WO2009027645A2 - Improvements in the preparation of a sample (e.g. involving dynamic nuclear polarisation) for analysis (e.g. by nmr or mri) - Google Patents

Improvements in the preparation of a sample (e.g. involving dynamic nuclear polarisation) for analysis (e.g. by nmr or mri) Download PDF

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Publication number
WO2009027645A2
WO2009027645A2 PCT/GB2008/002855 GB2008002855W WO2009027645A2 WO 2009027645 A2 WO2009027645 A2 WO 2009027645A2 GB 2008002855 W GB2008002855 W GB 2008002855W WO 2009027645 A2 WO2009027645 A2 WO 2009027645A2
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WO
WIPO (PCT)
Prior art keywords
sample
cup
analysis
operable
plug
Prior art date
Application number
PCT/GB2008/002855
Other languages
French (fr)
Other versions
WO2009027645A3 (en
Inventor
Walter Friedrich Kockenberger
Graham Murray Smith
Robert Andrew Slade
Martin Charles Townsend
Daniel Robert Strange
Gary Stables
Original Assignee
The Universtiy Of Nottingham
The University Court Of The University Of St Andrews
Oxford Instruments Molecular Biotools Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0811685A external-priority patent/GB0811685D0/en
Application filed by The Universtiy Of Nottingham, The University Court Of The University Of St Andrews, Oxford Instruments Molecular Biotools Limited filed Critical The Universtiy Of Nottingham
Publication of WO2009027645A2 publication Critical patent/WO2009027645A2/en
Publication of WO2009027645A3 publication Critical patent/WO2009027645A3/en

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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
    • 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
    • G01R33/30—Sample handling arrangements, e.g. sample cells, spinning mechanisms
    • G01R33/307—Sample handling arrangements, e.g. sample cells, spinning mechanisms specially adapted for moving the sample relative to the MR system, e.g. spinning mechanisms, flow cells or means for positioning the sample inside a spectrometer
    • 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
    • G01R33/60—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using electron paramagnetic resonance
    • 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
    • G01R33/62—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using double resonance
    • 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
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/445—MR involving a non-standard magnetic field B0, e.g. of low magnitude as in the earth's magnetic field or in nanoTesla spectroscopy, comprising a polarizing magnetic field for pre-polarisation, B0 with a temporal variation of its magnitude or direction such as field cycling of B0 or rotation of the direction of B0, or spatially inhomogeneous B0 like in fringe-field MR or in stray-field imaging
    • 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
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/4808—Multimodal MR, e.g. MR combined with positron emission tomography [PET], MR combined with ultrasound or MR combined with computed tomography [CT]

Definitions

  • Examples of the present invention relate to methods and apparatus for preparation of a sample for analysis.
  • Sample preparation for example, is required for analysis by magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR) spectroscopy.
  • MRI magnetic resonance imaging
  • NMR nuclear magnetic resonance
  • a sample may be brought to a solid state, for example by cooling.
  • the term 'solid state' includes the case of an amorphous solid in the glassy state.
  • the solid state sample is then given a high degree of nuclear spin polarisation.
  • DNP dynamic nuclear polarisation
  • the solid state sample contains suitable radical molecules and is exposed to a field of millimeter or micrometer electro-magnetic waves in order to increase the nuclear spin polarization in the sample above the level that can be obtained solely by thermal polarisation.
  • Analysis of the highly polarised sample can then be performed in a number of ways.
  • Examples of the present invention provide a method preparation of a sample for analysis, comprising:
  • a magnetic field may be maintained, within which the conversion and analysis are performed without the sample leaving the magnetic field.
  • a magnetic field may be maintained, within which the steps of providing and moving the sample are performed.
  • the steps of providing and moving the sample, and of conversion and analysis, may all be performed in the same magnetic field.
  • the analysis may be performed at the second location or close to the second location.
  • the sample may exhibit a parameter which changes with time at a rate which is faster when in the liquid state than when in the solid state.
  • the sample may be polarised in the solid state. The change may be a decay.
  • the sample may be polarised by dynamic nuclear polarisation (DNP).
  • DNP dynamic nuclear polarisation
  • the sample may be frozen to the solid state.
  • the solid state may be a glassy state.
  • the sample may be a powder, or beads.
  • the sample may be housed in a receptacle, the receptacle being moved to move the sample from the first location to the second location.
  • the receptacle may be a cup.
  • the sample may be converted by mating the cup with apparatus as defined in the further aspect of the invention, as defined below.
  • the sample may be converted by reheating.
  • Reheating may be provided by contact with a relatively hot liquid.
  • Reheating may be provided by a laser, such as a carbon dioxide laser.
  • Reheating may be provided by millimeter or micrometer electro-magnetic waves.
  • the sample may be flushed in the liquid state by a flushing medium, prior to performing the analysis.
  • the sample may be flushed to an analysis station.
  • the flushing medium may further act to convert the sample to the liquid state, prior to flushing.
  • the flushing medium may be a relatively hot liquid.
  • the analysis may be magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR) spectroscopy.
  • MRI magnetic resonance imaging
  • NMR nuclear magnetic resonance
  • examples of the invention also provide apparatus comprising:
  • a sample preparation station operable to prepare a sample in a solid state
  • a conversion station operable to convert a prepared sample to a liquid state
  • a transport mechanism operable to transport a sample in a solid state from the sample preparation station to the conversion station;
  • an analysis station operable to perform an analysis on a sample after conversion to the liquid state by the conversion station.
  • a magnet arrangement may be provided, operable to create a magnetic field within which the conversion and analysis are performed without the sample leaving the magnetic field.
  • a magnetic arrangement may be provided, operable to create a magnetic field within which the sample preparation and the transport of the sample are performed without the sample leaving the magnetic field.
  • the preparation, transport, conversion and analysis of the sample may all be performed in the same magnetic field.
  • the analysis station may be located at the second location or close to the second location.
  • the sample may exhibit a parameter which changes with time at a rate which is faster when in the liquid state than when in the solid state. The change may be a decay.
  • the sample preparation station may be operable to polarise the sample in the solid state.
  • the sample preparation station may be operable to polarize by dynamic nuclear polarisation (DNP).
  • DNP dynamic nuclear polarisation
  • the sample preparation station may be operable to freeze the sample to the solid state.
  • the solid state may be a glassy state.
  • the transport mechanism may include a receptacle in which the sample is housed, during use, the receptacle being movable to move the sample from the first location to the second location.
  • the receptacle may be a cup or an inverted cup.
  • the receptacle may be matable with apparatus as defined below in the further aspect of the invention.
  • the transport mechanism may include a wave guide having a tip at which the sample cup is located. The sample in the cup may be moved by moving the wave guide between two locations.
  • the conversion station may be operable to convert the sample by reheating.
  • the conversion station may be operable to provide a relatively hot liquid for reheating the sample.
  • the hot liquid may be generated within the conversion station. Alternatively, the hot liquid may be provided from an external source.
  • the conversion station may comprise a laser, such as a carbon dioxide laser, for reheating the sample.
  • the conversion station may comprise an arrangement to irradiate the sample with millimeter or micrometer electromagnetic waves.
  • the conversion station may be operable to flush the sample in the liquid state, by a flushing medium, to the analysis station.
  • the flushing medium may further act to convert the sample to the liquid state, prior to flushing.
  • the flushing medium may be a relatively hot liquid.
  • the flushing medium may be generated within the conversion station. Alternatively, the flushing medium may be provided from an external source.
  • the analysis station may provide magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR) spectroscopy.
  • MRI magnetic resonance imaging
  • NMR nuclear magnetic resonance
  • examples of the invention provide apparatus comprising:
  • a plug for mating with a cup containing a sample, to substantially close the cup; an inlet arrangement operable to supply flushing medium to a mated cup;
  • inlet and outlet arrangements enable the sample to be flushed from the cup through the outlet arrangement by means of flushing medium provided through the inlet arrangement.
  • the inlet arrangement may include an inlet valve arrangement.
  • the outlet arrangement may include an outlet valve arrangement.
  • the or each valve arrangement may include a passage through the plug, for communication with a cup mated with the plug.
  • the or each valve arrangement may be opened by the cup mating with the plug.
  • the plug may be movably mounted in a support, and movable by mating a cup with the plug, the or each valve arrangement being opened as the plug moves.
  • the or at least one of the valve arrangements may comprise a movable valve member, there being a coupling arrangement causing the valve member to be movable between an open and a closed condition by movement of the plug.
  • the valve member may be biased to close a port and to be movable away from the port by movement of the plug.
  • the plug may carry a projection which is movable through the port to move the plug away from the port.
  • the projection may include a passage in communication with a cup mated with the plug, and which provides communication from the cup, through the port, when the projection has moved the plug away from the port.
  • a sensor may be provided to sense the cup mating with the plug, the sensor being operable to control the valve arrangements to open when mating is sensed.
  • the sensor may be mechanical or non-mechanical.
  • the sensor may be optical.
  • the cup mating with the plug may be sensed from operation of a transport mechanism used to move the cup.
  • the transport mechanism may include a motor, such as a stepper motor, and motor controller, there being a feedback circuit of the motor controller used to control the opening of the valves.
  • the inlet valve arrangement may include a supply of flushing medium.
  • the flushing medium may be a hot liquid.
  • the flushing medium supply may comprise a heater operable to maintain the flushing medium at a working temperature.
  • the apparatus may further comprise a cup for containing a sample, and matable with the plug.
  • the apparatus may further comprise a magnet arrangement operable to create a magnetic field within which a sample will remain while a cup is mated with the plug, and the sample is flushed through the outlet arrangement.
  • the apparatus may further comprise an analysis station operable to perform an analysis on the sample after flushing through the outlet arrangement.
  • There may be a magnet arrangement operable to create a magnetic field within which a sample will remain while being flushed from the cup and during analysis.
  • the sample may be flushed to an analysis station to perform an analysis.
  • the analysis may be for magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR) spectroscopy.
  • the sample may be provided initially in a solid state, and converted to a liquid state prior to flushing.
  • the sample may exhibit a parameter which decays or changes with time at a rate which is faster when in the liquid state than when in the solid state.
  • the sample may be polarised in the solid state.
  • the nuclear spin system of the sample may be polarised such as by dynamic nuclear polarisation (DNP).
  • DNP dynamic nuclear polarisation
  • the sample may be frozen to the solid state.
  • the sample may consist of small frozen beads.
  • the sample may be a powder.
  • the sample cup may be moved to move the sample in a solid state from a first location to a second location.
  • the sample may be converted to a liquid state at the second location, by mating the cup with the plug.
  • the sample may be converted by reheating.
  • Reheating may be provided by contact with a relatively hot liquid.
  • the relatively hot liquid may be the flushing medium.
  • Reheating may be provided by a laser, such as a carbon dioxide laser.
  • Reheating may be provided by a suitable micrometer or millimeter electromagnetic wave field.
  • Figure 1 is a highly schematic diagram of apparatus according to one example of the invention simultaneously showing several different stages of the method being described;
  • Figure 2 illustrates in more detail an example apparatus of the type illustrated in figure 1 ; and Figure 3 is a schematic diagram of the method in which the apparatus of Figures 1 and 2 may be used.
  • Figure 1 illustrates in highly schematic form a method for preparing and analysing a sample.
  • a sample 10 is provided in a solid state at a sample preparation station at a first location 12.
  • the first location 12 may be within a magnetic coil 14 or other magnetic arrangement, such as a superconducting magnet.
  • the sample 10 may be provided in a solid state by freezing such as by a cryogenic system 15. Freezing may take place at the first location 12, or prior to introduction to the first location 12.
  • the sample is provided in a receptacle, such as an inverted cup 16 and is moved to the first location 12 by moving the cup 16 to the first location 12.
  • a receptacle such as an inverted cup 16
  • the magnetic coil 14 and millimeter or micrometer waves travelling through a waveguide 21a to the sample cup 16 from an external source allows the sample 10 to be further prepared by polarisation.
  • the nuclear spin system within the sample may be polarised by dynamic nuclear polarisation (DNP).
  • DNP dynamic nuclear polarisation
  • the cup 16 is moved to a conversion station at a second location 18, by an appropriate transport mechanism, such as a handling mechanism 19.
  • This handling mechanism may consist of a hollow wave guide 21a carrying the sample cup at its tip 21b.
  • the wave guide 21a may be attached to an actuator 21c that is controlled by a stepper motor.
  • the handling mechanism may consist of a rod (not shown) carrying the sample cup at its tip.
  • the rod may be attached to an actuator that is controlled by a stepper motor.
  • the waveguide 21a reaches into and then through the magnetic coil 14 and the first location 12, and then to the second location 18.
  • the sample 10 remains in the cup 16 and remains frozen in the solid state. Accordingly, the sample 10 is moved from the first location 12 to the second location 18 while in the solid state. This is preferentially done in vertical direction, however can also be implemented in a horizontal arrangement.
  • the second location 18 includes a docking station 20 by means of which the sample 10 can be returned to a liquid state at the second location 18. This is achieved by mating the cup 16 with the docking station 20, in a manner to be described.
  • the second location 18 also includes an analysis station 22 by which the sample may be analysed after conversion to the liquid state.
  • the analysis station in this example, is a NMR flow probe head.
  • a second magnetic coil 24, or superconducting magnet or other magnetic arrangement, is provided at the second location 18. Consequently, the preparation, transport and conversion of the sample from the solid state to the liquid state, and the analysis of the sample in the liquid state, are performed with the sample always being exposed to a magnetic field much higher than the magnetic field of the Earth. This is considered advantageous if the sample exhibits a parameter which decays or changes with time at a rate which is faster when in the liquid state than when in the solid state, as will be described.
  • the arrangement of the magnets 10 and 24 is such as to maintain the magnetic field through which the sample 10 is moved at a value well above the magnetic field of the Earth. This helps maintain the high degree of polarisation achieved by the DNP process.
  • the decay rate of the spin polarisation of many types of sample is much slower when in the solid state, than when in the liquid state.
  • the decay rate of spin polarization depends on longitudinal relaxation processes that are described by a time constant T1.
  • moving the sample in the solid state is expected to result in the sample having a much higher polarisation upon arrival at the second location 18, than if the sample was transported in a liquid state, and particularly if the sample 10 remains in the same magnetic field throughout the process being described.
  • the apparatus at the second location 18, including the docking station 20 and the analysis station 22, can now be described in more detail, by reference to the remaining drawings.
  • the docking station 20 has a plug 26 for mating with the cup 16 when containing a sample, to substantially close the cup 16. That is, when the cup 16 is mated with the plug 26, the interior of the cup 16 is substantially sealed against ingress or leakage.
  • an inlet valve arrangement 28 is provided to supply flushing medium to a mated cup 16, through an inlet passage 30, which passes through the plug 26.
  • a source 32 of flushing medium is also provided.
  • the flushing medium may be a relatively hot liquid.
  • An outlet valve arrangement 34 is provided, operable to drain flushing medium from the cup 16 by means of an outlet passage 36, which passes through the plug 26.
  • the valve arrangements 28, 34 enable the sample 10 to be flushed from the cup 16 through the outlet passage 36 by means of flushing medium provided through the inlet 30.
  • the outlet valve 34 is optional and is required if the location 12 is kept under vacuum.
  • the flushed sample 10 passes through the outlet passage 36 to the analysis station 22, which may provide analysis by magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR) spectroscopy.
  • MRI magnetic resonance imaging
  • NMR nuclear magnetic resonance
  • valve arrangements 28, 34 are opened when the cup 16 is detected mating with the plug 26.
  • a simple sensor arrangement is indicated at 38, to detect the presence of the cup 16 mated with the plug 26 and control the valve 28 to open when the cup 16 is properly mated.
  • the sensor may be mechanical or non-mechanical.
  • the sensor may be optical.
  • the valve 28 may be controlled by a simple electronic feedback circuit linked to the stepper motor controller of the actuator 21c that transports the sample 10. Accordingly, in the simple example illustrated in figures 1 and 2, the sample 10 is provided in a solid state in the cup 16, at the first location 12 and is prepared by freezing and DNP polarisation. The sample 10 is then moved in the cup 16 and in the solid state to the second location 18, where the cup 16 is mated with the plug 26.
  • Relatively hot liquid is then supplied from the source 32 to the cup 16 to flush the sample 10 through the outlet 36 to the analysis station 22.
  • the heat of the liquid supplied from the source 32 also has the effect of converting the sample 10 back to its liquid state prior to flushing through to the analysis station 22.
  • the liquid provided for flushing must be sufficiently hot to convert the sample 10 back to its liquid state and to avoid refreezing during flushing to the analysis station 22.
  • the source 32 may be located at location 18.
  • the hot liquid can be provided, such as through a pipe (not shown) from a source which is distant to location 18.
  • the hot liquid can be provided from a source which is distant to location 18 directly into the sample cup through a pipe (not shown) attached to the sample cup.
  • the sample 10 is then flushed into the docking station 20, and out through the outlet arrangement 34.
  • the sample 10 may be converted back to its liquid state by means of other heat sources, such as a laser (not shown). It is envisaged that a CO2 laser could be used in this manner. Alternatively, a suitable millimeter or micrometer electromagnet wave field may be used.
  • FIG. 3 illustrates an alternative arrangement for the docking station 20, particularly in relation to the manner in which the presence of a cup 16 is detected, and the valves 28, 34 controlled.
  • the plug 26 is movably mounted in a cavity 40 within a support 42.
  • the cavity 40 is sealed at 44 around the plug 26, to allow the plug 26 to move further into the cavity 40, or partially withdraw from the cavity 40.
  • the plug 26 can be pushed into the cavity 40 by mating the cup 16 with the plug 26.
  • the valve arrangements 28, 34 are provided in respective valve cavities 46a, b.
  • Each valve arrangement consists of a movable valve member 48 having a head 50 which is sufficiently large to close a port 52 through to the cavity 40.
  • the valve member 48 also has a shaft 54 guided in a bush 56 to allow the head 50 to move away from the port 52.
  • Spring arrangements (not shown) are provided to bias the valve members 48 toward the ports 52.
  • the plug 26 carries two projections 58 which are aligned with respective ports 52. As the plug 26 is pushed into the cavity 40, by mating a cup 16, the projections 58 move through their respective ports 52 to engage the head 50 of the respective valve member 48 and push the head 50 away from the port 52.
  • the inlet passage 30 extends through one of the projections 58 and the outlet passage 36 extends through the other projection 58, so that when the ports 52 have been opened by the projections 58 pushing the respective heads 50, the inlet 30 and outlet 36 are in communication with respective valve cavities 46a, b.
  • the ultimate outlet 60 of the arrangement is in communication with the valve cavity 46b. This allows material flushed from the cup 16 to pass through the outlet 36 into the valve cavity 46b and then out from the outlet 60 to the analysis station 22.
  • the other valve cavity 46a is provided with flushing medium from a source
  • the source 32 may include a boiler chamber 62 with a heater 64 for creating hot liquid within the chamber 62.
  • a passage 66 connects the chamber 62 to the valve cavity 46a, for supplying flushing medium from the chamber 62 through the inlet passage 32 the cup 16.
  • the period of time is short in which the sample 10 is in its liquid state prior to reaching the analysis station 22. This reduces the time in which the polarisation of the sample 10 can decay, prior to analysis. Furthermore, the provision of the magnets 24, and in particular, the location of the docking station 20 and analysis station 22 within the same magnetic field, further assist in maintaining polarisation between the time at which the sample 10 is returned to its liquid state, and the time at which the sample 10 arrives at the analysis station.
  • unfolded proteins may be freeze- dried to hold them in their unfolded state.
  • the freeze-dried unfolded proteins then form the solid state sample described above. They can be brought in solution in the docking station and then analysed almost immediately at the analysis station 22, to watch them fold. It is the folding of the proteins which corresponds with the changing parameter.
  • the sample may consist of ligands provided in powder form and converted to a liquid form at the docking station by a flushing medium which includes proteins.
  • the analysis station can then be used to analyse the manner in which the ligands bind with the proteins. This binding represents the changing parameter.
  • the sample may stick to the cup 16.
  • a mesh support may be used, allowing the powder to be retained, but flushed from the cup after return to the liquid state.
  • the samples are envisaged as small volume samples.
  • the solid state sample may be less than 1 ml_ and may be dissolved into a volume less than 2.5 mL It is envisaged that the dissolving step can be rapid, such as less than 1.5 seconds.

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  • Physics & Mathematics (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • General Physics & Mathematics (AREA)
  • Magnetic Resonance Imaging Apparatus (AREA)

Abstract

A method of preparation of a sample for analysis (such as a sample for dynamic unclear polarisation with subsequent analysis by NMR or MRI) comprises providing a sample (10) in a solid state at a first location (12); moving the sample (10) in the solid state to a second location (18); converting the sample (10) to a liquid state at. the second location (18); and performing an analysis on the sample (10) after conversion to the liquid state. Also according to the invention, sample preparation apparatus comprises: a sample preparation station (12) operable to prepare a sample (10) in a solid state; a conversion station (18) operable to convert a prepared sample (10) to a liquid state; a transport mechanism (19) operable to transport a sample (10) in a solid state from the sample preparation station (12) to the conversion station (18); and an analysis station (22) operable to perform an analysis on a sample (10) after conversion to the liquid state by the conversion station (18).

Description

Improvements in or Relating to Methods and Apparatus for Preparation of a Sample for Analysis
Examples of the present invention relate to methods and apparatus for preparation of a sample for analysis.
Sample preparation, for example, is required for analysis by magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR) spectroscopy. In each case, a sample may be brought to a solid state, for example by cooling. Specifically, the term 'solid state' includes the case of an amorphous solid in the glassy state. The solid state sample is then given a high degree of nuclear spin polarisation. For example, dynamic nuclear polarisation (DNP) techniques may be used, in which the solid state sample contains suitable radical molecules and is exposed to a field of millimeter or micrometer electro-magnetic waves in order to increase the nuclear spin polarization in the sample above the level that can be obtained solely by thermal polarisation. Analysis of the highly polarised sample can then be performed in a number of ways.
Examples of the present invention provide a method preparation of a sample for analysis, comprising:
providing a sample in a solid state at a first location;
moving the sample in the solid state to a second location;
converting the sample to a liquid state at the second location; and
performing an analysis on the sample after conversion to the liquid state. A magnetic field may be maintained, within which the conversion and analysis are performed without the sample leaving the magnetic field. A magnetic field may be maintained, within which the steps of providing and moving the sample are performed. The steps of providing and moving the sample, and of conversion and analysis, may all be performed in the same magnetic field. The analysis may be performed at the second location or close to the second location. The sample may exhibit a parameter which changes with time at a rate which is faster when in the liquid state than when in the solid state. The sample may be polarised in the solid state. The change may be a decay. The sample may be polarised by dynamic nuclear polarisation (DNP). The sample may be frozen to the solid state. The solid state may be a glassy state. The sample may be a powder, or beads.
The sample may be housed in a receptacle, the receptacle being moved to move the sample from the first location to the second location. The receptacle may be a cup. The sample may be converted by mating the cup with apparatus as defined in the further aspect of the invention, as defined below.
The sample may be converted by reheating. Reheating may be provided by contact with a relatively hot liquid. Reheating may be provided by a laser, such as a carbon dioxide laser. Reheating may be provided by millimeter or micrometer electro-magnetic waves.
The sample may be flushed in the liquid state by a flushing medium, prior to performing the analysis. The sample may be flushed to an analysis station. The flushing medium may further act to convert the sample to the liquid state, prior to flushing. The flushing medium may be a relatively hot liquid.
The analysis may be magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR) spectroscopy. In this aspect, examples of the invention also provide apparatus comprising:
a sample preparation station operable to prepare a sample in a solid state;
a conversion station operable to convert a prepared sample to a liquid state;
a transport mechanism operable to transport a sample in a solid state from the sample preparation station to the conversion station;
an analysis station operable to perform an analysis on a sample after conversion to the liquid state by the conversion station.
A magnet arrangement may be provided, operable to create a magnetic field within which the conversion and analysis are performed without the sample leaving the magnetic field. A magnetic arrangement may be provided, operable to create a magnetic field within which the sample preparation and the transport of the sample are performed without the sample leaving the magnetic field. The preparation, transport, conversion and analysis of the sample may all be performed in the same magnetic field. The analysis station may be located at the second location or close to the second location. The sample may exhibit a parameter which changes with time at a rate which is faster when in the liquid state than when in the solid state. The change may be a decay. The sample preparation station may be operable to polarise the sample in the solid state. The sample preparation station may be operable to polarize by dynamic nuclear polarisation (DNP). The sample preparation station may be operable to freeze the sample to the solid state. The solid state may be a glassy state.
The transport mechanism may include a receptacle in which the sample is housed, during use, the receptacle being movable to move the sample from the first location to the second location. The receptacle may be a cup or an inverted cup. The receptacle may be matable with apparatus as defined below in the further aspect of the invention. The transport mechanism may include a wave guide having a tip at which the sample cup is located. The sample in the cup may be moved by moving the wave guide between two locations.
The conversion station may be operable to convert the sample by reheating. The conversion station may be operable to provide a relatively hot liquid for reheating the sample. The hot liquid may be generated within the conversion station. Alternatively, the hot liquid may be provided from an external source. The conversion station may comprise a laser, such as a carbon dioxide laser, for reheating the sample. The conversion station may comprise an arrangement to irradiate the sample with millimeter or micrometer electromagnetic waves.
The conversion station may be operable to flush the sample in the liquid state, by a flushing medium, to the analysis station. The flushing medium may further act to convert the sample to the liquid state, prior to flushing. The flushing medium may be a relatively hot liquid. The flushing medium may be generated within the conversion station. Alternatively, the flushing medium may be provided from an external source.
The analysis station may provide magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR) spectroscopy.
In a further aspect, examples of the invention provide apparatus comprising:
a plug for mating with a cup containing a sample, to substantially close the cup; an inlet arrangement operable to supply flushing medium to a mated cup;
an outlet arrangement operable to drain flushing medium from a mated cup; and
wherein the inlet and outlet arrangements enable the sample to be flushed from the cup through the outlet arrangement by means of flushing medium provided through the inlet arrangement.
The inlet arrangement may include an inlet valve arrangement. The outlet arrangement may include an outlet valve arrangement. The or each valve arrangement may include a passage through the plug, for communication with a cup mated with the plug. The or each valve arrangement may be opened by the cup mating with the plug. The plug may be movably mounted in a support, and movable by mating a cup with the plug, the or each valve arrangement being opened as the plug moves. The or at least one of the valve arrangements may comprise a movable valve member, there being a coupling arrangement causing the valve member to be movable between an open and a closed condition by movement of the plug. The valve member may be biased to close a port and to be movable away from the port by movement of the plug. The plug may carry a projection which is movable through the port to move the plug away from the port. The projection may include a passage in communication with a cup mated with the plug, and which provides communication from the cup, through the port, when the projection has moved the plug away from the port.
Alternatively, a sensor may be provided to sense the cup mating with the plug, the sensor being operable to control the valve arrangements to open when mating is sensed. The sensor may be mechanical or non-mechanical. The sensor may be optical. Alternatively, the cup mating with the plug may be sensed from operation of a transport mechanism used to move the cup. The transport mechanism may include a motor, such as a stepper motor, and motor controller, there being a feedback circuit of the motor controller used to control the opening of the valves.
The inlet valve arrangement may include a supply of flushing medium. The flushing medium may be a hot liquid. The flushing medium supply may comprise a heater operable to maintain the flushing medium at a working temperature.
The apparatus may further comprise a cup for containing a sample, and matable with the plug.
The apparatus may further comprise a magnet arrangement operable to create a magnetic field within which a sample will remain while a cup is mated with the plug, and the sample is flushed through the outlet arrangement. The apparatus may further comprise an analysis station operable to perform an analysis on the sample after flushing through the outlet arrangement. There may be a magnet arrangement operable to create a magnetic field within which a sample will remain while being flushed from the cup and during analysis.
In further examples of the invention, there is provided a method comprising:
providing a sample in a sample cup;
mating the sample cup with a plug to substantially close the cup;
supplying flushing medium to the mated cup;
draining flushing medium from the mated cup to flush the sample from the cup by means of the flushing medium. The sample may be flushed to an analysis station to perform an analysis. The analysis may be for magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR) spectroscopy.
The sample may be provided initially in a solid state, and converted to a liquid state prior to flushing. The sample may exhibit a parameter which decays or changes with time at a rate which is faster when in the liquid state than when in the solid state. The sample may be polarised in the solid state. The nuclear spin system of the sample may be polarised such as by dynamic nuclear polarisation (DNP). The sample may be frozen to the solid state. The sample may consist of small frozen beads. The sample may be a powder.
The sample cup may be moved to move the sample in a solid state from a first location to a second location. The sample may be converted to a liquid state at the second location, by mating the cup with the plug.
The sample may be converted by reheating. Reheating may be provided by contact with a relatively hot liquid. The relatively hot liquid may be the flushing medium. Reheating may be provided by a laser, such as a carbon dioxide laser. Reheating may be provided by a suitable micrometer or millimeter electromagnetic wave field.
Examples of the present invention will now be described in more detail, with reference to the accompanying drawings, in which:
Figure 1 is a highly schematic diagram of apparatus according to one example of the invention simultaneously showing several different stages of the method being described;
Figure 2 illustrates in more detail an example apparatus of the type illustrated in figure 1 ; and Figure 3 is a schematic diagram of the method in which the apparatus of Figures 1 and 2 may be used.
Figure 1 illustrates in highly schematic form a method for preparing and analysing a sample. In figure 1, a sample 10 is provided in a solid state at a sample preparation station at a first location 12. The first location 12 may be within a magnetic coil 14 or other magnetic arrangement, such as a superconducting magnet. The sample 10 may be provided in a solid state by freezing such as by a cryogenic system 15. Freezing may take place at the first location 12, or prior to introduction to the first location 12.
The sample is provided in a receptacle, such as an inverted cup 16 and is moved to the first location 12 by moving the cup 16 to the first location 12.
The magnetic coil 14 and millimeter or micrometer waves travelling through a waveguide 21a to the sample cup 16 from an external source allows the sample 10 to be further prepared by polarisation. In particular, the nuclear spin system within the sample may be polarised by dynamic nuclear polarisation (DNP). After DNP polarisation is complete, the cup 16 is moved to a conversion station at a second location 18, by an appropriate transport mechanism, such as a handling mechanism 19. This handling mechanism may consist of a hollow wave guide 21a carrying the sample cup at its tip 21b. The wave guide 21a may be attached to an actuator 21c that is controlled by a stepper motor. Alternatively, the handling mechanism may consist of a rod (not shown) carrying the sample cup at its tip. The rod may be attached to an actuator that is controlled by a stepper motor. During this movement, the waveguide 21a reaches into and then through the magnetic coil 14 and the first location 12, and then to the second location 18. During this movement of the cup 16, the sample 10 remains in the cup 16 and remains frozen in the solid state. Accordingly, the sample 10 is moved from the first location 12 to the second location 18 while in the solid state. This is preferentially done in vertical direction, however can also be implemented in a horizontal arrangement.
The second location 18 includes a docking station 20 by means of which the sample 10 can be returned to a liquid state at the second location 18. This is achieved by mating the cup 16 with the docking station 20, in a manner to be described. The second location 18 also includes an analysis station 22 by which the sample may be analysed after conversion to the liquid state. The analysis station, in this example, is a NMR flow probe head.
A second magnetic coil 24, or superconducting magnet or other magnetic arrangement, is provided at the second location 18. Consequently, the preparation, transport and conversion of the sample from the solid state to the liquid state, and the analysis of the sample in the liquid state, are performed with the sample always being exposed to a magnetic field much higher than the magnetic field of the Earth. This is considered advantageous if the sample exhibits a parameter which decays or changes with time at a rate which is faster when in the liquid state than when in the solid state, as will be described.
The arrangement of the magnets 10 and 24 is such as to maintain the magnetic field through which the sample 10 is moved at a value well above the magnetic field of the Earth. This helps maintain the high degree of polarisation achieved by the DNP process. In particular, the decay rate of the spin polarisation of many types of sample is much slower when in the solid state, than when in the liquid state. The decay rate of spin polarization depends on longitudinal relaxation processes that are described by a time constant T1. Thus, moving the sample in the solid state is expected to result in the sample having a much higher polarisation upon arrival at the second location 18, than if the sample was transported in a liquid state, and particularly if the sample 10 remains in the same magnetic field throughout the process being described. The apparatus at the second location 18, including the docking station 20 and the analysis station 22, can now be described in more detail, by reference to the remaining drawings.
The docking station 20 has a plug 26 for mating with the cup 16 when containing a sample, to substantially close the cup 16. That is, when the cup 16 is mated with the plug 26, the interior of the cup 16 is substantially sealed against ingress or leakage. However, an inlet valve arrangement 28 is provided to supply flushing medium to a mated cup 16, through an inlet passage 30, which passes through the plug 26. A source 32 of flushing medium is also provided. The flushing medium may be a relatively hot liquid.
An outlet valve arrangement 34 is provided, operable to drain flushing medium from the cup 16 by means of an outlet passage 36, which passes through the plug 26. Thus, the valve arrangements 28, 34 enable the sample 10 to be flushed from the cup 16 through the outlet passage 36 by means of flushing medium provided through the inlet 30. The outlet valve 34 is optional and is required if the location 12 is kept under vacuum. The flushed sample 10 passes through the outlet passage 36 to the analysis station 22, which may provide analysis by magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR) spectroscopy.
The valve arrangements 28, 34 are opened when the cup 16 is detected mating with the plug 26. In figure 2, a simple sensor arrangement is indicated at 38, to detect the presence of the cup 16 mated with the plug 26 and control the valve 28 to open when the cup 16 is properly mated. The sensor may be mechanical or non-mechanical. The sensor may be optical. Alternatively, the valve 28 may be controlled by a simple electronic feedback circuit linked to the stepper motor controller of the actuator 21c that transports the sample 10. Accordingly, in the simple example illustrated in figures 1 and 2, the sample 10 is provided in a solid state in the cup 16, at the first location 12 and is prepared by freezing and DNP polarisation. The sample 10 is then moved in the cup 16 and in the solid state to the second location 18, where the cup 16 is mated with the plug 26. Relatively hot liquid is then supplied from the source 32 to the cup 16 to flush the sample 10 through the outlet 36 to the analysis station 22. The heat of the liquid supplied from the source 32 also has the effect of converting the sample 10 back to its liquid state prior to flushing through to the analysis station 22. The liquid provided for flushing must be sufficiently hot to convert the sample 10 back to its liquid state and to avoid refreezing during flushing to the analysis station 22. The source 32 may be located at location 18. Alternatively, the hot liquid can be provided, such as through a pipe (not shown) from a source which is distant to location 18.
In another example, the hot liquid can be provided from a source which is distant to location 18 directly into the sample cup through a pipe (not shown) attached to the sample cup. The sample 10 is then flushed into the docking station 20, and out through the outlet arrangement 34.
In other examples, the sample 10 may be converted back to its liquid state by means of other heat sources, such as a laser (not shown). It is envisaged that a CO2 laser could be used in this manner. Alternatively, a suitable millimeter or micrometer electromagnet wave field may be used.
Figure 3 illustrates an alternative arrangement for the docking station 20, particularly in relation to the manner in which the presence of a cup 16 is detected, and the valves 28, 34 controlled. In this example, the plug 26 is movably mounted in a cavity 40 within a support 42. The cavity 40 is sealed at 44 around the plug 26, to allow the plug 26 to move further into the cavity 40, or partially withdraw from the cavity 40. In particular, the plug 26 can be pushed into the cavity 40 by mating the cup 16 with the plug 26. In this example, the valve arrangements 28, 34 are provided in respective valve cavities 46a, b. Each valve arrangement consists of a movable valve member 48 having a head 50 which is sufficiently large to close a port 52 through to the cavity 40. The valve member 48 also has a shaft 54 guided in a bush 56 to allow the head 50 to move away from the port 52. Spring arrangements (not shown) are provided to bias the valve members 48 toward the ports 52.
The plug 26 carries two projections 58 which are aligned with respective ports 52. As the plug 26 is pushed into the cavity 40, by mating a cup 16, the projections 58 move through their respective ports 52 to engage the head 50 of the respective valve member 48 and push the head 50 away from the port 52.
This movement puts the ends of the projections 58 in the respective valve cavities 46a, b. The inlet passage 30 extends through one of the projections 58 and the outlet passage 36 extends through the other projection 58, so that when the ports 52 have been opened by the projections 58 pushing the respective heads 50, the inlet 30 and outlet 36 are in communication with respective valve cavities 46a, b.
The ultimate outlet 60 of the arrangement is in communication with the valve cavity 46b. This allows material flushed from the cup 16 to pass through the outlet 36 into the valve cavity 46b and then out from the outlet 60 to the analysis station 22.
The other valve cavity 46a is provided with flushing medium from a source
32. The source 32 may include a boiler chamber 62 with a heater 64 for creating hot liquid within the chamber 62. A passage 66 connects the chamber 62 to the valve cavity 46a, for supplying flushing medium from the chamber 62 through the inlet passage 32 the cup 16. Accordingly, in the arrangement of figure 3, the act of mating the cup 16 with the plug 26 and pushing the plug 26 more deeply into the cavity 40, results in the inlet valve 28 and outlet valve 34 being simultaneously opened by the action of the projections 58 on the heads 50, so that heated liquid is provided from the boiler chamber 62 to the interior of the cup 16. This results in the solid sample 10 being heated back to a liquid state and then flushed from the cup 16 to leave the outlet 60 and pass to the analysis station 22. The analysis station could be a NMR flow probe head.
Since the docking station 20 and the analysis station 22 are adjacent, the period of time is short in which the sample 10 is in its liquid state prior to reaching the analysis station 22. This reduces the time in which the polarisation of the sample 10 can decay, prior to analysis. Furthermore, the provision of the magnets 24, and in particular, the location of the docking station 20 and analysis station 22 within the same magnetic field, further assist in maintaining polarisation between the time at which the sample 10 is returned to its liquid state, and the time at which the sample 10 arrives at the analysis station.
The apparatus and methods described above have been described in relation to samples prepared for analysis by NMR and MRI techniques and in particular, by freezing to solid state, polarising, dissolving and then analysing.
Other examples of the invention are possible. Other situations arise in which a sample has a parameter which decays or changes more quickly when in a liquid state, than when in a solid state. For example, unfolded proteins may be freeze- dried to hold them in their unfolded state. The freeze-dried unfolded proteins then form the solid state sample described above. They can be brought in solution in the docking station and then analysed almost immediately at the analysis station 22, to watch them fold. It is the folding of the proteins which corresponds with the changing parameter. In other examples, the sample may consist of ligands provided in powder form and converted to a liquid form at the docking station by a flushing medium which includes proteins. The analysis station can then be used to analyse the manner in which the ligands bind with the proteins. This binding represents the changing parameter.
Appropriate arrangements will be necessary to retain the sample in the cup 16, particularly while moving from the first location to the second location.
These arrangements will depend on the nature of the sample 10. In the case of a frozen sample, the sample may stick to the cup 16. In the case of a powdered sample 10, a mesh support may be used, allowing the powder to be retained, but flushed from the cup after return to the liquid state. In the examples currently envisaged by the inventors, the samples are envisaged as small volume samples. For example, the solid state sample may be less than 1 ml_ and may be dissolved into a volume less than 2.5 mL It is envisaged that the dissolving step can be rapid, such as less than 1.5 seconds.
It is envisaged that by providing the dissolution of the sample at or very close to the analysis station, having transported the sample in solid state after initial preparation, the separate processes of initial preparation and dissolution can be separately optimised according to the requirements of the particular analysis being undertaken.
Many variations modifications can be made to the apparatus described above, particularly in relation to the materials, shapes, above-mentioned and relative dimensions of the docking station features described above.

Claims

1 . A method of preparation of a sample for analysis comprising: providing a sample in a solid state at a first location; moving the sample in the solid state to a second location; converting the sample to a liquid state at the second location; and performing an analysis on the sample after conversion to the liquid state.
2. A method according to claim 1 , in which a magnetic field is maintained, within which the conversion and analysis are performed without the sample leaving the magnetic field.
3. A method according to claims 1 or 2, in which a magnetic field is maintained, within which the steps of providing and moving the sample are performed.
4. A method according to claims 2 and 3, in which the steps of providing and moving the sample and of conversion and analysis, are all performed in the same magnetic field.
5. A method according to any of the preceding claims, in which the analysis is performed at the second location or close to the second location.
6. A method according to any of the preceding claims, in which the sample exhibits a parameter which changes with time at a rate which is faster when in the liquid state than when in the solid state.
7. A method according to claim 6, in which the change is a decay.
8. A method according to any of the preceding claims, in which the sample is polarised in the solid state.
9. A method according to claim 8, in which the sample is polarised by dynamic nuclear polarisation (DNP).
10. A method according to any of the preceding claims, in which the sample is frozen to the solid state.
11. A method according to any of the preceding claims, in which the solid state is a glassy state.
12. A method according to any of the preceding claims, in which the sample is a powder, or beads.
13. A method according to any of the preceding claims, in which the sample is housed in a receptacle, the receptacle being moved to move the sample from the first location to the second location.
14. A method according to claim 13, in which the receptacle is a cup.
15. A method according to claim 14, in which the sample is converted by mating the cup with sample preparation apparatus as defined in any of claims 53 to 73.
16. A method according to any of the preceding claims, in which the sample is converted by reheating.
17. A method according to claim 16, in which the reheating is provided by contact with a relatively hot liquid.
18. A method according to claim 16, in which the reheating is provided by a laser, such as a carbon dioxide laser.
19. A method according to claim 16, in which the reheating is provided by millimeter or micrometer electro-magnetic waves.
20. A method according to any of the preceding claims, in which the sample is flushed in the liquid state by a flushing medium, prior to performing the analysis.
21. A method according to claim 20, in which the sample is flushed to an analysis station.
22. A method according to claims 20 or 21 , in which the flushing medium acts to convert the sample to the liquid state, prior to flushing.
23. A method according to any of claims 20 to 22, in which the flushing medium is a relatively hot liquid.
24. A method according to any of the preceding claims, in which the analysis is magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR) spectroscopy.
25. Sample preparation apparatus comprising: a sample preparation station operable to prepare a sample in a solid state; a conversion station operable to convert a prepared sample to a liquid state; a transport mechanism operable to transport a sample in a solid state from the sample preparation station to the conversion station; an analysis station operable to perform an analysis on a sample after conversion to the liquid state by the conversion station.
26. Apparatus according to claim 25, in which a magnet arrangement is provided, operable to create a magnetic field within which the conversion and analysis are performed without the sample leaving the magnetic field.
27. Apparatus according to claims 25 or 26, in which a magnetic arrangement is provided, operable to create a magnetic field within which the sample preparation and the transport of the sample are performed without the sample leaving the magnetic field.
28. Apparatus according to claims 26 and 27, in which the preparation, transport, conversion and analysis of the sample are all performed in the same magnetic field.
29. Apparatus according to any of claims 25 to 28, in which the analysis station is located at the second location or close to the second location.
30. Apparatus according to claim 25, in which the sample exhibits a parameter which changes with time at a rate which is faster when in the liquid state than when in the solid state.
31. Apparatus according to claim 30, in which the change is a decay.
32. Apparatus according to claim 25 or any claim dependent thereon, in which the sample preparation station is operable to polarise the sample in the solid state.
33. Apparatus according to claim 32, in which the sample preparation station is operable to polarize by dynamic nuclear polarisation (DNP).
34. Apparatus according to claim 25 or any claim dependent thereon, in which the sample preparation station is operable to freeze the sample to the solid state.
35. Apparatus according to claim 25 or any claim dependent thereon, in which the solid state is a glassy state.
36. Apparatus according to claim 25 or any claim dependent thereon, in which the transport mechanism includes a receptacle in which the sample is housed, during use, the receptacle being movable to move the sample from the first location to the second location.
37. Apparatus according to claim 36, in which the receptacle is a cup or an inverted cup.
38. Apparatus according to claim 36 or 37, in which the receptacle is matable with apparatus as defined in any of claims 53 to 73.
39. Apparatus according to claim 37, or claim 38 when dependent on claim 37, in which the transport mechanism includes a wave guide having a tip at which the sample cup is located.
40. Apparatus according to claim 39, in which the sample in the cup is moved by moving the wave guide between two locations.
41. Apparatus according to claim 25 or any claim dependent thereon, in which the conversion station is operable to convert the sample by reheating.
42. Apparatus according to claim 41 , in which the conversion station is operable to provide a relatively hot liquid for reheating the sample.
43. Apparatus according to claim 42, in which the hot liquid is generated within the conversion station.
44. Apparatus according to claim 42, in which the hot liquid is provided from an external source.
45. Apparatus according to claim 41 , in which the conversion station comprises a laser, such as a carbon dioxide laser, for reheating the sample.
46. Apparatus according to claim 25 or any claim dependent thereon, in which the conversion station comprises an arrangement to irradiate the sample with millimeter or micrometer electro-magnetic waves.
47. Apparatus according to claim 25 or any claim dependent thereon, in which the conversion station is operable to flush the sample in the liquid state, by a flushing medium, to the analysis station.
48. Apparatus according to claim 47, in which the flushing medium acts to convert the sample to the liquid state, prior to flushing.
49. Apparatus according to claim 47 or 48, in which the flushing medium is a relatively hot liquid.
50. Apparatus according to any of claims 47 to 49, in which the flushing medium is generated within the conversion station.
51. Apparatus according to any of claims 47 to 49, in which the flushing medium is provided from an external source.
52. Apparatus according to claim 25 or any claim dependent thereon, in which the analysis station provides magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR) spectroscopy.
53. Sample preparation apparatus comprising: a plug for mating with a cup containing a sample, to substantially close the cup; an inlet arrangement operable to supply flushing medium to a mated cup; an outlet arrangement operable to drain flushing medium from a mated cup; and wherein the inlet and outlet arrangements enable the sample to be flushed from the cup through the outlet arrangement by means of flushing medium provided through the inlet arrangement.
54. Apparatus according to claim 53, in which the inlet arrangement includes an inlet valve arrangement.
55. Apparatus according to claims 53 or 54, in which the outlet arrangement includes an outlet valve arrangement.
56. Apparatus according to claims 54 or 55, in which the or each valve arrangement includes a passage through the plug, for communication with a cup mated with the plug.
57. Apparatus according to any of claims 54 to 56, in which the or each valve arrangement is opened by the cup mating with the plug.
58. Apparatus according to claim 57, in which the plug is movably mounted in a support, and movable by mating a cup with the plug, the or each valve arrangement being opened as the plug moves.
59. Apparatus according to claim 58, in which the or at least one of the valve arrangements comprises a movable valve member, there being a coupling arrangement causing the valve member to be movable between an open and a closed condition by movement of the plug.
60. Apparatus according to claim 59, in which the valve member is biased to close a port and to be movable away from the port by movement of the plug.
61. Apparatus according to claim 60, in which the plug carries a projection which is movable through the port to move the plug away from the port.
62. Apparatus according to claim 61 , in which the projection includes a passage in communication with a cup mated with the plug, and which provides communication from the cup, through the port, when the projection has moved the plug away from the port.
63. Apparatus according to claim 57, in which a sensor is provided to sense the cup mating with the plug, the sensor being operable to control the valve arrangements to open when mating is sensed.
64. Apparatus according to claim 63, in which the sensor is mechanical.
65. Apparatus according to claim 63, in which the sensor is optical.
66. Apparatus according to claim 63, in which the cup mating with the plug is sensed from operation of a transport mechanism used to move the cup.
67. Apparatus according to claim 66, in which the transport mechanism includes a motor, such as a stepper motor, and motor controller, there being a feedback circuit of the motor controller used to control the opening of the valves.
68. Apparatus according to claim 54 or any claim dependent thereon, in which the inlet valve arrangement includes a supply of flushing medium.
69. Apparatus according to claim 68, in which the flushing medium is a hot liquid.
70. Apparatus according to claims 68 or 69, in which the flushing medium supply comprises a heater operable to maintain the flushing medium at a working temperature.
71. Apparatus according to claim 53 or any claim dependent thereon, in which the apparatus further comprises a magnet arrangement operable to create a magnetic field within which a sample will remain while a cup is mated with the plug, and the sample is flushed through the outlet arrangement.
72. Apparatus according to claim 53 or any claim dependent thereon, in which the apparatus further comprises an analysis station operable to perform an analysis on the sample after flushing through the outlet arrangement.
73. Apparatus according to claim 72, in which the apparatus comprises a magnet arrangement operable to create a magnetic field within which a sample will remain while being flushed from the cup and during analysis.
74. A method of sample preparation comprising: providing a sample in a sample cup; mating the sample cup with a plug to substantially close the cup; supplying flushing medium to the mated cup; draining flushing medium from the mated cup to flush the sample from the cup by means of the flushing medium.
75. A method according to claim 74, in which the sample is flushed to an analysis station to perform an analysis.
76. A method according to claim 75, in which the analysis is for magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR) spectroscopy.
77. A method according to any of claims 74 to 76, in which the sample is provided initially in a solid state, and converted to a liquid state prior to flushing.
78. A method according to claim 77, in which the sample exhibits a parameter which decays or changes with time at a rate which is faster when in the liquid state than when in the solid state.
79. A method according to claims 77 or 78, in which the sample is polarised in the solid state.
80. A method according to claim 79, in which the nuclear spin system of the sample is polarised such as by dynamic nuclear polarisation (DNP).
81. A method according to any of claims 77 to 80, in which the sample is frozen to the solid state.
82. A method according claim 81 , in which the sample consists of small frozen beads.
83. A method according to any of claims 77 to 81 , in which the sample is a powder.
84. A method according to claim 77 or any claim dependent thereon, in which the sample cup is moved to move the sample in a solid state from a first location to a second location.
85. A method according to claim 84, in which the sample is converted to a liquid state at the second location, by mating the cup with the plug.
86. A method according to claim 85, in which the sample is converted by reheating.
87. A method according to claim 86, in which the reheating is provided by contact with a relatively hot liquid.
88. A method according to claim 87, in which the relatively hot liquid is the flushing medium.
89. A method according to claim 86, in which the reheating is provided by a laser, such as a carbon dioxide laser.
90. A method according to claim 86, in which the reheating is provided by a suitable micrometer or millimeter electro-magnetic wave field.
91. A method of sample preparation substantially as hereinbefore described and with reference to the accompanying drawings.
92. Sample preparation apparatus substantially as hereinbefore described and with reference to the accompanying drawings.
93. Any novel subject matter or combination including novel subject matter disclosed herein, whether or not within the scope of or relating to the same invention as any of the preceding claims.
PCT/GB2008/002855 2007-08-24 2008-08-22 Improvements in the preparation of a sample (e.g. involving dynamic nuclear polarisation) for analysis (e.g. by nmr or mri) WO2009027645A2 (en)

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Publication number Priority date Publication date Assignee Title
US8731640B2 (en) 2007-03-28 2014-05-20 General Electric Company Fluid path system for dissolution and transport of a hyperpolarized material
WO2010061191A1 (en) * 2008-11-27 2010-06-03 Oxford Instruments Molecular Biotools Limited Apparatus for dynamic nuclear polarisation

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