WO2007077218A1 - Système optique ; puce optique pour un système optique et procédé d'utilisation d'une puce optique pour une opération analytique - Google Patents

Système optique ; puce optique pour un système optique et procédé d'utilisation d'une puce optique pour une opération analytique Download PDF

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Publication number
WO2007077218A1
WO2007077218A1 PCT/EP2007/000029 EP2007000029W WO2007077218A1 WO 2007077218 A1 WO2007077218 A1 WO 2007077218A1 EP 2007000029 W EP2007000029 W EP 2007000029W WO 2007077218 A1 WO2007077218 A1 WO 2007077218A1
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Prior art keywords
chip
optical
sample
chamber
interface
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PCT/EP2007/000029
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English (en)
Inventor
Sergey I Bozhevolnyi
Mads Hoy Sorensen
Peter Theilade Thomsen
Michael Hansen
Kristjan Leosson
David Edward Williams
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Inverness Medical Switzerland Gmbh
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Publication of WO2007077218A1 publication Critical patent/WO2007077218A1/fr

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    • 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
    • G01N21/0303—Optical path conditioning in cuvettes, e.g. windows; adapted optical elements or systems; path modifying or adjustment
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • 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
    • G01N21/648—Specially adapted constructive features of fluorimeters using evanescent coupling or surface plasmon coupling for the excitation of fluorescence
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0654—Lenses; Optical fibres
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions

Definitions

  • This invention relates to an optical system allowing light incoupling (i.e., incoming light) in the total internal reflection (TIR) geometry to a sensing surface and light outcoupling (i.e., outgoing light) suitable for imaging/sensing the sensing surface onto a detector unit.
  • the invention also relates to an optical chip design with added functionality for use in biological research, drug discovery and diagnostics, specifically in studies of cellular events, surface binding events, blood, antibodies, protein/DNA detection. Furthermore the invention relates to a method of using an optical chip for an analytical operation that employs optical detection.
  • Molecular diagnostics is of critical importance to public health. This area of medical technology will facilitate the detection and characterization of disease, the monitoring of drug response, and the identification of genetic modifiers and disease susceptibility. Molecular diagnostics will also be used to identify food, water, and environmental contamination and the possible presence of biological warfare agents. Our method also supports nucleic acid-based methods to support DNA detection and analysis and to pinpoint changes in gene expression. This is done with high accuracy and reproducibility of the tests and literally no training required by users.
  • POC (point-of-care) nucleic acid methodologies could play a pivotal role in the early diagnosis of diseases, facilitating their prompt treatment.
  • the tests provide a powerful tool for identifying myriad microorganisms known to be associated with sexually transmitted diseases, infections of the immunocompromised host, and many other diseases. Further, these tests aid in the critical evaluation of disease predisposition.
  • test is completely self-contained, eliminating any risk of cross-contamination.
  • Our system may be included in or combined with gene chips, DNA probe technology, micro fluidics, and tandem mass spectrometry, among others. This will add high sensitivity to speed in probe-based tests.
  • Nucleic acid amplification techniques are a main focus of interest because of the general need for high sensitivity. This involves selective amplification of the target region of the molecule (which may also be used to label the product intended for detection), and specific detection of the amplified product. PCR is the dominant amplification technology considered but other methods may challenge this in various areas. Genomics-based assays represent an application too in relation to genomic tests such as Factor V Leiden and cystic fibrosis panels. Larger molecular infectious- disease opportunities such as viral load testing, viral genotyping, and detection of sexually transmitted diseases are considered too.
  • Infectious Diseases demands high sensitivity and specificity with rapid turnaround, all of which are offered by our chip platform. This expands to testing for pathogen identification, strain verification, viral load monitoring, and drug-resistant strains, pharmacogenomics will be used in concert. The capabilities of these tests will allow the physician not only to identify the illness-causing pathogen, but also to determine its resistance or susceptibility to a drug. Clinical Genetic Testing
  • Our chip may be used in current strategies for prenatal testing which rely primarily on biochemical assays and imaging methods for whole-chromosome analysis. Also genomic testing associated with preimplantation genetic diagnosis is considered. Paternity testing is based mostly on measuring the size of selected short tandem repeats, although some believe that this field will in time adopt testing for single- nucleotide polymorphisms (SNPs) as a more cost-effective approach. Many genetic diseases are detected through assays directed at proteins or metabolites rather than by characterizing DNA sequences. We keep a main focus on assays for thrombotic risk, cystic fibrosis, and certain other heritable genetic disorders, for human leukocyte antigen typing, and for predictive testing in selected populations.
  • SNPs single- nucleotide polymorphisms
  • Refractive index differences at an interface regulate how light is refracted or reflected as function of incident angle.
  • Light incident at any angles higher than the critical angle is totally reflected at the interface and generates a thin electromagnetic field near the surface of the lower refractive index media. This field is called the evanescent field and its intensity decays exponentially with distance from the surface, usually over 200 run.
  • This surface confined illumination principle allows selective monitoring of surface and binding events without introducing background signal as known from conventional illumination techniques, e.g. conventional epi- illumination.
  • the intensity of the evanescent field as function of the distance from the interface can be determined via solving standard boundary conditions obtained from Maxwells equations, in this document we refer to the results obtained by Nikolas Chronis, Luke P Lee, Lab Chip, 2004, 4, 125-130.
  • the TER. concept has been introduced in to microscope systems, e.g. Olympus, Nikon and Zeiss.
  • the newest systems use microscope objectives with high numerical aperture to enable light to be guided through the objective and onto an interface above the critical angle.
  • an object flows through or settles near the interface at which total internal reflection occurs, scattered light or fluorescence is emitted that allows imaging of the object.
  • the invention provides an optical system for use in analytical operations, comprising:
  • an optical chip with a chamber for a sample the sample having a lower refractive index than the material of at least the part of the optical chip defining a transparent window into the chamber, the interface between the transparent window and a sample in the chamber being defined as the chip- sample interface;
  • the light source is arranged to direct a light beam into the chip-sample interface to generate an evanescent field
  • the detector is arranged to collect light from objects in the sample induced by the evanescent field via the lens, which is either incorporated into the optical chip or is placed between the optical chip and the detector to collect and direct light to the detector.
  • the sample may be a fluid, such as a bodily fluid.
  • the sample may be an aqueous sample.
  • the invention provides an optical chip comprising:
  • the invention provides a method of using an optical chip for an analytical operation of a sample, comprising the steps of: - providing an optical chip with a chamber comprising a transparent window into the chamber, wherein the material of the window has a refractive index which is higher than the refractive index of the sample;
  • a lens and a detector to collect light from objects in the sample induced by the evanescent field, the lens being arranged between the optical chip and the detector.
  • the method may also comprise one or more washing steps.
  • the optical chip of the second aspect may be used in the optical system of the first aspect and/or the method of the third aspect.
  • the system also comprises at least one lens for collecting and focusing light.
  • the system further comprises a light source, which in principle may be any type of light source which can emit light to generate an evanescent field at the chip-sample interface, e.g. a laser.
  • the system comprises a detector for detecting light (such as fluorescence or scattered light) from objects in the sample induced by the evanescent field.
  • the critical angle is measured in relation to the normal incidence of light.
  • the optical chip which is a part of the system may in principle be any kind of optical chip which has a chamber for a sample and a transparent window into the chamber.
  • the optical chip of the optical system may e.g. be a micro fluidic device with or without incorporated optical devices.
  • Useful optical chips are e.g. as disclosed in US 6100541, which with respect to its design, fabrication and materials are hereby incorporated by reference.
  • the optical system may e.g. be used for biological application, specifically for studies of cellular events and surface binding events.
  • the system can be used for sensing/imaging biological samples, especially fluorescence or scattered light from metallic probes.
  • the method does not require the sample to be optically transparent.
  • the optical system may in one embodiment be used for intensity measurement, measuring the light intensity from the sample. In another embodiment the optical system is used for imaging of the sensed area. A combination of the two measurements is also possible.
  • the lens and the detector unit should preferably be selected to the desired measurement.
  • the lens and detector unit can be designed using geometric optics as described in standard text books in optics. Also, commercially available software is available to design optical systems, e.g. Zemax, OSLO.
  • the design criteria are related to the numerical aperture, depth of focus, wavelength, material, resolution, aperture stop and magnification of the optical system. Based on the design criteria ray tracing formulas are developed by applying the laws of refraction and ray propagation which the lens designer uses for adjusting the lens material, shape and position in attempt to optimize its performance.
  • the detector unit is capable of detecting light (such as fluorescence or scattered light) from objects in the sample induced by the evanescent field.
  • the detector can be any photosensitive device such as photodiodes and photomultipliers, intensified detectors, semiconductor sensors such as CCD and CMOS devices.
  • the detector can be an imaging detector.
  • a CCD, CMOS or intensified camera can be used to make measurements in viewing regions on the surface of the chip-sample interface.
  • the invention also relates to a particular optical chip (also called a TIR optical chip) which in one embodiment may be a part of the optical system.
  • a particular optical chip also called a TIR optical chip
  • the optical chip of the invention is as defined in the claims.
  • the invention relates to a TIR-based optical chip with integrated optics that provides a system which makes it more simple to use, as the optical chip makes the system essentially alignment free.
  • the optical chip consists of a polymer material like Polystyrene, TOPAS, PMMA or glass.
  • the chip may have chambers for biological samples. The samples are presumably a liquid solution like blood, other body liquid, or derivatives thereof.
  • Our device is based on a variety of substrate based technologies, such as lipid plates, chips or slides as well as solid beads or micro particles.
  • a number of chemical surface modifiers can be added to substrates to attach the probes to the substrates (see US patent 6,905,816).
  • the optical chip is designed to direct a light beam at an angle larger than the critical angle onto a chip-sample interface (e.g. a polymer-liquid interface).
  • the evanescent field near the surface of the sample can induce scattered light or fluorescence from objects located in the evanescent field.
  • the chip may consist furthermore of an optical readout/collection device.
  • One or more lenses may in one embodiment be integrated in the chip to thereby collect and direct fluorescence or scattered light from objects in the sample (e.g. a liquid solution) onto a detector unit.
  • the lens or lenses is/are not integrated into the optical chip, but is/are simply placed between the optical chip and the detector.
  • the detector unit can be an array type to allow imaging of an area or just a single-unit to detect the light intensity of scattered light and/or fluorescence.
  • the design of the optical chip makes it possible to position a light source without the need to align the light beam into the chip with high accuracy.
  • the light source can be integrated into the chip or be externally positioned. Light from the light source can be directed onto the chip-sample interface via a prism-like interface, grating interface or mirror-like interface to generate the evanescent field.
  • the optical chip of the invention comprises a chamber for a sample and a transparent window into the chamber, and an optical element for directing an incoming light beam towards the interface between the transparent window and the chamber to hit this interface, which is referred to as the chip-chamber interface if the chamber does not comprise a sample, and the chip-sample interface when the optical chip comprises a sample in its chamber.
  • the optical element of the optical chip of the invention is capable of providing a chip-chamber interface light incident at an angle above 50 degrees, such as above 55 degrees.
  • the optical element of the optical chip of the invention is capable of providing a chip-sample interface light incident with an angle above the critical angle when the chamber comprises a sample. In one embodiment the optical element of the optical chip of the invention is capable of providing a chip-sample interface light incident with an angle above the critical angle when the chamber comprises an aqueous sample.
  • the optical element is a prism, e.g. as shown in figure 6.
  • the optical element is a grating, e.g. as shown in figure 7.
  • the optical element is provided by arranging the chip-chamber interface with at least two sections including a side wall chip-chamber interface and a measuring area chip-chamber interface with an angle to each other, so that a light beam directed towards the side wall chip- chamber interface is reflected and redirected towards the measuring area chip- chamber interface in an angle generating an evanescent field.
  • the lens is integrated into the optical chip making the optical readout system robust and essentially alignment-free, hi another embodiment one or more lenses can be positioned externally.
  • the lens can in general be any shape performing the desired function such as spherical, aspheric, Fresneltype or microlens array.
  • the desired functions include magnifying, demagnifying, collimating, light delivery, light collection or focusing functions and the like.
  • the shape of the surface determines the lens properties.
  • the diameter of the lens, distance to the chip-sample interface plane and shape may be selected according to the optical chip application.
  • An optical chip with an integrated lens can be designed by the skilled person, based on the present teaching, to collect and focus light from the sensing area (the area where the evanescent field is generated) onto a detector, e.g. a photodiode, for intensity measurements. Such a configuration is shown below.
  • an optical chip can be designed with an integrated imaging lens to image part of the sensing area onto an array-type detector, e.g. CCD or CMOS sensor. Such a configuration is shown below in figure 3.
  • the imaging lens can be designed to produce a real image of very small objects in the sensing area onto a detector unit.
  • one or more lenses are externally positioned and can function either as a focusing lens/lenses for intensity measurements or as an imaging lens/lenses for imaging measurements.
  • a chip with integrated lens can be combined with one or more lenses for intensity or imaging purposes. Such a configuration is illustrated in Figure 4.
  • the incident light can be similarly coupled out and detected to obtain a calibration reference for the incident light as illustrated in Figure 2.
  • An image sensor CCD or CMOS or similar, can be used to image the sensing area.
  • an image (figure 5) shows a simulated sensor image provided by an optical system of the invention of an object density corresponding to 1 bead/100 image sensor pixels.
  • the images can be processed to evaluate the number of objects in the image.
  • the numbers of objects in the images can e.g. be related to the number of surface binding events.
  • the lens is arranged on the same side of the optical chip as the optical element capable of directing an incoming light.
  • the scattered light or fluorescence from the object generated by the evanescent field need not travel through the whole sample in the chamber, but only the few ran layer of sample between the chip-sample interface and the object. Therefore the sample need not be optically transparent.
  • the lens is arranged on the side of the optical chip opposite the optical element capable of directing an incoming light. In this embodiment it is desired that the sample is optically transparent because the scattered light or fluorescence from the object generated by the evanescent field, should be capable of traveling through the sample in the chamber.
  • One or more lenses can in one embodiment of the optical system be inserted between the chip and the detector unit to increase the imaging quality and/or relax the manufacturing and positioning tolerances.
  • the optical chip can be manufactured by any suitable method depending on which kind of material is used e.g. the method of producing a microfluidic device as disclosed in US 6100541.
  • the optical chip is manufactured using injection moulding.
  • the optical chip may include fluidic or micro fluidic sample transport, such as it is generally known from prior art microfluidic devices.
  • the design can in one embodiment incorporate multiple detection sites on the same optical chip.
  • the optical chip can in one embodiment consist of one chamber. In another embodiment the optical chip can contain one or more chambers. The chambers may also serve mixing, reaction, detection or other functionalities.
  • the light source has low divergence angle so that the light can easily be directed.
  • Sources suitable for such purposes include primarily laser sources such as gas laser, solid state laser, diode laser, VCSEL and liquid laser.
  • suitable sources also include sources such as e.g. an amplified stimulated emission (ASE) source, edge emitting light emitting diodes (EE-LEDS) and LEDs.
  • ASE amplified stimulated emission
  • E-LEDS edge emitting light emitting diodes
  • suitable sources can involve white light sources such as e.g. Xe- lamp
  • the invention also relates to a method of using an optical chip for an analytical operation of a sample. Several steps of the method have already been described above.
  • the method comprises the steps of
  • a lens and a detector to collect light (such as fluorescence or scattered light) from objects in the sample induced by the evanescent field, the lens being arranged between the optical chip and the detector.
  • the optical chip may preferably be an optical chip as described above.
  • Figure 1 is a diagrammatic representation of one optical chip in accordance with the invention.
  • FIG. 2 is a diagrammatic representation of another optical chip in accordance with the invention.
  • FIG. 3 is a diagrammatic representation of a further optical chip in accordance with the invention.
  • Figure 4 is a diagrammatic representation of a yet further optical chip in accordance with the invention
  • Figure 5 is a simulated image of an optical system in accordance with the invention with imaging properties
  • Figure 6 is a diagrammatic representation of a still further optical chip in accordance with the invention.
  • Figure 7 is a diagrammatic representation of a still further optical chip in accordance with the invention.
  • Figure 8 is a diagrammatic representation of a still further optical chip in accordance with the invention.
  • Figure 9 is a diagrammatic representation of a still further optical chip in accordance with the invention.
  • Figure 10 shows a graph of the intensity of the evanescent wave at the interface versus the incident angle
  • Figure 11 shows a graph of the theoretical angular dependence of the penetration depth
  • Figure 12 shows a graph of the theoretical wavelength dependence of the cross section for scattering of light from a gold sphere in a TIR geometry.
  • FIG. 1 The principle of the optical chip structure and path of a light beam is illustrated in figure 1.
  • An optical chip of the invention 1 is shown with a chamber with sample 4, a chip-sample interface 5, and an integrated lens 6.
  • An external lens 7 and detector 8 are also shown.
  • the path of light of the light incoupling 2 is shown entering the optical chip of the invention 1.
  • An optical element 3 directs the light in a TIR configuration.
  • the optical element shown in Figure 1 is a grating, though the element can also be a prism or mirror or combination thereof.
  • the ray of light in the light outcoupling 9 is also shown.
  • the example illustrates that the optical system can operate with multiple detection sites.
  • the example illustrates a case where a lens is integrated into the optical chip and a case without an integrated lens.
  • Figure 2 shows a chip with integrated lens designed to collect and focus light from the TIR sensing area onto a single-unit detector, e.g. a photodiode, for intensity measurements.
  • the example illustrates a case where a lens is integrated into the chip and a case where light is coupled out and detected to obtain a calibration reference for the incident light.
  • 1. Indicates the optical chip. 2. The path of light of the light incoupling. 3.
  • Optical element for directing the light in a TIR configuration this example illustrates a grating, the element can also be a prism or mirror or combination thereof. 4. Chamber with sample. 5. Chip-sample interface. 6. Integrated lens. 7.
  • Optical element for directing the light out of the chip this example illustrates a grating
  • the element can also be a prism or mirror or combination thereof.
  • Detector 9. Illustrating the ray of light in the light outcoupling. 10. Detector.
  • Figure 3 shows a chip with integrated imaging lens for imaging events from the TIR sensing area onto an array-type detector, e.g. a CCD or CMOS sensor.
  • the example illustrates a case where the imaging lens is integrated into the chip and a case where light is coupled out and detected to obtain a calibration reference for the incident light.
  • 1. Indicates the optical chip. 2. The path of light of the light incoupling. 3.
  • Optical element for directing the light in a TIR configuration this example illustrates a grating, the element can also be a prism or mirror or combination thereof. 4. Chamber with sample. 5. Chip-sample interface. 6. Integrated lens. 7.
  • Optical element for directing the light out of the chip this example illustrates a grating, the element can also be a prism or mirror or combination thereof.
  • Detector CCD or CMOS.
  • Detector CCD or CMOS
  • Figure 4 shows a chip with integrated and external imaging lenses for imaging events from the TIR sensing area onto an array-type detector, e.g. a CCD or CMOS sensor.
  • An array-type detector e.g. a CCD or CMOS sensor.
  • 1. Indicates the optical chip. 2. The path of light of the light incoupling. 3.
  • Optical element for directing the light in a TIR configuration this example illustrates a grating, the element can also be a prism or mirror or combination thereof. 4. Chamber with sample. 5. Chip-sample interface. 6. Integrated lens. 7. External lens. 8. Detector (CCD or CMOS). 9. Illustrating the ray of light in the imaging.
  • CCD or CMOS Detector
  • Figure 5 shows a simulated image of the optical system with imaging properties. A bead density of 1 bead/ 100 image sensor pixels is simulated.
  • Figure 6 shows a schematic of an optical system where the TER is obtained in a prism like configuration.
  • Light is incident at a measuring area at an angle greater than the critical angle so that TIR results.
  • the system includes a lens 6 that allows sensing/imaging of the measuring area onto a detector unit.
  • the angle of the tilted sidewall interface is defined to direct light onto a sensing/imaging surface above the critical angle. 1.
  • the path of light of the light incoupling. 3.
  • Optical element for directing the light in a TIR configuration this example illustrates a prism configuration.
  • Chamber with sample 5.
  • Figure 7 shows a schematic of an optical system where the TIR is obtained in a grating configuration.
  • Light is incident at a grating that is diffracted onto measuring area at an angle greater than the critical angle so that TER. results.
  • the system includes a lens that allows sensing/imaging of the measuring area onto a detector unit.
  • the periodicity of the grating is defined to direct light onto a sensing/imaging surface above the critical angle. 1.
  • Optical element for directing the light in a TIR configuration this example illustrates a grating configuration.
  • Chamber with sample 5. Chip- sample interface. 6. Integrated lens.
  • Figure 9 shows a schematic of an optical chip as described in figure 8.
  • the chip furthermore contains: 7.
  • the surface binding events are detected from scattered light from the metal colloids entering the evanescent field.
  • the chip platform may also be used for real time measurement and quantification of bound gold beads or other bead like structures or colloids. This can be done by counting the gold beads or measuring the overall intensity of a signal.
  • the binding mechanism may be DNA or protein mediated in the form of antibody-specific antigens or subunits thereof or any other intermediating substances. The measurements may be mediated by imaging involving a detector unit, e.g. a camera platform, and other hardware as well as software including specific algorithms.
  • the quantification may also be done using fluorescence and in the case of kinetic studies the binding may appear both linear and nonlinear.
  • the fluids to be examined may be any body fluid and components thereof and in particular blood. A quantitative analysis of the properties of the evanescent field and configuration for the optical chip has been performed.
  • An optical chip as disclosed in figure 8 is used.
  • a liquid sample of blood (or derivatives thereof) is introduced into the chamber. Thereafter an antibody labeled colloid metal is dissolved in the chip system.
  • the liquid reaches a reaction chamber where an antigen of interest can mediate the coupling of an Au-antibody to another Antibody which is immobilized into the reaction chamber.
  • the excess blood is removed at the end of the chip. After this one or more washing steps may follow (see figure 9).
  • a laser with wavelength 532 nm is used to provide a light beam with an incident between 62-75 degrees towards the chip-sample interface to generate an evanescent field.
  • a CCD camera is used to make measurements in viewing regions on the surface of the chip-sample interface.
  • Figure 10 shows a graph of the intensity of the evanescent wave at the interface versus incident angle. Left: p-polarization. Right: s-polarisation.
  • the critical angle for TIR is just above 60 degrees.
  • the horizontal axis displays the angle in degrees, the vertical axis displays the intensity in arbitrary units (normalized to incoming intensity).
  • Figure 10 depicts the theoretical angular dependence of the intensity of the evanescent field at the interface.
  • the s-polarized and p-polarized incident amplitudes at the interface are assumed to be unity. Large incident angles reduce the evanescent intensities reducing the scattering or fluorescence signal from an object in the field.
  • the analysis illustrates that the proposed chip design at angle close to the critical angle can produce an evanescent field comparable to the incoming field.
  • Figure 11 shows a graph of the angular dependence of the penetration depth. The horizontal axis displays the angle in degrees; the vertical axis displays the penetration depth in run (1/e).
  • Figure 11 depicts the theoretical angular dependence of the penetration depth of the evanescent field. The figure illustrates that the normal penetration depths are approximately 100 nm. At a very narrow window just above the critical angle higher penetration depths are possible.
  • Figure 12 depicts the wavelength dependence of the cross section for scattering of light from a gold sphere in a TIR geometry. The calculations are based on scattering from gold colloids with 40 nm radius.
  • Figure 12 depicts the theoretical wavelength dependence of the cross section for scattering of light from a gold sphere in a TIR geometry. The analysis illustrates that a wavelength around 530 nm yields the highest scattering efficiency. Analysis has also indicated that s-polarization will give the highest scattering efficiency perpendicular to the surface from a gold sphere.

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  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Abstract

La présente invention concerne un système optique pour une utilisation dans des opérations analytiques. Le système comprend une puce optique avec une chambre pour un échantillon ayant un indice de réfraction inférieur à celui du matériau d'au moins une partie de la puce optique définissant une fenêtre transparente dans la chambre. Le système comprend également au moins une lentille, une source lumineuse et un détecteur. La source lumineuse est agencée pour diriger un faisceau lumineux dans l'interface puce-échantillon afin de générer un champ évanescent, et le détecteur est agencé pour recueillir une lumière (telle qu'une lumière diffuse ou de fluorescence) provenant d’objets dans l'échantillon, induite par le champ évanescent par l'intermédiaire de la lentille, qui est soit incorporée dans la puce optique, soit placée entre la puce optique et le détecteur pour recueillir et diriger la lumière vers le détecteur. L'invention concerne également un procédé d'utilisation du système optique et une puce optique.
PCT/EP2007/000029 2006-01-03 2007-01-03 Système optique ; puce optique pour un système optique et procédé d'utilisation d'une puce optique pour une opération analytique WO2007077218A1 (fr)

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WO2010087999A1 (fr) * 2009-02-02 2010-08-05 Claros Diagnostics, Inc. Structures pour le contrôle des interactions de la lumière avec des dispositifs microfluidiques
GB2495703A (en) * 2011-10-12 2013-04-24 Crowcon Detection Instr Ltd Optical sensor without wavelength filter
WO2014207089A1 (fr) 2013-06-28 2014-12-31 Gothenburg Sensor Devices Ab Structure de guide d'onde
US8926906B2 (en) 2008-07-21 2015-01-06 Concordia University Microfluidic device and method for fabricating the microfluidic device
CN104502516A (zh) * 2015-01-27 2015-04-08 天津出入境检验检疫局工业产品安全技术中心 一种用于聚合甘油三酯的微流控示差折光检测方法
EP2119502B1 (fr) * 2008-05-14 2015-11-04 Sony Corporation Substrat de canal
EP3388816A1 (fr) * 2017-04-11 2018-10-17 Nederlandse Organisatie voor toegepast- natuurwetenschappelijk onderzoek TNO Procédés et instruments pour mesurer des échantillons dans une plaque à cupules
CN108786942A (zh) * 2018-06-15 2018-11-13 京东方科技集团股份有限公司 微流控芯片、微流控装置及其控制方法
CN108993620A (zh) * 2018-05-31 2018-12-14 京东方科技集团股份有限公司 微流控芯片和微流系统
WO2019025771A1 (fr) * 2017-07-31 2019-02-07 The University Of Bristol Procédé et appareil pour l'analyse bactérienne
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CN113832020A (zh) * 2020-06-24 2021-12-24 傅宗民 适用于pcr装置的光学模块、热循环模块、以及pcr装置
US11371931B2 (en) 2017-01-31 2022-06-28 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Methods and instruments for measuring samples in a well plate

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US10775369B2 (en) 2007-05-04 2020-09-15 Opko Diagnostics, Llc Fluidic systems for analyses
EP2119502B1 (fr) * 2008-05-14 2015-11-04 Sony Corporation Substrat de canal
US8926906B2 (en) 2008-07-21 2015-01-06 Concordia University Microfluidic device and method for fabricating the microfluidic device
US9827563B2 (en) 2009-02-02 2017-11-28 Opko Diagnostics, Llc Fluidic systems and methods for analyses
US8802029B2 (en) 2009-02-02 2014-08-12 Opko Diagnostics, Llc Structures for controlling light interaction with microfluidic devices
WO2010087999A1 (fr) * 2009-02-02 2010-08-05 Claros Diagnostics, Inc. Structures pour le contrôle des interactions de la lumière avec des dispositifs microfluidiques
US9827564B2 (en) 2009-02-02 2017-11-28 Opko Diagnostics, Llc Fluidic systems and methods for analyses
US9770715B2 (en) 2009-02-02 2017-09-26 Opko Diagnostics, Llc Structures for controlling light interaction with microfluidic devices
GB2495703A (en) * 2011-10-12 2013-04-24 Crowcon Detection Instr Ltd Optical sensor without wavelength filter
US10672503B2 (en) 2012-03-05 2020-06-02 Opko Diagnostics, Llc Methods and apparatuses for conducting analyses
US9606047B2 (en) 2013-06-28 2017-03-28 Gothenburg Sensor Devices Ab Waveguide structure
WO2014207089A1 (fr) 2013-06-28 2014-12-31 Gothenburg Sensor Devices Ab Structure de guide d'onde
CN104502516A (zh) * 2015-01-27 2015-04-08 天津出入境检验检疫局工业产品安全技术中心 一种用于聚合甘油三酯的微流控示差折光检测方法
US11371931B2 (en) 2017-01-31 2022-06-28 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Methods and instruments for measuring samples in a well plate
EP3388816A1 (fr) * 2017-04-11 2018-10-17 Nederlandse Organisatie voor toegepast- natuurwetenschappelijk onderzoek TNO Procédés et instruments pour mesurer des échantillons dans une plaque à cupules
WO2019025771A1 (fr) * 2017-07-31 2019-02-07 The University Of Bristol Procédé et appareil pour l'analyse bactérienne
CN108993620A (zh) * 2018-05-31 2018-12-14 京东方科技集团股份有限公司 微流控芯片和微流系统
CN108993620B (zh) * 2018-05-31 2021-01-22 京东方科技集团股份有限公司 微流控芯片和微流系统
CN108786942A (zh) * 2018-06-15 2018-11-13 京东方科技集团股份有限公司 微流控芯片、微流控装置及其控制方法
CN108786942B (zh) * 2018-06-15 2020-12-18 京东方科技集团股份有限公司 微流控芯片、微流控装置及其控制方法
WO2020125859A3 (fr) * 2018-12-20 2020-09-17 Leibniz-Institut Für Photonische Technologien E.V. Arrangement et procédé pour l'acquisition de propriétés optiques d'un échantillon, notamment pour la détection sélective de molécules biologiques et pour la lecture de l'occupation d'une molécule
CN113832020A (zh) * 2020-06-24 2021-12-24 傅宗民 适用于pcr装置的光学模块、热循环模块、以及pcr装置

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