Lee, Kuang-Sheng; (2002) Effects of chemotherapy on bone and bone regeneration using tissue engineering techniques. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Reconstructing segmental bone defects after resection of malignant bone tumours is a long-standing clinical problem. With the increased knowledge of mesenchymal stem cells (MSCs), it may now be possible to reconstruct segmental bone defects using a tissue engineering approach. Treatment of bone tumours such as osteosarcoma involves chemotherapy. These chemotherapeutic agents are potent inhibitors of cell division and these drugs may affect regeneration of bone from osteoprogenitor cells. The ultimate aim of this study was to investigate the use of mesenchymal stem cells for repairing segmental bone defects after tumour resection. The effects of chemotherapeutic drugs on (1) differentiation of mesenchymal stem cells; (2) natural repair of bone defects; (3) regeneration and remodeling of the bones were studied. The in vitro effects of fibroblast growth factor-2 on mesenchymal stem cells were investigated and it was found that there was time and dose-dependent effects of fibroblast growth factor-2 on proliferation and chondrogenic differentiation but not osteogenic differentiation of mesenchymal stem cells. Secondly, the toxicity of chemotherapy agents on mesenchymal stem cells was demonstrated. Cisplatin and doxorubicin significantly inhibited proliferation and osteogenic differentiation of mesenchymal stem cell. Methotrexate did not inhibit proliferation if the cells were pre-treated with osteogenic supplements. The systemic influences of these chemotherapy agents on the adult as well as the immature rat skeleton were also quantitatively analysed. Ultimate bending (p=0.018 in adult rats and 0.061 in immature rats) and torsional strength (p=0.026 in adult rats and p=0.056 in immature rats) of the femur as well as the ultimate shear strength of the distal femur physis (p=0.044) was significantly reduced following chemotherapy. A significant reduction of cell numbers within the growth plate (p 0.001) and a change of growth plate morphology was evident. Using dual energy X-ray absorptiometry, radiography and histology it was demonstrated that bone regeneration was delayed in chemotherapy-treated rats in a femoral bone defect model. Finally, bone regeneration in normal and chemotherapy-treated rats was enhanced with mesenchymal stem cells and injectable fibrin glue scaffolds. It was shown that MSCs with fibrin glue could remain viable for up to 96 hours in tissue culture. When MSCs were used in conjunction with fibrin glue in vivo then the effects of chemotherapy could be alleviated and bone formation significantly enhanced. These studies demonstrated that the effect of systemic administration of chemotherapeutic agents on bone strength, regeneration and repair and indicated that a tissue engineering approach in patients undergoing chemotherapy may be beneficial for treating segmental bone defects after tumour resection.

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