NIHRDataInsights/HRCSData huggingface dataset:
Title: Characterising the biomechanics of prenatal skeletal development using novel Cine-MR images of fetal movements
Funder: Arthritis Research UK

Abstract: Developmental dysplasia of the hip (DDH), a condition where the shape of the hip joint is abnormal, has been shown to increase the risk of OA in later life. Reduced or restricted movement either before birth (e.g., breech positioning) or after birth (e.g., straight leg swaddling) are significant risk factors for DDH. However, there is extremely sparse information on the biomechanical environment of the developing fetus, or on how fetal movements affect the developing skeleton, in either normal or abnormal intrauterine conditions. We will use a unique Cine-MRI dataset which shows fetal movements at a range of developmental ages. A computational simulation will be developed to predict what levels of biomechanical stimuli, such as stress and strain, are induced in the developing bones and joints by fetal movements at a range of developmental stages and for varying conditions. We will test the hypothesis that prenatal environments which lead to an increased risk of DDH (e.g., breech, oligohydramnios) lead to different biomechanical stimuli in the hip as compared to those in a normal intra-uterine environment. The model that we will develop will serve as a tool to predict postnatal joint health based on fetal activity patterns and intra-uterine environment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: A Computational Method to Specify Surgical Correction for Knee Realignment
Funder: Arthritis Research UK

Abstract: Knee osteoarthritis is caused by increased joint stress, which is often associated with knee malalignment. Evidence-based information on optimum malalignment correction is lacking and surgical outcomes have been unpredictable._x000D_ _x000D_ We aim to develop a generalised computational method to predict how much malalignment correction is required to minimise peak knee joint stress post-operatively. We have already validated one subject-specific knee joint finite element (FE) model. We will strengthen our model accuracy and generalisability to speed up prediction of joint contact mechanics._x000D_ _x000D_ We propose to build 10 additional FE subject-specific models and validate them with independently-collected cadaveric joint pressure, measured from the same specimens from which each model was built._x000D_ _x000D_ We will determine the contact mechanics for virtual osteotomies of each subject-specific 3D FE cadaveric knee model when loaded with the same boundary conditions. We will then evaluate the accuracy of predicting joint contact mechanics of a reference knee model by geometrically scaling the remaining FE models to match the reference model. This will demonstrate the feasibility of a generalised computer method to predict pre- and post-surgical joint stress._x000D_ _x000D_ The proposed computational method will help plan knee realignment surgery.and can be altered to plan surgical treatment of other joint diseases.


Research activity codes: 5.4 SURGERY
Health categories: MUSCULOSKELETAL
Title: Development of a remote electronic rehabilitation service to enable safe delivery and remote monitoring of lower limb rehabilitation in the community.
Funder: Arthritis Research UK

Abstract: The proposed technology through enabling interventions or targeted preventative work will improve assessment, diagnosis, specific treatment, reduction in pharmacology; as well as ensuring effective self management and symptom management of musculoskeletal long-term conditions for patients. Thus enabling accurate maintenance or recovery of function including social participation and work. For this one-year project we will initially focus on developing and trialling a remote rehabilitation device suitable for individuals with arthritis (rheumatoid and osteoarthritis) to be able to lead to further rehabilitation opportunities for other musculoskeletal patient groups.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: MUSCULOSKELETAL
Title: Synergistic microenvironments for non-union bone defects
Funder: Arthritis Research UK

Abstract: The overarching objective of this proposal is to develop a new therapeutic approach to promote bone regeneration in non-union defects. The system is based on the interactions between functional materials and fibronectin (FN) that will tune the effective presentation of rhBMP-2. These interactions promotes the self-organization of FN at the material interface into physiological-like fibrils, that we have called material-driven fibronectin fibrillogenesis and involves conformational changes in the FN molecule, upon adsorption, and the exposure of both cell adhesion and growth factor (GF) - binding domains. This material-based platform will synergistically present binding sites for both integrins and GF receptors to provide retention, delivery and presentation of rhBMP-2 within artificial matrices. More importantly, it will allow much lower rhBMP-2 doses to be used, which makes the system robust in terms of safety and effectiveness and, simultaneously, economically more competitive than current commercially available products. The final construct will be based on a structural - biodegradable 3D material coated with a functional material able to induce the required fibronectin fibrillogenesis. The technology is applicable across many structural materials (polymers ceramics and metals) and it allows combinatorial topologies in terms of porosity of the 3D structural system and even the presence of nanofeatures within the walls of the structural material that could further enhance the synergistic (integrin - GF) signalling provided by the functional coating. The 3D constructs will be investigated for their ability to drive mesenchymal stem cell differentiation in vitro towards the osteogenic lineage. Finally, the system will be investigated in vivo as an acellular system able to recruit stem cells and osteoblasts from the surrounding tissue and promote tissue healing and bone regeneration in non-union bone defects.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Novel Teriparatide (PTH) Formulation
Funder: Innovate UK

Abstract: Osteoporosis is a debilitating disease. About 55% of people over 50 are at risk of developing osteoporosis, with post-menopausal women at greatest risk. Osteoporosis affects 2 million people in the UK and 70,000 suffer hip fractures (among the worst in the EU). Treatment of hip fracture alone costs the NHS £2bn annually. Teriparatide (PTH) is currently the most effective medical intervention. Daily PTH injection has resulted in a 66-90% decrease in vertebral fractures and about a 50% drop in non-vertebral fractures. However, the current PTH product must be stored under refrigerated conditions. Whilst most bone physicians believe that PTH is a good drug, few actually prescribe it as its use is very restrictive in terms of travel and work, over a long treatment time (24 months) as well as the high cost. The aim of this project is to develop a generic version of PTH that is cost effective and can be used by patients "on the go" by use of the patented, needle free, Glide SDI® technology


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Early Stage Regenerative Remediation of hip OA by novel curvilinear arthroscopy
Funder: Innovate UK

Abstract: Early stage osteoarthritis (OA) of the knee and shoulder can be treated using Minimally Invasive Surgery (MIS), with such techniques having become widely adopted. In contrast, treatment of the OA in the hip is far more difficult as the joint is deep in the body and spherical. Variance between patients and the stiffness of the hip joint capsule and muscles makes access into and around the hip space very difficult because current arthroscopes are too large and operate with a 'line-of-sight'. Consequently, hip arthroscopy remains limited with low adoption. Our project seeks to overcome current limitations and develop a platform for 'ultra' MIS equipment that is both small and curvilinear, to enable complete access to hip lesions that are currently 'out-of-reach'. We seek to develop two prototype MIS tools. One that can accurately prepare the lesions to remove diseased cartilage and reveal the healthy bone below, and another to deliver new generative medicinal products into the target site.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL
Title: Advancing utrophin modulator SMTC1100 into clinical proof of concept trials for DMD
Funder: Innovate UK

Abstract: Duchenne Muscular Dystrophy (‘DMD’) is a fatal genetic disease that affects approximately 1,500 boys and young men in the UK. There is currently no disease modifying treatment for this progressive muscle wasting disease. Summit, a UK drug discovery and development company, is developing SMTC1100, a utrophin modulator drug that has the potential to treat all genetic forms of this disease. It has demonstrated significant potential in disease models of DMD and completed a Phase 1 clinical trial in healthy volunteers in 2012. The support of the TSB will allow this promising therapy to progress into patient clinical trials that aim to establish clinical proof of concept for SMTC1100 and validate it as a viable therapy for this devastating disease.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Late stage development & clinical evaluation of FibroFix Cartilage: A Mechanically Functional, Tissue Regenerative, Knee Cartilage Repair Implant
Funder: Innovate UK

Abstract: This project will develop an implant to reduce pain and restore mobility to patients suffering from injuries to the cartilage in their knees. The implant is made from a novel material called FibroFix™ which is formed from a protein extracted from silk fibres called fibroin. The properties of fibroin give FibroFix™ devices unique advantages, allowing them to be very strong, smooth and resilient like cartilage itself, while also capable of regenerating new cartilage tissue. This will allow the FibroFix™ implant to be used to treat large injuries to the articular cartilage in the knee where the painful condition osteoarthritis may already be present. The project will finalise development of this implant and complete testing in animal and laboratory trials, demonstrating that it is both safe and effective. Once this has been achieved, the project will investigate the implant’s performance in a clinical trial.


Research activity codes: 6.3 MEDICAL DEVICES;5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL
Title: A Targeted and Orchestrated Signalling Matrix for Clinically Challenging Defects
Funder: Innovate UK

Abstract: Our rapid increase in the understanding of the biology underlying many bodily repair processes has led to new perspectives in the design and use of materials to address disease or injury. For restorative stem cells to fully participate in tissue regeneration they need to be packaged in a delivery material that provides an optimal environment for them to function. This project will commercially develop a multi-functional tissue matrix that precisely locates an array of regenerative signals to service the requirements of tissue regeneration.The technology will be first directed towards bone repair applications, where earlier materials-based approaches are insufficient to heal large defects and in cases where more potent stimuli are required (e.g. for non-healing bone fractures and some spinal surgeries). The flexibility of the technology means that combinations of healing signals can be introdued into the matrix to make it more efficient and yield greater quantities of regenerated tissue. Further, a biologically-complex, highly active product can be produced with a low-cost formulation due to the re-purposing of existing, market-approved constituents.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Maintenance of functional capacity during lower limb immobilization and the potential for soft tissue repair for a novel form of neuromuscular electrostimulation
Funder: Innovate UK

Abstract: Soft tissue ankle injuries are the most common type of injury presented at NHS hospital A&E departments and account for almost 20% of all injuries; a total of approximately 200,000 cases per annum. Depending on the type of injury, the limb will require immobilising leading to a decrease in muscle strength and blood flow. The applicants wish to conduct a feasibility study of a new type of Neuro-Muscular Electro-Stimulation device (NMES): the firefly. This device has been shown to improve the circulation of blood in the lower leg by stimulating nerves in the leg and twitching the calf muscle. This action causes blood to pump around the body. The study hopes to demonstrate how the firefly can help the soft tissue repair itself and prevent muscle wasting during immobilisation. This will be achieved by a series of experiments using limb immobilization in healthy volunteers.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL
Title: Secondary pathogenetic mechanisms in XLMTM and CNM
Funder: SPARKS

Abstract: Myotubular and centronuclear myopathies are inherited muscle conditions associated with severe weakness. X-linked myotubular myopathy (XLMTM) is the most severe form and affects almost always boys, whereas those forms due to changes in the dynamin 2 (DNM2), amphiphysin 1 (BIN1) and skeletal muscle ryanodine receptor (RYR1) gene do not have any sex preference. Skeletal muscle and other organs such as the liver may also be affected. Although the genetic defects underlying the centronuclear myopathies are now largely known, the precise mechanisms by which those defects cause severe weakness and associated complications are currently not well understood. However, there is recent evidence that changes in the RYR1 and MTM1 gene may be associated with impairment of calcium release and muscle contraction, as well as with defects in the autophagy pathway, the latter being an important cellular housekeeping system, whose malfunction may cause some of the late complications of XLMTM. This team propose to investigate these mechanisms in biological samples obtained from patients affected by XLMTM and RYR1-related CNM and from muscle samples obtained from a model.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: p75NTR-Fc: a novel and safe biological for the treatment of chronic pain
Funder: Innovate UK

Abstract: With more than 1 billion people worldwide living with some type of chronic pain, a large unmet medical need for safe and effective analgesics exists. Traditional non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used drugs to treat pain and inflammation associated with osteoarthritis, but their use is limited by adverse effects on gastrointestinal and platelet function, as well as increased cardiovascular liability. Levicept Ltd is an UK based biotechnology company developing a novel, safe and efficacious biological therapy (p75NTR-Fc) for the treatment of chronic pain: including osteoarthritis and neuropathic pain. Our plans are to develop p75NTR-Fc and test its efficacy and safety in Phase I clinical trials in OA patients.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Combining stem cell science and Tissue engineering to study the development and repair of Human skeletal tissues
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The application of stem cells, select scaffolds and the incorporation of appropriate signalling cascades in the generation of new tissue is currently one of the most exciting and promising areas for disease treatment and reparative medicine. This has gained prominence given the demographic challenges of an advancing ageing population and the need for innovative approaches to augment and repair skeletal tissue. We propose that a paradigm shift in current research strategy is required if we are to meet the goal of skeletal tissue formation. We propose to enhance our understanding of skeletal developmental biology and apply this to underpin and inform the skeletal regenerative process. Currently, our progress in the isolation and culture of skeletal stem cells and in the application of scaffolds that control 3D architecture, soluble factor gradients and surface adhesion motifs has reached a point where we can mimic specific pathways used by the human body in skeletal tissue development and regeneration. Critically, mechanobiology has emerged as an important component in the regeneration of skeletal tissue. However, there remain significant challenges for the reconstruction of complex tissues, such as bone, that can only be informed by a thorough understanding of the developing tissue environment. Through Lola funding we propose that elucidation of the skeletal niche is critical in the identification of the key growth factors, matrix constituents and physiological conditions that will enhance and inform tissue regeneration. The approach advocated necessitates a truly inter- and multidisciplinary approach which could not be addressed through standard project routes of funding. The outcomes of this LOLA will be new in vitro and ex vivo models of human development translating to improved scaffolds and skeletal stem cell treatments for regenerative medicine. Joint with BB/G010587/1, BB/010579/1, BB/G010617/1. This joint project was co-funded by EPSRC under BBSRC Responsive Mode.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: The role of p38 MAPK in the adult muscle stem cell fate and regeneration in ageing
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Continued health depends on the ability of adult stem cells to maintain tissue integrity by generating precursor progeny with the potential to both differentiate and self-renew. Newly activated stem cells must undergo a period of proliferation, transit amplification, to provide sufficient cells for regeneration. In ageing, this is significantly impaired. Skeletal muscle adult stem cells (satellite cells) are an excellent exemplar; after the age of 50, muscle mass declines by 10% per decade, due to reduced proliferation of satellite cells. This is in large part due inappropriate extrinsic signalling to satellite cells, rather than intrinsic defects. p38 MAPK regulates the progression of transit amplifying cells to irreversible differentiation via phosphorylation of multiple targets to induce cell cycle exit and expression of myogenic genes. The aim of this project is to examine the role of p38 MAPK as a 'gateway' that integrates environmental cues into epigenetic changes to dictate gene expression and adult stem cell behavior. Four related hypotheses will be addressed: 1) p38 activation restricts lineage choice to differentiation at the expense of amplification in muscle precursor and stem cell pools, investigated by generation of conditional p38 knockout mice. 2) p38 has a crucial role in terminal differentiation genes by epigenetic mechanisms, via regulation of chromatin activation (TrxG) and suppression (PcG), determined by genome-wide ChIP-Seq (Illumina sequencing) for H3K4me3 and H3K27me3 in primary satellite cells. 3) p38 is activated in a strictly spatially and temporally regulated manner to ensure sufficient proliferation of progenitors in young animals. Candidate signals will be manipulated and subsequent p38 activity assessed. 4) During ageing, mechanisms that suppress premature p38 activation are impaired. Aged control and p38 knockout mice will be investigated with the expectation that decreased muscle mass will be ameliorated in the knockout mice.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Development of mechanically robust functionalised chitosan-based hyDr.ogels for tissue engineering applications in cartilaginous tissues
Funder: Engineering and Physical Sciences Research Council

Abstract: Tissue engineering offers a new generation of treatments for a range of age-related musculoskeletal conditions, such as intervertebral disc (IVD) degeneration; the leading cause of low back pain (LBP). The nucleus pulposus (NP) of the IVD is a highly-hyDr.ated, proteoglycan-rich tissue, containing chonDr.ocyte-like NP cells and it is this region which is predominantly affected during degeneration. For IVD regeneration, repair of the NP is essential, although degenerate NP cells are not a suitable cell source. Mesenchymal stem cells offer great potential and can be differentiated to cells with an NP-like phenotype. Successful tissue engineering requires a biomaterial with properties similar to the native gel-like NP tissue. HyDr.ogels, such as thermosensitive chitosan/glycerophosphate hyDr.ogels can support MSC differentiation to NP-like cells, but do not have the mechanical properties required for survival within the loaded environment of the spine. Thus our aim is to use state-of-the-art chemistries, combined with expertise in MSC biology and tissue engineering to develop novel chitosan-based hyDr.ogels, which are thermosensitive, mechanically robust and functionalised to enhance cell survival within the spine and prevent future disease reoccurrence. Initially, using innovative chemistry a new generation of chitosan-based hyDr.ogels with improved mechanical properties will be developed and evaluated for their ability to support MSC survival and differentiation. Successful gels will then be converted using Diels-Alder chemistry to thermosensitive injectable hyDr.ogels and tested using a novel human whole disc explant model of IVD degeneration housed within a loading bioreactor. Finally, mechanically robust thermosensitive hyDr.ogels will be functionalised through addition of factors to promote cell survival or prevent further tissue degeneration. Future application of this technology will revolutionise treatment of a range of age-related musculoskeletal disorders.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES;5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL