Diagnostic system for the analysis of biological samples

Abstract

The invention relates to a diagnostic system for analyzing biological samples (P), comprising a sample cartridge (1; 1a) which has an analysis body (35), in particular in the form of a Si chip (36; 36a) for the biological sample (P), preferably with an analysis device (40) for analyzing the biological sample (P), and with a heating device (30; 30a) for heating the biological sample (P) in the area of ​​the analysis body (35), wherein the heating device (30; 30a) and preferably the analysis device (40) are part of a diagnostic device (10) separate from the sample cartridge (1; 1a).

Description

Technical area

[0001] The invention relates to a diagnostic system for analyzing biological samples using a mobile diagnostic device, wherein the analysis involves amplification of DNA strands using the polymerase chain reaction (PCR). State of the art

[0002] A diagnostic system for analyzing biological samples known by the applicant's name Vivalytic® is known. This known diagnostic system enables the fully automated testing of various types of patient samples (e.g., oral swabs). The diagnostic device handles sample preparation, analysis, and evaluation. During the analysis, the patient sample is placed in a diagnosis-specific sample container, a so-called sample cartridge, which is inserted into the diagnostic device. The diagnostic device then carries out fully automated testing of the biological sample, for example, using a PCR test. Typically, the biological sample is heated and cooled several times to achieve amplification of DNA strands. The biological sample is typically heated using a heating device that heats the sample in contact with the cartridge.

[0003] From DE 10 2021 203 922 A1 of the applicant, a sample cartridge is known with a base body made of plastic, which forms an analysis chamber in which a medium, for example a patient sample, is arranged.

[0004] DE 10 2006 010 959 A1 discloses a device for detecting biochemical target molecules, in which a chip suitable for detecting biomolecules to be detected is arranged on a base of a connecting element.

[0005] Furthermore, DE 10 2016 213 412 A1 by the applicant discloses a device for coupling (laser) light into a semiconductor using surface emitters (VCSELs = vertical cavity surface emitting lasers). The device known from the cited document serves, for example, as a component of optical sensors for substance detection or concentration determination of gases and liquids. Disclosure of the invention

[0006] The diagnostic system according to the invention for analyzing biological samples with the features of claim 1 has the advantage that it specifically, i.e. locally, heats the region of the sample cartridge relevant for the replication of the DNA strands in the region of its analysis body (Si chip). This has the advantage that the material of the sample cartridge surrounding the analysis body is not heated, which facilitates and accelerates temperature regulation, particularly when carrying out repeated temperature changes. In particular, this reduces the inertia that typically occurs when the material of the sample cartridge (plastic) is also heated. In other words, this means that the diagnostic system according to the invention makes it possible to heat at least substantially only the analysis body or regions of the analysis body containing the patient sample.Furthermore, the diagnostic system according to the invention has the advantage of enabling good accessibility to the sample cartridge so that it can be analyzed or monitored, for example, using suitable means.

[0007] The invention is based on the idea of ​​designing the heating device in the form of a radiation device, wherein the material of the analysis body (Si chip) is matched to the wavelength of the radiation, in particular laser radiation, in such a way that the analysis body is designed to absorb the generated radiation. As a result, the heat input takes place at least substantially entirely in the material of the analysis body. This enables not only particularly rapid heating, but also relatively rapid cooling, as is desirable to reduce the process time when carrying out multiple temperature changes, since the material of the sample cartridge surrounding the analysis body, which has not been heated, enables good heat transfer and rapid cooling of the analysis body as soon as the heating device is switched off.Furthermore, a distance can be formed between the radiation device and the sample cartridge, which allows additional installation space or an advantageous arrangement of the components of the diagnostic device.

[0008] Against the background of the above explanations, the diagnostic system according to the invention for analyzing biological samples with the features of claim 1 therefore comprises a sample cartridge. Furthermore, an analysis body, in particular in the form of a Si chip, for the biological sample and preferably an analysis device for analyzing the biological sample are provided. A heating device serves to heat the biological sample in the region of the analysis body, wherein the heating device and preferably the analysis device are components of a diagnostic device separate from the sample cartridge, wherein the diagnostic device preferably has a receiving opening for inserting the sample cartridge, wherein the heating device is designed in the form of a radiation device, and wherein the material of the analysis body is designed to absorb the radiation generated by the radiation source.

[0009] Advantageous further developments of the diagnostic system according to the invention for analyzing biological samples are listed in the subclaims.

[0010] Preferably, the radiation device is arranged on the side of the analysis body facing away from the analysis device, at least partially, preferably completely overlapping the analysis body, such that the radiation from the radiation device impinges at least partially, preferably completely, at right angles on the essentially flat analysis body. This allows the analysis device to be very easily arranged on the side facing away from the radiation device. Furthermore, homogeneous heating of the analysis body is enabled with a small lateral extension and a compact design of the radiation device.

[0011] In an alternative embodiment, however, it can also be provided that the radiation device is arranged on the side of the analysis body facing away from the analysis device, preferably overlapping the analysis body at least partially, such that the radiation from the radiation device impinges at least partially, preferably completely, on the essentially flat analysis body at an oblique angle. This allows for additional installation space for arranging a component arranged in overlap with the analysis body.

[0012] In a preferred design embodiment of the latter radiation device, the radiation device comprises at least two sub-elements arranged laterally next to a component, in particular an optical component, wherein the optical component is arranged in overlap with the analysis body. The at least two sub-elements promote uniform or homogeneous heating of the analysis body.

[0013] It is preferred to design the radiation device in the form of a VCSEL array. Such a radiation device allows for a particularly simple and advantageous adaptation of the radiation to the materials of the cartridge or base body, as well as the analysis body. Furthermore, it is compact.

[0014] There are also different options regarding the design of the sample cartridge. In a first possible embodiment, the sample cartridge comprises a base body comprising plastic, in particular made of plastic, in which an analysis chamber is formed. The base body surrounds the analysis body within the analysis chamber, and the material of the plastic of the base body in the region of the analysis chamber is adapted to the radiation generated by the radiation device in such a way that the material of the plastic is transparent to the radiation.

[0015] In an alternative embodiment of the sample cartridge, it is provided that the sample cartridge has a base body comprising plastic, in particular consisting of plastic, in which an analysis chamber is formed, wherein the base body has an opening on the side facing the radiation device, which opening is covered by the analysis body, and wherein the analysis chamber is sealed in the region of the opening by the analysis body.

[0016] Preferably, the analysis body has a thickness that corresponds at least approximately, preferably exactly, to the absorption length of the material of the analysis body at the wavelength of radiation generated by the radiation source. "Approximately" can be understood to mean that the thickness of the analysis body, or alternatively, the wavelength value, is selected such that the thickness value deviates from the absorption length value by no more than 10%, preferably no more than 5%. This optimizes the energy or heat input into the analysis body.

[0017] In particular, the analysis body is designed as a Si chip with a thickness between 0.7 mm and 1.2 mm, preferably between 0.9 mm and 1.0 mm, wherein the wavelength of the radiation is approximately 1060 nm. For example, the wavelength lies in a window of 980 nm + / - 10% or + / - 5%. Alternatively, the analysis body is designed as a Si chip with a thickness between 50 µm and 400 µm, preferably between 100 µm and 200 µm, wherein the wavelength of the radiation is approximately 980 nm. For example, the wavelength in this case lies in a window of 980 nm + / - 10% or + / - 5%. In other words, this means that by appropriately matching the thickness of the Si chip and the wavelength of the radiation, it is possible to select the penetration depth of the radiation into the Si chip such that the chip is heated at least approximately across its entire height or thickness.

[0018] In particular, for controlling the radiation device or for carrying out several temperature cycles, it is provided that a preferably optically operating temperature measuring device is provided for detecting the temperature of the analysis body and / or the biological sample.

[0019] Alternatively, the temperature can also be recorded by having the analysis body with a temperature measuring device based on voltage or resistance measurement.

[0020] In order to improve the absorption of the radiation, it can further be provided that the analysis body is provided with an anti-reflection coating, in particular with a SiN layer, on the side facing the radiation device, preferably on the side of the analysis body facing away from the biological sample.

[0021] In addition, it can be provided that the analysis body is formed with a coating or similar that increases the absorption of radiation.

[0022] Further advantages, features and details of the invention will become apparent from the following description of preferred embodiments of the invention and from the drawings. Short description of the drawings Fig. 1 shows the essential components of a diagnostic system in a simplified representation, Fig. 2 a patient sample being transferred to a sample cartridge of the diagnostic system in perspective view, Fig. 3 a part of a diagnostic device of the diagnostic system according to Fig. 1 in the area of ​​an analysis device in a simplified sectional view, Fig. 4 one opposite Fig. 3 modified arrangement in the area of ​​the analysis device, Fig. 5 a section through a sample cartridge with a Si chip with an absorbing layer formed on the side of the Si chip and Fig. 6 a part of a diagnostic device of the diagnostic system according to Fig. 1 in the area of ​​an analysis device with a Fig. 3 and Fig. 4 modified sample cartridge in a simplified sectional view. Embodiments of the invention

[0023] Identical elements or elements with the same function are given the same reference numbers in the figures.

[0024] In the Fig. 1 shows a highly simplified representation of the essential components of a diagnostic system 100 for performing analyses of biological samples using a mobile diagnostic device 10. The diagnostic device 10 has a housing 12 with a receiving opening 14 for inserting a diagnosis-specific consumable in the form of a sample cartridge 1. Furthermore, the diagnostic device 10 includes a control device 15 with a program data memory 18 and a software module 16 with an electronic (software) memory 20. The program data memory 18 stores, in particular, diagnosis-specific software programs that serve to analyze a biological patient sample, obtained, for example, from a buccal swab, which is located in the sample cartridge 1 and can be introduced into the diagnostic device 10 via the receiving opening 14, for example using so-called PCR (polymerase chain reaction) tests.Such a known analysis or PCR test allows, for example, the detection of various diseases or pathogens in the patient sample (e.g. Sars-Covid-2 virus, sexually transmitted infections, etc.).

[0025] Diagnosis-specific sample cartridges 1 are used to detect the pathogen or disease in question, which can be examined by controlling the software programs stored in the program data memory 18.

[0026] Furthermore, the diagnostic device 10 comprises a scanner 26 which is designed to scan both a barcode BC1 of a sample container 28 containing the patient sample ( Fig. 2), as well as a barcode BC2 of the diagnosis-specific sample cartridge 1. The sample cartridge 1 further comprises an opening 2 for introducing or transferring the patient sample from the sample container 28 into the sample cartridge 1.

[0027] The analysis of a patient sample located in the sample cartridge 1 is carried out after scanning the two barcodes BC1 and BC2, whereupon the diagnostic device 10 controls the software program intended for analysis from the program data memory 18 in accordance with the diagnosis-specific sample cartridge 1 detected via the barcode BC2.

[0028] If a PCR test is to be performed using the diagnostic device 10, a key component of the PCR test is the amplification of DNA strands using the PCR method. The PCR method is characterized by a cyclical temperature process. At a very high temperature (approx. T = 94°C to 96°C), the double strands of DNA from the patient sample separate. After lowering the temperature to a lower temperature (depending on the primer sequence, e.g., 55°C to 65°C), the primers anneal to the specific location of the (separated) DNA strands, and at a medium temperature (depending on the polymerase used, e.g., 68°C to 72°C), the polymerase mediates the construction of the complementary strands from free nucleotides. These temperature levels are set one after the other, and the resulting cycle is repeated tens of times.

[0029] To heat the patient sample to the temperatures mentioned above or to carry out the temperature changes, the diagnostic device 10 is provided with a Fig. 3 and Fig. 4 a heating device 30, 30a is arranged. In the Fig. 3 and Fig. 4 also shows the base body 32 of the sample cartridge 1, which is preferably made of plastic and has a (microfluidic) analysis chamber 34 for the patient samples P. Arranged within the analysis chamber 34 is an analysis device in the form of a (flat) analysis body 35. The analysis body 35, known per se, is designed as a Si chip 36, which is arranged in operative connection with the patient sample P located in the analysis chamber 34.

[0030] In the Fig. 3, the heating device 30 is in the image plane of the Fig. 3 below the analysis body 35, on the side of the analysis body 35 facing away from an analysis device 40, aligned with or overlapping the analysis body 35. The analysis device 40 is designed in particular as an optical analysis device 40 and serves to detect the replicated DNA strands on the surface O of the Si chip 36. Both the analysis device 40 and the heating device 30 can be controlled by the control device 15 according to the sequence in the program data memory 18.

[0031] The heating device 30 is designed as a radiation device 42, in particular as a laser beam device with at least one VCSEL array 43, and generates radiation S having a wavelength for which the (plastic) material of the sample cartridge 1 is transparent in the region of the analysis chamber 34 and absorbent for the material of the analysis body 35 or the Si chip 36. Furthermore, the wavelength of the radiation S emitted by the VCSEL array 43 is preferably also adapted to the thickness d of the analysis body 35 or the Si chip 36. Thus, the penetration depth of the radiation S when using crystalline silicon and a wavelength of 1060 nm is approximately 1 mm. Longer wavelengths with a greater penetration depth would therefore largely penetrate the Si chip 36 (which typically has a thickness d of 1 mm) unused. At 980 nm, the penetration depth is approximately100µm, shorter wavelengths, and smaller penetration depths thus lead to very inhomogeneous heating of the Si chip 36. With a different thickness d of the analysis body 35 or the Si chip 36 and materials, the specified numerical values ​​change in a manner known to a person skilled in the art. Furthermore, the heating device 30 or radiation device 42 is arranged at a distance from, i.e., without contact with, the base body 32, and the radiation S strikes the analysis body 35 or the Si chip 36 at least substantially perpendicularly.

[0032] In the Fig. 4, the VCSEL array 43a has two sub-elements 44, 45, which are arranged laterally or at the edge regions of the analysis body 35 or Si chips 36, respectively, so that their radiation S impinges on the analysis body 35 at an oblique angle. The analysis device 40 (not shown) is located according to the Fig. 3 on the side of the Si chip 36 facing away from the VCSEL array 43a. This creates a space between the two sub-elements 44, 45 for an optical component 46, for example a component 46 for detecting the temperature of the surface O of the Si chip 36 by detecting infrared radiation.

[0033] To control the temperature of the biological patient sample or the analysis body 35, it is essential to record the temperature of the analysis body 35 or the Si chip 36 as accurately as possible so that the control device 15 can control the heating device 30, 30a accordingly. For example, a Fig. 3. The temperature sensor 48 is a temperature sensor 48 consisting of substances or material combinations that exhibit a color change or a change in optical reflection or scattering behavior when a temperature threshold is exceeded. For this purpose, the temperature sensor 48 can be arranged on a partial section of the surface O of the Si chip 36. An optical module 50, which is also connected to the control device 15, is provided for detecting the temperature sensor 48.

[0034] It should also be mentioned that instead of a temperature sensor 48, temperature sensors based on resistance or voltage measurements can also be integrated into the Si chip 36, which can be controlled via electrical contacts leading out of the sample cartridge 1 or wirelessly. Integrated photonics solutions on the Si chip 36 are also conceivable, e.g., waveguides with integrated Bragg gratings that allow optical temperature measurement.

[0035] Furthermore, the Si chip 36 can be modified to optimize heating or heat input. First, there are ways to improve the absorption of radiation S in the Si chip 36. The high refractive index of silicon naturally leads to strong Fresnel reflections on bare surfaces, which reduce the energy input of radiation S into the Si chip 36 and can heat other components of the diagnostic device 10 via the reflected power. To reduce the refractive index, the surface O of the Si chip 36 facing the radiation S can be provided with an anti-reflective coating 52. The anti-reflective coating 52 is preferably a SiN layer, the thickness of which is adjusted to efficiently couple the wavelength and direction of incidence of the radiation S.

[0036] Alternatively, self-organized surface modifications of the silicon such as “black silicon,” which have a very broadband effect and also ensure improved thermal radiation, thus also accelerating the cooling of the Si chip 36 when the VCSEL array 43, 43a is switched off, can be provided.

[0037] Furthermore, measures are possible to not absorb the energy of the radiation S equally throughout the volume of the Si chip 36, but to concentrate it on selected layers in order to generate high temperatures there locally. Fig. 5. There it can be seen that the Si chip 36a is provided on the side facing the patient sample P with a coating 54 which has a high absorption in the range of the used wavelength of the radiation S, for example in the form of a lithographic resist which is colored with a suitable pigment (for example carbon black). An advantageous wavelength of the radiation S would then be 980 nm or higher, because here the illumination from below (via the heating device 30 according to Fig. 3) will penetrate the crystalline silicon and very effectively heat only the layer on the sample side, which then becomes very hot. As soon as the VCSEL array 43 is switched off, the comparatively cold chip volume ensures rapid cooling of the patient sample P and helps to run the temperature cycles quickly.

[0038] Most recently, in the Fig. 6 shows a modified sample cartridge 1a. The sample cartridge 1a has an opening 55 in the area of ​​the analysis chamber 34 on the side facing the radiation device 42, which opening is sealed or closed by the analysis body 35. For this purpose, the sample cartridge 1a has a stepped recess 56 with a stop region 57 running parallel to the analysis body 35. To seal the analysis chamber 34 or the sample cartridge 1a, the analysis body 35 is integrally bonded to the sample cartridge 1a in the area of ​​the recess 56 by an adhesive 58.

[0039] The Fig.The sample cartridge 1a shown in Figure 6 has the advantage that the radiation S from the radiation device 42 impinges directly on the analysis body 35 and does not first have to penetrate the (plastic) material of the sample cartridge 1a. This makes the choice of material for the sample cartridge 1a less critical and does not need to be specifically matched to the wavelength of the radiation S.

[0040] The diagnostic device 10 described so far or the method described can be modified in many different ways without deviating from the inventive concept. QUOTES CONTAINED IN THE DESCRIPTION

[0000] This list of documents submitted by the applicant was generated automatically and is included solely for the convenience of the reader. This list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions. Cited patent literature

[0000] DE 10 2021 203 922 A1

[0003] DE 10 2006 010 959 A1

[0004] DE 10 2016 213 412 A1

[0005]

Claims

[1] Diagnostic system for the analysis of biological samples (P), with a sample cartridge (1; 1a) which has an analysis body (35), in particular in the form of a Si chip (36; 36a) for the biological sample (P), preferably with an analysis device (40) for analyzing the biological sample (P), and with a heating device (30; 30a) for heating the biological sample (P) in the region of the analysis body (35), wherein the heating device (30; 30a) and preferably the analysis device (40) are components of a diagnostic device (10) separate from the sample cartridge (1; 1a), wherein the diagnostic device (10) preferably has a receiving opening (14) for inserting the sample cartridge (1; 1a), wherein the heating device (30; 30a) is designed in the form of a radiation device (42), and wherein the material of the analysis body (35) is suitable for the radiation emitted by the radiation source (42). generated radiation (S) is designed to absorb. [2] Diagnostic system according to claim 1, characterized bythat the radiation device (42) is arranged on the side of the analysis body (35) facing away from the analysis device (40) in at least partial, preferably complete overlap with the analysis body (35), such that the radiation (S) of the radiation device (42) impinges at least partially, preferably completely at right angles on the essentially flat analysis body (35). [3] Diagnostic system according to claim 1, characterized by that the radiation device (42) is arranged on the side of the analysis body (35) facing away from the analysis device (40), preferably in at least partial overlap with the analysis body (35), such that the radiation (S) of the radiation device (42) impinges at least partially, preferably completely, at an oblique angle on the essentially flat analysis body (35). [4] Diagnostic system according to claim 3, characterized byin that the radiation device (42) has at least two partial elements (44, 45) which are arranged laterally next to a particularly optical component (46), wherein the optical component (46) is arranged in overlap with the analysis body (35). [5] Diagnostic system according to one of claims 1 to 4, characterized by that the radiation device (42) is designed in the form of a VCSEL array (43; 43a). [6] Diagnostic system according to one of claims 1 to 5, characterized by that the sample cartridge (1) has a base body (32) comprising plastic, in which an analysis chamber (34) is formed, wherein the base body (32) surrounds the analysis body (35) within the analysis chamber (34), and wherein the material of the plastic of the base body (32) in the region of the analysis chamber (34) is adapted to the radiation (S) generated by the radiation device (42) in such a way that the material of the plastic is transparent to the radiation (S). [7] Diagnostic system according to one of claims 1 to 5, characterized by that the sample cartridge (1a) has a base body (32) comprising plastic, in which an analysis chamber (34) is formed, wherein the base body (32) has an opening (55) on the side facing the radiation device (42), which opening is covered by the analysis body (35), and wherein the analysis chamber (34) is sealed in the region of the opening (55) by the analysis body (35). [8] Diagnostic system according to one of claims 1 to 7, characterized by that the analysis body (35) has a thickness (d) which corresponds at least approximately to the absorption length of the material of the analysis body (35) at the wavelength of the radiation (S) generated by the radiation source (42). [9] Diagnostic system according to claim 8, characterized bythat the analysis body (35) is designed as a Si chip (36; 36a) with a thickness (d) between 0.7 mm and 1.2 mm, preferably between 0.9 mm and 1.0 mm, and that the wavelength of the radiation (S) is approximately 1060 nm, or that the analysis body (35) is designed as a Si chip (36; 36a) with a thickness (d) between 50 µm and 400 µm, preferably between 100 µm and 200 µm, and that the wavelength of the radiation (S) is approximately 980 nm. [10] Diagnostic system according to one of claims 1 to 9, characterized by that a preferably optically operating temperature measuring device (48) is provided for detecting the temperature of the analysis body (35) and / or the biological sample (P). [11] Diagnostic system according to one of claims 1 to 9, characterized by that the analysis body (35) has a temperature measuring device based on voltage or resistance measurement. [12] Diagnostic system according to one of claims 1 to 10, characterized bythat the analysis body (35) is provided with an anti-reflection coating (52), in particular with a SiN layer, on the side facing the radiation device (42), preferably on the side of the analysis body (35) facing away from the biological sample (P). [13] Diagnostic system according to one of claims 1 to 12, characterized by that the analysis body (35) is formed with a coating (54) which increases the absorption of the wavelength of the radiation (S).

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