Device for analyzing a liquid or pasty sample provided as a drop by means of nuclear magnetic resonance of the sample

Description

[0001] The invention relates to a device for analyzing a liquid or pasty sample provided as drops using nuclear magnetic resonances of the sample.

[0002] Nuclear magnetic resonance spectroscopy (NMR spectroscopy) allows the investigation of the electronic environment of individual atoms and their interactions with neighboring atoms. NMR spectroscopy can be used to determine the components of samples and the structures of molecules. NMR spectroscopy also forms the basis of magnetic resonance imaging, which is frequently used in medical or biological fields to examine tissues and organs.

[0003] Many atomic nuclei have a nuclear spin other than zero and thus, as rotating charge carriers, a magnetic moment, such as 1< H or 13< C atoms. In a static magnetic field, the nuclear spins perform a precessing motion, known as Larmor precession, around the axis of the constant magnetic field. The atomic nuclei change the orientation of their nuclear spins relative to the magnetic field by absorbing or emitting alternating magnetic fields if these fields resonate with the Larmor frequency. This effect is also known as nuclear magnetic resonance. The possible magnetic angular momentum quantum states of the nuclear spins are equidistant and dependent on the Larmor frequency. The frequency and duration of the Larmor precession depend on the respective nuclear spin, as well as its spatial and chemical environment.The detection of Larmor precessions using Larmor frequencies thus enables a very precise determination of the chemical composition of the sample and the spatial structure of the molecules contained in the sample.

[0004] The alternating magnetic field is usually generated by a magnetic coil. In conventional NMR spectroscopy, inductive methods are often used to detect nuclear magnetic resonances. For example, the sample is often surrounded by an induction coil, in which an electrical voltage is generated by the alternating magnetic fields emitted by the precipitating nuclear spins. Typically, strong static magnetic fields of up to 25 T are used to polarize the nuclear spins in order to achieve a preferential polarization of similarly aligned nuclear spins and thus a magnetization that can be measured with conventional magnetic field sensors. This generally precludes miniaturization of NMR measuring instruments. The sample to be examined is usually placed in a long glass tube. The required sample volume is a few milliliters.However, this is a major disadvantage, especially in the life sciences sector, as the available sample volumes are often in the microliter range. For example, often only a few microliters of sample can be extracted from cell cultures or tissue samples.

[0005] A newer generation of magnetic field sensors falls into the category of so-called quantum sensors, which utilize a wide variety of quantum effects to determine various physical and / or chemical parameters. In the field of industrial process automation, such approaches are particularly interesting in light of the increasing drive toward miniaturization while simultaneously increasing the performance of the respective sensors.

[0006] Quantum sensors are based on the ability to very precisely control and read out specific quantum states of individual atoms. This enables, for example, precise and low-noise measurements of electric and / or magnetic fields, as well as gravitational fields, with resolutions in the nanometer range. In this context, various spin-based sensor arrangements have become known, which utilize atomic transitions in crystal bodies to detect changes in motion, electric and / or magnetic fields, or even gravitational fields. In addition, various systems based on quantum optical effects have also become known, such as quantum gravimeters or optically pumped magnetometers, the latter in particular being based on gas cells.

[0007] For example, in the field of spin-based quantum sensors, various devices have been developed that exploit atomic transitions, for example, in different crystal bodies, to detect even slight changes in motion, electric and / or magnetic fields, or even gravitational fields. Typically, the crystal bodies used are diamond with at least one silicon or nitrogen vacancy center, silicon carbide with at least one silicon vacancy, or hexagonal boron nitride with at least one vacancy color center. The crystal bodies can, in principle, have one or more vacancies.

[0008] Another area of ​​quantum sensors concerns gas cells, in which atomic transitions and spin states can be optically interrogated, among other things to determine magnetic and / or electrical properties. Typically, a gaseous alkali metal and a buffer gas are present in the gas cell. Magnetic properties of a surrounding medium can be determined by Rydberg states generated in the gas cell. For example, gas cells are used in quantum-based standards that provide physical quantities with high precision. They have long been used in frequency standards and atomic clocks, as described in EP 0 550 240 B1.

[0009] Devices for ODMR or NMR have become known, among others, from WO 2021 / 064687 A1, DE 199 27 976 A1 and DE 10 2014 219 561 A1.

[0010] It is therefore an object of the present invention to provide a device by means of which the nuclear magnetic resonances of small sample volumes, e.g. less than 100 µl, can be detected in a simple manner.

[0011] The object is achieved according to the invention by a device for the analysis of a liquid or pasty sample provided as drops based on nuclear magnetic resonances of the sample, with a first plate and a second plate, a mechanism by means of which a measuring position and a recording position can be set, wherein in the recording position the sample can be introduced between the first plate and the second plate, wherein in the measuring position the first plate and the second plate are arranged substantially parallel to one another and a spacer sets a defined distance between the first plate and the second plate, a sensor unit with a sensor component which forms at least a partial region of the first plate and / or the second plate and is at least partially in contact with the sample, wherein the sensor unit is designed to detect a quantity influenced by the nuclear magnetic resonances of the sample, an evaluation unit which is designed to determine at least one chemical and / or physical property of the sample based on the detected quantity.

[0012] In the device according to the invention, the sample is clamped between the first plate and the second plate. The sample is held statically by the interfacial tension between the sample and the two plates and the adhesion force of the sample to the two plates. With the help of the spacer, a defined distance between the two plates and thus a defined layer thickness of the sample is set, whereby the defined distance is adjusted depending on the properties of the sample and the surface properties of the two plates. The properties of the sample and the surface properties of the two plates relate in particular to their hydrophobicity / hydrophilicity and lipophilicity / lipophobicity, and in the case of the surface properties, to the roughness of the surfaces of the two plates facing the sample.

[0013] In the recording position of the device, the sample is applied to the first plate or the second plate, for example using a pipette. By adjusting the measuring position and the associated parallel arrangement of the two plates, the sample introduced as a drop is flattened, thus greatly increasing the contact area of ​​the sample to the first plate and the second plate. The defined distance between the first plate and the second plate is therefore generally set smaller than the height of the drop relative to the first plate and / or second plate. The device according to the invention can therefore be used with very small volumes of sample. By clamping the sample between the two plates, evaporation of the sample is also greatly limited or prevented.Due to the enlarged contact area between the sample and the first plate, as well as between the sample and the second plate, the detection of the quantity influenced by the sample's nuclear magnetic resonances is facilitated. The quantity influenced by the sample's nuclear magnetic resonances is, in particular, an optical quantity, and in particular, a quantity dependent on the nuclear magnetic resonances. The first plate and / or the second plate are, for example, transparent, as plastic or glass, if the sensor component forms part of the first plate and / or the second plate. It is also possible for the sensor component to form the first plate and / or the second plate entirely.

[0014] The mechanism for adjusting the measurement and recording positions can be designed so that the device can be constructed in one or two parts. The ability to adjust the recording position allows the device not only to be loaded with the sample but also to be easily cleaned.

[0015] In one embodiment, the sensor component comprises at least one crystal body with at least one defect or at least one gas cell. The gas cell is a cell enclosing at least one gaseous alkali metal.

[0016] Crystal bodies with at least one defect, as well as gas cells, exhibit a fluorescence signal under appropriate optical excitation, which depends, among other things, on a magnetic field applied to the crystal body or the gas cell. The nuclear magnetic resonances of the sample influence the magnetic field applied to the sensor component, so that at least one chemical and / or physical property of the sample can be determined based on the fluorescence signal. This requires contact between the sample and the sensor component. The increased contact area between the sample and the first plate, as well as between the sample and the second plate, increases the sensitivity of the device.Both the crystal body with at least one defect center and the gas cell lead to an improvement in the measurement accuracy of the detection of the sample's nuclear magnetic resonances and thus of the sample's at least one chemical and / or physical property due to their high sensitivity to magnetic fields. Furthermore, the fluorescence signal can be used to determine the magnetic flux density, magnetic susceptibility, magnetic permeability, or another parameter related to at least one of these variables.

[0017] In a further embodiment, the crystal body is a diamond with at least one nitrogen vacancy center, silicon carbide with at least one silicon vacancy center, or hexagonal boron nitride with at least one vacancy color center.

[0018] The sensor unit preferably comprises an excitation unit for optically exciting the sensor component and a detection unit for detecting a fluorescence signal from the sensor component influenced by the sample's nuclear magnetic resonances. In addition, additional optical elements such as filters, apertures, mirrors, etc., can optionally be used.

[0019] Advantageously, the excitation unit and / or the detection unit are arranged adjacent to the first plate and / or second plate such that an optical beam path through the sample can be generated. The first plate and the second plate must be at least partially transparent to the excitation light and the fluorescent light. The sample is arranged in particular between the excitation unit and the detection unit. This arrangement has the advantage that the sensor component can be formed both as a partial region of the first plate and as a partial region of the second plate, so that a large contact area between the sample and the sensor component and thus a high sensitivity of the device is achieved. Alternatively, the excitation unit and the detection unit are arranged either in the region of the first plate or the second plate.In this case, a reflection layer can additionally be applied to the plate opposite the excitation and detection unit in order to reflect the quantity influenced by the nuclear magnetic resonance to the detection unit.

[0020] In a further embodiment, the detection unit is configured such that the detection unit detects the fluorescence signal of the crystal body or the gas cell and does not detect the excitation light of the excitation unit. The detection unit essentially exclusively detects the fluorescence signal of the crystal body with at least one defect or of the gas cell. The fluorescence signal usually comprises at least one wavelength, typically several wavelengths or a band of wavelengths.

[0021] In a further embodiment, the detection unit is equipped with an absorption filter, wherein the absorption filter is arranged between the detection unit and the first plate or the second plate. The absorption filter serves to absorb the excitation light and, if necessary, other light from the environment, so that essentially only the fluorescence signal reaches the detection unit.

[0022] In a further embodiment, the mechanism is a folding mechanism, wherein the folding mechanism in particular comprises a hinge mechanism. The folding mechanism allows the device to be easily moved into the measuring and recording positions. In particular, no components of the device need to be disassembled; a single folding movement is sufficient to switch between the two positions.

[0023] Preferably, an inductor is provided which is designed to induce a preferential polarization of the nuclear spins of the sample. The inductor is in particular a magnetic field device which generates a, in particular static, magnetic field at least in one region of the sample and in the region of the sensor component. Instead of a magnetic field device, the inductor can be based on other methods of hyperpolarization, for example, in the form of para-hydrogen flowing through the sample. It is also possible to design the inductor as a laser source and / or microwave antenna and thus induce a preferential polarization in the electron spins of the sensor component and subsequently transfer this preferential polarization of the electron spins to the nuclear spins of the sample. The excitation unit can be used as the laser source, in particular.The microwave antenna can be used both to induce a preferential polarization of the nuclear spins of the sample and to excite the sensor component.

[0024] Advantageously, the magnetic field device is arranged adjacent to the excitation unit and / or detection unit, such that a homogeneous magnetic field can be generated in the region of the sample and in the region of the sensor component. The magnetic field device is designed, in particular, as a yoke or in two parts. In this embodiment, the sensor unit comprises an excitation unit for optically exciting the sensor component and a detection unit for detecting a fluorescence signal from the sensor component influenced by the nuclear magnetic resonances of the sample.

[0025] In a further embodiment, the sample has a volume of less than 100 µl, in particular less than 10 µl.

[0026] In a further embodiment, the defined distance between the first plate and the second plate is between 1 mm and 100 µm.

[0027] In a further embodiment, a microwave source is provided for exciting the sensor component.

[0028] In a further embodiment, the sensor component is designed as a coating on a surface of the first plate and / or the second plate facing the sample. In the case of a crystal body with at least one defect, this can be applied to the first plate and / or the second plate using a CVD or PVD process, for example. The first plate and / or the second plate serve as the substrate and are made of glass, for example.

[0029] In the following, the invention will be explained with reference to the figures Fig. 1 - 4 are explained in more detail. They show: Fig. 1 : a simplified energy scheme for a negatively charged NV center in diamond. Fig. 2 : a first embodiment of the device according to the invention. Fig. 3 : a second embodiment of the device according to the invention. Fig. 4 : a third embodiment of the device according to the invention.

[0030] In Fig. 1 A simplified energy scheme for a negatively charged nitrogen vacancy center (NV center) in a diamond is shown to illustrate the excitation and fluorescence of a vacancy in a crystal body. The following considerations can be applied to other crystal bodies with corresponding vacancies.

[0031] In diamond, each carbon atom is typically covalently bonded to four other carbon atoms. A nitrogen vacancy (NV) center consists of a defect in the diamond lattice, i.e., an unoccupied lattice site, and a nitrogen atom as one of the four neighboring atoms. The negatively charged NV centers are particularly important for the excitation and evaluation of fluorescence signals. In the energy scheme of a negatively charged NV center, in addition to a triplet ground state 3< A, there is an excited triplet state 3< E, each of which has three magnetic substates ms = 0, ±1. Furthermore, there are two metastable singlet states 1< A and 1< E between the ground state 3< A and the excited state 3< E. In the absence of an external magnetic field, a splitting of the two states ms = + / -1 from the ground state ms = 0 occurs, which is referred to as the zero-field splitting Δ and which depends on the temperature T.

[0032] Excitation light 1 from the green region of the visible spectrum, e.g., excitation light 1 with a wavelength of 532 nm, excites an electron from the ground state 3< A into a vibrational state of the excited state 3< E, which returns to the ground state 3< A by emitting a fluorescence photon 2 with a wavelength of 630 nm. This fluorescence signal is a measure of the zero-field splitting Δ and can be used to determine and / or monitor the temperature T.

[0033] An applied magnetic field with a magnetic field strength B leads to a splitting (Zeeman splitting) of the magnetic substates, so that the ground state consists of three energetically separated substates, each of which can be excited. However, the intensity of the fluorescence signal depends on the respective magnetic substate from which excitation occurred, so that, based on the distance between the fluorescence minima, for example, the magnetic field strength B can be calculated using the Zeeman formula. The magnetic field strength B is modified by the nuclear spins of sample 4 or results from them.

[0034] Within the scope of the present invention, further possibilities for evaluating the fluorescence signal are provided, such as evaluating the intensity of the fluorescent light, which is also proportional to the applied magnetic field. Electrical evaluation, in turn, can be performed, for example, using photocurrent detection of magnetic resonance (PDMR). In addition to these examples for evaluating the fluorescence signal, there are other possibilities that also fall within the scope of the present invention.

[0035] In Fig. 2A first embodiment of the device 3 according to the invention is shown. By means of the mechanism 7, a measuring position 8 is set, in which the sample 4 is enclosed between the first plate 5 and the second plate 6. The mechanism 7 can, for example, cause the device 3 to be opened or disassembled. In the measuring position 8, the first plate 5 and the second plate 6 are aligned substantially parallel to one another. A spacer 10 sets a defined distance between the first plate 5 and the second plate 6. For example, the defined distance is between 1 mm and 100 µm.

[0036] The sensor unit 11 has a sensor component 12, which forms at least a partial area of ​​the first plate 5 and / or the second plate 6. In the example of Fig. 2The first plate 5 and the second plate 6 consist entirely of the sensor component 12. The sensor component 12 is, for example, at least one crystal body with at least one defect or at least one gas cell. The crystal body is optionally a diamond with at least one nitrogen vacancy center or with at least one silicon vacancy center, silicon carbide with at least one silicon vacancy center, or hexagonal boron nitride with at least one vacancy color center. The gas cell contains, for example, a gaseous alkali metal in a cell.

[0037] The sensor unit 11 can optionally also include an excitation unit 14 for the optical excitation of the sensor component 12 and a detection unit 15 for detecting the fluorescence signal of the sensor component 12 influenced by the nuclear magnetic resonances of the sample 4, which are arranged, for example, adjacent to the first plate 5 and the second plate 6. In this way, an optical beam path through the sample 4 is possible. An evaluation unit 13 is also arranged to determine the at least one chemical and / or physical property of the sample 4 based on the detected variable. A transmitter unit and / or a display unit can optionally be present for displaying and / or transmitting the at least one chemical and / or physical variable to an external unit.

[0038] For the induction of a preferential polarization of the nuclear spins of sample 4, an optional inductor 17 is provided, which in the example of the Fig. 2as a magnetic field device 18. The magnetic field device 18 generates a homogeneous magnetic field at least in the area of ​​the sample 4 and in the area of ​​the sensor component and is in Fig. 2 It is designed in two parts. In measuring position 8, this creates a magnetic yoke.

[0039] In Fig. 3 A second embodiment of the device 3 according to the invention is shown, wherein the mechanism 7, in this example, has set a receiving position 9 by folding the device 3 between the first plate 5 and the second plate 6. The mechanism 7 is, for example, a folding mechanism and comprises a hinge mechanism. In the receiving position 9, the liquid or pasty sample 4 can be easily applied in the form of a drop onto the first plate 5 or the second plate 6. The sample has, for example, a volume of less than 100 µl, in particular less than 10 µl.

[0040] The detection unit 15 is optionally configured such that the detection unit 15 essentially only detects the fluorescence signal of the sensor component 12. For example, this is achieved with an absorption filter 16 arranged between the detection unit 15 and the second plate 6. Additionally, a microwave source 19 is arranged in the region of the sensor component 12 for exciting the sensor component 12. The sensor component 12 is illustrated by way of example as a coating on one surface each of the first plate 5 and the second plate 6, which each face the sample 4.

[0041] In Fig. 4 A fourth embodiment of the device 3 according to the invention is shown, which in this example is designed in two parts. In contrast to the figures Fig. 2-3This is not a side view, but a top view. In this example, the magnetic field device 18 is designed as a yoke that surrounds the first plate 5 in the receiving position 9. If the second plate 6 is, for example, clipped or attached to the mechanism 7, the second plate 6 is also surrounded by the magnetic field device 18 in the measuring position 8. List of reference symbols

[0042] 1Excitation light 2Fluorescence light 3Device 4Sample 5First plate 6Second plate 7Mechanism 8Measurement position 9Recording position 10Spacer 11Sensor unit 12Sensor component 13Evaluation unit 14Excitation unit 15Detection unit 16Absorption filter 17Inductor 18Magnetic field device 19Microwave source

Claims

1. Device (3) for analyzing a liquid or pasty sample (4) provided in the form of drops on the basis of nuclear magnetic resonances of the sample (4), comprising - a first plate (5) and a second plate (6), - a mechanism (7) by means of which a measuring position (8) and a receiving position (9) can be adjusted, wherein in the receiving position (9) the sample (4) can be introduced between the first plate (5) and the second plate (6), wherein in the measuring position (8) the first plate (5) and the second plate (6) are arranged essentially parallel to each other and a spacer (10) sets a defined distance between the first plate (5) and the second plate (6), - a sensor unit (11) with a sensor component (12) which forms at least a partial area of the first plate (5) and / or the second plate (6) and is at least partially in contact with the sample (4), wherein the sensor unit (11) is designed to detect a variable influenced by the nuclear magnetic resonances of the sample (4), - an evaluation unit (13) which is designed to determine at least one chemical and / or physical property of the sample (4) on the basis of the detected quantity.

2. Device according to claim 1, wherein the sensor component (12) has at least one crystal body with at least one defect or at least one gas cell, wherein the gas cell is a cell enclosing at least one gaseous alkali metal.

3. Device according to claim 2, wherein the crystal body is a diamond with at least one nitrogen vacancy center or with at least one silicon vacancy center, silicon carbide with at least one silicon vacancy center, or hexagonal boron nitride with at least one vacancy color center.

4. Device according to at least one of claims 1-3, wherein the sensor unit (11) has an excitation unit (14) for optically exciting the sensor component (12) and a detection unit (15) for detecting a fluorescence signal of the sensor component (12) influenced by the nuclear magnetic resonances of the sample (4).

5. Device according to claim 4, wherein the excitation unit (14) and / or the detection unit (15) are arranged adjacent to the first plate (5) and / or the second plate (6) in such a way that an optical beam path can be generated through the sample (4).

6. Device according to claim 5, wherein the detection unit (15) is designed such that the detection unit (15) detects the fluorescence signal of the sensor component (12) and does not detect the excitation light of the excitation unit (14).

7. Device according to claim 6, wherein the detection unit (15) is equipped with an absorption filter (16), wherein the absorption filter (16) is arranged between the detection unit (15) and the first plate (5) or the second plate (6).

8. Device according to at least one of claims 1-7, wherein the mechanism (7) is a hinge mechanism, wherein the hinge mechanism comprises in particular a hinge mechanism.

9. Device according to at least one of claims 1-8, wherein an inductor (17) is provided, which is designed to induce a preferential polarization of the nuclear spins of the sample (4), wherein the inductor (17) is in particular a magnetic field device (18) which generates a magnetic field at least in a region of the sample (4).

10. Device according to claim 9, wherein the sensor unit (11) has an excitation unit (14) for optically exciting the sensor component (12) and a detection unit (15) for detecting a fluorescence signal of the sensor component (12) influenced by the nuclear magnetic resonances of the sample (4) (12) influenced by the nuclear magnetic resonances of the sample (4), wherein the magnetic field device (18) is arranged adjacent to the excitation unit (14) and / or detection unit (15) in such a way that a homogeneous magnetic field can be generated in the region of the sample (4), wherein the magnetic field device (18) is designed in particular as a yoke or in two parts.

11. Device according to at least one of claims 1-10, wherein the sample (4) has a volume of less than 100 µl, in particular less than 10 µl.

12. Device according to at least one of claims 1-11, wherein the defined distance between the first plate (5) and the second plate (6) is between 1 mm and 100 µm.

13. Device according to at least one of claims 1-12, wherein the sensor component (12) is designed as a coating on a surface of the first plate (5) and / or the second plate (6) facing the sample (4).