Niemann Pick Type C (NPC) disease is a rare genetic disease which is most often diagnosed in children, causes tragic irreversible neurologic deterioration, and is universally fatal. Many therapies and treatments are in development and would benefit from improved methods of assessing disease progression and treatment response. A large amount of NPC research is carried out in animal models such as the Npc1^(-/-) mouse model of the most common type of NPC disease, NPC1. This dissertation investigates three methods of noninvasive assessments of disease state in the Npc1^(-/-) mouse model with the use of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS).MRI and MRS provide safe and widely available methods of measuring and visualizing internal tissue characteristics, suitable for longitudinal studies of disease progression and response to therapy. In this work, disease-associated dysmyelination of white matter tracts in the brain of Npc1^(-/-) mice was quantitatively measured at multiple time points with MRI methods of diffusion tensor imaging (DTI) and T2-mapping. These quantitative in vivo measures of disease status show promise as biomarkers for use in future studies of disease progression and treatment response in NPC disease models. High resolution MRI data was also collected and analyzed at multiple time points to quantify differences in both global and regional brain volumes in the Npc1^(-/-) mice as brain atrophy develops with disease progression. MRS was utilized to quantitatively examine changes in brain metabolite levels previously reported in clinical NPC disease studies. The results of the MRI and MRS studies in the Npc1^(-/-) mouse model demonstrate the ability to quantify changes in the brain due to neurodegeneration at multiple time points along the progression of neurological Npc1^(-/-) disease. MRI methods of quantifying white matter pathology with currently available DTI and T2-mapping techniques appear to be promising in vivo biomarkers of disease in the brain for future studies, while quantification of volumetric changes due to brain atrophy currently shows changes only at later disease stages. In vivo MRS with currently available methodology provides insight into the neurodegenerative disease pathology in the Npc1^(-/-) mouse but appears to lack sensitivity as a biomarker.

The development and verification of thermal models for use in hyperthermia treatment planning is essential for obtaining accurate predictions of temperature fields. This thesis presents a three-dimensional blood vessel network constructed from connected straightline segments. The geometry of this convective thermal model is an (approximate) cube. The model contains seven levels of different size arterial vessels. The calculations of the mean blood temperature inside the vessels are based on the convective energy balance equation for the bulk fluid temperature. The adjacent tissue temperature calculations are based on either pure conduction heat transfer or the bioheat transfer equation of Pennes (22). The validity of the convective thermal model is checked by comparing it's predictions to those of an analytical solution for a single vessel, and by checking the energy balance calculations of the whole control volume. The results show that the level-7 arteries still contribute a large percentage of the total heat transfer rate between the blood vessels and the surrounding tissues; and values of the Nusselt number being either 10% higher or 10% lower than 4 do not strongly affect the temperature field.

The objective of this thesis is to investigate how the human Electroencephalogram(EEG) is affected by anesthetic agents. The ultimate goal of the research is to improve clinical understanding of the EEG in anesthesia, and to determine the value of quantitative analytical techniques for generalizing or differentiating among anesthetic agents. Power spectrum and time domain analysis were conducted on EEG waveforms from 30 human, male volunteer subjects during sevoflurane and enflurane general anesthesia. Univariate parametric statistics and Discriminant Function Analysis (DFA) were performed to analyze and classify EEG spectral content. Statistically significant differences were found between the two anesthetics, duration of anesthetic period, and anesthetic depth levels. DFA classification of EEG epochs by anesthetic condition group was performed with a high degree of accuracy, especially when the stepwise analysis method was used.

The anatomy and physiology of the human heart, the historical development of heart transplantation and mechanical assistance, and total artificial heart and ventricular assist device systems are discussed. The focus of the investigation is on the detection of waveform indicators corresponding to full-filling of the artificial heart and ventricular assist device chambers. The developed software monitors the drive pressure waveform produced by the circulatory assist system until a full-fill indicator is detected. The event is verified by the detection of a corresponding indication during the same period within the flow waveform of the circulatory assist system. The appropriate alarm (for the right or left chamber) is updated each time a full-fill event is verified. When the user specified alarm limit is reached, an entry describing the alarm event is entered into the patient data file and a +5 volt analog signal is made available for external alarm activation.

Nuclear spin polarization <em>P</em> is a key factor in overall Magnetic Resonance (MR) sensitivity, and conventionally is of order 10^-6 owing to the tyranny of its induction by the strength of the detection magnetic field. But various hyperpolarization mechanisms applied externally to the detection field can temporarily increase nuclear spin polarization to near unity (<em>P</em> = 1). The resulting increased MR signal enables a variety of applications, including biomedical use of hyperpolarized (HP) contrast agents to assay cellular metabolism via Magnetic Resonance Imaging (MRI), typically ¹³C-labeled metabolites reporting on abnormal metabolism. In this work optimization of radiofrequency (RF) coils and hyperpolarizer automation are used to increase the detection sensitivity of hyperpolarized contrast agents (HCA) and improve their production. It is shown that low-field imaging can be more sensitive than corresponding high-field detection when using RF coils optimized to the resonant frequency. The feasibility of low-field molecular imaging of ¹H and ¹³C HCA with high spatial resolution (as fine as 94&#x00D7;94 &mu;m²) is demonstrated with low-field 38 mm inner diameter RF coils at a static magnetic field strength <em>B</em>₀ = 0.0475 T, achieving signal-to-noise ratios suitable for <em>in vivo</em> imaging studies.

Ultrasound is an imaging modality which provides spatial measurements of subsurface targets during surgical interventions without the radiation or logistical concerns of CT or MR imaging, respectively. However, image interpretation is known to be a challenging task without other sources of information. This is not only because of the noise characteristics of ultrasound, but also because manipulation and compression of soft tissue during imaging with an ultrasound probe can distort the size and position of targets. A system for tracking ultrasound images in 3D space was implemented with a novel framework for addressing these issues. A novel laser range scanner was first characterized with respect to its ability to create textured point clouds tracked in physical space. The geometric point cloud accuracy was determined using phantoms to be submillimetric, and the tracking accuracy of the system was found to be similar to other passive optical tracking tools. This study established a gold standard registration and surface measurement tool to be used in the tracked ultrasound framework. A strategy was developed for correcting tissue compression by using the pose of the ultrasound probe within the tissue. An initial image-to-physical registration of the tracked ultrasound to a patient-specific model was done to calculate this pose. After registration, the pose of the probe was used to assign boundary conditions to the tissue model. The solution of the model was then reversed to estimate the tissue in the uncompressed state. This strategy was found to be capable of reducing errors of approximately 1 cm to 2-3 mm. The correction strategy was then generalized to use a block mesh calibrated to the tip of the ultrasound probe. This strategy did not require a patient-specific mesh, and only required an intraoperative measurement of compression depth. The formulation of the generic model was also significantly faster than the patient-specific method and gave nearly the same correction accuracy. Future work will involve incorporation of accurate material properties into the model correction, as well as real-time surface point cloud information from stereovision cameras.

Novel dosimetric materials to ensure properly calibrated x-ray beam profiles are required to facilitate the implementation of Microbeam Radiation Therapy in cancer treatment. Indirect conversion dosimetric materials are explored for possible future applications in Microbeam Radiation Therapy devices. The indirect conversion materials barium borophosphates, barium fluorophosphates with sodium ion modifier, and barium aluminosilicates were synthesized and studied. Each synthesized compound was also doped (or additionally co-doped) with a rare-earth compound. The rare-earth compounds used for doping included samarium (III) oxide, and samarium (III) fluoride. Codoping was explored with the compound erbium (III) chloride. Synthesized samples were x-ray irradiated at the Biomedical Imaging and Therapy beamline of the Canadian Light Source and also at the University of Saskatchewan. Experimental characterization methods of dosimetric material samples included x-ray luminescence, photoluminescence, electron spin resonance, Raman spectroscopy, absorbance spectroscopy, x-ray diffraction, differential scanning calorimetry, and modulated differential scanning calorimetry. The materials are experimentally characterized and determined for their merit in further research and development. All materials were found to scintillate, and some were found to function as x-ray storage phosphors as well. The barium borophosphates and also the barium fluorophosphates with sodium ion modifier possessed x-ray storage functionality according to photoluminescence spectra. An absorbance peak was observed after x-ray irradiation for barium fluorophosphates. Electron spin resonance data suggest that x-ray irradiation forms two similar types of paramagnetic defects for barium borophosphates. It appears that these defects are oxygen hole centres, which form during the indirect conversion process of samarium dopant cations. Indirect conversion involves samarium cation valency change from the 3+ to 2+ oxidation state, occurring when an electron is captured by the cation. Thermal analysis of the barium fluorophosphates by differential scanning calorimetry and modulated scanning calorimetry indicate preferential properties and moderate glass forming ability for manufacturing processes. It is concluded that barium fluorophosphates are best suited for dosimetric detectors, and secondly, barium borophosphates. Finally, future studies on materials for dosimetry in Microbeam Radiation Therapy are recommended.

<p>We have yet to establish the optimum combination of hyperthermia with radiation and/or chemotherapy for effective treatment of bladder cancer. Convenient and affordable microwave applicators capable of well-localized non-invasive heating of murine, canine and human bladder cancers is essential for logical progression of studies from pre-clinical to multi-institution clinical trials, as needed to investigate the effects of hyperthermia as an adjuvant treatment for bladder cancer. </p><p>The primary objective of this research was to utilize state-of-the art segmentation and simulation software to optimize target-specific microwave antennas for more uniform heating in pre-clinical and clinical investigations of bladder hyperthermia.</p><p>The results of this research are:</p><p>1. The development of a reliable simulation-based approach for optimizing microwave applicators;</p><p>2. The design, construction and testing of an applicator for heating murine bladder to 40-43°C while maintaining surface and core temperatures normothermic;</p><p>3. The optimization, construction and testing of a fundamentally different type of antenna (metamaterial) for heating pediatric and/or canine bladder;</p><p>4. A preliminary effort towards the optimization, construction and testing of a metamaterial antennas for heating adult bladder.</p><p>One significant implication of this work is to enable essential pre-clinical bladder hyperthermia studies with the development of a reliable microwave applicator for heating murine bladder to 40-43°C while maintaining surface and core temperatures normothermic. It is clear that hyperthermia enhances the effects of chemo- and radio- therapies, and this device will allow scientists to investigate the basic principles underlying this phenomenon more systematically.</p><p>Another significant contribution of this work is the development of metamaterial antennas for deep tissue hyperthermia. These antennas decrease the cost and increase the comfort and portability of bladder hyperthermia devices. These improvements will enable the multi-institutional clinical trials required to apply for insurance reimbursement of deep-tissue thermal therapy and the subsequent widespread use of hyperthermia as an adjuvant to current cancer therapies.</p> / Dissertation

Regenerative medicine has the potential to revolutionize how medical professionals approach combating and treating disease. Over the past several decades, human mesenchymal stem cells (hMSCs) have become one of the most promising cell sources for regenerative medicine due to their autologous availability, self-renewal capacity, angiogenic effect, immunomodulatory effects, and multi-lineage differentiation potential. However, the individuals who would gain the most from stem cell-based therapies are typically those of advanced age, and the hMSCs they would otherwise provide are accompanied by detrimental abnormalities such as reduced self-renewal and differentiation potentials, thereby limiting their therapeutic efficacy. Furthermore, hMSC-mediated tissue regeneration would require exhaustive in vitro expansion to achieve sufficient numbers, and serially-expanded hMSCs demonstrate passage-associated abnormalities. This dissertation project aimed at tackling a significant issue in clinical translation of hMSCs, namely looking for material compositions that promote hMSC stem cell health for ex vivo expansion. A library of combinatorial copolymers utilizing FDA-approved synthetic polymers poly(ε-caprolactone) (PCL) and poly(ethylene glycol) (PEG) was synthesized and then fabricated into thin spin-coated films for cell culture. hMSC phenotype was characterized across the copolymer library and the copolymer surface features were interrogated by x-ray scattering and super resolution imaging methods. An ideal candidate copolymer was identified followed by verifying a molecular mechanism for the pro-therapeutic hMSC phenotype and demonstrating the universal effect of the copolymer by culturing patient-derived hMSC instead of commercial hMSCs. These findings will contribute to future biomaterial design to enable effective translation and scalability of regenerative medicine strategies using autologous hMSCs.

Increasing health information technology (HIT) adoption has led to growth in research on its implementation and use, the majority of which has been conducted in primary care and medical specialty settings. This thesis comprises three research projects that expand the knowledge base about HIT in surgery. A systematic review summarized the evidence about the effects of major categories of HIT (e.g., electronic health records, computerized order entry) on surgical outcomes and demonstrated improvement in the quality of surgical documentation, increased adherence to guidelines for perioperative prophylactic medication administration, and improvements in patient care with provider alerts. The review identified gaps in the literature about consumer HIT use by surgical patients and providers. A second study demonstrated modest use of a patient portal by surgical patients during hospitalizations and found increased inpatient use for patients who were white, male, and had longer lengths of stay. This study showed that a patient portal designed for the outpatient setting could be employed by surgical patients during hospitalizations. A third study analyzed the nature of the communications in patient portal messages threads between surgeons and their patients. Two-thirds of message threads involved medical care with predominantly straightforward and low complexity decision-making. This study highlighted the need for expanded models for compensation of online care. This thesis provides insights into the use and effects of HIT in surgical practice. As HIT continues to evolve, the unique perspectives of surgical providers and patients should be represented in the design, implementation, evaluation, and regulation of its use.