Particle deposition patterns formed in the lung upon inhalation are of interest to a wide spectrum of biomedical sciences, particularly for their influence on non-invasive therapies which deliver drugs to the respiratory track. Before reaching the alveoli, particles, or a collection of liquid droplets called aerosols, must transverse this bifurcating network. This dissertation proposes a multi-faceted strategy for optimizing current methods of drug delivery by analyzing particle deposition in a single bifurcation and a complex 3-dimensional tree as a model of the airways. In this thesis, previous probabilistic formulations of particle deposition in a single bifurcation were first examined, combined and verified by computational fluid dynamic modeling. The traditional single bifurcation model was then extended to a multigenerational network as a Markov chain. The probabilistic approach combined with detailed fluid mechanics in bifurcating structures, permits a more realistic treatment of particle deposition. The formulation enables a rapid comparative analysis among different flow policies, i.e. how varying modes of inhalation affect local particle deposition and total particle escape rates. For example, this approach showed that body position has a minimal effect on deposition pattern, while a specific flow profile maximize deposition into the periphery of the lung. Also included are novel experimental results of particle deposition. Most experimental deposition studies are restricted to total deposition. Regional deposition can only be estimated but not directly measured without the destruction of the lung like models. As a result, the measurement requires multiple models which adds to the variance. To this end a standard physical model for investigating effects of various ventilation strategies on regional particle deposition was developed. Results suggest that a brief pause in flow can increase deposition into regions of blocked airways where drugs would not otherwise enter. Experiments were also conducted to investigate the effects of inertia dominated flow in symmetric and asymmetric structures revealing novel features in 3D compared to 2D. This dissertation combines experimental and computation results to propose a strategy to efficiently move particles through a symmetric and asymmetric bifurcating structure. It also introduces possible strategies for maximizing deposition to a desired region of a lung structure.

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A study was done at Steve Biko Academic hospital to determine the influence that respiratory gating will have on target volumes used in radiotherapy treatment planning. The primary objective was to compare target volumes of respiratory gated scans to ungated scans and to determine whether it will be meaningful to permanently implement a 4D respiratory gating system on CT scanners in the South African public health sector and to use these images for target volume delineation in radiotherapy planning. The study consisted of three sections. In the first section, 4D respiratory gated CT images were obtained and delineated with 4D software. The full-inspiration and full-expiration phases of the gated scans were then fused to obtain ungated images which were also delineated. The gross tumor volumes (GTVs) of the gated phases were compared to the ungated GTVs, and found that on average the volumes decreased by 14.63% with a standard deviation of 7.96% when gating was applied. Yet another aim was to determine the influence that 4D imaging will have on radiotherapy treatment planning. One of the 4D study sets was imported to the XIO treatment planning system where IMRT treatment plans were created on both the gated and ungated scans. The plans conformed to the treatment aims and restrictions when clinical parameters such as DVHs were used to evaluate it. The planned target volume coverage differed by less than 1% between the gated and the ungated plans, but significant dose reductions to the OARs of up to 32.65% to the contralateral lung were recorded on the gated plan. In the second section of this study, respiratory gated CT scans were simulated by applying the breath-hold technique to lung cancer patients. The technique was applied during full-inspiration which fundamentally represents the maximum peak of the sinusoidal respiratory waveform. An ungated scan was also acquired during normal respiration. The clinical target volumes (CTVs) were identified on both scans by three oncologists and the average CTVs were compared. It was found that the CTVs decreased significantly by an average of 14.33%. Palliative patients receive parallel opposing field therapy which is planned from 2D films. It is very unlikely that these opposing field sizes will differ when gating is applied. It was therefore concluded that only radical lung patients, which was estimated to be a mere 0.03% of the total radiation therapy patient population, will benefit by implementing respiratory gating or any motion-reduction technique. For the third section of the study, respiratory gated PET scans were acquired on a PET/CT scanner to evaluate external, non-technical parameters that will influence respiratory gating. The results indicated that time and patient participation were not limiting factors. The biggest concerns however were the effectiveness of the gating system, software limitations and the gated results. These problems might be minimized with thorough training on the system. All three sections as well as the financial implications were considered to conclude that it will not be meaningful to implement 4D respiratory gating techniques in the South African public health sector Copyright / Dissertation (MSc)--University of Pretoria, 2013. / Medical Oncology / unrestricted

The spleen has been shown to contract in apneic situations in humans as well as in other diving mammals, expelling its stored red blood cell content into circulation. This natural blood boosting may increase the circulating hemoglobin concentration (Hb) by up to 10%, which would enhance the oxygen carrying capacity and likely increase performance. However, the triggers of this response in humans have not been fully clarified. Study I was therefore focused on the effect of hypoxia as a trigger of spleen contraction. It was found that 20 min of normobaric hypoxic breathing evoked a substantial reduction in spleen volume showing that hypoxia is an important trigger for spleen contraction. Knowing the role of hypoxia, Study II compared two different hypoxic situations – a 2 min apnea and 20 min normobaric hypoxic breathing – which resulted in the same level of arterial hemoglobin desaturation. Apnea evoked a twice as great spleen volume reduction, implying that variables other than hypoxia were likely involved in triggering spleen contraction. This may be hypercapnia which is present during apnea but not during normobaric hypoxic breathing. Study III therefore investigated the effects of breathing gas mixtures containing different proportions of CO2 prior to maximal apneas. Pre-breathing mixtures with higher percentages of CO2 resulted in greater spleen contraction, thus demonstrating hypercapnia's likely role as a trigger in addition to hypoxia. Study IV explored whether an all-or-nothing threshold stimulus for triggering spleen contraction existed, or if contraction was graded in relation to the magnitude of triggering stimuli. Exercise was therefore performed in an already hypoxic state during normobaria. Rest in hypoxia produced a moderate spleen volume reduction, with an enhanced spleen contraction resulting after hypoxic exercise, with a concomitant increase in Hb. This implies that spleen contraction is a graded response related to the magnitude of the stimuli. This could be beneficial in environments with varying oxygen content or work loads. Study V examined the possibility that spleen contraction is part of the acclimatization to altitude, during an expedition to summit Mt Everest. The long-term high altitude exposure, combined with physical work on the mountain, had no effects on resting spleen volume but resulted in a stronger spleen contraction, when provoked by apnea or exercise. This indicates that acclimatization to altitude may enhance the contractile capacity of the spleen, which may be beneficial for the climber. From these studies I concluded that hypoxia is an important trigger for spleen contraction but that hypercapnia also contributes in apneic situations. The spleen contraction likely provides a graded expulsion of erythrocytes in response to these stimuli, causing a temporary increase in gas storage capacity that may facilitate activities such as freediving and climbing. The storage of erythrocytes during rest serves to reduce blood viscosity, which would also be beneficial for the climber or diver. The human spleen contraction appears to become stronger with acclimatization, with beneficial effects at altitude. Such an upgraded response could be beneficial both in sports and diseases involving hypoxia.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21662号 / 医博第4468号 / 新制||医||1035(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 溝脇 尚志, 教授 上本 伸二, 教授 増永 慎一郎 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第24884号 / 医博第5018号 / 新制||医||1068(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 鈴木 実, 教授 小濱 和貴, 教授 中島 貴子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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