Phase-contrast imaging method for estimating the local stoichiometry of a sample

Abstract

The invention relates to a phase contrast imaging method for estimating the local stoichiometry of a sample by measuring the parameter δ and the imaginary part β of its complex optical index; said method is realized using an X-ray source for irradiating the sample placed between the source and a detector, a grid formed of holes placed between the sample and the detector, and a signal processing unit for processing the signals from the detector; the method comprises the steps of: - performing at least one measurement whilst irradiating the sample, in which the X-rays reach the detector and form a spot for each hole of the grid, - independently analysing for each measurement and for each hole of the grid the spots formed on the grid by determining the centroid of the spot using a centroid search method, - measuring the offset of the centroid with respect to a reference centroid and then measuring the local phase change based on the offset of the centroid; - measuring the amplitude of the X-rays forming the spot and then measuring the local attenuation compared to a reference amplitude, - measuring the parameter δ based on the local phase change, - measuring the imaginary part β based on the local attenuation.

Description

Detailed Description of the Invention

[0001] The present invention relates to a phase contrast imaging method for estimating the local stoichiometry of a sample by measuring the parameters δ and β of the real and imaginary parts of the complex optical index of the sample. A particularly interesting application of the method is for quantifying nanoparticles in the field of cancer therapy. However, the scope of the invention is broader, since the invention can be applied in the medical field in general, in agri-food, cultural heritage, energy, material science, etc.

[0002] Generally speaking, this X-ray technique can be used to qualitatively measure the total density without measuring the chemical composition. A first improvement consisted in producing two absorption images at two energies, thus measuring the density of, for example, human bones. This is the "dual-photon X-ray absorptiometry" technique. It can be seen that this technique is based only on absorption and therefore very indirectly on the estimation of the imaginary part of the optical index of the sample.

[0003] In some specific cases, it is possible to image a sample below and then above the atomic threshold to quantify the presence of a particular element. However, this technique has two important limitations. First, it does not show other elements in the sample. Second, when the atomic number of the element of interest is low, the atomic threshold is located at low energy, which makes it impossible to image objects with some thickness, such as animal or human bodies. For example, for iron, the threshold is below 7.1 keV.

[0004] US Patent No. 6,950,493 B2 describes a multispectral X-ray imaging system, in which the spectrum of the radiation source is altered to improve the contrast of the resulting image.

[0005] Juergen Fornaro et al., Dual- and multi-energy CT: approach to functional imaging', European Society of Radiology, (Austria), 2011, describes a multi-energy source system for characterizing several types of materials.

[0006] Peter RT Munro et al., A simplified approach to quantitative coded aperture X-ray phase imaging', Optical Society of America, (USA), 2013 describes the use of two grids to define coding and quantify the composition of a sample in a phase contrast imaging system.

[0007] Fabio A. Vittoria et al., 'Multimodal Phase-Based X-Ray Microtomography with Nonmicrofocal Laboratory Sources', PHYSICAL REVIEW APPLIED, (USA), 2017, Vol.8, 064009, describes a phase contrast imaging system that uses a grid placed between the X-ray source and the sample. This configuration involves many approximations that are detrimental to the efficiency of the system. The system also requires several imaging runs before it is possible to determine the index parameters.

[0008] Harold H. Wen, 'Single-shot x-ray differential phase-contrast and diffraction imaging using two-dimensional transmission gratings', OPTICS LETTERS, (USA), June 15, 2010, Vol.35, No.12 describes a phase-contrast imaging system using grids. A Fourier transform is applied to the entire image obtained to quantify the sample.

[0009] The object of the present invention is a method for quantifying a sample by determining its chemical composition. Another object of the present invention is a novel and robust method for rapidly measuring said chemical composition using X-rays.

[0010] At least one of the above mentioned objects is achieved with a phase contrast imaging method for estimating the local stoichiometric composition of a sample by measuring a parameter δ of the real part and β of the complex optical index of said sample; the method is realized using an X-ray source for irradiating the sample arranged between the X-ray source and a detector, a grid of holes arranged between the sample and the detector, and a unit for processing the signal from the detector;

[0011] The method comprises the following: - performing at least one measurement by irradiating the sample, such that X-rays reach the detector and form spots for each hole in the grid; - for each measurement and for each hole of the grid, independently analyzing the spots formed on the grid by determining the centroid of the spot using a centroid search method; - measuring the offset of the center of gravity from a reference center of gravity and then measuring a local phase change from the offset of the center of gravity; - measuring the amplitude of the X-rays forming the spot and then measuring the local attenuation compared to a reference amplitude; - measuring a parameter δ from the local phase changes; - measuring the imaginary part β from the local attenuation; Includes.

[0012] The detector is advantageously a matrix detector or a CCD camera. The grid can advantageously consist only of square bars which delimit the holes, which means that the holes do not contain phase modulating elements.

[0013] For amplitude measurements, the signals from all pixels within a spot are independently integrated to define a single equivalent signal for the spot. The amplitude of this single signal is measured. The integral over one spot is independent of the integral over another spot.

[0014] The method according to the invention is an improvement over X-ray imaging by providing a direct measurement that allows obtaining two different and independent measurements of the same spot, the deviation and the amount of reflected influx.

[0015] Generally speaking, in the field of X-rays, the optical index n of a sample, whatever the nature of the sample, is given by the following formula: n=1-δ+iβ (In the above formula, δ=n a r e λ 2 (f1 / 2π) β=n a r e λ 2 (f2 / 2π) is) It is expressed as In the above formula, n a , r e and λ are the atomic density, classical electron radius and wavelength, respectively. f1 and f2 are atomic scattering factors specific to the chemical composition of the sample.

[0016] The present invention allows for independent measurement of δ and β. The spots are processed independently of each other. This independence allows for the measurement of, in particular, the diffusion coefficient f i;1 and f i;2 It is possible to distinguish between the

[0017] The method according to the invention adds a new dimension (chemical composition) to the non-invasive study of samples by avoiding the need to cut or take pieces of the sample. Sample means any inert or biological material.

[0018] The method according to the invention allows for global or local measurement of the chemical composition of a sample. The technique can be used, for example, to quantify the local density of nanoparticles used to enhance the efficacy of radiotherapy, fermionic therapy and hadronic therapy in cancer treatment. The technique can also be used to quantify contaminants, for example in food processing, material science, ecology or medicine in general.

[0019] According to one advantageous feature of the invention, the reference centroid can be obtained during measurement by illuminating the detector through the grid, either without a sample or in the presence of a reference sample. A reference amplitude can be obtained during measurement by illuminating the detector through the grid either without a sample or in the presence of a reference sample.

[0020] The reference sample can be an object that produces a known modulation in the incident wave to determine with high precision the grid-detector distance for each hole / pixel pair: a diffractive hole producing a spherical wave, a rotating prism, or any other known object can be used.

[0021] If the size of the holes allows, it is also possible to simply diffract visible or UV light. If the wavelength (spectral line, laser) is known with a certain accuracy, the distance is also known with the same accuracy. Whether the shape of the holes is square, circular or anything else, the diffractive structure is known theoretically or numerically. By theoretically or numerically varying the grid-detector distance, it is sufficient to fit the theoretical or numerical results to the experiment and thus to measure this distance. This is quite accurate for e.g. monochromatic sources with known wavelengths.

[0022] According to one advantageous feature of the invention, the grid may consist of regularly or irregularly spaced holes. Unlike prior art systems which require a regular grid, the present invention can accommodate irregularly spaced holes without affecting the metrology. According to one advantageous embodiment of the invention, the pitch of the holes of the grid may be greater than or equal to the width of a pixel of the detector.

[0023] The size of the holes in the grid may be equal to or larger than the size of one pixel of the detector, where size means the surface area that the hole or pixel occupies. By determining the size of the hole according to the present invention, stress on the size of the detector can be alleviated, and therefore a cheaper detector can be used. For example, in combination with all of the above, the dimensions of the grid and the distance between the source, grid and detector can be determined such that the spot for each hole spans several pixels of the detector.

[0024] According to one embodiment of the present invention, the parameter δ is calculated according to the following equation: Δφ=∫δ×ldl (In the formula, Δφ is the local phase change and “l” is the distance traveled by the X-ray.) It is possible to measure using The imaginary part β is given by the following equation: I / I0=exp(-∫(4πβ / λ)dl) (where I / I0 is the attenuation, λ is the wavelength of the X-ray, and "l" is the distance traveled by the X-ray.) It is possible to measure using

[0025] These two equations give the integrated Δφ and I / I0 for the propagation of X-rays through a sample. For example, in X-ray tomography, the local phase change and the local absorption can be determined. In this case, the equations are dφ=δ×dl d(I / I0)=exp(-(4πβ / λ)dl) is transformed into.

[0026] This shows that it is possible to produce three-dimensional maps of the chemical composition in X-ray tomography using X-ray deflectometry or X-ray interferometry. According to one advantageous feature of the invention, the X-ray source may be a multi-energy source. Using several energy sources it is possible to reach high energies.

[0027] The present invention has found that at high energies the difference in delta values ​​between several chemical elements is large enough to allow unambiguous identification of these chemical elements. At high energies, the discrimination is based primarily on delta values ​​rather than beta values. It is this change in behavior that allows the chemical composition to be determined.

[0028] Advantageously, the combined use of a grid and a multi-energy source according to the invention makes it possible, in particular, to determine the real and imaginary components of the local optical index to estimate the local stoichiometric composition of a sample. Multi-energy sources allow measurements to be taken over a wide range of energies.

[0029] The present invention, Lens pitch: The grid is achromatic, allowing multiple energy measurements without changing the settings: Unlike systems for measuring δ and β with X-ray interferometers or deflectometry devices, which are highly chromatic devices and therefore always used at a single energy, several energies can be measured without having to reset the entire setup. Therefore, it is necessary to modify the settings every time the energy is changed.

[0030] According to one embodiment of the present invention, the multi-energy radiation source may comprise an anode with several K-alpha type filters. A mix of filters can be used to limit the spectrum, depending on the energies of interest, the sample acting as a spectral filter, and the filters available. Typically, but not limited to, 1-4 filters can be used. Two cases can be envisaged: a single anode or several anodes.

[0031] Changing the anode modifies the emission spectrum, mainly by emission of K (alpha and beta), L, M and rarely N rays, but also by continuous braking radiation or "bremsstrahlung". Whatever the anode, it is therefore preferable to reduce the spectral width by the use of one or more external filters.

[0032] According to another embodiment of the present invention, the multi-energy source may comprise an X-ray emission source and several filters outside the X-ray emission source. According to another embodiment of the invention, the detector is a photon counting detector in order to obtain several different energy levels.

[0033] Photon-counting detectors have electronics that allow spectral filtering of the incident radiation. In this case, the installation of external filters is no longer necessary. The use of multiple anodes to exploit K-, L-, M- or N-ray emissions may still be advantageous. According to one embodiment of the invention, on an impure sample several measurements are performed at different energy levels.

[0034] For example, for pure materials it may be advantageous to use at least two energies, either by the use of filters or by using photon counting detectors. Advantageously, it is possible to carry out 2i measurements at different energies, where "i" is the total number of chemical elements contained in the sample.

[0035] In fact, for mixtures or impure materials, the equations for δ and β given above become:

[0036] JPEG2025500970000002.jpg9133 (The subscript i in the formula indicates the "i" component in the mixture.) It becomes.

[0037] From the above equation, n a,i , and therefore the atomic density of a particular element, or of all n a,i It can be seen that can be determined by measuring δ and β at various wavelengths.

[0038] When investigating unknown chemical compositions, 2i measurements are taken at separate energies. i;1 and f i;2 Since x naturally follows well-known laws with the energy, it can be easily used to reduce the number of measurement points. For example, it is possible to detect abrupt changes in δ and, especially, in β that correspond to near thresholds. Furthermore, if the materials constituting the sample are known, then i / 2 measurements can be performed at various energies, where "i" is the total number of chemical elements contained in the sample.

[0039] The material in the sample is known, i.e., f i;1 and f i;2If is known, then i / 2 measurements can be performed at various energies to determine the density of each chemical element, which significantly reduces the number of measurements required to determine the parameters δ and β. Finally, prior knowledge about the sample, such as the total or local density of chemical molecules that may be present, can further reduce the number of independent measurements.

[0040] According to another aspect of the invention, an X-ray or X-ray tomography system is provided for implementing a method as described above.

[0041] It is therefore possible to measure δ and β by X-ray or X-ray tomography using the components according to the invention. The only difference between the two techniques is the number of viewing angles and therefore the possibility of reconstructing the sample in three dimensions for X-ray tomography. Further advantages and features of the invention will become apparent upon examination of the detailed description of the non-limiting implementation method and the accompanying drawings. [Brief description of the drawings]

[0042] [Figure 1] 1 is a simplified schematic diagram showing a system according to the invention for implementing a method according to the invention; [Diagram 2] Curve showing the change in δ as a function of X-ray energy. [Diagram 3] Curve showing the change in β as a function of X-ray energy. [Figure 4] Curve showing the evolution of the delta and beta values ​​as a function of energy for the chemical element Si3N4. [Diagram 5] Curve showing the evolution of delta and beta values ​​as a function of energy for the chemical element Si.

[0043] The embodiments described below are in no way limiting; in particular, if a feature is selected from among the features described below in isolation from the other features described, and this selection of feature provides a technical advantage or is sufficient to differentiate the invention over the prior art, it is possible to realize an alternative form of the invention comprising only this selected feature. This selection includes at least one, preferably functional, feature, without structural details, or with only a part of structural details, if this part alone provides a technical advantage or is sufficient to differentiate the invention over the prior art.

[0044] In particular, all the alternatives and all the embodiments described are intended to be combined with one another in any combination that is not hindered from a technical point of view. In FIG. 1 one can see a multi-energy radiation source 1 capable of emitting X-rays in the direction of a sample 2 containing several chemical elements with different optical indices. After passing through the sample 2, the X-rays pass through a grid 3 which is provided with regularly or irregularly distributed holes 4.

[0045] A detector 5 is positioned after the grid 3 so that the X-rays generated by the source 1 first pass through the sample 2 , then through the grid 3 and finally are detected by the pixels 6 of the detector 5 . Each hole 4 of the grid 3 has a larger surface area than each pixel 6 of the detector 5 .

[0046] The arrangement between the source 1, the grid 3 and the detector 5 is determined such that X-rays passing through the holes in the grid 3 form a spot 7 on the detector 5, which spot 7 extends at least partially over several pixels of the detector 5.

[0047] Furthermore, there is also a processing unit 8 equipped with the necessary software and hardware means for the method of the invention to be implemented. This processing unit 8 is in particular connected to the source 1 and to the detector 5 in order to control the emission of the X-rays and to process the signals received by the detector. The X-ray source may include a 50 W tungsten anode. Grid 3 is a transmission grid with 300x300 holes.

[0048] The shape of the holes can be square, circular or any other. The spacing of the holes is related to the size of the holes. It is preferable that at least one pixel remains between the diffraction spots recorded on the detector. The spot size on the other hand depends on the energy of the X-rays, the shape and size of the holes and the grid-detector distance. It is therefore a multi-parameter optimization. The Talbot distance is not used. The distance can be any distance. With Grid 3, the X-rays, through diffraction, project the grid pattern onto the camera in a neutral color.

[0049] The detector 5 is a water-cooled X-ray camera equipped with a 16-bit CCD matrix with a matrix size of 2045×2048 and a pixel size of 30 μm.

[0050] The detectors can be CCD detectors, CMOS detectors, photon counting detectors, or emission plate detectors with visible imaging and visible light detectors (CCD or CMOS). The number of pixels is not set. In general, the number of pixels is a compromise between price and maximum number. The pixel size is not set. The pixel size is a compromise between what exists: small pixels for good sampling, and not too small pixels for good dynamic range.

[0051] Sample 2 advantageously has the formula: n=1-δ+iβ (In the formula, δ=n a r e λ 2 (f1 / 2π) β=n a r e λ 2 (f2 / 2π) is) It is possible to define the optical index n of the sample by In the above formula, n a , r e and λ are the atomic density, classical electron radius and wavelength, respectively. f1 and f2 are atomic scattering factors specific to the chemical composition of the sample. The parameter β is responsible for the attenuation of the X-rays passing through the sample.

[0052] The parameter δ is responsible for phase effects: when X-rays pass through a sample, they undergo phase changes that are specifically a function of δ. The grid can transmit these phase changes as offsets of the spots on the detector.

[0053] To measure β and δ, a no-load, i.e. sample-free, measurement is performed to measure a reference amplitude and a reference position for each spot. Then another measurement is performed to measure the amplitude difference and the spot offset. The intention is to perform a no-load measurement for each energy considered. This allows the measurement train to be calibrated.

[0054] During the measurement, the image obtained on the detector is an interferogram, which is a two-dimensional phase gradient. The interferogram is a set of spots on the detector, which are formed by the X-rays passing through the holes in the grid. These spots are also a function of the path of the X-rays through the sample. By analyzing these spots, the parameters β and δ can be determined.

[0055] In other words, phase changes caused by a sample placed in the path of the X-rays cause a deformation of the interferogram which, when analyzed, gives the phase gradient of the sample.

[0056] The phase change Δφ caused by the sample can be calculated directly using the formula: Δφ=∫δ×ldl ("l" in the formula is the distance traveled by the X-rays) δ is obtained by From the radiation absorption I / I0, the formula: I / I0=exp(-∫(4πβ / λ)dl) (In the formula, λ is the wavelength of the X-ray and "l" is the distance traveled by the X-ray.) β is obtained by

[0057] These two equations give the integrated Δφ and I / I0 for the propagation of the X-rays through the sample. In X-ray tomography, the local phase change and the local absorption can be determined. In this case, the equations are dφ=δ×dl d(I / I0)=exp(-(4πβ / λ)dl) It becomes.

[0058] To measure Δφ and I / I, a centroid search method is applied to accurately locate the centroid of an arbitrarily shaped spot, and the signals from all pixels forming the spot are independently integrated to define the signal corresponding to the hole. These measurements are performed without a sample and then with a sample.

[0059] The centroid search method can use a weighted moment calculation technique and / or an iterative weighted Gaussian method. In particular, the first technique can be used, the results of which can then be fine-tuned using the second technique.

[0060] The difference in the centroid position between the current measurement and the reference measurement gives the refraction and therefore the parameter δ. The difference in the amplitude of the signal from each hole between the current measurement and the reference measurement gives the transmission and hence the parameter β. Using the same spot, two measurements are made independently: the deviation and the amount of reflected influx.

[0061] Thus, the present invention allows δ and β to be measured independently, particularly over a wide range of energies. The technique according to the invention makes it possible to limit the errors.

[0062] Instead of a sample, an object that produces a known change in the incident wave can be used for the reference measurement to obtain the grid-detector distance with very good accuracy for each hole / pixel pair. A diffractive hole producing a spherical wave, a rotating prism, or any other known object can be used.

[0063] 2 and 3, for example, illustrate the variation of δ and β as a function of X-ray energy for breast tissue and various shapes of microcalcifications, some morphologies being benign and others being malignant.

[0064] 4 and 5 illustrate the course of delta and beta values ​​as a function of energy. Two chemical elements to be identified are shown: Si and Si3N4. If the measurement is performed at 4 keV, the delta_ of Si3N4 is approximately 4.5*10 -5 and the beta of Si3N4 is approximately 1.5*10 -6 This is approximately 3*10 -5 is the delta of Si, and is approximately 1.5*10 -6 This is comparable to the beta of Si, which is 10 keV. There are slight differences in delta, but they are very small and therefore a source of error. However, if you look at the behavior at energies above 2, you can see a noticeable and therefore usable difference in this case. For example, at 10 keV, it is about 5*10 -6 is equal to Si's delta and is approximately 7*10 -8 Compared to the beta of Si, which is equal to , the delta of Si3N4 is about 7.5*10 -6 and the beta of Si3N4 is approximately 7*10 -8 At high energies, there is a difference for delta but not for beta. It is this change in behavior that allows us to determine the chemical composition.

[0065] In the present invention, a single grid is used, which has obvious advantages in terms of alignment, stability and robustness, which places few requirements on resolution and hole size, which means that there are also few technical requirements on the detector used.

[0066] The system according to the invention is compatible with high numerical aperture radiation, which leads to improved spatial resolution on the sample, and it is therefore possible to design a monolithic and therefore robust system.

[0067] Naturally, the invention is not limited to the embodiments described above, and numerous adjustments can be made to these embodiments without departing from the scope of the invention.

Claims

1. 1. A phase contrast imaging method for estimating the local stoichiometry of a sample by measuring a parameter δ of the real part and β of the imaginary part of the complex optical index of the sample; the method is realized using an X-ray source for irradiating the sample, which is placed between the source and a detector, a grid of holes, which is placed between the sample and the detector, and a unit for processing the signal from the detector; The method comprises: - performing at least one measurement by irradiating the sample, so that X-rays reach the detector and form a spot for each hole in the grid; - independently analyzing the spots formed on the grid by determining, for each measurement and for each hole of the grid, the centroid of the spot using a centroid search method; - measuring the offset of the centroid from a reference centroid and then measuring the local phase change from the centroid offset; - measuring the amplitude of the X-rays forming the spot and then measuring the local attenuation compared to a reference amplitude; - measuring the parameter δ from the local phase variation; - measuring the imaginary part β from the local attenuation; A method comprising:

2. 2. The method of claim 1, wherein the reference centroid is obtained during measurement by illuminating the detector through the grid without a sample or in the presence of a reference sample.

3. 3. A method according to claim 1 or 2, characterized in that the reference amplitude is obtained during measurement by illuminating the detector through the grid without a sample or in the presence of a reference sample.

4. 3. A method according to claim 1 or 2, characterized in that the grid consists of regularly or irregularly spaced holes.

5. 3. A method according to claim 1 or 2, characterized in that the pitch of the holes in the grid is equal to or greater than the pixel size of the detector.

6. 3. A method according to claim 1 or 2, characterized in that the size of the holes in the grid is equal to or greater than the width of the pixels of the detector.

7. 3. A method according to claim 1 or 2, characterized in that the dimensions of the grid and the distance between the source, the grid and the detector are determined so that the spot for each hole covers several pixels of the detector.

8. The parameter δ is given by the following equation: Δφ=∫δ×ldl (where Δφ is the local phase change and “l” is the distance traveled by the X-ray.) 3. The method according to claim 1 or 2, characterized in that the measurement is carried out using

9. The imaginary part β is given by the following equation: I / I ０ =exp(-∫(4πβ / λ)dl) (I / I in the formula ０ is the attenuation, λ is the wavelength of the X-ray, and "l" is the distance traveled by the X-ray) 3. The method according to claim 1 or 2, characterized in that the measurement is carried out using

10. 3. The method according to claim 1 or 2, characterized in that the X-ray source is a multi-energy source.

11. 11. A method according to claim 10, characterized in that the multi-energy radiation source comprises an anode with several K-alpha type filters.

12. 11. The method of claim 10, wherein the multi-energy source comprises an X-ray emission source and a plurality of filters external to the X-ray emission source.

13. 3. A method according to claim 1 or 2, characterized in that the detector is a photon counting detector in order to obtain several different energy levels.

14. 3. The method according to claim 1 or 2, characterized in that for impure samples multiple measurements are carried out at different energy levels.

15. 15. The method of claim 14, wherein 2i measurements are performed at different energies, where "i" is the total number of chemical elements contained in the sample.

16. 15. The method of claim 14, wherein i / 2 measurements are performed at different energies, where "i" is the total number of chemical elements contained in the sample, if the material constituting the sample is known.

17. 3. An X-ray fluoroscopy system for implementing the method according to claim 1 or 2.

18. An X-ray tomography system for implementing the method according to claim 1 or 2.

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