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Silverthorne, Kate Elizabeth
Languages: English
Types: Doctoral thesis
Subjects: QR, RK
Cartilage has only a limited capacity for self-regeneration following injury, leading to experimental and clinical attempts to induce healing of lesions. The use of biodegradable biomaterials for the delivery of bioactive agents or cells is key to facilitating tissue repair. This study focused on the regeneration of cartilage, with the hypothesis that a matrix that supports angiogenesis will, in the presence of, for example, bone morphogenetic protein-2 (BMP-2), stimulate rapid bone formation, while a matrix that inhibits angiogenesis will only undergo chondrogenesis. To provide a suitable matrix, this project characterised a hydrogel previously developed in this laboratory, formed by chemical crosslinking of an ethylenediamine derivative of hyaluronan. The crosslinking reaction could be carried out under physiological conditions, indicating that the hydrogel could be injected and crosslinked in situ. However, potentially toxic effects require further investigation. The hydrogel successfully delivered active BMP-2, to induce ectopic bone formation in a rat model. To inhibit angiogenesis, this project described the production of a truncated form of the vascular endothelial growth factor (VEGF) receptor, fins-like tyrosine kinase-1 (flt-1), consisting of the 3 N-terminal extracellular domains responsible for binding VEGF. This decoy receptor was demonstrated to bind VEGF. Preliminary angiogenesis and ossification assays revealed that higher levels of purity of the decoy receptor are required than achieved in this work, to determine if it can block VEGF- mediated angiogenesis and prevent progression of cartilage to bone. Nonetheless, this project demonstrated the suitability of the hyaluronan-based hydrogel, for the delivery of growth factors in regards to cartilage repair.
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