This proposal targets Respiratory Health (excludes lung cancer and mesothelioma).

There is currently no widespread clinical imaging modality to perform high-resolution functional lung imaging. Computed tomography (CT), conventional MRI (magnetic resonance imaging), and X-ray can only provide structural images of dense tissues, informing about pathologies like tumors and pneumonia but yielding little or no information about lung ventilation, perfusion, alveoli size, gas-exchange efficiency, etc. Deadly diseases such as chronic obstructive pulmonary disease (COPD), with >300 million affected people worldwide and ~3 million annual deaths, do not have any clinical imaging marker as of today. This state of affairs contrasts with cancer imaging, which includes MRI, CT, ultrasound, mammography, positron emission tomography (PET), and others, which collectively enable early detection via population screening, diagnoses, and monitoring response to treatment. Furthermore, CT scans (2D and 3D X-ray) expose the body to ionizing radiation and thus cannot be performed frequently due to increased risk associated with cancer-inducing radiation. On the other hand, MRI, particularly low-field MRI, involves no ionizing radiation and is effectively non-invasive.

The focus of this proposed work will be on developing a suite of inexpensive technologies to enable high-throughput and low-cost functional 3D MRI of lungs, providing three imaging biomarkers of lung diseases (asthma, COPD, Gulf War Illness [GWI], and others): ventilation (reporting on how well air is reaching different parts of the lungs during respiration), gas diffusion (reporting on lung alveoli size, i.e., clusters of air sacks in the lungs responsible for transferring oxygen to the blood), and the gas-exchange efficiency.

Therefore, it is the goal of this proposed work to enable imaging technologies by developing two gas contrast agents (and corresponding clinical-scale hyperpolarization equipment): (i) "hyperpolarized" xenon gas, (ii) "hyperpolarized" propane gas within (iii) a "low-field" (LF) MRI (1/60th the magnetic field strength of a conventional 3T MRI) by developing/engineering high-throughput clinical-scale fully-automated biomedical devices that can be mass-produced. This will involve the integration of a fully automated propane hyperpolarizer, fully automated 129Xe hyperpolarizer, and low-field MRI scanner into a single imaging solution.

The hyperpolarized 129Xe state (enhancing MRI sensitivity by orders of magnitude) is generated through the process of spin-exchange optical pumping, which utilizes infrared laser light to dramatically increase the magnetization of 129Xe, a non-radioactive, naturally occurring, and naturally abundant isotope. Once 129Xe is hyperpolarized, it can be used in MRI to provide 4-8 orders-of-magnitude signal enhancement, yielding images with high spatial and temporal resolution and high contrast. Xenon has other advantages: it is inert, a naturally abundant gas that is renewable, and it dissolves in tissues providing different MRI signatures that are distinguishable from xenon in the gas phase (therefore useful for studying gas exchange), and it is already approved by the Food and Drug Administration for patient administration. Therefore, 129Xe gas is a great candidate for providing imaging biomarkers of lung diseases. Hyperpolarized propane is generated through the process of parahydrogen-induced polarization (PHIP), and it was already shown to be useful for high-resolution MRI. Moreover, our recent pioneering work demonstrated a suitably long lifetime of hyperpolarized propane. While hyperpolarized propane is currently less studied than hyperpolarized 129Xe, it offers significant advantages: significantly lower production costs, faster production speed, and it can be imaged on any conventional MRI scanner. It also has characteristics that are complementary to 129Xe; it is a lighter gas and does not dissolve as much into tissues.

Recently, with advances in MRI detection coil technology, LF-MRI in combination with hyperpolarized contrast agents provides distinct advantages over conventional high-field MRI in that it can achieve and sometimes even exceed the detection sensitivity of conventional MRI scanners. LF-MRI is significantly cheaper to build, house, and operate, and patients can be scanned standing in the physiological upright position, enabling "true" lung functionality studies due to gravitational effects that cannot be observed in supine position. Furthermore, LF-MRI offers safer scans than conventional MRIs due to reduced heat deposition (in addition to the lower field), has virtually no exam hardware preparations (no magnet shimming), and has virtually no maintenance costs (e.g., expensive cryogens), unlike conventional high-field MRIs. Moreover, LF-MRI enables longer lifetime of hyperpolarized propane gas contrast agents, which makes it a potentially useful contrast agent. If successful, this suite of technologies has great potential to revolutionize lung healthcare with cheap and fast imaging exams similar to X-ray, but instead provide functional 3D information.

Military Service members and their families suffering from GWI and other obstructive pulmonary diseases will disproportionately benefit from this low-cost, high-throughput screening technology. Furthermore, this imaging suite of technologies can be deployed to remote locations to be used for imaging diagnostics for military personnel, including those on active duty.