RESTORE: engineeRing an Enhanced vesicle SysTem for coOrdinated fRacture rEpair

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Skeletal injuries such as bone fractures and lower back pain are extremely common amongst the elderly and present a growing worldwide medical and socioeconomic burden, with over 150,000 osteoporosis-related fractures alone costing more than £1.7 billion per annum to the UK economy. This number is expected to double by 2040, putting a tremendous strain on healthcare systems worldwide and severely impacting quality of life. At present, standard clinical approaches apply bone tissue grafted from one site to another in the same patient (autograft), from another patient (allograft) or synthetic bone graft substitutes (BGS). These approaches are suboptimal, reducing patient mobility and introducing an increased risk of infection. In the case of BGS, the resulting bone formed is often inferior to the patient's own tissue, increasing the likelihood of secondary fracture and further hospitalisation.Modern tissue engineering (TE) approaches have sought to combine a patient's own stem cells with 3D scaffolds designed to mimic the natural physical bone environment. These stem cells are thought to transform into bone cells when grafted in the patient, directly forming new bone tissue. However, despite initial positive results, no routine clinical applications exist. This is because it has not been possible to manufacture enough stem cells to translate the positive results observed in the laboratory into a real world clinical setting, with these cells either needing to be isolated directly from the patient or expanded from a frozen stock. This makes the derivation and expansion of cells in a hospital environment logistically impractical and renders the process incompatible with the requirements of the clinician. Furthermore, recent evidence has shown that the traditionally held view of direct stem cell regeneration is inaccurate, with many stem cells grafted at the site of tissue damage not directly contributing to bone repair. Rather, these cells achieve their positive therapeutic effects through the secretion of nanoparticles called extracellular vesicles (EVs). These vesicles are approximately 1000 times smaller than a cell and contain a wide variety of biological factors that drive early bone formation. Unlike stem cells, large numbers of EVs can be manufactured under defined conditions by using the cell as a biological factory. Unlike cells, these vesicles are relatively simple to isolate in large quantities, with their therapeutic effects able to be validated and quality checked prior to long-term storage and application. Perhaps most importantly, unlike stem cells, the content of EVs will not change when administered in a patient, increasing the safety profile of the resulting therapy. As such, the application of EVs could capture the advantages of a cellular approach, while offering enhanced levels of standardisation, scalability and quality control.This project will engineer an advanced regenerative platform for the local coordinated delivery of therapeutic EVs to RESTORE bone function. The platform will exploit the properties of EVs to drive key regenerative responses critical for healthy bone formation, such as the recruitment of local progenitor cells and formation of a natural mineral template to drive new tissue formation. This is a paradigm shift in how we approach fracture repair and TE, delivering a cell-free, yet biologically equivalent approach that captures the innate complexity of natural bone development in a controlled and reproducible manner. Immediate outcomes will evaluate the potential of this platform technology in non-weight bearing scenarios (e.g. elevated leg fractures). While further physical reinforcement (e.g. using a titanium cage) will permit broader application in instances of weight bearing, such as spinal surgeries. In the longer-term, it is anticipated that this approach will provide an adaptable platform technology that can be reconfigured for wider musculoskeletal applications.