Patent Publication Number: US-2015075183-A1

Title: Polarization insert for a cryogenic refrigerator

Description:
1. CLAIM OF PRIORITY 
     This application claims priority from U.S. Provisional Patent Application Ser. No. 61/878,424, filed Sep. 16, 2013, which is hereby incorporated by reference. 
    
    
     2. FIELD OF TECHNOLOGY 
     The prevent invention relates to sample handling in a cryogenic environment, and in particular to a polarization insert for use in a cryogenic environment comprising a pneumatic flow path that pneumatically expels a sample of magnetically polarized material from the cryogenic environment. 
     3. RELATED ART 
     A hyperpolarized nuclear spin system is one in which the nuclear magnetic moments of the sample are more strongly aligned with an external magnetic field (B 0 ) than in the Boltzmann thermal-equilibrium state for given temperature (T) and B 0 . Such samples can provide correspondingly large signals in NMR, MRI, magnetic resonance spectroscopy (MRS), or MRS imaging (MRSI). Molecular carriers of nuclear hyperpolarization are thus highly valued as high-sensitivity probes for imaging or spectroscopy. 
     U.S. Patent Application Publications US2009/0016964 and US2011/0062392, both incorporated herein by reference, describe a process to generate hyperpolarization for use at moderate temperatures, by first polarizing the sample at ultra-low temperature (ULT), for example from tens to hundreds of millikelvin (mK), and high field (e.g., B 0 &gt;5 T). This relies on the fact that the usual Boltzmann polarization from ULT and high-field conditions becomes hyperpolarization if transferred to higher T and/or lower B 0 . Co-pending U.S. patent application Ser. No. 14/161,172 discloses an improved sample preparation method for ultralow temperature hyperpolarization and is also hereby incorporated by reference. 
     U.S. Pat. No. 6,758,059 discloses a dilution refrigerator assembly. As discussed therein in order for a dilution refrigerator to be used to investigate samples in high magnetic environments, it is known to use an elongate, tubular extension to the mixing chamber which extends into the bore of the magnet. A problem with conventional elongate, tubular extensions, also known as an insert, is that the magnetically polarized sample material is not easily removed from the insert. 
     There is a need for an improved technique for removing magnetically polarized material from an insert within a cryogenic environment. 
     SUMMARY OF THE DISCLOSURE 
     A method includes pneumatically expelling a sample of magnetically polarized material along a pneumatic flow path from a cryogenic environment. The method may include actively cooling the pneumatic flow path. 
     A polarization insert for use in a refrigerator comprises a pneumatic flow path that pneumatically expels a sample of magnetically polarized material from a cryogenic environment. 
     The pneumatic flow path may comprise a pneumatic port that is connected to and provides a gas flow path with a gas tube having a gas tube distal end, where the gas tube comprises a plurality of gas tube heat exchangers in-line with the gas tube to cool gas within the gas tube. The pneumatic flow path may also include a sample port that is connected to and provides a flow path with an ejection tube, where the ejection tube is substantially parallel with the gas tube and has an ejection tube distal end connected to the gas tube distal end via a coupling that forms a gas flow path between the gas tube and the ejection tube, where the coupling includes a base surface having a metallic heat exchanger. 
     The polarization insert may be substantially U-shaped as formed by the gas tube, the coupling and the ejection tube. 
     A pulse of pressurized gas may be applied to the pneumatic port to provide a motive force that flows through the gas tube and is coupled to the ejection tube via the coupling to discharge the sample of magnetically polarized material located within the ejection tube at the ejection tube distal end from the sample port. The source of the motive pneumatic force may be helium gas. 
     The cryogenic environment may be produced using the dilution refrigerator. A superconducting magnet may be used to maintain a magnetic field on the sample. 
     The sample may contain at least one methyl rotor group. For example, the sample may contain MR active nuclei such as 1H, 13C, 15N, 129Xe, 31P. 
     The speed of expulsion of the sample may for example be in excess of 1 msec. The temperature of the sample may be for example less than about 20 K during expulsion. 
     The pneumatic flow path may comprise a pneumatic port that is connected to and provides a gas flow path with a gas tube having a gas tube distal end, where the gas tube comprises a plurality of gas tube heat exchangers adjacent to the gas tube to cool gas within the gas tube. The pneumatic flow path may also comprise a sample port that is connected to and provides a flow path with an ejection tube, where the ejection tube has an ejection tube distal end connected to the gas tube distal end via a coupling that forms a gas flow path between the gas tube and the ejection tube. 
     The coupler may comprise a metallic heat exchanger and a heating element that applies heat to a metallic coupler surface. A thermometer may provide a signal indicative of temperature at the metallic coupler surface. 
     In one embodiment a cryogenic refrigerator polarization insert includes a pneumatic port that is connected to and provides a gas flow path with a gas tube having a gas tube distal end, where the gas tube comprises a plurality of gas tube heat exchangers adjacent to the gas tube to cool gas within the gas tube. The insert also includes a sample port that is connected to and provides a flow path with an ejection tube, where the ejection tube is substantially parallel with the gas tube and has an ejection tube distal end connected to the gas tube distal end via a coupling that Bonus a gas flow path between the gas tube and the ejection tube. The gas tube and the ejection tube form a pneumatic flow path that pneumatically expels a sample of magnetically polarized material from an ejection tube proximal end in response to pressurized gas being applied to a proximal end of the gas tube. 
     In another embodiment a dilution refrigerator polarization insert includes a pneumatic port configured and arranged to provide a gas flow path with a gas tube having a gas tube distal end, where the gas tube comprises a plurality of gas tube heat exchangers adjacent to the gas tube to cool gas within the gas tube. The insert also includes a sample port that is connected to and provides the gas flow path with an ejection tube, where the ejection tube has an ejection tube distal end connected to the gas tube distal end via a coupling in the gas flow path between the gas tube and the ejection tube. A sample of magnetically polarized material is expelled from an ejection tube proximal end in response to pressurized gas being applied to the pneumatic port. 
     It is to be understood that the features mentioned above and those to be explained below can be used not only in the respective combinations indicated, but also in other combinations or in isolation. 
     These and other objects, features and advantages of the invention will become apparent in light of the detailed description of the embodiment thereof, as illustrated in the accompanying drawings. 
    
    
     
       DESCRIPTION OF THE DRAWINGS 
         FIG. 1A  illustrates an embodiment of a polarization insert for a dilution refrigerator. 
         FIG. 1B  illustrates a more detailed illustration of a distal end of the polarization insert of  FIG. 1A  showing the coupling of the ejection tube and the gas tube. 
         FIG. 1C  is a side view illustration of the structure set forth in  FIG. 1B . 
         FIGS. 2A and 2B  illustrate first and second heat exchangers respectively adjacent to (e.g., in line) with the gas introduction tube (shown here in −90° rotation relative to their positions for normal operation).  FIGS. 2A and 2B  depict the exchangers with nominal temperatures of 160 K and 5 K, respectively. In each, the spiral path of the tube is represented by adjacent cross sections through the tube, which are wrapped around a solid copper cylinder. 
         FIG. 3  illustrates the base region of a U-tube, where gas introduction and eject arms are adjoined (shown here in −90° rotation relative to position for normal operation). A portion of a thermal strap connects the base of the U-tube to a mixing-chamber (MC) plate is shown at the top of the figure. The mixing chamber plate, while not depicted here, may be situated to the far right of the portion in shown in this schematic. The strap makes close thermal contact to a high-purity copper piece at the base (left side in the figure). This piece contains a set of fingers into which the silver sinter is packed. Helium gas introduced at the gas introduction tube condenses at the adjoining space and contact this sinter, thus completing the transmission of cooling power from the mix chamber plate and on to the sample. The latter rests on a pair of wires depicted here as a vertical line cutting across the eject tube. 
         FIG. 4  illustrates a portion of the insert that may include a plurality of knife edges. 
         FIGS. 5A-5G  illustrate a plurality of views of an insert, including a perspective view and rotated views of the insert along with views of components thereof. 
         FIG. 6  illustrates an alternative embodiment closed cycle refrigerator polarizer. 
     
    
    
     The invention can be better understood with reference to the following drawings and descriptions. The components in the figures are not necessarily to scale, instead emphasis being placed on illustrating the principles of the invention. Moreover, in the figures like reference numerals designate corresponding parts. In the drawings: 
     DESCRIPTION 
     A dilution refrigerator (DR) is a cryogenic device that provides continuous cooling to temperatures as low as about 2 mK, via the heat of mixing of Helium-3 and Helium-4 isotopes. A dilution refrigerator is a common piece of cryogenic equipment used throughout the scientific world. In a preferred embodiment, a polarization insert may be used as an insert for a so called “top-loading” dilution refrigerator. For example, the polarization insert may be mated with an Oxford Instruments Model Kelvinox 400 Dilution Refrigerator, with a base temperature of less than about 10 mK, and maximum magnetic field (B 0 ) of about 14 T. Other embodiments for dilution refrigerator systems, providing a distinct base temperature and/or magnetic field, and from other manufacturers are of course contemplated in the context of the present invention. In addition, it is contemplated that the present invention may be used in cryogenic environments that use a cryogenic refrigerator other than a dilution refrigerator. 
     The inventive polarization insert transforms a dilution refrigerator into a nuclear-spin polarizer capable of accepting a material sample, polarizing its nuclear spins in an ultra-low temperature (ULT), high B 0  environment. Subsequently the polarization insert then ejects the sample from the polarizing environment, either for transport/storage in more-moderate conditions (i.e., a lower ratio of B 0  to T) or for immediate melting and usage. In completing that transport, the polarization insert converts the nuclear spin polarization established in ULT and high- B 0  conditions into ‘hyperpolarization’, i.e., a spin polarization that exceeds the well-known Boltzmann equilibrium value for the new conditions of lower (B 0 /T). 
     In primary applications for such hyperpolarized samples, the molecules are used as ultrasensitive probes for nuclear magnetic resonance (NMR), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and MRS imaging (MRSI). A polarization insert described herein utilizes the cooling power and ULT, high- B 0  environment of the dilution refrigerator to convert a molecule with near-zero spin polarization into one whose polarization approaches the ideal value of P=1. Traditional NMR/MRI/MRS/MRSI observe signals from only very weakly polarized nuclear spins (e.g., P˜10 −5 -10 −6 ). Thus, when the dilution refrigerator polarization insert instead provides P approaching 1 for in vivo use near room or body temperature, then dramatic imaging enhancements are available, namely ultrasensitive and essentially background-free detection of signals from the hyperpolarized nuclei. An example target molecule is pyruvic acid, typically enriched with  13 C at the C 1  carbon site. This and other molecules are well-known targets of MRI/MRS/MRSI measurements, for example, enabling the imaging of metabolic processes to illuminate cancer diagnoses, inform treatment protocols and to test drug efficacy. That is possible using  13 C hyperpolarization levels that yield nearly up to 5 orders-of-magnitude sensitivity enhancements. 
       FIG. 1A  illustrates an embodiment of a polarization insert  100  for a dilution refrigerator. In one embodiment, starting at the top of the inner vacuum chamber (IVC) of a dilution refrigerator and working down, the insert includes a room-temperature flange  102  at the top of the cryostat, several radiation baffles (e.g.,  104   a - 104   f ) between the room-temperature flange  102  and straps  106  that connect to a 4K plate for example, straps  108  that connect to a 1K plate, straps  110  that connect to a distillation (or ‘still’) plate, straps  112  that connect to a cold plate, and straps  114  that connect to a mixing chamber plate. The straps  114  of the mixing chamber plate is where the lowest temperatures in a dilution refrigerator are produced. The other plates and components allow for a controlled thermal gradient between these ULT values and the room-temperature environment outside the dilution refrigerator. The baffles  104   a - 104   f  may be for example, highly polished pieces of copper or aluminum that block room-temperature radiation from reaching the lower, colder areas of the dilution refrigerator. Any insert lowered into the top of the dilution refrigerator for purpose of introducing a sample to be cooled to millikelvin temperatures must be properly thermally connected, or ‘sunk’, to the various stages listed above. For this reason, the polarization insert  100  may include various plates and thermal braids made of for example high purity copper. These elements are purposefully located throughout the polarization insert  100  to transmit the cooling power to the insert from the various temperature stages, i.e., the plates listed above. These thermal connections prevent the heat that is transmitted down the insert from reaching the ultimate ULT stage. This allows the bottommost section of the insert  100  to reach millikelvin temperatures in spite of the modification of introducing an insert to the dilution refrigerator. 
     Referring still to the embodiment illustrated in  FIG. 1A , a basic form of the insert  100  is a U-shaped tube. One ‘arm’ of the U-shaped tube is narrower (e.g., about 0.25″ O.D., 0.21″ I.D.) and is used for both sample insertion and ejection from the polarization insert  100 , and may be referred to as an ejection tube  120 . A larger tube (e.g., up to about 0.375″ O.D. in parts) constitutes the other aim of the U-shaped tube, and is used to transmit gas from the top of the insert (the room-T environment outside the dilution refrigerator) to the bottom, and may be referred to as a gas tube  122 . The joining of these two tubes in a “U-shape” via a coupling  124  at the bottom of the insert enables rapid pneumatic ejection of the sample from the ejection tube  120 . A bayonet coupling at the top of the insert  100  to mate to the ejection tube  120  and the gas tube  122 . The ejection tube  120  may include a slight spiral  128  in it to prevent room temperature radiation from traveling down the inside of the tube to the ultra-low temperature region. Referring to  FIGS. 1A-1C , at the bottom of the ejection tube  120  are for example two stainless steel wires  129  (e.g., about 0.015″ diameter). These run across the tube diameter, perpendicular to the direction of sample travel and airflow. The wires act as a back-stop, holding samples aloft in the ULT environment, while also allowing a high throughput of gas necessary for later ejection of the sample. 
     The insert  100  may also include for example two heat exchangers  130 ,  132  adjacent to (e.g., in line with) the gas flow tube  122 . These are used to control the T of gas, e.g., when transmitted to the sample for ejection. Referring now to  FIGS. 1A ,  2 A and  2 B, each of the exchangers  130 ,  132  may be a spiraled copper tube, located at strategic places within the insert and cooled by appropriate thermal contacts. The uppermost heat exchanger  130  is located between the room temperature flange  102  at the top of the cryostat and the straps  106  connecting to the 4K plate. The first exchanger  130  is cooled to approximately 160 K by radiation and exchange gas to its nearby environment. The second heat exchanger  132  is located near the straps  106  connecting to the 4K plate and uses thermal braids to transmit cooling power from the 4K plate to its copper spiral. These thermal braids can be altered (e.g., in thickness) to vary the cooling power of the 4K heat exchanger. The two heat exchangers  130 ,  132  may be designed for example to cool incoming helium gas from about 290 K to about 20 K in cases where that gas is flowing at about 0.5 1/min for 10 minutes, followed by about 25 1/min for 1 second. This is needed, for example, as low-flow gas may be used to precool the ejection tube  120  after establishing high polarization and just before ejection, whereas a shorter pulse of high-flow gas to the gas tube  120  via the flange  134  allows sample ejection with a tolerably small increase in sample temperature. 
     The insert  100  may also include a third heat exchanger  136 , for example located at the bottom of the insert, where the flow and eject tubes are joined in a U, as shown in  FIGS. 1B ,  1 C and  3 . It has a distinct form and function relative to the other noted heat exchanges. The third heat exchanger  136  is designed to deliver cooling power in the millikelvin T regime from a mixing chamber plate of the refrigerator to the sample. This facilitates achieving the high nuclear spin polarizations in the sample that occur with ULT and high field. Referring to  FIGS. 1A-1C  and  3 , a large thermal strap  138 , made for example of either high purity copper or silver transmits the cooling power of the mixing chamber plate to this lower heat exchanger  136 . The third exchanger  136  may be composed of for example silver sinter  140  pressed into an array of high-purity copper fingers, which protrude up from the bottom of the U-tube. The silver sinter  140  may be for example a porous, high-surface-area material with excellent thermal conductivity. Its porosity, surface area and they properties facilitate the further transmission of cooling power into liquid helium within the U-tube. The liquid helium then carries this to the sample. Thus overall, the insert  100  transmits the cooling power of the mixing chamber plate through the large thermal strap  138 , into the silver sinter  140  at the base of the U-tube, then into liquid helium which penetrates that sinter and carries the cooling power to the sample. The last of these steps may entail sufficient helium to submerge the sample where it sits on the wires at the base of the ejection tube  120 , or merely enough that a helium film flows from the sinter, up some portion of the tube  120  and then covers the sample. The liquid helium may be pure Helium-4, Helium-3 or a Helium-4/Helium-3 mixture. 
     Because there will be liquid helium in the bottom of the U-shaped tube at millikelvin temperatures, the insert  100  accounts for the superfluid behavior, which is a well-known property of helium-4 at these extreme temperatures. One aspect of superfluid behavior is fluid ‘creep’ over all surfaces, defined as the flow of a thin film of high-thermal conductivity liquid helium over every surface of its container. Typically, this creep continues until the thin layer finds a region whose T is above the critical value at which helium-4 ceases to be a superfluid. Unfortunately, such films then act as superb conductors of heat from the region of elevated T to environment intended for ULT conditions. Thus, referring now to  FIG. 4 , to prevent this film flow, the insert  100  may include knife-edges  142  to stop superfluid creep. As shown in  FIG. 4 , the insert may include for example four knife edges. These occur on either side of a break in both the gas tube  122  and the ejection tube  120  that together form the U-shaped tube along with the coupler  124 . The breaks may be located along the U-tube in the region between the thermal straps to the cold plate and to the mixing chamber plate. A re-sealable indium-sealed junction reconnects the break in both the gas and ejection tubes. At the discontinuity, both sections of each tube  120 ,  122  are machined to a knife-edge to prevent liquid helium from creeping beyond the break and up to sections of the insert  100  that are at higher temperatures. If necessary, use of indium-sealed junctions also allow a film burning heater to be incorporated. Two of these (or one common to each arm) may be readily wound about the high-T side of the tubes. 
     Temperature monitoring and control are important throughout the insert. Thermometers and heaters may be attached to each heat exchanger. For example, referring to  FIG. 1C , thermometer  144  and heater  146  may be attached to the third heat exchanger. These enable observations of the helium gas as it flows to or over the sample in preparation of polarization and then later in preparation for and during ejection. 
     The sample may include a cylindrical film affixed or frozen to the interior of a form of some other rigid material that provides a carrier. See example, U.S. patent application Ser. No. 14/161,172, incorporated herein by reference. The form protects the sample, while allowing either helium submersion or film flow to transmit cooling power to a large surface area of the sample. In addition, to facilitate rapid sample ejection, in spite of this open geometry, the sample design may include a light-weight large cross-sectional area “wad” situated behind the sample with respect to the direction of flow. The wad reduces the amount of helium gas needed for ejection. 
     A gas handling system (GHS) located near the dilution refrigerator controls the flow of ultra-high purity (UHP) helium gas into the U-shaped tube. The GHS may include a gas source (e.g., a tank) to provide enough helium gas to liquefy and fill the lower section of the U-shaped tube to conduct the cooling power to the sample. The GHS can also control the flow rate and time for pulses of helium gas applied to the flange  134  for ejection of the sample from the ejection tube  120 . 
     Devices for extracting samples from a cryogenic environment are known in the art. Generally, these require removing the entire cryogenic device from a refrigerator, with the sample mounted internally to the device. A second method known in the art is to have a sample mounted on a long stick, and removing that stick from the refrigerator. In these approaches temperature control of the sample during warming is generally not considered important; that is, the sample is allowed to warm—usually back to room temperature—at whatever rate is imposed by ambient conditions. 
     In contrast, the insert  100  uses pneumatic pressure to eject samples from a cryogenic environment; this approach allows the sample to be maintained during expulsion. Moreover the insert allows the ambient temperature and magnetic field environment of the sample to be controlled during expulsion. The use of gas also allows the ejection tube  120  to be pre-cooled, which reduces sample warming during expulsion. 
     The components of the insert  100  are preferably designed such that they can be readily incorporated into any commercially available cryogenic environment including for example dilution refrigerator platforms such as so-called “wet”, “dry”, “bottom loading” or “top loading” units. With the addition of a substantial magnetic field, such as that produced by a superconducting magnet, the device can be used to introduce samples into, and expel samples from, a very high B/T environment suitable for producing large nuclear polarizations in a variety of molecules. 
     The insert  100  allows materials to be expelled from an ultra-low temperature environment, both rapidly and without excessive sample warming, using pneumatic flow. This is beneficial for polarization applications because nuclear polarization can decay rapidly once the sample is removed from the high B/T environment. This is especially the case when the target molecule contains one or more methyl rotor groups. As described in U.S. Patent Application Publication US2011/006239, the details of which are incorporated here by reference, the presence of a methyl rotor group can cause the rate of nuclear magnetization loss (known in the art as T I   −1 ) in one or more nuclei in the material to be very rapid. The rate of polarization loss is particularly severe if the temperature of the material is at or near where the rotational correlation frequency of the methyl group is close to that of the nuclear Larmor frequency. This temperature regime is known in the art as the “valley of death” and can cause the material to lose all or most of the polarization that was induced at lower temperatures. Relaxation times in the “valley of death” are also generally a function of the ambient magnetic field, becoming even faster as the field is lowered. 
     A proximal length (e.g., the upper half of the ejection tube) must be cooled prior to ejection to prevent the sample from warming into or near the “valley of death” during its travel through the tube. If not actively cooled, the upper half of the ejection tube  120  would have a temperature gradient across it from for example 6 K, near the 4 K plate, to room temperature (293 K), at the top of the insert. The sample, when ejecting from the insert  100 , would quickly equilibrate with the temperature of the ejection tube  120  which would greatly increase the rate of polarization loss. There are several methods for cooling the ejection tube  120 , such as for example, blowing cold helium gas (&lt;20 K) through the ejection tube, or thermally strapping the ejection tube to the 4 K plate of the dilution refrigerator. The insert  100  may include a copper section of the ejection tube  120 , or an outer sleeve of copper wrapped around the stainless steel ejection tube, in either case extending from the 4 K plate up to just below the bayonet coupling. This copper section would then be thermally strapped to the 4 K plate of the dilution refrigerator to provide cooling to the ejection tube. 
     Commercially available polarizers avoid this problem by rapidly melting the sample, typically by mixing it with superheated water or buffered solution, without first extracting it from the polarizing cryostat. However this has the consequence that the polarized material, now in solution form, must be utilized immediately; once in the liquid state nuclear polarizations generally only last a minute or two at most. 
     As described in U.S. Patent Application Publication US2011006239, expelling the sample in the solid state permits it to then be transported, if desired, from one site to another without excessive polarization loss. The insert facilitates maintaining the sample at a desired temperature and ambient magnetic field during expulsion. 
       FIGS. 5A-5G  illustrate a plurality of views of an insert including a perspective view, rotated views and views of components thereof. 
       FIG. 6  illustrates a closed cycle refrigerator polarizer  200 . The polarizer includes a gas inlet port  202  which provides a flow line through a first stage heat exchanger  204  (e.g., a 30 k heat exchanger) and then through a second stage heat exchanger  206  (e.g., a 5 k heat exchanger). The ultralow temperature gas (e.g., helium) is then provided along a flow path  208  to an insert assembly  210 . The insert assembly  210  receives the ultralow temperature gas via a gas inlet of the insert assembly. A distal end of the insert is located between superconducting electromagnet  214  to polarize a sample deposited into the insert. The insert  210  includes a sample port  218  into which the sample to be polarized is deposited, and from which the polarized sample is pneumatically ejected. As proximal length of the insert is preferably stainless steel, which a distal length of the insert is preferably formed from a more thermally conductive material such as for example cooper. A copper strap  220  may be used to connect the distal length of the insert to a flange (e.g., a  30   k  flange). 
     The sample deposited into the sample port  218  comes to rest at a base surface  223 . A pulse of gas of sufficient pressure and duration is supplied to the gas inlet port to provide a motive force to pneumatically expel a sample on the base surface to the port sample. 
     Although the present invention has been illustrated and described with respect to several preferred embodiments thereof, various changes, omissions and additions to the form and detail thereof, may be made therein, without departing from the spirit and scope of the invention.