Synchrotron based functional lung imaging of complex respiratory events

The current state of the art lung imaging tools are incapable of assessing lung function and respiratory airflows during highly complex and dynamic biological events. To better understand the mechanics of lung function, we must first possess the appropriate tools for measuring lung function. The literature review conducted within this thesis highlighted a lack of imaging tools that can simultaneously provide excellent temporal and spatial resolution in relation to measurements of lung function. This lack of combined temporal and spatial resolutions limits the use of imaging for assessments of complex biological events. The aim of this research was to develop imaging tools that are able to assess lung tissue motion and respiratory mechanics during respiratory events that involve high frequencies or complex out of phase motions. Of particular interest were respiratory events that involved internal airflow oscillations. Traditionally these respiratory events have been notoriously difficult to obtain regional data at appropriate sampling rates. To achieve simultaneous high temporal and high spatial resolutions of measurements, a synchrotron based imaging set-up was developed that was optimism for respiratory imaging. The set-up involved the use of high-sensitivity detectors and propagation based phase contrast imaging. To extract appropriate and valuable data from the images a modified particle image velocimetry analysis method was developed. As the lung is a dynamic organ that functions through motion, imaging of the lung is difficult especially when small amplitude and high frequency oscillations are occurring, such as during high frequency ventilation. The first application for this novel imaging and analysis method was to assess lung volume distributions in rabbit pups during high-frequency ventilation. It was found that decreasing tidal volume and increasing frequency of ventilation could maintain minute volume whilst simultaneously minimising lung tissue excursion. This shows that HFV is able to provide sufficient gas flow throughout the lungs without causing overdistention to the lung tissue. Pressure oscillations imparted at the airway opening can be used for assessing lung mechanics as well as for ventilation, yet the penetrance of these input signals is not well understood. Using a modified version of the synchrotron-based small animal imaging and analysis method, regional measurements of lung tissue oscillations were captured whilst murine subjects underwent forced oscillation tests. The spatial distribution of lung tissue oscillations identified that there is an uneven signal penetration into the lungs and as a result the measurements may be biased towards particular regions of the lung. In humans and mice, the heart is almost entirely encased by the lungs. As the heartbeats it imparts oscillations onto the surrounding lung tissue. By using a modified imaging and analysis method reconstructions of the airflow generated within the lungs due to the beating heart were generated. This was the first time cardiogenic oscillations have been mapped throughout the airway tree. In mice, the majority of gas mixing that occurs over a single breath is as a result of the physical action of the heart rather than from ventilation. This research into cardiogenic gas mixing has built knowledge in what was previously a poorly understood phenomenon. The techniques developed throughout this thesis represent critical advances in the field of lung function imaging. The techniques describe in this thesis were able to quantify the distribution of ventilation during high-frequency ventilation strategies, measure the airflow that results from the action of the heart compressing the neighbouring lung tissue, and assess the effectiveness of current forced oscillation testing techniques. This thesis comprises three peer-review publications in combination with a significant literature review. The research conducted throughout this thesis not only resulted in peer-reviewed publications, but also resulted in the invention of two new lung function imaging techniques, numerous patent applications and the formation of a startup company for the commercialisation of the imaging inventions.