Loss of large segments of bone creates critical size defects (CSDs). These fail to heal\ud spontaneously and present major clinical challenges to orthopaedic surgeons. The\ud research described in this thesis is based upon the hypothesis that the healing of\ud CSDs is responsive to the ambient mechanical environment, and can be accelerated\ud by mechanical modulation. This hypothesis was tested in rat, femoral CSDs treated\ud with recombinant, human, bone morphogenetic protein-2.\ud For this study I designed novel external fixators allowing experimental control over\ud the local mechanical environment. These were characterised by extensive\ud mechanical testing prior to evaluation in the rat model.\ud Low stiffness fixators induced callus formation 9 days after surgery, whereas rigid\ud fixation delayed it until 2 weeks. All defects were radiologically bridged after 3\ud weeks. Rats were euthanised after 8 weeks and the defects evaluated by a battery of\ud imaging, mechanical and histological tests. All confirmed the superiority of the\ud lowest stiffness fixators.\ud Based upon these data, I hypothesised that healing would be improved by imposing\ud low stiffness for the first two weeks of healing, followed by high stiffness for the\ud remaining six weeks. The experimental data confirm that this regimen dramatically\ud accelerated callus formation and maturation, and induced faster remodelling of\ud endosteal and periosteal callus. This was associated with higher failure strength,\ud fewer trabeculae, decreased callus size and thicker and more uniform distribution of\ud new cortical bone. Histologically it was not possible to detect cartilage within the\ud defects prior to the appearance of bone, suggesting that healing either does not occur\ud through endochondral ossification, or that this process is very rapid.\ud These data confirm that the healing of CSDs is highly responsive to the ambient\ud mechanical environment, allowing the rate and quality of healing to be manipulated.\ud This information will help develop more efficient ways to heal CSD clinically
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