Measurements of Mean Nuclear and Cell Sizes Using Ultra-Short Diffusion Times

Introduction: Tumor cell nuclear size is a diagnostic indicator of tumor malignancy (1, 2). A larger cell nuclear size usually corresponds to a more aggressive (high grade) tumor (3), and so measurements of nuclear size are of interest for clinical cancer diagnosis. However, at present tumor cell nuclear size can be found only by invasive biopsy. Diffusion-weighted magnetic resonance imaging (DWI) provides a unique means to obtain quantitative micro-structural information about biological tissues non-invasively, and it may have the potential to detect tumor cell nuclear size in vivo. However, due to the limitations of gradient strength and slew rate of normal gradient systems, conventional pulsed gradient spin echo (PGSE) methods employ relatively long diffusion times and thereby are insensitive to intracellular structures, such as nuclear size (4). In the present work, an oscillating gradient spin echo (OGSE) method has been applied to probe ultra-short diffusion times as low as ~0.13ms, corresponding to characteristic diffusion lengths ~0.7μm, which is much shorter than nuclear dimensions. In this work, simulations and experiments were performed to show how this approach may be used to measure mean cell and nuclear sizes. Methods: Modeling: Tissues were modeled as highly packed spherical cells with centric spherical nuclei. There are three distinct diffusion compartments: nuclear, cytoplasmic and extracellular space. The computer simulation predicts that, when the diffusion time is ultra-short (<1ms), the influence of water exchange between different compartments on MR signals is negligible (<2%) (5). Hence, the total signals can simply be expressed as the sum of signals arising from each compartment, namely ) ) (1 )ex exp( exp( p ) ( nuc nuc cyto cy nuc cyto to ex f f bD E f f β β = − + − − + − − [1]