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1. Enabling Clinical Technologies for Hyperpolarized ¹²⁹ Xenon Magnetic Resonance Imaging and Spectroscopy

   https://doi.org/10.1002/anie.202015200  

   Khan, Alixander S.; Harvey, Rebecca L.; Birchall, Jonathan R.; Irwin, Robert K.; Nikolaou, Panayiotis; Schrank, Geoffry; Emami, Kiarash; Dummer, Andrew; Barlow, Michael J.; Goodson, Boyd M.; et al (June 2021, Angewandte Chemie International Edition)

   Abstract Hyperpolarization is a technique that can increase nuclear spin polarization with the corresponding gains in nuclear magnetic resonance (NMR) signals by 4–8 orders of magnitude. When this process is applied to biologically relevant samples, the hyperpolarized molecules can be used as exogenous magnetic resonance imaging (MRI) contrast agents. A technique called spin‐exchange optical pumping (SEOP) can be applied to hyperpolarize noble gases such as¹²⁹Xe. Techniques based on hyperpolarized¹²⁹Xe are poised to revolutionize clinical lung imaging, offering a non‐ionizing, high‐contrast alternative to computed tomography (CT) imaging and conventional proton MRI. Moreover, CT and conventional proton MRI report on lung tissue structure but provide little functional information. On the other hand, when a subject breathes hyperpolarized¹²⁹Xe gas, functional lung images reporting on lung ventilation, perfusion and diffusion with 3D readout can be obtained in seconds. In this Review, the physics of SEOP is discussed and the different production modalities are explained in the context of their clinical application. We also briefly compare SEOP to other hyperpolarization methods and conclude this paper with the outlook for biomedical applications of hyperpolarized¹²⁹Xe to lung imaging and beyond. 

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2. Toward Lung Ventilation Imaging Using Hyperpolarized Diethyl Ether Gas Contrast Agent

   https://doi.org/10.1002/chem.202304071  

   Ariyasingha, Nuwandi M; Chowdhury, Md_Raduanul H; Samoilenko, Anna; Salnikov, Oleg G; Chukanov, Nikita V; Kovtunova, Larisa M; Bukhtiyarov, Valerii I; Shi, Zhongjie; Luo, Kehuan; Tan, Sidhartha; et al (May 2024, Chemistry – A European Journal)

   Abstract Hyperpolarized¹²⁹Xe gas was FDA‐approved as an inhalable contrast agent for magnetic resonance imaging of a wide range of pulmonary diseases in December 2022. Despite the remarkable success in clinical research settings, the widespread clinical translation of HP¹²⁹Xe gas faces two critical challenges: the high cost of the relatively low‐throughput hyperpolarization equipment and the lack of¹²⁹Xe imaging capability on clinical MRI scanners, which have narrow‐bandwidth electronics designed only for proton (¹H) imaging. To solve this translational grand challenge of gaseous hyperpolarized MRI contrast agents, here we demonstrate the utility of batch‐mode production of proton‐hyperpolarized diethyl ether gas via heterogeneous pairwise addition of parahydrogen to ethyl vinyl ether. An approximately 0.1‐liter bolus of hyperpolarized diethyl ether gas was produced in 1 second and injected in excised rabbit lungs. Lung ventilation imaging was performed using sub‐second 2D MRI with up to 2×2 mm²in‐plane resolution using a clinical 0.35 T MRI scanner without any modifications. This feasibility demonstration paves the way for the use of inhalable diethyl ether as a gaseous contrast agent for pulmonary MRI applications using any clinical MRI scanner. 

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3. Parahydrogen‐Induced Polarization of Diethyl Ether Anesthetic

   https://doi.org/10.1002/chem.202002528  

   Ariyasingha, Nuwandi_M; Joalland, Baptiste; Younes, Hassan_R; Salnikov, Oleg_G; Chukanov, Nikita_V; Kovtunov, Kirill_V; Kovtunova, Larisa_M; Bukhtiyarov, Valerii_I; Koptyug, Igor_V; Gelovani, Juri_G; et al (September 2020, Chemistry – A European Journal)

   Abstract The growing interest in magnetic resonance imaging (MRI) for assessing regional lung function relies on the use of nuclear spin hyperpolarized gas as a contrast agent. The long gas‐phase lifetimes of hyperpolarized¹²⁹Xe make this inhalable contrast agent acceptable for clinical research today despite limitations such as high cost, low throughput of production and challenges of¹²⁹Xe imaging on clinical MRI scanners, which are normally equipped with proton detection only. We report on low‐cost and high‐throughput preparation of proton‐hyperpolarized diethyl ether, which can be potentially employed for pulmonary imaging with a nontoxic, simple, and sensitive overall strategy using proton detection commonly available on all clinical MRI scanners. Diethyl ether is hyperpolarized by pairwise parahydrogen addition to vinyl ethyl ether and characterized by¹H NMR spectroscopy. Proton polarization levels exceeding 8 % are achieved at near complete chemical conversion within seconds, causing the activation of radio amplification by stimulated emission radiation (RASER) throughout detection. Although gas‐phaseT₁relaxation of hyperpolarized diethyl ether (at partial pressure of 0.5 bar) is very efficient, withT₁of ca. 1.2 second, we demonstrate that, at low magnetic fields, the use of long‐lived singlet states created via pairwise parahydrogen addition extends the relaxation decay by approximately threefold, paving the way to bioimaging applications and beyond. 

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4. Inflammation product effects on dilatational mechanics can trigger the Laplace instability and acute respiratory distress syndrome

   https://doi.org/10.1039/d0sm00415d  

   Barman, Sourav; Davidson, Michael L.; Walker, Lynn M.; Anna, Shelly L.; Zasadzinski, Joseph A. (July 2020, Soft Matter)

   In the lungs, the Laplace pressure, Δ P = 2 γ / R , would be higher in smaller alveoli than larger alveoli unless the surface tension, γ decreases with alveolar interfacial area, A , such that 2ε > γ in which ε = A (d γ /d A ) is the dilatational modulus. In Acute Respiratory Distress Syndrome (ARDS), lipase activity due to the immune response to an underlying trauma or disease causes single chain lysolipid concentrations to increase in the alveolar fluids via hydrolysis of double-chain phospholpids in bacterial, viral, and normal cell membranes. Increasing lysolipid concentrations decrease the dilatational modulus dramatically at breathing frequencies if the soluble lysolipid has sufficient time to diffuse off the interface, causing 2 ε < γ , thereby potentially inducing the “Laplace Instability”, in which larger alveoli have a lower internal pressure than smaller alveoli. This can lead to uneven lung inflation, alveolar flooding, and poor gas exchange, typical symptoms of ARDS. While the ARDS lung contains a number of lipid and protein species in the alveolar fluid in addition to lysolipids, the surface activity and frequency dependent dilatational modulus of lysolipid suggest how inflammation may lead to the lung instabilities associated with ARDS. At high frequencies, even at high lysolipid concentrations, 2 ε − γ > 0, which may explain the benefits ARDS patients receive from high frequency oscillatory ventilation. 

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5. Ratchet recruitment in the acute respiratory distress syndrome: lessons from the newborn cry

   https://doi.org/10.3389/fphys.2023.1287416  

   Nieman, Gary F.; Herrmann, Jacob; Satalin, Joshua; Kollisch-Singule, Michaela; Andrews, Penny L.; Habashi, Nader M.; Tingay, David G.; Gaver, Donald P.; Bates, Jason H.; Kaczka, David W. (November 2023, Frontiers in Physiology)

   Alysson Roncally Silva Carvalho (Ed.)

   Patients with acute respiratory distress syndrome (ARDS) have few treatment options other than supportive mechanical ventilation. The mortality associated with ARDS remains unacceptably high, and mechanical ventilation itself has the potential to increase mortality further by unintended ventilator-induced lung injury (VILI). Thus, there is motivation to improve management of ventilation in patients with ARDS. The immediate goal of mechanical ventilation in ARDS should be to prevent atelectrauma resulting from repetitive alveolar collapse and reopening. However, a long-term goal should be to re-open collapsed and edematous regions of the lung and reduce regions of high mechanical stress that lead to regional volutrauma. In this paper, we consider the proposed strategy used by the full-term newborn to open the fluid-filled lung during the initial breaths of life, by ratcheting tissues opened over a series of initial breaths with brief expirations. The newborn’s cry after birth shares key similarities with the Airway Pressure Release Ventilation (APRV) modality, in which the expiratory duration is sufficiently short to minimize end-expiratory derecruitment. Using a simple computational model of the injured lung, we demonstrate that APRV can slowly open even the most recalcitrant alveoli with extended periods of high inspiratory pressure, while reducing alveolar re-collapse with brief expirations. These processes together comprise a ratchet mechanism by which the lung is progressively recruited, similar to the manner in which the newborn lung is aerated during a series of cries, albeit over longer time scales. 

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