Revealing Pulmonary Structure and Function with Hyperpolarized Magnetic Resonance Imaging

MRI Machine
MRI Machine

Magnetic resonance imaging (MRI) is a common tool used to study the structure and function of bodily tissues in health and disease. Although MRI has undergone decades of technological advances and improvements, it still is fundamentally limited by low signal sensitivity.1,2 The technique of hyperpolarization may be one important approach to overcoming this limitation by temporarily enhancing the magnetization of polarizable atomic nuclei. The enhanced hyperpolarized (HP) state improves the MRI signal sensitivity more than 10,000-fold in most chemical species.1,2 Moreover, because the improved sensitivity results from altered nuclear spin orientations rather than ionizing radioactivity, HP MRI is safe for repeated use in humans.

One HP technique is based on increasing the nuclei spin polarization of gases, such as helium-3 (3He) or xenon-129 (129Xe). The long-time agent of choice for HP gas MRI has been 3He because it is both highly polarizable and completely chemically inert. In recent years, the field of MRI has been shifting toward the use of 129Xe because of its lower cost and wider availability. An important application of HP gas MRI is to study the structure and physiology of the pulmonary system.3,4 MRI of HP-gas-inflated lungs clearly distinguishes between the low-signal lung tissue and the high-signal air sac. This differentiation elucidates lung architecture and airway gas exchange.5 With easy uptake into the bloodstream and tissue, 129Xe is also being used for monitoring blood flow and receptor-targeted imaging, facilitating brain and kidney imaging, and broadening the applications of HP MRI technology.4–6

Another, more recent, HP strategy uses injectable carbon-13 (13C)‑based biological substrates. As with HP gas, this liquid-state HP MRI allows real-time dynamic imaging of substances that, although present in the body, are usually found in concentrations too low to detect using conventional proton-based MRI. The detection of individual molecular signatures informs about the localization of molecular binding sites and biochemical transformations in cells. Insight into the physiology of tissues (e.g., lung, liver, and heart) is gained by quantifying downstream metabolic products of the 13C-containing substrate (i.e., lactate). This approach is also being used to investigate processes that underlie the pathogenesis of many diseases by probing metabolism, tissue perfusion, and pH.7–9

As medical diagnostics and treatments evolve toward personalized models, the ability to measure metabolic processes regionally and in real-time is becoming increasingly important. Localized assessment of cellular activity can highlight disease-related changes that may not yet be reflected by conventional imaging of overall tissue structure or function.10–12 Follow-up HP MRI sessions may also assist in assessing treatment effectiveness.

The unique combination of safety and sensitivity makes HP MRI a powerful tool. The principal shortcoming of HP MRI is that the enhanced signal lasts from only a few seconds to a few minutes at most. This short half-life of nuclear magnetic polarization necessitates the creation of polarized agents that must take place on the premises. Also necessary is the development of special imaging techniques to enhance signal detectability.

The HyperSense MRI device used for small animal imaging. Photo courtesy of Dr. Rahim Rivi, University of Pennsylvania.
The HyperSense MRI device used for small animal imaging. Photo courtesy of Dr. Rahim Rivi, University of Pennsylvania.

The National Institutes of Health’s (NIH’s) Office of Research Infrastructure Programs (ORIP) Shared Instrumentation Program (S10) contributes to the advancement of biomedical research by providing access to state-of-the-art instrumentation that otherwise would not be available to many scientists. In the last 5 years (Fiscal Years [FY] 2013–2017), the S10 program awarded more than 500 instruments in a broad range of technologies, including nine hyperpolarizers. The Functional and Metabolic Imaging Group (FMIG) in the University of Pennsylvania, led by Dr. Rahim Rizi, Professor of Radiology, has conducted research on the non-invasive assessment of lung structure, function, and metabolism for the last 22 years. During FY 2009–2014 with S10 funding, Dr. Rizi acquired five instruments to support FMIG’s research; these instruments include polarizers for gas and 13C MRI for functional and metabolomic studies.

The Hypersense™ instrument uses the Dynamic Nuclear Polarization (DNP) technique to hyperpolarize 13C and produce imaging tracers. These tracers are used in small animal-based experiments to study pulmonary perfusion and inflammation, and metabolism of various cancers. A newer instrument, SPINlab™, produces sterile hyperpolarized 13C samples at volumes five times larger and at a 20-fold throughput increase compared to Hypersense™. Tracers synthesized with SPINlab™ support large animal- and human-based studies, including implementation of diagnostic protocols for different types of cancer and for the evaluation of cancer treatments. HP gas MRI at the FMIG is supported by the Xemed™ XeBox-E10 instrument. XeBox produces HP 129Xe at a rate of about 6 liters per hour, enabling the quantitative assessment of human lung function and structure. The ability to measure regional lung ventilation opens possibilities for early detection of pathological conditions and their diagnoses. Small animal experiments are supported by a 9.4T MRI scanner and a microCT imager.

Intravenous administration of hyperpolarized 13C pyruvate.
Intravenous administration of hyperpolarized 13C pyruvate. (Top) High resolution of rat lungs overlaid on a corresponding anatomical reference scan. (Bottom) Dynamic high-resolution HP 13C of the lungs. t = 0 s is the moment from the first image acquisition. Photo courtesy of Dr. Rahim Rizi, University of Pennsylvania.

According to Dr. Rizi, “With its dramatically improved temporal resolution, HP MRI enables the direct in vivo observation of dynamic biological processes, including the changes in cellular metabolism characteristic of essentially all disease processes.” Recent work by the FMIG has demonstrated that HP gas can detect smoking-related lung injuries more accurately than conventional diagnostic methods, such as pulmonary function tests.11 In another NIH-funded preclinical study, the FMIG is using gas-based HP MRI to quantify lung function and predict the side effects of radiation therapy in lung cancer.

The FMIG uses HP 13C MRI to investigate the physiology of ventilator-induced lung injury, with the goal of developing improved ventilator protocols to reduce the widespread inflammation that often precedes injury progression. The laboratory also aims to improve the assessment of lungs viable for transplantation and to better predict transplant rejection. To quantify the rejection process and to potentially identify factors that can slow it, the FMIG studies the changes in the lactate-to-pyruvate ratio, a marker of lung injury and disease. The FMIG also employs HP 13C MRI in animal models to examine a wide range of disorders, including prostate and lung cancers, cardiac disease and heart failure, renal failure, liver conditions, and several neural pathologies, aiming to translate the imaging protocols to human applications.13–19

In summary, the FMIG with its unique collection of instruments and special scientific expertise serves as a local and regional shared resource, supporting the development and uses of HP MRI techniques. Instruments described here also have been successfully used in studies of cardiac metabolism, kidney recovery after ischemia, heart and liver and lung redox state, animal models of liver cancer, and altered energy metabolism in diabetes.

For more information on ORIP’s S10 program, please visit the Office’s website.



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