NMR spectroscopy system

Abstract

An NMR spectroscopy system for studying a region of a sample to be analysed, includes a magnetoresistive transducer made up of superposed planar layers, which receives a response signal of the sample; a system for making an AC current flow, at a supply frequency f.sub.c, through the transducer; a system for generating a magnetic field H.sub.0 that is constant and uniform throughout a zone of interest in which the sample and transducer are placed; and an exciting coil to generate a magnetic field H.sub.1 that is uniform throughout the zone of interest and that varies at a resonant frequency f.sub.1; the field H.sub.0 is substantially perpendicular to the layers of the transducer. The system further includes a regulating system to ensure that the field H.sub.0 and the planar layers remain orthogonal, and a system for detecting a signal of frequency f.sub.cf.sub.1, f.sub.1f.sub.c or f.sub.c+f.sub.1.

Claims

1. NMR spectroscopy system for studying at least one region of a sample to be analysed, said system comprising: a magnetoresistive transducer with superimposed planar layers receiving a response signal from said sample; means suitable for making an alternating current flow, at a supply frequency f.sub.c, through said transducer; means for generating a magnetic field H.sub.0 that is constant and uniform throughout a zone of interest in which the sample and the transducer are placed; an exciting coil configured to generate a magnetic field H.sub.1 that is uniform throughout said zone of interest and variable at a resonance frequency f.sub.1 configured to excite the sample; wherein: said field H.sub.0 is substantially perpendicular to the planar layers of the transducer; said system comprises: regulating means arranged to ensure orthogonality between the field H.sub.0 and the planar layers of the transducer, said regulating means being laid out to modify an inclination of the transducer and/or a direction of the field H.sub.0; means for detecting signals of frequency f.sub.cf.sub.1, f.sub.1f.sub.c or f.sub.c+f.sub.1, said signals being coherent and in phase with the signal at the supply frequency f.sub.c and the signal at the resonance frequency f.sub.1.

2. The NMR spectroscopy system according to claim 1, wherein a dimension of the transducer is chosen as a function of a dimension of the region of the sample to be analysed.

3. The NMR spectroscopy system according to claim 1, wherein the transducer with superimposed planar layers is a giant magnetoresistance or tunnel magnetoresistance element.

4. The NMR spectroscopy system according to claim 1, wherein the regulating means to ensure orthogonality between the field H.sub.0 and the planar layers of the transducer include at least one test coil generating a magnetic field H.sub.T, said field H.sub.T being perpendicular both to the field H.sub.0 and to the field H.sub.1.

5. The NMR spectroscopy system according to claim 1, wherein the regulating means to ensure orthogonality between the field H.sub.0 and the planar layers of the transducer include systems for micrometric regulation of the position and the inclination of the transducer and the direction of the field H.sub.0.

6. The NMR spectroscopy system according to claim 1, wherein the sample to be analysed is constituted of the biological tissues of an animal or of a subject and wherein the transducer is produced on a needle-shaped support.

7. The NMR spectroscopy system according to claim 1, wherein the sample to be analysed is constituted of a liquid arranged in a microfluidic channel and wherein the transducer is produced in the form of a set of individual sensors arranged above or below the microfluidic channel over the whole width of the microfluidic channel, the planar dimensions of the set of individual sensors being substantially equal to the planar dimensions of the microfluidic channel.

8. The NMR spectroscopy system according to claim 1, further comprising a shielded enclosure in which the exciting coil, the sample to be analysed and the transducer are placed, and a permanent magnet, electromagnetic coils or a superconducting magnet placed outside of the shielded enclosure to create said uniform magnetic field H.sub.0.

9. The NMR spectroscopy system according to claim 1, wherein the magnetoresistive transducer has a C-shape or meander-shape and is connected to the two contacts.

10. A method for implementing the NMR spectroscopy system according to claim 1, comprising: generating a magnetic field H.sub.0 that is constant and uniform throughout the zone of interest in which the sample to be analysed and the transducer are placed; regulating the position and/or the inclination of the transducer and the direction of the field H.sub.0 to obtain orthogonality between H.sub.0 and the plane of the layers of the transducer 101, said regulation being carried out using: a test coil generating a field H.sub.T, said field H.sub.T being perpendicular both to the field H.sub.0 and to the field H.sub.1; regulating means arranged to ensure orthogonality between the field H.sub.0 and the planar layers of the transducer; generating the variable field H.sub.1 that is uniform throughout the zone of interest in which the sample and the transducer are placed; and detecting signals of frequency f.sub.cf.sub.1, f.sub.1f.sub.c or f.sub.c+f.sub.1, said signals being coherent and in phase with the signal at the supply frequency f.sub.c and the signal at the resonance frequency f.sub.1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) Other characteristics and advantages of the invention will become clear from the following description of particular embodiments, given as examples, with reference to the appended drawings, in which:

(2) FIG. 1 is a schematic sectional view showing as an example the elements constituting a GMR or TMR spin valve type magnetoresistive sensor;

(3) FIG. 2 is a view of the form of a GMR type magnetoresistive sensor that makes it possible to obtain a homogeneous measurement on a given volume with good sensitivity while having good immunity to an intense field and perpendicular to the plane of the layers;

(4) FIG. 3 shows a typical response curve of a GMR type sensor, such as for example that of FIG. 1, in the presence of a longitudinal polarisation field;

(5) FIGS. 4A and 4B are schematic views of configurations of a device respectively in the case of a measurement on a micro-fluidic channel and in the case of an in vivo measurement;

(6) FIG. 5 is a schematic view of a possible particular embodiment of a complete configuration in which the means for generating the field H.sub.0 are not represented because obvious for those skilled in the art or included in an NMR spectrometer; only the direction 104 of this field is represented.

(7) FIG. 6 is a curve giving the intensity of the signal measured as a function of the magnetic field applied in the case of an optimised GMR sensor.

DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS

(8) According to one preferential embodiment, the transducer or sensor with superimposed planar layers used in the present invention is a giant magnetoresistance (GMR) or tunnel magnetoresistance (TMR) element.

(9) One advantage of this embodiment is the possibility of using magnetoresistive elements having both great measurement sensitivity and reduced size, suited to local NMR measurements.

(10) FIG. 1 shows an example of representation of an assembly of thin films that constitutes a GMR type magnetoresistive sensor 10 having the structure of a spin valve.

(11) Such a spin valve typically contains a hard or blocked layer 22, that is to say a layer not very sensitive to the external magnetic field, and a soft or free layer 21, very sensitive to the magnetic field, that is to say of which the magnetisation is oriented very easily in an external field applied in the plane of the layer.

(12) The hard layer 22 may be formed either of an assembly of ferromagnetic layers having high coercivity, or of a mixture of antiferromagnetic layers, artificial or not, coupled to a ferromagnetic layer.

(13) The soft layer 21 is formed of very soft magnetic materials.

(14) As an example, the magnetoresistive sensor 10 of FIG. 1 may include, from the free surface, a tantalum protection layer 11, a soft magnetic layer 21 comprising a NiFe layer 12 and a CoFe layer 13. This soft layer 21 is oriented in the direction of the external magnetic field. The thickness of the layer must be such that the layer sufficiently resists the external magnetic field but is sufficiently thin to ensure good sensitivity of the GMR or TMR. A thickness of 5 nm of NiFe and 2 nm of CoFe are values that are suitable for working up to 1 Tesla.

(15) A hard magnetic layer 22 is separated from the soft layer 21 by a copper separating layer 14. The hard magnetic layer 22 may include, from the separating layer 14, a CoFe layer 15 and a PtMn layer 16. The hard layer 22 has a direction of magnetisationin general in the plane of the layerthat is set during manufacture. Alternatively, the layer 16 may contain PtMn and a CoFe/Ru bilayer with 0.8 nm of Ru. The CoFe/Ru/CoFe trilayer thereby formed is an artificial antiferromagnetic that is much more robust with respect to the application of a perpendicular field.

(16) A layer 17 of tantalum, ruthenium, NiFe or NiFeCr can serve as growth precursor of upper layers 16, 15, 14, 13, 12 and 11 added successively for the implementation of the circuit.

(17) The set of these layers is deposited by techniques specific to the manufacture of thin films (cathodic sputtering, evaporation, etc.) on a crystalline (silicon, sapphire, etc.) or amorphous (glass, quartz) or instead ceramic substrate. However the use of a strong field, typically greater than 0.1 T and thus implying resonance frequencies for the proton greater than 5 MHz, requires a very insulating substrate, and in this respect cannot accept even pure silicon. The use of glass, quartz or sapphire as substrate then becomes necessary. The substrate, below the seeding layer 17, is not represented in FIG. 1.

(18) As an example, the assembly of the layers of FIG. 1 may have a thickness of around 30 nm.

(19) Numerous stacks currently published in the technical literature could be suitable and notably spin valves with an artificial ferromagnetic material.

(20) As explained in the publication Low noise magnetoresistive sensors for current measurement and compasses Pannetier-Lecoeur, M; Fermon, C; de Vismes, A, et al. JOURNAL OF MAGNETISM AND MAGNETIC MATERIALS, Volume: 316, Issue: 2, Pages: E246-E248, Published in 2007, the use of C-shaped sensors makes it possible to reduce greatly low frequency magnetic noise. This shape may be generalised as short-circuited meanders, which makes it possible to have a square or rectangular measurement zone. In the case of the targeted application, the working frequency is high, between 5 MHz and 50 MHz, and thus low frequency noise is not a limit.

(21) FIG. 2 shows a preferential configuration which makes it possible to measure the resonance signal on a volume of 303030 m.sup.3. The sensitive GMR element 31 has a meander shape and is connected to the two contacts 30 which constitute a coaxial line of which the impedance is adapted to the resistance of the magnetoresistive meander.

(22) This preferential configuration is well suited for measurements in vivo or immersed in a liquid or instead well suited to a microfluidic channel 30 m wide.

(23) According to one embodiment, the dimension of the transducer 101 is chosen as a function of the dimension of the region of interest of the sample to be analysed.

(24) One advantage of this embodiment is to be able to carry out local NMR spectroscopy and to choose the dimension of the region of the sample to be analysed thanks to a transducer 101 of suitable dimension.

(25) FIG. 3 shows a typical response (output voltage) of a spin valve when the resistance is measured as a function of the field H applied in the plane of the layers composing the GMR, and the presence of a main external field having a residual longitudinal component of 2 mT.

(26) Such a curve has a high saturation plateau (section b1), a working zone (section c1) with a quasi-linear evolution and a low saturation plateau (section al).

(27) Complementary information concerning such a typical curve of a GMR type sensor may be found for example in the document FR 2876800 Al.

(28) To maximise the sensitivity of the magnetoresistive transducer 101 and to avoid saturation effects, the constant and uniform field H.sub.0 must be perpendicular to the plane of the layers of the transducer 101. To ensure orthogonality between H.sub.0 and the plane of the layers, the NMR spectroscopy system 100 according to the invention comprises regulating means 114.

(29) According to one embodiment, the regulating means 114 to ensure orthogonality between the field H.sub.0 104 and the planar layers of the transducer 101 include at least one test coil 115 generating a magnetic field H.sub.T, said field H.sub.T being perpendicular both to the field H.sub.0 and to the field H.sub.1.

(30) One advantage of this embodiment is to generate a test magnetic field H.sub.T directed along the direction 107 and used for the preliminary regulations to the NMR measurements. More particularly, by modifying the inclination of the transducer 101 and/or the direction of the field H.sub.0, orthogonality between the field H.sub.0 and the planar layers may be achieved while maximising the sensitivity of the transducer 101 with respect to the test magnetic field H.sub.T. According to one embodiment of the invention, the means for regulating between the field H.sub.0 and the planar layers of the transducer 101 include systems for micrometric regulation 114 of the position and the inclination of the transducer 101 and the direction of the field H.sub.0.

(31) One advantage of this embodiment is to provide micrometric regulations to ensure orthogonality between H.sub.0 and the planar layers of the transducer 101, which makes it possible to eliminate efficiently problems of saturation of the magnetoresistive transducer due to the presence of a component of the field H.sub.0 in the plane of the layers, while maximising the sensitivity of the transducer 101. The micrometric regulation systems may be, for example, micrometric screws.

(32) According to one embodiment of the invention, the sample is constituted of a liquid arranged in a microfluidic channel 46 and the transducer 101 is realised in the form of a set of individual sensors 41 arranged below or above the microfluidic channel 46 over the whole width of the microfluidic channel 46, the planar dimensions of the set of individual sensors 41 being substantially equal to the planar dimensions of the microfluidic channel 46.

(33) This embodiment is represented in FIG. 4A, which shows a configuration of GMR measurement device 40 well suited to an NMR spectroscopy measurement in the case of a liquid contained in a microfluidic channel 46 having a fluid input 42 and a fluid output 43. The planar dimensions (width*length) of the sensor constituted of a plurality of elementary magnetic sensors 41 then have to, in an optimal manner, correspond to the planar dimensions of the channel 46. The sensitivity axis is then situated in the plane and perpendicular to the channel 46. The main magnetic field H.sub.0 represented by the arrow 45 and created by the magnet 44 is then applied perpendicular to the plane of the GMR.

(34) One advantage of this configuration is that the probed volume is limited to the dimensions of the channel 46/microprobe 41 assembly, of micronic sizes, and the homogeneity required for the main field H.sub.0 is easily attainable by comparison with the homogeneity necessary for the MRI.

(35) According to one embodiment of the invention, the sample to be analysed is constituted of the biological tissues of an animal or of a subject 52 and the transducer 51 is produced on a needle-shaped support.

(36) This embodiment is represented in FIG. 4B, which shows a configuration of measurement device with GMR 50 well suited to a local in vivo measurement. A homogeneous main field H.sub.0 symbolised by the arrow 55 and created by an electromagnet 53, 54 is applied perpendicularly to the magnetoresistive sensor 51. The sensor 51 is produced on an insulating substrate cut to have a width as close as possible to that of the sensor and a sufficiently small thickness in the case of in vivo measurements in order to be able to penetrate into the tissues of the animal or of the subject 52 without significant damage. This device will be designated by the term microprobe in the remainder of the description.

(37) One advantage of this embodiment is to be able to carry out NMR measurements on biological tissues in vivo.

(38) According to one embodiment of the invention, the system 100 includes a shielded enclosure 106 in which the exciting coil 103, the sample to be analysed 102 and the transducer 101 are placed, and it further includes a permanent magnet or electromagnetic coils placed outside of the shielded enclosure 106 to create said uniform permanent ambient magnetic field H.sub.0.

(39) This embodiment is represented in FIG. 5, which shows a block diagram of an example of measuring device according to the invention. The resonance of the total volume of the sample 102 is measured with a large size resonance coil 103 which also serves as exciting coil making it possible to create a rotation of the spins and to trigger their precession. The microprobe 101, associated with the sample 102 and of which the direction of sensitivity is represented by the direction 107, is connected to a preamplifier 109 and its signal is recorded on the NMR spectrometer 110 in parallel with the signal coming from the preamplifier 108 associated with the resonance coil 103. The spectrometer 110 may be associated with an oscilloscope 111 and with a computer 112.

(40) A screen 106 shielding against alternating magnetic fields, but allowing continuous fields to get through, surrounds the sample 102.

(41) Advantageously, the shield screen 106 eliminates potential oscillating parasitic signals which can pollute the NMR measurements.

(42) In FIG. 5, the arrow 104 represents the main external magnetic field H.sub.0, constant and homogeneous, which is perpendicular to the microprobe 101, and the arrow 105 represents the magnetic field H.sub.1, variable and homogeneous, applied by the exciting coil 103.

(43) One method for implementing the system 100 according to the invention comprises the following steps: generating a magnetic field H.sub.0 that is constant and uniform throughout a zone of interest in which the sample (102) to be analysed and the transducer (101) are placed; regulating the position and/or the inclination of the transducer 101 and the direction of the field H.sub.0 to obtain orthogonality between H.sub.0 and the plane of the layers of the transducer 101, said regulation being carried out using: the test coil 115 generating a field H.sub.T, said field H.sub.T being perpendicular both to H.sub.0 and to H.sub.1; the means for regulating 114 the inclination of the transducer 101 and/or the direction of the magnetic field H.sub.0; generating the variable field H.sub.1 that is uniform throughout the zone of interest in which the sample 102 and the transducer 101 are placed; detecting signals of frequency f.sub.cf.sub.1, f.sub.1f.sub.c or f.sub.c+f.sub.1, said signals being coherent and in phase with the signal at the supply frequency f.sub.c and the signal at the resonance frequency f.sub.1.

(44) Advantageously, this embodiment provides a step of regulation, necessary to ensure orthogonality between H.sub.0 and the planar layers. This regulation is important for the correct operation of the device. This is explained by the fact that a small misalignment between H.sub.0 and the normal to the planar layers produces a component of H.sub.0 in the plane of the layers. The field H.sub.0 being very intense, even a small misalignment may cause the saturation of the transducer 101.

(45) A detailed description of particular modes for an in vivo measurement will be given below.

(46) In the case of an in vivo measurement, the particular optimal embodiment consists in producing a sensor of small size, typically 2020 pmt on a needle made of silicon or insulator material (glass, sapphire, ceramic), 50 to 100 m wide and of small thickness, typically 50 m. Furthermore, the needle has to have a pointed end in order to be able to penetrate easily into biological tissues without creating great damage.

(47) The animal or the subject is placed in a main magnetic field such as that created by an MRI or a magnet and it is then necessary to adjust the position of the animal or the subject in such a way that the field is perpendicular to the plane of the sensitive element. Alternatively, the main field may be slightly turned with auxiliary coils creating fields perpendicular to the main field.

(48) An NMR spectroscopy system is then connected. This system includes a global exciting coil which is situated around the animal or the subject and which also serves as global reception; and the magnetoresistive element, which is the detection element and which is then connected to the spectrometer.

(49) In this configuration a direct coupling between the microprobe and the exciting coil may be observed. In order to be free of this signal contamination, an optional improvement consists in using the magnetoresistive element as in situ demodulator. As described in the patent document EP 1991862, the GMR element is supplied at a non-zero frequency f.sub.c, the NMR signal is detected at a frequency f.sub.1 which is also the frequency of contamination by the global exciting coil and the local detection takes place at a frequency f.sub.cf.sub.1, f.sub.cf.sub.1 or f.sub.1f.sub.c. This in situ demodulation (symbolised by the reference 113 of FIG. 5) makes it possible to ensure that the spectroscopy measurement is indeed local.

(50) The NMR spectroscopy is then carried out in a conventional manner.

(51) A detailed description of particular embodiments for a measurement in a microfluidic channel will be given below.

(52) The preferential configuration is then to have the sensor placed above or below the microfluidic channel with a width equal to the width of the latter. It is necessary to provide an RF excitation which creates a homogeneous signal over the size of the sensitive element. This may advantageously be carried out by a coplanar antenna that passes over or under the guide and the magnetoresistive element, either parallel to the guide, or perpendicular. By passing perpendicularly, the advantage is not to couple directly with the sensitive axis of the sensor. The sensitivity axis of the magnetoresistive element will be preferentially chosen perpendicular to the microfluidic channel.

(53) The main field H.sub.0 could be applied to the microfluidic/microprobe assembly via external coils or by a permanent magnet system. The required homogeneity applies to the volume delimited by the channel and the microprobe below/above.

(54) The interfacing with the NMR spectrometer is done in the same way as in the case of the in vivo configuration. In the same way as in vivo, the in situ demodulation makes it possible to obtain an appreciable gain in signal to noise and to be free of different inductive couplings.