WO2006102593A2 - Dispositif, systeme et procede de detection de cibles dans un echantillon fluide - Google Patents

Dispositif, systeme et procede de detection de cibles dans un echantillon fluide Download PDF

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Publication number
WO2006102593A2
WO2006102593A2 PCT/US2006/010788 US2006010788W WO2006102593A2 WO 2006102593 A2 WO2006102593 A2 WO 2006102593A2 US 2006010788 W US2006010788 W US 2006010788W WO 2006102593 A2 WO2006102593 A2 WO 2006102593A2
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WIPO (PCT)
Prior art keywords
light
tube
measuring cell
sample
agent
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PCT/US2006/010788
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English (en)
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WO2006102593A3 (fr
Inventor
Stephane Andre Follonier
Pierre Francois Indermuhle
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Stephane Andre Follonier
Pierre Francois Indermuhle
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Application filed by Stephane Andre Follonier, Pierre Francois Indermuhle filed Critical Stephane Andre Follonier
Publication of WO2006102593A2 publication Critical patent/WO2006102593A2/fr
Publication of WO2006102593A3 publication Critical patent/WO2006102593A3/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • 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
    • 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
    • G01N21/05—Flow-through cuvettes
    • 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
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/7703—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • 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
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N21/05—Flow-through cuvettes
    • G01N2021/052—Tubular type; cavity type; multireflective
    • 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
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N2021/7769—Measurement method of reaction-produced change in sensor
    • G01N2021/7773—Reflection
    • 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
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N2021/7769—Measurement method of reaction-produced change in sensor
    • G01N2021/7786—Fluorescence
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/02—Mechanical
    • G01N2201/024—Modular construction
    • G01N2201/0245—Modular construction with insertable-removable part
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/18—Water
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/22—Fuels, explosives

Definitions

  • the present invention is directed to wave-guiding devices that can detect targets in fluid samples.
  • the amount of a target in a sample solution is determined by measuring differences in light transmission through the wave-guiding measuring cell before and after the target is bound by the capture agent on the inner surface of the wave- guiding tube.
  • the use of the cartridge unit can be expanded from pure biotechnological applications (DNA, proteins) to different functionalities such as chemicals, toxins, viruses and/or bacteria or any other targets in liquid samples for which a capture agent can be engineered.
  • Applications such as water quality monitoring, environmental safety monitoring, rapid diagnostic kits, portable field sensors, integrated point of care sensors are among the many possible applications.
  • Potential users include research institutes, pharmaceutical companies, analysis laboratories as well as point of care customers both in military and in civil applications.
  • FIG. 1 The biochemical detection system comprising an optical detection unit with one light emitting element (101), with one primary light connecting element (102), with one secondary light connecting element (103), and with one light detecting element (104).
  • the system further comprises an exchangeable cartridge unit (105) with light guiding tubes pre-coated with capture agent(s) and one fluid dispensing element (106).
  • FIGS. 2 and 3 The biochemical detection system comprising the measuring cell of the present invention in a 96-well array format.
  • this invention is directed to a measuring cell, which comprises at least one tube capable of both guiding light and capable of binding a target(s) from a liquid or gaseous sample facilitated by at least one capture agent immobilized on its inner surface.
  • the tube(s) comprises an input opening, an output opening and an inner surface coated with a binding agent(s),which is exposed to a sample by flowing, in an optionally regulated manner, the sample into the input opening, through the tube(s) and out from the output opening.
  • the flow of the sample through the tube can be regulated by pressure, gravity, capillary forces or electrophoresis.
  • the capture agent(s) may be bound directly to the inner surface of the tube(s) (or to one of the layers building it) or bound to an interstitial layer comprised of one or more layers.
  • This layer(s) may contain an additional agent(s) that prevents or retards non-specific adsorption and/or non-specific binding of the target(s) and/or other components of the sample.
  • the inner surface of the tube is coated with an additional layer, which interacts with the bound target in a way that changes the properties of the light guided through the tube.
  • this invention is directed to a system that comprises a light emitting element(s), a primary light connecting element(s), a measuring cell as described in the first aspect, a secondary light connecting element(s), a light detecting element(s) and a fluid dispensing element(s). It may also comprise a sample and a disposal reservoir.
  • the fluid dispensing element(s) dispenses in a regulated manner the liquid or gaseous sample from the sample reservoir into the measuring cell and from the measuring cell into the disposal reservoir.
  • the light, emitted by the light emitting element(s) is connected to the measuring cell by the primary light connecting element(s). It is guided through this measuring cell and then connected through the secondary light connecting element(s) to the light detecting element(s).
  • the change in the amount or in the properties of the detected light relates to the amount of the target(s) bound to the capture agent(s) on the inner surface of the tube(s) of the measuring cell, or to a change of at least one of its properties.
  • Examples of the light emitting element(s) are a laser, a Light Emitting
  • Diode Diode, a white light source, a Vertical cavity light emitting laser and an array of those elements.
  • the light detecting element(s) are a photomultiplier tube, a camera, a photodiode and an array of those elements.
  • Examples of light connecting element(s) are a Brewster angle window, a lenslet array, a grating index coupler, a partially reflecting mirror, a spectral or an intensity filter and a combination of two or more of the connecting elements described above.
  • the light connecting element(s) that may be the same or not, may also be a liquid dispensing element(s).
  • the light connecting element(s) is integrated in the tube(s) of the measuring cell.
  • the capture agent(s) may be bound directly to the inner surface of the tube(s) (or to one of the layers building it) or bound to an interstitial layer comprised of one or more layers.
  • This layer(s) may contain an additional agent(s) that prevents or retards non-specific adsorption and/or non-specific binding of the target(s) and/or other components of the sample.
  • the inner surface of the tube is coated with an additional layer, which interacts with the bound target in a way that changes the properties of the light guided through the tube.
  • this invention is directed to a method for detecting a target(s) in a liquid or gaseous sample.
  • This method comprises the introduction, using the fluid dispensing element(s), of a sample into the measuring cell(s), which comprises at least one tube capable of both guiding light and binding a target(s) from a sample.
  • This method also comprises the step of connecting the light emitted by the light emitting element(s) into the measuring cell using the primary light connecting element(s), wherein the light is then guided through the measuring cell where it interacts with the bound target(s).
  • it comprises the step of connecting light, by using the secondary light connecting element(s), from the measuring cell(s) to the light detecting element(s).
  • the detection, with the light detecting element(s), of the amount of light or of the variation of the property(ies) of the light that went through the measuring cell allows the determination or the calculation of the amount of target(s) bound to the capture agent(s) on the inner surface of the measuring cell, or of the properties of this target.
  • the mentioned tube(s) comprises an input opening, an output opening and an inner surface coated with binding agent(s).
  • the fluid dispensing element(s) dispenses the liquid or gaseous sample into the measuring cell from the sample reservoir and from the measuring cell into the disposal reservoir in a regulated manner.
  • the method comprises the introduction, after the sample is introduced to the measuring cell using a fluid dispensing element(s), of one cleaving and/or digesting agent into the at least one measuring cell, using at least one fluid dispensing element, after the at least one target is immobilized on the inner surface of the at least one measuring cell in a first step, and wherein the at least one cleaving and/or digesting agent modifies the structure of the at least one bound target.
  • the method comprises the introduction, after the sample is introduced to the measuring cell using a fluid dispensing element(s), of a second binding agent(s) into the measuring cell that binds to the target(s), which has been captured by the capture agent(s).
  • the second binding agent(s) emits light or absorbs light or has optical properties that enhance detection.
  • the interaction of the target(s) with any agent and/or any layer bound or immobilized on the inner surface of the tube may change the optical properties of either, the second binding agent(s), the bound target(s) or any agent and/or any layer bound or immobilized on the inner surface of the tube.
  • This interaction or the optical properties of the second binding agent(s) changes the amount of light or the property(ies) of the light that went through the measuring cell allowing the determination or the calculation of the amount of target(s) bound to the capture agent(s) on the inner surface of the measuring cell, or of the properties of this target.
  • the method comprises the introduction of an amplification agent(s) to the measuring cell(s), where the amplification agent(s) binds to the second binding agent(s).
  • the amplification agent(s) emits light or absorbs light or has optical properties that enhance detection.
  • the interaction of the target(s) with any agent and/or any layer bound or immobilized on the inner surface of the tube may change the optical properties of either the bound target(s) or any agent and/or any layer bound or immobilized on the inner surface of the tube.
  • This interaction or the optical properties of the amplification agent(s) changes the amount of light or the property(ies) of the light that went through the measuring cell allowing the determination or the calculation of the amount of target(s) bound to the capture agent(s) on the inner surface of the measuring cell, or of the properties of this target.
  • the sample undergoes a required number of sample preparation steps before being introduced into the measuring cell.
  • the method comprises or not a washing step between any immobilization or detection steps.
  • an optical fluid e.g. a liquid
  • said optical fluid having a refractive index high enough to render the at least one tube or the at least one tube with its surrounding material a light guide.
  • the optical fluid is introduced at any step of the method or between any step of the method or both.
  • the optical fluid is kept in the at least one tube of the at least one measuring cell during the time necessary to perform any desired measurement(s) .
  • the immobilization times are adequately chosen for each step of each embodiment of the method.
  • the present invention is directed to a measuring cell which comprises at least one tube capable of guiding light.
  • the interior walls of the tube are coated with at least one specific capture agent to bind at least one specific target from a sample containing known and/or unknown components.
  • the measuring cell may be used as a component of a system used to analyze samples for at least on specific target.
  • the system comprises a measuring cell capable of binding targets from a sample integrated in, for example, an exchangeable cartridge unit, which in turn is coupled to both a light source and a detection system.
  • These elements build an extremely sensitive, inexpensive and compact system for quantitative detection of targets in a sample (liquid or gaseous).
  • more than one measuring cell may be bundled together to measure the same sample multiple times or to measure the same sample for multiple targets.
  • the tube has one input opening and one output opening such that the fluid sample can be introduced into the tube and removed from the tube.
  • a sample may be introduced to the tube by first flowing an amount of a fluid sample into the tube that is sufficient to fill the tube and then stopping the flow. Alternatively, a predetermined amount of the sample solution may flow through the tube before the flow is stopped. For example from about InI to about 1 mL of sample may flow through the tube. In either case, the flow through the tube can be regulated through pressure, through capillary forces, through gravity, through electrophoresis, through pumps (Fluidigm Inc. South San Francisco, CA 94080), through passive or active valves or through an external flow control device. Also contemplated are systems where the sample flows continuously through the tube of the measuring cell.
  • the fluid sample may be liquid or gaseous.
  • Analysis of the sample for the desired target occurs once the sample has interacted with the capture agent immobilized on the inner surface of the tube. This interaction may take place immediately following the introduction of the sample to the tube. Alternatively, the sample may flow through the tube for a certain period of time and/or may require an incubation process before the measurement takes place.
  • the incubation time i.e. the total time during which the sample is in contact with the capture agent, can be set depending on the type of interaction and the desired sensitivity of the assay, typically between 1 minute and 4 days and preferably between 1 and 30 minutes.
  • continuous flow systems where the sample is continually flowed through the wave-guiding tube, and sample analysis occurs without stopping the flow of the sample. Similarly, continuous real-time monitoring are also possible.
  • the diameter and the length of the at least one tube depend on the sensitivity and sample volume requested by the application, typically from 5 microns to 1000 microns, preferably from about 50 to about 400 microns, for the diameter and from lmm to 1000mm for the length.
  • a length of 10mm for a diameter of 50 microns to 100 microns is a good fit.
  • Gaseous samples may require a longer tube (100mm to 1000mm) to increase the size of active surface to allow the detection of smaller amounts of targets in the sample.
  • the at least one tube has the ability to guide light. Wave-guiding properties are seen in devices where light is being propagated through a first material and that first material is bounded by a second material with a lower refractive index than the refractive index of the first material. When the light propagating through the first material encounters the boundary between the first and second material, the light is reflected instead of transmitted through the boundary.
  • the first material is the gas or liquid within the measuring cell and the second material is the walls of the measuring cell tube.
  • the interior wall of the measuring tube may be the same material as the rest of the tube. For example a fused silica tube with a solvent of higher refractive index inside the tube will guide light. Alternatively the interior walls of the tube may have a coating such as Teflon AF, or some other optical coating which becomes and integral part of the interior wall of the tube. Optical coatings for use in waver guides are known in the art.
  • Teflon AF polymer which has a low refractive index (n ⁇ 1.33)
  • Teflon AF can be used as the construction material (Biogeneral, Inc. San Diego, CA 92121), to fabricate the complete tube.
  • the low refractive index of the Teflon AF polymer coupled with a liquid sample that has a refractive index higher than « ⁇ 1.33 imparts the tube with the desired optical wave guiding characteristics. Because Teflon AF has such a low refractive index, aqueous samples (with no additional "optical fluid" ) have a refractive index sufficient to create the wave-guiding conditions.
  • a tube made out of glass, fused silica or another material becomes light guiding when filled with a fluid having a higher refractive index (Cargille Laboratories, Inc., Cedar Grove, NY 07009) than the effective refractive index of its own material.
  • a fluid having a higher refractive index Cargille Laboratories, Inc., Cedar Grove, NY 07009
  • the tube material has a refractive index lower than the refractive index of the sample solution, or of the solution within the tube when the analytical measurement is being made, the tube will act as a waveguide.
  • the sample solution should have an index of refraction higher than 1.46, typically 1.49. This can be accomplished by using a solvent with an inherently high refractive index.
  • additives such as glycerol, sucrose, and the like, can be added to the sample solution.
  • Sample solutions with a lower index of refraction can also be used with a fused silica tube if the index of refraction of the solution in the tube is increased, prior to making the analytical measurement, using additives and/or solvents similar to those discussed above.
  • Photonic bandgap crystals (US 6,571,045 May 27, 2003 Hasegawa et al.) commercially available from BlazePhotonics (Denmark), guide light due to a honeycomb structure that is constructed around the tube.
  • Any type of wave-guiding tube whose interior surface can be coated with capture agents is useful in the present invention.
  • Photonic bandgap crystals act as an optical waveguide when filled with a gas.
  • the capture agents may be bound directly to the inner surface of the tube through, for example, chemical bonding or adsorption.
  • the capture agent may be bonded indirectly to the interior surface of the tube through at least one interstitial layer.
  • interstitial layers are polymers (PLL-PEG, silanes, S elf- Assembled Monolayers (alcanethiols)).
  • the capture agents can be chemically bonded or adsorbed to the interstitial layer. Specifically, for tubes made from Teflon AF (i.e.
  • the inner surface of the tubes may be modified by oxygen plasma so that the capture agent(s) is(are) directly bonded to the inner surface;
  • the inner surface of the tube may also be coated with an interstitial layer of nitrocellulose or of e.g. Optodex (Arrayon Biotechnology SA, Neuchatel, 2007, Switzerland).
  • the capture agent may be bound to the tube inner surface by, for example, well known silane surface chemistry.
  • any of or a combination of the above surface chemistries may be used to bind the capture agents to the tube's inner surface.
  • the measuring cell is an assembly of one or more tubes that are pre-loaded with similar or different capture agents to allow for duplicates or to detect several targets in the same sample or to serve as calibration.
  • Several of such tubes can be held together by integration (Schott Glas, 55122 Mainz, Germany), before or after loading the capture agents.
  • the capture agent loading can be achieved in longer tubes that are cut to size in a second step, ensuring thus the most efficient homogeneity and facilitating the QC/QA process.
  • the measuring cell may be filled with a buffer or a preservation solution and sealed, to prevent any degradation of the active capture agents during the storage and shipping.
  • the input and output openings of the tube(s) may be sealed or may be covered with slits to allow an easier handling and protect the content of the measuring cell against any environmental contamination. These seals or slits will break or slide upon insertion of the measuring cell into the detection system unit or at the insertion of the sample into the tube.
  • the measuring cell may also be sealed to preserve the content's integrity until it is used.
  • the measuring cell may or may not comprise a primary light connecting element(s) and/or a secondary light connecting element(s) and/or a fluid dispensing element(s). These elements may or may not be integrated in the measuring cell.
  • the at least one measuring cell is provided with one primary light connecting element, one secondary light connecting element and a fluidic element.
  • the measuring cell can be packaged in a user friendly cartridge to be inserted in the detection system.
  • An exchangeable measuring cell (packaged in a cartridge unit) may be coupled to at least one light emitting element and at least one light detecting element. Further light connecting elements may be part of the detection system unit as well as a liquid dispensing unit, a sample reservoir and a waste reservoir.
  • FIG. 1 An analytical system using the measuring cell of the present invention is shown in Figure 1.
  • the light emitted by a light emitting element(s) ( Figure 1, (101)) is connected to one or more measuring cell ( Figure 1, (105)) through a primary light connecting element(s) ( Figure 1, (102)).
  • the light travels through the measuring cell(s) before being connected out of the measuring cell(s) and into a light detection element(s) ( Figure 1, (104)) by a secondary light connecting element(s) ( Figure 1, (103)).
  • the sample of interest is directed to the measuring cell(s) and its flow through the measuring cell(s) is regulated by the fluid dispensing element(s) ( Figure 1, (106)).
  • the amount of light guided through the tube or at least one property of this light is changed proportionally to the amount of target(s) bound to the capture agent(s).
  • the entrance and exit covers slide off the measuring cell(s) and/or the seals of the measuring cell(s) are automatically broken, allowing thus the introduction of the sample into the measuring cell(s).
  • a fluid dispensing element may be used to facilitate the sample flow through the measuring cell(s).
  • the flow of the sample through the measuring cell(s) may be driven by gravity, capillary forces, by electrophoresis or pressure or a combination of these.
  • the sample handling system maybe comprised of a device that increases the flow through the measuring cells.
  • the light emitted by the at least one light emitting element is connected to the measuring cell(s) of the exchangeable cartridge unit through the at least one primary light connecting elements.
  • the light travels through the at least one measuring cell before being connected out of the at least one measuring cell and into the at least one light detecting element by the at least one secondary light connecting elements.
  • the change of the amount of light guided through the tube, or the change of at least one other property of this light is measured.
  • the intensity at various wavelengths of the light guided through a measuring cell is changed by the interaction of this light with the target, and/or with the capture agent, and/or with the second binding agent, and/or with the amplification agent bound to the inner surface of the measuring cell(s).
  • Other optical processes such as scattering, or such as the interaction between two of the above species, or between one of the above species and one interstitial layer may also change at least one property of the transmitted light.
  • the amount of target bound to the capture agents can then be determined or computed by measuring these changes.
  • the at least one light emitting element may be emitting monochromatically or polychromatically in the visible and/or in the infrared and/or in the UV (e.g. Jameco Electronics Belmont, CA 94002). It maybe a simple light emitting diode or a laser diode or even a white light source (Newport Corporation, Irvine, CA 92606) or a Vertical Cavity Surface Emitting Laser. It may be an array of light emitting diodes or lasers or white light sources such that they can be inserted into the tubes. The wavelength(s) of interest may be selected through the at least one primary light connecting element that also serve the purpose of coupling the light into the tube.
  • the primary light connecting element transmits the light from the at least one light emitting element into at least one tube of the measuring cell and the secondary light connecting element transmits the light out of the at least one tube of the measuring cell into the at least one light detecting element.
  • the light connecting element and the fluidic element which regulates the flow of the sample through the tube of the measuring cell may be a single element with dual purpose. More specifically, for liquid samples and measuring tubes made out of Teflon AF, the tube (pre cut to size) is connected to glass Brewster windows that serve the purposes of guiding light into and out of the tube (light connecting elements) as well as guiding the sample into and out of the tube (fluidic dispensing elements).
  • the primary and secondary light connecting elements serve different purposes such as connecting light from the at least one light emitting element into the at least one measuring cell and out of the at least one measuring cell onto the at least one light detecting element. They can also serve other purposes such as focusing light into separate tubes (lenses, lenslet arrays, Control Optics, Chino, CA 91710), such as tailoring the properties of the light (wavelength and intensity filters Newport Corporation, Irvine, CA 92606), such as partially reflecting the light back and forth in the rube or such as coupling light into the tube or out of the tube with a grating index coupler.
  • the nature of the primary and the secondary light connecting elements are selected depending on the optical detection process that is used, e.g. fluorescence, absorption, Raman scattering.
  • the primary and secondary light connecting elements may be a multiplicity of the above described elements for each measuring cell. Besides connecting light into the measuring cell, the purpose of the connecting elements may be to ensure sample handling as well. These light connecting elements may or may not be integrated in the measuring cell.
  • the light detecting element may be a multiplicity of the above described elements for each measuring cell. Besides connecting light into the measuring cell, the purpose of the connecting elements may be to ensure sample handling as well. These light connecting elements may or may not be integrated in the measuring cell.
  • the processing circuit calculates the concentration in the sample of biologically or chemically relevant targets.
  • the fluid dispensing element dispenses the sample to the at least one measuring cell from the sample reservoir and from the at least one measuring cell to the disposal reservoir; the fluid dispensing element may be used to facilitate the sample flow through the measuring cell(s).
  • the flow of the sample through the measuring cell(s) may be driven by gravity, capillary forces, by electrophoresis or pressure or a combination of these.
  • the sample handling system may be comprised of a device that increases the flow through the measuring cells.
  • the fluid dispensing element may also be serving other purposes such as introducing different solutions into the tube (secondary binding agent, amplification agent, buffer, optical fluid), such as regulating the sample flow or such as performing sample preparation, including filtering, mixing or sample dilution.
  • the sample flow is controlled via capillarity from the input opening of the tube to the output opening of the tube.
  • the fluid dispensing element can be used to fill the cell(s) with an index fluid having a refractive index high enough to render the tube or the tube with its surrounding material a light guide.
  • the fluidic element or part of it may also serve other purposes such as introducing different samples into the tube (second binding agent, amplification agent, buffers), such as regulating the sample flow or such as performing sample preparation, including sample filtering, sample mixing or sample dilution.
  • the sample flow is controlled via gravity from the input opening of the tube to the output opening of the tube.
  • the fluidic element may also be used to introduce one or more fluids with a defined refractive index into the tube to control its light guiding properties.
  • a tube filled with gas or liquid may be turned into an optical waveguide by a specific design of its optical properties or by a specific choice of the optical properties of the fluid.
  • a change in the optical properties of the fluid filling the tube or a change of the properties of the interface between the tube and the fluid may induce a change in the amount or in the characteristics of the guided light.
  • the method described here uses the above principle to detect a target in a fluid sample: the inner surface of the tube is engineered such that the target will be immobilized or bound to this surface when the sample is flowed through the tube.
  • the optical characteristics of the target, or of an agent bound to the target e.g.
  • the interaction of the target, or of any agent, with the inner surface of the tube, or with any other agent may generate a variation in the amount or in the properties of the guided light, which can be detected. This variation is proportional to the amount of targets bound to the inner surface of the tube.
  • a capture agent is a molecule or a part of a molecule that is capable of binding a target, i.e. capable of immobilizing for a certain period of time another molecule or another part of a molecule contained in a sample.
  • targets are explosives, pathogens, bacteria, viruses, DNA strands or proteins.
  • capture agents are molecules/polymers with specific end-groups such as biotin or amine reactive terminals or more complex species such as antibodies, DNA strands.
  • a cleaving and/or digesting agent can be introduced into the measuring cell after the target is immobilized on the inner surface of the measuring cell in a first step.
  • Methods for immobilizing antibodies on surfaces are known in the art and are described, for example, in Harlow, E. and D. Lane, Antibodies: A Laboratory Manual, (1988) Cold Spring Harbor Laboratory, Cold Spring Harbor, N. Y. which is incorporated herein by reference.
  • Biacore www.biacore.com '
  • Biacore has accumulated protocols for numerous immobilization methods. Biacore makes this information available to the public via the internet or by publications which can be ordered.
  • a second binding agent(s) may interact with the target(s).
  • the second binding agent(s) may also serve as a second filter, by lowering the influence of non-specific binding to the capture agent(s). It maybe labeled with a fluorescent dye or with an absorbing molecule such that the interaction of the guided light with this dye or with this molecule results in a change of the properties of the guided light.
  • an amplification agent(s) may be bound to the second agent(s) serving a signal amplification purpose and a further filter.
  • Examples of a second binding agent(s) are secondary antibodies conjugated to HRP (horseradish peroxidase) with the corresponding amplification agent being a signal enhancement substrate (e.g. Tetra methyl Benzidine) (Molecular Probes Inc. Eugene, OR 97402). Washing steps maybe used to wash off excess of sample, second binding agent(s) or amplification agent(s).
  • HRP horseradish peroxidase
  • amplification agent e.g. Tetra methyl Benzidine
  • the measurement can occur simultaneously with the sample flow and can run continuously through the measuring cell.
  • Additional automated fluidic devices may allow for additional assay steps for the sample preparation as well as for targets and for agents that require rinsing and/or signal amplification after their immobilization/incubation.

Abstract

L'invention concerne un système de détection biochimique qui comprend une unité à cartouche interchangeable comportant des tubes de guidage de la lumière pré-enduits d'un ou de plusieurs agents de capture, ainsi qu'une unité de détection optique. Lorsque l'échantillon liquide ou gazeux contenant la ou les cibles s'écoule à travers l'unité à cartouche, ladite ou lesdites cibles se lient à l'agent ou aux agents de capture et sont détectées d'après la quantité de lumière ou la variation des propriétés de celle-ci lorsqu'elle est guidée à travers les tubes. L'unité de détection optique est constituée d'un ou de plusieurs éléments d'émission de lumière, d'un ou de plusieurs éléments de connexion de lumière et d'un ou de plusieurs éléments de détection de lumière fournissant la quantité de cibles dans l'échantillon examiné.
PCT/US2006/010788 2005-03-24 2006-03-23 Dispositif, systeme et procede de detection de cibles dans un echantillon fluide WO2006102593A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016181100A1 (fr) * 2015-05-12 2016-11-17 Cranfield University Cellules à gaz de guide d'ondes à fibres creuses

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6603556B2 (en) * 2000-10-12 2003-08-05 World Precision Instruments, Inc. Photometric detection system having multiple path length flow cell

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6603556B2 (en) * 2000-10-12 2003-08-05 World Precision Instruments, Inc. Photometric detection system having multiple path length flow cell

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016181100A1 (fr) * 2015-05-12 2016-11-17 Cranfield University Cellules à gaz de guide d'ondes à fibres creuses

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