US20180188152A1 - Radiation Carrier and Use Thereof in an Optical Sensor - Google Patents

Radiation Carrier and Use Thereof in an Optical Sensor Download PDF

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US20180188152A1
US20180188152A1 US15/580,674 US201615580674A US2018188152A1 US 20180188152 A1 US20180188152 A1 US 20180188152A1 US 201615580674 A US201615580674 A US 201615580674A US 2018188152 A1 US2018188152 A1 US 2018188152A1
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radiation
emission
detector
interest
region
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Dries Vercruysse
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Interuniversitair Microelektronica Centrum vzw IMEC
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N15/1434—Optical arrangements
    • G01N15/1436—Optical arrangements the optical arrangement forming an integrated apparatus with the sample container, e.g. a flow cell
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47—Scattering, i.e. diffuse reflection
    • G01N21/49—Scattering, i.e. diffuse reflection within a body or fluid
    • G01N21/51—Scattering, i.e. diffuse reflection within a body or fluid inside a container, e.g. in an ampoule
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N15/1434—Optical arrangements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N15/1484—Optical investigation techniques, e.g. flow cytometry microstructural devices
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65—Raman scattering
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B6/00—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings
    • G02B6/0001—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings specially adapted for lighting devices or systems
    • G02B6/0011—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings specially adapted for lighting devices or systems the light guides being planar or of plate-like form
    • G02B6/0033—Means for improving the coupling-out of light from the light guide
    • G02B6/0035—Means for improving the coupling-out of light from the light guide provided on the surface of the light guide or in the bulk of it
    • G02B6/0036—2-D arrangement of prisms, protrusions, indentations or roughened surfaces
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B6/00—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings
    • G02B6/10—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings of the optical waveguide type
    • G02B6/12—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings of the optical waveguide type of the integrated circuit kind
    • G02B6/122—Basic optical elements, e.g. light-guiding paths
    • G02B6/124—Geodesic lenses or integrated gratings
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B6/00—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings
    • G02B6/24—Coupling light guides
    • G02B6/26—Optical coupling means
    • G02B6/30—Optical coupling means for use between fibre and thin-film device
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N2015/1006—Investigating individual particles for cytology
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N2021/0346—Capillary cells; Microcells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N2021/6463—Optics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N2021/6482—Sample cells, cuvettes

Definitions

  • the present invention relates to the field of particle detection and optionally analysis. More specifically it relates to particle detection and optionally analysis via optical means. In particular, it relates to luminescence based detection, e.g. fluorescence based detection, of particles or detection of particles based on Raman scattering, in flow.
  • Cytometry in particular flow cytometry, consists in identification of analytes (e.g. tumor cells) based on morphological and/or chemical characteristics.
  • markers e.g. luminescent markers such as for instance fluorescent markers
  • luminescent markers such as for instance fluorescent markers
  • Luminescent, e.g. fluorescent, detection of particles is a technique whereby a particle of interest in a fluid sample is stained or labeled with one or more luminophores, e.g. fluorophores.
  • the luminophores, e.g. fluorophores, attached to the particle are activated by a light signal and luminescence, e.g. fluorescence, from the luminophores, e.g. fluorophores, is then detected by an optical detector.
  • a number of luminophores, e.g. fluorophores bind to the particle, and a remaining number of luminophores, e.g. fluorophores, do not bind.
  • waveguides In order to manipulate the laser input, waveguides are often used. However, the breadth of the frequency spectrum of luminescent, e.g. fluorescent, light (broadband spectrum) hinders or impedes an efficient input in a waveguide.
  • luminescent e.g. fluorescent
  • light broadband spectrum
  • the present invention provides a radiation carrier for a sensor, the radiation carrier being adapted for carrying at least a radiation beam, the radiation carrier comprising a surface.
  • the radiation carrier comprises at least one excitation grating on the surface of the at least one radiation carrier, positioned and adapted to couple an excitation radiation beam directionally out of the radiation carrier, thereby illuminating a region of interest (ROI), and further at least one structure positioned and adapted for redirecting, for instance for receiving and redirecting, such as for collecting and redirecting, e.g. for reflecting, emission radiation emanating from the region of interest.
  • Emission radiation emanating from the region of interest may be excitation radiation which is for instance simply reflected on e.g. particles present in the region of interest, or may be a type of radiation different from the excitation radiation, which is generated in the region of interest, by interaction of the excitation radiation with particles present in the region of interest, such as for instance fluorescence or phosphorescence radiation.
  • the structure for redirecting emission radiation may be a structure for reflecting emission radiation.
  • the structure for redirecting emission radiation may be a structure for transmitting the emission radiation.
  • the structure for redirecting emission radiation may include a structured or patterned surface.
  • the at least one structure for redirecting emission radiation may be at least one emission grating adapted for reflecting emission radiation to a detector. In alternative embodiments, it may be at least one emission grating adapted for coupling emission radiation into a radiation carrier.
  • This radiation carrier may be the radiation carrier for carrying the radiation beam, or it may be another, second, radiation carrier.
  • the second radiation carrier may be positioned in the plane of the radiation carrier for carrying the radiation beam, or angled, for instance substantially perpendicular, thereto.
  • the at least one structure positioned and adapted for redirecting emission radiation comprises planar optics, such as for instance a planar lens.
  • the radiation carrier comprises planar optics, for producing a spread radiation beam and directing it towards the region of interest. It is an advantage of embodiments of the present invention that a compact device can be obtained.
  • the present invention provides a sensor comprising
  • the radiation carrier for carrying at least a radiation beam
  • the radiation carrier comprising a surface
  • At least one excitation grating on the surface of the at least one radiation carrier, for directing at least an excitation radiation beam into a region of interest (ROI),
  • ROI region of interest
  • At least one structure for instance but not limited thereto, an emission grating or planar optics, for redirecting, e.g. reflecting, radiation from the region of interest into the at least one detector.
  • the at least one structure e.g. emission grating of planar optics
  • positioned and adapted for redirecting, e.g. reflecting, radiation may be adapted to further collimate the redirected, e.g. reflected, radiation from the region of interest to the at least one detector. Collimation of the radiation allows as much radiation as possible to hit the detector, such that a usable amount of radiation for getting reliable results hits the detector.
  • the at least one structure e.g. emission grating or planar optics, for redirecting, e.g. reflecting, radiation
  • the at least one structure e.g. emission grating or planar optics, for redirecting, e.g. reflecting, radiation
  • the at least one structure e.g. emission grating or planar optics, for redirecting, e.g. reflecting, radiation
  • the at least one radiation carrier may comprise planar optics for producing and directing a spread excitation radiation beam towards a region of interest.
  • a ROI may comprise a wide length or volume of a microfluidic channel, or a big area. A larger ROI can be created.
  • the present invention provides a microfluidic device comprising a sensor according to any of the embodiments of the first aspect, and further comprises a substrate being transparent for at least the radiation beam, wherein the region of interest is defined.
  • a microfluidic device according to embodiments of the present invention may furthermore be transparent for the redirected emission radiation.
  • the substrate may further comprise a microfluidic channel.
  • the at least one detector may be a detector array, and the microfluidic channel may be interlayered between the radiation carrier and the detector array.
  • the present invention provides a system that comprises, as separate devices
  • microfluidic chip comprising at least one microfluidic channel
  • the radiation carrier for carrying at least a radiation beam
  • the radiation carrier comprising a surface with at least one excitation grating, positioned and adapted to couple an excitation radiation signal directionally out of the radiation carrier thereby illuminating a pre-defined volume of the microfluidic channel, and at least one structure, e.g. emission grating or planar optics, positioned and adapted to redirect, e.g. reflect, emission radiation origination from the pre-defined volume;
  • a readout device adapted to be operatively coupled with the microfluidic chip, wherein the readout device comprises at least one detector for detecting the redirected emission radiation originating from the pre-defined volume, when the microfluidic chip and the readout device are operatively coupled.
  • the emitted radiation must travel a distance which may be several mm to cm. Therefore the radiation may have to be collimated if a usable amount of radiation should hit the detector.
  • the readout device may comprise a slot for receiving the microfluidic chip.
  • the present invention provides a diagnostic device comprising a sensor according to embodiments of the present invention, and an output unit for providing an output of the sensor on which a diagnose can be based.
  • the output unit may be adapted for outputting a signal representative for presence/absence or concentration of an analyte in a pre-defined volume of the microfluidic channel.
  • the present invention provides a method of performing particle detection.
  • the method comprises
  • providing radiation scattering centers may comprise attaching radiation scattering centers to analytes.
  • luminescence e.g. fluorescence
  • cytometry it is an advantage of embodiments of the present invention that luminescence, e.g. fluorescence, cytometry can be used with the present method.
  • attaching radiation scattering centers may comprise attaching at least one type of luminophores, e.g. fluorophores, or chromatophores, or a mixture thereof.
  • luminophores e.g. fluorophores, or chromatophores, or a mixture thereof.
  • inserting scattering centers within a region of interest may further comprise providing a flow of scattering centers through the region of interest.
  • inserting scattering centers within a region of interest may comprise attaching analyte carrying scattering centers to affinity probes.
  • FIG. 1 illustrates a lateral view of a radiation carrier according to embodiments of the present invention, comprising, as an example only, and not intended to be limiting for the present invention, excitation and emission gratings, a region of interest (ROI) and at least one detector.
  • excitation and emission gratings comprising, as an example only, and not intended to be limiting for the present invention, excitation and emission gratings, a region of interest (ROI) and at least one detector.
  • ROI region of interest
  • FIG. 2 illustrates a schematic perspective view of a planar waveguide according to embodiments of the present invention, comprising, as an example only, and not intended to be limiting for the present invention, excitation and emission gratings, a ROI, two detectors and a forward-scattering detector.
  • FIG. 3 shows a model of the angular distribution of the radiation from an oscillating dipole radiator before and after incidence on a collimating holographic detector.
  • FIG. 4 illustrates the front view of a planar waveguide according to embodiments of the present invention, with spread excitation gratings and focusing emission gratings, a system for introducing analytes in the ROI and three diagrams showing the results in time of the forward-scattering detector and the detectors receiving radiation from the emission gratings.
  • FIG. 5 illustrates the front view of an alternative arrangement of detectors with respect to the gratings, according to embodiments of the present invention.
  • FIG. 6 illustrates a flowchart of method according to embodiments of the present invention.
  • a particle or “particles”, this may refer to biological material such as, but not limited thereto, cells, exosomes, viruses.
  • a fluid sample may refer to a fluid of a biological nature, e.g. a body fluid such as, but not limited to, blood, saliva, urine.
  • the fluid sample may also refer to a fluid of a non-biological nature but suitable for transporting a particle as defined above, e.g. a saline solution.
  • planar laser beam reference is made to a laser sheet, for example a laser beam spread and formed into a thin sheet by a long focal length spherical lens and a cylindrical lens. Any suitable system may be used.
  • a “planar waveguide” is understood as a slab waveguide with substantially parallel flat surfaces, so the radiation travels inside via total internal reflection.
  • a grating e.g. an out-coupling grating
  • This beam may be used as an excitation beam for analyzing samples or particles, and it is referred to as “excitation grating”.
  • a grating that receives the beam after interaction with a sample or particle, and redirects it to a detector e.g. reflects the radiation or couples the radiation into a waveguide
  • the present invention is not limited to said waveguides, nor to optical lasers, nor to the presence of emission gratings.
  • the radiation carrier comprises a structure for redirecting emission radiation emanating from the region of interest.
  • region of interest or “ROI”
  • ROI region of interest
  • the ROI comprises a portion of a microchannel, for example in a microfluidic device.
  • optical sensor reference is made to a device suitable for sensing photons, for example using IR radiation, visible radiation, UV, etc.
  • luminescence of a target reference is made to emission of radiation by the target, not resulting from thermal emission.
  • luminescence will be photoluminescence, generated by absorption of photons; such as fluorescence or phosphorescence.
  • the present invention is not limited to this type of luminescence, and can also be applied in case of, for instance, bioluminescence or chemiluminescence (emission as a result of a (bio)chemical reaction by an organism) or electroluminescence (a result of an electric current passed through the target).
  • Raman scattering on the target reference is made to photons being scattered from the target when the latter is illuminated. Reference is made more particularly to inelastic scattering, where photons are scattered by an excitation, with the scattered photons having a frequency different from that of the incident photons.
  • the Raman effect differs from the process of photoluminescence in that for the latter, the incident radiation is absorbed and the system is transferred to an excited state from which it can go to various lower states.
  • the result of both processes is in essence the same: a photon with a frequency different from that of the incident photon is produced, and the molecule is brought to a different energy level.
  • the major difference is that the Raman effect can take place for any frequency of incident radiation, while photoluminescence occurs only at a particular frequency of incident radiation.
  • affinity probes refers to the substance having a certain affinity, e.g. a natural attraction, to the analyte, the substance having or not having a biological origin.
  • substance having a biological origin we intend to mean a substance that is present or produced in a living organism, or has similar properties and/or structure and/or composition.
  • the affinity probe may be an antibody, an antigen, an enzyme, a receptor, an aptamer, a nucleic acid aptamer, a peptide aptamer, or a molecularly imprinted polymer (MIP).
  • MIP molecularly imprinted polymer
  • the present invention relates to an optical sensor suitable for particle analysis, such as analysis via flow cytometry, the present invention not being limited thereto.
  • the optical sensor comprises a radiation source, advantageously a substantially coherent radiation source (e.g. laser). Radiation from the radiation source may be guided or transported by a waveguide. At least one excitation grating may be provided on the waveguide to direct the radiation beam towards a ROI, which may comprise a particle, a plurality of analytes in a flow of particles, etc. The radiation beam is made to interact with the at least one particle, which may be fluorescent in itself, or may be labeled with a fluorescent label.
  • One or more structures, for instance emission gratings may collect the radiation scattered from the ROI and redirect, e.g.
  • the structures may for example collimate the radiation from the ROI (upon redirecting, e.g. reflecting, it into one or more detectors), but the present invention is not limited to collimation, and alternatively the structures, e.g. emission gratings, may focus the redirected, e.g. reflected, radiation into one or more detectors.
  • the radiation source couples radiation into a radiation carrier comprising at least one excitation grating, for outcoupling radiation from the radiation source.
  • the radiation carrier is optimized for carrying laser beams.
  • the radiation carrier may be waveguide, for example a strip or planar waveguide or a slab waveguide.
  • the excitation grating on the radiation carrier may be a focusing grating, or a grating providing e.g. a planar excitation beam, and it may be patterned as a grating coupler, the present invention not limited thereto.
  • the focusing grating may comprise planar dielectric grating reflectors with focusing abilities, a Fresnel lens, etc.
  • the excitation grating may be patterned, oriented or adapted to direct or focus radiation on a ROI, for example it may comprise gratings and patterns on the surface of a waveguide, so upon passage of a laser beam travelling in a radiation carrier, e.g.
  • the beam may exit the radiation carrier and be directed to, e.g. focused into, a ROI.
  • the structure may be adapted to focus the radiation in a volume of substantially similar size as the expected cells. If the radiation is focused in a volume much smaller than a cell, the reliability of the detection system is reduced due to the strong variation of the signal. In embodiments of the present invention, on the other hand, the radiation is not necessarily focused on a volume smaller than a cell. A consistent illumination is obtained, which increases the reliability. Focusing radiation in a volume of size similar to the size of a cell may be done for instance by a dotted lens, which is a metalens formed by a structure of pillar elements in a close grid. A phase change is caused by passing the radiation through the pillar elements.
  • the phase change can be very accurately tuned.
  • the pillar design can be a good basis to create lenses with additional functionality, such as a strong spectral change.
  • the excitation grating may also, instead of focusing, spread the radiation on a ROI (e.g. providing a planar laser beam), for example on a line or an area of a transparent conduit such as a microfluidic channel. It may comprise material suitable for transmission of the radiation, such as silicon nitride.
  • the control of illumination in the ROI advantageously reduces noise, because the ultimately detected signal may stem solely from the ROI and not from neighboring regions.
  • the radiation carrier e.g. waveguide
  • the radiation carrier comprises at least one structure, for instance an emission grating or planar optics, for redirecting, e.g. reflecting, any radiation emanating from the ROI to one or more detectors.
  • the redirected, e.g. reflected, radiation is collimated to the one or more detectors.
  • the structure, e.g. gratings may focus the radiation towards the one or more detectors, rather than collimating the radiation.
  • radiation from the ROI may be laser radiation scattered for example by fluorescence, and it may be redirected, e.g. reflected, by the structure, e.g. emission grating, into one or more detectors.
  • the one or more structures may comprise a Fresnel lens, or any suitable optical element.
  • the structure can be a dielectric reflector.
  • the structure e.g. emission grating
  • one or more structures, e.g. emission gratings may be coplanar and may be located next to the excitation grating.
  • a structure e.g. an emission grating
  • the detector When used in reflection mode, the detector will be located at a same side of the radiation carrier as the structure, e.g. emission grating.
  • the detector When used in transmission mode, the detector will be located at an opposite side of the radiation carrier compared to the structure, e.g. emission grating, and the detected radiation is sent substantially transversally through the radiation carrier to a detector.
  • the structure, e.g. emission grating may for instance be formed by a Fresnel lens that directs radiation to the other side of the radiation carrier.
  • the at least one structure e.g. emission grating, and the excitation grating may extend on a same surface of the waveguide.
  • the structure may be implemented as an emission grating, and the emission grating and the excitation grating may be combined into a single grating region.
  • one continuous grating surface comprising an emission grating and an excitation grating, may be formed, with optimized patterns in different zones for one or another behavior (obtaining excitation beam or reflecting radiation).
  • part of the continuous surface may comprise solely dielectric grating, while part of the surface (the emission gratings) may comprise an additional reflective layer such as a metal layer.
  • the grating surface may have a homogeneous or preferably an inhomogeneous pattern in the whole surface.
  • the same type of gratings can be used for the emission grating and the excitation grating.
  • Fresnel lenses can be used.
  • Dielectric gratings can also be used, but since these are designed for particular wavelengths, they might cause more aberrations.
  • a laser beam traveling through the radiation carrier may be transmitted through a grating acting as an excitation grating and may be focused on a ROI, in a point or on a line. Any radiation scattered by particles in the ROI may be reflected by the same grating surface, but by the section acting as an emission grating, into a detector. This may be possible by fine tuning of the patterning, for example.
  • different zones of the structure positioned and adapted for redirecting emission radiation emanating from a region of interest may be adapted to redirect, e.g. reflect, different parts of the spectrum, e.g. by adapting its grating, properties of a reflective layer, etc.
  • particle discrimination by redirecting, e.g. reflecting, signals from a first predetermined wavelength range to a first detector and from a further predetermined wavelength range to a different further detector.
  • a first type of scattering centers e.g.
  • a first type of fluorophores may attach to a first type of analyte, while a further type of scattering centers (e.g. one or more different types of fluorophores) may attach to a further type of analyte.
  • the first analyte may be detected by a first detector while the further analyte may be detected by a further detector.
  • the signals from first and second analyte may e.g. be signals from different fluorescent markers, e.g. different fluorophores labelling correspondingly different types of cells, viruses, exosomes, etc.
  • Particle discrimination may be obtained alternatively or additionally by including a filter on the structure, e.g. emission grating, or on the detection system. With a diffractive grating, part of the filtering may be done by the grating itself.
  • the at least one detector may be a plurality of detectors, such as specialized detectors, which may be only sensitive to a part of the spectrum, e.g. infrared or ultraviolet detectors, or detectors of radiation within a particular region of the visible range.
  • a plurality of different spectral filters each filter having a different central wavelength, may filter the signal before it reaches a corresponding detector in a system with a plurality of detectors.
  • the plurality of detectors may be used to each detect a signal corresponding to a different part of the spectrum.
  • both excitation and collection systems may be aligned or at least roughly aligned, reducing or even avoiding calibration and alignment steps.
  • the system so built may be compact and low cost, as it does not require multiple pieces or complex assembling.
  • the sensor may be used in flow cytometry and an additional detector, collinear with the source of radiation and the ROI, may be used for counting particles and obtaining data regarding characteristic compound on a cell. Scattering date may be used to determine size.
  • inorganic and organic dyes may be used.
  • one or more types of target cells, or viruses, or any other analyte may be labelled with tagging antibodies comprising chromatophores, fluorophores, etc.
  • Some embodiments of the present invention may be applied to detect and analyze quantum dots, for example using UV laser. This may be useful in biological analysis (quantum dots as tagging particles), but it may also be used in semiconductor technology. In general, the present invention may suitable be for fields of technology involving optical analysis of particles.
  • FIG. 1 Some embodiments of the sensor of the present invention are described with reference to FIG. 1 , FIG. 2 and FIG. 4 , FIG. 5 .
  • FIG. 1 shows a lateral view of a radiation carrier 100 , such as a waveguide, comprising a grating 101 on its top surface 102 .
  • the radiation carrier 100 may be an optical fiber, or more preferably a rectangular waveguide.
  • the radiation carrier 100 may be made from any suitable material, such as for instance glass, polymer or suitable semiconductor material.
  • Radiation 103 emanating from a radiation source (not illustrated) is coupled into the radiation carrier 100 , and travels there through, for instance by total internal reflection, until it exits through an excitation grating 101 .
  • the thus exciting excitation beam 104 may be adapted for being focused into a ROI 105 , which in the figure illustrated contains a particle 106 , for example a cell.
  • the grating 101 may be adapted to focus the beam 104 into the whole ROI, or more than half of the ROI, or advantageously into a volume of the same order of magnitude as the particles to be analyzed, for example a volume of one or more cells.
  • the radiation 107 scattered from the particle 106 present in the ROI 105 falls into an emission grating 108 , where it is reflected and collimated, such that the reflected and collimated beam 109 is suited for entering a detector 110 .
  • an emission grating 108 In the embodiment illustrated in FIG. 1 , only one emission grating is shown, but the invention is not limited thereto, and also encompasses embodiments with more than one emission grating.
  • FIG. 2 shows a perspective view of a planar waveguide 200 comprising an excitation grating 201 on the waveguide surface 202 , with a radiation signal 203 travelling within the waveguide 200 , for example via total internal reflection.
  • the excitation grating 201 disturbs the surface 202 of the planar waveguide 200 , and radiation escapes from the waveguide 200 , thus forming an excitation beam 204 .
  • the excitation grating 201 has a pattern that allows focusing the excitation beam 204 on a ROI 205 .
  • a fluorescent analyte 206 e.g. an analyte such as a cell showing fluorescence (e.g.
  • the radiation reflected by the at least one emission grating 208 may be focused onto a detector surface.
  • a further (optional) forward-detector 213 may be placed so as to detect a shadow as a hologram of the cells moving through the ROI.
  • the forward detector 213 detects along the same axis as the incoupled excitation beam 204 .
  • the signal from the forward detector 213 can be used as comparative signal (e.g. to detect whether a particle 206 or analyte passes through the ROI 205 ), or as an indication of the size of the particle 206 or analyte in the ROI 205 .
  • This may be advantageous for distinguishing different bodies passing through the ROI 205 , for example for distinguishing bodies with attached luminophores, e.g. fluorophores, from unattached luminophores, e.g. fluorophores.
  • the patterns of the gratings in accordance with embodiments of the present invention may be made so as to spread, collimate or focus the radiation.
  • Different types of gratings excitation grating, emission grating
  • the excitation gratings 101 , 201 of FIG. 1 and FIG. 2 may be adapted (e.g. patterned, by adding a lens system, by forming a Fresnel lens, etc.) for focusing the excitation beam 104 , 204 which exits the radiation carrier 100 , 200 , into the ROI 105 , 205 .
  • no extra patterning like an extra Fresnel pattern, is needed to focus the excitation beam 104 , 204 coupled out of the waveguide, as the excitation grating per se can do the job.
  • the one or more emission gratings 108 , 208 of FIG. 1 and FIG. 2 may be patterned for collimating the reflected radiation 107 , 207 into the detectors 211 , 212 . Collimation using emission gratings 108 , 208 can be highly accurate.
  • the diagrams of FIG. 3 show a model of the angular distribution of radiation from an oscillating dipole radiator, which can be used for modelling a point source radiator, e.g. a Raman scattering molecule or a luminescent molecule such as e.g. a fluorescent molecule.
  • the left diagram 300 of FIG. 3 shows the angular distribution of the radiation reaching the emission grating. It is spread over an angle between approximately 35° (on the 45° direction) and 25° (on the 90° direction).
  • the right hand diagram 310 of FIG. 3 shows the angular distribution of the radiation after being reflected and collimated by the emission grating. The angular distribution of the radiation is concentrated in a single direction, at 10°.
  • FIG. 4 shows a front view of a planar waveguide 400 comprising an excitation grating 401 on a surface 402 , surrounded by a first and second emission gratings 403 a , 403 b .
  • FIG. 4 also schematically illustrates a radiation signal 203 traveling within the waveguide 400 .
  • the excitation grating 401 spreads the exiting excitation beam 404 on the ROI 205 .
  • the spread excitation beam 404 may be planar and may extend over a length defining the ROI 205 , for instance it may span the width of the microfluidic channel.
  • emission gratings 403 a , 403 b are designed to focus the radiation in a point on a detection surface.
  • a scattering center e.g. a fluorescent analyte
  • the scattered radiation is collected in the first and second emission gratings 403 a , 403 b .
  • the emission gratings 403 a , 403 b may each reflect radiation of the complete spectrum, or they may reflect radiation within a first range of wavelengths and a second range of wavelengths, respectively.
  • the radiation falling on the first and second emission gratings 403 a , 403 b may be reflected and focused (instead of being collimated) and sent into detectors such as the ones of FIG. 2 or into a detector array 405 like the one shown in FIG. 4 .
  • the detector array 405 may comprise a plurality of detecting regions 406 , 407 , 408 , for example a plurality of regions 406 , 408 for detecting radiation scattered from the ROI and a region 407 for detecting shadows as a hologram of the particles moving in the ROI 205 .
  • the lateral position of cells in a ROI can be obtained as an image, for example.
  • the shadow of the excitation line that falls on detecting region 407 can be used to verify the particles and possibly to do a size measurement.
  • FIG. 1 and FIG. 2 illustrate embodiments with a focusing excitation grating and one or more collimating emission gratings.
  • FIG. 4 illustrates an embodiment with a spreading excitation grating and a plurality of focusing emission gratings.
  • this is not intended to be limiting for the present invention, and also other combinations of types of excitation gratings and emission gratings are envisioned to be part of the present invention.
  • any suitable type of excitation grating e.g. focusing, collimating, spreading
  • any suitable type of emission grating e.g. focusing, collimating, spreading
  • any suitable type of emission grating e.g. focusing, collimating, spreading
  • Embodiments of the first aspect of the present invention may further comprise microfluidic channels, for example a microfluidic chip in combination with a radiation carrier, excitation and emission gratings and optionally any planar or strip optics, and one or more detectors.
  • the one or more detectors can be integrated in the microfluidic chip.
  • the imager can be on top of the microfluidic chip.
  • FIG. 4 An example of embodiments comprising a microfluidic channel is shown in FIG. 4 , in which a transparent substrate 409 comprises a microfluidic channel 410 .
  • the region of the channel 410 illuminated by the excitation radiation 404 comprises the ROI 205 .
  • the excitation grating 401 spreads the radiation over substantially the whole of the width of the channel 410 , optimizing the ROI 205 within the channel 410 .
  • the radiation may be spread e.g. in a planar sheet, for example a planar laser beam, although the present invention is not limited thereto. If a particle, e.g. a fluorescent marker attached to an analyte, crosses the ROI 205 , excitation radiation is scattered on or by the fluorescent marker.
  • a particle e.g. a fluorescent marker attached to an analyte
  • Back-scattered radiation from the ROI 205 is in this case reflected and focused by the emission gratings 403 a , 403 b into a point just above the microfluidic chip, e.g. into the zones 406 , 408 of a detector array 405 , which may be a line array, a camera, etc.
  • the transparent substrate 409 may further focus the radiation reflected by the emission gratings.
  • This configuration may advantageously simplify the microfluidics as well as increase the throughput.
  • the detectors may be placed a few millimeters away from the emission grating, or at least a distance enough to allow the definition of a ROI (e.g. allow the placement of microfluidic channels for defining a ROI).
  • the three diagrams 420 , 421 and 422 at the top of FIG. 4 show the signal measured by the detector array region 406 on the left, the region 407 on the center and the region 408 on the right, respectively, as a function of time.
  • the central diagram 421 the shadow or hologram region, would detect the passing of particles (e.g. via forward-scattering).
  • the left diagram 420 may detect one type of scattering centers, e.g. red fluorophores attached to a first type of analytes, while the right diagram 422 may detect a second type of scattering centers, e.g. green fluorophores attached to a second type of analytes.
  • the analysis of the graphs produces a reconstruction of the particles flowing through the channel, in addition to the fluorescent signal that matches these particles.
  • the present invention is not limited to the distribution of optical elements as illustrated in FIG. 4 .
  • a radiation carrier as illustrated in FIG. 4
  • detector arrays may be placed aside the radiation carrier, e.g. waveguide, as illustrated in FIG. 5 .
  • a plurality of detectors planes may be available.
  • FIG. 5 shows two detector arrays 501 , 502 substantially perpendicular to the surface of the radiation carrier 400 containing the excitation grating 401 (e.g. a grating for spreading the beam as in FIG. 4 ) and the emission gratings 503 , 504 (e.g. collimating gratings).
  • the radiation scattered from the ROI 205 may be collected in the detector arrays 501 , 502 after reflection by the emission gratings 503 , 504 (focused or, as shown in the image, collimated).
  • This geometry may be advantageous for avoiding circuitry or other elements in the top part of the circuit. For instance, analytes may be introduced through the top of the device into the ROI 205 , instead of through the zone between the excitation grating 401 and the detector array.
  • the embodiment of FIG. 5 may comprise affinity probes in the ROI 205 .
  • the microfluidics are provided, e.g. patterned, in or on top of a chip (e.g. a CMOS chip) and are closed by a transparent cover, so that the radiation (e.g. light) reflected by the emission gratings can reach at least one detector.
  • the microfluidics may force a fluid comprising particles through a channel comprising the ROI, for instance by capillary action or driven e.g. by using pumps or similar, so that the particles interact with the focus spot of the excitation grating and emission gratings.
  • Embodiments of the present invention may further comprise a first and a second microfluidic compartment fluidically interconnected via at least one micro-fluidic channel comprising a ROI.
  • the second micro-fluidic compartment may comprise or may be connected to a capillary pump for pumping a fluid sample from the first to the second micro-fluidic compartment via the at least one microfluidic channel.
  • the chip may comprise also an on-chip radiation source such as a light source, optically coupled to the radiation carrier (e.g. a waveguide).
  • Embodiments of the first aspect of the present invention have been described where particles to be detected or analyzed are in flow.
  • Alternative embodiments of the present invention may comprise a substrate comprising affinity probes suitable for binding the particles under interest, for being investigated in a static situation.
  • analytes are fixed to at least a portion of a substrate provided with relevant affinity probes, e.g. antibodies, antigens, enzymes, receptors, aptamers, nucleic acid aptamers, peptide aptamers or molecularly imprint polymers (MIP).
  • relevant affinity probes e.g. antibodies, antigens, enzymes, receptors, aptamers, nucleic acid aptamers, peptide aptamers or molecularly imprint polymers (MIP).
  • MIP molecularly imprint polymers
  • At least a portion of the substrate comprising thus fixed analytes is placed in the ROI.
  • the analytes may further comprise one or more types of attached scattering centers. It is
  • FIG. 1 may depict a waveguide and multiple excitation gratings, for irradiating, e.g. illuminating, multiple ROIs, e.g. in a single or a plurality of microfluidic channels (e.g. comprising particles attached to different types of luminophores, e.g. fluorophores), or in a plurality of affinity probes.
  • a waveguide and multiple excitation gratings for irradiating, e.g. illuminating, multiple ROIs, e.g. in a single or a plurality of microfluidic channels (e.g. comprising particles attached to different types of luminophores, e.g. fluorophores), or in a plurality of affinity probes.
  • the present invention relates to a method of performing particle detection.
  • the method is suitable for detecting analytes, e.g. Raman scattering particles or luminophore labeled particles, such as fluorophore labelled particles, although the present invention is not limited thereto.
  • the method includes irradiating particles or cells in a ROI (e.g. a volume of the same order of magnitude of the particles or cells to be analyzed), for example using an excitation grating for producing emission of radiation characteristic of the particle or cell, collecting that emitted radiation in at least one grating, and sending (e.g. by reflection) said radiation to a detector (e.g. optical detector, fluorescence detector, etc.).
  • a detector e.g. optical detector, fluorescence detector, etc.
  • providing 600 scattering centers may comprise providing particles that scatter radiation within a particular wavelength range, for example laser radiation.
  • the scattering centers may for instance be fluorescent labels.
  • the scattering centers may be attached 601 to analytes.
  • different types of scattering centers having the feature of radiation scattering at different wavelengths, may be attached to different types of analytes.
  • one type of scattering center may be attached to tumor cells while others may be attached to healthy cells.
  • the scattering centers may be present in a fluid, such as blood, urine, saliva, buffer, a solution, etc., and providing scattering centers may comprise binding scattering centers to analyte while the analyte is present in the bulk of a liquid, optionally in flow.
  • the analyte may be bound to affinity probes, and providing scattering centers may comprise binding scattering centers to analyte bound to affinity probes.
  • a further step comprises outcoupling 610 radiation from a radiation carrier, via an excitation grating.
  • Providing radiation may comprise providing 611 laser radiation, with a wavelength for example between IR and UV wavelengths.
  • the type of radiation and its characteristics can be selected to obtain a suitable scattering of the scattering centers, for example via fluorescence.
  • the radiation may be provided continuously or discontinuously.
  • a further step comprises inserting 620 the scattering centers within a ROI.
  • they may be introduced 621 in a fluid through a microfluidic channel (in flow), or affinity probes may be placed 622 in the ROI, to which analyte under interest has bound or may bind.
  • the interaction of the radiation beam from the excitation grating with the scattering centers will produce scattered radiation, e.g. fluorescence, which shall be collected and directed 630 from the ROI, via emission gratings, to at least one detector.
  • Directing 630 radiation from the ROI to a detector may comprise directing 631 radiation within a predetermined wavelength range to a predetermined detector, and radiation within a further predetermined wavelength range to another predetermined detector.
  • the reflection in the emission grating may comprise either focusing 632 or collimating 633 the radiation to the at least one detector.
  • a further step comprises monitoring 640 emission of radiation from the ROI.
  • This step comprises monitoring emissions reflected by the one or more emission gratings, and it may further comprise monitoring forward scattered radiation.
  • any suitable technique may be used, such as photoelectric cells, analog to digital converters, outputs, etc.
  • a step of filtering 641 radiation within a predetermined range of wavelengths may be included, for example a threshold filter, chromatic filter, polarization filter, etc. Further steps such as performing 642 peak detection or labelling 643 scattering centers may be applied.
  • Different particles may present different response to the same radiation. It is possible to discern between different responses in embodiments of the present invention, e.g. by use of filters for filtering the radiation impinging on the detectors.
  • some embodiments of the present invention may comprise laser-induced fluorescence.
  • different types of luminophores e.g. fluorophores
  • different spectral filters may be used in the detector or detectors to filter the emission radiation signal. As an advantage, detection of emission radiation may be performed more efficiently. For example, a peak in the emission radiation signal may be detected more efficiently.
  • a single emission waveguide may be optically connected to an optical detector having at least two spectral filters.
  • the optical detector may comprise at least two photodiodes, each photodiode being covered with a different spectral filter.
  • Luminescence, e.g. fluorescence, falling onto the optical detector is filtered by each spectral filter before being detected. This gives rise to at least two luminescence, e.g. fluorescence, signals which may be correlated to improve peak detection.
  • the present invention may be used for cytometry, like flow cytometry. It may be applied to immunophenotyping, ploidy analysis, cell counting or GFP expression analysis.
  • the method and device are advantageous for luminescent flow cytometry, e.g. fluorescent flow cytometry, as a compact and low cost device is obtained, which may be integrated in a chip. It may be easy to use, as it requires little alignment and it is easy to implement in medical devices, either as a microfluidic device or with affinity probes.
  • the senor comprising both the radiation carrier with the at least one excitation grating, the at least one structure positioned and adapted for redirecting emission radiation emanating from a pre-defined volume, and the at least one detector may be integrally built, i.e. may be a single device.
  • Alternative embodiments of the present invention also cover a system comprising different separable parts, e.g. a sample analyzing device and a readout device.
  • the sample analyzing device may be a microfluidic chip comprising at least one microfluidic channel for transporting a fluid sample through the system, and at least one radiation carrier for carrying a radiation beam.
  • the radiation carrier comprises, for instance on a surface thereof, at least one excitation grating, positioned and adapted to couple the excitation radiation signal carried by the radiation carrier directionally out of the radiation carrier thereby illuminating a pre-defined volume of the microfluidic channel, and at least one structures such as for instance an emission grating, positioned and adapted to redirect, e.g. reflect, emission radiation origination from the pre-defined volume.
  • the readout device may comprise at least one detector, for instance a detector array, for detecting the redirected, e.g. reflected, emission radiation originating from the pre-defined volume.
  • the readout device may be adapted, for instance may be provided with a slot, for receiving the sample analyzing device.
  • the sample analyzing device may have the shape and size of an SD card, for instance the shape and size of a micro-SD card or similar.
  • the sample analyzing device may include a radiation source, e.g. a light source, for coupling radiation into the radiation carrier.
  • the radiation source may be provided on or in the readout device, such that radiation may be coupled into the radiation carrier of the sample analyzing device, when the sample analyzing device and the readout device are operatively coupled to one another.
  • Device features of the system comprising different separable parts are as explained in the embodiments of the integrally built device, and are not repeated here for sake of conciseness.

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CN107850537A (zh) 2018-03-27
US20210072141A1 (en) 2021-03-11
CN107850537B (zh) 2020-05-19
JP6505260B2 (ja) 2019-04-24
WO2017001609A1 (fr) 2017-01-05
CA2991087C (fr) 2019-12-03

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