Pilot Quality-Assurance Study of a Third-Generation Batch-Mode Clinical-Scale Automated Xenon-129 Hyperpolarizer.

We present a pilot quality assurance (QA) study of a clinical-scale, automated, third-generation (GEN-3) 129Xe hyperpolarizer employing batch-mode spin-exchange optical pumping (SEOP) with high-Xe densities (50% natural abundance Xe and 50% N2 in ~2.6 atm total pressure sourced from Nova Gas Technologies) and rapid temperature ramping enabled by an aluminum heating jacket surrounding the 0.5 L SEOP cell. 129Xe hyperpolarization was performed over the course of 700 gas loading cycles of the SEOP cell, simulating long-term hyperpolarized contrast agent production in a clinical lung imaging setting. High levels of 129Xe polarization (avg. %PXe = 51.0% with standard deviation σPXe = 3.0%) were recorded with fast 129Xe polarization build-up time constants (avg. Tb = 25.1 min with standard deviation σTb = 3.1 min) across the first 500 SEOP cell refills, using moderate temperatures of 75 °C. These results demonstrate a more than 2-fold increase in build-up rate relative to previously demonstrated results in a comparable QA study on a second-generation (GEN-2) 129Xe hyperpolarizer device, with only a minor reduction in maximum achievable %PXe and with greater consistency over a larger number of SEOP cell refill processes at a similar polarization lifetime duration (avg. T1 = 82.4 min, standard deviation σT1 = 10.8 min). Additionally, the effects of varying SEOP jacket temperatures, distribution of Rb metal, and preparation and operation of the fluid path are quantified in the context of device installation, performance optimization and maintenance to consistently produce high 129Xe polarization values, build-up rates (Tb as low as 6 min) and lifetimes over the course of a typical high-throughput 129Xe polarization SEOP cell life cycle. The results presented further demonstrate the significant potential for hyperpolarized 129Xe contrast agent in imaging and bio-sensing applications on a clinical scale.

Automated Low-Cost In Situ IR and NMR Spectroscopy Characterization of Clinical-Scale 129Xe Spin-Exchange Optical Pumping.

We present on the utility of in situ nuclear magnetic resonance (NMR) and near-infrared (NIR) spectroscopic techniques for automated advanced analysis of the 129Xe hyperpolarization process during spin-exchange optical pumping (SEOP). The developed software protocol, written in the MATLAB programming language, facilitates detailed characterization of hyperpolarized contrast agent production efficiency based on determination of key performance indicators, including the maximum achievable 129Xe polarization, steady-state Rb-129Xe spin-exchange and 129Xe polarization build-up rates, 129Xe spin-relaxation rates, and estimates of steady-state Rb electron polarization. Mapping the dynamics of 129Xe polarization and relaxation as a function of SEOP temperature enables systematic optimization of the batch-mode SEOP process. The automated analysis of a typical experimental data set, encompassing ∼300 raw NMR and NIR spectra combined across six different SEOP temperatures, can be performed in under 5 min on a laptop computer. The protocol is designed to be robust in operation on any batch-mode SEOP hyperpolarizer device. In particular, we demonstrate the implementation of a combination of low-cost NIR and low-frequency NMR spectrometers (∼$1,100 and ∼$300 respectively, ca. 2020) for use in the described protocols. The demonstrated methodology will aid in the characterization of NMR hyperpolarization hardware in the context of SEOP and other hyperpolarization techniques for more robust and less expensive clinical production of HP 129Xe and other contrast agents.

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

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 as 129 Xe. Techniques based on hyperpolarized 129 Xe 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 hyperpolarized 129 Xe 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 hyperpolarized 129 Xe to lung imaging and beyond.

High-Pressure Clinical-Scale 87% Parahydrogen Generator.

We present an automated parahydrogen generator (ParaSun) for clinical-scale applications in parahydrogen-induced polarization (PHIP) and signal amplification by reversible exchange (SABRE) at high pressures. The device employs a vacuum-pumped, Sunpower cryo-cooler (typically employed for cooling cellular network antennas) to achieve up to ∼87% parahydrogen enrichment at a temperature as low as ∼40 K and a maximum outlet pressure of ∼490 PSI. The device reaches the target temperature set-point in under 1 h. It employs a FeO(OH) catalyst for the ortho- to para-state conversion. A mass-flow controller (MFC) facilitates the controlled flow of H2 gas at a rate of 150 standard cubic centimeters per minute (sccm). This design bridges the gap between rudimentary 50% enrichment liquid-N2 baths and far costlier, near-unity-enrichment configurations employing high-H2 throughputs and <25 K temperatures. The design presented here should be of interest for those pursuing a wide variety of PHIP applications, including those involving the production of inhalable or injectable hyperpolarized contrast agents for biomedical imaging.

Batch-Mode Clinical-Scale Optical Hyperpolarization of Xenon-129 Using an Aluminum Jacket with Rapid Temperature Ramping.

We present spin-exchange optical pumping (SEOP) using a third-generation (GEN-3) automated batch-mode clinical-scale 129Xe hyperpolarizer utilizing continuous high-power (∼170 W) pump laser irradiation and a novel aluminum jacket design for rapid temperature ramping of xenon-rich gas mixtures (up to 2 atm partial pressure). The aluminum jacket design is capable of heating SEOP cells from ambient temperature (typically 25 °C) to 70 °C (temperature of the SEOP process) in 4 min, and perform cooling of the cell to the temperature at which the hyperpolarized gas mixture can be released from the hyperpolarizer (with negligible amounts of Rb metal leaving the cell) in approximately 4 min, substantially faster (by a factor of 6) than previous hyperpolarizer designs relying on air heat exchange. These reductions in temperature cycling time will likely be highly advantageous for the overall increase of production rates of batch-mode (i.e., stopped-flow) 129Xe hyperpolarizers, which is particularly beneficial for clinical applications. The additional advantage of the presented design is significantly improved thermal management of the SEOP cell. Accompanying the heating jacket design and performance, we also evaluate the repeatability of SEOP experiments conducted using this new architecture, and present typically achievable hyperpolarization levels exceeding 40% at exponential build-up rates on the order of 0.1 min-1.

Hyperpolarizing Concentrated Metronidazole 15 NO2 Group over Six Chemical Bonds with More than 15 % Polarization and a 20†Minute Lifetime.

The NMR hyperpolarization of uniformly 15 N-labeled [15 N3 ]metronidazole is demonstrated by using SABRE-SHEATH. In this antibiotic, the 15 NO2 group is hyperpolarized through spin relays created by 15 N spins in [15 N3 ]metronidazole, and the polarization is transferred from parahydrogen-derived hydrides over six chemical bonds. In less than a minute of parahydrogen bubbling at approximately 0.4 µT, a high level of nuclear spin polarization (P15N ) of around 16 % is achieved on all three 15 N sites. This product of 15 N polarization and concentration of 15 N spins is around six-fold better than any previous value determined for 15 N SABRE-derived hyperpolarization. At 1.4 T, the hyperpolarized state persists for tens of minutes (relaxation time, T1 ≈10 min). A novel synthesis of uniformly 15 N-enriched metronidazole is reported with a yield of 15 %. This approach can potentially be used for synthesis of a wide variety of in vivo metabolic probes with potential uses ranging from hypoxia sensing to theranostic imaging.

Ultra-Low-Cost Disposable Hand-Held Clinical-Scale Propane Gas Hyperpolarizer for Pulmonary Magnetic Resonance Imaging Sensing.

Hyperpolarized magnetic resonance imaging (MRI) contrast agents are revolutionizing the field of biomedical imaging. Hyperpolarized Xe-129 was recently FDA approved as an inhalable MRI contrast agent for functional lung imaging sensing. Despite success in research settings, modern Xe-129 hyperpolarizers are expensive (up to $1M), large, and complex to site and operate. Moreover, Xe-129 sensing requires specialized MRI hardware that is not commonly available on clinical MRI scanners. Here, we demonstrate that proton-hyperpolarized propane gas can be produced on demand using a disposable, hand-held, clinical-scale hyperpolarizer via parahydrogen-induced polarization, which relies on parahydrogen as a source of hyperpolarization. The device consists of a heterogeneous catalytic reactor connected to a gas mixture storage can containing pressurized hyperpolarization precursors: propylene and parahydrogen (10 bar total pressure). Once the built-in flow valve of the storage can is actuated, the precursors are ejected from the can into a reactor, and a stream of hyperpolarized propane gas is ejected from the reactor. Robust operation of the device is demonstrated for producing proton sensing polarization of 1.2% in a wide range of operational pressures and gas flow rates. We demonstrate that the propylene/parahydrogen gas mixture can retain potency for days in the storage can with a monoexponential decay time constant of 6.0 ± 0.5 days, which is limited by the lifetime of the parahydrogen singlet spin state in the storage container. The utility of the produced sensing agent is demonstrated for phantom imaging on a 3 T clinical MRI scanner located 100 miles from the agent/device preparation site and also for ventilation imaging of excised pig lungs using a 0.35 T clinical MRI scanner. The cost of the device components is less than $35, which we envision can be reduced to less than $5 for mass-scale production. The hyperpolarizer device can be reused, recycled, or disposed.

Quantifying the effects of quadrupolar sinks via15N relaxation dynamics in metronidazoles hyperpolarized via SABRE-SHEATH.

15N spin-lattice relaxation dynamics in metronidazole-15N3 and metronidazole-15N2 isotopologues are studied for rational design of 15N-enriched biomolecules for signal amplification by reversible exchange in microtesla fields. 15N relaxation dynamics mapping reveals the deleterious effects of interactions with the polarization transfer catalyst and a quadrupolar 14N nucleus within the spin-relayed 15N-15N network.

Helium-rich mixtures for improved batch-mode clinical-scale spin-exchange optical pumping of Xenon-129.

We present studies of spin-exchange optical pumping (SEOP) using ternary xenon-nitrogen-helium gas mixtures at high xenon partial pressures (up to 1330 Torr partial pressure at loading, out of 2660 Torr total pressure) in a 500-mL volume SEOP cell, using two automated batch-mode clinical-scale 129Xe hyperpolarizers operating under continuous high-power (~170 W) pump laser irradiation. In this pilot study, we explore SEOP in gas mixtures with up to 45% 4He content under a wide range of experimental conditions. When an aluminum jacket cooling/heating design was employed (GEN-3 hyperpolarizer), 129Xe polarization (%PXe) of 55.9 ± 0.9% was observed with mono-exponential build-up rate γSEOP of 0.049 ± 0.001 min-1 for the 4He-rich mixture (1000 Torr Xe/900 Torr He, 100 Torr N2), compared to %PXe of 49.3 ± 3.3% at γSEOP of 0.035 ± 0.004 min-1 for the N2-rich gas mixture (1000 Torr Xe/100 Torr He, 900 Torr N2). When forced-air cooling/heating was used (GEN-2 hyperpolarizer), %PXe of 83.9 ± 2.7% was observed at γSEOP of 0.045 ± 0.005 min-1 for the 4He-rich mixture (1000 Torr Xe/900 Torr He, 100 Torr N2), compared to %PXe of 73.5 ± 1.3% at γSEOP of 0.028 ± 0.001 min-1 for the N2-rich gas mixture (1000 Torr Xe and 1000 Torr N2). Additionally, %PXe of 72.6 ± 1.4% was observed at a build-up rate γSEOP of 0.041 ± 0.003 min-1 for a super-high-density 4He-rich mixture (1330 Torr Xe/1200 Torr 4He/130 Torr N2), compared to %PXe = 56.6 ± 1.3% at a build-up rate of γSEOP of 0.034 ± 0.002 min-1 for an N2-rich mixture (1330 Torr Xe/1330 Torr N2) using forced air cooling/heating. The observed SEOP hyperpolarization performance under these conditions corresponds to %PXe improvement by a factor of 1.14 ± 0.04 at 1000 Torr Xe density and by up to a factor of 1.28 ± 0.04 at 1330 Torr Xe density at improved SEOP build-up rates by factors of 1.61 ± 0.18 and 1.21 ± 0.11 respectively. Record %PXe levels have been obtained here: 83.9 ± 2.7% at 1000 Torr Xe partial pressure and 72.6 ± 1.4% at 1330 Torr Xe partial pressure. In addition to improved thermal stability for SEOP, the use of 4He-rich gas mixtures also reduces the overall density of produced inhalable HP contrast agents; this property may be desirable for HP 129Xe inhalation by human subjects in clinical settings-especially in populations with heavily impaired lung function. The described approach should enjoy ready application in the production of inhalable 129Xe contrast agent with near-unity 129Xe nuclear spin polarization.

Pilot multi-site quality assurance study of batch-mode clinical-scale automated xenon-129 hyperpolarizers.

We present a pilot quality assurance (QA) study of spin-exchange optical pumping (SEOP) performed on two nearly identical second-generation (GEN-2) automated batch-mode clinical-scale 129Xe hyperpolarizers, each utilizing a convective forced air oven, high-power (~170 W) continuous pump laser irradiation, and xenon-rich gas mixtures (~1.30 atm partial pressure). In one study, the repeatability of SEOP in a 1000 Torr Xe/900 Torr N2/100 Torr 4He (2000 Torr total pressure) gas mixture is evaluated over the course of ~700 gas loading cycles, with negligible decrease in performance during the first ~200 cycles, and with high 129Xe polarization levels (avg. %PXe = 71.7% with standard deviation σPXe = 1.5%), build-up rates (avg. γSEOP = 0.019 min-1 with standard deviation σγ = 0.003 min-1) and polarization lifetimes (avg. T1 = 90.5 min with standard deviation σT = 10.3 min) reported at moderate oven temperature of ~70 °C. Although the SEOP cell in this study exhibited a detectable performance decrease after 400 cycles, the cell continued to produce potentially useable HP 129Xe with %PXe = 42.3 ± 0.6% even after nearly 700 refill cycles. The possibility of "regenerating" "dormant" (i.e., not used for an extended period of time) SEOP cells using repeated temperature cycling methods to recover %PXe is also demonstrated. The quality and consistency of results show significant promise for translation to clinical-scale production of hyperpolarized 129Xe contrast agents for imaging and bio-sensing applications.

XeUS: A second-generation automated open-source batch-mode clinical-scale hyperpolarizer.

We present a second-generation open-source automated batch-mode 129Xe hyperpolarizer (XeUS GEN-2), designed for clinical-scale hyperpolarized (HP) 129Xe production via spin-exchange optical pumping (SEOP) in the regimes of high Xe density (0.66-2.5 atm partial pressure) and resonant photon flux (~170 W, Δλ = 0.154 nm FWHM), without the need for cryo-collection typically employed by continuous-flow hyperpolarizers. An Arduino micro-controller was used for hyperpolarizer operation. Processing open-source software was employed to program a custom graphical user interface (GUI), capable of remote automation. The Arduino Integrated Development Environment (IDE) was used to design a variety of customized automation sequences such as temperature ramping, NMR signal acquisition, and SEOP cell refilling for increased reliability. A polycarbonate 3D-printed oven equipped with a thermo-electric cooler/heater provides thermal stability for SEOP for both binary (Xe/N2) and ternary (4He-containing) SEOP cell gas mixtures. Quantitative studies of the 129Xe hyperpolarization process demonstrate that near-unity polarization can be achieved in a 0.5 L SEOP cell. For example, %PXe of 93.2 ± 2.9% is achieved at 0.66 atm Xe pressure with polarization build-up rate constant γSEOP = 0.040 ± 0.005 min-1, giving a max dose equivalent ≈ 0.11 L/h 100% hyperpolarized, 100% enriched 129Xe; %PXe of 72.6 ± 1.4% is achieved at 1.75 atm Xe pressure with γSEOP of 0.041 ± 0.001 min-1, yielding a corresponding max dose equivalent of 0.27 L/h. Quality assurance studies on this device have demonstrated the potential to refill SEOP cells hundreds of times without significant losses in performance, with average %PXe = 71.7%, (standard deviation σP = 1.52%) and mean polarization lifetime T1 = 90.5 min, (standard deviation σT = 10.3 min) over the first ~200 gas mixture refills, with sufficient performance maintained across a further ~700 refills. These findings highlight numerous technological developments and have significant translational relevance for efficient production of gaseous HP 129Xe contrast agents for use in clinical imaging and bio-sensing techniques.