Grant: Discovery Grants Program - Individual

Histological images provide microscopic information but are limited to static pictures from small tissue volumes. Magnetic resonance imaging (MRI) examines living tissues with larger fields-of-view but resolution is too coarse to see individual cells. However, MRI signal intensity is sensitive to microscopic features. For example, diffusion MRI is sensitive to water motion, including its interaction with surrounding structures. Relating the signal to specific features is difficult because many factors influence signal. This work proposes two advanced diffusion MRI techniques and new analysis methods to extract parameters related to the water exchange rate, cell size distributions and fibre patterns. The first diffusion MRI method explores longer diffusion times and therefore slower processes, such as water crossing the cell membrane. Long times have lower signal in conventional diffusion due to a process known as T2 relaxation. The proposed method stores magnetization along the longitudinal axis to preserve signal. In addition, there are no simple equations for analyzing water exchange so we propose to use numerical methods. These will first be applied in acute myeloid leukemia cells where water exchange has been previously characterized using a contrast agent-based method, so this system can be used to validate the diffusion measurement. Water exchange will then be estimated in breast cells. The second diffusion method examines fibre patterns within voxels. Conventional diffusion is sensitive to differences in water motion with direction when fibrous structures are highly aligned (high anisotropy). Low anisotropy is difficult to interpret; it can result from an absence of fibres or fibres that spread out in different directions. We will use an emerging MRI sequence where the diffusion gradient varies over time in different directions to reveal new information about anisotropy at the microscopic level. This method identifies crossing fibres in the brain but a new protocol and analysis method are needed for other tissues. For example, no current methods to analyze this sequence incorporate water restriction, which limits studies to small structures and limited diffusion weightings. Our analysis method incorporates restriction and is therefore suitable for a broader range of tissues and diffusion parameters. This will be tested on breast cells grown in collagen scaffolds with different fibre densities and alignments and compared to histology. This program will provide a validated tool for non-invasive characterization of microscopic features in breast tissue, which can be replicated to examine other tissue types. It is an in vivo method that covers large fields-of-view to yield information that is not currently available from histology. It has the potential to provide new insights into apoptotic cell death, collagen fibre reorientation during wound healing and other processes with structural changes in cells and their surrounding environment.