DE102020100936A1 - Device for detecting a marking substance in at least one sample - Google Patents

Abstract

A device 10, 10 'for detecting a marking substance in at least one sample 80a, 80b, 80c comprises a sample carrier unit 14 which has at least two cavities 20, 20a, 20b, 20c for receiving one sample 80a, 80b, 80c each, and one Detector unit 12 with at least two detector elements 68, 68a, 68b, 68c, 68'a, 68'b, 68'c for detecting radiation emanating from the marking substance. Each of the two detector elements 68, 68a, 68b, 68c, 68'a, 68'b, 68'c is assigned to one of the two cavities 20, 20a, 20b, 20c. The device 20 further comprises an evaluation unit 100 which, for each of the samples 80a, 80b, 80c, determines the presence and / or the amount of the marking substance depending on the amount determined by the two detector elements 68, 68a, 68b, 68c, 68'a, 68'b , 68'c determined for the respective sample 80a, 80b, 80c detected radiation.

Description

The invention relates to a device for detecting a marking substance in at least one sample. The invention also relates to a sample carrier unit which is suitable for use in a device according to the aforementioned type.

In the life sciences, marking substances, so-called tracers, are used in particular to carry out pharmacodynamic, chemical and metabolic studies of biological samples. The marking substances are mostly short-lived radionuclides or substances mixed with short-lived radionuclides. The radionuclides used as or in marking substances are mostly β ⁺ emitters, ie they disintegrate into another nuclide while emitting a positron. This positron annihilates on contact with any electron in the sample to form two photons with an energy of 511 keV each. Due to the conservation of momentum, these photons are emitted in exactly opposite directions.

The detection of such high-energy photons is complex. While particle radiation, for example α- and β-radiation, can be detected simply and precisely due to their interaction with matter, high-energy photons - also called γ-radiation in the following - can only be detected through attenuation over a longer distance. Since the γ-radiation generated by marking substances is caused by a nuclear disintegration process, i.e. a random process, measurements must also be carried out over a longer period of time in order to be able to make a reliable statement, for example about the amount of marking substance in a sample. Furthermore, the γ-radiation generated by marking substances is distributed isotropically, i.e. there is no preferred direction for the emission of the photons. This means that a detector must cover as large a solid angle as possible in order to enable a reliable measurement.

The aforementioned properties of radioactive labeling substances have hitherto prevented them from being used in highly automated laboratory methods, such as high-throughput screening, with the aid of which many samples can be examined in the shortest possible time. In such methods, so-called microtiter plates are often used as sample carriers, the dimensions of which are specified in the standards by the Society for Laboratory Automation and Screening ANSI / SLAS 1-2004 until ANSI / SLAS 4-2004 are normalized. Samples to be examined are arranged in microtiter plates in up to 3456 cavities arranged on one level. This closely spaced arrangement of the samples makes it difficult, in particular, to unambiguously assign a detected photon to a sample. This means that no reliable statement can be made about the presence or amount of radioactive labeling substances in the samples.

Out Nucl Instrum Methods Phys Res A. 2014 Dec 11; 767: 146-152 the so-called iQID camera (ionizing radiation quantum imaging detector) is known. The iQID camera is a high-resolution detector for ionizing radiation based on a scintillation element. The iQID camera was developed from a detector for use in single-photon emission computed tomography and is difficult or impossible to use in laboratory automation systems that are used in highly automated methods such as high-throughput screening.

Furthermore, arrangements for so-called positron emission tomography (PET) are known from the prior art. These arrangements include PET cameras arranged in a ring around a ring tunnel, also called a gantry, for detecting photons emitted in the event of a positron decay. The actual imaging takes place using a computer tomograph. PET arrangements are designed to determine the distribution of a radioactive marker substance in a human body and are correspondingly large and expensive. Furthermore, the resolution of the PET arrangements is not high enough to distinguish, for example, individual samples arranged in a microtiter plate. This means that PET arrangements are not suitable for use in laboratory automation systems either.

It is the object of the invention to provide a device by means of which a marking substance can be detected easily and reliably in at least one sample. It is also an object of the invention to specify a sample carrier unit for use in a device according to the aforementioned type.

The object is achieved by a device with the features of claim 1 and by a sample carrier unit with the features of the further independent claim. Advantageous further developments are given in the dependent claims.

The device for detecting a marking substance in at least one sample according to claim 1 comprises a sample carrier unit which has at least two cavities for receiving one sample each, and a detector unit with at least two detector elements for detecting radiation emanating from the marking substance. Each of the two detector elements is assigned to one of the two cavities. the The device further comprises an evaluation unit which determines the presence and / or the amount of the marking substance for each of the samples as a function of the radiation detected by the two detector elements for the respective sample.

The radiation emanating from the marking substance can be radiation which was emitted by the marking substance or which has passed through the marking substance. The radiation detected by the two detector elements can be electromagnetic radiation and / or particle radiation.

The device according to the invention has one detector unit for each cavity of the sample carrier unit. Since a sample is arranged in each cavity, the device according to the invention thus has one detector element for each sample to be examined. This allows the device to examine several samples simultaneously and independently of one another. This can significantly reduce the time required to examine the samples. By providing one detector element for each sample to be examined, a simple assignment of detection events registered by the detection elements to one of the samples to be examined is also possible. This means that the presence and / or the amount of the marking substance in the respective sample to be examined can be reliably determined. The device according to the invention thus enables the marking substance to be detected in at least one sample more quickly and more reliably than previously known.

The marking substance is in particular a radioactive marking substance, preferably a radionuclide or a substance which contains a radionuclide which decays with the emission of a positron. Alternatively, the marking substance can be a dye, preferably a fluorescent dye. In a further embodiment, the marking substance is a substance which absorbs electromagnetic radiation of at least one specific wavelength range.

In a preferred embodiment, the device has a further detector unit which has at least two detector elements. Each of the two detector elements is assigned to one of the two cavities. The two cavities can be arranged between the respectively assigned detector elements of the first detector unit and the further detector unit. It is advantageous if the evaluation unit is designed to determine the presence and / or the amount of the marking substance for each of the samples as a function of the radiation detected for the respective sample by the two detector elements assigned to the respective sample.

The provision of two detector elements per cavity of the sample carrier unit on the one hand increases the solid angle that is covered by a detector element for each sample to be examined. As a result, more detection events can be recorded by the detector elements for each sample to be examined. The more detection events that are recorded, the more reliably the presence and / or the amount of the marker substance in the sample to be examined can be determined. The arrangement in each case of a cavity of the sample carrier unit between the two detector elements assigned to the cavity also allows the properties of positron-emitting marking substances to be used in an advantageous manner. A positron emitted by the marking substance annihilates into two high-energy photons while still in the sample. Due to the conservation of momentum, these two high-energy photons are emitted in exactly opposite directions. This means that if the two detector elements assigned to a cavity detect a high-energy photon at the same time or in direct succession, that these photons can be assigned to the sample with a very high degree of probability. With the help of this so-called coincidence measurement, the presence and / or the amount of the marking substance in the respective sample to be examined can be determined even more reliably.

It is advantageous if a detection volume of the two detector elements of the detector unit and / or of the two detector elements of the further detector unit that is sensitive to the radiation emanating from the marking substance has a greater extent in the direction of a first direction than in the direction of a second direction, the first direction is parallel to a longitudinal axis of the cavity assigned to the respective detector element and the second direction is perpendicular to the first direction. The ratio between the extension of the two detector elements of the detector unit and / or the two detector elements of the further detector unit in the first direction and the extension of the two detector elements of the detector unit and / or the two detector elements of the further detector unit in the second direction is preferably between 10: 2 and 10: 4, particularly preferably 10: 3. For example, the detection area of the two detector elements of the detector unit and / or of the two detector elements of the further detector unit each have the dimensions 6 mm × 6 mm × 20 mm.

The detection of a high-energy particle or a high-energy photon by one of the detector elements takes place by slowing down the particle or by shifting the wavelength of the photon to a longer wavelength in the detection volume of the detector element and by converting the energy transmitted by the particle or photon to the detector element during this process into an electrical or optical signal . The longer the distance of the particle or photon to be detected through the detection volume, the more energy is deposited in the detector element by the particle. If more energy is deposited in the detector element by a photon, this particle or photon can be detected more reliably by the detector element. The above-described advantageous geometry of the two detector elements of the detector unit and / or of the two detector elements of the further detector unit increases the distance that a particle or photon emitted in one of the two cavities of the sample carrier unit in the detector unit and / or the detector units assigned to the cavity is increased. In other words, the advantageous geometry of the detection volume described above allows a more reliable detection of particles or photons that have been generated in one of the cavities of the sample carrier unit by the detector element or elements associated with this cavity.

The two detector elements of the detector unit and / or the two detector elements of the further detector unit preferably each have a greater extent in the direction of a first direction than in a second direction, the first direction pointing in the direction of the cavity assigned to the respective detector element and the second direction perpendicular to the first direction is.

It is advantageous if a radiation-attenuating element is arranged between the two detector elements of the detector unit and / or between the two detector elements of the further detector unit.

In the present application, a radiation-damping element is understood to mean an element whose half-value layer thickness for γ radiation with an energy of 511 keV is less than 70 mm. The half-value layer thickness of the radiation-damping element for γ radiation with an energy of 511 keV preferably has a value of 3.85 mm or more. In the present application, the half-value layer thickness of the element is that thickness of the irradiated element which reduces the radiation intensity by half.

High-energy photons and / or particles give off energy to this element when they pass through the radiation-damping element. This reduces the probability that the high-energy photon and / or the particle will be detected in more than one detector element of the detector unit or the further detector unit. By preventing this so-called crosstalk, the reliability with which the presence and / or the amount of the marking substances in the samples to be examined is determined is further increased. Alternatively or additionally, the known attenuation factor of the radiation-attenuating element can be used to assign two detection events, which are generated by a single photon and / or particle in a detector element of the detector unit and / or the further detector unit, to one another. This so-called coincidence measurement prevents multiple counting of individual photons and / or particles, which further increases the reliability of the detection.

To dampen ionizing radiation, the radiation-damping element can be made in particular from a non-radioactive material with a high mass and a high atomic number, in particular lead. The radiation-attenuating element can also be an optically non-transparent element.

In a preferred embodiment, the two detector elements of the detector unit and / or the two detector elements of the further detector unit each comprise at least one scintillator element, a gas ionization detector element or a semiconductor detector element.

In the present application, a scintillator element is understood to mean a body which brakes a continuous high-energy photon or a charged particle and converts the energy lost by the photon or the charged particle during this braking process into an optical signal. The optical signal can be converted into an electronic signal, for example by means of a photomultiplier.

In the present application, a gas ionization detector element is understood to mean any detector element in which a photon or a charged particle is detected with the aid of a gas-filled sensor. The gas ionization detector element is in particular a gas electron multiplier, also GEM (gas electron multiplier).

In the present application, a semiconductor detector element is understood to mean any detector element in which a photon or a charged particle is detected with the aid of a semiconductor detector or an array of semiconductor detectors. It is the semiconductor detector element in particular a CMOS or CCD element or a CMOS or CCD array.

In an alternative embodiment to this, the device comprises a laser light source for optically exciting the marking substance. The two detector elements of the detector unit are designed to detect detection light emanating from the optically excited marking substance. It is advantageous if the cavities are transparent, optically transparent or open in the direction of the respectively assigned detector elements for the radiation emitted by the marking substance. In this alternative embodiment, the marking substance is preferably a fluorescent dye which can be excited by means of laser light emitted by the laser light source to emit the detection light in the form of fluorescent light. In this embodiment, the detection light forms the radiation emanating from the sample. The use of fluorescent dyes as marking substance has the advantage over the use of radioactive marking substances that fluorescent dyes are much more gentle on the sample and no radioactive waste is produced when examining the samples.

In a preferred embodiment, the detector unit and / or the further detector unit each comprises 6, 12, 24, 48, 96, 384, 1536 or 3456 detector elements, each arranged in a grid of 2x3, 3x4, 4x6, 6x8, 8x12, 16x24, 32x48 or 48x72 detector elements are arranged. In this preferred embodiment, the arrangement of the detector elements of the detector unit and / or the further detector unit corresponds to the arrangement of cavities in a microtiter plate. This makes it possible to adapt the dimensions of the sample carrier unit to the dimensions of a microtiter plate. This makes it possible to use the sample carrier units in fully or at least partially automated laboratory automation systems, as in highly automated methods such as high throughput screening.

In a further preferred embodiment, the device comprises at least one positioning element for positioning and holding the sample carrier unit. The positioning element can be formed, for example, by dowel pins connected to the detector unit and in each case by a bore in the sample carrier unit assigned to a dowel pin. Alternatively, the sample carrier unit has dowel pins and the detector unit each have a bore assigned to a dowel pin. As a result, the sample carrier unit can be held reliably in the detector unit.

In a further preferred embodiment, the evaluation unit is designed to determine, on the basis of the radiation detected by the detector elements, a number of disintegration events that have taken place in the samples assigned to the detector elements, in order to then determine the amount of marking substance for on the basis of this determined number of disintegration events to determine the respective sample. The detector elements each cover only a small solid angle around the sample assigned to the detector elements, i.e. the detector elements can only detect radiation in a small solid angle around the respectively assigned sample. The number of decay events for each sample is therefore greater than the number of photons detected by the detector elements assigned to the sample. In this preferred embodiment, it is first determined for each sample how many decay events have taken place during a predetermined measurement period. On the basis of the actual number of decay events, the amount of the marking substance can then be determined very reliably.

Another aspect of the invention relates to a sample carrier unit which has at least two cavities for receiving samples. The sample carrier unit also has a radiation-damping element which is arranged between the two cavities.

In a preferred embodiment, the sample carrier unit has a base carrier and at least one insert element. The insert element comprises the two cavities and can be introduced into the base support and removed from the base support. Usually, the sample carrier unit is only used once to examine samples. This is to prevent mutual contamination of samples that are to be examined one after the other. In this preferred embodiment, the samples to be examined only come into contact with the at least one insert element. This at least one insert element can be disposed of separately from the base support. By designing the sample carrier unit as a unit formed from the base carrier and the at least one insert element, unnecessary waste can thus be avoided. In particular, the base support can be reused, i.e. used for several examinations with different insert elements.

It is advantageous if the base support forms the radiation-damping element, the radiation-damping element being arranged between the two cavities when the insert element is introduced into the base support. The radiation-damping element slows down high-energy photons and / or particles generated in the two cavities. This prevents high-energy photons and / or particles from one of the two cavities in the other of the two Get cavities. In this way, on the one hand, mutual contamination of the marking substance present in the samples is prevented. On the other hand, it is ensured in this way that the high-energy photons and / or particles leave the cavity only in the direction of the detector element (s) of the detector unit and / or the further detector unit which are each assigned to the cavity. By preventing this crosstalk, the reliability with which the presence and / or the amount of the marking substances can be determined in the samples arranged in the cavities is further increased.

In a preferred embodiment, the sample carrier unit has 6, 12, 24, 48, 96, 384, 1536 or 3456 cavities, which are each arranged in a grid of 2x3, 3x4, 4x6, 6x8, 8x12, 16x24, 32x48 or 48x72 cavities. In this preferred embodiment, the arrangement of the cavities of the sample carrier unit corresponds to the arrangement of cavities in a microtiter plate. This makes it possible to use the sample carrier units in fully or at least partially automated laboratory automation systems, such as these in highly automated methods that are used, for example, for high throughput screening. However, sample carrier units with up to 3456 or with another number of cavities customary for microtiter plates can also be advantageously used.

It is advantageous if the radiation-damping element is made of lead. Of all non-radioactive elements, lead is the element with the greatest atomic number and mass. This makes it particularly suitable for damping ionizing radiation.

It is advantageous if the sample carrier unit is a microtiter plate. As a result, the sample carrier unit can be used in connection with a large number of laboratory automation systems which are designed for the use of microtiter plates as sample carriers, for example pipetting robots, conveyor belts, incubators and / or washing devices.

It is advantageous if the sample carrier unit has a cover element for closing the two cavities. As a result, the samples arranged in the cavities are protected from environmental influences and mutual contamination during transport of the sample carrier unit and / or during an examination.

Further features and advantages emerge from the following description, which explains an exemplary embodiment in connection with the accompanying figures.

• 1 eine schematische isometrische Ansicht einer Vorrichtung zum Detektieren einer Markierungssubstanz in mindestens einer Probe gemäß einem Ausführungsbeispiel;
• 2 eine schematische isometrische Explosionsdarstellung einer Probenträgereinheit der Vorrichtung nach 1;
• 3 eine schematische perspektivische Schnittdarstellung eines Einlegeelements der Probenträgereinheit nach 2;
• 4 eine schematische isometrische Ansicht einer Detektoreinheit und einer Auswerteeinheit der Vorrichtung nach 1;
• 5a eine Untersicht der Detektoreinheit nach 4;
• 5b eine Aussparung eines Grundträgers der Detektoreinheit nach 5a;
• 6a eine Draufsicht eines Abdeckelements der Detektoreinheit nach den 4, 5a und 5b;
• 6b eine Schnittdarstellung des Abdeckelements entlang einer Schnittlinie B-B nach 6a;
• 7a eine Draufsicht eines Grundträgers der Detektoreinheit nach den 4, 5a und 5b;
• 7b eine Seitenansicht von rechts des Grundträgers nach 7a;
• 8a eine Untersicht eines Rahmenelements der Detektoreinheit nach 4;
• 8b eine Schnittdarstellung des Rahmenelements entlang einer Schnittlinie A-A nach 8a;
• 8c eine Draufsicht des Rahmenelements nach den 8a und 8b;
• 9 eine schematische Darstellung von Kavitäten der Probenträgereinheit und von Detektorelementen der Detektoreinheit der Vorrichtung nach 1;
• 10 ein Diagramm mit einer beispielhaften Zeitreihenmessung, die mit der Vorrichtung nach 1 durchgeführt wurde;
• 11 eine schematische isometrische Ansicht der Vorrichtung gemäß einem weiteren Ausführungsbeispiel; und
• 12 eine schematische Darstellung von Kavitäten der Probenträgereinheit und von Detektorelementen der Detektoreinheit der Vorrichtung nach 11.

Show it:

• 1 a schematic isometric view of a device for detecting a marking substance in at least one sample according to an embodiment;
• 2 a schematic isometric exploded view of a sample carrier unit of the device according to 1 ;
• 3 a schematic perspective sectional illustration of an insert element of the sample carrier unit according to FIG 2 ;
• 4th a schematic isometric view of a detector unit and an evaluation unit of the device according to FIG 1 ;
• 5a a bottom view of the detector unit 4th ;
• 5b a recess in a base support of the detector unit 5a ;
• 6a a plan view of a cover element of the detector unit according to FIGS 4th , 5a and 5b ;
• 6b a sectional view of the cover element along a section line BB according to 6a ;
• 7a a plan view of a base support of the detector unit according to the 4th , 5a and 5b ;
• 7b a side view from the right of the base support 7a ;
• 8a a bottom view of a frame element of the detector unit according to 4th ;
• 8b a sectional view of the frame element along a section line AA according to 8a ;
• 8c a plan view of the frame member according to the 8a and 8b ;
• 9 a schematic representation of cavities of the sample carrier unit and of detector elements of the detector unit of the device according to FIG 1 ;
• 10 a diagram with an exemplary time series measurement made with the device according to 1 was carried out;
• 11 a schematic isometric view of the device according to a further embodiment; and
• 12th a schematic representation of cavities of the sample carrier unit and of detector elements of the detector unit of the device according to FIG 11 .

1 Figure 3 shows a schematic isometric view of a device 10 for detecting a marker substance in at least one sample according to an embodiment. The device 10 has a detector unit 12th , a sample carrier unit 14th and another detector unit 16 .

The sample carrier unit 14th is between the detector unit 12th , hereinafter also the first detector unit 12th called, and the further detector unit 16 , hereinafter also the second detector unit 16 called, arranged. The device 10 thus has a sandwich-like structure in which the sample carrier unit 14th from above and below one of the two detector units 12th , 16 contacted. The two detector units 12th , 16 are with an evaluation unit 100 connected, which the first detector unit 12th from above and the second detector unit 16 contacted from below. In an alternative embodiment, the evaluation unit is designed as a separate element that is connected to the first detector unit 12th and the second detector unit 16 for example connected by cable.

The sample carrier unit 14th is used below in connection with the 2 and 3 described in more detail. The two detector units 12th , 16 are described below in connection with the 4th until 8c described in more detail.

2 shows a schematic isometric exploded view of the sample carrier unit 14th the device 10 to 1 . In the representation after 2 hidden elements are shown by dashed lines. The same element or elements with the same function are denoted by the same reference symbols.

The sample carrier unit 14th has an insert element 18th , a cover element 22nd , a basic carrier 24 and a frame member 26th . The insert element 18th comprises 96 cavities, which are used to arrange samples and which are referred to below with the common reference number 20th are designated. The cavities 20th are in twelve rows of eight cavities each 20th arranged. The cavities 20th are in the embodiment shown, for example, designed as cylinders, the longitudinal axis of which extends from bottom to top. Alternatively, the cavities could 20th also through recesses in the insert element 18th be educated. Also need the cavities 20th not be cylindrical. It is also conceivable that the cavities are designed in any other geometry that is compatible with the functionality, for example cuboid or conical. In the embodiment shown according to 2 are the cavities 20th open at the top and closed at the bottom. The insert element 18th also has one of the cavities 20th surrounding wall 28 and is based on the 3 described in more detail below.

The cover element 22nd serves to cover and / or close the cavities 20th of the insert 18th . For this purpose, the cover element 22nd from above onto the insert element 18th be put on. The cover element 22nd is made of a transparent material, for example an acrylic glass.

The basic carrier 24 is in the embodiment shown a solid cuboid made of lead, which has a total of 96 recesses extending from bottom to top, which are referred to below with the common reference number 30th are designated. These cutouts 30th are so complementary to the cavities in their dimensions and in their arrangement 20th of the insert 18th formed that each has a recess 30th a cavity 20th is assigned and each has a cavity 20th into a recess 30th is insertable when the insert element 18th with the basic carrier 24 is connected. The insert element 18th can hereby in such a way with the base support 24 be connected that between each two of the cavities 20th a radiation-absorbing element 32 is arranged by the base support 24 is formed.

The frame element 26th has through a surrounding wall 34 formed recess 36 for preferably flush mounting of the base support 24 . The basic carrier 24 can be inserted into the recess from above 36 of the frame element 26th can be used. The recess 36 of the frame element 26th is from below through a base plate 38 limited. This floor slab 38 knows holes, which are referred to below with the common reference numerals 40 are designated. These holes 40 correspond in their arrangement to the recesses 30th of the basic carrier 24 and the cavities 20th of the insert element 18th . Every hole 40 is exactly one recess 30th of the basic carrier 24 and a cavity 20th of the insert element 18th assigned. As an alternative or in addition, the base plate 38 transparent for radiation to be detected and / or for radiation to be supplied to the sample.

In an assembled state of the sample carrier unit 14th is the basic carrier 24 from above into the recess 36 of the frame element 26th inserted so that the base support 24 from the surrounding wall 34 of the frame element 26th is enclosed. The insert element 18th is from above on the roof bars 24 and the frame element 26th placed in such a way that between each two of the cavities 20th of the insert element 18th one of the radiation-absorbing elements 32 of the basic carrier 24 is arranged. It encloses the wall 28 of the insert element 18th both the basic carrier 24 as well as the frame element 26th Completely. The cover element 22nd is from above on the insert element 18th put on and thus closes the cavities 20th of the insert element 18th . One of the cavities each 20th and one each of the holes 40 of the frame element 26th align such that an observation one in the cavity 20th arranged sample from below through the hole 40 is possible.

The sample carrier unit 14th in the embodiment according to 2 When assembled, has the dimensions of a microtiter plate, the dimensions of which are specified in the standards by the Society for Laboratory Automation and Screening ANSI / SLAS 1-2004 until ANSI / SLAS 4-2004 are normalized. Since the dimensions of the sample carrier unit 14th essentially through the insert element 18th are defined, also has the insert element 18th in itself the dimensions of a microtiter plate. This is both the assembled sample carrier unit 14th as a whole as well as the insert element 18th with or without the attached cover element 22nd Can be used in most laboratory automation systems, as these are often designed for the use of microtiter plates as sample carriers.

3 shows a schematic perspective sectional illustration of an insert element 18th the sample carrier unit 14th to 2 . The cutting plane lies in 3 parallel to one long side of the insert element 18th .

The insert 18th includes a plate 42 at the edges of which is the surrounding wall 28 extends downwards. The cavities 20th are as down from the plate 42 protruding hollow cylindrical body 21 formed. On top of the plate 42 is a circumferential edge 44 educated. Each of the hollow cylindrical bodies 21 is through a circular bottom from below 46 closed and is open at the top. In 3 is an example of one of the longitudinal axes of the hollow cylindrical body 21 shown and with the reference number A. designated. The plate 42 who have favourited cavities 20th and the surrounding wall 28 define a cavity 48 , in which the basic carrier 24 can be included.

In the embodiment according to 3 is the insert 18th made in one piece from a transparent plastic.

4th shows a schematic isometric view of the first detector unit 12th and the evaluation unit 100 the device 10 to 1 . The first detector unit 12th comprises a frame element 50 and a cover element 52 . The cover element 52 contacts the frame element 50 from below and is by means of fasteners 54 releasably connected to this. The cover element 52 can thus from the frame element 50 can be removed, thereby providing access to the inside of the frame element 50 arranged elements is enabled, the following in connection with the 5a and 5b are described in more detail below. The evaluation unit 100 is in the embodiment shown above the first detector unit 12th arranged.

The first detector unit 12th and the second detector unit 16 have the same or equivalent elements and are functionally identical. The two detector units 12th , 16 are each aligned in such a way that the cover element 52 each in the direction of the sample carrier unit 14th shows. This means that the cover element 52 the first detector unit 12th on an underside of the first detector unit 12th is arranged. The cover element of the second detector unit 16 is correspondingly on an upper side of the second detector unit 16 arranged.

5a shows a bottom view of the first detector unit 12th to 4th without the cover element 52 . The frame element 50 includes a circumferential wall 56 who have a basic carrier 58 encloses. On the bottom, i.e. in 5a the side facing the viewer is a circumferential to the base support 58 facing fold 60 educated. In this fold 60 can the cover 52 preferably be recorded flush. The surrounding wall 56 also has four holes 62 for receiving the fasteners 54 through which the cover element 52 with the frame element 50 is releasably connected.

The basic carrier 58 the first detector unit 12th has 96 recesses 64 that are arranged in twelve rows with eight recesses each 64 are arranged. These cutouts 64 are designed to each receive one of 96 detector elements that are in the 5b and 9 shown by way of example and there with the reference numerals 68 , 68a , 68b , 68c are designated. In the embodiment shown, the base support is 58 designed as a monolithic component made of lead.

5b shows one of the recesses 64 of the basic carrier 58 the first detector unit 12th . The recess 64 has a square cross-section, with the corners of the cross-section having a circular cut 66 exhibit. In the recess 64 is a detector element 68 of the detector elements of the first detector unit 12th arranged. In 5b is the position of one of the cavities by a dashed line 20th the sample carrier unit 14th relative to the recess 64 shown when the device 10 in the in 1 is the composite state shown. In the assembled state of the device 10 , one longitudinal axis is aligned in each case B. the recess 64 of the basic carrier 58 the first sample carrier unit 12th with one of the longitudinal axes A. one of the cavities 20th the sample carrier unit 14th . The two longitudinal axes A. , B. are in the representation according to 5b perpendicular to the image plane.

6a shows a top view of the cover element 52 the first detector unit 12th to 4th . The cover element 52 includes a plate 70 made of a transparent material such as acrylic glass. This record 70 has four holes 72 that with the holes 62 the surrounding wall 56 align when the cover element 52 in the fold 60 of the frame element 50 is arranged. The fasteners 54 can through the holes 72 the flap 70 are guided to the cover element 52 and the frame element 50 the first detector unit 12th releasably connect. In other embodiments, there can also be more or fewer holes in the cover element 52 be present or no hole. Alternatively or additionally, other connecting means, such as a latching element, can be used to connect the cover element 52 with the frame element 50 the first detector unit 12th can be used.

6b shows a sectional view of the cover element 52 to 6a along the section line BB. The cutting plane runs through two of the holes 72 .

7a shows a top view of the base support 58 the first detector unit 12th to 4th . Between every two of the recesses 64 and thus between two detector elements 68 is a bar-shaped radiation-absorbing element 74 educated. The side edges 76 of the basic carrier 58 are rounded.

7b shows a side view from the right of the base support 58 to 7a . The basic carrier 58 is rectangular when viewed from the side.

8a shows a bottom view of the frame element 50 the first detector unit 12th to 4th . The frame element 50 has a base plate 78 who have favourited 96 holes 80 having. The surrounding wall 56 and the bottom plate 78 define a recess 82 of the frame element 50 for preferably flush mounting of the base support 58 . The holes 80 the base plate 78 are arranged in such a way that each has a hole 80 the base plate 78 of the frame element 50 with one of the cutouts 64 of the basic carrier 78 aligns when the base support 58 in the recess 82 of the frame element 50 is recorded. Through the holes 80 the base plate 78 can in particular cables for connecting one detector element in each case 68 with the evaluation unit 100 be guided.

8b shows a sectional view of the frame element 50 to 8a along the section line AA. The frame element 50 has a rectangular cross-section. In the embodiment shown, the holes are 62 for example designed as bores with an internal thread for receiving screws. In the embodiment shown, these screws form the fastening means 54 for releasable connection of the cover element 52 with the frame element 50 . In the present embodiment, countersunk head screws in particular are used as fastening means, the heads of which are in the chamfered holes 72 be recorded flush.

8c Figure 3 shows a top view of the frame member 50 after the 8a and 8b . The underside of the frame element 50 is through the bottom plate 78 educated.

9 shows a schematic representation of cavities 20a , 20b , 20c the sample carrier unit 14th , of detector elements 68a , 68b , 68c the first detector unit 12th the device 10 to 1 and from detector elements 69a , 69b , 69c the second detector unit 16 the device 10 to 1 . Between every two of the cavities 20a , 20b , 20c one of the radiation-damping elements 32a, 32b is arranged. In each of the cavities 20a , 20b , 20c a sample 80a, 80b, 80c is included. The samples 80a, 80b, 80c are each in an embedding medium 82 embedded and each comprise a radioactive marker substance. In the embodiment shown, this radioactive marking substance is a radionuclide which decays radioactively with the emission of a positron. This positron annihilates with any electron to form two photons with an energy of 511 keV each. In 9 five such photons are shown by way of example and are given the reference numerals 84a to 84g designated. Due to the conservation of momentum, the two photons that are generated when the positron is annihilated with the electron are emitted in exactly opposite directions. This is in 9 using two photons as an example 84e , 84f shown. The location within the sample 80c at which the positron is annihilated with the electron is in 9 marked by an X. The two photons 84e , 84f are almost simultaneously in one detector element each 68c the first detector unit 12th and a detector element 69c the second detector unit 16 detected. This means that these two photons 84e , 84f with high reliability of the sample 80c, to that of the two detector elements 68c , 69c assigned cavity 20c can be assigned.

If a photon 84c passes through a radiation-attenuating element 32a of the sample carrier unit 14th , this photon 84c is attenuated. This means that the photon 84c gives off part of its energy to the radiation-attenuating element 32a. If this photon 84c hits a detector element 68a the first detector unit 12th , it deposits less energy there than a photon 84a , 84b, which is in one of the detector element 68a assigned cavity 20a was issued. Thus, the photons 84a , 84b, which is in the detector element 68a assigned cavity 20a were emitted, can be distinguished from the photon 84c, which is in a further cavity 20b generated by another detector element 68b assigned.

Between every two of the detector elements 68a , 68b , 68c , 69a , 69b , 69c is one by the basic carrier 58 the first or second detector unit 12th , 16 formed radiation-attenuating element 74a , 74b , 75a , 75b arranged. The radiation-absorbing elements 74a , 74b , 75a , 75b prevent any of the photons 84a until 84f into a first of the detector elements 68a , 68b , 68c , 69a , 69b , 69c enters, exits from this again, into a further detector element of the detector elements 68a , 68b , 68c , 69a , 69b , 69c enters and is detected there. In other words: the radiation-absorbing elements 74a , 74b , 75a , 75b prevent a photon 84a until 84f in more than one of the detector elements 68a , 68b , 68c , 69a , 69b , 69c is detected.

10 shows a flowchart of a sequence for determining the presence and / or the amount of the marking substance by means of the device 10 .

The process is started in step S10. Then in step S12 by means of the detector elements 68a , 68b , 68c , 69a , 69b , 69c of the two detector units 12th , 16 detects the radiation emanating from the samples 80a, 80b, 80c during a predetermined measurement period. Each high-energy photon of the radiation emanating from the samples 80a, 80b, 80c that passes through one of the detector elements 68a , 68b , 68c , 69a , 69b , 69c is detected, generates a detector event that is detected by the evaluation unit 100 is further processed. The detector event includes the information about which of the detector elements 68a , 68b , 68c , 69a , 69b , 69c the photon has captured and how much energy the photon has in the detector element 68a , 68b , 68c , 69a , 69b , 69c deposited, ie on the detector element 68a , 68b , 68c , 69a , 69b , 69c has submitted.

The detector elements 68a , 68b , 68c , 69a , 69b , 69c only a small area of the solid angle around that of the detector element 68a , 68b , 68c , 69a , 69b , 69c respectively assigned sample 80a, 80b, 80c, ie the detector elements 68a , 68b , 68c , 69a , 69b , 69c can only detect radiation in a small solid angle range around the respectively assigned sample 80a, 80b, 80c. It is therefore necessary not to pass through the detector elements 68a , 68b , 68c , 69a , 69b , 69c to reconstruct detected decay events in samples 80a, 80b, 80c. This takes place in step S14. This can be done in particular with the help of sparse recovery algorithms, such as those in Laurent Jacques, Jason N. Laska, Petros T. Boufounos, and Richard G. Baraniuk . Robust 1-bit compressive sensing via binary stable embeddings of sparse vectors. IEEE Trans. Inf. Theor., 59 (4): 2082 {2102, April 2013 and Yaniv Plan and Roman Vershynin . Robust 1-bit compressed sensing and sparse logistic regression: A convex programming approach. IEEE Trans. Inf. Theor., 59 (1): 482 {494, January 2013 . An example of a sparse recovery algorithm is shown in formula (1): $$f^{\#}=\underset{z\in T}{{\displaystyle \text{Max}}}y\cdot \mathrm{A.}z-\frac{1}{\lambda }{\Vert z\Vert }_2^2$$

Here, f ^{# is} a so-called estimator, ie a vector that describes with a statistically significant probability all decay events that have occurred in one of the samples 80a, 80b, 80c during the measurement period, y is a vector that describes all of the detector events of the Detector element assigned to sample 80a, 80b, 80c 68a , 68b , 68c , 69a , 69b , 69c describes, and A is a matrix of the dimension m × N, which describes the measurement process. Furthermore, T is a convex hull of a union of subspaces of the vector space ℝ ^N , which represents a simple model of the signal structure of f, and λ is an optimization parameter. A solution to the algorithm described in formula (1) can be found effectively, in particular with internal point methods. In particular, it can be reliably determined for the algorithm described in formula (1) how many detector events are for each detector element 68a , 68b , 68c , 69a , 69b , 69c must be recorded in order to obtain a reliable statement about the number of decay events in the detector element 68a , 68b , 68c , 69a , 69b , 69c to be able to make respectively assigned samples 80a, 80b, 80c. If, for example, s decay events are expected for the sample 80a, 80b, 80c to be examined, it is sufficient to acquire s · polylog (N) entries of the vector y in order to be able to make a statistically significant statement about the decay events that occurred in the sample during the measurement period 80a, 80b, 80c have taken place.

In step S16, the amount of marker substance present in samples 80a, 80b, 80c is then determined on the basis of the number of decay events previously determined in step S14 that took place in samples 80a, 80b, 80c during the measurement period. In order to be able to determine the amount of the marking substance present in one of the samples 80a, 80b, 80c, it must be known how the number of decay events in this sample 80a, 80b, 80c is related to the amount of the marking substance. The relationship between the number of disintegration events and the amount of marking substance depends on the one hand on the marking substance used itself, in particular on the activity of the marking substance. On the other hand is this one Relationship depends on the sample, for example on a cell culture used in the sample. This relationship can, for example, in the evaluation unit 100 the device 10 be stored preset and in particular manually by an operator in the device 10 can be entered.

In particular, however, it is also possible for a large number of such relationships for different marking substances and samples to be determined in advance and in the form of a functional relationship in a memory element of the evaluation unit 100 get saved. These functional relationships can then be checked by the evaluation unit 100 can be queried and used to determine the amounts of the marking substance in the sample 80a, 80b, 80c to be examined. In particular, this multitude of relationships can be in the form of a multitude of polynomial, preferably linear or quadratic, functions in the storage element of the evaluation unit 100 get saved. However, it is also possible for this multitude of relationships to be stored in the memory element as a multitude of neural networks. The process is finally ended in step S18.

11 Figure 3 shows a schematic isometric view of the device 10 ' for detecting the marking substance in the at least one sample according to a further exemplary embodiment. The device 10 ' to 11 differs from the device 10 to 1 essentially in that the device 10 ' to 11 only a single detector unit 12 ' Has. Identical or equivalent elements are in the 1 and 11 denoted by the same reference numerals.

12th shows a schematic representation of cavities 20a , 20b , 20c the sample carrier unit 14th , of detector elements 68'a, 68'b, 68'c of the detector unit 12 ' the device 10 ' to 11 . Identical or equivalent elements are in the 9 and 11 denoted by the same reference numerals.

List of reference symbols

10, 10 '

contraption

12, 12 '

Detector unit

14th

Sample carrier unit

16

Detector unit

18th

Insert element

20, 20a, 20b, 20c

cavity

22nd

Cover element

24

Basic carrier

26th

Frame element

28

wall

30th

Recess

32

Radiation damping element

34

wall

36

Recess

38

Base plate

40

hole

42

plate

44

edge

46

floor

48

cavity

50

Frame element

52

Cover element

54

Fasteners

56

wall

58

Basic carrier

60

Fold

62

hole

64

Recess

66

Removal

68, 68a, 68b, 68c, 68'a, 68'b, 68'c, 69a, 69b, 69c

Detector element

70

plate

72

hole

74, 74a, 74b, 75a, 75b

Radiation damping element

76

Edge

78

Base plate

80

hole

82

Recess

84a to 84g

photon

100

Evaluation unit

AWAY

Longitudinal axes

QUOTES INCLUDED IN THE DESCRIPTION

This list of the documents listed by the applicant was generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Non-patent literature cited

• ANSI / SLAS 1-2004 [0004, 0048]
• ANSI / SLAS 4-2004 [0004, 0048]
• Nucl Instrum Methods Phys Res A. 2014 Dec 11; 767: 146-152 [0005]
• This can be done in particular with the aid of sparse recovery algorithms, as described, for example, in Laurent Jacques, Jason N. Laska, Petros T. Boufounos, and Richard G. Baraniuk [0069]
• Robust 1-bit compressive sensing via binary stable embeddings of sparse vectors. IEEE Trans. Inf. Theor., 59 (4): 2082 {2102, April 2013 and Yaniv Plan and Roman Vershynin [0069]
• Robust 1-bit compressed sensing and sparse logistic regression: A convex programming approach. IEEE Trans. Inf. Theor., 59 (1): 482 {494, January 2013 are [0069]

Claims (15)

Device (10, 10 ') for detecting a marker substance in at least one sample (80a, 80b, 80c) with a sample carrier unit (14) which has at least two cavities (20, 20a, 20b, 20c) for receiving one sample (80a, 80b, 80c) each, with a detector unit (12, 12 ') with at least two detector elements (68, 68a-68c, 68'a-68'c) for detecting radiation emanating from the marking substance, wherein each of the two detector elements (68, 68a-68c, 68 'a - 68'c) is assigned to one of the two cavities (20, 20a, 20b, 20c), and with an evaluation unit (100) which, for each of the samples (80a, 80b, 80c), determines the presence and / or the amount of the marking substance as a function of the amount determined by the two detector elements (68, 68a-68c, 68'a-68'c) for the respective sample (80a, 80b, 80c) detected radiation is determined. Device (10) according to Claim 1 , characterized by a further detector unit (16) which has at least two detector elements (69a-69c), each of the two detector elements (69a-69c) being assigned to one of the two cavities (20, 20a, 20b, 20c) and the two Cavities (20, 20a, 20b, 20c) can be arranged between the detector elements (68, 68a-68c, 68'a-68'c, 69a-69c) of the first detector unit (12) and the further detector unit (16) assigned to them . Device (10) according to Claim 2 , characterized in that the evaluation unit (14) 100 is designed for each of the samples (80a, 80b, 80c) the presence and / or the amount of the marking substance depending on the amount determined by the two detector elements (68, 68a-68c, 68'a - 68'c, 69a-69c), which are assigned to the respective sample (80a, 80b, 80c), to determine the detected radiation for the respective sample (80a, 80b, 80c). Device (10, 10 ') according to one of the preceding claims, characterized in that a detection volume of the two detector elements (68, 68a-68c, 68'a-68'c) of the detector unit (12, 12 ') and / or the two detector elements (69a-69c) of the further detector unit (16) each have a greater extent in the direction of a first direction than in the direction of a second direction, the first direction being parallel to a longitudinal axis (A) of the respective detector element (68, 68a-68c, 68'a-68'c, 69a-69c) associated cavity (20, 20a, 20b, 20c) and the second direction is perpendicular to the first direction. Device (10, 10 ') according to one of the preceding claims, characterized in that between the two detector elements (68, 68a-68c, 68'a-68'c) of the detector unit (12, 12') and / or between the two Detector elements (69a-69c) of the further detector unit (16) a radiation-damping element (74, 74a, 74b, 75a, 75b) is arranged. Device (10, 10 ') according to one of the preceding claims, characterized in that the two detector elements (68, 68a - 68c, 68'a - 68'c) of the detector unit (12, 12') and / or the two detector elements ( 69a-69c) of the further detector unit (16) each comprise at least one scintillator element, a gas electron multiplier element or a semiconductor detector element. Device (10, 10 ') according to one of the Claims 1 until 5 , characterized by a laser light source for optically exciting the marking substance, the two detector elements (68, 68a-68c, 68'a-68'c) of the detector unit (12, 12 ') being designed to detect detection light emanating from the optically excited marking substance . Device (10, 10 ') according to one of the preceding claims, characterized in that the cavities (20, 20a, 20b, 20c) in the direction of the respectively assigned detector elements (68, 68a-68c, 68'a-68'c, 69a - 69c) are each transparent, optically transparent or open for the radiation emitted by the marking substance. Device (10, 10 ') according to one of the preceding claims, characterized in that the detector unit (12, 12') and / or the further detector unit (16) each have 6, 12, 24, 48, 96, 384, 1536 or 3456 Detector elements (68, 68a - 68c, 68'a - 68'c, 69a - 69c) each in a grid of 2x3, 3x4, 4x6, 6x8, 8x12, 16x24, 32x48 or 48x72 detector elements (68, 68a - 68c, 68'a - 68'c, 69a - 69c) are arranged. Device (10, 10 ') according to one of the preceding claims, characterized by at least one positioning element for positioning and holding the sample carrier unit (14). Device (10, 10 ') according to one of the preceding claims, characterized in that the evaluation unit (100) is designed on the basis of the data provided by the detector elements (68, 68a-68c, 68'a-68'c, 69a-69c) detected radiation to determine a number of decay events that have occurred in the samples (80a, 80b, 80c) respectively assigned to the detector elements (68, 68a-68c, 68'a-68'c, 69a-69c), and on the basis of this determined number of disintegration events to determine the amount of marking substance for the respective sample (80a, 80b, 80c). Sample carrier unit (14) for use in a device (10, 10 ') according to one of the preceding claims, with at least two cavities (20, 20a, 20b, 20c) for receiving samples (80a, 80b, 80c) and with a radiation-damping element (32a, 32b), which is arranged between the two cavities (20, 20a, 20b, 20c). Sample carrier unit (14) according to one of the preceding claims, characterized in that the sample carrier unit (14) has a base carrier (24) and at least one insert element (20), the insert element (20) having the two cavities (20, 20a, 20b, 20c ) and wherein the insert element (20) can be introduced into the base support (24) and removed from the base support (24). Sample carrier unit (14) after Claim 13 , characterized in that the base support (24) forms the radiation-damping element (32a, 32b), the radiation-damping element (32a, 32b) being arranged between the two cavities (20, 20a, 20b, 20c) when the insert element (20 ) is introduced into the base support (24). Sample carrier unit (14) according to one of the preceding claims, characterized in that the sample carrier unit (14) has 6, 12, 24, 48, 96, 384, 1536 or 3456 cavities (20, 20a, 20b, 20c), each in one Grid of 2x3, 3x4, 4x6, 6x8, 8x12, 16x24, 32x48 or 48x72 cavities (20, 20a, 20b, 20c) are arranged.

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