Advances in sophisticated imaging methods have enabled new approaches for structural and functional characterization of pulmonary disorders. High Resolution Computed Tomography (HRCT) is clearly the current leader, by providing high spatial resolution, speed, and allowing the best distinction of tissue density However, HRCT has the fundamental drawback of exposing the subject to ionizing radiation and only providing information about lung structure. Conventional MRI provides a safer platform but also suffers from the low signal-to-noise ratio of water protons in the lung parenchyma resulting in inferior images. Recent developments in hyperpolarized gas MRI however have overcome the shortcomings of conventional MRI by directly imaging the nuclei of a gas (3He or 129Xe) in the airways. It is thus the most practical technique for moving beyond measurements based on tissue-density toward high-resolution imaging of lung function. Despite this promise, it is important to note that further progress in the field of hyperpolarizd gas MRI requires resolution of the fundamental challenges of the technology: the limited worldwide supply and significant expense of 3He gas, and the (currently) limited ability to generate sufficient quantities of highly polarized 129Xe gas without prohibitively complex and expensive devices. The main goal of this proposal is to develop a new platform for generating large quantities of highly polarized 129Xe gas. Specifically, we propose to use Dynamic Nuclear Polarization technique to make one mole of highly polarized gas in one day (~22.4 liters at >50% polarization level). Furthermore, we plan to make it practical to deliver this gas to a regional network of clinical test sites while retaining high levels of polarization n order to enable large- scale human lung studies. We plan to accomplish our objective through the following specific aims: 1) Achieve high 129Xe polarization in a large solid sample at the cryogenic temperature: Using our developed 129Xe NMR diagnostic methods that can measure in situ temperature and relaxation rates during DNP, an optimized system for increasing the surface area/volume ratio of xenon/radical/solvent mixture and the superfluid helium bath will be engineered to polarize large volumes of xenon in a few hours in the frozen state~ 2) Develop methods for polarization retention during the warm-up of frozen xenon to room temperature and phase separation from the liquid glassing agent: Using the known dependence of 129Xe relaxation rates on temperature, magnetic field, and xenon isotopic composition, a rapid and efficient thawing and phase-separation procedure in the fringe-field of the DNP magnet will be developed~ 3) Develop methods for transportation of polarized solid xenon over regional distances of several hundred miles: A cryogenic trap mounted in a permanent portable 1-T Hallbach magnet will be tested and used to sustain the low temperature of the immersed solid xenon and preserve a significant fraction of its polarization over the duration of a 4-5 hour trip~ 4) Develop new techniques for 129Xe imaging in large animals: We will show the feasibility of fractional ventilation / PAO2 imaging in normal pigs and those with perfusion defects, with a particular focus on the effect of Xe's differing physical properties on the imaging techniques.
The proposed instrument will represent significant enhancement to our current ability to generate, store and transport gas phase contrast agents for pulmonary imaging across multiple sites and dispatched from one or several centralized facilities. The ability to perform large scale studies on human subjects across multiple sites is a key missing component in objective assessments of this potentially powerful imaging modality for diagnosis and monitoring lung diseases and to help develop respiratory therapeutics faster, more effectively and at a lower cost to healthy system.