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Supporting videos attached / The nanoscale structure of fully dense human cortical bone is explored using advanced transmission electron microscopy (TEM) techniques. Studies of fully dense cortical bone are rare because of the sample preparation challenges. In this work, cryogenic ion milling is compared favourably with traditional ultramicrotoming methods because of the clearer imaging results and better preservation of biological structures in the ion milled samples. Ion milled samples were prepared parallel, perpendicular and at a 45 degree angle to the long axis of a human femur. The samples are cooled with liquid nitrogen while being milled to prevent heating damage to the bone structure. Bright-field and dark-field imaging show that mineral mainly occurs as 65 nm wide, 5 nm thick mineral structures, external to the collagen fibrils, and with the long axis of the mineral running parallel to the fibrils. In samples cut parallel to the long axis of the bone, the mineral structures have their c-axes aligned with the collagen fibril long axis. In these sections the mineral structures extend up to 200 nm and are grouped into stripe-like bunches, 53 nm apart. Samples cut perpendicular to the long axis of the bone show open areas roughly 45 nm in diameter. These open areas are assumed to be the location of collagen fibrils within the structure and are tangentially surrounded by 65 nm wide, 5 nm thick mineral structures. On average, there are 22 nm of mineral structures between adjoining collagen fibrils. Samples cut at 45 degrees to the long axis of the bone confirm that the open structure seen in the perpendicular section is not an artefact of sample preparation. By tilting the sample, the 45 degree sample shows the structure of both the parallel and perpendicular sections. The parallel structure strongly resembles images of embryonic bone and other mineralized tissues seen in the literature, so the perpendicular open structure is not caused by sample preparation. An examination of ultramicrotoming’s effect on mineral structure size compared with that of ion milling shows that the mineral structures in ion milled samples are twice as long as in ultramicrotomed samples, indicating that bone mineral may be damaged by the forces applied to the complex composite structure existing in fully dense cortical bone. Using energy dispersive X-ray spectroscopy (EDXS) results and a simplified model of the locations of mineral within the collagen/mineral framework, a calculation of the percentage of external mineral was performed. The result showed that 80+_ 6 % of the mineral in fully dense cortical bone must be external to the collagen fibrils to obtain the EDXS results. Finally, Z-contrast tomography, based on the use of high angle annular darkfield (HAADF) imaging, was used to prepared tomographic reconstructions of the external mineral in fully dense cortical bone. Unlike bright-field tomography, the Z-contrast technique allows examination of crystalline materials as the contrast in HAADF images is mass-thickness dependent instead of diffraction based. These reconstructions again showed the mineral tangentially surrounding 50 nm diameter cylindrical holes, assumed to be the location of collagen fibrils in all directions. This work shows the importance of mineral that is external to the collagen fibrils to the nanoscale structure of fully dense cortical bone. / Thesis / Doctor of Philosophy (PhD)

The analgesic effect of 600 mg and 1500 mg of a pain killing drug to metastatic bone pain, and associated side effects, were assessed. The experimental design was a double-blind cross over clinical trial involving 44 patients known to suffer from metastatic bone pain. Each patient received the active drug in one of two dosages and the placebo in a random order, each lasting about 14 consecutive days. The data consisted of daily measurements of several pain and side effect variables. A few covariates were available. It was found that the patient and the investigator achieved a high degree of agreement on the blinded preference of the active drug to the placebo. A multivariate analysis of variance (MANOVA) on three different summary scores (mean, median, trmean) calculated on the daily measurements for which the patient received the active drug and on those for which the patient received the placebo was conducted. It was found that for the group of pain variables the order of application and the treatment do not have a significant effect marginally, but that they interact significantly. Variation between subjects was also significant. For the group of side effect variables, however, only significant variation between subjects was found. This suggests that the drug does not have noticeable overall side effects. To account for correlations among the response measurements within each patient, the methodology of generalized estimating equations was used to assess the significance of the effects of the predictors. Although the results are less reliable as they depend on the asymptotic behaviour of statistics, it was found that regardless of the level of correlation within patient response measurements, only the interaction of order of application with treatment has a significant effect on each of the pain variables. All the statistical analyses were carried out using Minitab, SAS, Matlab and Splus. / Thesis / Master of Science (MS)

The objectives of this research were to evaluate non-invasive measures of bone mineral content (BMC) and bone mineral density (BMD) as rapid, on-farm tools to assess phosphorus (P) status in dairy cows. In addition, the effects of parity and stage of lactation on measures of BMC of the fused 3rd and 4th metacarpal bone and of caudal vertebrae 14 and 15 were assessed. The caudal vertebrae and right front metacarpal (sample pairs) were excised from 107 Holstein cull cows following slaughter. Parity, age, and days in milk (DIM) of the donor animal were obtained for 43 pairs of samples. Samples were grouped by parity (1, 2, 3, and >4) and stage of lactation (Stage 1 = < 90 DIM, Stage 2 = > 90 and < 150 DIM, Stage 3 = >150 and < 250 DIM and Stage 4 = > 250 DIM). Samples were analyzed for BMC and BMD with dual energy X-ray absorptiometry (DXA), BMC with radiographic photometry (RP), breaking strength with mechanical methods, and mineral content with chemical procedures. Estimates of BMC obtained with RP and DXA were poorly related to chemical measures of actual BMC and to measures of breaking strength. In caudal vertebrae 14 and 15, increasing stage of lactation decreased energy to peak load with the lowest values observed in late lactation. Stage of lactation had no effect on BMC measured chemically in the caudal vertebrae or metacarpal. Parity did not affect breaking strength of the metacarpal or caudal vertebrae or total ash or P content of any bone. Results indicated that imaging techniques are not useful measures of BMC in mature dairy cattle. / Master of Science

published_or_final_version / Orthopaedic Surgery / Doctoral / Doctor of Philosophy

published_or_final_version / Dentistry / Master / Master of Dental Surgery

published_or_final_version / Medicine / Master / Master of Philosophy

No description available.

No description available.