Continuous Delivery of Hyperpolarized Xenon-129 Gas Using a “Stopped-Flow” Clinical-Scale Cryogen-Free Hyperpolarizer

Abstract

In 2022, the FDA approved hyperpolarized (HP) ¹²⁹Xe gas as an inhalable contrast agent for functional lung imaging. For clinical imaging, HP ¹²⁹Xe is usually given as a bolus inhalation. However, for preclinical applications (e.g., pulmonary imaging in small rodents), the continuous delivery of HP ¹²⁹Xe is greatly desired to enable MRI scanning under conditions of physiological continuous animal breathing patterns. Moreover, HP ¹²⁹Xe gas can be utilized for other applications including materials science and bioanalytical chemistry, where a continuous flow of hyperpolarized gas through an NMR sample over several minutes is also desired for sensing of ¹²⁹Xe inside an NMR spectrometer. ¹²⁹Xe is often hyperpolarized using continuous-flow spin-exchange optical pumping, which employs a lean (1–2%) mixture of Xe and a carrier gas (e.g., He and N₂). The low Xe concentration in the produced output reduces the NMR detection sensitivity, and thus, Xe cryo-collection is typically employed to achieve near-100% pure gas-phase Xe before administration to the sample or subject. However, the need for cryo-collection undermines a key advantage of continuous-flow production, i.e., the continuous flowing in a hyperpolarizer HP ¹²⁹Xe gas is trapped inside the hyperpolarizer, and the produced HP ¹²⁹Xe gas is released at once when the production cycle (30–60 min) is completed. An alternative HP ¹²⁹Xe production technology employs a “stopped-flow” approach, where a batch of HP gas is hyperpolarized over time and quickly released from a hyperpolarizer. Here, a clinical-scale “stopped-flow” ¹²⁹Xe hyperpolarizer was employed to hyperpolarize a 1.3 L-atm batch of 50:50 Xe:N₂ gas mixture inside a glass cell with an ultralong lifetime of the HP ¹²⁹Xe state (T₁ > 2 h). The produced HP ¹²⁹Xe gas was slowly delivered into a 5 mm NMR tube via PEEK tubing under a wide range of gas flow rates: 3–180 standard cubic centimeters per minute (sccm). The polarization of the gas ejected from the hyperpolarizer was quantified using in situ low-field NMR polarimetry and additionally verified using a 0.35 T clinical MRI scanner. Continuous-flow delivery of HP ¹²⁹Xe was demonstrated for up to 15 min with a gas flow rate of 45–150 sccm over a 2.5-m length of PEEK tubing, suffering only small losses in ¹²⁹Xe polarization. These observations are additionally supported by ¹²⁹Xe relaxation measurements inside the PEEK tubing employed for gas delivery and the 5 mm NMR tube employed for polarimetry. ¹²⁹Xe polarization of 16–19% was obtained in the delivered gas, starting with an “in-polarizer” ¹²⁹Xe polarization of 19%. We envision that this method can be employed for on-demand cryogen-free delivery of hyperpolarized gas using “stopped-flow” ¹²⁹Xe hyperpolarizers for a broad range of applications, from preclinical imaging to biosensors, and to spectroscopy of materials surfaces.