Method and measuring device for X-ray fluorescence measurement
阅读说明：本技术 用于x射线荧光测量的方法和测量设备 (Method and measuring device for X-ray fluorescence measurement ) 是由 F·格吕纳 C·赫申 F·布卢门多夫 于 2018-04-06 设计创作，主要内容包括：一种用于X射线荧光测量的方法,其中在待检查的物体(1)中捕捉发荧光的目标粒子的存在,存在的目标粒子在物体(1)中定位,所述方法包括以下步骤：(a)通过源装置(10)产生X射线束(2),其中X射线束(2)沿与第一投影方向平行的X射线束方向延伸穿过物体(1),(b)在第一投影平面中的多个扫描位置处用X射线束(2)辐照物体(1),其中扫描位置由扫描装置(20)设定,通过所述扫描装置,源装置和物体(1)相对于彼此移动,(c)使用牢固地连接到源装置(10)的检测器阵列装置(30)在每个扫描位置检测沿多个空间方向从物体(1)发射的X射线辐射,其中检测器阵列装置(30)包括：多个光谱选择性检测器元件(31),其布置成能检测沿多个空间方向的X射线辐射；以及多个筛片(32),其沿相对于X射线束方向的径向方向延伸,筛片屏蔽检测器元件(31)以免受物体(1)中散射的X射线辐射,筛片布置成使得检测器元件(31)能够检测来自物体(1)中X射线束体积区内的所有位置的X射线辐射,以及(d)处理检测器元件的检测器信号,以便在检测到的X射线辐射中捕捉目标粒子的X射线荧光,以及以便如果捕捉到X射线荧光则定位物体(1)中的目标粒子,其中针对多个预定扫描位置中的每一个预定扫描位置寻找显著性检测器元件的子集(31),所述显著性检测器元件的检测器信号有助于与其余检测器元件(31)相比以提高的统计显著性捕捉目标粒子的X射线荧光,并且如果在至少一个扫描位置发现显著性检测器元件(31),则捕捉到目标粒子的存在,并将该扫描位置建立为目标扫描位置,在所述目标扫描位置处目标粒子定位于第一投影平面中,或者如果没有在扫描位置发现显著性检测器元件(31),则捕捉到不存在目标粒子。还描述了一种X射线荧光测量设备。(A method for X-ray fluorescence measurements, wherein the presence of fluorescent target particles is captured in an object (1) to be examined, the target particles present being localized in the object (1), the method comprising the steps of: (a) generating an X-ray beam (2) by means of a source arrangement (10), wherein the X-ray beam (2) extends through the object (1) in an X-ray beam direction parallel to the first projection direction, (b) irradiating the object (1) with the X-ray beam (2) at a plurality of scanning positions in a first projection plane, wherein the scanning positions are set by a scanning arrangement (20) by which the source arrangement and the object (1) are moved relative to each other, (c) detecting X-ray radiation emitted from the object (1) in a plurality of spatial directions at each scanning position using a detector array arrangement (30) fixedly connected to the source arrangement (10), wherein the detector array arrangement (30) comprises: a plurality of spectrally selective detector elements (31) arranged to be able to detect X-ray radiation along a plurality of spatial directions; and a plurality of sieve sheets (32) extending in a radial direction with respect to the direction of the X-ray beam, the sieve sheets shielding the detector elements (31) from X-ray radiation scattered in the object (1), the sieve sheets being arranged such that the detector elements (31) are capable of detecting X-ray radiation from all positions within the X-ray beam volume in the object (1), and (d) processing detector signals of the detector elements so as to capture X-ray fluorescence of target particles in the detected X-ray radiation, and so as to locate target particles in the object (1) if X-ray fluorescence is captured, wherein for each of a plurality of predetermined scanning positions a subset (31) of significance detector elements is sought, the detector signals of the significance detector elements contributing to capture the X-ray fluorescence of the target particles with an improved statistical significance compared to the remaining detector elements (31), and capturing the presence of the target particle if a significance detector element (31) is found at least one scanning position and establishing the scanning position as a target scanning position at which the target particle is positioned in the first projection plane, or capturing the absence of the target particle if no significance detector element (31) is found at the scanning position. An X-ray fluorescence measurement device is also described.)
1. A method for X-ray fluorescence measurements, wherein the presence of fluorescent target particles is detected in an object (1) to be examined, the target particles present being localized in the object (1), the method comprising the steps of:
(a) generating an X-ray beam (2) by means of a source device (10), wherein the X-ray beam (2) extends through the object (1) in an X-ray beam direction parallel to a first projection direction,
(b) irradiating the object (1) with an X-ray beam (2) at a plurality of scanning positions in a first projection plane, wherein the scanning positions are set by a scanning device (20) by which the source device and the object (1) are moved relative to each other,
(c) detecting X-ray radiation emitted from the object (1) in a plurality of spatial directions at each scanning position using a detector array arrangement (30) being securely connected to the source arrangement (10), wherein the detector array arrangement (30) comprises: a plurality of spectrally selective detector elements (31) arranged to be able to detect X-ray radiation along a plurality of spatial directions; and a plurality of sieve sheets (32) extending in a radial direction with respect to the direction of the X-ray beam, the sieve sheets shielding the detector elements (31) from X-ray radiation scattered in the object (1), the sieve sheets being arranged such that the detector elements (31) are capable of detecting X-ray radiation from all positions within a volume area of the X-ray beam in the object, and
(d) processing detector signals of the detector elements for detecting X-ray fluorescence of target particles in the detected X-ray radiation and for locating the target particles in the object (1) if X-ray fluorescence is detected, wherein,
-for each of a plurality of predetermined scan positions, measuring with each detector element the energy spectrum of the X-ray radiation emerging from the object and finding a subset (31) of significant detector elements whose detector signals contribute to the detection of the X-ray fluorescence of the target particles with an improved statistical significance compared to the remaining detector elements (31), and
-detecting the presence of a target particle if a significance detector element (31) is found at least one scanning position and establishing the scanning position as a target scanning position at which the target particle is positioned in the first projection plane, or detecting the absence of a target particle if no significance detector element (31) is found at any scanning position.
2. The method of claim 1, wherein,
-for each of a plurality of predetermined scan positions, finding a subset of significance detector elements (31) such that the detector signals of the significance detector elements (31) contribute to the detection of the X-ray fluorescence of the target particle with maximum statistical significance.
3. The method of any one of the preceding claims,
-for each of a plurality of predetermined scan positions, finding a subset of significant detector elements (31) by discarding the detector elements (31) whose detector signals do not achieve any improvement in the statistical significance of the sum signals of the remaining detector elements (31).
4. The method of any one of the preceding claims,
-for each of a plurality of predetermined scan positions, finding a subset of saliency detector elements (31) using a two-stage selection, wherein,
-in a first selection step, discarding detector elements (31) that mainly detect background X-ray scatter radiation, and
-in a second selection step, discarding further detector elements (31) whose detector signals do not achieve any improvement in the statistical significance of the sum signals of the remaining detector elements (31).
5. The method of any one of the preceding claims,
-for each of a plurality of predetermined scan positions, finding a subset of salient detector elements (31) among a pre-selected subset of detector elements (31), the pre-selected subset being pre-established based on a priori information about the object (1) being examined.
6. The method of any one of the preceding claims,
-performing steps (a) to (d) in a preliminary measurement with a first X-ray beam having a first diameter in order to establish a preliminary target scanning position representing a target scanning area in a first projection plane if the presence of a target particle is detected, and thereafter
-performing steps (a) to (d) in a main measurement with a second X-ray beam having a second diameter, which is the same as or smaller than the first diameter, thereby establishing a sought target scanning position within the target scanning area.
7. The method of any one of the preceding claims,
-the detector array arrangement (30) comprises an arrangement of detector elements (31) on a surface covering half the space of the forward direction of the X-ray beam, and/or
-the detector array arrangement (30) comprises an arrangement of detector elements (31) on a spherical surface or a cylindrical surface.
8. Method according to any of the preceding claims, wherein if at least one target scanning position is established, the following further steps are provided:
-oscillating the source and detector array arrangement (10, 30) such that the X-ray beam (2) extends parallel to a second projection direction, which second projection direction is offset from the first projection direction,
-irradiating the object (1) with an X-ray beam (2) at a plurality of scanning positions along a scan line in a second projection plane, which second projection plane is offset from the first projection plane, wherein the scan line comprises a target scanning position, and
-detecting the position of the target particle along the scan line.
9. The method of claim 8, wherein,
the pivoting of the source and detector array arrangement (10, 30) takes place in such a way that the second projection direction is oriented perpendicularly to the first projection direction and the second projection plane is oriented perpendicularly to the first projection plane.
10. The method according to any one of the preceding claims, having the further step of:
-collecting at least one absorption projection image of the object (1).
11. The method of any one of the preceding claims,
-the object (1) is a human test subject, and/or
The target particles contain atoms with mass numbers in the range of mass numbers from iodine to gold and are functionalized with a labeling substance or drug.
12. An X-ray fluorescence measurement apparatus (100) configured to be able to locate fluorescing target particles in an object (1) to be examined, the X-ray fluorescence measurement apparatus (100) comprising:
a holding device (50) configured to be able to accommodate the object (1),
a source arrangement (10) configured to be able to generate an X-ray beam extending through an object (1) to be examined in an X-ray beam direction parallel to the first projection direction,
-a detector array device (30) being securely connected to the source device (10), the detector array device (30) being configured to be able to detect X-ray radiation emanating from the object (1) in a plurality of spatial directions, the detector array device (30) comprising a plurality of spectrally selective detector elements (31) arranged to be able to detect X-ray radiation in the plurality of spatial directions and a plurality of sieve sheets (32) extending in a radial direction with respect to the X-ray beam direction, the sieve sheets shielding the detector elements (31) from X-ray radiation scattered in the object (1), the sieve sheets being arranged such that the detector elements (31) are able to detect X-ray radiation from all positions within an X-ray beam volume in the object,
-a scanning device (20) by means of which the source and detector array devices (10, 30) and the holding device (50) are movable relative to each other such that the object (1) can be scanned by the X-ray beam (2) at a plurality of projection positions in a first projection plane, and
-a control device (40) configured to be able to process detector signals of the detector elements in order to detect X-ray fluorescence of target particles in the detected X-ray radiation and in order to target particles in the object (1) if X-ray fluorescence is detected, wherein,
-the control device (40) is configured to be able to find for each of a plurality of predetermined scan positions a subset of significance detector elements (31) whose detector signals contribute to the detection of X-ray fluorescence of the target particles with an improved statistical significance compared to the remaining detector elements (31), the control device (40) being further configured to: if a saliency detector element (31) is found at least one scan position, detecting a presence of a target particle and establishing the scan position as a target scan position at which the target particle is located in the first projection plane; or detecting the absence of target particles if no significance detector element (31) is found at the scanning position.
13. The X-ray fluorescence measurement apparatus according to claim 12,
-the control means (40) are configured to be able to find a subset of significance detector elements (31) whose detector signals contribute to the detection of the X-ray fluorescence of the target particles with a maximum statistical significance.
14. The X-ray fluorescence measurement apparatus according to any one of claims 12 to 13,
-the control means (40) are configured to be able to find a subset of the significance detector elements (31) by discarding the detector elements (31) whose detector signals do not achieve any improvement of the statistical significance of the sum signals of the remaining detector elements (31).
15. The X-ray fluorescence measurement apparatus according to any one of claims 12 to 14,
-the control means (40) are configured to be able to find a subset of significance detector elements (31) based on a two-stage selection, wherein,
-in a first selection step, discarding detector elements (31) that mainly detect background X-ray scatter radiation, and
-in a second selection step, discarding further detector elements (31) whose detector signals do not achieve any improvement in the statistical significance of the sum signals of the remaining detector elements (31).
16. The X-ray fluorescence measurement apparatus according to any one of claims 12 to 15,
-the detector array arrangement (30) comprises an arrangement of detector elements (31) on a surface covering half the space of the forward direction of the X-ray beam, and/or
-the detector array arrangement (30) comprises an arrangement of detector elements (31) on a spherical surface or a cylindrical surface.
17. The X-ray fluorescence measurement device of any one of claims 12-16, comprising:
-a wobble device (60) with which the source device and the detector array device (10, 30) can be wobbled such that the X-ray beam (2) extends parallel to a second projection direction, which is offset from the first projection direction, wherein,
-the scanning device (20) is configured for moving the source and detector array device (10, 30) and the holding device (50) relative to each other such that the X-ray beam (2) can scan the object (1) along a scan line in a second projection plane offset from the first projection plane, and
-the control device (40) is configured to: if at least one target scan position has been established, the position of the target particles is detected along the scan line.
18. The X-ray fluorescence measurement apparatus according to claim 17,
-the swinging means (60) for swinging the source and detector array means (10, 30) are configured such that the second projection direction is oriented perpendicular to the first projection direction and the second projection plane is oriented perpendicular to the first projection plane.
19. The X-ray fluorescence measurement apparatus according to any one of claims 12 to 18,
-the detector array means (30) and the control means (40) are configured to be able to take at least one absorption projection image of the object (1).
Technical Field
The invention relates to a method for X-ray fluorescence measurement, in particular for X-ray fluorescence imaging, wherein the presence of fluorescent target particles in an object to be examined, in particular in the body of a test object to be examined, is detected and wherein the target particles present in the object are localized. The invention also relates to an X-ray fluorescence measurement device for performing such a method, more particularly to an X-ray fluorescence imaging device. The application of the invention resides in X-ray fluorescence imaging, more particularly for medical purposes, and in this respect more particularly for objects having a size scale with respect to humans.
Background
The task of medical imaging is to detect, characterize and monitor pathological changes and/or pharmacokinetics of the body under examination, and thereby measure the distribution of drugs in vivo. In order to improve these methods, so-called "molecular imaging" techniques are being developed, for example in order to allow early diagnosis of tumors and better characterization of tumor tissues or pharmacokinetic examinations. In this regard, the characterization allows for a layered approach to treatment, thereby increasing the chances of a cure. Molecular imaging in medicine is more specifically directed to the localization of in vivo biomarkers (e.g. antibodies in tumor tissue) and allows in vivo measurement of the distribution of drugs in vivo in order to examine the proportion of the amount of drug administered that occurs at any time and where. This allows the effectiveness of new drugs to be tested more quickly in the trial phase, since there is not a sufficient amount of drug at the target site to have a clinical effect.
To date, in the field of molecular imaging, Positron Emission Tomography (PET) has been established, although as a nuclear medicine method, it has serious drawbacks for patients. These include relatively high dose, exposure of unaffected organs, short life of the radiopharmaceutical such that subsequent examination requires new injections, low spatial resolution of 4 to 6mm, and limited temporal resolution such that relevant processes in oncology care or therapy cannot be examined. Thus, in particular, a longer period of pharmacokinetic examination is less likely to be performed. The "diagnostic time window" for PET is too short if the drug is to be carried through the drug carrier to the target site and released there.
The disadvantages of PET can be avoided with X-ray fluorescence imaging (XRF imaging), which has been discussed for many years now as an alternative to PET. In XRF imaging, for example, the biomarkers are bound to gold nanoparticles that are excited by the scanned X-ray beam to emit X-ray fluorescence. The detection of X-ray fluorescence allows localization of the biomarkers. Since the XRF imaging signal is in a narrowly limited energy range in the measured spectrum of the X-ray radiation emitted from the human body, detection of biomarkers by energy selective detection of X-ray fluorescence is supported. However, conventional XRF imaging methods have the disadvantage that they can only be tested to date on small animal models (mice, small animal phantoms) with relatively low sensitivity and at radiation doses that are too high for medical use, whereas examination objects with the size of a patient have not been examined to date.
The main disadvantage of XRF imaging methods is that it is not background-free compared to PET and the amplitude of the background increases dramatically with the size of the object under examination. Thus, the sensitivity of conventional XRF imaging methods to large objects is too low to make clinical use of these techniques for patients impossible. While the expected concentrations of, for example, gold nanoparticles are known from small animal models (see, for example, "Quantitative imaging of gold nanoparticle distribution in a tubular-imaging using a branched fluorescent X-ray fluorescence-computed tomogry" published in "Sci Rep" 6:22079 by n.manohar et al (2016)), such XRF imaging methods cannot detect these quantities of gold nanoparticles in humans, as the sensitivity will no longer be sufficient.
The background of XRF imaging grows with the size of the object because at the same time the probability increases that the irradiated X-ray photons undergo multiple Compton scattering. Due to the scattering, the energy of the photon is reduced, so that the scattered photon is detected in the same energy range as the fluorescence photon. The sensitivity of biomarker detection is limited because these signal photons cannot be distinguished from background photons within a common energy range. In the suspected XRF imaging energy range (approximately 100 million photons) without background reduction, for example 1000 signal photons may be lost in the background because the signal is not statistically significant. To date, collimator geometries have been proposed to reduce the XRF imaging background, but their function requires prior information about the location of the contrast-rich volume in the object. Furthermore, conventional collimators limit the field of view of the detector elements, with the result that signal losses can only be compensated for by higher doses of radiation.
Finally, until now, X-ray fluoroscopic imaging has only been examined on large synchrotron facilities or with conventional compact X-ray tubes. However, neither of these methods is suitable for clinical applications, since the synchrotron facilities are too large and conventional X-ray tubes often emit radiation of too low intensity in rays with too large a divergence and/or with small a divergence, and have too large an energy bandwidth.
X-ray fluorescence analysis of the diffusion of contrast agents in an object using a collimated X-ray source filtered in the lower energy range is described in
Disclosure of Invention
It is an object of the present invention to provide an improved method for X-ray fluorescence measurements, in particular for X-ray fluorescence imaging, and/or an improved X-ray fluorescence measurement apparatus, with which the disadvantages of the conventional techniques are avoided. The invention should in particular make it possible to detect the X-ray fluorescence of target particles in an object with increased sensitivity, to suppress the background more effectively, to reduce the radiation intensity and/or to increase the spatial resolution. Furthermore, the invention should more particularly allow examination of larger objects, which was not possible before, and facilitate clinical X-ray fluorescence imaging, more particularly in humans.
These objects are achieved by a method for X-ray fluorescence measurement and an X-ray fluorescence measurement device having the features of the independent claims. Advantageous embodiments and applications of the invention will be apparent from the dependent claims.
According to a first general aspect of the present invention, the above object is achieved by a method for X-ray fluorescence measurement, wherein the presence of fluorescent target particles is detected in an object to be examined, and any target particles that may be present are located in at least one projection plane (hereinafter referred to as first projection plane) in the object.
An X-ray beam is generated by means of a source device, which X-ray beam is directed through the object in an X-ray beam direction parallel to the first projection direction. The X-ray beam is preferably a needle beam (pencil beam) with a constant diameter or a small divergence (e.g.. ltoreq.1 mrad). The diameter of the X-ray beam defines the spatial resolution of the XRF imaging method and is therefore preferably at least 0.1mm, more particularly at least 0.2mm, and/or at most 1mm, more particularly at most 2 mm.
The object is irradiated (scanned) with an X-ray beam at a plurality of scanning positions in a first projection plane. The scanning position (the position where irradiation takes place) is set by means of a scanning device, by means of which the source device and the object are moved relative to each other. For each scan position, the X-ray beam intersects the first projection plane at a different coordinate. Preferably, the X-ray beam is oriented perpendicularly to the first projection plane. The scanning positions are distributed in the first projection plane, for example in rows and columns in a matrix.
At each scanning position, X-ray radiation emanating from the object in a plurality of spatial directions is detected using a detector array arrangement that is fixedly connected to the source arrangement. By means of the scanning device, the source device and the detector device and the object are moved relative to each other. Preferably, the source device and the detector device move relative to the statically mounted object.
The detector array arrangement has an arrangement of spectrally selective detector elements (also referred to as pixels) which are distributed around the object in a plurality of different spatial directions. The detector elements are arranged along an array surface which is curved, sectionally curved and/or consists of a flat component surface. For each scanning position, the energy spectrum of the detected X-ray photons leaving the object is measured with each spectrally sensitive detector element, and these individual energy spectra can be combined to a total energy spectrum of selected and/or all detector elements. The energy spectrum measurement with the detector elements is essentially different from DE102012023344a1, in DE102012023344a1, in which the detector can only measure signal photons with a specific energy and emitted perpendicularly to the direction of the X-ray beam. Furthermore, forming a resultant spectrum (resultant signal) has in particular the advantage over considering the spectrum of the individual detector elements that, in the case of a desired small number of target particles, for example from the small animal models mentioned above, the number of signal photons in the individual detector elements will be so small that any determination of significance will be difficult or even excluded.
The detector elements are arranged for detecting X-ray radiation in a plurality of spatial directions. The "detector element" may be a single spectrally resolved detection element, a combination of a plurality of (e.g. 4 x 4) detection elements or a detection member consisting of a plurality of detection sub-elements. The combination of a plurality of detection elements may be particularly advantageous for the statistics of the detected X-ray photons. The component consisting of subelements is particularly advantageous in terms of spectrally resolved detection when using a laser-based Thomson source as source device, since in this respect the photons are detected almost simultaneously and it is ensured by the subelements that each subelement detects no more than 1 photon in each detector time window.
The detector array arrangement further has a plurality of screening sheets extending between the object and the detector elements in a radial direction with respect to the X-ray beam in the object and shielding the detector elements from X-ray radiation that is scattered in the object either singly or multiply, in particular outside the X-rays, and arranged such that the detector elements are able to detect X-ray radiation from all positions within the X-ray beam volume in the object. More particularly, each individual detector element may detect X-ray radiation from all positions within the X-ray beam volume in the object. The screening sheets are arranged such that a free (unobstructed) line of sight extends from the entire volume of the X-ray beam in the object to the detector elements, while a line of sight from other, not directly irradiated volume in the object to the detector elements is blocked by the screening sheets. The screen sheet may preferably be a flat blade, each having a constant thickness, or alternatively having a thickness variation that narrows towards the beam. Due to the finite size of the sieve plate, a small fraction of the signal photons are absorbed, but are negligible as errors in the X-ray fluorescence measurement, since the proportion of the signal photons absorbed is preferably less than 10%.
The screening sheet advantageously provides a first contribution to the background reduction by shielding scattered radiation from volumetric regions of the object outside the volumetric region being irradiated at the scanning position.
The detector signals of the detector elements are processed in order to detect the X-ray fluorescence of the target particles in the detected X-ray radiation and in order to locate the target particles in the object in case of a detected X-ray fluorescence. To this end, according to the invention, for each of a plurality of predetermined scanning positions, a subset of detector elements (referred to as significance detector elements or identified detector elements) is identified, the detector signals of which contribute to the detection of the X-ray fluorescence of the target particles with an improved statistical significance compared to the remaining detector elements. For example, the groups of significant (or identified) detector elements are searched for each scan position accordingly or only for selected scan positions (e.g., every other scan position in the scan position matrix). In this regard, more particularly, the significance of the resultant signal (resultant spectrum) of the detector element (i.e., of the identified subset) is compared to the significance of the resultant signal (resultant spectrum) of each of the other subsets of detector elements.
If a significant detector element is found at least one scanning position, the presence of a target particle and the scanning position at which the significant detector element is found are determined as at least one target scanning position based on the detector signals of the significant detector element and without taking into account the detector signals of the remaining detector elements. The target scan position represents coordinates where the target particle is located in the first projection plane. Otherwise, if no significance detector element is identified at any scanning position, it is detected that no target particle is detected in the object.
The choice of saliency detector elements provides a significant, advantageously maximal contribution to the background reduction. This aspect of the invention is more particularly based on the inventors' close examination of the intrinsic background resulting from multiple compton scattering of photons irradiated within the body. The key to reducing the background is to find that the background is direction-dependent, i.e. anisotropic, whereas the fluorescence signal of the target particle is emitted isotropically, i.e. without distinguishing any direction. In other words, the inventors have found that due to multiple compton scattering, the background X-ray radiation has a non-uniform specific distribution (anisotropy), especially for large objects as in clinical applications. At a scanning position, where the X-ray beam hits a target particle and X-ray fluorescence is generated, the detector elements of the detector array arrangement detect X-ray fluorescence along different spatial directions (with respect to the X-ray beam direction) and correspondingly different backgrounds. By looking for significant detector elements, those detector elements are detected that detect the X-ray fluorescence resultant spectrum of the detector element with a relatively low background signal compared to the remaining detector elements. Thus, the quantitative finding of the anisotropy of the intrinsic background is translated into a reduction of the background by means of a direction-dependent detection.
The inventors have more particularly found that the anisotropy of photons having energies within the signal energy range due to multiple compton scattering is related to the energy of the X-ray photon used for excitation. The X-ray photons used for excitation preferably have an energy at which the anisotropy is maximal. Advantageously, this contributes to a particularly effective suppression of the background. The energy at which anisotropy takes a maximum can be determined by experimental tests (e.g. phantom) or numerical simulations. Particularly preferably, the energy of the photons of the excitation X-ray beam is selected from a narrow energy interval above the K-edge of the fluorescent elements in the target particles, in the case of gold target particles about 85 keV.
By means of computer simulations, the inventors have been able to demonstrate that the background can be reduced by a factor of about 600 to 1000, with correspondingly effective improvement in significance, and in fact using a test phantom with a diameter of 30cm and a minimum dose, thereby satisfying the requirements for imaging a human. Advantageously in clinical applications, for example in tumor diagnosis, whereby small amounts of test particles can be detected in an object, for example a human being. This is achieved by measuring the signal and the background only in a specific direction, i.e. more specifically by means of a resultant spectrum of the identified detector elements. It is clear that these directions form only about 30% to 40% of the total cube angle, for example. However, this limitation is key to effectively increase significance. The significant improvement achieved according to the invention enables the sensitivity required for medical imaging of humans to be achieved.
The method according to the invention differs from all conventional XRF imaging methods in which measurements are typically made in only one direction (typically 90 degrees or more than 90 degrees relative to the irradiation direction) and/or the collimator always allows only a part of the beam volume to be viewed. So far, it is not known to use individual contributions to the overall significance of the fluorescence signal in all directions for quantitative examination of the detection along the entire beam volume. More particularly, a significantly improved yield of detection of fluorescence photons from all spatial directions and a detection with a drastically reduced background signal are achieved compared to the technique according to DE102012023344a1, thereby achieving a significantly higher efficiency of the method with respect to dose and irradiation time.
The inventors have also found that isotropic detection of the maximum fluorescence signal in all spatial directions is expected to yield maximum background detection simultaneously. The significance of the generated fluorescence signal will then be so small that especially for human test object sized objects one will only be able to measure the number of e.g. medically irrelevant sized gold nanoparticles. In contrast to this, it is proposed in the invention to select in advance the spatial direction of the detected X-ray radiation by selecting the saliency detector elements. Numerical analysis by the inventors has shown, for example, that detection provides a significant background reduction in about 40% of all possible spatial directions. The quantitative examination of compton background anisotropy with respect to large objects, which was carried out for the first time by the inventors, more particularly provides the basic concept of the present invention to measure only the resultant signal from significant (identified) detector elements in an X-ray fluorescence measurement.
The present invention enables such a drastic reduction of the intrinsic background, so that X-ray fluorescence imaging can be used in clinical practice as an imaging means on humans. Although the achievable sensitivity of conventional techniques such as CT and MRT is too low, for use as an early tumour diagnosis, the X-ray fluorescence measurement according to the invention enables a significant improvement in sensitivity to be achieved, while at the same time avoiding the above-mentioned disadvantages of PET imaging. The present invention makes it possible to quantify the improvement in sensitivity. Thus, the potential of X-ray fluorescence imaging can be said to be quantitatively characterized compared to other imaging modalities.
According to a second general aspect of the present invention, the above object is achieved by an X-ray fluorescence measurement device configured to be able to locate fluorescent target particles in an object to be examined, the X-ray fluorescence measurement device comprising: a holding device for receiving the object; a source arrangement for generating an X-ray beam extending through the object to be examined in an X-ray beam direction parallel to the first projection direction; a detector array arrangement for detecting X-ray radiation emitted from the object in a plurality of spatial directions; scanning means by which the source means and the detector array means and the holding means are movable relative to each other; and control means for receiving and processing detector signals of the detector array means. Preferably, the X-ray fluorescence measuring device is designed for performing a method according to the first general aspect of the invention.
The source arrangement is preferably a compact laser-based Thomson source (X-ray radiation source) which generates X-ray radiation based on Thomson scattering of relativistic electrons by the laser, as described by k.khrenikov et al ("turbo All-Optical quaternary ammonium heterocyclic nitrogen X-ray source in the Nonlinear region") in "phys.rev.lett" 2015 at 144, 195003, but it may also comprise a synchrotron source or a conventional X-ray source in general, such as an X-ray tube, which generates X-ray radiation with sufficiently low divergence and high intensity, in particular in an energy range above the K-edge of the target particle element. The detector array arrangement is fixedly connected to the source arrangement, the detector array arrangement having a plurality of spectrally selective detector elements and a plurality of sieve sheets, as described above with reference to the first aspect of the invention. With the scanning device, firstly the source device and the detector array device and secondly the holding device can be moved relative to one another such that the X-ray beam can scan the object in a plurality of scanning positions in the first projection plane.
The control means (also referred to as calculation means, evaluation means or control and evaluation means) are configured to be able to identify for each of a plurality of predetermined scanning positions a subset of significance detector elements whose detector signals (in particular a resultant signal, preferably a resultant spectrum) contribute to the detection of the X-ray fluorescence of the target particle with an improved statistical significance compared to the remaining detector elements, the control means being further configured to detect the presence of the target particle and establish the scanning position as a target scanning position in which the target particle is located in the first projection plane if a significance detector element is found in at least one scanning position, or as no detectable target particle if no detector element is found at any scanning position. The control device is, for example, a computer on which a program for executing the processing of the detector signals runs or a special-purpose computer configured to execute the processing of the detector signals. The control device is coupled to the components of the X-ray fluorescence measurement apparatus, for example, to control or receive signals from the source device, the scanning device and the detector array device.
According to a preferred application of the invention in X-ray fluorescence imaging, the object under examination is a human or animal test object or a body part of the object. The target particles are supplied to the test subject beforehand, for example, by oral or other administration means or injection. The preliminary step of supplying target particles, more specifically by injection into the body of a test subject, is not part of the present invention. Alternatively, other non-biological objects may be examined. The target particles comprise particles, more particularly nanoparticles, adapted for exciting X-ray fluorescence with photons of radiation, more particularly with an energy of at least 15keV, and preferably with a mass number in the range of the mass number of iodine to gold. The advantage of these elements is that the K-layer fluorescence photons have sufficient transmittance in the test object body so that the target particles (as opposed to optical fluorescence) can be detected at any depth. Furthermore, the target particles are functionalized with a labeling substance. The labeling substance (or biomarker) includes a substance that specifically binds to some portion of the object under examination (e.g., to a predetermined cell or group of cells or to a predetermined tissue, such as a tumor cell or tissue). However, the target particles may also be functionalized with a drug, in order to thus allow in vivo pharmacokinetic examination.
The presence of fluorescent target particles in the object to be examined means that the previously introduced target particles have been enriched in at least one sub-region of the object under examination by specific binding, for example by oral or other means administration or injection. Detecting the presence of the target particles comprises detecting the enrichment (concentration) of the target particles in at least one sub-region, e.g. in a tissue or cell population. The positioning of the target particle comprises the detection of the enrichment site at least with respect to the first projection plane, however preferably with respect to all three spatial dimensions. For medical applications, the invention has the following advantages, among others. The intrinsic background of medical X-ray fluorescence imaging can be drastically reduced such that at an acceptable radiation dose small amounts of functionalized gold nanoparticles can be detected in vivo, so that e.g. early tumor diagnosis can be performed.
According to a preferred embodiment of the invention, for each predetermined position of the plurality of predetermined scanning positions, a subset of the significance detector elements is sought, such that the detector signals, more particularly the sum signal, of the significance detector elements contribute to the detection of the X-ray fluorescence of the target particle with maximum statistical significance. The control means is configured to be able to select detector elements from which the detector signal resultant signal can detect the sought X-ray fluorescence of the target particle with maximum statistical significance. Thus, a maximum sensitivity of the X-ray fluorescence measurement is advantageously achieved. In this connection, maximum sensitivity more particularly means that any other subset of detector elements has a resultant signal with a lower signal significance.
Advantageously, different methods may be used to identify the subset of saliency detector elements. According to a first preferred variant, a single-stage method is provided, wherein, preferably with the control means, the detector signals of the detector elements are subjected stepwise to an appearance analysis of the sought X-ray fluorescence of the target particle at the considered scanning position, thereby checking the statistical significance of the X-ray fluorescence in the sum signal of the detector signals of the considered detector element and the remaining detector elements. Discarding those detector elements whose detection signals do not achieve any improvement in the statistical significance of the resultant signals of the remaining detector elements. All non-discarded detector elements form a group of significant detector elements. The single-stage method has, inter alia, the advantage that significance detector elements can be established at high processing speeds.
According to a second preferred variant, a two-stage method is provided, wherein in the first selection step detector elements that mainly detect background X-ray scatter radiation are discarded, and in the second selection step further detector elements are discarded, the detection signals of which do not achieve an increase in the statistical significance of the sum signals of the remaining detector elements. The detection of the detector elements in the first selection step, which mainly detect background X-ray scatter radiation, is based on spectrally selective detection with the detector elements. The (background) energy range in which only background photons will occur is used as a reference for evaluating the (fluorescence) energy range in which both background photons and fluorescence photons can occur. If the detector signal of the detector element under consideration provides an amplitude in the background energy range which is statistically not significantly different from the signal amplitude in the pure background energy range, in particular is significantly greater than the expected signal amplitude (in the fluorescence range), this detector element is detected as primarily detecting background X-ray scatter radiation and is therefore discarded. The two-stage method, which is preferably carried out by the control device, has the advantage, inter alia, that the significance detector element can be established accurately and reproducibly.
Advantageously, the above variant may more particularly be combined with a preselection in which, for each of a plurality of predetermined scan positions, an initial subset of detector elements is preselected, which initial subset is established beforehand on the basis of a priori information about the object under examination (advance information), so that within the preselected initial subset a subset of saliency detector elements to be identified is sought. The a priori information may e.g. be based on numerical simulations, experimental simulations, existing images of the object (e.g. patient images from CT or MRT examinations), and/or known localization of the target particle, e.g. localization of a disease (e.g. liver tumor) or as target volume for pharmacokinetic examinations. Advantageously, the selection of saliency detector elements is simplified and the processing speed is increased in view of the initial subset.
According to a further advantageous embodiment of the invention, the X-ray fluorescence measurement is carried out in two phases with a preliminary measurement and a main measurement, wherein the method according to the invention is carried out using X-ray beams having a first, larger diameter and a second, smaller diameter, respectively, with different local resolutions. However, the first beam does not have to be larger. It may be as large as the second beam, but with a smaller applied dose, and then add adjacent pixels to obtain enough data for statistical evaluation. The advantage of this variant is that the data of the preliminary scan can be further used for the second measurement. In a preliminary measurement, a preliminary target scan position representing a target scan area in a first projection plane is established using a first X-ray beam having a first diameter if the presence of a target particle is detected. In a main measurement with a second X-ray beam having a second diameter, a sought target scanning position is established within the target scanning area. Advantageously, preliminary measurements may be used in order to quickly find out whether a target particle is detectable in the object and in what target scanning area the target particle may be located. The main measurement may be omitted if the X-ray fluorescence of the target particle is not detected. The main measurement provides a precise positioning of the target particle if the X-ray fluorescence of the target particle is detected, so that the time required for the main measurement can be reduced by limiting only to the target scan area ("zooming" to the target area).
The detector array arrangement may completely surround the object except for the solid angle area, to radiate the X-ray beam through the irradiation window and optionally to introduce the object into the detector array arrangement through an introduction window (4 pi detector). The irradiation window has a small lateral dimension which is adapted to the diameter of the X-ray beam. The lateral dimensions of the introduction window are related to the shape and size of the object and optionally the components of the holding device. Advantageously, substantially all X-ray photons from the object are thereby detected.
According to an alternative embodiment of the invention, the detector array arrangement comprises an arrangement of detector elements on a surface which covers only, more particularly approximately, half the space in the direction of advance of the X-ray beam. The inventors have found that the saliency detector elements are found predominantly in half the space in the forward direction. Advantageously, this embodiment of the invention enables a simplified arrangement of the detector array arrangement and a simplified access to the object under examination.
According to a further preferred embodiment of the invention, the detector array arrangement may comprise an arrangement of detector elements along a spherical surface and/or a cylindrical surface. In this case, the radial arrangement of the screen blades is simplified.
The positioning of the target particle in the first projection plane already provides in principle evaluable image information about the object to be examined and the position of the target particle in the object. To accomplish the imaging, according to a particularly preferred embodiment of the invention, after the target particle has been positioned in the first projection plane, a wobbling of the source arrangement and the detector array arrangement relative to the object is provided such that, in a wobbling state, the X-ray beam extends through the object parallel to a second projection direction, which deviates from the first projection direction. In order to perform the pivoting, the X-ray fluorescence measuring device is provided with a pivoting device with which the source arrangement and the detector array arrangement, preferably together with the scanning device, can be rotated relative to the holding device of the object such that the X-ray beam extends parallel to the second projection direction.
In the swung state, the object is further irradiated with an X-ray beam at a plurality of scanning positions, in which case the irradiation is limited to scanning lines in a second projection plane deviating from the first projection plane, wherein the scanning lines contain the previously established target scanning positions, the positions of the target particles being detected along the scanning lines, preferably by means of the control means. The position of the target particle in the object is fully characterized by means of the position information about the scanning position in the first projection plane and the scanning position on the scanning line in the second projection plane.
The second projection direction is not substantially parallel to the first beam direction, i.e. the second projection direction must only allow the scanning directions to spatially intersect each other, so that if both scanning directions each show a signal, the intersection point will then mark the position of the target particle. However, according to a preferred variant of the invention, the generating source arrangement and the detector array arrangement are swung such that the second projection direction is oriented perpendicularly to the first projection direction and the second projection plane is oriented perpendicularly to the first projection direction.
According to a further preferred embodiment of the invention, a recording of at least one absorption projection image (absorptionprojejektionbildes) of the object can be provided. Advantageously, in this case the detector element fulfils a dual function to detect X-ray fluorescence and to detect conventional X-ray absorption images, for example to establish anatomical information about the test object under examination. Preferably, the absorption projection image is combined with a complete characterization of the target scan position in the first projection plane or the target position in space in order to obtain an image of the object, for example for later diagnosis.
Drawings
Further details of the invention are described below with reference to the accompanying drawings, in which:
fig. 1 to 6: schematic illustration of a preferred embodiment of an X-ray fluorescence measurement device according to the invention, wherein the detector elements are arranged on a spherical surface;
fig. 7 to 9: schematic illustration of a preferred embodiment of an X-ray fluorescence measurement device according to the invention, wherein the detector elements are arranged on a cylindrical surface;
fig. 10 and 11: a flow chart showing the features of a preferred embodiment of the method according to the invention;
FIG. 12: a graphical representation of saliency detector element selection;
FIG. 13: a graphical representation of the spectral sum signal at the target scan location, an
FIG. 14: graphical representation of background suppression achieved using measurable X-ray spectra in accordance with the present invention.
Detailed Description
Embodiments of the invention are described below with reference to features of an X-ray fluorescence measurement apparatus and method for, inter alia, detecting the presence of fluorescent target particles in an object to be examined and, if fluorescent target particles are detected, for localization of the target particles. The details of the X-ray fluorescence measuring device, for example of the source device, the scanning device, the detector element or the oscillating device, can be implemented as known per se from corresponding mechanical, electrical or X-ray optical components of conventional technology, and are therefore not described in detail here. For applications in medical imaging, the X-ray fluorescence measuring device may be provided with other components, as known per se from the conventional art, for example a driver for actuating the holding means, an operating means, a display means, etc.
By way of example, reference is made to an embodiment in which the source device and the detector array device are moved relative to a stationary positioned object to set the scanning position. The invention can be used, for example, with respect to stationary sources, such as conventional synchrotron sources, respectively, to move an object relative to a stationary positioned source arrangement and detector array arrangement.
Fig. 1 to 6 schematically show different perspective views of an X-ray
According to fig. 1, the X-ray
The
Fig. 7 to 9 schematically show different perspective views of an X-ray
The X-ray fluorescence measurement according to the invention is carried out on an
The X-ray fluorescence measurement according to the invention is based inter alia on the following considerations of the inventors. In addition to the knowledge of the directional dependence or anisotropy of the background, this method also meets two basic requirements:
(1) this method does not presuppose that the position of the target particle along the
(2) multiple compton scattering will be minimized. Only compton scattered photons cannot be blocked because they come from the same region as the fluorescence photons.
The requirement (1) excludes collimators and/or measuring methods (for example in DE102012023344a 1) which allow only a limited viewing volume along the scanning beam. Nevertheless, many other methods still use this limitation because it can greatly reduce the background, but also weaken the signal so much that the sensitivity cannot be maximized. However, the requirement (2) allows for a collimator that does not, of course, reduce the volumetric region of the needle beam, but that maximally blocks all regions outside the beam volumetric region.
Both requirements can be met by
The basic gain in background reduction, for example by a factor of 570, is achieved by so-called "spatial filtering" of the detector signal as described above, i.e. by identifying a subset of all existing detector elements after the first background reduction due to the
(1) Each detector element (or pixel) 31 (e.g. surrounding the
(2) Each of the
(3) The background reduction according to the invention is based on the pixel selection such that not all pixels are read anymore, but only certain pixels are read. If one reads too many (or even all) pixels, too much background is detected and the signal photons are completely masked. Conversely, if one reads only a few pixels, the background may decrease, but the signal will also decrease. The method according to the invention enables an approximate or even a significant optimization to be achieved by iteratively discarding pixels from the signal processing, the removal of which increases the significance of the resultant signal of the remaining pixels, precisely in each case. The pixel selection method terminates when the next pixel to be deleted does not bring about an additional improvement in significance. The situation in fig. 12B is then reached: the resultant spectrum of pixels still present has the greatest signal significance, as a result of which a signal curve is reached, as shown in the example in fig. 13, i.e. the fluorescence signal can now be perceived.
Fig. 10 and 11 show a two-stage variation of the identification of significant detector elements, wherein in a first selection step (in fig. 10, the unfit background-based pixel selection) detector elements that mainly detect background X-ray scatter radiation are discarded, and in a second selection step (fig. 11, the pixel selection based on significance with fit) further detector elements whose detection signals do not achieve any improvement in the statistical significance of the sum signals of the remaining detector elements are discarded. Alternatively, the performance of the identification of saliency detector elements may be limited to the method according to fig. 10.
Before the salient detector elements are identified, the needle-shaped
Thereafter, the identified detector elements are individually selected for each scanning position (this may be done simultaneously with or after the detection; i.e. data is stored during the detection of all detector elements):
if there is a fluorescence signal, i.e. two gold fluorescence lines (see fig. 13), then in the energy spectrum of the resultant signal of the detector element under consideration these fluorescence lines will be separated from each other by a pure background region, and there will likewise be background regions on the left and right of the signal region (see fig. 13): in the background region, there are only background photons, and no signal photons. These areas are therefore reference values. If there is no fluorescent signal, the signal region will not be statistically significantly different from the background region.
Through steps S1_3 to S1_7, the method according to fig. 10 abandons further consideration of the detector elements (i.e. ignores the detected energy spectrum of these pixels) until the input in the three background regions B1, B2 and B3 (fig. 13) has been reduced to a value, if any, at which the statistical significance of the background rise in the two signal regions exceeds a value of e.g. ≧ 2 (test in step S1_ 2). If there is no signal, the termination criterion will never be reached and the algorithm stops at the last remaining pixels (or for example when 80% of all pixels have been discarded) (step S1_ 10).
If the test requirements (transition conditions) are fulfilled in step S1_2, the second algorithm (fig. 11) now starts: for further pixel selection, all spectra of the remaining pixels are summed to form a sum spectrum, and the signal significance is determined directly by means of the two signal regions using a fitting function (steps S2_1 to S2_ 8). The key advantage of this algorithm is that the fitting function maps the background regions better (in the first step of fig. 10, the background is assumed to be constant over all regions, however this is only an approximation), and the fluorescence signal can be distinguished from the background by fitting, i.e. by fitting only, the number of fluorescence photons versus background photons can be determined from the resultant spectrum, and thus pixels that contribute more to the background than to the signal are discarded.
Once the next detector element to be removed is no longer further raised (step S2_10), but rather is less significant (one would not obtain because only one would remove additional background, but thus too much signal), this "fit-based" pixel selection stops. Therefore, the identified optimal selection of detector elements is output in step S2_ 11. Then, the scanning position at which the target particle is detected is output as a target scanning position.
Thereafter, the combination comprising the
Fig. 14 shows a further illustration of the advantages of the present invention using a simulated X-ray spectrum of the
The features of the invention disclosed in the above description, the drawings and the claims are of significance both individually and in combination or sub-combination for the realization of the invention in its different embodiments.
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