Device for detecting chemical substances in a sample

Abstract

The present invention relates to an apparatus for detecting one or more chemicals in a sample, comprising a scanning unit comprising a light source configured to scan the sample with a light beam having a linear illumination, a dispersive element configured to receive light from the sample and to spatially disperse the received light in parallel, a spatial light modulator configured to receive the dispersed light and to select one or more wavelength bands of the dispersed light, and a detection unit comprising a one-dimensional array detector configured to receive the selected one or more wavelength bands and detect the one or more chemicals in the sample based on the selected one or more wavelength bands, wherein each detector of the detector array is a photon detector having a detection surface with a dimension in the direction of the linear illumination of less than 50 μm.

Description

[Technical field]

[0001] The present invention relates to optical instruments, and more particularly to the use of optical instruments in measuring chemical properties. [Background technology]

[0002] Raman scattered light is widely used to identify chemicals based on inelastic scattering of photons by the chemicals. However, chemical detection using Raman scattered light can involve large data sizes that require time for acquisition and post-processing. Solutions exist to limit the size of data acquired in Raman scattering experiments, for example by optical post-processing and selecting the wavelengths transmitted to the detector. For example, US Pat. No. 5,999,333 discloses a method to measure Raman scattered light intensity passed through a programmable binary optical mathematical filter designed to minimize errors in the chemical classification (or concentration) variable of interest. Theoretical results are implemented and verified using a digital compressive detection setup incorporating a diode-pumped laser with spot-like illumination, a digital micromirror device (DMD) spatial light modulator, and a single-photon counting photodiode detector.

[0003] However, the speed of chemical analysis of existing solutions is still limited by detectors such as optical arrays (e.g., charge-coupled devices or CCDs) in conventional Raman spectroscopy, or single-pixel detectors in experiments with programmable optical filters. In particular, the speed of chemical analysis experiments is limited by detector size, readout, and response time. Existing solutions cannot perform in vivo imaging due to motion artifacts such as respiratory motion, blood flow, and the movement of cells and organelles within cells. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 9,476,824 [Non-patent literature]

[0005] [Non-Patent Document 1] Soldevila et.al,Fast compressive Raman bio-imaging via matrix completion,6,3,341-346,Optica,2019 Summary of the Invention

[0006] These problems are solved or alleviated by the apparatus and method of the present invention.

[0007] Instead of using spot illumination, the present invention uses linear illumination, which allows fast scanning of the sample.Furthermore, digital micromirror device is combined with one-dimensional array detector, such as single pixel detector.Thus, by combining linear illumination with digital micromirror device that allows wavelength selection in one direction and one-dimensional array detector in vertical direction, each single pixel detector in the array is adapted to detect chemicals simultaneously, improving chemical analysis speed, for example, enabling high-speed experiments required for high-speed chemical screening applications (e.g. pharmaceutical or cytometry applications) and in vivo imaging.

[0008] A first aspect of the present invention provides an apparatus for detecting one or more chemicals in a sample, the apparatus comprising a scanning unit comprising a light source configured to scan the sample with a light beam having a linear illumination, a dispersive element configured to receive light from the sample and disperse the received light in a parallel spatial manner, a spatial light modulator configured to receive the dispersed light and select one or more wavelength bands of the dispersed light, and a detection unit comprising a one-dimensional array detector configured to receive the selected one or more wavelength bands and detect one or more chemicals in the sample based on the selected one or more wavelength bands, each detector of the detector array being a photon detector having a detection surface with a dimension in the direction of the linear illumination of less than 50 μm.

[0009] Optionally, the scanning unit is configured to scan the sample in a scanning direction different from a direction of the linear illumination. Optionally, the dispersive element lies on a plane having a first direction corresponding to a direction of the linear illumination and a second direction corresponding to a scanning direction. Optionally, the dispersive element is a planar diffraction grating. Optionally, the scanning unit is configured to scan the sample in a raster scan using the light beam. Optionally, the detector is a single-photon avalanche diode detector. Optionally, the spatial light modulator comprises a digital micromirror device. Optionally, the spatial light modulator is configured to select N wavelength bands, and the one-dimensional array detector comprises M detectors, each of the M detectors configured to receive a respective wavelength band of the N wavelength bands. Optionally, the spatial light modulator comprises at least N mirrors configured to direct the N wavelength bands onto M detectors. Optionally, the N wavelength bands include spectra corresponding to each of one or more chemical substances. Optionally, the spatial light modulator is configured to filter the spectrum using one or more binary mathematical filters, each of the one or more binary mathematical filters corresponding to a respective one of the one or more chemicals. Optionally, the light received from the sample includes Raman scattered light.

[0010] A second aspect of the present invention provides a method for parallel detection of one or more chemicals in a sample, the method comprising the steps of scanning a sample with a light beam having a linear illumination, receiving light from different points of the sample at a dispersive element and spatially dispersing the received light using the dispersive element, receiving the dispersed light at a spatial light modulator and selecting one or more wavelength bands of the dispersed light using the spatial light modulator, and receiving the selected one or more wavelength bands at a one-dimensional array detector and detecting one or more chemicals in the sample based on the selected one or more wavelength bands using the one-dimensional array detector. Each detector in the detector array is a photon detector having a detection surface with a dimension in the direction of the linear illumination of less than 50 μm. The small dimensions of the detectors allow the M detectors to be significantly scaled up, thus improving the acquisition speed. [Brief description of the drawings]

[0011] [Figure 1a] FIG. 1a is a schematic diagram of an apparatus for detecting one or more chemicals in a sample according to one embodiment. [Figure 1b] FIG. 1b is a schematic diagram of a portion of an apparatus for detecting one or more chemicals in a sample according to one embodiment. [Diagram 2] FIG. 2 is a flow diagram illustrating a method for parallel detection of one or more chemicals in a sample, according to one embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] An embodiment of the present invention will now be described with reference to the accompanying drawings. Figure 1a is a schematic diagram of an apparatus 100 for detecting one or more chemicals in a sample according to one embodiment. Figure 1a is a two-dimensional representation of the apparatus 100.

[0013] The sample 108 may comprise, for example, biological tissue or cells, and the device 100 may be used to detect chemicals such as DNA, proteins or lipids. In an embodiment, the device 100 may be used to detect chemicals in in vivo experiments, such as respiratory movements or blood flow. The device 100 comprises a scanning unit 102 comprising a light source 104 configured to scan the sample 108 using a light beam 112 having a linear illumination. The light source may be, for example, a continuous wave (CW) laser. For example, a CW laser may emit the light beam 112 at 532 nm. The scanning unit 102 comprises a microscope 110 comprising an objective lens 116. The microscope may also comprise one or more lenses (not shown) allowing to focus the light beam 112 at the back focal plane of the objective lens 114, the sample 108 being placed in the focal plane of the microscope 110. The scanning unit 102 comprises a cylindrical lens 114 used to obtain a linear illumination for scanning the sample 108. In particular, the cylindrical lens 114 enables the light received from the light source 104 to be focused onto a single axis v.

[0014] Further, the scanning unit 102 may include a scanning system 106, which may be an automatic scanning system. The scanning system 106 may be used to control the scanning of the sample 108. For example, the scanning system 106 may define a pattern, such as a raster scan, to scan the sample 108 with a linear illumination. For example, the scanning system 106 may include a galvanometer mirror used to automatically scan the sample. In another example, the sample may be scanned by moving the sample (e.g., the sample may be placed on a moving stage). Furthermore, the scanning system 106 may define a scanning speed or an area of ​​the sample 108 to be scanned. The linear illumination may correspond to a dimension of the sample 108 (e.g., the length or width of the sample 108) and may have a direction v perpendicular to a side of the sample 108. However, in another example, the linear illumination may have a dimension different from the dimension of the sample 108 and may have a direction different from the side of the sample 108. The length of the cylindrical lens 114 defines the dimension of the linear illumination, which may define the scanning speed. In particular, the cylindrical lens 114 can be optimized so that the dimension of the linear illumination corresponds to the longest dimension of the sample 108. In other words, the length of the cylindrical lens 114 can be adapted to the area of ​​the sample 108 to be scanned.

[0015] In one embodiment, the scanning unit 102 may be configured to scan the sample 108 in a scanning direction u that is different from the direction v of the linear illumination. The direction u may be perpendicular to the direction v. Alternatively, the directions u and v may have an angle different from 90°. Additionally or alternatively, the scanning unit 102 may be configured to scan the entire surface of the sample 108, or one or more portions of the sample 108 defined by the scanning system 106. For example, the linear illumination may have a dimension that corresponds to a length or width of the sample 108.

[0016] The scanning system 106 may be implemented using hardware, software, and / or a combination thereof. For example, a hardware device may be implemented using a processing circuit, such as, but not limited to, a processor, a central processing unit (CPU), a controller, an arithmetic logic unit (ALU), a digital signal processor, a microcomputer, a field programmable gate array (FPGA), a system on a chip (SoC), a programmable logic unit, a microprocessor, or any other device capable of responding in a defined manner and executing instructions. Software may include computer programs, program code, instructions, or combinations thereof, for independently or collectively directing or configuring the hardware devices to perform desired operations. Computer programs and / or program code may include programs or computer readable instructions, software components, software modules, data files, data structures, and / or the like, executable by one or more of the hardware devices (e.g., one or more of the hardware devices described above). If the hardware device is a computer processing device (e.g., a CPU, a controller, an ALU, a digital signal processor, a microcomputer, a microprocessor, etc.), the computer processing device may be configured to execute the program code by performing arithmetic operations, logical operations, and input / output operations according to the program code. Each unit may also include one or more storage devices. The one or more storage devices may be tangible or non-transitory computer-readable storage media, such as random access memory (RAM), read-only memory (ROM), permanent mass storage device (e.g., disk drive), solid-state (e.g., NAND flash) device, and / or any other similar data storage mechanism capable of storing and recording data.The one or more storage devices may be configured to store one or more operating systems and / or computer programs, program codes, instructions, or any combination thereof for implementing the exemplary embodiments described herein. The computer programs, program codes, instructions, or any combination thereof may also be loaded from a separate computer-readable storage medium into the one or more storage devices and / or one or more computer processing devices using a drive mechanism. Such separate computer-readable storage media include Universal Serial Bus (USB) flash drives, memory sticks, Blu-ray / DVD / CD-ROM drives, memory cards, and / or other similar computer-readable storage media.

[0017] 1a, slit 126 can be used to control the amount of light allowed to reach detector 124. For example, the opening of slit 126 can be altered to increase or decrease the amount of light transmitted to detector 124. In this example, slit 126 can be positioned between dichroic mirror 130 and detector 124.

[0018] Furthermore, the apparatus 100 comprises a dispersive element 120 configured to receive light from the sample 108 and to spectrally disperse the received light in a spatially parallel manner. In particular, the dispersed light beams are parallel to each other. The light received from the sample 108 may include, for example, Raman scattered light. In this example, the apparatus 100 comprises a dichroic mirror 130 used to separate the light received from the light source 104 and the light received from the sample 108 (e.g., Raman scattered light or fluorescence). The dispersive element 120 may be, for example, a diffraction grating, for example a planar holographic diffraction grating. In another example, the dispersive element 120 may be a volume holographic diffraction grating or a prism. The dispersive element 120 lies on a plane having a first direction y and a second direction x. For example, the first direction y may correspond to a direction v of the linear illumination, and the second direction x may correspond to a scanning direction u. This configuration ensures that light received from the sample 108 is dispersed by the dispersive element 120 while scanning across the sample 108 .

[0019] The dispersed light is then received by the spatial light modulator 122. For example, the dispersed light can be collimated by the lens 10c and focused onto the spatial light modulator 122. The spatial light modulator 122 may comprise, for example, a digital micromirror device (DMD) (for binary amplitude modulation). In another example, the spatial light modulator 122 may be a liquid crystal (for analog amplitude and / or phase modulation). The dispersive element 120 allows the light to be dispersed onto the surface of the DMD and thus onto the mirrors of the DMD. For example, the DMD 122 may comprise an array of 1920×1080 aluminum mirrors (pitch 10.8 μm) tiltable ±12° relative to the flat state of the array, controlled by an interface card. The spatial light modulator 122 may comprise a processor or controller. In another example, the DMD 122 and the scanning system 106 can implement the same hardware and / or software. The DMD 122 is configured to select one or more wavelength bands of the dispersed light. In particular, the mirrors in each column of the array are set to the same angle, and the columns are divided into adjacent groups (note that the roles of rows and columns are interchangeable). For example, groups of 15 adjacent columns are set in unison to separate the photons into 128 "bins" defined by bands of photon energy.

[0020] As shown in FIG. 1a perpendicular to the light dispersion and FIG. 1b parallel to the light dispersion, the DMD 122 is mounted perpendicular to the direction v of the dispersed light to spatially separate the incident and reflected photons. Thus, the light (e.g., Raman scattered light) received by the DMD 122 is separated into selected wavelength bands, which are received by the detection unit 124. In one embodiment, the reflected photons are recombined in the second dispersive element 128 and focused onto the detection unit 124. In particular, the second dispersive element 128 allows the linear reflected photons received to be imaged onto the detection unit 124. For example, the second dispersive element 128 may be a diffraction grating. In another example, one or more lenses may be used to image the linear reflected photons received onto the detection unit 124.

[0021] The detection unit 124 comprises a one-dimensional array detector configured to receive one or more selected wavelength bands and detect one or more chemicals in the sample based on the one or more selected wavelength bands. Each detector in the detector array is a single photon detector having a detection surface with a dimension in the direction of the linear illumination v of less than 50 μm. For example, the detection surface may be less than 50 μm in diameter. In another example, the detection surface may be a square surface, with the side of the square being less than 50 μm. In another example, the detection surface may be a rectangular surface, with one side of the rectangle being less than 50 μm, with the side being in the direction of the linear illumination v. For example, the detection surface of the single photon detector has a diameter of tens of micrometers. Preferably, the detection surface of the single photon detector has a diameter between 10 μm and 50 μm. For example, the detection surface of each single photon detector has a diameter of about 26 μm. Having a small single photon detector is advantageous because it allows the number of parallel measurements to be scaled up, thus providing faster imaging. That is, the smaller the detector, the faster the imaging.

[0022] Single-photon detectors have the advantage, compared to e.g. CCD cameras, that they generate less noise regardless of the readout speed, since single photons are detected directly. In particular, CCD cameras are not direct single-photon detectors, instead incident photons are converted into electronic charges, and these charges are then read out by the CCD camera electronics. The charge readout can result in spurious noise, which increases with faster readout speeds in CCD cameras. Furthermore, the combination of a DMD-based spectrometer with a single pixel single-photon detector allows for data compression. CCD cameras have long acquisition speeds, since the data transmission bandwidth is limited by the current CCD electronics, and are much slower than the present invention.

[0023] In one embodiment, each detector of the one-dimensional array detector 124 may be a single photon avalanche diode detector (SPAD). For example, the detection unit 124 may comprise a SPAD that is part of a two-dimensional pixelated sensor and can be coupled with a field programmable gate array (FPGA). In one embodiment, a microlens can be used to improve the photon collection efficiency of the SPAD. The combination of the two-dimensional pixelated sensor with an FBGA allows for processing photon events such as histogram aggregation or coincidence detection. Each detector of the one-dimensional array detector 124 receives a selected wavelength band from the DMD. The dimensions of the DMD are adapted to the dimensions of the one-dimensional array detector 124. In particular, the spatial light modulator 122 can be configured to select N wavelength bands. The number N of wavelength bands is defined by the spatial light modulator 122. For example, the number N of wavelength bands can be defined by the number of pixels of the DMD in the direction u. Further, the one-dimensional array detector 124 may comprise M detectors, each of the M detectors configured to receive a respective wavelength band or group of wavelength bands of the N wavelength bands. M defines the number of single photon detectors in the detector array. For example, each of the N wavelength bands may represent a chemical to be detected in the sample 108, and the spatial light modulator 122 may be configured to select only the N bands representing the respective chemical. In one embodiment, the spatial light modulator 122 may comprise at least M mirrors configured to direct the N wavelength bands to the M detectors. The N wavelength bands may include spectra corresponding to each of one or more chemicals. In particular, instead of post-processing the entire spectrum emitted by the chemicals contained in the sample 108, the DMD 122 selects only a portion of the entire spectrum contained in the different wavelength bands. Each wavelength band includes a portion of the entire spectrum that may represent a chemical or combination of chemicals. For example, each portion of the spectrum may be compared to, for example, a reference spectrum to identify the chemical (and thus the chemical contained in the sample 108) corresponding to the portion of the spectrum.The spatial light modulator 122 can be configured to filter the spectrum using one or more binary mathematical filters, each of which corresponds to one or more respective chemicals. In particular, the binary optical mathematical filters can be used to minimize the uncertainty of chemical detection. For example, the method described in U.S. Pat. No. 6,399,436 can be used to optimize the detection of chemicals using binary optical mathematical filters while using the elements of the device 100 described above. In another example, the method described in U.S. Pat. No. 6,399,436 can be used to optimize the detection of chemicals using spectral filters for chemical quantification. Additionally, lenses 10a, 10b, 10c, 10d, and 10e can be used in the device 100. For example, lens 10a can be used to image light emitted from the sample 108 under illumination onto the slit 126. Lenses 10b and 10c can form a telescope to reimage the slit 126 onto the DMD 122. Lenses 10d and 10e can be used to image the DMD 122 onto the one-dimensional array detector 124.

[0024] By spatially parallelizing the above system, the following equation:

[0025]

number

[0026] [In the formula, N SPAD is the number of spatial pixels, and PDE is the SPAD photon detection efficiency of the array or single pixel. It should be noted that this can speed up retrieval by Thus, the above-described system makes it possible to achieve faster acquisition speeds than CCD cameras or large single-photon detectors by using an array of small detectors.

[0027] 2 is a flow diagram illustrating a method 300 for detecting one or more chemicals in a sample in parallel, according to one embodiment. For example, the method 300 can be performed by the apparatus 100 described above with reference to FIG. 1a.

[0028] In block 302, the method includes scanning the sample 108 using a light beam 112 having a line illumination. For example, a raster may be used to scan the sample 108.

[0029] At block 304, the method includes receiving light from various points on the sample 108 at a dispersive element 120 and spatially dispersing the received light using the dispersive element 120. For example, the received light may be received at a diffraction grating 120.

[0030] At block 306, the method includes receiving the dispersed light at a spatial light modulator and selecting one or more wavelength bands of the dispersed light using the spatial light modulator 122. For example, the spatial light modulator 122 may be a DMD. In one embodiment, the one or more wavelength bands correspond to one or more chemicals contained in the sample 108.

[0031] At block 308, the method includes receiving the selected one or more wavelength bands with a one-dimensional array detector 124 and detecting one or more chemicals in the sample 108 based on the selected one or more wavelength bands using the one-dimensional array detector 124. For example, the detector 124 may be a SPAD. Each detector of the SPAD 124 may be adapted to detect one type of chemical. For example, the DMD 122 may select N wavelength bands, and each of the detectors 124 may receive a set of the N wavelength bands. Each received wavelength band may include a spectrum that may be compared to a reference spectrum (e.g., in a lookup table). A chemical corresponding to each spectrum may be determined based on the comparison.

[0032] The above-mentioned inventions enable fast chemical analysis. In particular, by using linear illumination, fast scanning of the sample is achievable. Furthermore, by using spatial light modulators in combination with one-dimensional array detectors such as single-photon avalanche photodiodes, it is possible to simultaneously analyze multiple wavelength bands while limiting post-processing time. Furthermore, by using single-photon avalanche photodiodes instead of CCD cameras, it is possible to reduce the cost of chemical analysis while, for example, increasing the speed. Furthermore, SPADs allow reading out individual time bins on ultrafast timescales, not possible with CCD or CMOS cameras, allowing, for example, lifetime estimation or extraction of time-of-flight data.

[0033] Although the invention has been described and illustrated in detail with the help of preferred embodiments, the invention is not limited to the disclosed examples. Those skilled in the art can derive other modifications without departing from the scope of protection of the invention. For example, various lenses with different focal lengths can be used. Depending on the configuration of the device 100, additional lenses can be used. Furthermore, other light sources can be used. Furthermore, the device can be implemented in existing Raman spectroscopy devices. Furthermore, although the invention is illustrated for the application of Raman spectroscopy, the described device 100 can be used for other applications such as fluorescence, absorption and emission spectroscopy.

Claims

1. An apparatus (100) for detecting one or more chemicals in a sample (108), the apparatus comprising: a scanning unit (104) comprising a light source adapted to scan the sample with a light beam (112) having a linear illumination; a dispersive element (120) configured to receive light from the sample and to disperse the received light in a spatially parallel manner; a spatial light modulator (122) configured to receive the dispersed light and to select one or more wavelength bands of the dispersed light; and a detection unit (124) comprising a one-dimensional array detector configured to receive the one or more selected wavelength bands and to detect the one or more chemicals in the sample based on the one or more selected wavelength bands; wherein each detector of the detector array is a photon detector having a detection surface with a dimension in the direction (v) of the linear illumination of less than 50 μm.

2. 2. The apparatus of claim 1, wherein the scanning unit is configured to scan the sample in a scanning direction (u) different from the direction (v) of the linear illumination.

3. 3. The apparatus of claim 2, wherein the dispersive element lies in a plane having a first direction (y) corresponding to the direction of the linear illumination and a second direction (x) corresponding to the scanning direction.

4. 4. The apparatus of claim 1, wherein the dispersive element is a planar diffraction grating.

5. The apparatus of claim 4 , wherein the scanning unit is configured to scan the sample in a raster scan using the light beam.

6. 4. The apparatus of claim 1, wherein the detector is a single-photon avalanche diode detector.

7. 4. The apparatus of claim 1, wherein the spatial light modulator comprises a digital micromirror device.

8. the spatial light modulator is configured to select N wavelength bands; the one-dimensional array detector comprises M detectors; 4. The apparatus of claim 1, wherein each of the M detectors is configured to receive a respective one of the N wavelength bands.

9. 9. The apparatus of claim 8, wherein the spatial light modulator comprises at least N mirrors configured to direct the N wavelength bands onto the M detectors.

10. The apparatus of claim 8 , wherein the N wavelength bands include spectra corresponding to each of the one or more chemical substances.

11. the spatial light modulator is configured to filter the spectrum using one or more binary mathematical filters; The apparatus of claim 10 , wherein each of the one or more binary mathematical filters corresponds to a respective one of the one or more chemical substances.

12. The apparatus of claim 1 , wherein the light received from the sample comprises Raman scattered light.

13. 1. A method (300) for parallel detection of one or more chemicals in a sample (108), the method comprising: - scanning the sample with a light beam having a linear illumination; - receiving light from different points of the sample at a dispersive element (120) and spatially dispersing the received light using the dispersive element; receiving the dispersed light at a spatial light modulator (122) and selecting one or more wavelength bands of the dispersed light using the spatial light modulator; and receiving the selected one or more wavelength bands at a one-dimensional array detector (124) and detecting the one or more chemicals in the sample based on the selected one or more wavelength bands using the one-dimensional array detector; A method wherein each detector of the detector array is a photon detector having a detection surface with a dimension in the direction (v) of the line illumination of less than 50 μm.

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