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Hotham, William 


One of the greatest requirements of modern medicine is the ability to treat patients suffering from osteoarthritis (OA) and bone fractures. Currently, there is no long-term therapy for OA; symptoms can be managed with anti-inflammatories and analgesics until they worsen to the extent that the damage becomes debilitating, and joint arthroplasty, is necessitated. However, these replacements are not perfect; firstly, there is the need for surgery and secondly, if the patient is young, the prosthetic can deteriorate, engendering further surgery. Bone fractures are regularly seen in orthopaedic clinics and are commonly repaired using fixation techniques or biomaterials. After any intervention, the fracture site can remain compromised, potentially engendering re-fracture and/or further surgical involvement. Regenerative strategies for both OA and bone fracture aim to alleviate pain, whilst maintaining or restoring damaged tissues to healthy states. Mesenchymal stem/stromal cells (MSC) are thought to facilitate tissue repair via either progenitor or secreaome functions. BM-MSC have, in previous work, been investigated as a therapy for OA via either their direct application or through their secreted Extracellular Vesicles (EV). In this study, MSC have been successfully isolated from bone marrow, and from these isolated cells, EV have been captured and characterised. The isolated EV have been shown to be readily internalised by chondrocytes and, in order to determine the method of EV internalisation by chondrocytes, in vitro drug inhibition studies were performed on labelled EV. Via inhibition of the caveolin dependent endocytosis pathway, EV uptake was prevented, thus indicating that this method of endocytosis is the method of EV internalisation. In regenerative medicine for knee OA, it is likely that MSC and EV would be injected into the knee. In order to determine if the MSC and EV would reside in the joint, both were labelled with gold nanostars and Supra Magnetic Iron Oxide Nanoparticles (SPION). These labelled cells and EV were then injected into a sheep stifle 1 week post creation of an OA model (meniscal transection model). These labelled cells and EV could then be seen within the knee for up to 4 weeks post injection, as ascertained via Magnetic Resonance Imaging (MRI) and MultiSpectral Optoacoustic Tomography (MSOT). Upon evaluating the regenerative effects of the MSC and EV, no difference in cartilage damage could be seen. During bone fracture, MSC and osteoblasts are recruited to the site of injury. Bioglasses have been used previously as a material to improve bone repair through the release of ions and conditioning the local environment. Our work has shown that conditioned media from bioglasses can influence both MSC and osteoblasts to augment the bone repair process. Through screening bioglasses on MSC and osteoblasts, the potential for bioglasses to alter MSC derived EV to promote osteogenesis has been shown. As a conclusion, this study has shown that the BM-MSC are a source of EV, and that both the MSC and EV can potentially be used in a musculoskeletal scenario of regenerative medicine.





McDonnell, Stephen
Henson, Frances
McCaskie, Andrew




Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Starstem Horizon 2020