key mediator of OA initiation/progression, critically integrating matrix deregulation and tissue remodelling/inflammatory damage. The PAR-2/matriptase axis thus links pain to tissue destruction, offering significant potential as a novel therapeutic target in OA. This Programme exploits our robust track record in this area to systematically delineate mechanisms whereby this pathway modulates cartilage and bone biology. We employ tissue-specific PAR-2/Matriptase knockout mice in integrated in vitro and in vivo studies, validated in relevant human tissues/cells. Our collaborative, multicentre approach assimilates clinical and translational expertise in arthritis, cartilage and bone biology, animal models and imaging. We will determine the effect of PAR-2 deficiency on joint tissues in OA, establish the principal roles of matriptase and PAR-2 in OA, investigate how altered biomechanics mediates OA pathology via this pathway, and compare the underlying molecular mechanisms in model systems of human tissues/cells in order to validate identified tractable DMOAD targets for OA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Identification of low frequency and rare variants associated with osteoarthritis and related traits.
Funder: Versus Arthritis

Abstract: Osteoarthritis (OA) is a complex heterogeneous disease with a genetic component. We have previously performed the largest genome-wide association study of OA (arcOGEN GWAS) bringing the total of established OA loci in Europeans to eleven. In keeping with other complex traits, the OA-associated loci are represented by common variants with small effect sizes explaining a small proportion of OA heritability. Part of this missing heritability can be ascribed to low frequency and rare variants which are hypothesized to have larger effect sizes and hence higher translational potential. This work aims to identify low frequency and rare variant associations with OA and related traits. We will use exome chip genotyping to interrogate rare variation with a high prior probability of being functional. This will provide near-exhaustive coverage of the full allelic frequency spectrum in coding regions of the genome. Imputation approaches will then be used to combine the GWAS and exome chip data with low-depth whole-genome sequence data from a large UK reference panel (UK10K) to assess association with variants across the whole genome. This work will advance our understanding of the genetic architecture of OA and related traits and can potentially identify predictive markers of disease and its processes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Rejuvenation of mesenchymal cells for authentic cartilage regeneration in osteoarthritis.
Funder: Versus Arthritis

Abstract: We have succeeded in rejuvenating mesenchymal stromal/stem cells (MSCs) obtained from aged donors, which will transform regenerative medicine prospects for osteoarthritis (OA). The skeletogenic differentiation potential of MSCs makes them attractive therapeutic cells for OA. However, the quality and efficiency of MSC differentiation, particularly from aged patients, is clinically inadequate so there is an urgent need for developmentally younger, autologous cell sources. We have unveiled a new paradigm in cell therapy; a mechanism to rejuvenate aged cells through controlled autophagy to maximise clinical benefit. By exposing OA-MSCs to different 3D in vitro environments we have been able to scale the autophagic response to optimise cytoplasmic clearing, organelle remodelling and metabolic transition to establish a primitive ground state, with enhanced differentiation potency. The technique is rapid, efficient and safe (absence of teratoma formation), without requiring genetic manipulation and is suitable for scale-up. The proposed work will use rejuvenated MSCs for developmentally-appropriate, efficient cartilage regeneration in comparison to other recognised adult and embryonic stem cells. The rejuvenation capacity of joint defect-resident articular chondrocytes and the suitability of pharmacological autophagy mimetics to condition cells prior to implantation will be tested, in addition to targeting host cells in situ.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Adjustable in vivo joint loading to identify the mechanical drivers of osteoarthritis
Funder: Versus Arthritis

Abstract: Osteoarthritis is the disastrous product of mechanics and genetics, typified by articular cartilage (AC) damage with spontaneously increasing severity. The precise character of osteoarthritogenic mechanics that initiate and drive progression are, however, undefined. Our proposal tests whether localized high shear stress produces lesions that progress to osteoarthritis due solely to repetitive habitual joint use, by: i) determining mechanical factors that, applied only transiently, produce AC lesions, ii) defining progression rates after AC lesion induction in genetically-prone mice, and iii) comparing transcriptional signatures that accompany load-induced AC responses and osteoarthritis progression. Exploiting our model’s capacity to create compartment-specific load-induced AC lesions, mice with natural osteoarthritis, different loading regimens and an interdisciplinary, multi-scale approach, our goal is to define crucial roles for loading in AC lesion induction and speed of osteoarthritic devastation of joint function. Our team is ready to combine ultra-high resolution tomography for non-invasive imaging of intact mouse joints and real-time imaging during loading, finite element modelling to describe inherent stresses and strains and our unique adjustable non-invasive loading model in which histological, molecular and transcriptional changes in AC can be studied, to decipher the role of mechanics in the initiation and progression of OA in normal and osteoarthritis-prone mice.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: MUSCULOSKELETAL AUTOPHAGY - SirT1 regulation of autophagy in bone and joint; causes, consequences and diagnostic potential
Funder: Versus Arthritis

Abstract: Efficient ‘housekeeping’ is essential to preserve optimal cell function. Autophagy, regulates the clearing of debris within cells. Defective autophagy leads to accumulated cytoplasmic protein aggregates, and is linked to ageing in all tissues. However the level of autophagy within cells of the bone and joint, the potential for targeting autophagic mechanisms and the relevance to musculoskeletal disease is only beginning to be studied.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Centre for Musculoskeletal Health and Work
Funder: Versus Arthritis

Abstract: We aim to establish a world-leading centre, addressing major research questions to minimise the adverse impacts of musculoskeletal disorders (MSDs) in the workplace, with benefits for patients, workers, employers, and society at large. We propose an integrative, cross-disciplinary centre of excellence, which will:


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: MUSCULOSKELETAL
Title: Functional analysis of the osteoarthritis susceptibility locus residing at the nuclear receptor coactivator 3 gene NCOA3
Funder: Versus Arthritis

Abstract: Osteoarthritis (OA) has a major genetic component and robust susceptibility loci are now being identified by genome wide association scans (GWAS). Meta-analysis of several GWASs, including the Arthritis Research UK funded arcOGEN study, has identified a compelling OA signal at chromosome 20q13 marked by the single nucleotide polymorphism (SNP) rs6094710. This association has a p-value of 7.9x10-9 and an odds ratio of 1.28 in patients with hip OA. The signal encompasses two genes, the transcriptional co-activator NCOA3 and the sulphatase SULF2. Our pilot data reveals that both genes are up-regulated in OA hip cartilage, and that genotype at rs6094710 correlates with allelic expression imbalance (AEI) of NCOA3 in cartilage. We thus hypothesise that the hip OA association marked by rs6094710 is caused by a cis-acting regulatory variant(s) that modulates the expression of one or both genes. We shall test this hypothesis by performing a number of experiments, including the use of patient joint tissues, to identify and then fully characterize cis-acting polymorphic elements that correlate with the association signal. By so doing we shall be able to pinpoint the causal polymorphism(s) and the gene through which it is acting to increase the risk of hip OA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Microscale mechanics and chemistry of articular cartilage: relationships to in vivo loading and susceptibility to degeneration
Funder: Versus Arthritis

Abstract: The association between cartilage degeneration and joint loading is well established. However, because of the complex spatial pattern of variation in joint loading we postulate that the mechanisms underlying this association can only be understood by investigating the relationships between the mechanics of the tissue, the structure of the extracellular matrix and cellular function on a microscopic scale. We shall compare the micromechanical properties of regions of equine metacarpophalangeal and human patellar cartilage exposed to different loading patterns and with different susceptibility to disease. Testing will be performed on the stage of a multimodal multiphoton microscope which will enable us to determine micro-scale strain fields in collagen and elastin networks, in the pericellular matrix and the cells in living tissue. Raman microspectrometry will be used to determine variations in matrix and cellular chemistry on the same scale. Together, these measurements should enable us to identify local variations in tissue structure and/or mechanics that pre-dispose degeneration or are early indicators of the process. The research will inform the development of new diagnostic approaches and may lead to the development of restorative or regenerative procedures tailored to specific cartilage regions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Defining the mechanisms by which CTGF protects joints from injury-induced osteoarthritis
Funder: Versus Arthritis

Abstract: Osteoarthritis is the most common form of arthritis in the UK affecting more than 25% of the population aged over 60. Over-expression of CTGF/CCN2 was recently shown to inhibit osteoarthritis development with ageing, however the mechanism remains unknown. Our aim is therefore to determine the mechanism by which CTGF protects the joint from osteoarthritis and whether it can be used for therapy. We propose to use a murine trauma model of osteoarthritis that shows hallmarks of human osteoarthritis and allows us to distinguish between the different phases of joint degeneration. Our first aim will define whether CTGF acts though the TGFß/SMAD signalling pathway, which is known to play an important role in joint health and dysregulated in disease. Our second aim will be to determine whether the protective influence of CTGF is achieved through inhibition of the speed of progression using a chondrocytes specific CTGF over-expressing and deficient transgenic mice. Our third aim will elucidate whether the administration of exogenous recombinant CTGF to the joint can impact upon osteoarthritis. Together, these aims will determine whether modulation of CTGF or downstream mediators are potential targets for therapeutic approaches in OA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Maintaining Musculoskeletal Health (MAmMOTH) Study
Funder: Versus Arthritis

Abstract: An Arthritis Research UK think-tank report in 2012, identified prevention of fibromyalgia as a research priority. We have previously shown short and long-term effectiveness (determined by patient global assessment of their condition) of Cognitive Behaviour Therapy delivered by telephone (tCBT) for chronic widespread pain (CWP), the cardinal feature of fibromyalgia. We have now developed statistical models which predict the future development of CWP sufficiently well to make prevention studies possible. We therefore hypothesise, that amongst patients identified as being at high risk of developing CWP, a short course of tCBT, will reduce the risk of its development. We plan a two-arm randomised controlled trial testing a short course of tCBT against usual care. Subjects will be eligible if they are evaluated as at “high risk” of developing CWP, namely have had a primary care consultation with regional pain and at least two of: a maladaptive behavioural response to illness, a high number of somatic symptoms and/or sleep disturbance. If successful this study would provide general practitioners with an intervention option to reduce the risk of CWP development. This will be the first such trial of which we are aware, internationally, to attempt to prevent the onset of CWP.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: MUSCULOSKELETAL
Title: An integrated functional immunogenomics approach to understanding pathogenesis and improving treatment in ankylosing spondylitis
Funder: Versus Arthritis

Abstract: Ankylosing spondylitis (AS) is highly heritable with over 40 disease-associated loci on recent genome-wide association studies (GWAS). In most cases, associations involve regulatory DNA and the specific modulated gene(s), pathways and mechanism of action remain unresolved, limiting translational utility. The goal of this research is to determine the functional basis for genetic associations with AS to advance understanding of disease pathogenesis and define opportunities for therapeutic intervention. We propose a study design adopting functional immunogenomics approaches and focused on primary cells and tissue samples relevant to disease. We will integrate GWAS for AS with our recent data mapping regulatory variants associated with differential gene expression; generate genome-wide maps of physical interactions between AS GWAS variants and target genes using high throughput chromosome conformation capture; and map the epigenomic landscape of AS in which variants act by DNase I hypersensitivity mapping to resolve regulatory elements, analysis of histone modifications, DNA methylation, short and long non-coding RNAs and epigenetic regulators to interpret disease-associated genetic variants. We will functionally characterise specific disease-associated loci including HLA-B27, CARD9 and a gene desert at chr21q22. We will use this functional epigenomic approach to enable novel drug target identification and opportunities for drug repurposing in AS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Arthritis Research UK Biomechanics & Bioengineering Centre (Cardiff)
Funder: Versus Arthritis

Abstract: The Centre has had a number of significant successes so far, including three patent applications for possible new treatments for arthritis, and has also established a unique foundation for further research and started several longer term studies which will yield results during the next five years.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: MUSCULOSKELETAL