Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
  • G01R33/00—Arrangements or instruments for measuring magnetic variables
  • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
  • G01R33/28—Details of apparatus provided for in groups G01R33/44 - G01R33/64
  • G01R33/282—Means specially adapted for hyperpolarisation or for hyperpolarised contrast agents, e.g. for the generation of hyperpolarised gases using optical pumping cells, for storing hyperpolarised contrast agents or for the determination of the polarisation of a hyperpolarised contrast agent
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
  • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
  • A61K49/1806—Suspensions, emulsions, colloids, dispersions
  • A61K49/1815—Suspensions, emulsions, colloids, dispersions compo-inhalant, e.g. breath tests
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C1/00—Pressure vessels, e.g. gas cylinder, gas tank, replaceable cartridge
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C1/00—Pressure vessels, e.g. gas cylinder, gas tank, replaceable cartridge
  • F17C1/16—Pressure vessels, e.g. gas cylinder, gas tank, replaceable cartridge constructed of plastics materials
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
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  • F17C13/00—Details of vessels or of the filling or discharging of vessels
  • F17C13/002—Details of vessels or of the filling or discharging of vessels for vessels under pressure
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C13/00—Details of vessels or of the filling or discharging of vessels
  • F17C13/005—Details of vessels or of the filling or discharging of vessels for medium-size and small storage vessels not under pressure
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C3/00—Vessels not under pressure
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2201/00—Vessel construction, in particular geometry, arrangement or size
  • F17C2201/01—Shape
  • F17C2201/0128—Shape spherical or elliptical
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2201/00—Vessel construction, in particular geometry, arrangement or size
  • F17C2201/01—Shape
  • F17C2201/0147—Shape complex
  • F17C2201/0157—Polygonal
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2201/00—Vessel construction, in particular geometry, arrangement or size
  • F17C2201/01—Shape
  • F17C2201/0176—Shape variable
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2203/00—Vessel construction, in particular walls or details thereof
  • F17C2203/03—Thermal insulations
  • F17C2203/0304—Thermal insulations by solid means
  • F17C2203/0308—Radiation shield
  • F17C2203/032—Multi-sheet layers
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2203/00—Vessel construction, in particular walls or details thereof
  • F17C2203/06—Materials for walls or layers thereof; Properties or structures of walls or their materials
  • F17C2203/0602—Wall structures; Special features thereof
  • F17C2203/0604—Liners
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2203/00—Vessel construction, in particular walls or details thereof
  • F17C2203/06—Materials for walls or layers thereof; Properties or structures of walls or their materials
  • F17C2203/0602—Wall structures; Special features thereof
  • F17C2203/0612—Wall structures
  • F17C2203/0614—Single wall
  • F17C2203/0619—Single wall with two layers
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2203/00—Vessel construction, in particular walls or details thereof
  • F17C2203/06—Materials for walls or layers thereof; Properties or structures of walls or their materials
  • F17C2203/0634—Materials for walls or layers thereof
  • F17C2203/0636—Metals
  • F17C2203/0646—Aluminium
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2203/00—Vessel construction, in particular walls or details thereof
  • F17C2203/06—Materials for walls or layers thereof; Properties or structures of walls or their materials
  • F17C2203/0634—Materials for walls or layers thereof
  • F17C2203/0658—Synthetics
  • F17C2203/066—Plastics
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2203/00—Vessel construction, in particular walls or details thereof
  • F17C2203/06—Materials for walls or layers thereof; Properties or structures of walls or their materials
  • F17C2203/068—Special properties of materials for vessel walls
  • F17C2203/0697—Special properties of materials for vessel walls comprising nanoparticles
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2205/00—Vessel construction, in particular mounting arrangements, attachments or identifications means
  • F17C2205/01—Mounting arrangements
  • F17C2205/0103—Exterior arrangements
  • F17C2205/0115—Dismountable protective hulls
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2205/00—Vessel construction, in particular mounting arrangements, attachments or identifications means
  • F17C2205/03—Fluid connections, filters, valves, closure means or other attachments
  • F17C2205/0302—Fittings, valves, filters, or components in connection with the gas storage device
  • F17C2205/0323—Valves
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2205/00—Vessel construction, in particular mounting arrangements, attachments or identifications means
  • F17C2205/03—Fluid connections, filters, valves, closure means or other attachments
  • F17C2205/0302—Fittings, valves, filters, or components in connection with the gas storage device
  • F17C2205/0323—Valves
  • F17C2205/0329—Valves manually actuated
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2205/00—Vessel construction, in particular mounting arrangements, attachments or identifications means
  • F17C2205/03—Fluid connections, filters, valves, closure means or other attachments
  • F17C2205/0302—Fittings, valves, filters, or components in connection with the gas storage device
  • F17C2205/0352—Pipes
  • F17C2205/0364—Pipes flexible or articulated, e.g. a hose
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2205/00—Vessel construction, in particular mounting arrangements, attachments or identifications means
  • F17C2205/03—Fluid connections, filters, valves, closure means or other attachments
  • F17C2205/0388—Arrangement of valves, regulators, filters
  • F17C2205/0394—Arrangement of valves, regulators, filters in direct contact with the pressure vessel
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2221/00—Handled fluid, in particular type of fluid
  • F17C2221/01—Pure fluids
  • F17C2221/016—Noble gases (Ar, Kr, Xe)
  • F17C2221/017—Helium
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2221/00—Handled fluid, in particular type of fluid
  • F17C2221/07—Hyperpolarised gases
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
  • F17C2223/00—Handled fluid before transfer, i.e. state of fluid when stored in the vessel or before transfer from the vessel
  • F17C2223/01—Handled fluid before transfer, i.e. state of fluid when stored in the vessel or before transfer from the vessel characterised by the phase
  • F17C2223/0107—Single phase
  • F17C2223/0123—Single phase gaseous, e.g. CNG, GNC
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
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  • F17C2260/00—Purposes of gas storage and gas handling
  • F17C2260/01—Improving mechanical properties or manufacturing
  • F17C2260/013—Reducing manufacturing time or effort
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
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  • F17C2260/00—Purposes of gas storage and gas handling
  • F17C2260/01—Improving mechanical properties or manufacturing
  • F17C2260/018—Adapting dimensions
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  • F17C2270/00—Applications
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  • F17C2270/025—Breathing

Definitions

• the present invention relates to processing, storage, transport and deliver ⁇ ' containers for hyperpolarized noble gases.
• MRI Magnetic Resonance Imaging
• polarized noble gases can produce improved images of certain areas and regions of the body which have heretofore produced less than satisfactory images in this modality.
• Polarized Helium-3 C' 3 He and Xenon- 129 (“ 129 Xe”) have been found to be particularly suited for this purpose.
• the polarized state of the gases are sensitive to handling and environmental conditions and. undesirably, can decay from the polarized state relatively quickly.
• Hyperpolarizers are used to produce and accumulate polarized noble gases.
• Hyperpolarizers artificially enhance the polarization of certain noble gas nuclei (such as l29 Xe or ⁇ e) over the natural or equilibrium levels, i.e.. the Boltzmann polarization. Such an increase is desirable because it enhances and increases the MRI signal intensity, allowing physicians to obtain better images of the substance in the body. See U. S. Patent No. 5,545,396 to Albert et al, the disclosure of which is hereby incorporated herein by reference as if recited in full herein.
• the noble gas is typically blended with optically pumped alkali metal vapors such as rubidium (“Rb")- These optically pumped metal vapors collide with the nuclei of the noble gas and hyperpolarize the noble gas through a phenomenon known as "spin-exchange".
• the "optical pumping" of the alkali metal vapor is produced by irradiating the alkali-metal vapor with circularly polarized light at the wavelength of the first principal resonance for the alkali metal (e.g., 795 rrrn for Rb). Generally stated, the ground state atoms become excited, then subsequently decay back to the ground state.
• the hyperpolarized gas is separated from the alkali metal prior to introduction into a patient to form a non-toxic or sterile composition.
• the hyperpolarized gas can deteriorate or decay (lose its hyperpolarized state) relatively quickly and therefore must be handled, collected, transported, and stored carefully.
• the "Ti" decay constant associated with the hyperpolarized gas's longitudinal relaxation time is often used to describe the length of time it takes a gas sample to depolarize in a given container.
• the handling of the hyperpolarized gas is critical, because of the sensitivity of the hyperpolarized state to environmental and handling factors and the potential for undesirable decay of the gas from its hyperpolarized state prior to the planned end use. i.e., delivery to a patient. Processing, transporting, and storing the hyperpolarized gases — as well as delivery of the gas to the patient or end user — can expose the hyperpolarized gases to various relaxation mechanisms such as magnetic gradients, ambient and contact impurities, and the like.
• hyperpolarized gases such as I29 Xe and ⁇ e have been collected in relatively pristine environments and transported in specialty glass containers such as rigid PyrexTM containers. However, to extract the majority of the gas from these rigid containers, complex gas extraction means are typically necessary. Hyperpolarized gas such as " ⁇ e and 129 Xe has also been temporarily stored in single layer resilient Tedlar® and Teflon® bags. However, these containers have produced relatively short relaxation times.
• a first aspect of the invention is directed to a container for receiving a quantity of hyperpolarized gas.
• the container includes at least one wall comprising inner and outer layers configured to define an enclosed chamber for holding a quantity of hyperpolarized gas.
• the inner layer has a predetermined thickness and an associated relaxivity value which inhibits contact-induced polarization loss of the hyperpolarized gas.
• the outer layer defines an oxygen shield overlying the inner layer.
• the two layers can be integrated into one, if the material chosen acts as a polarization-friendly contact surface and is also resistant to the introduction of oxygen molecules into the chamber of the container.
• the container also includes a quantity of hyperpolarized noble gas and a port attached to the wall in fluid communication with the chamber for capturing and releasing the hyperpolarized gas therethrough.
• the container material(s) are selected to result in effective Ti's of greater than 6 hours for 3 He and greater than about 4 hours for 129 Xe due to the material alone.
• the oxygen shield is configured to reduce the migration of oxygen into the container to less than about 5 x 10 "6 amgt/min, and more preferably to less than about lxl 0 "7 amgt/min.
• the inner layer thickness ("L t h”) is at least as thick as the polarization decay length scale ("L p ") which can be determined by the equation:
• T p is the noble gas nuclear spin relaxation time in the polymer and D p is the noble gas diffusion coefficient in the polymer.
• a contact surface which has a thickness which is larger than the polarization decay length scale can minimize or even prevent the hyperpolarized gas from sampling the substrate (the material underlying the first layer).
• surfaces with polymer coatings substantially thinner than the polarization decay length scale can have a more detrimental effect on the polarization than surfaces having no such coating at all. This is because the polarized gas can be retained within the underlying material and interact with the underlying or substrate material for a longer time, potentially causing more depolarization than if the thin coating is not present.
• An additional aspect of the present invention is directed to a container with a wall formed of a single or multiple layers of materials which defines an expandable chamber.
• the inner surface of the wall is formed of a material which has a low relaxivity value for the (non-toxic) hyperpolarized fluid (hyperpolarized gas which is at least partially dissolved or liquefied) held therein .
• the wall is configured to define an oxygen shield to inhibit the migration of oxygen into the chamber.
• the T ⁇ of the hyperpolarized fluid held in the container is greater than about 6 hours.
• the container of the instant invention is configured to receive hyperpolarized 3 He and the inner layer is at least 16-20 microns thick.
• the container is an expandable polymer bag.
• the polymer bag includes a metallized coating positioned over the polymer which suppresses the migration of oxygen into the polymer and ultimately into the polarized gas holding chamber.
• a third layer is added onto the metallized layer (opposite the polymer chamber) for puncture resistance.
• the captured hyperpolarized gas can be delivered to the inhalation interface of a subject by exerting pressure on the bag to collapse the bag and cause the gases to exit the chamber. This, in turn, removes the requirement for a supplemental delivery mechanism.
• the container use seals such as O-rings which are substantially free of paramagnetic impurities.
• seals or O-rings be formed from substantially pure polyolefins such as polyethylene, polypropylene, copolymers and blends thereof.
• fillers which are friendly to hyperpolarization can be used (such as substantially pure carbon black and the like).
• the O-ring or seal can be coated with a surface material such as LDPE or deuterated HDPE or other low-relaxivity and property material and/or also preferably materials which have a low permeability for the hyperpolarized gas held in the chamber.
• the container can be configured such that once the gas is captured in the container to isolate a major portion of the hyperpolarized gas in the container away from potentially depolarizing components (such as fittings, valves, and the like) during transport and/or storage.
• another aspect of the present invention is a multi-layer resilient container for holding hyperpolarized gas.
• the container comprises a first layer of a first material configured to define an expandable chamber to hold a quantity of hyperpolarized gas therein.
• the first layer has a predetermined thickness sufficient to inhibit surface or contact depolarization of the hyperpolarized gas held therein wherein the first layer material has a relaxivity value "Y". It is also preferred that the relaxivity value "Y" is less than about 0.0012cm/min for 3 He and less than about O.Olcm/min for 129 Xe.
• the container also includes a second layer of a second material positioned such that the first layer is between the second layer and the chamber, wherein the first and second layers are concurrently responsive to the application of pressure and one or both of the first and second layers acts as an oxygen shield to suppress oxygen permeability into the chamber. Additional layers of materials can be positioned intermediate the first layer and the second layer.
• hyperpolarized gas has a low relaxivity value in the first layer material and the second layer preferably comprises a material which can shield the migration of the oxygen into the first layer.
• the resilient container has a first layer formed of a metal film (which can act both as an oxygen shield and contact surface).
• the relaxivity values are less than about .0023 cm/min and .0008 cm/min for 129 Xe and ⁇ e respectively.
• the hyperpolarized gas have a high mobility on the metal surface or small absorption energy relative to the metal contact surface such that the Ti of the gas in the container approaches > 50% of its theoretical limit.
• An additional aspect of the present invention is directed to a method for storing, transporting, and delivering hyperpolarized gas to a target.
• the method includes introducing a quantity of hyperpolarized gas into a multi-layer resilient container.
• the container has a wall comprising at least one material which provides an oxygen shield (i.e., is resistant to the transport of oxygen into the container).
• the container is expanded to capture the quantity of hyperpolarized gas.
• the container is sealed to contain the hyperpolarized gas therein.
• the container is transported to a site remote from the hyperpolarization site.
• the hyperpolarized gas is delivered to a target by compressing the chamber and thereby forcing the hyperpolarized gas to exit therefrom.
• the container in order to maintain the hyperpolarized state, is substantially continuously, from the time of polarization to the delivery, shielded and/or exposed to a proximately maintained homogeneous magnetic field to protect it from undesired external magnetic fields and/or field gradients. It is further preferred that the container be configured to be re- useable (after re-sterilization) to ship additional quantities of hyperpolarized gases.
• a further aspect of the present invention is configuring single or multi-layer resilient bags as described above with a capillary stem. The capillary stem is configured to restrict the flow of the hyperpolarized gas from the container when the valve is closed.
• the capillary stem is preferably positioned intermediate the container port and a valve member and, as such, forms a portion of the hyperpolarized gas (or liquid) entrance and exit path.
• the capillary stem is preferably configured with an inner passage which is sized and configured to inhibit the flow of the hyperpolarized gas and includes a gas contact surface formed of a polarization- friendly material.
• the capillary stem is preferably operably associated with a valve for the resilient container to allow the gas to be releasably captured and yet protected from any potentially depolarizing affect of the gas when the valve is closed. Similarh .
• a further aspect of the present invention is configuring single or multi-layer resilient bags as described above with an isolation means for directing the gas or fluid away from the bag port during transport and storage.
• the isolation means inhibits a major portion of the hyperpolarized gas or fluid from contacting selected components (fittings, valves, O-rings) operably associated with the bag.
• the isolation means is provided by a clamp positioned to compress the portion of the bag proximate to the port to inhibit the movement of gas thereabove.
• An additional aspect of the present invention is a method for preparing an expandable storage container for receiving a quantity of hyperpolarized gas.
• the method includes providing a quantity of substantially pure purge gas such as nitrogen or helium (preferably Grade 5 or better) into the hyperpolarized gas container and expanding the hyperpolarized gas container.
• the container is then collapsed to remove the purge gas.
• the oxygen in the container walls is outgassed by decreasing the oxygen partial pressure in the container, thereby causing a substantial amount of the oxygen trapped in the walls of the container to migrate into the chamber of the container in the gas phase where it can be removed.
• the container is filled with a quantity of storage gas such as nitrogen (again, preferably Grade 5 or better).
• the gas is introduced into the container at a pressure which reduces the pressure differential across the walls of the container to inhibit further outgassing of the container.
• the container is then stored for future use (the use being spaced apart in time from the point of preconditioning).
• the storage nitrogen and outgassed oxygen are removed from the container before filling with a quantity of hyperpolarized gas.
• the nitrogen is removed by evacuating the container before filling with a quantity of hyperpolarized gas.
• Another aspect of the present invention is directed to a method for determining the hyperpolarized gas ( 129 Xe or 3 He) solubility in a (unknown) polymer or a particular fluid.
• the method includes introducing a first quantity of hyperpolarized noble gas into a container having a known free volume and measuring a first relaxation time of the hyperpolarized gas in the container.
• a substantially clean sample of desired material is positioned into the container and a second quantity of hyperpolarized noble gas is introduced into the container.
• a second relaxation time of the second hyperpolarized gas is measured in the container with the sample material.
• the gas solubility of the sample is determined based on the difference between the two measured relaxation times.
• the material sample can be a structurally rigid sample (geometrically fixed) with a known geometric surface area/volume which is inserted into the free volume of the chamber or container. Alternatively, the material sample can be a liquid which partially fills chamber.
• the methods and containers of the present invention can improve the relaxation time (lengthen Ti) of the hyperpolarized gas or liquid or combinations of same held therein.
• the containers are configured such that the surface contacting the hyperpolarized gas (the hyperpolarized gas contact surface) has a minimum depth or thickness of a low-relaxivity value material relative to the hyperpolarized noble gas.
• the containers are configured to also inhibit oxygen migration into the gas chamber of the container.
• the container itself can define the contact surface by forming the container out of a resilient material such as a metallic or polymer bag.
• the bags are configured to inhibit the hyperpolarized gas from contacting potentially depolarizing components associated with the bag during transport or storage.
• the container is preferably a multi-layer container wherein each material layer provides one or more of strength, puncture resistance, and oxygen resistance to the container. Further, at least the inner surface is configured to provide a polarization friendly contact surface. This resilient configuration provides a relatively non- complex container and increased Tj's and can conveniently be re-used.
• the gas contact surface is preferably formed of either a polymer or a high purity metal.
• the resilient or collapsible containers can be used to deliver the gas into the patient interface without the need for additional delivery vehicles/ equipment. This can reduce the exposure, handling, and physical manipulation of the hyperpolarized gas which, in turn, can increase the polarization life of the hyperpolarized gas.
• Resilient containers with high purity contact surfaces can be extremely advantageous for both 129 Xe and 3 He as well as other hyperpolarized gases; however, the expandable (polymer) container and coatings/layers are especially suited for hyperpolarized ⁇ e.
• the instant invention preferably positions the container with the hyperpolarized gas in a homogenous magnetic field within a shipping container to shield the gas from stray magnetic fields, especially deleterious oscillating fields which can easily dominate other relaxation mechanisms.
• the present invention can be used to determine the gas solubility in polymers or fluids which in the past has proven difficult and sometimes inaccurate, especially for helium.
• one aspect of the present invention now provides a way to model the predictive behavior of surface materials and is particularly suited to determining the relaxation properties of polymers used as contact materials in physical systems used to collect, process, or transport hypeipolarized gases.
• the present invention successfully provides relaxation properties of various materials (measured and/or calculated). These relaxation values can be used to determine the relaxation time (T ⁇ ) of hyperpolarized gas in containers corresponding to the solubility of the gas, the surface area of the contact material, and the free gas volume in the container. This information can be advantageously used to extend the hypeipolarized life of the gas in containers over those which were previously achievable in high-volume production systems.
• Figure 1 is a schematic diagram of a spin-down station used to measure relaxation times according to one aspect of the present invention.
• Figure 2 is a graph showing the polarization level of a gas associated with the distance x the gas moves into a polymer.
• Figure 3 is a graph showing the results of the standardized relaxation times plotted against solubility (measured and theoretical) for various materials (T ⁇ cc representing the relaxation time for 12 Xe hyperpolarized gas in a one cubic centimeter sphere).
• Figure 4 is a graph similar to Figure 3 showing the results of standardized relaxation times for ⁇ e.
• Figure 5 is a detailed chart of experimental material values for Xenon and Helium.
• Figure 6 is a detailed chart of predicted material values for Xenon and Helium.
• Figure 7 is a perspective view of a hypeipolarized gas container according to one embodiment of the present invention in a deflated state.
• Figure 8 is a perspective view of the container of Figure 7, shown in an inflated state.
• Figure 9 is a sectional view of an alternate embodiment of a container according to the present invention.
• Figure 10 is an enlarged partial cutaway section view of the container wall according to another embodiment of the present invention.
• Figure 11 is an enlarged partial cutaway section view of an additional embodiment of a container wall according to the present invention.
• Figure 12 is an enlarged partial cutaway section view of yet another embodiment of a container wall according to the present invention.
• Figure 13 is a perspective view of a preferred embodiment of a container with a seal according to the present invention.
• Figure 14 illustrates the container of Figure 13 with an alternative external seal according to an additional embodiment of the present invention.
• Figure 15 illustrates another container with an alternative seal arrangement according to another embodiment of the present invention.
• Figure 15A is an exploded view of the container shown in Figure 15.
• Figure 16 is a side perspective view of a shielded shipping receptacle configured to receive the container according to one embodiment of the present invention.
• Figure 17 is a schematic illustration of the resilient container of Figure 13 shown attached to a user interface adapted to receive the container for delivering the hype ⁇ olarized gas therein to the user according to one embodiment of the present invention.
• Figure 18 shows the container of Figure 17 in a deflated condition after forces on the container cause the hyperpolarized gas to exit the container and enter the target.
• Figure 19 is a schematic illustration of the container of Figure 15 shown attached to a user interface according to one embodiment of the present invention.
• Figure 20 is a block diagram of a method for determining gas solubility in a polymer according to one embodiment of the present invention.
• Figures 21A-21C are perspective views of an alternative embodiment of a container with a port isolation means according to the present invention.
• the hyperpolarized gas described herein can be a hyperpolarized gas composition/ mixture (non-toxic such that it is suitable for in vivo introduction) such that the hype ⁇ olarized noble gas can be combined with other noble gases and/or other inert or active components.
• the term "hype ⁇ olarized gas” can include a product where the hype ⁇ olarized gas is dissolved into another liquid (such as a carrier) or processed such that it transforms into a substantially liquid state, i.e., "a liquid polarized gas”.
• a liquid polarized gas includes the word "gas”
• this word is used to name and descriptively track the gas produced via a hype ⁇ olarizer to obtain a polarized "gas” product.
• gas has been used in certain places to descriptively indicate a hype ⁇ olarized noble gas which can include one or more components and which may be present in one or more physical forms.
• Preferred hype ⁇ olarized noble gases are listed in Table I. This list is intended to be illustrative and non-limiting. TABLE I
• the alkali metals capable of acting as spin exchange partners in optically pumped systems include any of the alkali metals.
• Preferred alkali metals for this hype ⁇ olarization technique include Sodium-23, Potassium-39, Rubidium-85, Rubidium-87, and Cesium-133.
• Alkali metal isotopes, and their relative abundance and nuclear spins are listed in Table II, below. This list is intended to be illustrative and non-limiting.
• the noble gas may be hype ⁇ olarized using metastability exchange.
• metastability exchange See e.g., Schearer, L. D., Phys. Rev., 180:83 (1969); Laloe, F. et al, AIP ConfProx #131 (Workshop on Polarized 3 He Beams and Targets) (1984)).
• the technique of metastability exchange involves direct optical pumping of, for example, He without need for an alkali metal intermediary.
• the method of metastability exchange usually involves the excitation of ground state 3 He atoms (1 'S 0 ) to a metastable state (2 J S ⁇ ) by weak radio frequency discharge.
• the 2 3 S ⁇ atoms are then optically pumped using circularly polarized light having a wavelength of 1.08 ⁇ m in the case of 3 He.
• the light drives transitions up to the 2 3 P states, producing high polarizations in the metastable state to which the 2 3 S atoms then decay.
• the polarization of the 2 3 S ⁇ states is rapidly transferred to the ground state through metastability exchange collisions between metastable and ground state atoms.
• Metastability exchange optical pumping will work in the same low magnetic fields in which spin exchange pumping works. Similar polarizations are achievable, but generally at lower pressures, e.g., about 0-10 Torr.
• a gas mixture is introduced into the hype ⁇ olarizer apparatus upstream of the polarization chamber.
• Most xenon gas mixtures include a buffer gas as well as a lean amount of the gas targeted for hype ⁇ olarization and is preferably produced in a continuous flow system.
• the pre-mixed gas mixture is typically about 85-89% He, about 5% or less 129 Xe, and about 10% N 2 .
• a mixture of 99.25% ⁇ e and 0.75% N? is pressurized to 8 atm or more and heated and exposed to the optical laser light source in a batch mode system.
• a 5-20 Gauss alignment field is typically provided for the optical pumping of
• the hyperpolarized gas is collected (as well as stored, transported, and preferably delivered) in the presence of a magnetic field. It is preferred for solid (frozen) 129 Xe that the field be on the order of at least 500 Gauss, and typically about 2 kilo Gauss, although higher fields can be used. Lower fields can potentially undesirably increase the relaxation rate or decrease the relaxation time of the polarized gas. As regards 3 He, the magnetic field is preferably on the order of at least 5-30 gauss although, again, higher (homogeneous) fields can be used. The magnetic field can be provided by electrical or permanent magnets.
• the magnetic field is provided by a plurality of permanent magnets positioned about a magnetic yoke which is positioned adjacent the collected hype ⁇ olarized gas.
• the magnetic field is homogeneously maintained around the hype ⁇ olarized gas to minimize field induced degradation.
• Ti of the polarized gas based on the collisional relaxation explained by fundamental physics, i.e., the time it takes for a given sample to decay or depolarize due to collisions of the hype ⁇ olarized gas atoms with each other absent other depolarizing factors.
• fundamental physics i.e., the time it takes for a given sample to decay or depolarize due to collisions of the hype ⁇ olarized gas atoms with each other absent other depolarizing factors.
• He atoms relax through a dipole-dipole interaction during He- 3 He collisions
• 129 Xe atoms relax through N-I spin rotation interaction (where N is the molecular angular momentum and I designates nuclear spin rotation) during
• magnetic interactions can alter the time constant of relaxation, referred to as the longitudinal relaxation time (Ti), and typically occur when different atoms encounter one another.
• Ti longitudinal relaxation time
• the nuclear magnetic moments of the gas atoms interact with the surface materials to return the gas to the equilibrium or non-hype ⁇ olarized state.
• the strength of the magnetic moment can be a determinative factor in determining the relaxation rate associated with the surface material. Since different atoms and molecules have different magnetic moments, relaxation rates are material-specific.
• the term “relaxivity” is used to describe a material property associated with the rate of depolarization ("1/T ⁇ ") of the hype ⁇ olarized gas sample.
• V c a chamber volume
• p a probability of depolarizing.
• the rate of depolarization (1/T ⁇ ) of this gas sample in the chamber can then be described by p times the rate at which gas atoms collide with the surface ("R").
• the average surface collision rate (R) per gas atom is known from statistical mechanics, R. R ⁇ if, Fundamentals of Statistical and Thermal Physics, McGraw-Hill, Ch. 12-14, pp. 461-493 (1965):
• relaxivity is a material property that can describe the depolarizing effect that a specific material has on a hype ⁇ olarized gas sample.
• the containers are configured and sized to decrease the value of the ratio A/N ⁇ i.e., to increase the volume relative to the area of the container, as will be discussed further below.
• Equation 2.4 can be used to calculate relaxivity of the gas if surface relaxation is the only (dominant) depolarizing effect at work. In the case of practical material studies, this is not the case.
• the surfaces of the test chamber, the chamber seal, and other impurities also contribute to the relaxation of the gas.
• the characteristic relaxivity of the material can be determined.
• T ⁇ a can represent the relaxation effect of the test chamber surface
• T t , 1 can represent the effect of the hype ⁇ olarized gas atoms colliding with one another, and so on.
• the relaxation rate can be described by adding the surface effects of the material sample and the test chamber.
• V is the free gas volume in the chamber.
• V c is the volume of the chamber
• V m is the volume of the container occupied by the material sample.
• the relaxivity of a given material can easily be translated back into a more intuitive characteristic relaxation time.
• the hype ⁇ olarized gas samples were used in a materials testing center known as the Spin Down Station.
• This apparatus was constructed to test various material samples in a controlled environment.
• the system consists of a materials testing chamber, a Pulse-NMR Spectrometer, and a LabView user interface.
• I 90 system allows various chambers or bags to be cleaned and filled with polarized ⁇ Xe or ⁇ e.
• the Pulse-NMR system then charts the deterioration of signal from these containers over time.
• FIG 1 is a schematic diagram of the Spin Down Station.
• This apparatus consists of a Helmholtz pair generating a stable Helmholtz magnetic field 151 around the glass test chamber labeled the Spin Down Chamber 152.
• the applied magnetic field remains constant, the coil must be tuned to switch between the two gases.
• the field strength was adjusted to result in the same frequency response for both gases.
• a current of 1.0 A (7 G field) for 3 He and 2.5 A (21 G field ) for 129 Xe was applied to the Helmholtz pair noted by the Helmholtz field shown in Figure 1.
• Helmholtz field 151 rested one of the two spin down chambers 152 used in these tests. Both chambers were valved to evacuate (base pressure -30 milliTorr) and fill the chamber with hype ⁇ olarized gas. Each chamber could be opened to insert polymer samples (typically 10mmx20mmxlmm). As shown, the NMR coil 153 rests beneath the chamber in the center of the Helmholtz field 151.
• the first spin down chamber was made of PyrexTM coated with dimethyl dichlorosilane (DMDCS) and used a TeflonTM coated rubber O-ring as the vacuum seal.
• This chamber had a 110 minute characteristic T lc suitable for observing the surface relaxation effects of various polymer samples 154. Notably, after numerous tests, the Ti c would often decrease. A thorough cleaning with high-purity ethanol restored the chamber to the baseline value. Unfortunately, the T ⁇ c for the PyrexTM chamber with ⁇ e was not long enough to distinguish good from bad materials for He. Tests of various glasses in the PyrexTM spin down chamber showed that a chamber made of 1724 aluminosilicate glass would have a sufficiently long T ⁇ c for 3 He.
• the 1724 ⁇ e chamber was constructed with a ground seal requiring ApiezonTM vacuum grease.
• the chamber had a characteristic T ⁇ c of 12 hours on average.
• the ApiezonTM grease used to seal both the chamber and the entry valve caused the chamber T ic to fluctuate significantly more than the PyrexTM chamber.
• the grease was removed by cleaning the chamber with high-purity Hexane.
• the particular polymers were chosen to represent a wide range of solubilities to Xe and He gases.
• solubility solubility
• D diffusion coefficient
• P permeability
• S solubility
• D diffusion coefficient
• P permeability
• This differential equation describes the spatial distribution of magnetization in the presence of diffusion and relaxation.
• the distribution of magnetization in a one- dimensional chamber is shown in Figure 2.
• the chamber is a gas volume of width "2a" bounded on each side by infinite polymer walls.
• the polarization of gas in this chamber has two specific regions of interest. In the free gas portion of the container, the polarization is relatively homogenous with respect to spatial variable x. In contrast, polarization drops exponentially with distance x into the polymer surface. This profile reflects a much faster relaxation rate inside the polymer as opposed to in free space.
• Equation (2.14) can be used to solve for the spatial magnetization of the gas and polymer regions independently.
• equation (2.14) becomes:
• the polymer region has diffusion coefficient "D p " and relaxation rate F p
• the first boundary condition maintains continuity of polarization across the polymer gas boundary. Recalling that magnetization is the product of polarization and gas number density yields:
• V c is the internal volume of the chamber
• A is the exposed surface area of the polymer
• S is the solubility of the gas in the polymer
• the resulting length scale is about 20 ⁇ m, many times smaller than the lmm polymer samples used in the study described herein.
• Equation (2.21) to predict Ti values for hype ⁇ olarized gases in the presence of various polymer surfaces requires knowledge of the test environment (V C ,A P ), as well as parameters linking the specific gas and polymer (T ⁇ p , S and D). Unfortunately, the solubility and diffusion data linking gas and polymers is scattered and sometimes nonexistent. On the other hand, the test environment is typically known. Advantageously, this data can be used to calculate the T ⁇ p .
• the relaxation mechanism that dominates hype ⁇ olarized gas relaxation in polymers is the interaction with the nuclear magnetic moments of the hydrogen nuclei (in hydrogen based polymers).
• the 1H nuclei are the only source of magnetic dipoles to cause relaxation.
• Huang and Freed developed an expression for the relaxation rate of spin 1/2 gas diffusing through a polymer matrix. See L.P. Hwang et al., "Dynamic effects of pair correlation functions on spin relaxation by translational diffusion in liquids," 63 J. Chem. Phys. No. 9, pp. 4017-4025 (1975); J.H. Freed, "Dynamic effects of pair correlation functions on spin relaxation by translational diffusion in liquids.
• ⁇ 2 is the gyromagnetic ratio of the noble gas
• Y H is the gyromagnetic ratio of the protons
• s is the proton spin number (1/2)
• N a is Avogadro's number
• [ ⁇ ] is the molar density of protons in the matrix
• b is the distance of closest approach of the noble gas to a proton.
• so ⁇ tion based relaxation model along with the experimental apparatus to test relaxivity allows the comparison of a theoretical model of surface relaxation with experimental results. Confirmation of this model enables quantitative predictions of surface relaxation for selecting appropriate and preferred materials to contact hype ⁇ olarized gases.
• the spin down station was used to measure the relaxation effects of 7 different polymers on hyperpolarized I29 Xe and ⁇ e. In order to compare this experimental data with the theoretical, solubility of both gases in each polymer was measured.
• Solubility is the only remaining unknown in the formula to predict Ti of hype ⁇ olarized gases in polymers (2.21). The equation is restated here for reference:
• So ⁇ tion data for various polymers is tabulated in sources such as the Polymer Handbook. S. Pauly, Permeability and Diffusion Data, The Polymer Handbook VI/435.
• the polymer group at the Chemical Engineering Department at North Carolina State University measured the solubility of both xenon and helium gases in the 7 polymers that were to be used to verify the polymer relaxation theory.
• the results of helium and xenon solubility measurements are compared to the available literature values in Table 4.1 below (note that some data was not available).
• the measurements were obtained by placing polymer samples in an evacuated chamber. A known pressure of gas was then introduced into the chamber. As the gas dissolved into the polymer, the decrease in chamber pressure was recorded. By knowing the volume of the test chamber and carefully maintaining the temperature of the apparatus, the solubility of the gas in the polymer can be calculated from the pressure vs. time data.
• there are many intrinsic difficulties in polymer so ⁇ tion measurements Because of the low diffusion coefficients in some polymers such as polyimide. it can take a long time for gas to permeate the entire sample and establish equilibrium. Even the thinnest samples available must be allowed to remain in the chamber for many days. Another problem, evident in He measurements, is that pressure differences observed for materials with low solubilities are extremely small, resulting in significant measurement uncertainty.
• Figure 3 is a plot of T ⁇ cc vs. the product S[1H] 'D , representing the two significant terms in the expression for Ti (2.21) developed in the polymer so ⁇ tion relaxation model.
• the y error bars on the graph represent the cumulative error in the relaxation measurement.
• the x error bars are associated with the solubility measurements described above. The data confirms that solubility can be used to predict Ti for hype ⁇ olarized 129 Xe on polymer surfaces. While the experimental data points follow the trend predicted by the theoretical model remarkably well, certain discrepancies merit further discussion.
• Pt metal which is paramagnetic
• the diffusion coefficient becomes an important parameter.
• PI polyimide
• PTFE polyimide
• the diffusion of Xe into the polymer is so slow that it takes weeks for the Xe to equilibrate completely. This time scale is much longer than the 1-2 hour time scale of the relaxation measurements. Since the T ⁇ p of
• 190 190 Xe in PI is on the order of 100 ms (based on LDPE), the Xe atoms only sample a tiny layer ( ⁇ 5 ⁇ m, based on a diffusion coefficient D ⁇ 10 '8 cm /s), of the surface of the polymer sample.
• This surface layer may have different so ⁇ tion characteristics than the bulk polymer that was used in the solubility measurements. While solubility can typically only be measured for the bulk sample, the region of interest is only 0.5 ⁇ m out of 1 mm, or 0.5xl0 "6 /l .OxlO "3 (about 1/2000) of the actual sample.
• polyimide (PI) and nylon 6 show markedly different results between the two studies.
• One distinction that might explain this result is the difference between amorphous and semicrystalline polymers.
• LDPE, HDPE, and PP are amoiphous polymers that should exhibit uniform solubility.
• semicrystalline polymers such as PTFE, nylon 6, and PI might exhibit spatial diffusion and thus exhibit regional solubilities that differ from the bulk solubility measured in the polymer lab.
• Impurities introduced into the test environment could also account for measurement errors. Dust, finge ⁇ rints, and other contaminants may be introduced into the test chamber when the chamber is opened to insert the sample. All of these contaminants have a depolarizing effect that is not included in the so ⁇ tion model. The most significant confirmed contaminant in the test environment is the presence of 0 2 in the test chamber.
• Equation 2.21 In determining the relaxation time (Ti) of a hype ⁇ olarized noble gas in a polymer container, equation 2.21 can be restated as:
• the relaxation rate of a noble gas in the polymer can be expressed as stated in
• LDPE low-density polyethylene
• the relaxation time of He on a LDPE surface will be nearly 40 times longer than for Xe.
• the noble gas polarization level is not spatially uniform in the polymer.
• the polarization is constant for the gaseous phase but falls off exponentially with distance into the polymer.
• the thickness of the coating preferably exceeds the polarization decay length scale "L p " (equation 2.22) in order for the gas depolarization time to depend on the polymer properties in a predictable way.
• L p polarization decay length scale
• polarized gas can sample the substrate underneath the polymer, and potentially undergo undesirably fast relaxation.
• T p also depends linearly on "D p ,” the depolarization length scale is proportional to the gas diffusion coefficient.
• the polymer contact layer, or the thickness of the coating or film is preferably several times the critical length scale.
• the thickness is above about 16 micrometers and more preferably at least 100-200 micrometers thick in order to be effective.
• coatings that are substantially thinner than "L p " can be more deleterious than having no coating at all, because the mobility of the noble gas once into the coating is reduced.
• a noble gas dissolved in a thin coating can interact with the surface underneath for a much longer period of time than if the coating were not present. Indeed, the probability of depolarization appears to increase as the square of the interaction time.
• the relatively long relaxation times achievable with polymers (coatings or container materials) make the development of polymer bags for hype ⁇ olarized gas storage appealing. Further, bags are a desirable storage and delivery device for magnetic resonance imaging using inhaled hype ⁇ olarized 3 He because the gas can be completely extracted by collapsing the bag. In contrast, a rigid container typically requires a more sophisticated gas extraction mechanism.
• amgt "Nuclear relaxation of ⁇ e in the presence of O 2 ,” Phys. Rev. A, 52, p. 862 (1995).
• a pressure of oxygen as small as 1/1000 of an atmosphere can result in a ⁇ e relaxation time of only 38 minutes even with perfect surfaces.
• tremendous care should be taken to reduce the oxygen content in the storage container through careful preconditioning of the container, such as by pumping and pure gas purging methods.
• a bag is susceptible to permeation of oxygen through the polymer which can disadvantageous ⁇ build substantial oxygen concentration over time.
• the volume of oxygen transmitted through the polymer material depends on several factors, including the polymer-specific oxygen permeability coefficient "Qo 2 "- For small quantities of oxygen transfer, the rate of oxygen concentration build-up in the bag is nearly constant, and can be expressed by equation (2.33).
• a one hour duration (3600 seconds) will give 1 x 10 "3 amgt, which corresponds to a Ti of about 38 minutes.
• the O 2 permeability is smaller (0.139 x 10 "13 cm 2 /s Pa- 158 times less permeable than LDPE).
• one hour of permeation will give an O 2 induced Ti of about 99 hours, but after 10 hours the Ti drops to only 10 hours.
• the contact surface layer itself can be formed as a polymer having reduced permeability to O 2 and/or with increased thickness ⁇ x.
• Another layer of material is preferably used to suppress oxygen permeability. So long as the thickness of polymer in contact with the polarized gas is greater than L p , the secondary material used for oxygen permeability suppression does not need to be non-depolarizing.
• a metal film such as aluminum can be very effective in such an application.
• the container is sized and configured to provide a A/V ratio of about less than 1.0cm '1 , and even more preferably less than about 0.75 cm "1 .
• the container is substantially spherical, such as a round balloon-like container.
• Preferred polymers for use in the inventions described herein include materials which have a reduced solubility for the hype ⁇ olarized gas.
• the term "polymer” is broadly construed to include homopolymers, copolymers, te ⁇ olymers and the like.
• the term “blends and mixtures thereof includes both immiscible and miscible blends and mixtures. Examples of suitable materials include, but are not limited to, polyolefms (e.g., polyethylenes, polypropylenes).
• the coating or surface of the container comprise one or more of a high-density polyethylene, low density polyethylene, polypropylene of about 50% crystallinity, polyvinylchloride, polyvinylflouride, polyamide, polyimide, or cellulose and blends and mixtures thereof.
• the polymers can be modified. For example, using halogen as a substituent or putting the polymer in deuterated (or partially deuterated) form (replacement of hydrogen protons with deuterons) can reduce the relaxation rate associated with same.
• Methods of deuterating polymers are known in the art. For example, the deuteration of hydrocarbon polymers is described in U.S. Patent Nos. 3,657,363, 3,966,781, and 4,914,160, the disclosures of which are hereby incorporated by reference herein. Typically, these methods use catalytic substitution of deuterons for protons.
• Preferred deuterated hydrocarbon polymers and copolymers include deuterated paraffins, polyolefms, and the like. Such polymers and copolymers and the like may also be cross-linked according to known methods.
• the polymer be substantially free of paramagnetic contaminants or impurities such as color centers, free electrons, colorants, other degrading fillers and the like. Any plasticizers or fillers used should be chosen to minimize any magnetic impurities contacting or positioned proximate to the hype ⁇ olarized noble gas.
• the first layer or contact surface can be formed with a high purity (and preferably non-magnetic) metal surface such as a metallic film.
• the high purity metal surface can provide advantageously low relaxivity/depolarization- resistant surfaces relative to hype ⁇ olarized noble gases. Preferred embodiments will be discussed further below.
• the high purity metal film can be combined with the materials discussed above or can be used with other materials to form one or more layers to provide a surface or abso ⁇ tion region which is resistant to contact- induced depolarization interactions.
• any of these materials can be provided as a surface coating on an underlying substrate or formed as a material layer to define a polarization friendly contact surface.
• the coating can be applied by any number of techniques as will be appreciated by those of skill in the art (e.g., by solution coating, chemical vapor deposition, fusion bonding, powder sintering and the like). Hydrocarbon grease can also be used as a coating.
• the storage vessel or container can be rigid or resilient. Rigid containers can be formed of PyrexTM glass, aluminum, plastic, PVC or the like.
• Resilient vessels are preferably formed as collapsible bags, preferably collapsible multi-layer bags comprising several secured material layers.
• the multiple layer configuration can employ material layers formed of different materials, i.e., the material layers can be selected and combined to provide a collapsible bag which is oxygen resistant, moisture resistant, puncture resistant, and which has a gas contacting surface which inhibits contact-induced depolarization.
• oxygen resistant means that the bag is configured to inhibit the migration of oxygen into the gas holding portion of the bag.
• the bag is configured to provide an oxygen leak rate or oxygen permeability rate of less than about 5x10 "6 amgt min, more preferably less than 5.2 x 10 "7 amgt/min, and still more preferably less than about lxlO "7 amgt/min at one atmosphere of pressure.
• Figures 7 and 8 illustrate a preferred embodiment of a resilient container 10 for hype ⁇ olarized gas according to the instant invention.
• Figure 7 shows the container 10 in the collapsed (empty or void) position and Figure 8 shows the container 10 when inflated (filled).
• the container 10 includes a front wall 12 and a rear wall 13 and a gas (or liquid) holding chamber 14 formed between the walls 12, 13.
• the walls 12, 13 are co-joined by a perimeter seal 15.
• the container 10 includes an outwardly extending port connector 20 in fluid communication with the port 22.
• the port connector 20 is preferably attached to the container 10 via a fitting 28.
• the fitting 28 can be heat sealed to the inside of the wall 12 to secure the fitting 28 to the inside of the container wall 12 in an airtight manner.
• a gasket or O-ring 27a can be used to seal the fitting 28 to the container 10.
• the fitting 28 extends up through the container wall 12 and is secured against the outside of the container wall 12 via compression with a nut coupling member 27 and an intermediately positioned O-ring 27a.
• the nut coupling member 27 is positioned opposite the multi-layer container wall 12 and is configured such that it includes an aperture with internal threads which is positioned over and threadably mates with the external threads of the fitting 28c.
• the seal provided by the nut coupling member 27, the associated O-ring 27a, and the fitting 28 are preferably configured to withstand up to about 3 atm of pressure and also are preferably configured to provide a vacuum-tight seal.
• the port connector 20 is configured to define a portion of the fluid flow path 22f.
• the port connector 20' is configured to function as a second top coupling nut which threadably engages with the fitting 28 separate from the nut coupling member 27.
• the port connector 20' includes an O-ring 20a positioned intermediate a bottom portion of the port connector 20b and a portion of the fitting 28b.
• this seal between the fitting 28 and the port connector 20' also be configured in an airtight arrangement and be configured to withstand pressures up to about 3 atm (and is also preferably leak-tight at vacuum pressures used to condition the container, as will be discussed further below).
• the container 10 includes a capillary stem 26s and a valve member 26.
• the port connector 20' is configured to engage the capillary stem 26s which extends away from the chamber of the container 14 and which is in fluid communication with the valve member 26.
• the valve member 26 is operably associated with the chamber 14 such that it releasably controls the intake and release of the fluid. That is, in operation, the valve 26 is opened and hype ⁇ olarized gas (or liquid) is directed through the outlet 29 through the body of the valve 26 and through the capillary stem 26s into the chamber 14, thereby forcing the container 10 to expand ( Figure 8) and capture the hype ⁇ olarized gas (or liquid).
• the capillary stem 26s can be formed as an integral part of the valve member 26, or as a separate component.
• the valve member 26 can include a body portion formed of glass such as Pyrex or the like, and the capillary stem 26s can be directly formed onto an end portion thereof as a glass such as Pyrex or an aluminosilicate, or other material to extend therefrom as a continuous body co-joined to the lower portion of the valve member 26.
• the valve illustrated in Figure 9 includes a plug portion 26p with an O-ring 26o which longitudinally translates to engage with the lower nozzle end of the valve chamber 26n to close the flow path 22f in the valve closed position.
• the valve plug 26p moves away from the nozzle end 26n to allow the gas to flow through the port 22, the capillary stem 26s, and the valve body 26b and in (or out) the valve outlet 29.
• the capillary stem 26s is configured such that a major portion of the hype ⁇ olarized gas, once in the chamber 14, remains therein when the valve member 26 is closed. That is, the dimensions and shape of the capillary stem 26s are such that diffusion of the hype ⁇ olarized gas away from the container chamber 14 is inhibited.
• the capillary stem 26s can reduce the amount of exposure for a major portion of the hype ⁇ olarized gas with the valve 26 and any potentially depolarizing components operably associated therewith.
• the capillary stem 26s also provides a portion of the gas flow path 22f therethrough.
• the capillary stem 26s includes an internal passage which is preferably sized and configured in a manner which inhibits the flow of gas from the chamber during storage or transport while also allowing the gas to exit the chamber 14 at its ultimate destination without undue or significant impedance.
• the capillary stem 26s is operably associated with the valve member 26 and is configured to retain a major portion of the gas in the bag chamber 14, and away from the valve body 26b when the valve member 26 is closed.
• the capillary stem 26s helps keep a majority of the hype ⁇ olarized gas away from the valve member 26 (such as retained at least below the O-ring in the nozzle end of the valve designated by the stepped down portion of the valve body in Figure 9) to thereby inhibit any contact-induced depolarization which may be attributed thereto.
• the capillary stem 26s has a length which is at least about 2.0 inches with a 1/8 inch inner diameter and a 0.2 inch outer diameter. For a 7x7 inch bag (or approximately one liter) container, this length is greater than about 20% the length or width of the container 10.
• valve member 26 includes an externally accessible adjustment knob 26a which rotates to open and close the valve member 26.
• valve member 26 includes a plurality of O-rings 26o therein.
• a suitable glass valve is available from Kimble Kontes Valves located in Vineland, NJ.
• the capillary stem 26s is positioned intermediate the valve member 26 and the container chamber 14 to inhibit the migration of the hyperpolarized substance into the valve member 26 to reduce the exposure to any potentially depolarizing materials therein (which potentially includes one or more of the O-rings 26o).
• all sealing and structural materials associated with the container 10 and other container assembly components which come into contact with hyperpolarized gas are selected or formed of materials which are preferably substantially non-depolarizing.
• the capillary stem 26s is formed with a substantially rigid body.
• the term "rigid” means that it can structurally help support the weight of a valve member 26 when assembled to the container 10 to minimize the stress/strain which may be introduced onto the juncture of the fitting 28.
• the rigid body of the capillary stem 26s can be provided by a rigid substrate, such as a plastic, a PVC material, a glass, Pyrex, or aluminosilicate material, a metal, and the like.
• the hype ⁇ olarized gas or fluid contacting surfaces of the capillary stem 26s are preferably formed with a material or coating which is substantially non-depolarizing to the hype ⁇ olarized gas or liquid held therein (low relaxivity and or solubility for the hype ⁇ olarized gas).
• the capillary stem 26s is an elongated cylindrical stem, but other configurations are also possible.
• the inner passage (shown as a diameter) of the capillary stem 26s is configured to inhibit or restrict the flow of fluid from the chamber of the bag 14 when the valve member 26 is closed.
• the valve member 26 is configured with an end portion which holds the outlet 29 away from the capillary stem 26s which forms the hype ⁇ olarized gas inlet and outlet port.
• the outlet 29 is configured with a sealing means 25 which allows the container to mate and engage with an external device at the ultimate destination or delivery point (in an air tight manner) to facilitate the delivery of the gas or liquid without exposure to atmosphere.
• this sealing means 25 includes an O-ring 25a which is configured to sealably engage with the external device. In operation, the sealing means 25 compresses the O-ring 25a to matably engage with the delivery or input device (not shown).
• the container chamber 14, the fitting 28, the capillary stem 26s, a portion of the valve member 26, and the end portion of the valve member 29 define the hype ⁇ olarized fluid flow path 22f.
• the fluid flow path 22f extends from the container chamber 14 through the capillary stem 26s to an external device or source such as a hype ⁇ olarizer dispensing port
• the chamber 14 is engaged with a destination interface.
• the container 10 when compressed, expels the gas directly into a patient interface mask 90 so that a patient can inhale or breathe the gas therefrom.
• conduit 70 without a capillary stem 26s is illustrated in Figure 17.
• various materials can be used for the conduit.
• An example of one suitable material alternative is polymer tubing attached to the fitting 28 and/or connector 20 and in fluid communication with the chamber 14.
• the tubing is formed such that at least the inner surface comprises a polarization friendly material with a suitable relaxivity or solubility value to provide a sufficiently long Ti and the outer layer material comprises a mechanically stable (i.e., self supporting), oxygen resistant flexible polymer matrix.
• the tubing can be formed as a unitary single layer body wherein the inner surface and outer layer material are the same, or the tubing can include a coated inner surface and a different material outer surface or wall layer.
• Figures 21A, 21B, and 21C illustrate yet another preferred embodiment of a container 10. As shown, this embodiment is similar to that shown in Figure 7, except that the fitting 28 can be further isolated from the main volume of gas (or liquid) held in the chamber 14 as shown in Figure 21B.
• the container is configured to position the port 22 at an edge portion of the container body.
• an isolation means 31 is positioned intermediate the port and main volume of the chamber to isolate the port 22 and port fittings 28 or other components from the gas or liquid in the container during transport and storage. As such the gas or liquid's exposure to the port 22 or port fittings 28 is reduced.
• the container is in an unfilled (deflated position) as shown in Figure 21 A.
• Flexible tubing such as tygon® is attached to the container as shown in Figure 21B. It is also preferred that the tubing be operably associated with a sealing means such as a clamp, valve or the like as discussed herein for other embodiments.
• an isolation means 31i is attached or formed onto the bag to pinch or enclose the bag portion with the port 22 and/or fitting 28 in a manner which will inhibit the contact of the main volume of hype ⁇ olarized gas or liquid with this region of the bag or container.
• the isolation means 31i is a clamp having opposing clamping bars 31, 32 compressed together by fastener 33.
• other isolation means can also be used such as heat sealing, tying, restrictive (pinching) with bag configurations or holding fixtures and the like.
• the bag container can be sized and configured with the port on an edge portion, preferably, proximate to a corner, and the container partially filled so that the corner can be folded against the body of the container and held in place simply by attaching a portion of the external wall to an opposing wall such as via an adhesive attachment means, velcroTM, hook, and the like.
• the fold line acts to "pinch" off the main chamber of the container from the port (not shown) in a manner which is substantially air tight.
• a fold bar or other device can be used to facilitate a tight fold line between the port region and the major volume of the bag.
• a multi-layer (3 ply) resilient container 10 having a capillary stem 26s and valve member 26, as shown in Figure 9, can provide a corrected Ti (taking into account the material properties alone) for hypeipolarized J He gas of at least about 450 minutes (7.5 hours), and more preferably a corrected Ti of at least about 600 minutes (10 hours) and an associated oxygen permeability rate of about 5.2 x 10 " amgt/min (at one atmosphere of pressure).
• the walls 12, 13 are configured with two layers 41, 44.
• the first layer 41 includes the inner contact surface 12a of the chamber 14 that holds and thus contacts the hype ⁇ olarized gas.
• the hype ⁇ olarized noble gas is susceptible to contact-induced depolarization depending on the type of material and the depth of the material used to form this layer.
• this surface is preferably formed by a coating or a material layer with a sufficient thickness for preventing the hype ⁇ olarized gas from sampling the underlying substrate.
• the surface should have a low relaxivity relative to the hype ⁇ olarized gas.
• both the material and the thickness are chosen and configured to inhibit the surface-induced depolarization of the gas.
• the thickness it is preferred that the thickness be greater than the critical decay scale length L p and more preferably greater than a plurality of the decay length scale. For example, for 3 He and HDPE, the critical length scale is about 8 ⁇ m so a preferred material layer depth is greater than about 16-20 ⁇ m.
• the material have a relaxivity value less than about .0013 cm/min and more preferably less than .0008 cm/min.
• the material have a relaxivity value less than about .012 cm/min and more preferably less than about .0023 cm min.
• Reduced solubility is meant to describe materials for which the hype ⁇ olarized gas has a reduced solubility.
• the solubility is less than about 0.75, and more preferably less than about 0.4.
• the solubility is preferably less than about 0.03, and more preferably less than about 0.01.
• the second layer 44 includes the external surface 12b that is exposed to air which includes components which can be potentially degrading to the hype ⁇ olarized gas in the chamber. For example, as discussed above, paramagnetic oxygen can cause depolarization of the gas if it migrates into the contact surface 12a or the chamber 14. As such, it is preferred that the second layer 44 be configured to suppress oxygen migration.
• the second layer 44 can be formed as an oxygen-resistant substrate, a metal layer, or metallized deposit or coating formed over another layer.
• the second layer 44 (alone or in combination with other layers) prevents demagnetizing amounts of 0?
• the second layer can be alternatively chosen or configured to shield other environmental contaminants such as moisture.
• a first layer may have a very low permeability for O 2 but may be sensitive to moisture.
• the second layer 44 can be configured with a protective polyethylene coating to compensate for this property and provide an improved T ⁇ container.
• the inner surface 12a can be configured as a high purity (non-magnetic) metal film applied to an underlying substrate, polymer, or other container material.
• High purity metal surfaces can provide even better protection against depolarization relative to other surfaces. Because the hype ⁇ olarized gas contacts the metal, the underlying material is not required to have a low solubility for the hype ⁇ olarized gas.
• the container is resiliently configured as a collapsible bag with the inner surface 12a formed from a high purity metal film (preferably a thickness within the range of about lOnm to about 10 microns).
• the first layer 41 is the metallized layer and can provide the oxygen resistance/shield as well as protection against contact depolarization.
• Preferred metals include those that are substantially paramagnetically pure (i.e., they do not introduce magnetic moments) and resistant to contact depolarization of the hype ⁇ olarized gases. Stated differently, the metal used should be chosen to minimize the adsorption time of the gas on the metal surface, i. e. , such that the noble gas has a low adso ⁇ tion energy on the metal surface. Examples of suitable materials include, but are not limited to, aluminum, gold, silver, indium, beryllium copper, copper, and mixtures and blends thereof. As used herein, "high purity” includes materials which have less than 1 ppm ferrous or paramagnetic impurities and more preferably less than 1 ppb ferrous or paramagnetic impurities.
• the inner surface 12a can be formed as a hybrid surface (a blend or side by side disposition of high purity metal film and polymer) or as a high purity metal formed over a polymer substrate.
• a metal film can be layered over a polymer with good relaxivity properties to compensate for cracks or gaps which may develop in the metal film layer.
• the inner surface 12a is formed directly by the inner wall of a polymer bag and the outer or intermediate surface is formed by a metallized coating or material positioned over and directly contacting the polymer bag.
• intermediate layers 42, 43 positioned between the inner layer 41 and outer layer 44 can also be used.
• the container has three layers 41,42,44.
• the first layer 41 is 0.004" linear LDPE; the second layer 42 is
• the third layer 44 is 48 gauge polyester.
• the first LDPE layer provides a polarization-friendly surface with a relatively long T t
• the second aluminum foil layer inhibits oxygen permeation
• the polyester layer provides strength and puncture resistance.
• the outer layers 41 and 44 are secured to the middle layer 42 with urethane adhesive. Typically the layers are cemented or bonded together but other joining or securing means can be used as will be recognized by those of skill in the art.
• a container 10 with this three-layer configuration has been observed to have a corrected Ti (due to material only) for He of about 490 minutes (over 8 hours) and an oxygen leak rate of about 3.9 x 10° amgt min. This Ti is contrast to that obtained in the single layer bag used in the past. For example, the Ti for 3 He in a conventional 1 liter single layer Tedlar® bag (pre-conditioned such as described hereinbelow) has been estimated to be under about 4 hours.
• the container 10 has four layers 41, 42, 43, 44.
• the inner layer 41 is not a coating but is defined by the expandable polymer (or modified polymer) bag hairing a thickness sufficient to inhibit contact depolarization.
• the intermediate layers can be formed from any number of alternative materials, preferably resilient materials so as to contract and expand with the inner layer 41.
• the inner layer 41 is about 0.0025 "(inches) of linear LDPE (LLDPE); the second layer 42 is about 0.003 inches of Al; the third layer 43 is 71b PE, and the outer layer 44 is 48 gauge PET.
• a bag container with this multilayer configuration has been shown to have a corrected Ti (due to material alone) of about 14 hours and an oxygen leak rate substantially less than about 3x10 " amgt min at one atmosphere.
• a bag with five layers is used: the first layer is 35 ⁇ m of HDPE; the second layer 42 is 35 ⁇ m of polyamide; the third layer 43 is 1 ⁇ m of aluminum; the fourth layer 44 is 35 ⁇ m of polyvinylidene chloride; and the fifth layer (not shown) is 35 ⁇ m of polyester.
• the multiple layers can provide additional strength and/or puncture and pressure resistance.
• alternative materials and numbers of layers can also be employed according to the present invention.
• a coating can be placed on the inner surface 12a of the polymer bag to define the proper depth of the contact layer either alone or in combination with the thickness of the polymer bag.
• the two layers can be formed as one layer if the container material employed has a low-relaxivity for the hype ⁇ olarized gas and if the material is sufficiently impermeable to environmental contaminants such as O 2 .
• examples of such materials include but are not limited to PET (polyethylene te ⁇ hthalate), PVDC (polyvinylidene dichloride), cellophane and polyacrylonitrile.
• the container 10 also includes a sealing means operably associated with the entry port 22 and used to capture the hype ⁇ olarized gas within the chamber 30.
• the sealing means closes off the passage 22a in communication with the bag entry port 22 ( Figure 7), thereby retaining the hype ⁇ olarized gas substantially within the chamber 14 of the container.
• the sealing means can be configured in a number of ways, either with valves integrated with the bag ( Figure 9) and or with clamps or other devices which are positioned onto the flow path of the container.
• the coupling member 20 includes a conduit 70 extending outwardly therefrom in the flow path, and the sealing means is a clamp or heat seal applied to the conduit.
• suitable sealing means include, but are not limited to, a clamp 72 (Figure 13) a heat seal 74 ( Figure 14) and a membrane seal 76 ( Figure 15).
• the valve 26 Figure 9
• a stop-cock and other fittings and/or seals (gaskets, hydrocarbon grease, O-rings) (not shown) can be used to control the release of the hype ⁇ olarized gas.
• care is taken to insure all fittings, seals, and the like which contact the hype ⁇ olarized gas or which are located relatively near thereto are manufactured from materials which are friendly to polarization or which do not substantially degrade the polarized state of the hype ⁇ olarized gas.
• commercially available seals include fluoropolymers or fillers and the like which are not particularly good for the preservation of ⁇ e hypeipolarized gases because of the solubility of the material with the hype ⁇ olarized gas.
• the containers of the present invention employ seals, O-rings, gaskets and the like with substantially pure (substantially without magnetic impurities) hydrocarbon materials such as those containing polyolefms.
• suitable polyolefms include polyethylene, polypropylene, copolymers and blends thereof which have been modified to minimize the amount of magnetically impure fillers used therein.
• valve is used to contain the gas in the chamber 30, it is preferably configured with a magnetically pure (at least the surface) O-ring and/or with hydrocarbon grease.
• a valve is preferably configured with a magnetically pure (at least the surface) O-ring and/or with hydrocarbon grease.
• fillers and plasticizers are employed, then it is preferred that they be selected to minimize the magnetic impurities such as substantially pure carbon black.
• the O-ring seal can be configured with the exposed surface coated with a high purity metal as discussed for the container surface.
• the O-ring or seal can be coated or formed with an outer exposed layer of a polymer at least "L p " thick.
• a layer of pure polyethylene can be positioned over a commercially available O-ring.
• One preferred commercially available O-ring material for 129 Xe is a TeflonTM coated rubber O-ring or a low- relaxivity polymer as discussed above.
• TeflonTM although a fluoropolymer, do not affect 129 Xe as much as it does 3 He because 129 Xe is much larger than fluorine, which is much larger than 3 He.
• fluoropolymers can be used as seals with l29 Xe but are not preferable for use with arrangements where the seal may contact the hypeipolarized ⁇ e.
• Figures 13 and 14 illustrate preferred embodiments of a seal arrangement used to ship or store the filled container. Each acts to seal the fluid passage 22a by pinching the conduit 70 shut in at least one position therealong.
• Figure 13 shows the use of an external clamp 72 and
• Figure 14 shows the use of a redundant heat seal 74. In operation, each is easily employed with little impact on the polarization of the gas in the container 10.
• an in-process clamp (not shown) is inserted over the conduit 70 such that it closes off the passage 22a. Heat is applied to the conduit 70 as the conduit wall is collapsed to provide a heat seal 74 to at least one side of the in-process clamp. The bag is then ready to transport. Once at the desired delivery location site, the heat seal 74 can be cut away and a temporary clamp can be placed on the conduit 70. As shown in Figure 17, the conduit 70 can be directly engaged with a breathing apparatus or patient interface 90. As illustrated in Figure 18, the hype ⁇ olarized gas can be forced out of the bag and into the interface 90 such as by externally depressing/compressing the walls of the container 10.
• a membrane seal 76 is positioned directly over the external portion of the entry port 22.
• the membrane seal 76 can be attached by heat, or an anchoring member such as a polymer washer threadably attached over the peripheral portion of the coupling member 22, preferably leaving the central portion 76a externally accessible.
• the container 10 can be transported to the use site and inserted directly into a patient interface 90'.
• the membrane seal 76 is inserted into the interface 90' such that it is positioned internal to the air tight coupling provided by the joint 130 between the coupling member 20 and the interface 90'.
• the interface 90' can include a puncture 79 recessed within the receiving area to open the central portion of the membrane seal 76 after the coupling member 20 forms the external joint 120 such that the container is sealed to the interface 90'.
• a puncture 79 recessed within the receiving area to open the central portion of the membrane seal 76 after the coupling member 20 forms the external joint 120 such that the container is sealed to the interface 90'.
• the gas in the container can be easily released and directed to the patient.
• the gas can be easily extracted or forced out of the container 10 by depressing the walls 12, 13 of the container 10 or via inhalation.
• such a configuration removes the requirement for relatively complex or sophisticated gas extraction mechanisms and also reduces the amount of physical manipulation and/or interfaces required to deliver the gas to the subject.
• a shipping box 80 is preferably used to hold the bag
• the box 80 include magnet means to provide a desired static magnetic (substantially homogeneous) field around the hype ⁇ olarized gas.
• the box 80 can be configured to form a shield from undesirable stray magnetic fields as will be discussed further below.
• the present invention provides containers which improve on the relaxation time of the hype ⁇ olarized gas.
• the container is sized and configured and the contact surface formed from a suitable material such that the hype ⁇ olarized gas in the container has a relaxation time greater than about 6 hours and more preferable greater than about 20 hours for 3 He.
• the container is preferably sized and configured such and the contact surfaces formed from a suitable material that the I29 Xe hype ⁇ olarized gas in the container has a relaxation time greater than about 4 hours, preferably more than about 6 hours, and more preferably greater than about 8 hours.
• the present invention recognizes that unless special precautions are taken, relaxation due to external magnetic fields (static and/or time dependent) can dominate all other relaxation mechanisms. Both gradients in the static field and (low frequency) oscillating magnetic fields experienced by the hype ⁇ olarized gas can cause significant relaxation.
• an (externally) applied substantially static magnetic holding field "B H " can substantially protect the hype ⁇ olarized gas from depolarizing effects attributed to one or more of the EMI and gradient fields during transport.
• the instant invention employs a magnetic holding field which raises the Larmor frequency of the hyperpolarized gas above the region of noise (1/f), ' e. the region where the intensity of ambient electromagnetic noise is typically high (this noise is typically under about 5 kHz).
• a magnetic holding field is also preferably selected such that it raises the frequency of the hype ⁇ olarized gas to a level which is above those frequencies associated with large acoustic vibrations (these acoustic vibrations are typically less than about 20 kHz).
• the increased frequency associated with the applied magnetic holding field advantageously allows a transport unit ( Figure 16) to have greater electromagnetic shielding effectiveness for a given housing thickness (the housing used to hold the hype ⁇ olarized gas therein during transport and/or storage).
• the skin depth " ⁇ " of a conductive shielding material is inversely proportional to the square root of the frequency.
• an exemplary skin depth for aluminum is about 0.5 mm, as compared to about 2.0 mm at 1.6 kHz.
• the magnetic holding field of the instant invention is selected so that any external field-related fluctuations are small in magnitude compared to the field strength of the holding field; in this way the holding field can minimize the hype ⁇ olarized gas ' s response to unpredictable external static field gradient- induced relaxation.
• This can be accomplished by applying to the hyperpolarized gas a proximately positioned magnetic holding field which is sufficiently strong and homogeneous so that it minimizes the unpredictable static field-related relaxation during transport and storage.
• a sufficiently homogeneous holding field preferably includes (but is not limited to) a magnetic holding field which has homogeneity which is on the order of about at least 10 '3 cm "1 over the central part of the holding field (i.e., the part in which the gas resides).
• the magnetic holding field homogeneity is about at least 5 xlO "4 cm “1 .
• the magnetic holding field should be positioned, sized, and configured relative to the hype ⁇ olarized gas such that it also minimizes the EMI or oscillating magnetic field depolarization effects.
• the depolarizing effect of EMI is preferably (substantially) diminished by applying the magnetic holding field (B H ) proximate to the gas so that the resonant frequency of the hype ⁇ olarized gas is preferably above or outside the bandwidth of prevalent time- dependent fields produced by electrically powered or supplied sources.
• the external interference can be shielded by positioning a substantially continuous shield or shipping container having at least one layer formed of a conductive material such as metal around the hype ⁇ olarized gas in the container.
• the preferred shielding thickness is related to the spatial decay constant of an electromagnetic wave or skin depth ⁇ .
• the Larmor radiation wavelength is long (-10 km), and is much larger than the container size.
• the shielding effectiveness is therefore dependent upon the container geometry as well as the shielding thickness. For a thin spherical conductor of radius a and thickness t, the shielding factor for wavelengths ⁇ »a is given approximately by
• the shielding effectiveness increases as the size (radius) of the shield is increased. It is therefore preferred that a metallic enclosure used to shield or surround the hype ⁇ olarized gas be configured to define an internal volume which is sufficient to provide increased shielding effectiveness. Stated differently, it is preferred that the walls of the enclosure are spaced apart a predetermined distance relative to the position of the gas container.
• a transport unit can be configured with at least one layer formed from about 0.5 mm thick of magnetically permeable material, such as ultra low carbon steel soft iron, or mu-metals (by virtue of their greater magnetic permeability).
• magnetically permeable material such as ultra low carbon steel soft iron, or mu-metals (by virtue of their greater magnetic permeability).
• these materials may significantly influence the static magnetic field and must be designed accordingly not to affect the homogeneity adversely.
• a homogeneous magnetic holding field proximate to the hype ⁇ olarized gas can help minimize the gas depolarization by virtue of decreasing the skin depth ⁇ , which is inversely proportional to the square root of the frequency. Further, it helps by pushing the resonant frequency of the gas outside the bandwidth of common AC fields. It is preferred that the resonant frequency of the hype ⁇ olarized gas be raised such that it is above about 10 kHz. and more preferably be raised such that it is between about 20- 30 kHz. Stated differently, it is preferred that for shielding, the applied magnetic holding field have a field strength of about 2 to 35 gauss.
• the magnetic holding field is preferably at least about 20 Gauss; and for He, the magnetic holding field is preferably at least about 7 Gauss.
• the storage container 10 is preconditioned to remove contaminants. That is, it is processed to reduce or remove the paramagnetic gases such as oxygen from within the chamber and container walls.
• the paramagnetic gases such as oxygen from within the chamber and container walls.
• UHV vacuum pumps can be connected to the container to extract the oxygen.
• a roughing pump can also be used which is typically cheaper and easier than the UHV vacuum pump based process for both resilient and non-resilient containers.
• the bag is processed with several purge/pump cycles, e.g., pumping at or below 20 mtorr for one minute, and then directing clean buffer gas (such as Grade 5 or better nitrogen) into the container at a pressure of about one atm or until the bag is substantially inflated.
• the oxygen partial pressure is then reduced in the container. This can be done with a vacuum but it is preferred that it be done with nitrogen.
• the oxygen realizes the partial pressure imbalance across the container walls, it will outgas to re-establish equilibrium. Stated differently, the oxygen in the container walls is outgassed by decreasing the partial pressure inside the container chamber.
• Typical oxygen solubilities are on the order of .01 -.05; thus, 95-99% of the oxygen trapped in the walls will transition to a gas phase.
• the container Prior to use or filling, the container is evacuated, thus harmlessly removing the gaseous oxygen.
• polymer bag containers can continue to outgas (trapped gases can migrate to the chamber because of pressure differentials between the outer surface and the inner surface) even after the initial purge and pump cycles. Thus, care should be taken to minimize this behavior especially when the final filling is not temporally performed with the preconditioning of the container.
• a quantity of clean filler gas (such as Grade 5) is directed into the bag (to substantially equalize the pressure between the chamber and ambient conditions) and sealed for storage in order to minimize the amount of further outgassing that may occur when the bag is stored and exposed to ambient conditions. This should substantially stabilize or minimize any further outgassing of the polymer or container wall materials.
• the filler gas is preferably removed (evacuated) prior to final filling with the hype ⁇ olarized gas.
• the container of the instant invention can be economically reprocessed (purged, cleaned, etc.) and reused to ship additional quantities of hype ⁇ olarized gases.
• the container or bag be sterilized prior to introducing the hype ⁇ olarized product therein.
• the term "sterilized” includes cleaning containers and contact surfaces such that the container is sufficiently clean to inhibit contamination of the product such that it is suitable for medical and medicinal pu ⁇ oses.
• the sterilized container allows for a substantially sterile and non-toxic hype ⁇ olarized product to be delivered for in vivo introduction into the patient. Suitable sterilization and cleaning methods are well known to those of skill in the art.
• hype ⁇ olarized gas relaxation time, Ti is now determined to be proportional to gas solubility.
• hype ⁇ olarized noble gases such as He and 12 Xe can be used to determine or measure the gas solubility in a polymer or liquid. This information can be valuable for quickly assessing the structures of the
• a given polymer sample can be evaluated using both Xe and 3He gases, as each can give complimentary information. For example, ⁇ e will sample a greater depth of the polymer based on its greater diffusion coefficients.
• a first quantity of a hype ⁇ olarized gas is introduced into a container (Block 300).
• a first relaxation time is measured of the hype ⁇ olarized gas in the container (Block 310).
• a selected material sample is positioned in the container (Block 320).
• a second quantity of a hyperpolarized noble gas is introduced into the container (Block 330).
• a second relaxation time is measured associated with the sample and the gas in the container (Block 340).
• the gas solubility is determined based on the difference between the two relaxation times (Block 350). Preferably this is determined according to equation (2.23c).
• the material sample can be a physical or solid sample or a liquid as described above.
• the method can also be used to determine gas solubilities in liquids or fluids.
• a liquid can be introduced instead of placing a polymer sample into the chamber.
• the liquid will preferably be introduced in a quantity which is less than the free volume of the chamber as it will conform to the shape of the chamber to define an associated volume and surface area.
• the polarized gas can then be directed into the chamber with the liquid and the relaxation rate determined due to the specific liquid. This can be especially helpful in formulating carrier substances for injection formulations of hype ⁇ olarized Xe and He.
• the polymer contact surface is assumed to be present at a depth corresponding to a plurality of critical length scales as discussed above.
• An exemplaiy one liter patient delivery bag such as is shown in Figure 7, is a 7 inch x 7 inch square.
• the expected T ⁇ for 3 He can be determined using (Equation 2.4) and the theoretical relaxivity of LDPE for 3 He quoted in Table 4.3.
• metal film coatings are used as the contact surface.
• the 7" x 7" square bag described in Example 1 is employed but coated or formed with high purity aluminum on its internal contact surface (the surface in contact with the hyperpolarized gas).
• the relaxivity of high purity aluminum for 129 Xe has been recently measured to be about 0.00225 cm/min. (One readily available material suitable for use is Reynold'sTM heavy duty freezer foil). Doing the calculation, one can obtain a container with an extended T ⁇ for xenon of about 11.43 hours. This is a great improvement in Ti for Xe.
• metal film surfaces for 3He can generate Tf s in the range of thousands of hours (the container no longer being a limiting factor as these Ti's are above the theoretical collisional relaxation time described above).
• Metals other than aluminum which can be used include indium, gold, zinc, tin, copper, bismuth, silver, niobium, and oxides thereof.
• "high purity" metals are employed (i.e., metals which are substantially free of paramagnetic or ferrous impurities) because even minute amounts of undesirable materials or contaminants can degrade the surface.
• another high purity aluminum sample tested had a relaxivity of about 0.049 cm/min, a full 22 times worse than the sample quoted above.
• ferrous or paramagnetic impurities such as iron, nickel, cobalt, chromium and the like.
• the metal is chosen such that it is well below lppm in ferrous or paramagnetic impurity content.
• Example 1 Using the bag configured as noted in Example 1 , one can determine the effects of the addition of multiple materials. For example, a 5cm " silicone gasket positioned on the 1 liter deuterated HDPE bag (described in Example 1 (for ⁇ e)) with a starting T] of 132 hours will reduce the container's associated relaxation time. As pointed out in Equations 2.5, 2.6. relaxation rates are additive. Thus, to properly determine the container or equipment relaxation time, the relaxivities and corresponding surface areas of all the materials adjacent the free volume should be evaluated.
• the hypothetical silicone gasket with an exemplary area "A" of 5cm , the measured relaxivity of 0.0386cm/min (p.
• the relaxivity for an available "off the shelf silicone O-ring for Xe was measured at about 0.2-0.3 cm/min. For example, using the measured 129 Xe relaxivity numbers for the 3 He deuterated HDPE container will reduce the 132 hour bag down to just 15 hours (a full order of magnitude deterioration).
• every gasket, coupling, valve, tubing or other component that is added to the bag or container is preferably made of the friendliest possible material relative to the hype ⁇ olarized state.
• a spin-down chamber such as that described herein can be used to determine two relaxation times for a hype ⁇ olarized gas.
• HP hyper (“hypeipolarized gas") is introduced therein, and the relaxation time Ti is measured.
• the chamber is opened, a sample of known surface area is inserted, and the process is repeated to measure a new T
• the new Ti will be less than the old because a new relaxing surface has been added while keeping the free volume roughly the same.
• the difference between the two relaxation times is attributed to the relaxivity of the added material specimen.
• the difference can be used to calculate the material relaxivity using equation (2.10).
• Figures 4.1 and 4.2 show the calculated and experimental Ti values for Xe and He, respectively, in a 1 cc sphere for different surface materials as plotted against the product of solubility (S) and the square root of the molar density of protons in the material matrix [1H] ' ⁇
• the lcc sphere value inco ⁇ orates both volume and surface area and is a useful Ti metric corresponding to conventional evaluations, and as such is typically more readily descriptive than the relaxivity parameters described herein.
• the Ti value according to equation (2.23c) depends on a number of fixed constants and then depends inversely on gas solubility and the square root of the proton concentration.
• Experimental values of the measured one cubic centimeter sphere Ti (T ⁇ cc ) for all the polymers are plotted as well and show substantial agreement between theory and experiment, thus validating the so ⁇ tion model described herein.

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