NIHRDataInsights/HRCSData huggingface dataset:
Title: Enhancing calvarial regeneration: the differential regenerative capacity of frontal and parietal calvarial bones.
Funder: Medical Research Council

Abstract: Craniofacial skeletal reconstruction is challenging because the capacity of skeletal tissue to regenerate is poor. Autogenous bone, allogeneic bone and prosthetic materials carry drawbacks. Identifying targets for future pharmacological modulation of calvarial regeneration is the goal. The skull vault is made up of disparate embryonic origin. Frontal bones arise from neural crest and parietal bones from paraxial mesoderm. Frontal bone osteoblasts have a higher osteogenic potential than parietal, conferring an enhanced healing capacity to frontal bones. Certain signaling pathways determine this difference. 1: Identify genes expressed differentially at specified levels of significance, in frontal and parietal bone. Obtain bone samples from wild type mouse parietal and frontal bone. Perform microarray analysis and identify any significant differences in gene expression. Use preliminary microarray data from e15.5 and e 18.5 mice to provide insights into which subpopulations of genes might be appropriate to investigate. 2: Identify differences in gene expression between frontal and parietal bone at the healing edge of calvarial defects. At 24, 48 and 72 hours following the creation of a 2 mm calvarial defect, a 1 mm rim of bone will be taken. DNA microarray analysis will be performed on these samples to analyze gene expression profiles during healing. 3: Comparative in vitro osteogenic assays and in vivo calvarial defect healing assays in frontal and parietal bones in wild type and Sostdc1-/- mutant mice. From preliminary F v P microarray data in e15.5 and e18.5 mice, the Liu lab has identified one key regulator, Sostdc1. Sostdc1 is a signaling molecule that dually inhibits BMP and Wnt, and is expressed robustly in frontal bone. Mouse mutants in Sostdc1 have a short skull, indicating its requirement for ossification of the head. The role of Sostdc1 will be investigated by performing the same assays as for aim 2 in the mutants, and by assessing healing using microCT.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Bone Marrow Lesions and Central and Peripheral Drivers of Knee Osteoarthritis Pain. A Pre and Post Total Knee Replacement Study.
Funder: Medical Research Council

Abstract: Despite the success of total knee replacement surgery (TKR), 20% of patients continue to experience chronic pain post operatively. The cause of this pain remains unclear and requires further investigation. Bone marrow lesions (BMLs) within the subchondral bone visualised by Mr.I correlate with OA pain. Whether BMLs also contribute to post-operative pain after TKR and the biological processes involved is unknown. I aim to study 50 patients with painful knee OA to investigate BMLs, and central and peripheral drivers of knee OA pain, pre and post TKR surgery. I hypothesise: 1.That TKR normalises altered central pain processing (assessed by functional nociceptive Mr.I using mechanical knee stimulation) and central sensitisation (assessed by QST and questionnaires) in patients without BMLs after TKR. 2.That the continued (or new) presence of residual bone marrow lesions (BMLs) within the subchondral bone after TKR surgery (assessed by quantitative Mr.I and preoperative histology) is a source of continuous nociceptive input maintaining pain, altered central processing and central sensitization post TKR surgery (assessed by fMr.I, QST, questionnaires). 3.That BMLs contain increased numbers of osteoclasts and nerves when compared to areas of subchondral bone that do not have bone marrow lesions (assessed by histology). Design of the Study Fifty patients with unilateral painful osteoarthritis of the knee awaiting TKR will be recruited as part of this prospective cohort study. The number of patients in the study is achievable within the timeline of the fellowship. It will give clear evidence of the variability of the techniques and provides data to inform further studies.


Research activity codes: 6.4 SURGERY;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Development of computational models of bone formation and resorption to predict changes in bone in preclinical intervention studies.
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: We will develop new computational models capable of predicting the extent and anatomical location of bone formation and/or resorption following bone anabolic interventions. We will use models of osteoporosis as proof of concept but the models developed will be applicable to any given intervention of genetic, metabolic, surgical, pharmacological, or functional nature. We will use a combination of in vitro data and data collected by the non-destructive in vivo micro computed tomography (microCT). This will allow the accurate three-dimensional measurement of bone tissue morphometry changes over time due to the intervention under investigation in the same region of the skeleton of the same animal. Once validated, this quantitative information will be fed into a computer model that will determine the relationship between each specific intervention, the time, and the bone remodelling each point of the bone. These models will then be used to make predictions on how the tissue morphology in a region of the mouse skeleton would change over a given time because of a given intervention. The accuracy of these predictions will be confirmed at the next time points, by simply comparing the computer predictions to the data generated by the in vivo microCT scanning. The way in which candidate interventions are approved for human trials involves animal use for proof of principle studies in physiological models and uses large numbers of animals to generate statistically robust data at each time point. This technology will replace most of this in vivo testing and will require reduced number of animals to test at the chosen stratification due to the higher accuracy of the serial in vivo imaging technique. Moreover it will generate better quality data and allow a better understanding of the advantages and limitations of mouse models in testing interventions compared to human subjects.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: MUSCULOSKELETAL
Title: 3D gene knockout tissue models using adult human stem cells
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: The tissues in our bodies are three-dimensional (3D) arrays of different cell types, whose behaviour is largely determined by the genes they express. Understanding the function of individual genes of cells within tissues is essential if we are to know more about human health and disease, and the development of new and better treatments. A common experiment to determine gene function is to "knockout" specific genes in animal models, usually mice, and examine the effects. However, producing knockout mice is difficult, inefficient, requires large numbers of animals and results may not translate satisfactorily to human physiology. Adult human stem cells can now be grown in the laboratory and induced to generate different tissue types. We have isolated so-called mesenchymal stem cells (MSCs) from human bone marrow and generated an immortal MSC "line" that appears to live forever when grown in a culture dish. This provides us with an opportunity to perform long-term genetic manipulations, which would not normally be possible in standard short-lived cells. We have also developed new techniques where MSCs in specialised Petri dishes can be coaxed into forming 3D tissues containing both bone and cartilage, in a manner similar to how our skeletons form. In this project, we will use sophisticated gene targeting methods to knockout particular genes in the MSCs that are normally involved in the development of healthy and diseased skeletons. We will then find out how the gene knockouts affect the ability of the MSCs to form 3D microskeletons in the laboratory. This system will using human stem cells, capable of complex tissue formation, in a system that is highly controllable and recognises the 3D nature of true tissues. If successful, this work will have far-reaching implications for cost and efficiency of biological research, our understanding of gene function and will contribute significantly to the replacement of mouse knockout experiments.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Bone healing and regeneration in an ex vivo bioreactor – evaluation of angiogenesis and reparation for clinical application
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Skeletal tissue loss as a result of injury or disease causes a significantly reduced quality of life at a high socioeconomic cost. We are investigating tissue engineered cellular constructs, onsisting of a novel smectite hydrogel and a highly potent source of skeletal stem cells derived from human fetal femurs as a potential tissue replacement. To test the efficacy of such constructs in promoting tissue healing and regeneration, we propose to develop a new ex vivo model to study bone formation that accurately model bone repair and regeneration without the need for often highly invasive surgical procedures in murine hosts. Our primary aim is to refine animal use in our research by substituting these surgical procedures in sentient mouse models with realistic and novel models of bone regeneration in a natural painless bioincubator – the chorioallantoic membrane (CAM) of the chicken egg.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Creating an in vitro model of pathogenic ossification to explore methods for dispersion
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Pathological ossification can occur as a symptom of disease (ankylosing spondylitis) or following trauma due to surgery or following exposure to an explosion. The ossification that occurs is frequently very painful and requires resection of the affected tissue or in the case of less severe mineralisation, temporary immobilisation. In some cases, such as the mineralised ligament and tendon in AS, there is no real adequate treatment and the patient permanently loses mobility. The aetiology of many of these ossifications is unclear and this partly due to our inability to probe factors that may influence hard tissue formation in the existing animal models. Currently, in vivo models of mineralisation rely on the production of a modified mouse strain that overexpresses bone morphogenic protein and is prone to pathological mineralisation. These animals can require physical injury in order to induce the formation of the ossification and clearly this, in addition to the chronic debilitating effects of the ossification, mean that the animals endure significant suffering during their lifetime. Furthermore, the animal models that are used provide a poor approximation of the mineralisation that can occur in a human patient. Mice, for example, have a considerably higher rate of metabolism than humans and can be more refractory. In addition, the absolute volume of bone formation is typically significantly lower. This means that the nature of the newly formed mineral in the mouse differs from the mature bone that can be found in cases of heterotopic ossification. The proposed project would develop an in vitro model of pathological mineralisation, so that we can improve on existing animal models, eventually eliminating the need for them. The model will also enable us to systematically investigate the factors that might influence hard tissue formation. It will also help us to evaluate how existing drugs and other treatments may be used to disperse the ossification


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: High-resolution MRI on the influence of ligaments in symptoms, phenotype and diagnosis of hand osteoarthritis
Funder: Department of Health (England)

Abstract: Objectives: To utilise high-resolution imaging (MRI and ultrasound) to delineate the microanatomical basis for hand osteoarthritis (OA), investigating the unifying hypothesis that ligaments influence the symptom development, phenotypic expression and diagnosis of hand OA. The following hypotheses will be tested: 1) The degree of ligament damage and inflammation in hand OA is related to symptoms2) The bone remodelling response in hand OA (osteophyte formation) is related to ligament inflammation. Furthermore, these Â“anabolic responsesÂ” may be greater in magnitude than cartilage loss at disease presentation. 3) The pattern of ligament abnormalities on MRI can be used to distinguish hand OA from psoriatic and rheumatoid arthritis (PsA and RA). 4) Ultrasonography can be used to differentiate hand OA from PsA and RA. This will be compared to MRI to validate ultrasonography as a diagnostic procedure for early hand OA.Design and Techniques: Prospective observational hypothesis-driven, using high-resolution MRI and ultrasound of the hands, to study ligament abnormalities, bone remodelling patterns (with histology confirmation), relating abnormalities to symptoms, and follow-up (of undifferentiated hand arthritis) to determine diagnostic factors. Patients: 420 subjects (220 OA, 30 normal, 70 RA, 70 PsA, 30 undifferentiated) will be recruited. Measurements: Analysis will be focussed on the ligaments and associated changes as I have previously published, and related to symptoms, bone remodelling responses, and its diagnostic value.Outcomes: This research is important for understanding OA anatomical and pathogenic mechanisms and could eventually improve OA diagnosis and therapy, and reduce the burden of OA on patients and the NHS.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: The role of womens' beliefs in their adherence to osteoporosis medication
Funder: Department of Health (England)

Abstract: Objectives:To design a psycho-educational intervention to improve adherence to osteoporosis medication and evaluate it using in-depth case-studies. Design: The intervention will be tailored to the needs of each patient and evaluated longitudinally using adherence, fractures, changes in illness and risk perceptions as outcome measures. Feasibility and patients’ perceptions of the intervention will also be evaluated. Anticipated outcomes: Knowledge about the effectiveness of different components of the intervention, a method for tailoring interventions, recommendations for improving medication adherence in osteoporosis patients. Anticipated benefits: Increased osteoporosis medication adherence will improve medication effectiveness, reduce fractures, and reduce treatment costs.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: MUSCULOSKELETAL
Title: Ensure GPs and Physiotherapists offer treatments and services that help people with musculoskeletal pain and disability, so they can cope with and reduce pain, preventing common joint and back pain from restricting their lives
Funder: Department of Health (England)

Abstract: Prof. Foster's research will support the development, piloting and testing of treatments and services for common and costly musculoskeletal problems in primary care, including lower back, knee and shoulder pain. She will develop and test the clinical and cost-effectiveness of different treatments and services, including early identification of musculoskeletal problems, support for patients of working age and approaches that better match patients to the right treatments.


Research activity codes: 5.7 PHYSICAL;6.7 PHYSICAL
Health categories: MUSCULOSKELETAL
Title: A randomised controlled trial of total resurfacing versus hemi resurfacing in the treatment of primary osteoarthritis of the shoulder.
Funder: Department of Health (England)

Abstract: Background The shoulder is the third most common joint requiring arthroplasty surgery (artificial joint) between 6,000 to 7,000 operations performed in the NHS each year. Shoulder replacement surgery has been a highly successful treatment for patients with severe arthritis. Shoulder resurfacing is a newer type of arthroplasty that maintains the humeral head. It is rapidly becoming the arthroplasty of choice because it preserves bone stock and anatomy. Both replacement and resurfacing can either be of just the humeral head (hemi) or of both the humeral head and the glenoid (total). Shoulder resurfacing has mid-term results comparable to shoulder replacement. However, there are currently no trials which directly compare hemi resurfacing and total resurfacing. Aims There are four main objectives of this pilot randomised controlled trial: 1. To quantify and draw inferences on observed differences in primary and secondary outcomes measures between total resurfacing and hemi resurfacing at one year post-operatively. 2. To estimate the distibution of outcome measures within a trial and compare with published observational studies. 3. To determine the feasibility of the randomisation process and trial processes. 4. To evaluate the optimal sample size for the full clinical trial. Plan of Investigation We intend to conduct a pragmatic multi-centre randomised controlled trial of total resurfacing versus hemi resurfacing in the treatment of patients with severe arthritis of the shoulder joint. This application is for a single centre pilot trial in preparation for the full clinical trial. Any patient who is suitable for a total resurfacing will be eligible to take part in the study. The trial will employ a 1:1 randomisation sequence. Patients will be followed-up at 6 weeks, 3, 6 and 12 months post-operatively. The primary outcome measure is a patient-reported functional assessment: the Oxford Shoulder Score. The secondary outcome measure will be the EuroQol (EQ-5D). Furthermore, a note will be made of any complications occurring in the post-operative period. Potential Impact Traditional shoulder replacement has provided good functional results for patients with severe arthritis of the shoulder joint for many years. However, shoulder resurfacing has the advantage of restoring anatomy and preserves as much bone as possible (to facilitate later revision surgery). Resurfacing is rapidly becoming the preferred arthroplasty for the shoulder in the UK and worldwide. However, there are currently no studies which directly compare total resurfacing with hemi resurfacing for patients with severe arthritis of the shoulder joint. This pilot trial will provide the first high-quality evidence to aid in the design of a full multi-centre trial and support a future application for a full trial.


Research activity codes: 6.4 SURGERY
Health categories: MUSCULOSKELETAL
Title: The efficacy and cost effectiveness of a multidisciplinary intervention strategy for the treatment of benign joint hypermobility syndrome in childhood
Funder: Department of Health (England)

Abstract: Background Hypermobility in childhood occurs in up to 30% of children between 5 and 17 and accounts for a large proportion of referrals for musculoskeletal pain to paediatric rheumatology clinics (where it is classified as the benign joint hypermobility (BJH) syndrome). BJH is frequently associated with prolonged periods of pain and disruption of physical activity, home life and schooling. Current management is empirical involving a combination of modalities delivered through clinicians and allied health professionals. However, treatment varies widely between physicians and centres both in extent and availability. There is little knowledge of the clinical and cost effectiveness of commonly employed treatment strategies and an absence data from of randomised trials. Aims To conduct a randomised clinical trial to assess the clinical and cost effectiveness of a specifically designed structured programme of multidisciplinary care compared with standard care in the management of childhood BJH. To provide the first objective data on the optimum approach to treating patients with this condition To provide an indication of the most appropriate allocation of health service resources to the management of childhood BJH. Plan of Investigation The randomised trial will be undertaken in children with new onset BJH presenting to the paediatric rheumatology clinics at the Norfolk and Norwich University Hospital. The trial will be conducted in parallel groups, comparing usual care with a structured multidisciplinary programme involving input from rheumatologists, physiotherapists and OTs, together with an education package delivered to children, parents, schools and the wider community with which the children interact. A total of 100 children between the ages of 5 and 17 will be recruited over 18 months. Outcomes will be evaluated at 3 and 12 months post-intervention through interview and examination and by standard questionnaires to assess pain and physical functioning. A health economic analysis will be undertaken. Potential Impact Objective knowledge of the clinical and cost effectiveness of the multidisciplinary approach to treating childhood BJH will provide detailed guidance on the most appropriate management of this condition and will be of direct and tangible benefit to children suffering with this disease. The results of this study will have the potential to change clinicians’ attitudes towards BJH as a disease entity and to change the existing treatment paradigm. They will provide the first indication of the extent to which hospital and community resources should be committed to the treatment of this common childhood condition.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;6.7 PHYSICAL
Health categories: MUSCULOSKELETAL