Contrast agent device

Abstract

Provided herein are systems and components for generating and / or storing hyperpolarized contrast agent for magnetic resonance imaging (MRI) applications.

Description

CONTRAST AGENT DEVICECROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 624,434, filed January 24, 2024, which is entirely incorporated herein by reference.STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

[0002] This present disclosure was made with government support under R43 OD034168 and R43 MH129007 awarded by National Institutes of Health. The government has certain rights in the disclosure.FIELD OF THE INVENTION

[0003] The present disclosure relates to systems, devices, and methods for facilitating biomedical imaging, particularly magnetic resonance imaging (MRI).BACKGROUND

[0004] Magnetic resonance imaging (MRI) relies on the alignment of nuclear spins with a magnetic field to create detectable signals. In many MRI applications, contrast agents are injected into the body to enhance and improve image quality and / or enable MRI to capture metabolic information. In recent years, hyperpolarized contrast agents have been developed and used to enhance MRI anatomical and metabolic imaging. Hyperpolarized contrast agents coupled with MRI can increase sensitivity to directly and noninvasively image in vivo molecular transformations in real-time and provide unique scientific and clinical insights into disease. Parahydrogen-induced hyperpolarization uses parahydrogen (pH?) as a source of spin order to generate hyperpolarization in target substrates through chemical addition or exchange reactions. Signal Amplification by Reversible Exchange (SABRE) uses a catalyst (e.g., an organometallic catalyst) to transfer spin order from pH? to a target substrate, e.g., a contrast agent, to generate hyperpolarized contrast agent. Hyperpolarization approaches have been prohibitively expensive, and typical hyperpolarization agents for use in human and animal subjects have short lifetimes of under one minute, rendering them of limited use in clinical settings.

[0005] For at least these reasons, improved systems, devices, and methods for facilitating biomedical imaging, particularly MRI, and the generation and use of hyperpolarized contrast agents with MRI, are desired.SUMMARY

[0006] Aspects of the present disclosure provide a method of conducting magnetic resonance imaging (MRI) on a subject, the method comprising: (a) generating a hyperpolarized contrast agent for administration to the subject; (b) administering the hyperpolarized contrast agent to the subject; and (c) using an MRI instrument, conducting MRI of the subject.

[0007] In some embodiments, generating the hyperpolarized contrast agent is timed to generate the hyperpolarized contrast agent within about 30 min, within about 10 min, or within about 1 min of administration to the subject. In some embodiments, conducting MRI of the subject is started within about 5 min, within about 1 min, or within about 3 seconds of administering the hyperpolarized contrast agent to the subject. In some embodiments, generating the hyperpolarized contrast agent comprises transferring spin order from parahydrogen (pH?) gas to a contrast agent. In some embodiments, generating the hyperpolarized contrast agent comprises contacting the contrast agent with the pH? gas and subjecting the contrast agent to a magnetic field. In some embodiments, the method further comprises, prior to applying the magnetic field, introducing a catalyst to the contrast agent, or prior to contacting the contrast agent with the pH? gas, introducing a catalyst to the contrast agent. In some embodiments, the catalyst comprises a metal catalyst. In some embodiments, the catalyst comprises an organometallic catalyst. In some embodiments, the method further comprises recycling at least a portion of the catalyst in a volume of liquid waste. In some embodiments, generating the hyperpolarized contrast agent is accomplished using a hyperpolarization instrument. In some embodiments, the hyperpolarization instrument outputs the hyperpolarized contrast agent into an administration device coupled to the hyperpolarization instrument. In some embodiments, the administration device is a manual syringe, an auto-injection syringe, or an infusion pump.

[0008] In some embodiments, the method further comprises collecting used hydrogen (H?) gas into a tank. In some embodiments, the method further comprises recycling the used H? gas to create additional pH? gas. In some embodiments, the method further comprises absorbing used H? gas into a filter. In some embodiments, the filter comprises metal-organic framework, carbon nanotube, or graphite. In some embodiments, the filter is disposable. In some embodiments, the filter is recyclable.

[0009] In some embodiments, the pH? gas is provided in a gas container. In some embodiments, the diameter of the gas container is less than or equal to 1 meter (m), has a storage volume of about 1 millimeter (mL) to about 100 liters (L), and / or has a weight of less than or equal to about 30 lbs. In some embodiments, the volume of pH? gas packaged and stored in the gas container is sufficient for use of a single imaging session for one subject. In some embodiments, the gas container is a single use container. In some embodiments, the single use container has avolume ranging from about 100 microliters (pL) to about 5 L. In some embodiments, the pH? is provided in a multi-use container. In some embodiments, the multi-use container has a volume ranging from about 1 L to about 100 L. In some embodiments, the volume of pH? in the multiuse container is sufficient for use for multiple imaging sessions for multiple subjects or for a single subject. In some embodiments, an interior of the gas container has a shape which is substantially a spheroid, a cylinder, or a spherocylinder. In some embodiments, the gas container has a storage volume for storing the volume of the plfc gas, wherein the storage volume has a shape selected to prevent more than 15% loss of spin order of the pH2 gas over 90 days. In some embodiments, the gas container has a storage volume for storing the volume of the plfc gas, wherein at least 80% of an inner lining of the storage volume is curved. In some embodiments, the gas container has a storage volume for storing the volume of the pffc gas, wherein no portion of an inner lining of the storage volume has a radius of curvature of greater than 30 cm. In some embodiments, the gas container is capable of storing pH2 gas for an extended period of time.

[0010] In some embodiments, the gas container has a storage volume for storing the volume of the pH2gas; and the storage volume is lined with an interface material in contact with the pH2 gas, the material being selected to prevent loss of more than 15% spin order of the pH2 gas over 90 days. In some embodiments, the interface material of the storage volume of the gas container comprises aluminum or a plastic material. In some embodiments, the plastic material is selected from the group consisting of poly ether ether ketone (PEEK), poly etherketoneketone (PEKK), polycarbonate, polyamide-imide (PAI), polyetherimide (e.g., Ultem®, available from SABIC GLOBAL TECHNOLOGIES B.V.), polyphenylene sulfide (PPS), polytetrafluoroethylene (PTFE), and / or nylon. In some embodiments, the interface material of the storage volume of the gas container comprises an amorphous silicon based material (e.g., SulfiNert® or SilcoNert®, available from SilkoTek Corporation of Bellefonte, PA).

[0011] In some embodiments, the gas container is capable of containing high pressure. In some embodiments, the high pressure is from 10 to 2,000 PSI. In some embodiments, the gas container is pressurized to under 700 PSI. In some embodiments, the gas container comprises an inlet or multiple inlets. In some embodiments, the method further comprises coupling the gas container to a hyperpolarization instrument. In some embodiments, the method further comprises testing the gas container at a point of manufacture of the gas container or at a user site. In some embodiments, the quality of pH2 gas is checked prior to use. In some embodiments, the quality of the pH2 gas is checked via nuclear magnetic resonance (NMR) or Raman spectroscopy (RS) when the pH2 gas is dispensed into the container. In some embodiments, the quality of the pH2 gas is checked via NMR or RS at a user site. In some embodiments, the pH2 gas is checked upon failure of a quality assurance or quality control step.

[0012] In some embodiments, the method further comprises running an inert gas through the hyperpolarization instrument between uses to clear out fluid paths. In some embodiments, inert gas comprises nitrogen (N2), helium (He), or argon (Ar).

[0013] In some embodiments, the method further comprises running a cleaning process, the cleaning process comprising flowing a cleaning or purging consumable through the hyperpolarization instrument. In some embodiments, the cleaning or purging consumable comprises isopropanol, ethanol, saline, water, OTS antibacterial cleaning solution, or any combination thereof. In some embodiments, the method comprises running the cleaning process after each use of the hyperpolarization instrument, at least once a day for each day that the hyperpolarization instrument is used, or at least once a month.

[0014] In some embodiments, the hyperpolarized contrast agent is generated by mixing a volume of a liquid reagent and a mass of a solid reagent. In some embodiments, the liquid reagent is stored in a liquid reagent container and the solid reagent is stored in a solid reagent container. In some embodiments, the liquid reagent container and the solid reagent container are encased in a reagent cartridge. In some embodiments, the liquid reagent is a solvent or a mixture of solvents. In some embodiments, the liquid reagent comprises one or more of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), methyl tertbutyl ether (MTBE), or any combinations thereof. In some embodiments, the liquid reagent comprises a deuterated solvent. In some embodiments, the deuterated solvent comprises at least 90% deuteration. In some embodiments, the solid reagent comprises a substrate. In some embodiments, the substrate comprises one or more of pyruvate, alpha-ketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate. In some embodiments, solid reagent further comprises a catalyst. In some embodiments, the catalyst comprises a ligand and a metal center. In some embodiments, the ligand is l,3-bis(2,4,6-trimethylphenyl)imidazol-2- ylidine (IMes) or l,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes). In some embodiments, the metal center is Ir, Rh, Co, Ag, Au, Cu, Fe, Ru, Pd, Ni, or a combination thereof. In some embodiments, the catalyst comprises Ir-IMes or Ir-SIMes.

[0015] In some embodiments, the hyperpolarized contrast agent is generated by mixing a volume of a first liquid reagent and a volume of a second liquid reagent. In some embodiments, the first liquid reagent is stored in a first liquid reagent container and the second liquid reagent is stored in a second liquid reagent container. In some embodiments, the first liquid reagent container and the second liquid reagent container are encased in a reagent cartridge. In some embodiments, the first liquid reagent comprises a substrate and one or more solvents. In some embodiments, the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), andmethyl tert-butyl ether (MTBE). In some embodiments, the second liquid reagent comprises a catalyst and one or more solvents. In some embodiments, the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), and methyl tert-butyl ether (MTBE). In some embodiments, the first liquid reagent comprises a deuterated solvent. In some embodiments, the deuterated solvent comprises at least 90% deuteration. In some embodiments, the second liquid reagent comprises a deuterated solvent. In some embodiments, the deuterated solvent comprises at least 90% deuteration. In some embodiments, the substrate comprises one or more of pyruvate, alphaketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate. In some embodiments, the catalyst comprises a ligand and a metal center. In some embodiments, the ligand is l,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidine (IMes) or 1,3-Bis(2,4,6- trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes). In some embodiments, the metal center is Ir, Rh, Co, Ag, Au, Cu, Fe, Ru, Pd, Ni, or a combination thereof. In some embodiments, the catalyst comprises Ir-IMes or Ir-SIMes.

[0016] In some embodiments, the hyperpolarized contrast agent is generated by mixing a substrate and a catalyst in one or more solvents. In some embodiments, the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), and methyl tert-butyl ether (MTBE). In some embodiments, the one or more solvents comprise a deuterated solvent. In some embodiments, the deuterated solvent comprises at least 90% deuteration. In some embodiments, the substrate comprises one or more of pyruvate, alpha-ketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate. In some embodiments, the catalyst comprises a ligand and a metal center. In some embodiments, the ligand is l,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidine (IMes), l,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes), or a N- heterocyclic carbene (NHC). In some embodiments, the metal center is Ir, Rh, Co, Ag, Au, Cu, Fe, Ru, Pd, Ni, or a combination thereof. In some embodiments, the catalyst comprises Ir-IMes or Ir-SIMes.

[0017] In some embodiments, the gas container is compliant with 49 CFR and IATA standards for hazardous material shipping.

[0018] Aspects of the present disclosure provide a method of providing a hyperpolarized contrast agent, the method comprising: (a) coupling a gas container to a source or a generator of parahydrogen (pH?) gas; (b) conveying a volume of pH? gas to the gas container; and (c) storing the pH? gas in the gas container, the gas container capable of storing the pH? gas for an extended period of time of at least three months and allowing less than about 15% loss of spin order of the pH? gas during the extended period of time.

[0019] In some embodiments, the method further comprises: (1) storing a first reagent in a first reagent container; (2) storing a second reagent in a second reagent container; (3) coupling the gas container, the first reagent container, and the second reagent container to a hyperpolarization instrument; (4) transferring one or more reagents comprising a contrast agent to the hyperpolarization instrument; and (5) conveying spin order from the pH? gas to the contrast agent with the hyperpolarization instrument, thereby generating the hyperpolarized contrast agent.

[0020] In some embodiments, the method comprises mixing a first reagent and a second reagent. In some embodiments, two or more of the gas containers, the first reagent container, or the second reagent container are provided within a single cartridge. In some embodiments, two or more of the gas containers, the first reagent container, or the second reagent container are provided within separate cartridges. In some embodiments, the first reagent container and the second reagent container are encased in a reagent module. In some embodiments, the gas container is capable of containing high pressure, optionally wherein the high pressure is from 10 to 2,000 psi. In some embodiments, the gas container has a storage volume for storing the volume of the pH? gas; and the storage volume is lined with an interface material in contact with the pH? gas, the material being selected to prevent loss of less than 15% spin order of the pH? gas. In some embodiments, the interface material of the storage volume of the gas container comprises aluminum or a plastic selected from the group consisting of polyether ether ketone (PEEK), polyetherketoneketone (PEKK), polycarbonate, polyamide-imide (PAI), polyetherimide (e.g., Ultem®), polyphenylene sulfide (PPS), polytetrafluoroethylene (PTFE), and / or nylon. In some embodiments, the interface material of the storage volume of the gas container comprises an amorphous silicon-based material (e.g., SulfiNert® or SilcoNert®). In some embodiments, the gas container has a storage volume of about 1 mL to 100 L. In some embodiments, the gas container is pressurized to about 10 to 2,000 PSI. In some embodiments, the gas container is pressurized to under 700 PSI. In some embodiments, the gas container has a storage volume for storing the volume of the parahydrogen gas, wherein the storage volume has the shape of a spheroid, a cylinder or a spherocylinder. In some embodiments, the gas container has a storage volume for storing the volume of the pH? gas, wherein at least 80% of an inner lining of the storage volume is curved. In some embodiments, the gas container comprises an inlet or multiple inlets. In some embodiments, gas container has a diameter of less than or equal to 1 meter. In some embodiments, gas container is a single-use container, and wherein the volume of parahydrogen gas packaged and stored in the gas container is sufficient for use of a single imaging session for one subject. In some embodiments, the gas container is a multi-use container, and wherein the volume of parahydrogen gas packaged and stored in the gas containeris sufficient for use of multiple imaging session for multiple subjects or a single subject. In some embodiments, the method further comprises testing the gas container at a point of manufacture of the gas container or at a user site. In some embodiments, the quality of pH? gas is checked prior to use. In some embodiments, the quality of the pH? gas is checked via nuclear magnetic resonance (NMR) or Raman spectroscopy (RS) when the pH2 gas is dispensed into the container. In some embodiments, the quality of the pH2 gas is checked via NMR or RS at a user site. In some embodiments, the plfc gas is checked upon failure of a quality assurance or quality control step. In some embodiments, the method further comprises running an inert gas through the hyperpolarization instrument between uses to clear out fluid paths. In some embodiments, the inert gas is nitrogen (N2), helium (He), or argon (Ar). In some embodiments, the first reagent container has a volume of less than or equal to IL. In some embodiments, the first reagent comprises a liquid reagent and the second reagent comprises a solid reagent. In some embodiments, the liquid reagent is a solvent or a mixture of solvents. In some embodiments, the liquid reagent comprises one or more of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), methyl tert-butyl ether (MTBE), or any combinations thereof. In some embodiments, the liquid reagent comprises a deuterated solvent. In some embodiments, the deuterated solvent comprises at least 90% deuteration. In some embodiments, the solid reagent comprises a substrate. In some embodiments, the substrate comprises one or more of pyruvate, alpha-ketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate. In some embodiments, the solid reagent further comprises a catalyst. In some embodiments, the catalyst comprises a ligand and a metal center. In some embodiments, the ligand is l,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidine (IMes), 1,3- Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes), or a N-heterocyclic carbene (NHC. In some embodiments, the metal center is Ir, Rh, Co, Ag, Au, Cu, Fe, Ru, Pd, Ni, or a combination thereof. In some embodiments, the catalyst comprises Ir-IMes or Ir-SIMes. In some embodiments, the first liquid reagent comprises a liquid reagent and the second reagent comprises a second liquid reagent. In some embodiments, the first liquid reagent comprises a substrate and one or more solvents. In some embodiments, the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), and methyl tert-butyl ether (MTBE). In some embodiments, the second liquid reagent comprises a catalyst and one or more solvents. In some embodiments, the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), and methyl tert-butyl ether (MTBE). In some embodiments, the first liquid reagent comprises a deuterated solvent. In some embodiments, the deuterated solvent comprises at least 90% deuteration. In someembodiments, the second liquid reagent comprises a deuterated solvent. In some embodiments, the deuterated solvent comprises at least 90% deuteration. In some embodiments, the substrate comprises one or more of pyruvate, alpha-ketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate. In some embodiments, the catalyst comprises a ligand and a metal center. In some embodiments, the ligand is l,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidine (IMes), l,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes), or a N- heterocyclic carbene (NHC). In some embodiments, the metal center is Ir, Rh, Co, Ag, Au, Cu, Fe, Ru, Pd, Ni, or a combination thereof. In some embodiments, the catalyst comprises Ir-IMes or Ir-SIMes.

[0021] In some embodiments, the method comprises mixing a substrate and a catalyst in one or more solvents. In some embodiments, the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate- buffered saline (PBS), and methyl tert-butyl ether (MTBE). In some embodiments, the one or more solvents comprise a deuterated solvent. In some embodiments, the deuterated solvent comprises at least 90% deuteration. In some embodiments, the substrate comprises one or more of pyruvate, alpha-ketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate. In some embodiments, the catalyst comprises a ligand and a metal center. In some embodiments, the ligand is l,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidine (IMes), 1,3- Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes), or a N-heterocyclic carbene (NHC). In some embodiments, the metal center is Ir, Rh, Co, Ag, Au, Cu, Fe, Ru, Pd, Ni, or a combination thereof. In some embodiments, the catalyst comprises Ir-IMes or Ir-SIMes.

[0022] In some embodiments, the method further comprises a cleaning process, the cleaning process comprising flowing a cleaning or purging consumable through the hyperpolarization instrument. In some embodiments, the cleaning or purging consumable is contained in a cleaning module. In some embodiments, the cleaning or purging consumable comprises ethanol, isopropanol, ethanol, saline, water, OTS antibacterial cleaning solution, or any combination thereof. In some embodiments, the cleaning process is run after each use, each day, or each month.

[0023] In some embodiments, conveying spin order from the pH? gas to the contrast agent comprises contacting a catalyst with the contrast agent. In some embodiments, the method further comprises subjecting the contrast agent to a magnetic field. In some embodiments, the method further comprises recycling at least a portion of the catalyst in a volume of liquid waste from the hyperpolarization instrument. In some embodiments, the catalyst comprises a metal catalyst. In some embodiments, the catalyst comprises an organometallic catalyst.

[0024] In some embodiments, the method further comprises collecting used H2 gas in a tank to the hyperpolarization instrument. In some embodiments, the method further comprises recycling the used H2 gas to create more pEE. In some embodiments, the gas container is compliant with 49 CFR and IATA standards for hazardous material shipping.

[0025] Aspects of the present disclosure provide a system comprising a hyperpolarization instrument comprising one or more valves and power controls electronically coupled to and controlled by a computer, wherein the computer is programmed to perform any of the foregoing methods.

[0026] Aspects of the present disclosure provide a device for storing parahydrogen (pEE) gas, the device comprising: a gas container having a storage volume for storing the pH2 gas, wherein the gas container is container capable of storing the pH2 gas for an extended period of time of at least three months and minimizing loss of spin order of the pH2 gas during the extended period of time. In some embodiments, the gas container is capable of containing high pressure. In some embodiments, the high pressure is from 10 to 2,000 PSI. In some embodiments, the gas container has a storage volume for storing the volume of the parahydrogen gas, wherein the storage volume is lined with an interface material in contact with the parahydrogen gas, the material being selected to minimize loss of spin order of the parahydrogen gas. In some embodiments, the interface material of the storage volume of the gas container comprises aluminum or a plastic material selected from the group consisting of polyether ether ketone (PEEK), polyetherketoneketone (PEKK), polycarbonate, polyamide-imide (PAI), polyetherimide (e.g., Ultem®), polyphenylene sulfide (PPS), polytetrafluoroethylene (PTFE), and / or nylon. In some embodiments, the interface material of the storage volume of the gas container comprises an amorphous silicon-based material (e.g., SulfiNert® or SilcoNert®). In some embodiments, the gas container has a storage volume of about 1 mL to about 100 L. In some embodiments, the gas container is pressurized to under 700 PSI. In some embodiments, the gas container has a storage volume for storing the volume of the pEE gas, wherein the storage volume has a shape selected to minimize loss of spin order of the pEE gas. In some embodiments, the gas container has a storage volume for storing the volume of the pEE gas, wherein the storage volume has the shape of a sphere, spheroid (oblate or prolate), ovoid, ellipsoid, globoid, cylinder, or spherocylinder. In some embodiments, the gas container has a storage volume for storing the volume of the pEE gas, wherein the storage volume has a flat top and bottom portion. In some embodiments, the gas container has a storage volume for storing the volume of the pEE gas, wherein the storage volume has a curved top and bottom portion. In some embodiments, the gas container has a storage volume for storing the volume of the pEE gas, wherein at least 80% of an inner lining of the storage volume is curved. In someembodiments, the gas container has a storage volume for storing the volume of the pH? gas, wherein no portion of an inner lining of the storage volume has a radius of curvature of greater than 30 cm. In some embodiments, the gas container has a diameter of less than or equal to 1 meter. In some embodiments, the gas container is a single-use container, and wherein the volume of pEb gas packaged and stored in the gas container is sufficient for use of a single imaging session for one subject. In some embodiments, the gas container is a multi-use container, and wherein the volume of pH? gas packaged and stored in the gas container is sufficient for use of multiple imaging session for multiple subjects or for a single subject. In some embodiments, the device further comprises at least one port coupled to the storage volume and also configured to couple to one or more of a generator of the pH2 gas or a hyperpolarized contrast agent hyperpolarization instrument. In some embodiments, the at least one port comprises a plurality of ports.

[0027] Aspects of the present disclosure provide a kit comprising a packaged set of gas containers of pH2, wherein the gas container is any one of gas containers disclosed herein.

[0028] Aspects of the present disclosure provide a kit for aiding magnetic resonance imaging, the kit comprising: (i) the device disclosed herein for storing parahydrogen (pEb) gas; (ii) a first reagent container for storing a first reagent; and (iii) a second reagent container for storing a second reagent, wherein the device for storing pH2 gas, the first reagent container, and the second reagent container are each configured to removably couple to a hyperpolarization instrument configured to generate a hyperpolarized contrast agent based on the first reagent and the second reagent and convey spin order from the pH2 gas to the contrast agent, thereby generating the hyperpolarized contrast agent. In some embodiments, the first reagent comprises a liquid reagent and the second reagent comprises a solid reagent. In some embodiments, the liquid reagent is a solvent or a mixture of solvents. In some embodiments, the liquid reagent comprises one or more of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), methyl tert-butyl ether (MTBE), or any combinations thereof. In some embodiments, the liquid reagent comprises a deuterated solvent. In some embodiments, the deuterated solvent comprises at least 90% deuteration. In some embodiments, the solid reagent comprises a substrate. In some embodiments, the substrate comprises one or more of pyruvate, alpha-ketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate. In some embodiments, the solid reagent further comprises a catalyst. In some embodiments, the catalyst comprises a ligand and a metal center. In some embodiments, the ligand is l,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidine (IMes) or 1,3-Bis(2,4,6- trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes). In some embodiments, the metal center is Ir, Rh, Co, Ag, Au, Cu, Fe, Ru, Pd, Ni, or a combination thereof. In someembodiments, the catalyst comprises Ir-IMes or Ir-SIMes. In some embodiments, the first reagent comprises a first liquid reagent and the second reagent comprises a second liquid reagent. In some embodiments, the first liquid reagent comprises a substrate and one or more solvents. In some embodiments, the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), and methyl tert-butyl ether (MTBE. In some embodiments, the second liquid reagent comprises a catalyst and one or more solvents. In some embodiments, the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), and methyl tert-butyl ether (MTBE). In some embodiments, the first liquid reagent comprises a deuterated solvent. In some embodiments, the deuterated solvent comprises at least 90% deuteration. In some embodiments, the second liquid reagent comprises a deuterated solvent. In some embodiments, the deuterated solvent comprises at least 90% deuteration. In some embodiments, the substrate comprises one or more of pyruvate, alpha-ketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate. In some embodiments, the catalyst comprises a ligand and a metal center. In some embodiments, the ligand is l,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidine (IMes) or 1,3- Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes). In some embodiments, the metal center is Ir, Rh, Co, Ag, Au, Cu, Fe, Ru, Pd, Ni, or a combination thereof; and / or the catalyst comprises Ir-IMes or Ir-SIMes. In some embodiments, the first reagent comprises a first liquid reagent and the second reagent comprises a second liquid reagent. In some embodiments, the kit further comprises a waste fluid collection container configured to removably couple to the hyperpolarization instrument to collect used hydrogen (Eb). In some embodiments, the waste fluid collection container comprises a tank. In some embodiments, the kit further comprises an ejection module. In some embodiments, the ejection module comprises one or more processing or output components for a solution ejection. In some embodiments, the ejection module comprises one or more vessels, filters, or processing solutions. In some embodiments, the one or more processing or output components are contained in a same housing. In some embodiments, the one or more processing or output components are contained in separate housings. In some embodiments, the kit further comprising a cleaning module. In some embodiments, the cleaning module is configured to provide a cleaning or purging consumable through the hyperpolarization instrument. In some embodiments, the cleaning or purging consumable comprises ethanol, isopropanol, ethanol, saline, water, OTS antibacterial cleaning solution, or any combination thereof. In some embodiments, the kit further comprises a purge gas module. In some embodiments, the purge gas module comprises inert gas selected from the group consisting of N2, Ar, and He.

[0029] In some embodiments, the kit may further comprise a separation component container (or module). In some embodiments, the separation component module may be configured to store and provide a separation component to purify the hyperpolarized contrast agent. In some embodiments, the separation component may induce phase separation of the reacted mixture after the hyperpolarization to an aqueous phase and a non-aqueous phase. In some embodiments, the separation component may comprise any separation component disclosed in this application. In some embodiments, the separation component may comprise butyl acetate. In some embodiments, the kit may further comprise an additional gas container, configured to provide a gas to gas-strip an aqueous phase comprising the hyperpolarized contrast agent. In some embodiments, the kit may further comprise a filter module, configured to filter an aqueous phase comprising the hyperpolarized contrast agent. In some embodiments, the kit may further comprise a receiver or receiving module configured to collect the purified hyperpolarized contrast agent. In some embodiments, any of the modules or containers disclosed herein may be a single use module or container. In some embodiments, any of the modules or containers disclosed herein may be a multiple use module or container. In some embodiments, any of the modules or containers disclosed herein may be a disposable module or container. In some embodiments, any of the modules or containers disclosed herein may be a reusable module or container. In some embodiments, any of the modules or containers disclosed herein may be reused.

[0030] Aspects of the present disclosure provide an ejection module, comprising one or more processing or output components for a solution ejection. In some embodiments, the ejection module comprises one or more vessels, filters, or processing solutions. In some embodiments, the one or more processing or output components are contained in a same housing. In some embodiments, the one or more processing or output components are contained in separate housings.

[0031] Aspects of the present disclosure provide a reagent module, comprising: a liquid reagent container for storing a volume of liquid reagent; and a solid reagent container for storing a mass of solid reagent. In some embodiments, the liquid reagent comprises one or more of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), butyl acetate, methyl tert-butyl ether (MTBE), or any combinations thereof. In some embodiments, the liquid reagent comprises a deuterated solvent. In some embodiments, the deuterated solvent comprises at least 90% deuteration. In some embodiments, the solid reagent comprises a substrate. In some embodiments, the substrate comprises one or more of pyruvate, alphaketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate. In some embodiments, the solid reagent comprises a catalyst. In some embodiments, the catalystcomprises a ligand and a metal center. In some embodiments, the ligand is l,3-bis(2,4,6- trimethylphenyl)imidazol-2-ylidine (IMes) or l,3-Bis(2,4,6-trimethylphenyl)-4,5- dihydroimidazol-2-ylidene (SIMes). In some embodiments, the metal center is Ir, Rh, Co, Ag, Au, Cu, Pt, Fe, Ru, Pd, Ni, or a combination thereof. In some embodiments, the catalyst comprises Ir-IMes or Ir-SIMes. In some embodiments, the liquid reagent container has a volume from about 100 pL to 1 L. In some embodiments, the liquid reagent container comprises a syringe, a glass vial, a plastic vial, a plastic vessel, or a bag. In some embodiments, the solid reagent container has a volume of about 100 pL to 100 mL. In some embodiments, the mass of solid reagent if from about 1 mg to 100 g.

[0032] Aspects of the present disclosure provide a reagent module, comprising: a first reagent container for storing a first liquid reagent; and a second reagent container for storing a second liquid reagent. In some embodiments, the first liquid reagent comprises one or more of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), butyl acetate, methyl tert-butyl ether (MTBE), or any combinations thereof. In some embodiments, the first liquid reagent comprises a substrate and one or more solvents. In some embodiments, the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), and methyl tert-butyl ether (MTBE). In some embodiments, second liquid reagent comprises a catalyst and one or more solvents. In some embodiments, the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), butyl acetate, and methyl tert-butyl ether (MTBE). In some embodiments, the first liquid reagent comprises a deuterated solvent. In some embodiments, the deuterated solvent comprises at least 90% deuteration. In some embodiments, the second liquid reagent comprises a deuterated solvent. In some embodiments, the deuterated solvent comprises at least 90% deuteration. In some embodiments, the substrate comprises one or more of pyruvate, alphaketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate. In some embodiments, the catalyst comprises a ligand and a metal center. In some embodiments, the ligand is l,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidine (IMes) or 1,3-Bis(2,4,6- trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes). In some embodiments, the metal center is Ir, Rh, Co, Ag, Au, Cu, Fe, Ru, Pd, Ni, or a combination thereof. In some embodiments, the catalyst comprises Ir-IMes or Ir-SIMes. In some embodiments, the liquid reagent container has a volume from about 100 pL to 1 L. In some embodiments, the first reagent container and / or the second reagent container comprise a syringe, a glass vial, a plastic vial, a plastic vessel, or a bag.

[0033] Aspects of the present disclosure provide a cartridge device for storing one or more precursors to a hyperpolarized contrast agent, the cartridge device comprising one or more of (i) parahydrogen (pH?) gas module; (ii) reagent module; (iii) ejection module; (iv) cleaning module; or (v) purge gas module. In some embodiments, each module or combination of modules is independently replaceable as a unit. In some embodiments, each module may be suitable for multiple or single use. In some embodiments, the pH? gas module comprises a gas container pressurized with pH? gas. In some embodiments, the reagent module comprises a liquid reagent module and a solid reagent module. In some embodiments, the liquid reagent module comprises ethanol, saline, and / or methanol. In some embodiments, the solid reagent module comprises a catalyst and / or a substrate. In some embodiments, the reagent module comprises multiple substrates to be hyperpolarized at once or in parallel. In some embodiments, the catalyst comprises Ir-IMes or Ir-SIMes. In some embodiments, the substrate comprises one or more of pyruvate or alpha-ketoglutarate. In some embodiments, the cleaning module comprises a purge gas and / or a sterile cleaning solution. In some embodiments, the purge gas comprises an inert gas selected from the group consisting of Ar, N? and He. In some embodiments, the sterile cleaning solution comprises ethanol. In some embodiments, the purge gas and the sterile cleaning solution are configured to run through a device in sequence or separately. In some embodiments, the cleaning module is configured to be inserted and used with each cycle or on an hourly, daily, or monthly basis. In some embodiments, the ejection module comprises one or more vessels, filters, or processing solutions. In some embodiments, the one or more processing or output components are contained in a same housing. In some embodiments, the one or more processing or output components are contained in separate housings.INCORPORATION BY REFERENCE

[0034] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0035] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0036] FIG. 1A illustrates an exemplary gas container, and FIG. IB illustrates a cross section view of an exemplary reagent cartridge, according to many embodiments;

[0037] FIG. 2 illustrates a cross section view of the exemplary reagent cartridge of FIG. IB with a fluid line adapter apparatus, according to many embodiments;

[0038] FIG. 3 illustrates a cross section view of the exemplary reagent cartridge of FIG. IB with a fluid line adapter apparatus coupled to the reagent cartridge, according to many embodiments;

[0039] FIG. 4 illustrates a perspective view of the upper portion of a fluid line adapter apparatus, according to many embodiments;

[0040] FIG. 5 illustrates a top-down view of the bottom portion of the fluid line adapter apparatus of FIG. 4, according to many embodiments;

[0041] FIG. 6 illustrates a cross section view of a reagent cartridge, wherein the upper portion of a fluid line adapter apparatus is not coupled / inserted to the reagent cartridge, according to many embodiments;

[0042] FIG. 7 illustrates a cross section view of the reagent cartridge of FIG. 6, wherein the upper portion of the fluid line adapter apparatus is coupled / inserted to the reagent cartridge, according to many embodiments;

[0043] FIG. 8 illustrates a cross section view of an exemplary ejection module, according to many embodiments;

[0044] FIG. 9 illustrates a schematic diagram of an exemplary cartridge system, according to many embodiments;

[0045] FIG. 10 illustrates a schematic diagram of an exemplary cartridge system, according to many embodiments;

[0046] FIG. 11 illustrates a schematic diagram of an exemplary cartridge system, according to many embodiments;

[0047] FIG. 12 illustrates a schematic diagram of an exemplary cartridge system, according to many embodiments;

[0048] FIG. 13 illustrates a schematic diagram of an exemplary cartridge system, according to many embodiments;

[0049] FIG. 14 illustrates a schematic diagram of an exemplary cartridge system, according to many embodiments;

[0050] FIG. 15 illustrates a schematic diagram of an exemplary cartridge system, according to many embodiments;

[0051] FIG. 16 illustrates a computer system that is programmed or otherwise configured to implement methods provided herein, according to many embodiments;

[0052] FIG. 17 illustrates an exemplary hyperpolarization process, according to many embodiments; and

[0053] FIG. 18A illustrates a comparison of parahydrogen relaxation in an uncoated aluminum cylinder and a stainless-steel cylinder with amorphous silicon-based coating, and FIG. 18B illustrates a comparison of parahydrogen relaxation in a stainless-steel cylinder coated with amorphous silicon-based coating or PTFE coating, according to many embodiments.DETAILED DESCRIPTION

[0054] The document presents numerous examples of the disclosed concept for illustrative purposes. Skilled artisans will recognize that there are many possible modifications, variations, and alternatives to these examples that are still within the scope of the disclosure. Other approaches and embodiments not explicitly described here can also be readily envisioned without deviating from the essence of the disclosed concept.Terminology

[0055] As used herein, the following terms have the meanings given:

[0056] The singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a gas” includes, but is not limited to, mixtures or combinations of two or more such gases, and the like.

[0057] “Comprising” indicates the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by,” “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” includes examples and aspects encompassed by the terms “consisting essentially of’ and “consisting of.” Similarly, the term “consisting essentially of’ includes examples encompassed by the term “consisting of’.

[0058] “ Consumable” refers to devices which are intended to be single use or multiple use and disposed of after said single use or said multiple use.

[0059] “Hyperpolarization” may comprise aligning the nuclear spins in a molecule (e.g., a gas molecule such as hydrogen, helium, or xenon) in the same direction. Hyperpolarization can achieve nuclear spin polarization far beyond thermal equilibrium conditions (e.g., at room temperature or standard metric conditions or about 15 °C). Hyperpolarization can align all or substantially all spins of the same molecule, achieving nuclear magnetic resonance (NMR) signal enhancement.

[0060] “Hyperpolarized gas” means a gas that has been subjected to hyperpolarization.

[0061] “Orthohydrogen” (0H2 or 0-H2) is an isomeric form of molecular hydrogen. In 0-H2, the spins of both nuclei are symmetrically aligned.

[0062] “Parahydrogen” (pH2 or p-Ffc) is a second isomeric form of molecular hydrogen. In pH2, the spins of both nuclei are anti-symmetrically aligned.

[0063] “Parahydrogen Induced Polarization” or “PHIP”, refers to a hyperpolarization technique using pH2as a source of spin transfer for inducing hyperpolarization.

[0064] “Polarization level” means a measure the of polarization level of the nuclear spins in a composition expressed as a percentage, representing the proportion of nuclear spins aligned in one direction versus random distribution (which is the case at thermal equilibrium). In various embodiments, the polarization level of a hyperpolarized gas is at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%.

[0065] “Signal amplification by reversible exchange” or “SABRE”, refers to a technique that can increase the visibility of compounds for the purpose of magnetic resonance spectroscopy (NMR) and magnetic resonance imaging (MRI) analysis, which in turn allows lower detection limits and shorter scan times in NMR, as well as higher contrast and higher resolution in MRI imaging. For example, in a SABRE process, a catalyst (e.g., an organometallic catalyst) can transfer spin order from parahydrogen to a target substrate, which can then be imaged or analyzed by NMR or MRI.

[0066] “ Thermal polarization” refers to the fraction of nuclear spins that align with a magnetic field under normal conditions. This is typically a small number and can be measured in units of parts per million (ppm), even in a strong magnetic field.Hyperpolarized gas (e.g., pHi) storage device

[0067] In one aspect, the present disclosure provides a device for storing a hyperpolarized gas, such as a parahydrogen (pH2) gas. The storage device may comprise a gas container. The gas container may enclose a storage volume. The storage volume may be used for storing the hyperpolarized gas. The gas container may include a wall which defines the storage volume. The gas container may have properties rendering it capable of storing a hyperpolarized gas for an extended period of time. The gas container may have properties rendering it capable of minimizing loss of spin order of the hyperpolarized gas during the extended period of time.

[0068] In some embodiments, the extended period of time may be at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 12 months, or more.

[0069] In some embodiments, the gas container may be capable of containing high pressure. In some embodiments, the high pressure may be from about 10 psi to about 50 psi, from about 10 psi to about 100 psi, from about 10 psi to about 200 psi, from about 10 psi to about 300 psi, from about 10 psi to about 400 psi, from about 10 psi to about 500 psi, from about 10 psi to about 600 psi, from about 10 psi to about 700 psi, from about 10 psi to about 800 psi, from about 10 psi to about 900 psi, from about 10 psi to about 1000 psi, from about 10 psi to about 1500 psi, from about 10 psi to about 2000 psi, from about 50 psi to about 100 psi, from about 50 psi to about 200 psi, from about 50 psi to about 300 psi, from about 50 psi to about 400 psi, from about 50 psi to about 500 psi, from about 50 psi to about 600 psi, from about 50 psi to about 700 psi, from about 50 psi to about 800 psi, from about 50 psi to about 900 psi, from about 50 psi to about 1000 psi, from about 50 psi to about 1500 psi, from about 50 psi to about 2000 psi, from about 100 psi to about 200 psi, from about 100 psi to about 300 psi, from about 100 psi to about 400 psi, from about 100 psi to about 500 psi, from about 100 psi to about 600 psi, from about 100 psi to about 700 psi, from about 100 psi to about 800 psi, from about 100 psi to about 900 psi, from about 100 psi to about 1000 psi, from about 100 psi to about 1500 psi, from about 100 psi to about 2000 psi, from about 200 psi to about 300 psi, from about 200 psi to about 400 psi, from about 200 psi to about 500 psi, from about 200 psi to about 600 psi, from about 200 psi to about 700 psi, from about 200 psi to about 800 psi, from about 200 psi to about 900 psi, from about 200 psi to about 1000 psi, from about 200 psi to about 1500 psi, from about 200 psi to about 2000 psi, from about 300 psi to about 400 psi, from about 300 psi to about 500 psi, from about 300 psi to about 600 psi, from about 300 psi to about 700 psi, from about 300 psi to about 800 psi, from about 300 psi to about 900 psi, from about 300 psi to about 1000 psi, from about 300 psi to about 1500 psi, from about 300 psi to about 2000 psi, from about 400 psi to about 500 psi, from about 400 psi to about 600 psi, from about 400 psi to about 700 psi, from about 400 psi to about 800 psi, from about 400 psi to about 900 psi, from about 400 psi to about 1000 psi, from about 400 psi to about 1500 psi, from about 400 psi to about 2000 psi, from about 500 psi to about 600 psi, from about 500 psi to about 700 psi, from about 500 psi to about 800 psi, from about 500 psi to about 900 psi, from about 500 psi to about 1000 psi, from about 500 psi to about 1500 psi, from about 500 psi to about 2000 psi, from about 600 psi to about 700 psi, from about 600 psi to about 800 psi, from about 600 psi to about 900 psi, from about 600 psi to about 1000 psi, from about 600 psi to about 1500 psi, from about 600 psi to about 2000 psi, from about 700 psi to about 800 psi, from about 700 psi to about 900 psi, from about 700 psi to about 1000 psi, from about 700 psi to about 1500 psi, from about 700 psi to about 2000 psi, from about 800 psi to about 900 psi, from about 800 psi to about 1000 psi, from about 800 psi to about 1500 psi, from about 800 psi to about 2000 psi, from about 900 psi to about 1000 psi,from about 900 psi to about 1500 psi, from about 900 psi to about 2000 psi, from about 1000 psi to about 1500 psi, from about 1000 psi to about 2000 psi, or from about 1500 psi to about 2000 psi.

[0070] In some embodiments, the gas container may be pressurized to at least about 100 psi, at least about 200 psi, at least about 300 psi, at least about 400 psi, at least about 500 psi, at least about 600 psi, at least about 700 psi, at least about 800 psi, at least about 900 psi, or at least about 1000 psi.

[0071] In some embodiments, the storage volume may be lined with an interface material in contact with the pH? gas. In some embodiments, the interface material may be selected to prevent loss of spin order of the pH? gas over an extended period of time. In some embodiments, the interface material may be selected to prevent more than 20%, more than 15%, more than 10%, or more than 5% loss of spin order of the pH2 gas. In some embodiments, the extended period of time may be over 30 days, over 40 days, over 50 days, over 60 days, over 70 days, over 80 days, over 90 days, over 100 days, over 110 days, over 120 days, over 150 days, over 200 days, or over 250 days. In some embodiments, the extended period of time may be sufficient for transportation of the gas container storing the hyperpolarized gas from one location to another, for example, a first location where the gas is hyperpolarized to a second location different from the first location. In some embodiments, the second location may be a place where spin transfer occurs. In some embodiments, the distance between the first location and the second location may be at least a walking distance of about 5 minutes (min), at least a walking distance of about 10 min, at least a walking distance of about 15 min, at least a walking distance of about 20 min, at least a walking distance of about 30 min, at least a walking distance of about 40 min, at least a walking distance of about 50 min, at least a walking distance of about 60 min, or more. In some embodiments, the distance between the first location and the second location may be at least about 500 meters, at least about 1 kilometer (km), at least about 2 km, at least about 3 km, at least about 4 km, at least about 5 km, at least about 10 km, at least about 15 km, at least about 20 km, at least about 25 km, at least about 50 km, at least about 100 km, or more.

[0072] In some embodiments, the interface material of the storage volume of the gas container may comprise aluminum. In some embodiments, the interface material of the storage volume of the gas container may comprise a plastic material. In some embodiments, the plastic material may be selected from the group consisting of polyether ether ketone (PEEK), poly etherketoneketone (PEKK), polycarbonate, polyamide-imide (PAI), poly etherimide (e.g., Ultem®, available from SABIC GLOBAL TECHNOLOGIES B.V.), polyphenylene sulfide (PPS), polytetrafluoroethylene (PTFE), or nylon, or a combination thereof. In someembodiments, the interface material of the storage volume of the gas container may comprise an amorphous silicon-based material (e.g., SulfiNert® or SilcoNert®, available from SilkoTek Corporation of Bellefonte, PA).

[0073] In some embodiments, the gas container may comprise an opening. In some embodiments, the gas container may comprise multiple openings. In some embodiments, the gas container may comprise a valved opening. In some embodiments, the gas container may comprise multiple valved openings. In some embodiments, the gas container may comprise an inlet. In some embodiments, the gas container may comprise multiple inlets. In some embodiments, the gas container may comprise an outlet. In some embodiments, the gas container may comprise multiple outlets.

[0074] In some embodiments, at least one region of a wall enclosing the storage volume may be flat. In some embodiments, at least one region of the top portion and bottom portion of the storage volume may be flat. In some embodiments, at least one region of the top portion and bottom portion of the storage volume may be curved. In some embodiments, one region of the top portion and bottom portion of the storage volume may be flat, and the other region of the top portion and bottom portion of the storage volume may be curved.

[0075] In some embodiments, the storage volume may have a flat top portion. In some embodiments, the storage volume may have a flat bottom portion. In some embodiments, the storage volume may have a flat top portion and a flat bottom portion.

[0076] In some embodiments, the storage volume may have a curved top portion. In some embodiments, the storage volume may have a curved bottom portion. In some embodiments, the storage volume may have a curved top portion and a curved bottom portion.

[0077] In some embodiments, the storage volume may have a shape configured to minimize loss of spin order of the hyperpolarized gas (e.g., pH? gas). In some embodiments, the shape may comprise a sphere, spheroid (oblate or prolate), ovoid, ellipsoid, globoid, cylinder, or spherocylinder. In some embodiments, an interior of the gas container may have a shape which is substantially a spheroid, a cylinder, or a spherocylinder.

[0078] In some embodiments, the gas container may be capable of storing pfh gas for an extended period of time. In some embodiments, the gas container may have a storage volume for storing the volume of the pH? gas, wherein the storage volume may have a shape selected to prevent loss of spin order of the pH2 gas over an extended period of time. In some embodiments, the shape may be selected to prevent more than about 20%, more than about 15%, more than about 10%, or more than about 5% loss of spin order of the pfh gas. In some embodiments, the extended period of time may be at least about 30 days, at least about 40 days, at least about 50days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 110 days, or at least about 120 days.

[0079] In some embodiments, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95% or more of an inner lining of the storage volume may be curved.

[0080] In some embodiments, no portion of an inner lining of the storage volume may have a radius of curvature of greater than about 20 cm, greater than about 25 cm, greater than about 30 cm, greater than about 35 cm, greater than about 40 cm, or greater than about 50 cm.

[0081] In some embodiments, the gas container may have a diameter of less than or equal to about 1 meter (m), less than or equal to about 0.9 m, less than or equal to about 0.8 m, less than or equal to about 0.7 m, less than or equal to about 0.6 m, less than or equal to about 0.5 m, or less.

[0082] In some embodiments, the gas container may have a storage volume of about 1 millimeter (mL) to about 5 mL, 1 mL to about 10 mL, about 1 mL to about 50 mL, about 1 mL to about 100 mL, about 1 mL to about 500 mL, about 1 mL to about 1 L, about 1 mL to about 10 L, about 1 mL to about 50 L, about 1 mL to about 100 L, about 5 mL to about 50 mL, about 5 mL to about 100 mL, about 5 mL to about 500 mL, about 5 mL to about 1 L, about 5 mL to about 10 L, about 5 mL to about 50 L, about 5 mL to about 100 L, about 10 mL to about 50 mL, about 10 mL to about 100 mL, about 10 mL to about 500 mL, about 10 mL to about 1 L, about 10 mL to about 10 L, about 10 mL to about 50 L, about 10 mL to about 100 L, about 50 mL to about 100 mL, about 50 mL to about 500 mL, about 50 mL to about 1 L, about 50 mL to about 10 L, about 50 mL to about 50 L, about 50 mL to about 100 L, about 100 mL to about 500 mL, about 100 mL to about 1 L, about 100 mL to about 10 L, about 100 mL to about 50 L, about 100 mL to about 100 L, about 500 mL to about 1 L, about 500 mL to about 10 L, about 500 mL to about 50 L, about 500 mL to about 100 L, about 1 L to about 10 L, about 1 L to about 50 L, about 1 L to about 100 L, about 10 L to about 50 L, about 10 L to about 100 L, or about 50 L to about 100 L.

[0083] In some embodiments, the gas container may have a weight of less than or equal to about 50 pounds (lbs), less than or equal to about 40 lbs, less than or equal to about 30 lbs, less than or equal to about 20 lbs, less than or equal to about 10 lbs, less than or equal to about 5 lbs, or less than or equal to about 1 lb.

[0084] In some embodiments, the gas container may be a single-use container. In some embodiments, the volume of pLL gas packaged and stored in the gas container may be sufficient for use of a single imaging session for one subject. In some embodiments, the single use container may have a volume ranging from about 100 microliters (pL) to about 5 L.

[0085] In some embodiments, the gas container may be a multi-use container. In some embodiments, the volume of pEE gas packaged and stored in the gas container may be sufficient for use for multiple imaging sessions for one subject. In some embodiments, the volume of pH? gas packaged and stored in the gas container may be sufficient for use for at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or more imaging sessions for one subject. In some embodiments, the volume of pEE gas packaged and stored in the gas container may be sufficient for use for multiple imaging sessions for more than one subject. In some embodiments, the volume of pEE gas packaged and stored in the gas container may be sufficient for use for at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or more imaging sessions for at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or more subjects. In some embodiments, the multiuse container may have a volume ranging from about 1 L to about 100 L.

[0086] In some embodiments, the gas container may further comprise at least one port coupled to the storage volume. In some embodiments, the at least one port may comprise a plurality of ports. In some embodiments, the gas container may be configured to couple to one or more generators of the pEE gas. In some embodiments, the gas container may be configured to couple to a hyperpolarized contrast agent hyperpolarization instrument.

[0087] In some embodiments, the gas container may be compliant with 49 CFR and IATA standards for hazardous material shipping.

[0088] FIG. 1A shows an exemplary gas container. The gas container comprises a gas container wall 2110. In some embodiments, the gas container wall can comprise stainless steel or aluminum. In some embodiments, the gas container comprises a gas container coating 2100 in the interior of the gas container wall 2110. In some embodiments, the gas container coating can comprise polyether ether ketone (PEEK), polyetherketoneketone (PEKK), polycarbonate, polyamide-imide (PAI), polyetherimide (e.g., Ultem®), polyphenylene sulfide (PPS), polytetrafluoroethylene (PTFE), or nylon, or a combination thereof. In some embodiments, the gas container coating can comprise an amorphous silicon-based material (e.g., SulfiNert® or SilcoNert®). The gas container can comprise a gas container valve 2200. In some embodiments, the gas container valve can comprise a CGA 320, CGA 350, CGA 580, CGA 940, or 0.750"-16UNF valve. The gas container can comprise a mating component 2250. In some embodiments, the mating component can comprise a CGA 870 medical oxygen, 2-pin yoke with a A" MNPT inlet or CGA 350 to 1 / 4" MNPT adapter.Reagent module

[0089] The present disclosure provides a reagent module for generating a hyperpolarized contrast agent. In some embodiments, the reagent module may be configured to contain the precursors for the hyperpolarized contrast agent.

[0090] In some embodiments, the reagent module may comprise one or more liquid reagent containers for storing one or more liquid reagents; and one or more solid reagent containers for storing one or more solid reagents.

[0091] In some embodiments, the one or more liquid reagents may comprise one or more of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), butyl acetate, methyl tert-butyl ether (MTBE), or any combinations thereof. In some embodiments, one liquid reagent container may store one liquid reagent. In some embodiments, one liquid reagent container may store two or more liquid reagents.

[0092] In some embodiments, any of the liquid reagents provided herein can be a deuterated solvent. In some embodiments, any of the liquid reagents provided herein can comprise a deuteration level of at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, at least about 99.5%, or more.

[0093] In some embodiments, the one or more solid reagents may comprise a substrate. In some embodiments, the substrate may comprise one or more of pyruvate, alpha-ketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate.

[0094] In some embodiments, the substrate may comprise a [l-13C]pyruvate. In some embodiments, the substrate may comprise [1-13C] sodium pyruvate, [1-13C] potassium pyruvate, or [ 1 -13C] pyruvate salt with another positive counter ion (e.g., calcium, lithium, magnesium). In some embodiments, the substrate may comprise a [2-13C]pyruvate. In some embodiments, the substrate may comprise [2-13C] sodium pyruvate, [2-13C] potassium pyruvate, or [2-13C] pyruvate salt with another positive counter ion (e.g., calcium, lithium, magnesium). In some embodiments, the substrate may comprise any of the substrate that has a hetero atom substitution of19F,29Si, or31P. In some embodiments, the substrate may comprise any combination of the substrates disclosed herein. In some embodiments, the substrate may be partially or fully deuterated. In some embodiments, the substrate may have at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or more deuteration.

[0095] In some embodiments, the one or more solid reagents may comprise a catalyst. In some embodiments, the catalyst may comprise a ligand and a metal center. In some embodiments, the ligand may comprise a N-heterocyclic carbene (NHC). In some embodiments, the NHC can comprise substituents on the heterocyclic ring. In some embodiments, the NHC can compriseany one of N,N-diaryl and N,N-dialkyl imidazolinylidene compounds, N,N-dialkyl and N,N- diaryl imidazolylidene compounds, N,N-dialkyl and N,N-diaryl bicyclic imidazolinylidene and imidazolylidene compounds. In some embodiments, the ligand may comprise l,3-bis(2,4,6- trimethylphenyl)imidazol-2-ylidine (IMes) or l,3-Bis(2,4,6-trimethylphenyl)-4,5- dihydroimidazol-2-ylidene (SIMes).

[0096] In some embodiments, the metal center may comprise Ir, Rh, Co, Ag, Au, Cu, Pt, Fe, Ru, Pd, or Ni, or a combination thereof. In some embodiments, the catalyst may be in a pre-catalyst form. In some embodiments, the catalyst may be converted to an active catalytic form (e.g., activated) when contacting the substrate and / or pH?. In some embodiments, the catalyst may be converted to an active catalytic form by a hydrogenation of the ligand, e.g., IMes or cyclooctadiene. In some embodiments, the catalyst may be converted to an active catalytic form by a hydrogenation to reduce the metal center and introduce exchangeable hydride species on the metal center. In some embodiments, the catalyst may be converted to an active catalytic form by mixing pFL with a mixture of the catalyst under pressurization. In some embodiments, the catalyst may be activated upon pressurizing the miscible solution and / or mixing with the parahydrogen gas.

[0097] In some embodiments, the catalyst may comprise Ir-IMes or Ir-SIMes.

[0098] In some embodiments, a liquid reagent container may comprise a syringe, a glass vial, a plastic vial, a plastic vessel, or a bag. In some embodiments, the liquid reagent container may have a volume from about 100 pL to about 1 mL, from about 100 pL to about 10 mL, from about 100 pL to about 100 mL, from about 100 pL to about 1 L, from about 1 mL to about 10 mL, from about 1 mL to about 100 mL, from about 1 mL to about 1 L, from about 10 mL to about 100 mL, from about 10 mL to about 1 L, or from about 100 mL to about 1 L.

[0099] In some embodiments, a solid reagent container may have a volume from about 100 pL to about 1 mL, from about 100 pL to about 5 mL, from about 100 pL to about 10 mL, from about 100 pL to about 50 mL, from about 100 pL to about 100 mL, from about 1 ml to about 5 mL, from about 1 ml to about 10 mL, from about 1 ml to about 50 mL, from about 1 ml to about 100 mL, from about 5 ml to about 10 mL, from about 5 ml to about 50 mL, from about 5 ml to about 100 mL, about 10 ml to about 50 mL, from about 10 ml to about 100 mL, or from about 50 ml to about 100 mL.

[0100] In some embodiments, the mass of a solid reagent may be from about 1 mg to about 1 g, from about 1 mg to about 10 g, from about 1 mg to about 50 g, from about 1 mg to about 100 g, from about 1 g to about 10 g, from about 1 g to about 50 g, from about 1 g to about 100 g, from about 10 g to about 50 g, from about 10 g to about 100 g, or from about 50 g to about 100 g.

[0101] In some embodiments, the reagent module may be provided as a reagent cartridge. In some embodiments, the reagent module may be configured to be removably coupled to any module of the modules disclosed herein in this application.

[0102] In some embodiments, the reagent module can comprise a first reagent container for storing a first liquid reagent; and a second reagent container for storing a second liquid reagent.

[0103] In some embodiments, the first liquid reagent may comprise a substrate and one or more solvents. In some embodiments, the one or more solvents in the first reagent container can be any one of the solvents disclosed in the present disclosure.

[0104] In some embodiments, the second liquid reagent may comprise a catalyst and one or more solvents. In some embodiments, the one or more solvents in the second reagent container can be any one of the solvents disclosed in the present disclosure.

[0105] In some embodiments, the substrate can be any one of the substrates disclosed in the present disclosure. In some embodiments, the catalyst can be any one of the catalysts disclosed in the present disclosure.

[0106] In some embodiments, the first reagent container and / or the second reagent container can comprise a syringe, a glass vial, a plastic vial, a plastic vessel, or a bag. In some embodiments, the first reagent container and / or the second reagent container can have a volume from about 100 pL to about 1 mL, from about 100 pL to about 10 mL, from about 100 pL to about 100 mL, from about 100 pL to about 1 L, from about 1 mL to about 10 mL, from about 1 mL to about 100 mL, from about 1 mL to about 1 L, from about 10 mL to about 100 mL, from about 10 mL to about 1 L, or from about 100 mL to about 1 L.

[0107] In some embodiments, the reagent module may comprise a liquid reagent container for storing one or more solvents, a first solid reagent container for storing a substrate, and a second solid reagent container for storing a catalyst. In some embodiments, the one or more solvents may comprise water and / or deuterated water. In some embodiments, the one or more solvents may comprise acetone and / or deuterated acetone. In some embodiments, the one or more solvents may comprise water (and / or deuterated water) and acetone (and / or deuterated acetone). In some embodiments, the one or more solvents may further comprise DMSO and / or deuterated DMSO. In some embodiments, the ratio of water (and / or deuterated water) to acetone (and / or deuterated acetone) may be from about 1 : 10 to about 10: 1. In some embodiments, the one or more solvents of the liquid reagent container may be stored in separate liquid reagent containers prior to being added to the liquid reagent container.

[0108] In some embodiments, the reagent container may comprise a substate, a catalyst, and one or more solvents. In some embodiments, the one or more solvents in the second reagent container can be any one of the solvents disclosed in the present disclosure. In someembodiments, the substrate can be any one of the substrates disclosed in the present disclosure. In some embodiments, the catalyst can be any one of the catalysts disclosed in the present disclosure.

[0109] FIG. IB shows an exemplary reagent cartridge 100. The reagent cartridge 100 may comprise a first reagent container 101 and a second reagent container 102. The reagent cartridge 100 may further comprise a cartridge seal 111. In some embodiments, the cartridge seal 111 comprises a sealing mechanism. In some embodiments, the sealing mechanism comprises gasket, O-ring, ball valve, umbrella valve, or duckbill valve. In some embodiments, the first reagent container 101 is a liquid reagent container, and the second reagent container 102 is a liquid reagent container, as disclosed in the present disclosure. In some embodiments, the first reagent container 101 is a liquid reagent container and the second reagent container 102 is a solid reagent container, as disclosed in the present disclosure.

[0110] In some embodiments, as shown in FIG. 2, the reagent cartridge 100 may further comprise a fluid line adapter apparatus 109a and 109b, wherein 109a is the upper portion of the fluid line adapter apparatus and 109b is the bottom portion of the fluid line adapter apparatus. In FIG. 2, the fluid line adapter apparatus is not coupled / inserted into the reagent cartridge.

[0111] FIG. 3 shows the configuration of an exemplary reagent cartridge 100, wherein the fluid line adapter apparatus (109a and 109b) is coupled / inserted into the reagent cartridge.

[0112] FIG. 4 shows a perspective view of the upper portion of the fluid line adapter apparatus 109a. In some embodiments, the upper portion of the fluid line adapter apparatus 109a can access the reagent cartridge by piercing or opening a seal on the cartridge.

[0113] FIG. 5 shows a top-down view of the bottom portion of the fluid line adapter apparatus 109b. In some embodiments, the bottom portion of the fluid line adapter apparatus 109b can be used for seating of a cartridge and / or localizing the cartridge features with the corresponding device features.

[0114] FIG. 6 shows a cross section view of the reagent cartridge 100, wherein the upper portion of the fluid line adapter apparatus 109a is not coupled / inserted to the reagent cartridge 100. The upper portion of the fluid line adapter apparatus 109a may comprise a balancing mechanism 130, e.g., spring(s) to adjust or regulate the connection of upper portion of the fluid line adapter apparatus 109a and the reagent cartridge 100. The reagent cartridge may further comprise a mixing apparatus 106 and an interface 120.

[0115] FIG. 7 shows a cross section view of the reagent cartridge 100, wherein the upper portion of the fluid line adapter apparatus 109a is coupled / inserted to the reagent cartridge 100. The reagent cartridge may further comprise a mixing apparatus 106 and an interface 120. The mixing apparatus can be located at the bottom of the reagent cartridge 100 or lateral to thereagent cartridge 100. In some embodiments, the mixing apparatus 106 is configured to receive a portion of the liquid reagent from the liquid reagent container 101 and a portion of the solid reagent from the solid reagent container 102, thereby allowing a reaction to take place to generate the hyperpolarized contrast agent.

[0116] In some embodiments, the fluid line adapter apparatus may regulate or control the flow of one or more solvents within the reagent cartridge. In some embodiments, the fluid line adapter apparatus may regulate or control the flow of a liquid reagent from a liquid reagent container to a solid reagent container, wherein the liquid reagent may be mixed with the solid reagent in the solid reagent container. In some embodiments, the fluid line adapter apparatus may regulate or control the flow of a solid reagent from a solid reagent container to a liquid reagent container, wherein the liquid reagent may be mixed with the solid reagent in the liquid reagent container.

[0117] In some embodiments, the fluid line adapter apparatus may regulate or control the flow of (i) one or more liquid reagents from one or more liquid reagent containers to a mixing apparatus and (ii) one or more solid reagents from one or more solid reagent containers to the mixing apparatus, wherein the one or more liquid reagents and the one or more solid reagents may be mixed in the mixing apparatus. In some embodiments, the fluid line adapter apparatus may control a mass or volume of a solid reagent or a liquid reagent to be mixed.Ejection module

[0118] The present disclosure provides an ejection module for generating hyperpolarized contrast agent with a hyperpolarized contrast agent preparation system and / or a hyperpolarization device. In some embodiments, the ejection module comprises one or more processing or output components for a solution ejection.

[0119] In some embodiments, the ejection module comprises one or more vessels, filters, or processing solutions. In some embodiments, the filters can comprise silica of any form, PES membrane, or PDMS membrane.

[0120] In some embodiments, the one or more processing or output components may be contained in a same housing.

[0121] In some embodiments, the one or more processing or output components may be contained in separate housings.

[0122] FIG. 8 shows an exemplary ejection module 800. The ejection module 800 may comprise an ejection vessel 801, an ejection adapter apparatus 802, and a cartridge interface localizer 803.

[0123] In some embodiments, the ejection module may be provided as an ejection cartridge. In some embodiments, the ejection module may be configured to be removably coupled to any module of the modules disclosed herein in this application.

[0124] In some embodiments, the ejection module can be used for mixing the hyperpolarized solution. In some embodiments, the mixing can be performed in a series of syringes or vessels with a processing solution. In some embodiments, the mixed hyperpolarized solution can be extracted through a single filter or a series of filters.Cleaning module

[0125] The present disclosure provides a cleaning module for a hyperpolarized contrast agent preparation system and / or a hyperpolarization device.

[0126] In some embodiments, the cleaning module may comprise a purge gas and / or a sterile cleaning solution.

[0127] In some embodiments, the purge gas may comprise an inert gas selected from the group consisting of Ar, N2 and He.

[0128] In some embodiments, the sterile cleaning solution may comprise water, alcohol, or a mixture thereof. In some embodiments, the alcohol can comprise methanol, ethanol, isopropanol, or a mixture thereof.

[0129] In some embodiments, the purge gas and the sterile cleaning solution may be configured to run through a device in sequence or separately.

[0130] In some embodiments, the cleaning module may be configured to be inserted and used with each cycle or after two or more cycles, or on an hourly, daily, or monthly basis.

[0131] In some embodiments, the cleaning module may be provided as a cleaning cartridge. In some embodiments, the cleaning module may be configured to be removably coupled to any module of the modules disclosed herein in this application.Purge gas module

[0132] The present disclosure provides a purge gas module (or an inert gas module) for a hyperpolarized contrast agent preparation system and / or a hyperpolarization device.

[0133] In some embodiments, the purge gas module may be provided as a purge gas cartridge. In some embodiments, the purge gas module may be configured to be removably coupled to any module of the modules disclosed herein in this application. In some embodiments, the purge gas module may be configured to provide purge gas to any of the modules disclosed herein.

[0134] The purge gas cartridge can comprise an inert gas, e.g., Ar, He, or N2.Gas filter module

[0135] The present disclosure provides a gas filter module for a hyperpolarized contrast agent preparation system and / or a hyperpolarization device.

[0136] In some embodiments, the gas filter module may be provided as a gas filter cartridge. In some embodiments, the gas filter module may be configured to be removably coupled to any module of the modules disclosed herein in this application.

[0137] In some embodiments, the gas filter may be configured to absorb, process, or purify used H2 gas. In some embodiments, the gas filter may comprise metal-organic framework, carbon nanotube, or graphite, or a combination thereof.

[0138] In some embodiments, the gas filter may be disposable. In some embodiments, the gas filter may be recyclable.

[0139] In some embodiments, used H2 gas may be collected into a container, e.g., a tank, before supplying to the gas filter. In some embodiments, the used H2 can be recycled to create additional pfh gas.Consumable cartridge system

[0140] The present disclosure provides consumable cartridge systems for generating hyperpolarized contrast agent and / or for aiding an NMR and / or MRI process.

[0141] FIG. 9 shows an exemplary cartridge system 900. The cartridge system 900 can comprise a hyperpolarized contrast agent preparation section 901 and a device flushing / cleaning section 920. The hyperpolarized contrast agent preparation section 901 can comprise a pfh gas cartridge 912. The pH2 gas cartridge can be a single use cartridge or a multiple use cartridge. The pH2gas cartridge can have a 3 to 12 months shelf life. The pfh gas cartridge can reflect storage considerations of pfh gas, e.g., safety, regulatory, and / or shelf life.

[0142] The hyperpolarized contrast agent preparation section 901 can further comprise a liquid reagent cartridge or a contrast agent solvents cartridge 903. The liquid reagent cartridge 903 can be configured to store one or more liquid reagents for hyperpolarized contrast agent generation. The liquid reagent cartridge 903 can contain different reagents needed for hyperpolarization process. The liquid reagent can comprise methanol and / or saline. In some embodiments, the one or more liquid reagents may comprise water and / or deuterated water. In some embodiments, the one or more liquid reagents may comprise acetone and / or deuterated acetone. In some embodiments, the one or more liquid reagents may comprise water (and / or deuterated water) and acetone (and / or deuterated acetone). In some embodiments, the one or more liquid reagents may further comprise DMSO and / or deuterated DMSO. In some embodiments, the one or moreliquid reagents may be stored in separate liquid reagent containers prior to being added to the liquid reagent cartridge.

[0143] In some embodiments, the liquid reagent cartridge may comprise a miscible solution. In some embodiments, the miscible solution may be biocompatible. In some embodiments, the miscible solution may comprise an aqueous component and a non-aqueous component. In some embodiments, the aqueous component may comprise water or deuterated water. In some embodiments, the aqueous component may comprise water and deuterated water. In some embodiments, the miscible solution may comprise at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, or more, water. In some embodiments, the miscible solution may comprise about 10% water. In some embodiments, the miscible solution may comprise about 20% water. In some embodiments, the miscible solution may comprise about 50% water. In some embodiments, the miscible solution may comprise buffer compounds. In some embodiments, the buffer compounds may comprise Tris, phosphate buffer, sodium bicarbonate buffer, or another biologically compatible aqueous buffer.

[0144] In some embodiments, the aqueous component may comprise at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or more deuterated water. In some embodiments, the aqueous component may comprise at most about 99%, at most about 90%, at most about 80%, at most about 70%, at most about 60%, at most about 50%, at most about 40%, at most about 30%, or less deuterated water.

[0145] In some embodiments, the non-aqueous component may comprise an organic solvent selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, t- butyl alcohol, acetone, methyl ethyl ketone (MEK), tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile, dioxane, and dimethyl sulfoxide (DMSO). In some embodiments, the nonaqueous component may comprise a derivative of the organic solvent disclosed herein. In some embodiments, the derivative may comprise a deuterated or fluorinated compound of the organic solvent as disclosed herein. In some embodiments, the non-aqueous component can comprise a combination of the organic solvents or derivatives as disclosed herein. In some embodiments, the non-aqueous component may comprise at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or more deuteration.

[0146] In some embodiments, the substrate may be substantially soluble in the aqueous component. In some embodiments, the substrate may be substantially non-soluble in the nonaqueous component. In some embodiments, the substrate may be partially soluble in the nonaqueous component. In some embodiments, the substrate may have a solubility in the aqueouscomponent that is at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, or more than a solubility in the non-aqueous component.

[0147] In some embodiments, the catalyst may be substantially soluble in the non-aqueous component. In some embodiments, the catalyst may be substantially non-soluble in the aqueous component. In some embodiments, the catalyst may be partially soluble in the aqueous component. In some embodiments, the catalyst may have a solubility in the non-aqueous component that is at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, or more than a solubility in the aqueous component.

[0148] In some embodiments, the volume ratio of the aqueous component to the non-aqueous component may be from about 1 : 10 to about 1 :9, from about 1 : 10 to about 1 :8, from about 1 : 10 to about 1 :7, from about 1 : 10 to about 1 :6, from about 1 : 10 to about 1 :5, from about 1 : 10 to about 1 :4, from about 1 : 10 to about 1 :3, from about 1 : 10 to about 1 :2, from about 1 : 10 to about 1 : 1, from about 1 : 10 to about 2: 1, from about 1 : 10 to about 3 : 1, from about 1 : 10 to about 4: 1, from about 1 : 10 to about 5: 1, from about 1 : 10 to about 6: 1, from about 1 : 10 to about 7: 1, from about 1 : 10 to about 8: 1, from about 1 : 10 to about 9: 1, or from about 1 : 10 to about 10:1.

[0149] In some embodiments, the substrate may be substantially soluble in the miscible solution. In some embodiments, the catalyst may be substantially soluble in the miscible solution. In some embodiments, the volume ratio of the aqueous component to the non-aqueous component may be selected to increase the solubility of the substrate and the catalyst in the miscible solution. In some embodiments, the volume ratio of the aqueous component to the nonaqueous component may be selected to increase the degree of polarization of the substrate. In some embodiments, the volume ratio of the aqueous component to the non-aqueous component may be selected to maximize the degree of polarization of the substrate.

[0150] In some embodiments, the miscible solution may comprise an additional component. In some embodiments, an additional component may be added to facilitate the exchange (i) between the pH? and the catalyst and / or (ii) between the pH? and the substrate in the presence of the catalyst. In some embodiments, the additional component may increase the miscibility of the aqueous component and the non-aqueous component. In some embodiments, the additionalcomponent may increase the solubility of the catalyst. In some embodiments, the additional component may increase the solubility of the substrate. In some embodiments, the additional component may comprise DMSO, ammonia, histidine, benzylamine, or a combination thereof. In some embodiments, the additional component may be from about 5% to about 10%, from about 5% to about 50%, or from about 10% to about 50%, of the total amount of the aqueous component and the non-aqueous component. In some embodiments, the additional component may be from about 1 mM to about 10 mM, from about 1 mM to about 100 mM, or from about 10 mM to about 100 mM, in the aqueous component and / or the non-aqueous component.

[0151] In some embodiments, the aqueous component and non-aqueous component may be combined in a liquid reagent container to form the miscible solution prior to mixing with the one or more solid reagents.

[0152] In some embodiments, the aqueous component may be mixed with the substrate to form a substrate solution in a first container. In some embodiments, the non-aqueous component may be mixed with the catalyst to form a catalyst solution in a second container. In some embodiments, the substrate solution and the catalyst solution may be mixed for the hyperpolarization reaction.

[0153] The liquid reagent cartridge can be single use cartridge or a multiple use cartridge. The liquid reagent cartridge can have a shelf life of at least about 3 months, at least about 6 months, at least about 9 months, or at least about 12 months.

[0154] The hyperpolarized contrast agent preparation section 901 can further comprise a solid reagent cartridge or a contrast agent reagents cartridge 904. The solid reagent cartridge 904 can be configured to store one or more solid reagents for hyperpolarized contrast agent generation. The one or more solid reagents may be dry and require solubilization in device for hyperpolarization solution. The one or more solid reagents can comprise a substrate, e.g., pyruvate. The one or more solid reagents can further comprise a catalyst, e.g., Ir-IMes. In some embodiments, the one or more solid reagents may be stored in separate containers in the solid reagent cartridge.

[0155] The solid reagent cartridge 904 can be single use cartridge or a multiple use cartridge. The solid reagent cartridge can have a shelf life of at least about 3 months, at least about 6 months, at least about 9 months, or at least about 12 months.

[0156] The device flushing / cleaning section 920 can comprise a purge gas cartridge 921. The device flushing / cleaning section 920 can further comprise a flushing / cleaning cartridge 922. The solution contained in the flushing / cleaning cartridge can comprise a sterile cleaning solution, e.g., ethanol.

[0157] The purge gas cartridge 921 can be single use cartridge or a multiple use cartridge. The purge gas cartridge 921 can have a shelf life of at least about 3 months, at least about 6 months, at least about 9 months, or at least about 12 months.

[0158] The flushing / cleaning cartridge 922 can be single use cartridge or a multiple use cartridge. The flushing / cleaning cartridge 922 can have a shelf life of at least about 3 months, at least about 6 months, at least about 9 months, or at least about 12 months.

[0159] Insertion of purge gas cartridge and / or cleaning cartridge may be timed, e.g., hourly, daily, or cyclic, e.g., after each hyperpolarized contrast agent preparation process. Purge gas and cleaning solution can be supplied to the reaction device in sequence or separately.

[0160] The cartridges described in FIG. 9, e.g., pH? gas cartridge, liquid reagent cartridge, solid reagent cartridge, purge gas cartridge, and cleaning cartridge, can be combined or separate.

[0161] FIG. 10 illustrates a schematic diagram of an exemplary cartridge system, according to many embodiments. A cartridge system 1000 can comprise multiple cartridges encased in a common device housing 985. The cartridge system 1000 can comprise a reagent and ejection cartridge 170 (Cartridge #1). The reagent and ejection cartridge 170 can comprise a reagent cartridge 100 and an ejection cartridge 115. The reagent cartridge 100 can comprise a fluid section (or a liquid reagent container) 101 and a solid section (or a solid reagent container) 102. The ejection cartridge 115 can comprise an ejection processing solution 117, ejection vessel(s) 103, and a filtration cartridge 105. In some embodiments, the reagent cartridge 100 can be single use. In some embodiments, the reagent cartridge 100 can be multiple use. In some embodiments, the ejection cartridge 115 can be single use. In some embodiments, the ejection cartridge 115 can be multiple use.

[0162] The cartridge system 1000 can further comprise a parahydrogen gas cartridge 171 (Cartridge #2) for storage and supply of parahydrogen gas 212. In some embodiments, the parahydrogen gas cartridge 171 can be single use. In some embodiments, the parahydrogen gas cartridge 171 can be multiple use.

[0163] The cartridge system 1000 can further comprise an inert gas cartridge 172 (Cartridge #3) for storage and supply of inert gas 214. In some embodiments, the inert gas cartridge 172 can be single use. In some embodiments, the inert gas cartridge 172 can be multiple use.

[0164] The cartridge system 1000 can further comprise a flushing solution cartridge 173 (Cartridge #4) for storage and supply of flushing solution (e.g., cleaning solution, sterile solution) 166. In some embodiments, the flushing solution cartridge 173 can be single use. In some embodiments, the flushing solution cartridge 173 can be multiple use.

[0165] The cartridge system 1000 can further comprise a gas filter cartridge 174 (Cartridge #5) comprising at least one gas filter 318 for filtering, absorbing, or processing gas waste (e.g.,hydrogen gas waste). In some embodiments, the gas filter cartridge 174 can be single use. In some embodiments, the gas filter cartridge 174 can be multiple use.

[0166] FIG. 11 illustrates a schematic diagram of an exemplary cartridge system, according to many embodiments. A cartridge system 1100 can comprise multiple cartridges encased in a common device housing 981. The cartridge system 1100 can comprise a reagent and ejection cartridge 150 (Cartridge #1). The reagent and ejection cartridge 150 can comprise a reagent cartridge 100, an ejection cartridge 115, and a flushing solution cartridge 104. The reagent cartridge 100 can comprise a fluid section (or a liquid reagent container) 101 and a solid section (or a solid reagent container) 102. The ejection cartridge 115 can comprise an ejection processing solution 117, ejection vessel(s) 103, and a filtration cartridge 105. The flushing solution cartridge 104 can be used for storage and supply of flushing solution (e.g., cleaning solution, sterile solution). In some embodiments, the reagent cartridge 100 can be single use. In some embodiments, the reagent cartridge 100 can be multiple use. In some embodiments, the ejection cartridge 115 can be single use. In some embodiments, the ejection cartridge 115 can be multiple use. In some embodiments, the flushing solution cartridge 104 can be single use. In some embodiments, the flushing solution cartridge 104 can be multiple use.

[0167] The cartridge system 1100 can further comprise a parahydrogen gas cartridge 151 (Cartridge #2) for storage and supply of parahydrogen gas 212. In some embodiments, the parahydrogen gas cartridge 151 can be single use. In some embodiments, the parahydrogen gas cartridge 151 can be multiple use.

[0168] The cartridge system 1100 can further comprise an inert gas cartridge 152 (Cartridge #3) for storage and supply of inert gas 214. In some embodiments, the inert gas cartridge 152 can be single use. In some embodiments, the inert gas cartridge 152 can be multiple use.

[0169] The cartridge system 1100 can further comprise a gas filter cartridge 153 (Cartridge #4) comprising at least one gas filter 318 for filtering, absorbing, or processing gas waste (e.g., hydrogen gas waste). In some embodiments, the gas filter cartridge 153 can be single use. In some embodiments, the gas filter cartridge 153 can be multiple use.

[0170] FIG. 12 illustrates a schematic diagram of an exemplary cartridge system, according to many embodiments. A cartridge system 1200 can comprise multiple cartridges encased in a common device housing 987. The cartridge system 1200 can comprise a reagent, ejection, and parahydrogen cartridge 180 (Cartridge #1). The reagent, ejection, and parahydrogen cartridge 180 can comprise a reagent cartridge 100, an ejection cartridge 115, and a parahydrogen gas cartridge 232. The reagent cartridge 100 can comprise a fluid section (or a liquid reagent container) 101 and a solid section (or a solid reagent container) 102. The ejection cartridge 115 can comprise an ejection processing solution 117, ejection vessel(s) 103, and a filtrationcartridge 105. The parahydrogen cartridge 232 can be used for storage and supply of parahydrogen gas. In some embodiments, the reagent cartridge 100 can be single use. In some embodiments, the reagent cartridge 100 can be multiple use. In some embodiments, the ejection cartridge 115 can be single use. In some embodiments, the ejection cartridge 115 can be multiple use. In some embodiments, the parahydrogen gas cartridge 232 can be single use. In some embodiments, the parahydrogen gas cartridge 232 can be multiple use.

[0171] The cartridge system 1200 can further comprise a flushing solution cartridge 181 (Cartridge #2) for storage and supply of flushing solution (e.g., cleaning solution, sterile solution). In some embodiments, the flushing solution cartridge 181 can be single use. In some embodiments, the flushing solution cartridge 181 can be multiple use.

[0172] The cartridge system 1200 can further comprise an inert gas cartridge 182 (Cartridge #3) for storage and supply of inert gas 214. In some embodiments, the inert gas cartridge 182 can be single use. In some embodiments, the inert gas cartridge 182 can be multiple use.

[0173] The cartridge system 1200 can further comprise a gas filter cartridge 183 (Cartridge #4) comprising at least one gas filter 318 for filtering, absorbing, or processing gas waste (e.g., hydrogen gas waste). In some embodiments, the gas filter cartridge 183 can be single use. In some embodiments, the gas filter cartridge 183 can be multiple use.

[0174] FIG. 13 illustrates a schematic diagram of an exemplary cartridge system, according to many embodiments. A cartridge system 1300 can comprise multiple cartridges encased in a common device housing 989.

[0175] The cartridge system 1300 can comprise a reagent cartridge 100 (Cartridge #1). The reagent cartridge 100 can comprise a fluid section (or a liquid reagent container) 101 and a solid section (or a solid reagent container) 102. In some embodiments, the reagent cartridge 100 can be single use. In some embodiments, the reagent cartridge 100 can be multiple use.

[0176] The cartridge system 1300 can comprise an ejection cartridge 115 (Cartridge #2). The ejection cartridge 115 can comprise an ejection processing solution 117, ejection vessel(s) 103, and a filtration cartridge 105. In some embodiments, the ejection cartridge 115 can be single use. In some embodiments, the ejection cartridge 115 can be multiple use.

[0177] The cartridge system 1300 can further comprise a parahydrogen gas cartridge 192 (Cartridge #3) for storage and supply of parahydrogen gas 212. In some embodiments, the parahydrogen gas cartridge 192 can be single use. In some embodiments, the parahydrogen gas cartridge 192 can be multiple use.

[0178] The cartridge system 1300 can comprise a flushing solution cartridge 193 (Cartridge #4) for storage and supply of flushing solution 166 (e.g., cleaning solution, sterile solution). Insome embodiments, the flushing solution cartridge 193 can be single use. In some embodiments, the flushing solution cartridge 193 can be multiple use.

[0179] The cartridge system 1300 can further comprise an inert gas cartridge 194 (Cartridge #5) for storage and supply of inert gas 214. In some embodiments, the inert gas cartridge 194 can be single use. In some embodiments, the inert gas cartridge 194 can be multiple use.

[0180] The cartridge system 1300 can further comprise a filter / collection cartridge 195 (Cartridge #6) comprising at least one gas filter / collection vessel 318 for filtering, absorbing, collecting, disposing, or processing gas waste (e.g., hydrogen gas waste). In some embodiments, the filter / collection cartridge 195 can be single use. In some embodiments, the filter / collection cartridge 195 can be multiple use.

[0181] FIG. 14 illustrates a schematic diagram of an exemplary hyperpolarization (HP) device 1400, according to many embodiments. The HP device 1400 comprises a cartridge system.

[0182] The cartridge system comprises fluid and reagent cartridges 150. The fluid and reagent cartridges 150 may comprise a reagent cartridge 100, an ejection cartridge 115, and a flushing solution cartridge 104. The reagent cartridge 100 may comprise a fluid section 101 and a solid section 102. The ejection cartridge 115 may comprise an ejection vessel 103, ejection processing solution 117, and a filtration cartridge 105. The flushing solution cartridge 104 may comprise a flushing or cleaning solution. The reagent cartridge 100 can be operatively coupled to a mixing apparatus 106, a temperature control apparatus 107, and a cartridge scanner 108. The reagent cartridge 100, the ejection cartridge 115, and the flushing cartridge 104 can be operatively coupled or connected to a fluid line switching apparatus 109 and / or a fluid line adapter apparatus 110. The fluid line switching apparatus 109 and / or a fluid line adapter apparatus 110 may supply or modulate the injection of fluid from the reagent cartridge 100, the ejection cartridge 115, and / or the flushing cartridge 104 to the fluid and gas reactor 401. The fluid line adapter apparatus can comprise a hermetically sealed quick connect fluid cartridge interface apparatus. This example shows an exemplary hyperpolarization process with a hyperpolarization (HP) device comprising any one of the cartridge systems disclosed herein.

[0183] The cartridge system may further comprise gas cartridges 210. The gas cartridges 210 may comprise a pH? gas cartridge 212 and an inert gas cartridge 214. The gas cartridges can comprise gas cartridge adapter apparatuses 216 for supplying or modulating the injection of pH? and / or inert gas to the fluid and gas reactor 401 and / or the flushing solution cartridge 104. The gas cartridges 210 can comprise sensors to determine the quality of the gases.

[0184] The HP device can further comprise a cartridge placement verification apparatus 112 for the position check and confirmation after a cartridge is inserted into the cartridge system.

[0185] The HP device can further comprise a placement sensor to monitor the components in the fluid and reagent cartridges.

[0186] The HP device can move the fluid and gas reactor to a magnetic control field X 415 for the hyperpolarization reaction. In some embodiments, the HP device can comprise an axial movement apparatus 411 to move the fluid and gas reactor 401 to a magnetic control field Y 416.

[0187] The HP device can comprise a gas filter cartridge 318 to absorb and / or process the hydrogen gas waste from the fluid and gas reactor. The purified / filtered hydrogen gas can be recycled back to the gas cartridges to regenerate pH? gas.

[0188] FIG. 15 illustrates a schematic diagram of an exemplary hyperpolarization (HP) device 1500, according to many embodiments. The cartridge system comprises fluid and reagent cartridges 150. The components of the HP device 1500 are similar to the HP device 1400, except that the reagent cartridge 100, the ejection cartridge 115, the flush solution cartridge 104, and gas cartridges 230 (including the pH? gas cartridge 232 and the inert gas cartridge 234) are encased in a common housing.

[0189] In some embodiments, the hyperpolarization device disclosed herein in this application may further comprise an additional reagent container for storing and providing the additional component. In some embodiments, the additional reagent container may be removably coupled to the hyperpolarization instrument. In some embodiments, the additional component (e.g., DMSO) may be injected automatically to the mixing apparatus. In some embodiments, the additional reagent container may be encased in the reagent cartridge. In some embodiments, the additional reagent container may be separate from the reagent cartridge.

[0190] In some embodiments, after the hyperpolarization, the hyperpolarized contrast agent may be purified. In some embodiments, the reaction mixture may be transferred to a purification cartridge. In some embodiments, the purification cartridge may be encased in the hyperpolarization device. In some embodiments, the purification cartridge may be separate from the hyperpolarization device. In some embodiments, the reaction mixture may be purified in the mixing apparatus directly without transferring to a purification cartridge.

[0191] In some embodiments, the hyperpolarization device may comprise a separation component container (or module) for storing and providing a separation component. In some embodiments, the separation component container may be removably coupled to the hyperpolarization instrument. In some embodiments, the separation component may be injected automatically to the reaction mixture (e.g., in the mixing apparatus or in the purification cartridge). In some embodiments, the separation component container may be provided as a standalone cartridge. In some embodiments, the separation component container may be encasedin the purification cartridge. In some embodiments, after the phase separation, the aqueous phase may be transferred to an additional purification cartridge for further purification. In some embodiments, after the phase separation, the non-aqueous phase may be removed and the remaining aqueous phase in the mixing apparatus or the purification cartridge may be further purified.

[0192] In some embodiments, the hyperpolarization device may further comprise an additional gas container for storing and providing a gas for gas-stripping the aqueous solution. In some embodiments, the additional gas container may be removably coupled to the hyperpolarization instrument. In some embodiments, the gas may be applied automatically to the isolated aqueous phase. In some embodiments, the additional gas container may be provided as a standalone cartridge. In some embodiments, the additional gas container may be encased in the purification cartridge.

[0193] In some embodiments, the hyperpolarization device may further comprise a receiving container for collecting the hyperpolarized substrate. In some embodiments, the receiving container may be coupled to a filter configured to filter the aqueous phase comprising the hyperpolarized substrate. In some embodiments, the receiving container may be removably coupled to the hyperpolarization instrument. In some embodiments, the receiving container may be provided as a standalone cartridge. In some embodiments, the receiving container may be encased in the purification cartridge. In some embodiments, the receiving container comprising the purified hyperpolarized contrast agent may be transported to the MRI site for MRI analysis of a subject.

[0194] In some embodiments, the present disclosure provides a kit comprising a packaged set of gas containers of pH2, wherein the gas container may be any one of gas containers disclosed herein. In some embodiments, the present disclosure provides a kit for aiding magnetic resonance imaging, the kit comprising: (i) the device disclosed herein for storing parahydrogen (pH2) gas; (ii) a first reagent container for storing a first reagent; and (iii) a second reagent container for storing a second reagent, wherein the device for storing pH2gas, the first reagent container, and the second reagent container may be each configured to removably couple to a hyperpolarization instrument configured to generate a hyperpolarized contrast agent based on the first reagent and the second reagent and convey spin order from the pH2gas to the contrast agent, thereby generating the hyperpolarized contrast agent. In some embodiments, the first reagent comprises a liquid reagent and the second reagent comprises a solid reagent. In some embodiments, the liquid reagent is a solvent or a mixture of solvents disclosed herein. In some embodiments, the solid reagent comprises a substrate disclosed herein. In some embodiments, the solid reagent further comprises a catalyst disclosed herein. In some embodiments, the firstreagent comprises a first liquid reagent and the second reagent comprises a second liquid reagent. In some embodiments, the first liquid reagent comprises a substrate disclosed herein and one or more solvents disclosed herein. In some embodiments, the second liquid reagent comprises a catalyst disclosed herein and one or more solvents disclosed herein. In some embodiments, the first reagent comprises a first liquid reagent and the second reagent comprises a second liquid reagent. In some embodiments, the kit further comprises a waste fluid collection container configured to removably couple to the hyperpolarization instrument to collect used hydrogen (H2). In some embodiments, the kit further comprises an ejection module disclosed herein. In some embodiments, the kit further comprising a cleaning module disclosed herein. In some embodiments, the kit further comprises a purge gas module disclosed herein. In some embodiments, the kit may further comprise a separation component container (or module) disclosed herein. In some embodiments, the separation component may comprise any separation component disclosed in this application. In some embodiments, the kit may further comprise an additional gas container, configured to provide a gas to gas-strip an aqueous phase comprising the hyperpolarized contrast agent. In some embodiments, the kit may further comprise a filter module, configured to filter an aqueous phase comprising the hyperpolarized contrast agent. In some embodiments, the kit may further comprise a receiver or receiving module configured to collect the purified hyperpolarized contrast agent.

[0195] In some embodiments, any of the modules or containers disclosed herein may be a single use module or container. In some embodiments, any of the modules or containers disclosed herein may be a multiple use module or container. In some embodiments, any of the modules or containers disclosed herein may be a disposable module or container. In some embodiments, any of the modules or containers disclosed herein may be a reusable module or container. In some embodiments, any of the modules or containers disclosed herein may be reused. The cartridge system or kit provided herein may enable the storage of precursors of the hyperpolarized contrast agent, the supplying of the precursors to generate the hyperpolarized contrast agent, and the purification of the hyperpolarized contrast agent. The cartridge system or kit may enable the storage of the precursors for an extended period of time. The cartridge system or kit may enable automated supplying of the precursors to a hyperpolarized device for generating the hyperpolarized contrast agent. The cartridge system or kit may enable monitoring of the polarization process. The cartridge system or kit may enable automated purification of the hyperpolarized contrast agent. Any of the modules or containers disclosed herein may be independently coupled to or decoupled from the hyperpolarization device, enabling easy and fast installation and / or replacement of the modules or containers.Method of generating hyperpolarized contrast agent

[0196] The present disclosure provides a method of generating a hyperpolarized contrast agent. The method comprises transferring spin order from parahydrogen (pH?) gas to a contrast agent. In some embodiments, the generating of a hyperpolarized contrast agent may be performed with Signal Amplification by Reversible Exchange (SABRE).

[0197] During the SABRE process, the contrast agent (or substrate) and the pH? molecule may reversibly bind to a catalyst, e.g., a metal center of the catalyst. The reversible bound of the pH? molecule and the contrast agent to the catalyst may form a catalytic complex. Singlet spin order of the pH? molecule may be converted into detectable nuclear magnetic polarization due to the symmetry breaking of the molecule. Polarization may flow through the temporary spin network formed in the catalytic complex, and the spin order of the pH? molecule can be transferred to the contrast agent to form a hyperpolarized contrast agent. The hyperpolarized contrast agent may detach or be released from the catalytic complex into the solution.

[0198] In some embodiments, generating a hyperpolarized contrast agent may comprise contacting the contrast agent with the pH? gas and subjecting the contrast agent to a magnetic field.

[0199] In some embodiments, generating the hyperpolarized contrast agent may be accomplished using a hyperpolarization instrument. In some embodiments, the hyperpolarization instrument can comprise a gas management system, fluid management system, and magnetic field control.

[0200] In some embodiments, the pH? gas may be provided in a gas container. In some embodiments, the gas container may be any of the gas container disclosed herein in this application.

[0201] In some embodiments, the method may further comprise coupling the gas container to the hyperpolarization instrument. In some embodiments, the gas container may be coupled to the hyperpolarization instrument by a pin adapter, push-to-connect adapter, NPT threads, or BSPT threads.

[0202] In some embodiments, the method may further comprise testing the gas container at a point of manufacture of the gas container. In some embodiments, the method may further comprise testing the gas container at a user site. In some embodiments, the quality of pH? gas may be checked prior to use. In some embodiments, the pH? gas may be checked upon failure of a quality assurance or quality control step. In some embodiments, the quality of the pH? gas may be checked via nuclear magnetic resonance (NMR) or Raman spectroscopy (RS) when the pH? gas is dispensed into the container. In some embodiments, the quality of the pH? gas may be checked via NMR or RS at a user site.

[0203] In some embodiments, the contrast agent may comprise any substrate as disclosed herein. In some embodiments, the contrast agent may comprise [ 1 -13C] sodium pyruvate. In some embodiments, the contrast agent may comprise [2-13C] sodium pyruvate.

[0204] In some embodiments, generating the hyperpolarized contrast agent may comprise mixing a volume of a liquid reagent and a mass of a solid reagent.

[0205] In some embodiments, the liquid reagent may be stored in a liquid reagent container and the solid reagent may be stored in a solid reagent container.

[0206] In some embodiments, the liquid reagent container and the solid reagent container may be encased in a reagent cartridge.

[0207] In some embodiments, the liquid reagent may comprise one or more solvents. In some embodiments, the one or more solvents can be any solvent disclosed herein in this application. In some embodiments, the liquid reagent may comprise a miscible solution as disclosed herein.

[0208] In some embodiments, the solid reagent may comprise a substrate. In some embodiments, the solid reagent may comprise a catalyst. In some embodiments, the substrate can be any substrate disclosed herein in this application. In some embodiments, the catalyst can be any catalyst disclosed herein in this application. In some embodiments, the liquid reagent container and solid reagent container may be encased in a reagent module.

[0209] In some embodiments, generating the hyperpolarized contrast agent may comprise mixing a volume of a first liquid reagent and a volume of a second liquid reagent. In some embodiments, the first liquid reagent may be stored in a first liquid reagent container and the second liquid reagent may be stored in a second liquid reagent container. In some embodiments, the first liquid reagent container and the second liquid reagent container may be encased in a reagent cartridge.

[0210] In some embodiments, the first liquid reagent may comprise a substrate and one or more solvents. In some embodiments, the second liquid reagent may comprise a catalyst and one or more solvents. In some embodiments, the one or more solvents in the first reagent container and the one or more solvents in the second reagent container can be any solvent disclosed herein in this application.

[0211] In some embodiments, the substrate can be any substrate disclosed herein in this application. In some embodiments, the catalyst can be any catalyst disclosed herein in this application.

[0212] In some embodiments, generating the hyperpolarized contrast agent may comprise mixing a substrate and a catalyst in one or more solvents. In some embodiments, the one or more solvents can be any solvent disclosed herein in this application. In some embodiments, the substrate can be any substrate disclosed herein in this application. In some embodiments, thecatalyst can be any catalyst disclosed herein in this application. In some embodiments, the one or more solvents may comprise a miscible solution as disclosed herein in this application.

[0213] In some embodiments, the method may further comprise, subjecting the solution comprising the substrate and the catalyst to a magnetic field.

[0214] In some embodiments, the method may further comprise applying pH? gas to the solution comprising the substrate and the catalyst.

[0215] In some embodiments, conveying spin order from the pH? gas to the contrast agent may comprise contacting the catalyst with the contrast agent. In some embodiments, the catalyst may comprise a metal catalyst. In some embodiments, the catalyst may comprise an organometallic catalyst. In some embodiments, the catalyst may comprise a pre-catalyst. In some embodiments, the pre-catalyst may be activated to an active catalyst upon contacting with a pH? gas and / or a substrate. In some embodiments, the catalyst, or a polarization transfer catalyst, may comprise a metal containing catalyst that transiently binds both contrast agent molecule and pH?, thereby allowing polarization to transfer from the pH? to the contrast agent in a magnetic field. In some embodiments, the metal in the polarization transfer catalyst may comprise iridium. In some embodiments, the iridium may be coordinated with species containing aromatic rings and / or nitrogen heterocycles.

[0216] In some embodiments, the catalyst may comprise a ligand and a metal center. In some embodiments, the ligand may comprise a N-heterocyclic carbene (NHC). In some embodiments, the NHC can comprise substituents on the heterocyclic ring. In some embodiments, the NHC can comprise any one ofN,N-diaryl and N,N-dialkyl imidazolinylidene compounds, N,N-dialkyl and N,N-diaryl imidazolylidene compounds, N,N-dialkyl and N,N-diaryl bicyclic imidazolinylidene and imidazolylidene compounds. In some embodiments, the ligand may comprise l,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidine (IMes) or 1,3-Bis(2,4,6- trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes).

[0217] In some embodiments, the metal center may comprise Ir, Rh, Co, Ag, Au, Cu, Pt, Fe, Ru, Pd, Ni, or a combination thereof.

[0218] In some embodiments, the catalyst may comprise Ir-IMes or Ir-SIMes.

[0219] In some embodiments, the catalyst can be immobilized on a surface. In some embodiments, the catalyst can be immobilized on a surface of a solid carrier, e.g., silica beads. In some embodiments, immobilizing the catalyst on a surface can aid in the removal of the catalyst from solutions. In some embodiments, the removal of the catalyst can comprise passing the solutions through a filter that traps the solid carrier the catalyst is immobilized on. In some embodiments, the catalyst can be recycled.

[0220] In some embodiments, the method may further comprise subjecting the contrast agent to a magnetic field. In some embodiments, the means for controlling the magnetic field within the reactor, e.g., the mixing apparatus, can be a radio frequency coil. In some embodiments, the means for controlling the magnetic field within the reactor can be a shielding mechanism to reduce the influence of Earth’s magnetic field. In some embodiments, such a shielding mechanism can allow access to a microTesla magnetic field in the reactor. In some embodiments, the means for controlling the magnetic field within the reactor can be a solenoid powered with a direct current to establish the desired magnetic field. In some embodiments, the means for controlling the magnetic field can be a permanent magnet array. In some embodiments, the means for controlling the magnetic field can be a superconducting magnet. In some embodiments, two or more of these means for controlling the magnetic field can be used simultaneously or sequentially. In some embodiments, the ideal magnetic field can be selected based on the chemical system and the spin physics of the hyperpolarization transfer process from parahydrogen to other nuclei. In some embodiments, the shielding mechanism is or incorporates mu metal. In some embodiments, mu-metal is a nickel-iron soft ferromagnetic alloy with very high permeability useful in shielding applications. In some embodiments, a mu-metal composition can comprise 77% nickel, 16% iron, 5% copper, and 2% chromium or molybdenum. In some embodiments, a mu-metal composition can comprise 80% nickel, 5% molybdenum, small amounts of silicon and / or other elements, and 12% to 15% iron. In some embodiments, the shielding mechanism can be a commercial product such as, for example, a Twinleaf MS- 1 L compact magnetic shield (Twinleaf LLC).

[0221] In some embodiments, the method may further comprise running an inert gas through the hyperpolarization instrument between uses to clear out fluid paths. In some embodiments, the inert gas comprises nitrogen (N2), helium (He), or argon (Ar).

[0222] In some embodiments, the inert gas may be stored and provided by an inert gas module / cartridge as disclosed herein in this application.

[0223] In some embodiments, the method may further comprise running a cleaning process. In some embodiments, the cleaning process may comprise flowing a cleaning or purging consumable through the hyperpolarization instrument. In some embodiments, the cleaning or purging consumable may comprise isopropanol, ethanol, saline, water, OTS antibacterial cleaning solution, or any combination thereof.

[0224] In some embodiments, the method may comprise running the cleaning process after each use of the hyperpolarization instrument.

[0225] In some embodiments, the method may comprise running the cleaning process at least once a month, at least twice a month, at least 3 times a month, at least 4 times a month, at leastonce a week, at least twice a week, at least 3 times a week, at least 4 times a week, at least 5 time a week, or more. In some embodiments, the cleaning process may be run at least once a day for each day that the hyperpolarization instrument is used.

[0226] In some embodiments, after hyperpolarization, the method may further comprise purifying the hyperpolarized contrast agent. In some embodiments, after the hyperpolarization, the hyperpolarized contrast agent may be purified through a series of processes to remove the catalyst and the non-aqueous solvents. The purification may generate pure or substantially pure hyperpolarized substrate that is biocompatible and may be injected directly into a subject for MRI analysis.

[0227] In some embodiments, the purification may comprise liquid-liquid extraction (LLE), selective absorption, filtration, adiabatic cycling, distillation, or gas stripping, or a combination thereof.

[0228] In some embodiments, the purification may comprise liquid-liquid extraction (LLE). The reacted solution may comprise the one or more solvents (e.g., water, acetone, and DMSO), the catalyst, the contrast agent, and the hyperpolarized contrast agent. With the LLE, the reacted solution may phase separate to an aqueous phase and a non-aqueous phase. In some embodiments, the LLE may separate the aqueous phase from the non-aqueous phase of the reacted solution. The aqueous phase may comprise the hyperpolarized contrast agent and nonaqueous phase may comprise the catalyst. In some embodiments, the aqueous phase may comprise trace catalyst and / or the non-aqueous solvent (e.g., acetone). In some embodiments, the LLE may comprise adding a separation component to the reacted solution. In some embodiments, the separation component may induce phase-separation of the reacted solution to the aqueous phase and the non-aqueous phase. In some embodiments, the separation component may comprise a Q3C Class 3 solvent as defined by the FDA, with solubility in water lower than 30,000 ppm and a boiling point higher than 40 °C. In some embodiments, the separation component may comprise a Q3C Class 3 solvent as defined by the FDA, with solubility in water lower than 20,000 ppm and a boiling point higher than 40 °C. In some embodiments, the separation component may comprise an ester. In some embodiments, the ester may be butyl acetate. In some embodiments, the ester may be isobutyl acetate. In some embodiments, the ester may be propyl acetate. In some embodiments, the ester may be isopropyl acetate. In some embodiments, the separation component may comprise an ether. In some embodiments, the ether may be methyl tert-butyl ether. In some embodiments, the ether may be diethyl ether. In some embodiments, the ether may be isopropyl ether. In some embodiments, the ether may be anisole. In some embodiments, the separation component may comprise methyl acetate, ethyl acetate, heptane, pentane, isoamyl alcohol, 1 -pentanol, ethyl formate, isobutyl acetate, 1 -butanol, 2-butanol, 3 -methyl- 1 -butanol, methyl ethyl ketone, 2-methyl-l -propanol, or triethylamine. In some embodiments, the separation component may comprise water or an aqueous buffer. In some embodiments, the aqueous buffer may comprise TrisHCl buffer, phosphate buffer, citrate buffer, or another biological buffer. In some embodiments, the separation component may comprise a salt, e g., NaCl, KC1, NaO2CCH3, KO2CCH3, NaOH, KOH, NaHCOs, KHCO3, Na2CO3, or K2CO3.

[0229] In some embodiments, the separation component may be added at an amount from about 10 wt% to about 20 wt%, from about 10 wt% to about 50 wt%, from about 10 wt% to about 100 wt%, from about 10 wt% to about 500 wt%, from about 10 wt% to about 1000 wt%, from about 10 wt% to about 5000 wt%, from about 10 wt% to about 10000 wt%, from about 20 wt% to about 50 wt%, from about 20 wt% to about 100 wt%, from about 20 wt% to about 500 wt%, from about 20 wt% to about 1000 wt%, from about 20 wt% to about 5000 wt%, from about 20 wt% to about 10000 wt%, from about 50 wt% to about 100 wt%, from about 50 wt% to about 500 wt%, from about 50 wt% to about 1000 wt%, from about 50 wt% to about 5000 wt%, from about 50 wt% to about 10000 wt%, from about 100 wt% to about 500 wt%, from about 100 wt% to about 1000 wt%, from about 100 wt% to about 5000 wt%, from about 100 wt% to about 10000 wt%, from about 500 wt% to about 1000 wt%, from about 500 wt% to about 5000 wt%, from about 500 wt% to about 10000 wt%, from about 1000 wt% to about 5000 wt%, from about 1000 wt% to about 10000 wt%, or from about 5000 wt% to about 10000 wt%.

[0230] In some embodiments, the separation component may be added at an amount (relative to the miscible solution) from about 10 vol% to about 20 vol %, from about 10 vol% to about 50 vol%, from about 10 vol% to about 100 vol%, from about 10 vol% to about 500 vol%, from about 10 vol% to about 1000 vol%, from about 10 vol% to about vol%, from about 10 vol% to about 10000 vol%, from about 20 vol% to about 50 vol%, from about 20 vol% to about 100 vol%, from about 20 vol% to about 500 vol%, from about 20 vol% to about 1000 vol%, from about 20 vol% to about 5000 vol%, from about 20 vol% to about 10000 vol%, from about 50 vol% to about 100 vol%, from about 50 vol% to about 500 vol%, from about 50 vol% to about 1000 vol%, from about 50 vol% to about 5000 vol%, from about 50 vol% to about 10000 vol%, from about 100 vol% to about 500 vol%, from about 100 vol% to about 1000 vol%, from about 100 vol% to about 5000 vol%, from about 100 vol% to about 10000 vol%, from about 500 vol% to about 1000 vol%, from about 500 vol% to about 5000 vol%, from about 500 vol% to about 10000 vol%, from about 1000 vol% to about 5000 vol%, from about 1000 vol% to about 10000 vol%, or from about 5000 vol% to about 10000 vol%.

[0231] In some embodiments, after the extraction solvent is added to the miscible solution, the resulting solution may be aspirated during the separation process (e.g., LLE). In some embodiments, the aspiration may use an inert gas, e.g., nitrogen, argon, or helium.

[0232] In some embodiments, after the LLE, the hyperpolarized contrast agent may be substantially in the aqueous phase and the catalyst may be substantially in the non-aqueous phase. In some embodiments, the LLE can recover at least about 70%, at least about 80%, at least about 90%, at least about 95%, or more hyperpolarized contrast agent. In some embodiments, after the phase separation, the aqueous phase comprising the hyperpolarized contrast agent can be collected. In some embodiments, the non-aqueous phase can be collected.

[0233] In some embodiments, the aqueous phase comprising the hyperpolarized contrast agent may comprise trace catalyst and / or non-aqueous solvent(s). In some embodiments, the aqueous phase comprising the hyperpolarized contrast agent can be further subjected to one or more LLEs. In some embodiments, the aqueous phase can be mixed with an additional separation component. Following the mixing, the mixture may be phase separated to an additional aqueous phase comprising the hyperpolarized contrast agent and an additional non-aqueous phase comprising the additional separation component. After the phase separation, the additional aqueous phase comprising the hyperpolarized contrast agent can be collected. In some embodiments, the purification can be repeated multiple times. In some embodiments, the purification may remove any residual catalyst in the aqueous phase. In some embodiments, the purification may increase the purity of the hyperpolarized contrast agent, e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%. In some embodiments, water or deuterated water can be added to the non-aqueous phase to extract at least a portion of the remaining hyperpolarized contrast agent from the non-aqueous phase. In some embodiments, the extraction can be performed multiple times to collect substantially all hyperpolarized contrast agent. In some embodiments, the aqueous phases from the LLE and subsequent LLEs can be combined. In some embodiments, the separated hyperpolarized contrast agent can be further purified.

[0234] In some embodiments, the aqueous phase comprising the hyperpolarized contrast agent may be further purified to remove one or more non-aqueous solvents. In some embodiments, the further purification may comprise subjecting the aqueous phase to a gas stripping process. In some embodiments, the gas stripping process may comprise applying (e.g., flowing or blowing) a gas to the aqueous phase. In some embodiments, the gas may comprise hydrogen, nitrogen, or argon. In some embodiments, the gas may remove or reduce the concentration of the one or more non-aqueous solvents from the aqueous phase. In some embodiments, the one or more non-aqueous solvents may comprise the non-aqueous component, the additional non-aqueouscomponent, and / or the separation component. In some embodiments, the one or more nonaqueous solvents may comprise acetone, DMSO, and / or butyl acetate.

[0235] In some embodiments, the gas-stripping may comprise applying a gas flow to the aqueous solution for about 1 second (s) to about 60 s. In some embodiments, the gas-stripping may comprise applying a gas flow to the aqueous solution for at least about 1 s, at least about 3 s, at least about 5 s, at least about 7 s, at least about 10 s, at least about 15 s, at least about 20 s, at least about 30 s, at least about 40 s, at least about 50 s, at least about 60 s, at least about 10 min, at least about 20 min, at least about 40 min, or at least about 60 min. In some embodiments, the gas-stripping may comprise applying a gas flow to the aqueous solution for at most about 60 min, at most about 40 min, at most about 20 min, at most about 10 min, at most about 1 min, at most about 50 s, at most about 40 s, at most about 30 s, at most about 20 s, at most about 10 s, at most about 7 s, at most about 5 s, or at most about 3 s.

[0236] In some embodiments, the gas-stripping may comprise applying a gas flow to the aqueous solution at a flow rate of at least about 10 standard cubic centimeters per minute (seem), at least about 50 seem, at least about 100 seem, at least about 500 seem, at least about 1000 seem or 1 standard liter per minute (slm), at least about 5 slm, or at least about 10 slm. In some embodiments, the flow rate may be at most about 10 slm, at most about 5 slm, at most about 1 slm, at most about 500 seem, at most about 100 seem, at most about 50 seem, or at most about 10 seem.

[0237] In some embodiments, the gas-stripping may be performed at a temperature of at least about 50 °C, at least about 60 °C, at least about 70 °C, at least about 80 °C, at least about 90 °C, at least about 100 °C, at least about 110 °C, at least about 120 °C, at least about 130 °C, at least about 140 °C, or at least about 150 °C. In some embodiments, the gas-stripping may be performed at a temperature of at most about 150 °C, at most about 140 °C, at most about 130 °C, at most about 120 °C, at most about 110 °C, at most about 100 °C, at most about 90 °C, at most about 80 °C, at most about 70 °C, at most about 60 °C, or at most about 50 °C.

[0238] In some embodiments, the gas-stripping may be performed at a pressure from about 1 pounds per square inch gauge (psig) to about 5 psig, from about 1 psig to about 10 psig, from about 1 psig to about 50 psig, from about 1 psig to about 100 psig, from about 5 psig to about 10 psig, from about 5 psig to about 50 psig, from about 5 psig to about 100 psig, from about 10 psig to about 50 psig, from about 10 psig to about 100 psig, or from about 50 psig to about 100 psig,

[0239] In some embodiments, the aqueous phase comprising the hyperpolarized contrast agent may be further purified to remove the trace catalyst. In some embodiments, the further purification may comprise filtration. In some embodiments, the filtration may comprise passing the aqueous phase through a filter. In some embodiments, the filter may comprise a membranefilter, silica (e.g., C18 silica) filter, metal-organic framework (MOF) filter, graphite filter, graphene filter, carbon nanotube filter, zeolite filter, or selectively absorptive material (e.g., Tenax). In some embodiments, the filter may be encased in a filtration cartridge. In some embodiments, the filtration cartridge may have a cross-section (CS) dimension (e.g., a diameter) from about 1 mm to about 5 mm, from about 1 mm to about 10 mm, from about 1 mm to about 20 mm, from about 1 mm to about 50 mm, from about 1 mm to about 100 mm, from about 5 mm to about 10 mm, from about 5 mm to about 20 mm, from about 5 mm to about 50 mm, from about 5 mm to about 100 mm, from about 10 mm to about 20 mm, from about 10 mm to about 50 mm, from about 10 mm to about 100 mm, from about 20 mm to about 50 mm, from about 20 mm to about 100 mm, or from about 50 mm to about 100 mm. In some embodiments, the filtration cartridge may have a length from about 1 mm to about 5 mm, from about 1 mm to about 10 mm, from about 1 mm to about 30 mm, from about 1 mm to about 50 mm, from about 1 mm to about 100 mm, from about 1 mm to about 300 mm, from about 1 mm to about 500 mm, from about 5 mm to about 10 mm, from about 5 mm to about 30 mm, from about 5 mm to about 50 mm, from about 5 mm to about 100 mm, from about 5 mm to about 300 mm, from about 5 mm to about 500 mm, from about 10 mm to about 30 mm, from about 10 mm to about 50 mm, from about 10 mm to about 100 mm, from about 10 mm to about 300 mm, from about 10 mm to about 500 mm, from about 30 mm to about 50 mm, from about 30 mm to about 100 mm, from about 30 mm to about 300 mm, from about 30 mm to about 500 mm, from about 50 mm to about 100 mm, from about 50 mm to about 300 mm, from about 50 mm to about 500 mm, from about 100 mm to about 300 mm, from about 100 mm to about 500 mm, or from about 300 mm to about 500 mm.

[0240] In some embodiments, the purified hyperpolarized contrast agent can be concentrated. In some embodiments, the separated hyperpolarized contrast agent can be diluted. In some embodiments, the separated hyperpolarized contrast agent can be used directly as the contrast agent in an MRI imaging. In some embodiments, the separated hyperpolarized contrast agent can be transferred to a buffered saline solution for use in an MRI imaging.

[0241] Any separation and / or purification process disclosed herein may be combined and be carried out in any suitable order and any suitable times.

[0242] In some embodiments, the hyperpolarized substrate may be purified through an LLE process, followed by a gas-stripping process, and followed by a filtration process. In some embodiments, the purification may comprise one or more additional LLE processes.

[0243] In some embodiments, the purification may be automated. In some embodiments, the purification may be fully automatic. In some embodiments, the purification may be semiautomatic.

[0244] In some embodiments, the hyperpolarization instrument outputs the hyperpolarized contrast agent into an administration device coupled to the hyperpolarization instrument. In some embodiments, the administration device may comprise a manual syringe, an auto-injection syringe, or an infusion pump.

[0245] In some embodiments, the method may further comprise recycling at least a portion of the catalyst in a volume of liquid waste. In some embodiments, the catalyst can be recycled by a method comprising acid and base extraction of the catalyst dissolved in hydrochloric acid solution

[0246] In some embodiments, the method may further comprise collecting used hydrogen (H2) gas into a tank. In some embodiments, the method may further comprise recycling the used H2 gas to create additional plfc gas. In some embodiments, the method may further comprise absorbing used Ifc gas into a filter. In some embodiments, the filter may comprise metal-organic framework, carbon nanotube, or graphite. In some embodiments, the filter is disposable. In some embodiments, the filter is recyclable.

[0247] In some embodiments, the present disclosure provides a method of providing a hyperpolarized contrast agent, the method comprising: coupling a gas container to a source or a generator of parahydrogen (plb) gas; conveying a volume of pH2 gas to the gas container; and storing the pH2 gas in the gas container, the gas container is capable of storing the plfc gas for an extended period of time of at least three months and allowing less than about 15% loss of spin order of the plfc gas during the extended period of time.

[0248] In some embodiments, the method may further comprise: storing a volume of liquid reagent in a liquid reagent container; storing a mass of solid reagent in a solid reagent container; coupling the gas container, the liquid reagent container, and the solid reagent container to a hyperpolarization instrument; mixing the liquid reagent and the solid reagent in the hyperpolarization instrument; and conveying spin order from the pH2 gas to a contrast agent with the hyperpolarization instrument, thereby generating the hyperpolarized contrast agent.

[0249] In some embodiments, the gas container, the liquid reagent container, or the solid reagent container may be provided within a single cartridge. In some embodiments, the gas container, the liquid reagent container, or the solid reagent container may be provided within separate cartridges.Method of conducting magnetic resonance imaging (MRI)

[0250] The present disclosure provides a method of conducting magnetic resonance imaging (MRI) on a subject. In some embodiment, the method comprising: a) generating a hyperpolarized contrast agent for administration to a subject; b) administering thehyperpolarized contrast agent to the subject; and c) using an MRI instrument, conducting MRI of the subject.

[0251] In some embodiments, generating the hyperpolarized contrast agent is timed to generate the hyperpolarized contrast agent within about 1 minute (min) to about 1 hour (h) of administration to the subject. In some embodiments, generating the hyperpolarized contrast agent is timed to generate the hyperpolarized contrast agent within about 1 min, within about 2 min, within about 5 min, within about 10 min, within about 20 min, within about 30 min, within about 40 min, within about 50 min, or within about 60 min of administration to the subject.

[0252] In some embodiments, conducting MRI of the subject is started within about 3 seconds (s) to within about 10 min of administering the hyperpolarized contrast agent to the subject. In some embodiments, conducting MRI of the subject is started within about 3 s, within about 10 s, within about 20 s, within about 30 s, within about 40 s, within about 50 s, within about 60 s, within about 70 s, within about 80 s, within about 90 s, within about 100 s, within about 110 s, within about 120 s, within about 3 min, within about 4 min, within about 5 min, within about 6 min, within about 7 min, within about 8 min, within about 9 min, or within about 10 min of administering the hyperpolarized contrast agent to the subject.

[0253] In some embodiments, MRI is a hyperpolarized gas MRI which utilizes a hyperpolarized gas as a contrast agent. In some embodiments, the MRI is a qualitative MRI which focuses on qualitative interpretation of MR data by acquiring spatial maps of relative variations in signal strength which are "weighted" by certain parameters. In some embodiments, the MRI is a quantitative MRI which determines spatial maps of accurate tissue relaxometry parameter values or magnetic field, or measures the size of certain spatial features. In some embodiments, the MRI is a real time MRI which continuously images a moving object in a real time.Computer systems

[0254] The present disclosure provides computer systems that are programmed to implement methods of the disclosure. FIG. 16 shows a computer system 1601 that is programmed or otherwise configured to, for example, regulate various aspects of hyperpolarized contrast agent generation, pH? gas transfer, MRI, and / or system monitoring as disclosed herein. In some cases, the computer system 1601 can be an electronic device of a user or a computer system that is remotely located with respect to the electronic device. The electronic device can be a mobile electronic device.

[0255] The computer system 1601 includes a central processing unit (CPU, also “processor” and “computer processor” herein) 1605, which can be a single core or multi core processor, or a plurality of processors for parallel processing. The computer system 1601 also includes memoryor memory location 1610 (e.g., random-access memory, read-only memory, flash memory), electronic storage unit 1615 (e.g., hard disk), communication interface 1620 (e.g., network adapter) for communicating with one or more other systems, and peripheral devices 1625, such as cache, other memory, data storage and / or electronic display adapters. The memory 1610, storage unit 1615, interface 1620 and peripheral devices 1625 are in communication with the CPU 1605 through a communication bus (solid lines), such as a motherboard. The storage unit 1615 can be a data storage unit (or data repository) for storing data. The computer system 1601 can be operatively coupled to a computer network (“network”) 1630 with the aid of the communication interface 1620. The network 1630 can be the Internet, an internet and / or extranet, or an intranet and / or extranet that is in communication with the Internet. The network 1630 in some cases is a telecommunication and / or data network. The network 1630 can include one or more computer servers, which can enable distributed computing, such as cloud computing. The network 1630, in some cases with the aid of the computer system 1601, can implement a peer-to-peer network, which may enable devices coupled to the computer system 1601 to behave as a client or a server.

[0256] The CPU 1605 can execute a sequence of machine-readable instructions, which can be embodied in a program or software. The instructions may be stored in a memory location, such as the memory 1610. The instructions can be directed to the CPU 1605, which can subsequently program or otherwise configure the CPU 1605 to implement methods of the present disclosure. Examples of operations performed by the CPU 1605 can include fetch, decode, execute, and writeback.

[0257] The CPU 1605 can be part of a circuit, such as an integrated circuit. One or more other components of the system 1601 can be included in the circuit. In some cases, the circuit is an application specific integrated circuit (ASIC).

[0258] The storage unit 1615 can store files, such as drivers, libraries and saved programs. The storage unit 1615 can store user data, e.g., user preferences and user programs. The computer system 1601 in some cases can include one or more additional data storage units that are external to the computer system 1601, such as located on a remote server that is in communication with the computer system 1601 through an intranet or the Internet.

[0259] The computer system 1601 can communicate with one or more remote computer systems through the network 1630. For instance, the computer system 1601 can communicate with a remote computer system of a user. Examples of remote computer systems include personal computers (e.g., portable PC), slate or tablet PC’s (e.g., Apple® iPad, Samsung® Galaxy Tab), telephones, Smart phones (e.g., Apple® iPhone, Android-enabled device, Blackberry®), or personal digital assistants. The user can access the computer system 1601 via the network 1630.

[0260] Methods as described herein can be implemented by way of machine (e.g., computer processor) executable code stored on an electronic storage location of the computer system 1601, such as, for example, on the memory 1610 or electronic storage unit 1615. The machine executable or machine readable code can be provided in the form of software. During use, the code can be executed by the processor 1605. In some cases, the code can be retrieved from the storage unit 1615 and stored on the memory 1610 for ready access by the processor 1605. In some situations, the electronic storage unit 1615 can be precluded, and machine-executable instructions are stored on memory 1610.

[0261] The code can be pre-compiled and configured for use with a machine having a processer adapted to execute the code, or can be compiled during runtime. The code can be supplied in a programming language that can be selected to enable the code to execute in a pre-compiled or as-compiled fashion.

[0262] Aspects of the systems and methods provided herein, such as the computer system 1601, can be embodied in programming. Various aspects of the technology may be thought of as “products” or “articles of manufacture” typically in the form of machine (or processor) executable code and / or associated data that is carried on or embodied in a type of machine readable medium. Machine-executable code can be stored on an electronic storage unit, such as memory (e.g., read-only memory, random-access memory, flash memory) or a hard disk. “Storage” type media can include any or all of the tangible memory of the computers, processors or the like, or associated modules thereof, such as various semiconductor memories, tape drives, disk drives and the like, which may provide non-transitory storage at any time for the software programming. All or portions of the software may at times be communicated through the Internet or various other telecommunication networks. Such communications, for example, may enable loading of the software from one computer or processor into another, for example, from a management server or host computer into the computer platform of an application server. Thus, another type of media that may bear the software elements includes optical, electrical and electromagnetic waves, such as used across physical interfaces between local devices, through wired and optical landline networks and over various air-links. The physical elements that carry such waves, such as wired or wireless links, optical links or the like, also may be considered as media bearing the software. As used herein, unless restricted to non-transitory, tangible “storage” media, terms such as computer or machine “readable medium” refer to any medium that participates in providing instructions to a processor for execution.

[0263] Hence, a machine readable medium, such as computer-executable code, may take many forms, including but not limited to, a tangible storage medium, a carrier wave medium or physical transmission medium. Non-volatile storage media include, for example, optical ormagnetic disks, such as any of the storage devices in any computer(s) or the like, such as may be used to implement the databases, etc. shown in the drawings. Volatile storage media include dynamic memory, such as main memory of such a computer platform. Tangible transmission media include coaxial cables; copper wire and fiber optics, including the wires that comprise a bus within a computer system. Carrier-wave transmission media may take the form of electric or electromagnetic signals, or acoustic or light waves such as those generated during radio frequency (RF) and infrared (IR) data communications. Common forms of computer-readable media therefore include for example: a floppy disk, a flexible disk, hard disk, magnetic tape, any other magnetic medium, a CD-ROM, DVD or DVD-ROM, any other optical medium, punch cards paper tape, any other physical storage medium with patterns of holes, a RAM, a ROM, a PROM and EPROM, a FLASH-EPROM, any other memory chip or cartridge, a carrier wave transporting data or instructions, cables or links transporting such a carrier wave, or any other medium from which a computer may read programming code and / or data. Many of these forms of computer readable media may be involved in carrying one or more sequences of one or more instructions to a processor for execution.

[0264] The computer system 1601 can include or be in communication with an electronic display 1635 that comprises a user interface (UI) 1640 for providing, for example, (i) display of the reaction parameters of hyperpolarization process, (ii) display of the system parameters (e.g., temperature, pressure, magnetic field, flow rate), (iii) the ability for the user to adjust a reaction parameter as disclosed herein, etc. Examples of UFs include, without limitation, a graphical user interface (GUI) and web-based user interface.

[0265] Methods and systems of the present disclosure can be implemented by way of one or more algorithms. An algorithm can be implemented by way of software upon execution by the central processing unit 1605. The algorithm can, for example, determine the level of polarization or the optimized reaction parameters for the hyperpolarization process.EXAMPLES

[0266] The following examples are provided to further illustrate some embodiments of the present disclosure, but are not intended to limit the scope of the disclosure; it will be understood by their exemplary nature that other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.Example 1: Hyperpolarization process

[0267] This example shows an exemplary hyperpolarization process (FIG. 17) with a hyperpolarization (HP) device comprising any one of the cartridge systems disclosed herein.

[0268] Step 17-1 : A user inserts gas filter cartridge (e.g., 318) into the HP device, followed by a gas filter cartridge position check. The gas filter cartridge position check can be performed manually by the user, or automatically by a cartridge replacement verification module 112.

[0269] Step 17-2: The user cleans and initializes a gas cartridge adapter apparatus 216.

[0270] Step 17-3: The user inserts gas cartridges, e.g., pH? gas cartridge 212 and inert gas cartridge 214, followed by gas cartridge position check. The gas cartridge position check can be performed manually by the user, or automatically by a cartridge replacement verification module 112. The pH2gas cartridge 212 and inert gas cartridge 214 can be separately or encased in a common housing, e.g., gas cartridge 210.

[0271] Step 17-4: The HP device runs a gas pressure check.

[0272] Step 17-5: The HP device runs pH2quality check.

[0273] Step 17-6: The user cleans and initializes fluid cartridge adapter apparatus 109.

[0274] Step 17-7: The user inserts fluid and reagent cartridges 150. The fluid and reagent cartridges 150 can comprise a reagent cartridge 100 comprising a fluid section 101 and a solid section 102, an ejection cartridge 115, and a flushing solution cartridge 104.

[0275] Step 17-8: The user closes or initializes the fluid line switching apparatus 109 and the fluid cartridge adapter apparatus 110.

[0276] Step 17-9: The HP device scans the reagent cartridge to determine system parameters, e.g., pressure, volume, etc. The scanning can be performed with a cartridge scanner 108.

[0277] Step 17-10: The HP device mixes the pre-HP solution, e.g., a contrast agent solution, or a solution to produce the hyperpolarized contrast agent, and stabilizes the temperature of the preHP solution using a temperature control apparatus 107. The mixing can be performed with a mixing apparatus 106.

[0278] Step 17-11 : The HP device injects the pre-HP solution into a reaction vessel (or fluid and gas reactor 401).

[0279] Step 17-12: The HP device pressurizes and hyperpolarizes the solution in the reaction vessel.

[0280] Step 17-13: The HP device moves the reaction vessel into a magnetic control field X 415.

[0281] Step 17-14: After the reaction is complete, the reaction vessel is depressurized.

[0282] Step 17-15: Ejection processing solution for extraction of the hyperpolarized material and aqueous phase is injected into the reaction vessel from the ejection cartridge by the fluid line switching apparatus and the fluid line adapter apparatus.

[0283] Step 17-16: The ejection cartridge (e.g., syringe) is removed for use of the hyperpolarized contrast agent.

[0284] Step 17-17: The user runs HP experiment.

[0285] Step 17-18: The user removes single user cartridge and starts new cycle from step 17-5.Example 2: Parahydrogen storage

[0286] This example shows the impact of coatings for parahydrogen storage and relaxation.

[0287] FIG. 18A shows a comparison of parahydrogen relaxation in an uncoated 1.7 L 6061 aluminum cylinder (solid diamonds) and a 1.0 L 306 stainless steel cylinder with an amorphous silicon-based coating (e.g., a SilcoNert® coating) (open triangles). The y-axis is the amount of parahydrogen gas in the cylinder and the x-axis is the time (in hours) from the initial cylinder filling with parahydrogen. The cylinder with the amorphous silicon-based coating retained about 75% of pH2for about 240 hours after cylinder filling. The cylinder without coating retained about 71% of pH2for about 240 hours after cylinder filling. Despite a smaller cylinder size for a similar cylinder design generally relaxes faster, the 1.0 L amorphous silicon-based coating coated cylinder relaxes slower than the uncoated aluminum cylinder, demonstrating improvement of the parahydrogen relaxation through decreased magnetic interactions with an inert coating relative to an impure aluminum cylinder.

[0288] FIG. 18B shows a comparison of parahydrogen relaxation in a 0.3 L 306 stainless steel cylinder coated with an amorphous silicon-based coating (e.g., a SilcoNert® coating) (open circles) or PTFE coating (solid squares). The y-axis is the amount of parahydrogen gas in the cylinder and the x-axis is the time (in hours) from the initial cylinder filling with parahydrogen. The cylinder with the amorphous silicon-based coating retained about 78% of pH2over one week after cylinder filling. The cylinder with PTFE coating retained about 66% of pH2over one week after cylinder filling. The cylinder with the amorphous silicon-based coating had approximately 10% higher parahydrogen percentage than the cylinder with PTFE coating over one week after cylinder filling.

[0289] The preferred examples shown are just one way of presenting the concept; there are many other possible variations and modifications that fit within the scope of this disclosure. A wide range of alterations, modifications, and replacements are possible. A wide range of alternatives to the embodiments of the present disclosure are possible.

Claims

CLAIMSWhat is claimed is:

1. A method of conducting magnetic resonance imaging (MRI) on a subject, the method comprising:(a) generating a hyperpolarized contrast agent for administration to the subject;(b) administering the hyperpolarized contrast agent to the subject; and(c) using an MRI instrument, conducting MRI of the subject.

2. The method of claim 1, wherein the generating the hyperpolarized contrast agent is timed to generate the hyperpolarized contrast agent within about 30 min of administration to the subject.

3. The method of claim 1, wherein the generating the hyperpolarized contrast agent is timed to generate the hyperpolarized contrast agent within about 10 min of administration to the subject.

4. The method of claim 1, wherein the conducting MRI of the subject is started within about 5 min of administering the hyperpolarized contrast agent to the subject.

5. The method of claim 1, wherein the conducting MRI of the subject is started within about 1 min of administering the hyperpolarized contrast agent to the subject.

6. The method of any one of claims 1-5, wherein the generating the hyperpolarized contrast agent comprises transferring spin order from parahydrogen (pH?) gas to a contrast agent.

7. The method of claim 6, wherein the generating the hyperpolarized contrast agent comprises contacting the contrast agent with the pH? gas and subjecting the contrast agent to a magnetic field.

8. The method of claim 7, further comprising, prior to applying the magnetic field, introducing a catalyst to the contrast agent.

9. The method of claim 7, further comprising, prior to contacting the contrast agent with the pH? gas, introducing a catalyst to the contrast agent.

10. The method of claim 8 or 9, further comprising recycling at least a portion of the catalyst in a volume of liquid waste.

11. The method of any one of claims 6-10, wherein the generating the hyperpolarized contrast agent is accomplished using a hyperpolarization instrument.

12. The method of claim 11, wherein the hyperpolarization instrument outputs the hyperpolarized contrast agent into an administration device coupled to the hyperpolarization instrument.

13. The method of claim 12, wherein the administration device is a manual syringe, an autoinjection syringe, or an infusion pump.

14. The method of any one of claims 6-13, further comprising collecting used hydrogen (H2) gas into a tank.

15. The method of claim 14, further comprising recycling the used H2 gas to create additional pffc gas.

16. The method of claim 14, further comprising absorbing used H2 gas into a filter.

17. The method of claim 16, wherein the filter comprises metal-organic framework, carbon nanotube, or graphite.

18. The method of claim 16, wherein the filter is disposable.

19. The method of claim 16, wherein the filter is recyclable.

20. The method of any one of claims 6-19, wherein the pffc gas is provided in a gas container.

21. The method of claim 20, wherein the diameter of the gas container is less than or equal to 1 meter (m).

22. The method of claim 20, wherein the gas container has a storage volume of about 100 microliters (pL) to about 100 liters (L).

23. The method of claim 20, wherein the gas container has a weight of less than or equal to about 30 lbs.

24. The method of claim 20, wherein the volume of pffc gas packaged and stored in the gas container is sufficient for use of a single imaging session for one subject.

25. The method of claim 20, wherein the gas container is a single use container.

26. The method of claim 20, wherein the pffc is provided in a multi-use container.

27. The method of claim 26, wherein the volume of pffc in the multi-use container is sufficient for use for multiple imaging sessions for multiple subjects or for a single subject.

28. The method of any one of claims 20-27, wherein an interior of the gas container has a shape which is substantially a spheroid, a cylinder, or a spherocylinder.

29. The method of any one of claims 20-28, wherein the gas container has a storage volume for storing the volume of the pffc gas, wherein the storage volume has a shape selected to prevent more than 15% loss of spin order of the pfb gas over 90 days.

30. The method of any one of claims 20-28, wherein the gas container has a storage volume for storing the volume of the pffc gas, wherein at least 80% of an inner lining of the storage volume is curved.

31. The method of any one of claims 20-28, wherein the gas container has a storage volume for storing the volume of the pH? gas, wherein no portion of an inner lining of the storage volume has a radius of curvature of greater than 30 cm.

32. The method of any one of claims 20-28, wherein the gas container is capable of storing pH2gas for an extended period of time.

33. The method of any one of claims 20-28, wherein:(a) the gas container has a storage volume for storing the volume of the pH2gas; and(b) the storage volume is lined with an interface material in contact with the pH2gas, the material being selected to prevent loss of more than 15% spin order of the pH2gas over 90 days.

34. The method of claim 33, wherein the interface material of the storage volume of the gas container comprises aluminum.

35. The method of claim 33, wherein the interface material of the storage volume of the gas container comprises a plastic material.

36. The method of claim 35, wherein the plastic material is selected from the group consisting of PEEK, PEKK, polycarbonate, PAI, poly etherimide, PPS, PTFE, nylon, and an amorphous silicon-based material.

37. The method of any one of claims 20-36, wherein the gas container is capable of containing high pressure.

38. The method of claim 37, wherein the high pressure is from 10 to 2,000 PSI.

39. The method of any one of claims 20-38, wherein the gas container comprises an inlet.

40. The method of any one of claims 20-38, wherein the gas container comprises multiple inlets.

41. The method of any one of claims 20-38, further comprising coupling the gas container to a hyperpolarization instrument.

42. The method of any one of claims 20-38, further comprising testing the gas container at a point of manufacture of the gas container.

43. The method of any one of claims 20-38, further comprising testing the gas container at a user site.

44. The method of any one of claims 20-38, wherein the quality of pH2gas is checked prior to use.

45. The method of any one of claims 20-38, wherein the quality of the pH2gas is checked via nuclear magnetic resonance (NMR) or Raman spectroscopy (RS) when the pH2gas is dispensed into the container.

46. The method of any one of claims 11-45, further comprising running an inert gas through the hyperpolarization instrument between uses to clear out fluid paths.

47. The method of claim 46, wherein the inert gas comprises nitrogen (N2), helium (He), or argon (Ar).

48. The method of any one of claims 11-45, further comprising running a cleaning process, the cleaning process comprising flowing a cleaning or purging consumable through the hyperpolarization instrument.

49. The method of claim 48, wherein the cleaning or purging consumable comprises isopropanol, ethanol, saline, water, OTS antibacterial cleaning solution, or any combination thereof.

50. The method of claim 48, comprising running the cleaning process after each use of the hyperpolarization instrument.

51. The method of claim 48, comprising running the cleaning process at least once a day for each day that the hyperpolarization instrument is used.

52. The method of claim 6, wherein (a) comprises mixing a volume of a liquid reagent and a mass of a solid reagent.

53. The method of claim 52, wherein the liquid reagent is stored in a liquid reagent container and the solid reagent is stored in a solid reagent container.

54. The method of claim 52, wherein the liquid reagent container and the solid reagent container are encased in a reagent cartridge.

55. The method of claim 52, wherein the liquid reagent is a solvent or a mixture of solvents.

56. The method of claim 52, wherein the liquid reagent comprises one or more of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), butyl acetate, methyl tert-butyl ether (MTBE), or any combinations thereof.

57. The method of claim 52, wherein the liquid reagent comprises a deuterated solvent.

58. The method of claim 52, wherein the solid reagent comprises a substrate.

59. The method of claim 58, wherein the solid reagent further comprises a catalyst.

60. The method of claim 6, wherein (a) comprises mixing a volume of a first liquid reagent and a volume of a second liquid reagent.

61. The method of claim 60, wherein the first liquid reagent is stored in a first liquid reagent container and the second liquid reagent is stored in a second liquid reagent container.

62. The method of claim 60, wherein the first liquid reagent container and the second liquid reagent container are encased in a reagent cartridge.

63. The method of claim 60, wherein the first liquid reagent comprises a substrate and one or more solvents.

64. The method of claim 63, wherein the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate- buffered saline (PBS), butyl acetate, and methyl tert-butyl ether (MTBE).

65. The method of claim 60, wherein the second liquid reagent comprises a catalyst and one or more solvents.

66. The method of claim 65, wherein the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate- buffered saline (PBS), butyl acetate, and methyl tert-butyl ether (MTBE).

67. The method of claim 60, wherein the first liquid reagent comprises a deuterated solvent.

68. The method of claim 60, wherein the second liquid reagent comprises a deuterated solvent.

69. The method of claim 6, wherein a) comprises mixing a substrate and a catalyst in one or more solvents.

70. The method of claim 69, wherein the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate- buffered saline (PBS), butyl acetate, and methyl tert-butyl ether (MTBE).

71. The method of claim 69, wherein the one or more solvents comprise a deuterated solvent.

72. The method of any one of claims 58, 63, or 69, wherein the substrate comprises one or more of pyruvate, alpha-ketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate.

73. The method of any one of claims 59, 65, or 69, wherein the catalyst comprises a ligand and a metal center.

74. The method of claim 73, wherein the ligand is l,3-bis(2,4,6-trimethylphenyl)imidazol-2- ylidine (IMes), l,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes), or a N-heterocyclic carbene (NHC).

75. The method of claim 73, wherein the metal center is Ir, Rh, Co, Ag, Au, Cu, Fe, Ru, Pd, Ni, or a combination thereof.

76. The method of any one of claims 59, 65, or 69, wherein the catalyst comprises Ir-IMes or Ir-SIMes.

77. The method of claim 20, wherein the gas container is compliant with 49 CFR and IATA standards for hazardous material shipping.

78. A method of providing a hyperpolarized contrast agent, the method comprising:(a) coupling a gas container to a source or a generator of parahydrogen (pH?) gas;(b) conveying a volume of pH? gas to the gas container; and(c) storing the pH? gas in the gas container, the gas container capable of storing the pH? gas for an extended period of time of at least three months and allowing lessthan about 15% loss of spin order of the pH? gas during the extended period of time.

79. The method of claim 78, further comprising:(1) storing a first reagent in a first reagent container;(2) storing a second reagent in a second reagent container;(3) coupling the gas container, the first reagent container, and the second reagent container to a hyperpolarization instrument;(4) transferring one or more reagents comprising a contrast agent in the hyperpolarization instrument; and(5) conveying spin order from the pH? gas to the contrast agent with the hyperpolarization instrument, thereby generating the hyperpolarized contrast agent.

80. The method of claim 79, wherein (4) comprises mixing a first reagent and a second reagent.

81. The method of claim 79 or 80, wherein two or more of the gas containers, the first reagent container, or the second reagent container are provided within a single cartridge.

82. The method of any one of claims 79-81, wherein two or more of the gas containers, the first reagent container, or the second reagent container are provided within separate cartridges.

83. The method of any one of claims 79-81, wherein the first reagent container and the second reagent container are encased in a reagent module.

84. The method of any one of claims 78-83, wherein the gas container is capable of containing high pressure.

85. The method of any one of claims 78-84, wherein:(a) the gas container has a storage volume for storing the volume of the pEE gas; and(b) the storage volume is lined with an interface material in contact with the pEE gas, the material being selected to prevent loss of less than 15% spin order of the pEE gas.

86. The method of claim 85, wherein the interface material of the storage volume of the gas container comprises aluminum.

87. The method of claim 85, wherein the interface material of the storage volume of the gas container comprises a plastic selected from the group consisting of PEEK, PEKK, polycarbonate, PAI, polyetherimide, PPS, PTFE, and nylon.

88. The method of claim 85, wherein the interface material of the storage volume of the gas container comprises an amorphous silicon-based material.

89. The method of any one of claims 78-88, wherein the gas container has a storage volume of about 1 mL to 100 L.

90. The method of any one of claims 78-89, wherein the gas container is pressurized to about 10 to 2,000 PSI.

91. The method of any one of claims 78-90, wherein the gas container has a storage volume for storing the volume of the parahydrogen gas, wherein the storage volume has the shape of a spheroid, a cylinder or a spherocylinder.

92. The method of any one of claims 78-91, wherein the gas container has a storage volume for storing the volume of the pH? gas, wherein at least 80% of an inner lining of the storage volume is curved.

93. The method of any one of claims 78-92, wherein the gas container comprises an inlet.

94. The method of any one of claims 78-92, wherein the gas container comprises multiple inlets.

95. The method of any one of claims 78-94, wherein the gas container has a diameter of less than or equal to 1 meter.

96. The method of any one of claims 78-95, wherein the gas container is a single-use container, and wherein the volume of parahydrogen gas packaged and stored in the gas container is sufficient for use of a single imaging session for one subject.

97. The method of any one of claims 78-95, wherein the gas container is a multi-use container, and wherein the volume of parahydrogen gas packaged and stored in the gas container is sufficient for use of multiple imaging session for multiple subjects or a single subject.

98. The method of any one of claims 78-97, further comprising testing the gas container at a point of manufacture of the gas container or at a user site.

99. The method of claim 98, wherein the quality of the plfc gas is checked via nuclear magnetic resonance (NMR) or Raman spectroscopy (RS) when the plfc gas is dispensed into the container.

100. The method of claim 98, wherein the quality of the plfc gas is checked via NMR or RS at a user site.

101. The method of any one of claims 98-100, wherein the plfc gas is checked upon failure of a quality assurance or quality control step.

102. The method of any one of claims 79-101, further comprising running an inert gas through the hyperpolarization instrument between uses to clear out fluid paths.

103. The method of claim 102, wherein the inert gas is nitrogen (N2), helium (He), or argon (Ar).

104. The method of any one of claims 79-103, wherein the first reagent container has a volume of less than or equal to IL.

105. The method of any one of claims 80-104, wherein the first reagent comprises a liquid reagent and the second reagent comprises a solid reagent.

106. The method of claim 105, wherein the liquid reagent is a solvent or a mixture of solvents.

107. The method of claim 105, wherein the liquid reagent comprises one or more of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), butyl acetate, methyl tert-butyl ether (MTBE), or any combinations thereof.

108. The method of claim 105, wherein the liquid reagent comprises a deuterated solvent.

109. The method of claim 105, wherein the solid reagent comprises a substrate.

110. The method of claim 109, wherein the solid reagent further comprises a catalyst.

111. The method of any one of claims 80-104, wherein the first liquid reagent comprises a liquid reagent and the second reagent comprises a second liquid reagent.

112. The method of claim 111, wherein the first liquid reagent comprises a substrate and one or more solvents.

113. The method of claim 112, wherein the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate- buffered saline (PBS), butyl acetate, and methyl tert-butyl ether (MTBE).

114. The method of claim 111, wherein the second liquid reagent comprises a catalyst and one or more solvents.

115. The method of claim 114, wherein the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate- buffered saline (PBS), butyl acetate, and methyl tert-butyl ether (MTBE).

116. The method of claim 111, wherein the first liquid reagent comprises a deuterated solvent.

117. The method of claim 112, wherein the second liquid reagent comprises a deuterated solvent.

118. The method of any one of claims 79-104, wherein (4) comprises mixing a substrate and a catalyst in one or more solvents.

119. The method of claim 118, wherein the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate- buffered saline (PBS), butyl acetate, and methyl tert-butyl ether (MTBE).

120. The method of claim 118, wherein the one or more solvents comprise a deuterated solvent.

121. The method of any one of claims 109, 112, and 118, wherein the substrate comprises one or more of pyruvate, alpha-ketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate.

122. The method of any one of claims 110, 114, and 118, wherein the catalyst comprises a ligand and a metal center.

123. The method of claim 122, wherein the ligand is l,3-bis(2,4,6-trimethylphenyl)imidazol- 2-ylidine (IMes), l,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes), or a N-heterocyclic carbene (NHC).

124. The method of claim 122, wherein the metal center is Ir, Rh, Co, Ag, Au, Cu, Fe, Ru, Pd, Ni, or a combination thereof.

125. The method of any one of claims 110, 114, and 118, wherein the catalyst comprises Ir- IMes or Ir- SIMes.

126. The method of any one of claims 79-125, further comprising a cleaning process, wherein the cleaning process comprises flowing a cleaning or purging consumable through the hyperpolarization instrument.

127. The method of claim 126, wherein the cleaning or purging consumable is contained in a cleaning module.

128. The method of claim 126, wherein the cleaning or purging consumable comprises ethanol, isopropanol, ethanol, saline, water, OTS antibacterial cleaning solution, or any combination thereof.

129. The method of claim 126, wherein the cleaning process is run after each use.

130. The method of claim 126, wherein the cleaning process is run each day.

131. The method of claim 126, wherein the cleaning process is run each month.

132. The method of claim 79, wherein conveying spin order from the pkh gas to the contrast agent comprises contacting a catalyst with the contrast agent.

133. The method of claim 132, wherein (5) further comprises subjecting the contrast agent to a magnetic field.

134. The method of claim 126, further comprising recycling at least a portion of the catalyst in a volume of liquid waste from the hyperpolarization instrument.

135. The method of claim 79, further comprising collecting used H2 gas in a tank to the hyperpolarization instrument.

136. The method of claim 135, further comprising recycling the used H2 gas to create more pH2.

137. The method of claim 78, wherein the gas container is compliant with 49 CFR and IATA standards for hazardous material shipping.

138. A system comprising a hyperpolarization instrument comprising one or more valves and power controls electronically coupled to and controlled by a computer, wherein the computer is programmed to perform any of the preceding methods.

139. A device for storing parahydrogen (pH?) gas, the device comprising: a gas container having a storage volume for storing the pH? gas, wherein the gas container is capable of storing the pH? gas for an extended period of time of at least three months and minimizing loss of spin order of the pH? gas during the extended period of time.

140. The device of claim 139, wherein the gas container is capable of containing high pressure.

141. The device of claim 140, wherein the high pressure is from 10 to 2,000 PSI.

142. The device of claim 139, wherein the gas container has a storage volume for storing the volume of the parahydrogen gas, wherein the storage volume is lined with an interface material in contact with the parahydrogen gas, the material being selected to minimize loss of spin order of the parahydrogen gas.

143. The device of claim 142, wherein the interface material of the storage volume of the gas container comprises aluminum.

144. The device of claim 142, wherein the interface material of the storage volume of the gas container comprises a plastic material selected from the group consisting of PEEK, PEKK, polycarbonate, PAI, polyetherimide, PPS, PTFE, and nylon.

145. The device of claim 142, wherein the interface material of the storage volume of the gas container comprises an amorphous silicon-based material.

146. The device of claim 139, wherein the gas container has a storage volume of about 1 mL to about 100 L.

147. The device of claim 139, wherein the gas container has a storage volume for storing the volume of the pH? gas, wherein the storage volume has a shape selected to minimize loss of spin order of the pH? gas.

148. The device of claim 139, wherein the gas container has a storage volume for storing the volume of the pH? gas, wherein the storage volume has the shape of a sphere, spheroid, ovoid, ellipsoid, globoid, cylinder, or spherocylinder.

149. The device of claim 139, wherein the gas container has a storage volume for storing the volume of the pH? gas, wherein the storage volume has a flat top and bottom portion.

150. The device of claim 139, wherein the gas container has a storage volume for storing the volume of the pH? gas, wherein the storage volume has a curved top and bottom portion.

151. The device of claim 139, wherein the gas container has a storage volume for storing the volume of the pH? gas, wherein at least 80% of an inner lining of the storage volume is curved.

152. The device of claim 139, wherein the gas container has a storage volume for storing the volume of the pH? gas, wherein no portion of an inner lining of the storage volume has a radius of curvature of greater than 30 cm.

153. The device of claim 139, wherein the gas container has a diameter of less than or equal to 1 meter.

154. The device of claim 139, wherein the gas container is a single-use container, and wherein the volume of pffc gas packaged and stored in the gas container is sufficient for use of a single imaging session for one subject.

155. The device of claim 139, wherein the gas container is a multi-use container, and wherein the volume of pffc gas packaged and stored in the gas container is sufficient for use of multiple imaging session for multiple subjects or for a single subject.

156. The device of claim 140, further comprises at least one port coupled to the storage volume and also configured to couple to one or more of a generator of the pTb gas or a hyperpolarized contrast agent hyperpolarization instrument.

157. The device of claim 156, wherein the at least one port comprises a plurality of ports.

158. A kit comprising a packaged set of gas containers of pEb, wherein the gas container is any one of claims 139-157.

159. A kit for aiding magnetic resonance imaging, the kit comprising:(a) the device of claim 139 for storing parahydrogen (pEb) gas;(b) a first reagent container for storing a first reagent; and(c) a second reagent container for storing a second reagent, wherein the device for storing pEE gas, the first reagent container, and the second reagent container are each configured to removably couple to a hyperpolarization instrument configured to generate a hyperpolarized contrast agent based on the first reagent and the second reagent and convey spin order from the pEE gas to a contrast agent, thereby generating the hyperpolarized contrast agent.

160. The kit of claim 159, wherein the first reagent comprises a liquid reagent and the second reagent comprises a solid reagent.

161. The kit of claim 160, wherein the liquid reagent is a solvent or a mixture of solvents.

162. The kit of claim 160, wherein the liquid reagent comprises one or more of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), butyl acetate, methyl tert-butyl ether (MTBE), or any combinations thereof.

163. The kit of claim 160, wherein the liquid reagent comprises a deuterated solvent.

164. The kit of claim 160, wherein the solid reagent comprises a substrate.

165. The kit of claim 164, wherein the solid reagent further comprises a catalyst.

166. The kit of claim 159, wherein the first reagent comprises a first liquid reagent and the second reagent comprises a second liquid reagent.

167. The kit of claim 166, wherein the first liquid reagent comprises a substrate and one or more solvents.

168. The kit of claim 167, wherein the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate- buffered saline (PBS), butyl acetate, and methyl tert-butyl ether (MTBE).

169. The kit of claim 166, wherein the second liquid reagent comprises a catalyst and one or more solvents.

170. The kit of claim 169, wherein the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate- buffered saline (PBS), butyl acetate, and methyl tert-butyl ether (MTBE).

171. The kit of claim 166, wherein the first liquid reagent comprises a deuterated solvent.

172. The kit of claim 166, wherein the second liquid reagent comprises a deuterated solvent.

173. The kit of claim 164 or 167, wherein the substrate comprises one or more of pyruvate, alpha-ketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate.

174. The kit of claim 165 or 169, wherein the catalyst comprises a ligand and a metal center.

175. The kit of claim 174, wherein the ligand is l,3-bis(2,4,6-trimethylphenyl)imidazol-2- ylidine (IMes) or l,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes).

176. The kit of claim 174, wherein the metal center is Ir, Rh, Co, Ag, Au, Cu, Fe, Ru, Pd, Ni, or a combination thereof.

177. The kit of claim 174, wherein the catalyst comprises Ir-IMes or Ir-SIMes.

178. The kit of claim 160, further comprising a waste fluid collection container configured to removably couple to the hyperpolarization instrument to collect used hydrogen (Ek).

179. The kit of claim 178, wherein the waste fluid collection container comprises a tank.

180. The kit of claim 159, further comprising an ejection module.

181. The kit of claim 180, wherein the ejection module comprises one or more processing or output components for a solution ejection.

182. The kit of claim 180, wherein the ejection module comprises one or more vessels, filters, or processing solutions.

183. The kit of claim 181, wherein the one or more processing or output components are contained in a same housing.

184. The kit of claim 181, wherein the one or more processing or output components are contained in separate housings.

185. The kit of claim 159, further comprising a cleaning module.

186. The kit of claim 185, wherein the cleaning module is configured to provide a cleaning or purging consumable through the hyperpolarization instrument.

187. The kit of claim 186, wherein the cleaning or purging consumable comprises ethanol, isopropanol, ethanol, saline, water, OTS antibacterial cleaning solution, or any combination thereof.

188. The kit of claim 159, further comprising a purge gas module.

189. The kit of claim 188, wherein the purge gas module comprises inert gas selected from the group consisting of N2, Ar, and He.

190. The kit of claim 159, further comprising a separation component module.

191. The kit of claim 190, wherein the separation component module is configured to store and provide a separation component to purify the hyperpolarized contrast agent.

192. The kit of claim 191, wherein the separation component comprises butyl acetate.

193. The kit of claim 159, further comprising an additional gas container, configured to provide a gas to gas-strip an aqueous phase comprising the hyperpolarized contrast agent.

194. The kit of claim 159, further comprising a filter module, configured to filter an aqueous phase comprising the hyperpolarized contrast agent.

195. An ejection module, comprising one or more processing or output components for a solution ejection.

196. The ejection module of claim 195, wherein the ejection module comprises one or more vessels, filters, or processing solutions.

197. The ejection module of claim 196, wherein the one or more processing or output components are contained in a same housing.

198. The ejection module of claim 196, wherein the one or more processing or output components are contained in separate housings.

199. A reagent module, comprising:(a) a liquid reagent container for storing a volume of liquid reagent; and(b) a solid reagent container for storing a mass of solid reagent.

200. The reagent module of claim 199, wherein the liquid reagent comprises one or more of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), butyl acetate, methyl tert-butyl ether (MTBE), or any combinations thereof.

201. The reagent module of claim 199, wherein the liquid reagent comprises a deuterated solvent.

202. The reagent module of claim 199, wherein the solid reagent comprises a substrate.

203. The reagent module of claim 200, wherein the substrate comprises one or more of pyruvate, alpha-ketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate.

204. The reagent module of claim 199, wherein the solid reagent comprises a catalyst.

205. The reagent module of claim 204, wherein the catalyst comprises a ligand and a metal center.

206. The reagent module of claim 205, wherein the ligand is l,3-bis(2,4,6- trimethylphenyl)imidazol-2-ylidine (IMes) or l,3-Bis(2,4,6-trimethylphenyl)-4,5- dihydroimidazol-2-ylidene (SIMes).

207. The reagent module of claim 205, wherein the metal center is Ir, Rh, Co, Ag, Au, Cu, Pt, Fe, Ru, Pd, Ni, or a combination thereof.

208. The reagent module of claim 204, wherein the catalyst comprises Ir-IMes or Ir-SIMes.

209. The reagent module of claim 199, wherein the liquid reagent container has a volume from about 100 pL to 1 L.

210. The reagent module of claim 199, wherein the liquid reagent container comprises a syringe, a glass vial, a plastic vial, a plastic vessel, or a bag.

211. The reagent module of claim 199, wherein the solid reagent container has a volume of about 100 pL to 100 mL.

212. The reagent module of claim 199, wherein the mass of solid reagent if from about 1 mg to 100 g.

213. A reagent module, comprising:(a) a first reagent container for storing a first liquid reagent; and(b) a second reagent container for storing a second liquid reagent.

214. The reagent module of claim 213, wherein the first liquid reagent comprises one or more of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), butyl acetate, methyl tert-butyl ether (MTBE), or any combinations thereof.

215. The reagent module of claim 213, wherein the first liquid reagent comprises a substrate and one or more solvents.

216. The reagent module of claim 215, wherein the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), butyl acetate, and methyl tert-butyl ether (MTBE).

217. The reagent module of claim 213, wherein the second liquid reagent comprises a catalyst and one or more solvents.

218. The reagent module of claim 217, wherein the one or more solvents are selected from the group consisting of ethanol, DMSO, methanol, water, saline, acetone, diethyl ether, phosphate-buffered saline (PBS), butyl acetate, and methyl tert-butyl ether (MTBE)219. The reagent module of claim 213, wherein the first liquid reagent comprises a deuterated solvent.

220. The reagent module of claim 213, wherein the second liquid reagent comprises a deuterated solvent.

221. The reagent module of claim 215, wherein the substrate comprises one or more of pyruvate, alpha-ketoglutarate, oxaloacetate, metronidazole, histidine, citrate, lactate, or glutamate.

222. The reagent module of claim 217, wherein the catalyst comprises a ligand and a metal center.

223. The reagent module of claim 222, wherein the ligand is l,3-bis(2,4,6- trimethylphenyl)imidazol-2-ylidine (IMes) or l,3-Bis(2,4,6-trimethylphenyl)-4,5- dihydroimidazol-2-ylidene (SIMes).

224. The reagent module of claim 222, wherein the metal center is Ir, Rh, Co, Ag, Au, Cu, Fe, Ru, Pd, Ni, or a combination thereof.

225. The reagent module of claim 217, wherein the catalyst comprises Ir-IMes or Ir-SIMes.

226. The reagent module of claim 213, wherein the liquid reagent container has a volume from about 100 pL to 1 L.

227. The reagent module of claim 213, wherein the first reagent container and / or the second reagent container comprise a syringe, a glass vial, a plastic vial, a plastic vessel, or a bag.

228. A cartridge device for storing one or more precursors to a hyperpolarized contrast agent, the cartridge device comprising one or more of (i) parahydrogen (pH?) gas module; (ii) reagent module; (iii) ejection module; (iv) cleaning module; or (v) purge gas module.

229. The cartridge device of claim 228, wherein each module or combination of modules is independently replaceable as a unit.

230. The cartridge device of claim 228, wherein each module may be suitable for multiple or single use.

231. The cartridge device of claim 228, wherein the pH? gas module comprises a gas container pressurized with pH? gas.

232. The cartridge device of claim 228, wherein the reagent module comprises a liquid reagent module and a solid reagent module.

233. The cartridge device of claim 232, wherein the liquid reagent module comprises ethanol, saline, and / or methanol.

234. The cartridge device of claim 232, wherein the solid reagent module comprises a catalyst and / or a substrate.

235. The cartridge device of claim 234, wherein the reagent module comprises multiple substrates to be hyperpolarized at once or in parallel.

236. The cartridge device of claim 234, wherein the catalyst comprises Ir-IMes or Ir-SIMes.

237. The cartridge device of claim 234, wherein the substrate comprises one or more of pyruvate or alpha-ketoglutarate.

238. The cartridge device of claim 228, wherein the cleaning module comprises a purge gas and / or a sterile cleaning solution.

239. The cartridge device of claim 238, wherein the purge gas comprises an inert gas selected from the group consisting of Ar, N2 and He.

240. The cartridge device of claim 238, wherein the sterile cleaning solution comprises ethanol.

241. The cartridge device of claim 238, wherein the purge gas and the sterile cleaning solution are configured to run through a device in sequence or separately.

242. The cartridge device of claim 238, wherein the cleaning module is configured to be inserted and used with each cycle or on an hourly, daily, or monthly basis.

243. The cartridge device of claim 228, wherein the ejection module comprises one or more vessels, filters, or processing solutions.

244. The cartridge device of claim 243, wherein the one or more processing or output components are contained in a same housing.

245. The cartridge device of claim 243, wherein the one or more processing or output components are contained in separate housings.

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