Method and apparatus for generating hyperpolarized materials

Methods and apparatuses for generating hyperpolarized materials are disclosed. In one embodiment, a flexible fluid path is provided for use in a polarizer system. In a further embodiment, a polarizer system is provided with an electromechanical assembly for controlling the movement of a fluid path, when present, within a sample path of the polarizer system. In a further embodiment, a polarizer system is provided having a sample path entry point at a convenient height for use by a user standing on the ground.

BACKGROUND OF THE INVENTION

The subject matter disclosed herein relates generally to nuclear magnetic resonance imaging, and more particularly to the generation of contrast materials for use with nuclear magnetic resonance imaging technologies.

The nuclear magnetic properties of compositions, including those materials forming the body, have been utilized in the field of non-invasive imaging to provide both structural and functional information about the internal workings of the body. In particular, magnetic resonance imaging (MRI) and nuclear magnetic resonance (NMR) spectroscopy have both found used in the field of medical diagnostics and research. In general, such magnetic resonance imaging systems operate based on the interactions between one or more compositions of interest and various magnetic fields produced by an imaging system. For example, certain nuclear components, such as hydrogen nuclei in water molecules, have characteristic behaviors in response to the external magnetic fields generated by an MRI or NMR system. One response includes the spin of certain nuclear components in varying relations to one another. The precession of spins of such nuclear components can be influenced by manipulation of the magnetic fields to generate signals that are indicative of the responses and that can be detected, processed, and used to derive useful structural information (e.g., an image) and/or functional information (e.g., a composition or the metabolism of such a composition).

To enhance the signal generated by the magnetic resonance process, a polarized imaging agent can be administered to the subject undergoing imaging. Such polarized materials may have a short life span and are therefore produced at or near the imaging site for timely administration to the subject. However, the equipment used in the production of such polarized materials may be cumbersome and/or awkward to use, making the production process undesirably difficult.

BRIEF DESCRIPTION OF THE INVENTION

In one embodiment, a flexible fluid path is provided. The flexible fluid path includes a flexible double-walled tube comprising an inner tube and an outer tube. The flexible fluid path also includes a terminal portion in fluid communication with both the inner tube and the outer tube. The flexible fluid path also includes a first vessel in fluid communication with only one of the inner tube or the outer tube.

In a further embodiment, a polarizer system is provided. The polarizer system includes a vacuum chamber as well as a cryogenic cooling system and a magnet disposed within the vacuum chamber. The polarizer system includes a sample path extending through the cryogenic cooling system and an electro-mechanical assembly configured to control the movement of a fluid path, when present, within the sample path.

In an additional embodiment, a polarize system is provided. The polarizer system includes a vacuum chamber as well as a cryogenic cooling system and a magnet disposed within the vacuum chamber. The polarizer system includes a sample path extending through the cryogenic cooling system. The sample path has an entry point disposed at a height within a suitable control zone for access by a user standing on the ground

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure generally relates to a polarizer system and fluid path for use in such a system. The polarizer system and fluid path are used in the production of polarized agents to be administered to a subject undergoing a magnetic resonance imaging procedure. In particular, the polarizer system discussed herein is used to improve the polarization of nuclear spins of a sample provided in a solid phase, i.e., a frozen sample. The sample is then dissolved in a solution and administered to a patient undergoing imaging to enhance the imaging process. Such techniques are commonly referred to as hyperpolarization techniques. As used herein, the term “polarize” refers to the modification of the physical properties of a material (e.g., the sample) to enhance the properties of the material in a magnetic resonance imaging process. Likewise, the term “hyperpolarize” refers to polarizing a material at a level beyond what is observed at room temperature and at 1 Tesla.

In one embodiment, the polarizer system is configured to allow the fluid path to be loaded by a technician who remains on the ground (i.e., the technician does not have to climb up a ladder or other object) and who performs the loading operation between waist and chin level (e.g., at approximately chest height). For example, in one such embodiment, the fluid path loading operation is performed at a height between approximately 3 feet and approximately 5 feet from the floor on which the polarizer system rests. In one such embodiment, the fluid path if formed from a flexible material that allows the path to bend during the loading process and during operation. An automated apparatus may be provided to facilitate loading of a portion of the fluid path into the polarizer system. In certain implementations, more than one fluid path may be loaded into the polarizer system concurrently.

With the foregoing in mind and turning toFIG. 1, a simplified schematic diagram of a polarizer system10is depicted. In the depicted embodiment, the polarizer system10includes a vacuum chamber12that surrounds the internal components of the system. The depicted vacuum chamber12includes an antechamber or air lock14that seals a sample path16through which a sample is inserted into the polarizer system10.

In the depicted example, a fluid path18, here depicted as a flexible, double walled tube, is inserted into the sample path16. In such a double-walled implementation, an inner tube20may be used to deliver a solvent to a sample22at a terminal portion26of the fluid path18and an outer tube24may be used to recover a solution of the dissolved sample. In other embodiments, this arrangement may be reversed such that the outer tube24may be used to deliver the solvent to the sample22and the inner tube20may be used to recover a solution of the dissolved sample. In certain embodiments, the terminal portion26of the fluid path18contains the sample22within a vial or other sample container provided as an attached or integral portion of the fluid path18. In general, the fluid path18provides a sterile barrier between the sample22(and the resulting solution generated using the sample22) and the surrounding environment. The sample22may be frozen during hyperpolarization and subsequently dissolved for injection into a patient undergoing imaging. In one embodiment, the sample22may be13C1-pyruvate, though other agents may also be provided as the sample22.

The sample path16extends through a cryogenic cooling system28(such as a liquid helium bath30) that cools both the sample22and a magnet32(such as a superconducting magnet). When the fluid path18is inserted into the sample path16, the sample22contained within the fluid path18is positioned within the magnet32, which surrounds the sample path16. The cryogenic cooling system28and magnet32together act to hyperpolarize the sample22. In one embodiment, the magnet32provides a magnetic field on the order of 3.5 Tesla or higher to hyperpolarize the sample22.

The depicted polarizer system10also includes a heater component34in which a pressure vessel or syringe36may be situated. The pressure vessel or syringe36may be attached to or proved as part of the fluid path18and may be filled with a dissolution medium38(e.g., a solvent). When the pressure vessel or syringe36is placed within the heater component34, the heater component can heat the dissolution medium38and/or can maintain the dissolution medium38at an elevated temperature. In one embodiment, the heater component34is suitable for heating the dissolution medium38to a temperature suitable for dissolving the cryogenically frozen sample22.

The fluid path18may also include or be attached to a product vessel or syringe40that receives the dissolved and hyperpolarized sample. For example, once generated, the hyperpolarized sample solution may be transferred into the product vessel or syringe40, which may be removed by a clinician and used to administer the dose of hyperpolarized sample solution to a patient undergoing imaging. In one embodiment, the vessel or syringe40used to receive the sample solution may be disposed in a holding receptacle42while the hyperpolarization and dissolution process is performed.

In certain embodiments the receptacle42includes one or more quality testing devices that perform automated quality control tests on the hyperpolarized solution produced by the polarizer system10. Such quality control tests may be performed prior to the hyperpolarized solution entering the syringe40or after the hyperpolarized solution has filled the syringe40. In addition, the receptacle42may include structures (e.g., valves, fluid inlets, and so forth) for controlling the pressure of the hyperpolarized solution (such as to adjust the temperature of the hyperpolarized solution) and/or for diluting the hyperpolarized solution with additional fluid, such as water or saline (such as to adjust the temperature, concentration, and/or pH of the hyperpolarized solution). For example, the temperature of the hyperpolarized solution may be adjusted from about 80° C. to about 50° C. or lower (e.g., 37° C. or 38° C.). The quality control tests and/or temperature adjustments may be performed prior to placing the hyperpolarized solution in the syringe40for patient injection.

In addition, the polarizer system10may include a loading assembly44(such as an electro-mechanical loading assembly) that may aid in the loading and unloading of the fluid path18in the polarizer system10. For example, in one embodiment the loading assembly44may engage a portion of the fluid path18containing the sample22in a designated receptacle or location. Once received at this location, the loading assembly may automatically (or after initiation by a user) engage the fluid path18and lower the portion of the fluid path18containing the sample22into the polarizer system10such that the sample22is at a specified location within the system10for a specified time. In one embodiment, the loading assembly may also control the temperature and administration of the dissolution medium38for dissolving the hyperpolarized sample. In one such embodiment, an electro-mechanical actuator assembly in the heater component34applies pressure to a syringe36or vessel containing the dissolution medium38, as described below, such that the dissolution medium38is forced through a solvent path, such as inner tube20, of the fluid path18to reach the sample.

In the depicted embodiment, the operation of the loading assembly44, the heater component34, and/or the receptacle42may be controlled by control circuitry46. For example, such control circuitry46may control the loading of a fluid path18into the sample path16by controlling the operation of one or more rollers, motors, or other mechanized components of the loading assembly44. In one embodiment, the control circuitry46executes an automated loading routine, either upon sensing a fluid path in the vicinity of the loading mechanism44or upon receiving a user input. In one such embodiment, the control circuitry46operates a motor connected to rollers engaged with the fluid path18so that the rollers are rotated, causing the engaged fluid path to be fed into the sample path16up to a specified depth and for a specified time. As part of this process, the control circuitry46may vary the depth of the terminal portion26of the fluid path at different times in the hyperpolarization protocol, e.g., the fluid path may be partially raised when the heated dissolution medium38is injected. In addition, in certain embodiments, the control circuitry46may receive input from different components of the polarizer system10, such as temperature information from one or more temperature sensors49disposed in the sample path16. In one such embodiment, the control circuitry46may take into account the temperature information in executing a hyperpolarization protocol such that temperature, time, or temperature and time together determine the positioning and/or movement of the fluid path18within the sample path16. Once the hyperpolarization protocol is completed, the control circuitry46may cause the fluid path18to be unloaded from the polarizer system10, such as by operation of the motor and rollers.

The control circuitry46may also control operation of the heater component34. For example, the control circuitry46may control the temperature at which the heater component34maintains the dissolution medium38and/or may control the automated injection of the dissolution medium38through the fluid path. Likewise, in one embodiment the control circuitry46controls the automated quality control tests performed on the sample solution in the receptacle42and/or the operation of any air or fluid inlets of valves in the receptacle42to adjust the pressure, pH, temperature, and so forth of the sample solution in the receptacle42. In one embodiment, the control circuitry46may include one or more user input structures48, such as a keys, switches, buttons, and so forth, that a user may interact with to execute or control a hyperpolarizer protocol using the polarizer system10and a fluid path18. For example, a user might push respective buttons, keys, or other control structures to initiate the loading of a fluid path18, to initiate the injection of the dissolution medium38, to initiate a quality control test of the hyperpolarized solution, and/or to cause the unloading of the fluid path18or of the syringe40.

Turning toFIG. 2, one embodiment of a fluid path system18for use with polarizer system10is depicted. In one such embodiment the fluid path18is approximately one meter in length. The fluid path18can be made from medical grade materials suitable for use in a clinical setting, e.g., in a patient imaging setting where the patient is injected with a solution generated using the hyperpolarized sample22. Examples of such materials include plastics of validated quality in terms of chemical leaching and in terms of chemical and temperature stability. For example, materials for use in the fluid path18may be selected based on their thermal, chemical, and mechanical properties, such as their suitability for use at both superheated temperatures and cryogenic temperatures as well as at high pressures. One example of such a material is polyetheretherketone (PEEK).

In the depicted embodiment the fluid path18includes a sliding seal50that forms a junction or interface with the vacuum chamber12of the polarizer system10to help maintain the vacuum. The sliding seal50may freely slide along a tubing portion52of the fluid path18that is inserted into the polarizer system10so that an airtight seal is maintained when the fluid path18is loaded into the sample path16.

As noted above, the fluid path18may include a terminal portion26, in the form of an integral or attached vial or sample container, for holding the sample22. A specified or prescribed dose (e.g., 2 ml) of the sample22is typically provided in the terminal portion26of the fluid path18to be mixed with a dissolution medium38(e.g., an aqueous solvent) used to dissolve the sample22to form a solution for injection into a patient. In one embodiment, the terminal portion26of the fluid path18is formed of the same material (such as PEEK) as the double-walled tubing of the fluid path18. Typically, the material used to form the portions of the fluid path18that contact the sample22will be non-reactive with respect to the sample22and with solvents or solutions that might be used to dissolve the sample22.

In operation the fluid path18is used to position the sample22so that it may be polarized in the polarizer system10and to facilitate dissolving the sample22and transporting the dissolved sample out of the polarizer system10to another vessel for administration to a patient. As noted above, in one embodiment the fluid path18may include or be connected to a syringe36(which may be motor powered or pneumatic in certain embodiments) or other pressure vessel containing the dissolution medium38used to dissolve the sample22. The syringe36is used to inject the dissolution medium38through the fluid path18to the terminal portion26where the sample22is located.

In one implementation, the dissolution medium38may include one or more of a base solvent (e.g., sodium hydroxide) for neutralizing an acid constituent present in the sample22(e.g., pyruvic acid), an ion chelator (e.g., EDTA), and/or a buffering agent (e.g., a buffering salt, such as TRIS). In other implementations, the dissolution medium38may be water, saline, Ringer solution, or other media which may be suitable for dissolving the sample22and generating a solution that is suitable for injection into a patient.

The dissolution medium38may be maintained in a heated state (such as via heater component34in which the syringe36may be positioned) to facilitate dissolution of the frozen sample22after the sample22has been hyperpolarized but while the sample22is still surrounded by the cryogenic cooling system28. In one embodiment, the dissolution medium38may be heated to a temperature of up to about 150° C.

As noted above, in one embodiment the fluid path18includes a flexible, double-walled tubing section52that is formed from an inner tube20and an outer tube24, as depicted inFIG. 3. In one such embodiment, the inner tube20defines a lumen through which the dissolution medium38travels from the syringe36(as depicted inFIG. 2) to the sample22in the terminal portion26of the fluid path18. In the depicted embodiment, an input end of the inner tube20is connected to the syringe36containing the dissolution medium38. In one such implementation, the inner tube20is composed of a material having low thermal conductivity so as to maintain the temperature (e.g., a heated or elevated temperature) of the dissolution medium38as it moves from the syringe36to the sample22. In addition, one or more valves may be located within the inner tube20to control the flow of the dissolution medium38from the syringe36to the sample22, such as to limit the amount of dissolution medium38injected through the inner tube20to dissolve the sample22.

As depicted inFIG. 3, an output end60of the inner tube20extends into the terminal portion26of the fluid path18holding the sample22. Once the heated dissolution medium38reaches the terminal portion26of the fluid path18, the dissolution medium38mixes with, and dissolves, some or all of the frozen sample22to form a solution of the hyperpolarized sample22. The hyperpolarized solution may be administered (such as by intravenous injection) to a patient undergoing or preparing to undergo magnetic resonance imaging.

To recover the hyperpolarized solution for administration to the patient, a delivery or recovery path is provided in the fluid path18, such as a lumen or space defined between the outer tube24and the inner tube20, as depicted inFIGS. 1 and 3. Thus, in such an embodiment, the dissolution medium38is delivered to the terminal portion26of the fluid path18via the inner tube20and the resulting hyperpolarized solution is recovered from the terminal portion26via a separate path defined between the inner tube20and the outer tube24. While nested inner and outer tubes as discussed herein is one possible embodiment, it should be appreciated that other arrangements of tubing, such as side-by-side arrangements are also contemplated as possible implementations. In the depicted embodiment, an end62of the outer tube24is hermetically sealed to terminal portion26of the fluid path18that contains the sample22.

In practice, to recover the hyperpolarized solution, as dissolution medium38is injected into the terminal portion26to dissolve the sample22, the dissolution medium38continues to be injected thereby increasing the volume of the hyperpolarized solution and forcing the hyperpolarized solution through the solution recovery path defined by the outer tube24. The hyperpolarized solution flows through the outer tube24where it is collected by a receiving vessel, such as a syringe40suitable for administering the hyperpolarized solution to a patient. As depicted inFIG. 2, in one embodiment the fluid path18includes a valve or fluid redirector62that can be connected to tubing attached to the syringe40such that the contents of the outer tube24of the fluid path are directed through the connected tubing64to the syringe40. In other embodiments, the syringe40and/or the connecting tubing may be provided as an integral part of the fluid path18. One or more delivery valves may be present in the solution recovery path, such as in the outer tube24. In addition, the solution recovery path for the hyperpolarized solution may also include a filter used to remove an electron paramagnetic agent and/or other processing agents from the hyperpolarized solution.

As noted above, in one implementation, the fluid path18is formed using flexible materials, such as PEEK. In such an implementation, the polarizer system10may be configured such that the flexibility of the fluid path18provides a more manageable user experience. For example, turning now toFIG. 4, an example of a polarizer system10is depicted in which the fluid path18may be loaded and managed at a height between a users waist and shoulders (i.e., in an optimal control zone), such as between about three feet and five feet above the ground. That is, one or more of the heater component34(for holding the syringe36containing the dissolution medium38), the receptacle42(for holding the destination syringe40for receiving the dissolved hyperpolarized sample), and/or the loading assembly44(for loading the terminal portion26of the fluid path18into the polarizer system10) are provided within this suitable control zone such that the user may quickly and efficiently perform the polarizing operation and retrieve the polarized sample solution.

For example, in the depicted embodiment, a user may load a syringe36filled with dissolution medium38in a chamber of the heater component34the tubing portion52of the fluid path18connects the syringe36and the terminal portion26of the fluid path, which is fed into an opening70of the polarizer system. the receptacle42holding the destination syringe40may or may not be positioned proximate tot the heating component34, however the destination syringe40may be in fluid communication with the fluid path18via the connected tubing64. For example, the receptacle40may, in certain embodiments, be situated proximate to quality control analysis circuitry, fluid or air pumps or vents, and or other devices that may be used to test or prepare the final solution of the polarized sample prior to patient administration. In the depicted embodiment, the connected tubing64is merely depicted as terminating at a syringe holder72provided as the receptacle42. Thus, in the depicted embodiment, the fluid path18as well as the syringes attached to or in communication with the fluid path18are all handled at a convenient height (e.g., chest height, such as between four and five feet above the ground) during the loading, polarization, and unloading operations.

As noted above, various aspects of the polarization process may be automated to simplify the process for a user. For example, turning toFIG. 5, a fluid path loading assembly44, such as an electro-mechanical assembly, may be provided as part of a polarizer system10, such as that depicted inFIG. 4. In one such embodiment, the loading assembly44includes a motor80and rollers82that act in combination to engage the fluid path18, to load the fluid path18into the polarizer system10, to control the height of the terminal portion26of the fluid path18in the polarizer system10during the hyperpolarization process, and to unload the fluid path18upon completion of the hyperpolarization process. For example, in such an embodiment, a user may insert a portion of the fluid path18, such as the terminal portion26, into an opening70of the polarizer system10where the fluid path engages the rollers82. Once the fluid path is engaged with the rollers82, control circuitry46in communication with the loading assembly44may activate the motor80in response to a signal from the rollers82that a fluid path18is present or in response to an input provided by a user using provided input structures. Once activated the motor80may turn the rollers82to lower the terminal portion26of the fluid path a specified depth into the polarizer system10. During the course of a polarization operation, the control circuitry46, in accordance with one or more of specified programming, user inputs, or inputs from the polarizer system10(e.g., temperature, time, magnetic field strength, and so forth) may vary the height of the terminal portion26of the fluid path18within the polarizer system10. Once the polarization operation is completed, the control circuitry46may operate the motor80and rollers82to raise (i.e., unload) the fluid path18from the polarizer system10in response to automated programming or a user input.

Further, the control circuitry46, as previously noted, may automate other functions of the polarizer system10, such as the operation of the heater component,34, the administration of the dissolution medium38, the quality control analysis of the recovered hyperpolarized solution, and so forth. In one embodiment, the control circuitry46may be implemented as one or more general or special purpose processors executing suitable code for implementing these functionalities. In such embodiments, the code may be stored in one or more memory or mass storage components (e.g., magnetic storage media, optical storage media, solid state memory devices, and so forth) provides as part of the control circuitry46or as a separate component of the polarizer system10in communication with the control circuitry46. In this manner, some or all of the control circuitry functionality described herein may be provided, stored, and executed as computer or processor-implemented code.

Technical effects of the invention include the generation of a hyperpolarized solution for use in a medical imaging procedure. Other technical effects include the automated or facilitated loading and/or handling of a fluid path in a polarizer system used to produce a hyperpolarized solution for image enhancement. In addition, a technical effect as described herein is the use of a flexible fluid path to generate a hyperpolarized solution. Such a flexible fluid path may be used with a polarizer system10that allows loading, handling, and/or unloading of the flexible fluid path within a reasonable control zone of a user.