WO2011085728A1 - Microfluidic system comprising a light emitting device - Google Patents

Microfluidic system comprising a light emitting device Download PDF

Info

Publication number
WO2011085728A1
WO2011085728A1 PCT/DK2011/000001 DK2011000001W WO2011085728A1 WO 2011085728 A1 WO2011085728 A1 WO 2011085728A1 DK 2011000001 W DK2011000001 W DK 2011000001W WO 2011085728 A1 WO2011085728 A1 WO 2011085728A1
Authority
WO
WIPO (PCT)
Prior art keywords
transparent
temperature
fluid
communicating network
fluid communicating
Prior art date
Application number
PCT/DK2011/000001
Other languages
French (fr)
Inventor
Kasper Paasch
Original Assignee
Flowsion Aps
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Flowsion Aps filed Critical Flowsion Aps
Priority to US13/519,692 priority Critical patent/US20130052085A1/en
Priority to CN2011800060149A priority patent/CN102782476A/en
Priority to EP11702569A priority patent/EP2524206A1/en
Publication of WO2011085728A1 publication Critical patent/WO2011085728A1/en

Links

Classifications

    • 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
    • G01N21/15—Preventing contamination of the components of the optical system or obstruction of the light path
    • 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
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N21/0332—Cuvette constructions with temperature control
    • 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
    • G01N21/62—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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/143—Quality control, feedback systems
    • B01L2200/147—Employing temperature sensors
    • 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
    • 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
    • B01L2300/16—Surface properties and coatings
    • B01L2300/168—Specific optical properties, e.g. reflective coatings
    • 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
    • G01N2021/056—Laminated construction
    • 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
    • G01N21/15—Preventing contamination of the components of the optical system or obstruction of the light path
    • G01N2021/155—Monitoring cleanness of window, lens, or other parts
    • G01N2021/157—Monitoring by optical means
    • 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
    • G01N2201/06—Illumination; Optics
    • G01N2201/062—LED's
    • 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
    • G01N2201/06—Illumination; Optics
    • G01N2201/062—LED's
    • G01N2201/0623—Use of a reference LED
    • 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
    • G01N2201/06—Illumination; Optics
    • G01N2201/062—LED's
    • G01N2201/0627—Use of several LED's for spectral resolution
    • 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
    • G01N2201/06—Illumination; Optics
    • G01N2201/063—Illuminating optical parts
    • G01N2201/0636—Reflectors

Definitions

  • the present invention relates to microfluidic analysis systems where the emitted light of an emitting source is measured by optic detection, and where a transparent body separates the emitting source from the optic detector.
  • the invention especially relates to optic calibration of the device, the calibration being related to changes in the transparency of the transparent body and / or changes in the temperature of the emitting source.
  • Microfluidic systems are widely used, for example to measure concentrations of a substance in fluid, such as a substance in a body fluid for example glucose.
  • WO 2008/089764 describing a system based on the extraction of the substances from the medium by diffusion across a semi-permeable membrane to be collected by a sweeping fluid, or perfusion fluid.
  • This substance enriched fluid is then fed to a microfluid system, especially being formed as a microfluidic chip, where different reactions with the substances emit light at an intensity to be correlated to the concentration of the substances in the medium.
  • An optical detector forms part of an electrical part of the system connected to the microfluidic chip, where the optical detector is positioned so that it detects the light emitted from the reactions.
  • the electrical part and the microfluidic chip are separated by a transparent medium or body such as glass.
  • the state of the transparency of the transparent medium will also influence the measurements, such as if the transparent medium gets covered with dirt and moieties or simply is scratched and gets cracks. The same may be the problem of a transparent cover of the channels of the microfluidic chip of the system.
  • enhancers may be introduced such as described in WO9105872A1 , describing an enhanced chemiluminescent assay, in which a dihydrophthalazinedione such as luminol, a peroxidase such as HRP and an oxidant such as H202 are co-reacted in the presence of an enhancer such as (p)-iodophenol.
  • the enhancer is generated by enzyme-catalysed reaction of a pro-enhancer, e.g. (p)-iodophenol phosphate is cleaved by alkaline phosphatase, enabling this enzyme to be assayed instead of peroxidase.
  • an anti-enhancer such as (p)-nitrophenol is generated by enzymatic reaction of a pro-anti-enhancer such as (p)- nitrophenol phosphate and the reduction in luminescent emission is measured.
  • chemi-luminescent assays are described as "enhanced" in the sense that the total light emission of the reaction and/or the signal /background ratio is larger than that obtained in the same reaction carried out in the absence of an enhancer. Summary of the system
  • the present invention introduces a method of estimating present state of the system especially for calibration purposes. This is done by introducing a device with a fluidic part comprising,
  • the electronic part further comprises a light emitting device.
  • the present invention is especially, but not exclusively, suitable for devices forming part of an analysis system, especially where the analysis is based on optical detection formed by reactions in fluids present in the fluid communicating network, the detector being an optic detector.
  • the reactions in the fluids may be related to a concentration of specific substances to be measured by the device.
  • the transparent wall section and the electronic part are separated by a transparent body.
  • the light emitting device is used to estimate the transparency of the transparent body and/or the transparent wall section by reflection.
  • the light emitting device is used to estimate the temperature of the fluid(s) in the fluid communicating network.
  • the correlation of the system is in a preferred embodiment of the present invention based to the estimation of the transparency, the method being to detect light emitted from the light source being scattered and reflected in and by the transparent body, and comparing the detected value(s) or spectral distribution to reference value(s) or a reference spectral distribution.
  • the light emitting device emits light at a narrow spectral span being substantially different to the light formed by the reactions in the fluids.
  • the light emitting device is a light diode.
  • a temperature responsive element characterized by having reflection characteristics related to its temperature is positioned into or in connection with the fluid communicating network, and in further embodiment; a heating element is positioned in contact with the fluid communicating network. These may be used to estimate the temperature of the fluids and the fluid communicating network, the method being to detect light emitted from the light source being reflected by the temperature responsive element, and comparing the detected value(s) or spectral distribution to reference value(s) or a reference spectral distribution.
  • the present invention thus further introduces a method of regulating the temperature of the fluid of the device, wherein the method is to regulate the temperature of the heating element in accordance with the estimated temperature.
  • the fluidic part further comprises at least one optically reflective surface.
  • the reflective surface is formed at the internal surface(s) of the fluid communicating network at least where the wall section is transparent. In another specific embodiment, the reflective surface is formed at the side opposite to the detector of the fluid communication network at least where the wall section is transparent. To focus the emitted light, in yet another embodiment the reflective surface is shaped having a focus point roughly at the position of the detector.
  • the fluidic part is a fluidic chip where ridges are formed in the surface of at least a first body, the ridges formed into channels by covering the first body with a second body having at least a transparent area.
  • the present invention in general relates to calibrating a system where the emitted light of an emitting source is measured by optic detection, and where a transparent body separates the emitting source from the optic detector.
  • the invention especially relates to optic calibration of the device, the calibration being related to changes in the transparency of the transparent body and / or changes in the temperature of the emitting source.
  • Fig. 1 shows a typical form of a microfluidic system where the present invention may advantageously be applied.
  • Fig. 2 shows a transparent body separating a fluidic part from an electrical part comprising a sensor.
  • Fig. 3 shows how the transparency of a transparent body may change.
  • Fig. 4 shows the transparent body separating a fluidic part from an electrical part comprising a sensor, where the electrical part further comprises a light emitting device according to an embodiment of the present invention.
  • 5 shows the transparent body separating a fluidic part from an electrical part comprising a sensor, where the electrical part further comprises a light emitting device, and the microfluidic part a temperature responsive element according to a further embodiment of the present invention.
  • FIG. 6 shows the transparent body separating a fluidic part from an electrical part comprising a sensor, where the electrical part further comprises a light emitting device, and where the microfluidic part further comprises a focused reflecting surface within the flow communication system of the microfluidic part.
  • Fig. 7 shows the transparent body separating a fluidic part from an electrical part comprising a sensor, where the electrical part further comprises a light emitting device, and where the microfluidic part further comprises ; focused reflecting surface below the flow communication system of the microfluidic part.
  • FIG. 1 shows one non-limiting example of a setup of an microfluidic analysis system whereto the present invention with advantage would apply, the system comprising a fluidic part (1) illustrated in a non-limiting example is formed as a first body with a network of grooves formed in at least one surface, where the grooves form a fluid communicating network (2) when the surface of the first body is covered with a second body (optionally a sheet, foil, etc.).
  • a fluidic part (1) illustrated in a non-limiting example is formed as a first body with a network of grooves formed in at least one surface, where the grooves form a fluid communicating network (2) when the surface of the first body is covered with a second body (optionally a sheet, foil, etc.).
  • the fluid communicating network (2) may comprise any number of branches for feeding any number of different fluids (5, 6) into the system for mixing, and a mixing section (3) where the fluids gets time to mix sufficiently to give some reactions with an observable effect representative of the desired quantity to be measured.
  • the fluid communicating network (2) may further comprise a detection section (4) where the observable effect may be measured or detected.
  • Fig. 2 shows a side view of the same fluidic part (2) where a cover (10) is positioned on top of the first body covering at least part of the detection section (4).
  • the cover (10) may be the second body forming the grooves into a fluid communicating network (2), or any additional not shown such cover layers may also be present.
  • the cover (10) would at least cover part of the detection section (4) or would cover a part of or the whole of the remaining surface of the first body of the fluidic part (1) too.
  • the reactions in the detection section (4) lead to an observable effect (11), where the effect non-limiting in the following description is an optical effect, such as emitting light at some spectral distribution.
  • the cover (10) and any other optional second bodies covering the fluid communicating network (2) are transparent to the observable effect (11), at least where it / they cover(s) the detection section (4).
  • An electrical part (9) having an optical sensor or cell (12) is positioned on top of the fluidic part (1) such that the optical sensor (12) is at least partly aligned with the detection section (4).
  • One of the fluids for example (5), may be a sample fluid, in the present context being defined as a carrier fluid enriched with substances of interest at some concentration representative of the concentration of the species in some medium.
  • the medium may be the human tissue or waste water.
  • the remaining of the fluids (6) may thus be reagent fluids to be mixed to the sample fluid to give some observable effect, in the following exampled as a optical effect.
  • this example setup could in one embodiment be that a sample fluid (5) is mixed with reagent fluid(s) (6) to emit light with an intensity corresponding to the concentration of substances. This intensity is then measured by the optical sensor (12) and the measurements are optionally processed in a computer to give an indication of the concentration of the substances of interest in the sample fluid.
  • the fluids may finally leave the system (7) or be collected in a waste storage.
  • Fig. 3 illustrates some of the reasons for such 'external' effects, such as cracks (13) appearing in the cover (10) or moieties, dirt, substances, etc. (14)
  • Fig. 4 shows a first aspect in one preferred embodiment of the present invention, where a light emitting device (15), such as but not excluded to a light diode, is included in the electrical part (9).
  • the light emitting device (15) preferably emits light within a specified narrow spectral span substantially different from the light emitted by the reactions (11), and with a well known intensity.
  • the light emitted by the light emitting device (15) will be scattered in the system of cover (11), channels (2, 3, 4) and the main body of the fluidic part (1), and a fraction of it will be measured by the optical sensor (12). Thus the light emitted by the light emitting device (15) will be affected in the same manner by
  • the idea of the invention therefore is from time to time to emit light by the light emitting device (15) and use the intensity measured by the optical sensor (12) to estimate the present transparency of the cover (10) (and other optional covers / second bodies), using this for calibration purposes.
  • a threshold limit could be introduced to give off a signal when the measured intensity gets below this threshold limit, indicating the system may no
  • a further aspect of the present invention illustrated in Fig. 5, is related to temperature dependencies in the light emission (11) from the reactions in the mixed fluids, this also being due to changing viscosities of the fluids, leading to changing flow rates. It would' therefore be an advantage at least to be able to estimate the present temperature of the mixed fluids, especially, but not excluded to, being present in the reaction section (4).
  • the idea of the present invention is to use a light emitting device (16) to estimate the temperature by introducing in the fluid communicating network (2), especially in contact with the detection section (4), a temperature responsive element (17) characterized by having reflection characteristics related to its temperature.
  • the light emitting device (16) emits light and the reflected light from the temperature responsive element (17) is measured by the optical sensor (12) and the temperature of the temperature responsive element (17), being in contact with and therefore related to the temperature of the fluids in the fluid communication network (2), is calculated.
  • a heating and/or cooling element (18) is positioned in contact with the fluid communicating network (2), especially in contact with the detection section (4). This element will then be controlled in its heating and/or cooling in response to the temperature measurements, thereby making it possible to regulate the temperature of the fluids to a desired temperature.
  • the light emitting device (16) used for temperature measurements may be the same device as the light emitting device (15) used to measure the transparency of the cover (10), optionally able to emit light at two different spectral spans, one used to estimate the transparency of the cover (10), and one used for temperature measurements. In another embodiment two separate light emitting devices (15) and (16) are introduced in the system.
  • the fluidic part (1) in yet another embodiment of the present invention, the fluidic part (1)
  • this at least one reflective surface (19) is formed at the bottom of the fluid communicating network (2), preferably at the detection section (4).
  • the reflective surface (19) is shaped in such a manner that it comprises a focus point being located at the optical sensor (12). If, for example, the at least one reflective surface (19) is formed in the bottom surface of the channel(s) of the detection section (4) (or part of or the whole of the fluid communicating network (2)), this shaping with a focus point may be formed by shaping the heights (20) of the channel(s) by introducing varying heights (20) so that the bottoms of the channels would 'fit' to a parabolic surface.
  • Fig. 6 shows an alternative way of introducing a reflective surface (19)
  • the reflective surface (19) then could be introduced below the fluid communicating network (2), for example, at the bottom surface of the first body of the fluidic part (1), or even within this first body.
  • the present invention may comprise one of or any combination of the

Abstract

The present invention relates to especially microfluidic analysis systems where the emitted light of a emitting source is measured by optic detection, and where a transparent body separates the emitting source from the optic detector. The invention especially relates to optic calibration of the device, the calibration being related to changes in the transparency of the transparent body and / or changes in the temperature of the emitting source.

Description

MICROFLUIDIC SYSTEM COMPRISING A LIGHT EMITTING DEVICE
The present invention relates to microfluidic analysis systems where the emitted light of an emitting source is measured by optic detection, and where a transparent body separates the emitting source from the optic detector. The invention especially relates to optic calibration of the device, the calibration being related to changes in the transparency of the transparent body and / or changes in the temperature of the emitting source.
Background of the invention
Microfluidic systems are widely used, for example to measure concentrations of a substance in fluid, such as a substance in a body fluid for example glucose.
One example of such a system is found in WO 2008/089764, describing a system based on the extraction of the substances from the medium by diffusion across a semi-permeable membrane to be collected by a sweeping fluid, or perfusion fluid. This substance enriched fluid is then fed to a microfluid system, especially being formed as a microfluidic chip, where different reactions with the substances emit light at an intensity to be correlated to the concentration of the substances in the medium. An optical detector forms part of an electrical part of the system connected to the microfluidic chip, where the optical detector is positioned so that it detects the light emitted from the reactions. The electrical part and the microfluidic chip are separated by a transparent medium or body such as glass.
The importance of being able to accurately and continuously measure substance concentrations within a medium, such as tissue or some fluid like bodily fluid, is well known in the field of medical art or science. For patients suffering from diabetes it is often vital to monitor the levels of glucose, since it is known that elevated levels of glucose in the blood are indicative of conditions such as hyperglycemia and glycosuria resulting from inadequate production or utilization of insulin. Alternatively, abnormally low glucose concentrations may be an indication of overproduction of insulin. Therefore measurement of blood glucose concentration is an important tool for diagnosing, treating or controlling a variety of disorders in which the glucose concentration is known to be an indicator of the existence or severity of the condition. Situations thus exist in which the amount of insulin present is either in excess of or less than that required to handle the specific blood glucose level at any given time. Such situations are especially severe when an individual with a diabetic condition is under stress conditions, such as surgery or during childbirth.
Not only diabetics, but also non-diabetic patients may have the need of having a surveillance of their blood glucose level, like acutely ill patients treated with a pharmacologic dose of corticosteroid. Within biotechnology other interesting applications are to maintain and control specific concentration levels of nutrients, such as glucose, in cell culture reactors, where a long-term stability is needed in order to provide feedback information required to control computerized delivery systems so that a particular chemical can be maintained within preset limits.
In a system as the one disclosed in, for example WO 2008/089764, where a transparent medium separates the optical detector from the emitting source, the state of the transparency of the transparent medium will also influence the measurements, such as if the transparent medium gets covered with dirt and moieties or simply is scratched and gets cracks. The same may be the problem of a transparent cover of the channels of the microfluidic chip of the system.
Among examples are as also described in WO 2008/089764 and its references, the document disclosing that examples of measuring the concentration of a specific chemical, such as glucose, in a solution is described in a number of documents, such as WO9939629A1 and US4452887. The latter describes a determination method where a test material or the reaction product thereof is oxidized using an oxidase enzyme, and hydrogen peroxide formed simultaneously with the oxidation is determined by various means. This has recently become important. The reason for this is that the determination of hydrogen peroxide can be accurately performed by a colorimeteric
determination after a dye-forming reaction using peroxidase or by means of an electrode reaction. According to US4452887 a colorimeteric method based on the foregoing principle using a Trinder reagent is well known. In this method, hydrogen peroxide formed by the action of an oxidase enzyme is reacted with peroxidase to catalyze the oxidative coupling reaction of aminoantipyrine and a phenol and the dye thus formed is colorimetrically determined. The merit of the reaction system is that the same detection system can be utilized for different kinds of oxidase enzymes and the application of the system for various kinds of analyses is being investigated. Among these oxidase enzymes, particularly important enzymes in clinical chemistry are glucose oxidase, cholesterol oxidase, uricase, glycerol oxidase, phosphoglucose oxidase, etc.
In order to improve the systems enhancers may be introduced such as described in WO9105872A1 , describing an enhanced chemiluminescent assay, in which a dihydrophthalazinedione such as luminol, a peroxidase such as HRP and an oxidant such as H202 are co-reacted in the presence of an enhancer such as (p)-iodophenol. The enhancer is generated by enzyme-catalysed reaction of a pro-enhancer, e.g. (p)-iodophenol phosphate is cleaved by alkaline phosphatase, enabling this enzyme to be assayed instead of peroxidase.
Alternatively, the enhancer is added, an anti-enhancer such as (p)-nitrophenol is generated by enzymatic reaction of a pro-anti-enhancer such as (p)- nitrophenol phosphate and the reduction in luminescent emission is measured.
The chemi-luminescent assays are described as "enhanced" in the sense that the total light emission of the reaction and/or the signal /background ratio is larger than that obtained in the same reaction carried out in the absence of an enhancer. Summary of the system
The present invention introduces a method of estimating present state of the system especially for calibration purposes. This is done by introducing a device with a fluidic part comprising,
- fluid communicating network,
- at least a part of the fluid communicating network having a transparent wall section,
and an electronic part comprising a detector configured in connection with the transparent part of the fluid communicating network,
wherein, the electronic part further comprises a light emitting device.
The present invention is especially, but not exclusively, suitable for devices forming part of an analysis system, especially where the analysis is based on optical detection formed by reactions in fluids present in the fluid communicating network, the detector being an optic detector.
The reactions in the fluids may be related to a concentration of specific substances to be measured by the device.
In one more specific embodiment of the present invention, the transparent wall section and the electronic part are separated by a transparent body.
In a further embodiment, the light emitting device is used to estimate the transparency of the transparent body and/or the transparent wall section by reflection.
In another or additional embodiment, the light emitting device is used to estimate the temperature of the fluid(s) in the fluid communicating network.
The correlation of the system is in a preferred embodiment of the present invention based to the estimation of the transparency, the method being to detect light emitted from the light source being scattered and reflected in and by the transparent body, and comparing the detected value(s) or spectral distribution to reference value(s) or a reference spectral distribution.
To clearly separate the correlation light from the emitted light from the reactions in the system, the light emitting device emits light at a narrow spectral span being substantially different to the light formed by the reactions in the fluids.
In one preferred embodiment, the light emitting device is a light diode. In another preferred embodiment of the present invention, a temperature responsive element characterized by having reflection characteristics related to its temperature is positioned into or in connection with the fluid communicating network, and in further embodiment; a heating element is positioned in contact with the fluid communicating network. These may be used to estimate the temperature of the fluids and the fluid communicating network, the method being to detect light emitted from the light source being reflected by the temperature responsive element, and comparing the detected value(s) or spectral distribution to reference value(s) or a reference spectral distribution. The present invention thus further introduces a method of regulating the temperature of the fluid of the device, wherein the method is to regulate the temperature of the heating element in accordance with the estimated temperature. In order to improve the reflection of the emitted light to an optical detector, the present invention in another embodiment introduces that the fluidic part further comprises at least one optically reflective surface.
In one specific embodiment, the reflective surface is formed at the internal surface(s) of the fluid communicating network at least where the wall section is transparent. In another specific embodiment, the reflective surface is formed at the side opposite to the detector of the fluid communication network at least where the wall section is transparent. To focus the emitted light, in yet another embodiment the reflective surface is shaped having a focus point roughly at the position of the detector.
In a further embodiment of the present invention the fluidic part is a fluidic chip where ridges are formed in the surface of at least a first body, the ridges formed into channels by covering the first body with a second body having at least a transparent area.
The present invention in general relates to calibrating a system where the emitted light of an emitting source is measured by optic detection, and where a transparent body separates the emitting source from the optic detector. The invention especially relates to optic calibration of the device, the calibration being related to changes in the transparency of the transparent body and / or changes in the temperature of the emitting source. Figures
Fig. 1 shows a typical form of a microfluidic system where the present invention may advantageously be applied. Fig. 2 shows a transparent body separating a fluidic part from an electrical part comprising a sensor.
Fig. 3 shows how the transparency of a transparent body may change. Fig. 4 shows the transparent body separating a fluidic part from an electrical part comprising a sensor, where the electrical part further comprises a light emitting device according to an embodiment of the present invention. 5 shows the transparent body separating a fluidic part from an electrical part comprising a sensor, where the electrical part further comprises a light emitting device, and the microfluidic part a temperature responsive element according to a further embodiment of the present invention.
6 shows the transparent body separating a fluidic part from an electrical part comprising a sensor, where the electrical part further comprises a light emitting device, and where the microfluidic part further comprises a focused reflecting surface within the flow communication system of the microfluidic part.
Fig. 7 shows the transparent body separating a fluidic part from an electrical part comprising a sensor, where the electrical part further comprises a light emitting device, and where the microfluidic part further comprises ; focused reflecting surface below the flow communication system of the microfluidic part.
Detailed description of the invention Fig. 1 shows one non-limiting example of a setup of an microfluidic analysis system whereto the present invention with advantage would apply, the system comprising a fluidic part (1) illustrated in a non-limiting example is formed as a first body with a network of grooves formed in at least one surface, where the grooves form a fluid communicating network (2) when the surface of the first body is covered with a second body (optionally a sheet, foil, etc.).
The fluid communicating network (2) may comprise any number of branches for feeding any number of different fluids (5, 6) into the system for mixing, and a mixing section (3) where the fluids gets time to mix sufficiently to give some reactions with an observable effect representative of the desired quantity to be measured. The fluid communicating network (2) may further comprise a detection section (4) where the observable effect may be measured or detected. Fig. 2 shows a side view of the same fluidic part (2) where a cover (10) is positioned on top of the first body covering at least part of the detection section (4). The cover (10) may be the second body forming the grooves into a fluid communicating network (2), or any additional not shown such cover layers may also be present. The cover (10) would at least cover part of the detection section (4) or would cover a part of or the whole of the remaining surface of the first body of the fluidic part (1) too.
The reactions in the detection section (4) lead to an observable effect (11), where the effect non-limiting in the following description is an optical effect, such as emitting light at some spectral distribution. The cover (10) and any other optional second bodies covering the fluid communicating network (2) are transparent to the observable effect (11), at least where it / they cover(s) the detection section (4).
An electrical part (9) having an optical sensor or cell (12) is positioned on top of the fluidic part (1) such that the optical sensor (12) is at least partly aligned with the detection section (4). One of the fluids, for example (5), may be a sample fluid, in the present context being defined as a carrier fluid enriched with substances of interest at some concentration representative of the concentration of the species in some medium. As non-limiting examples the medium may be the human tissue or waste water. The remaining of the fluids (6) may thus be reagent fluids to be mixed to the sample fluid to give some observable effect, in the following exampled as a optical effect.
The operation of this example setup could in one embodiment be that a sample fluid (5) is mixed with reagent fluid(s) (6) to emit light with an intensity corresponding to the concentration of substances. This intensity is then measured by the optical sensor (12) and the measurements are optionally processed in a computer to give an indication of the concentration of the substances of interest in the sample fluid. The fluids may finally leave the system (7) or be collected in a waste storage.
Since the measurements depend on an observable effect being correlated to the quantity to be measured, such as an optical reaction being related to the concentration of substances in a fluid, it is essential that no 'external' effects to the quantity affect the measurements, or at least, that they are correlated for by calibrating the system accordingly. Fig. 3 illustrates some of the reasons for such 'external' effects, such as cracks (13) appearing in the cover (10) or moieties, dirt, substances, etc. (14)
depositing on the surfaces of the cover (10), all of theminfluencing the
transparency of the cover (10), and therefore, for example the emitted light from the reactions will be inhibited from reaching the optical sensor (12) thereby 'lowering' the measured concentration of substances in the sample fluid.
Fig. 4 shows a first aspect in one preferred embodiment of the present invention, where a light emitting device (15), such as but not excluded to a light diode, is included in the electrical part (9). The light emitting device (15) preferably emits light within a specified narrow spectral span substantially different from the light emitted by the reactions (11), and with a well known intensity.
The light emitted by the light emitting device (15) will be scattered in the system of cover (11), channels (2, 3, 4) and the main body of the fluidic part (1), and a fraction of it will be measured by the optical sensor (12). Thus the light emitted by the light emitting device (15) will be affected in the same manner by
'external' effects like (13) and (14) as the light emitted by the reactions (11).
The idea of the invention therefore is from time to time to emit light by the light emitting device (15) and use the intensity measured by the optical sensor (12) to estimate the present transparency of the cover (10) (and other optional covers / second bodies), using this for calibration purposes. Optionally, a threshold limit could be introduced to give off a signal when the measured intensity gets below this threshold limit, indicating the system may no
longeroperate properly, and should be exchanged, repaired or cleaned.
A further aspect of the present invention illustrated in Fig. 5, is related to temperature dependencies in the light emission (11) from the reactions in the mixed fluids, this also being due to changing viscosities of the fluids, leading to changing flow rates. It would' therefore be an advantage at least to be able to estimate the present temperature of the mixed fluids, especially, but not excluded to, being present in the reaction section (4). The idea of the present invention is to use a light emitting device (16) to estimate the temperature by introducing in the fluid communicating network (2), especially in contact with the detection section (4), a temperature responsive element (17) characterized by having reflection characteristics related to its temperature. With given intervals the light emitting device (16) emits light and the reflected light from the temperature responsive element (17) is measured by the optical sensor (12) and the temperature of the temperature responsive element (17), being in contact with and therefore related to the temperature of the fluids in the fluid communication network (2), is calculated.
In one preferred embodiment a heating and/or cooling element (18) is positioned in contact with the fluid communicating network (2), especially in contact with the detection section (4). This element will then be controlled in its heating and/or cooling in response to the temperature measurements, thereby making it possible to regulate the temperature of the fluids to a desired temperature.
The light emitting device (16) used for temperature measurements may be the same device as the light emitting device (15) used to measure the transparency of the cover (10), optionally able to emit light at two different spectral spans, one used to estimate the transparency of the cover (10), and one used for temperature measurements. In another embodiment two separate light emitting devices (15) and (16) are introduced in the system.
In yet another embodiment of the present invention, the fluidic part (1)
comprises at least one reflective surface (19). In one embodiment shown in Fig. 5 this at least one reflective surface (19) is formed at the bottom of the fluid communicating network (2), preferably at the detection section (4).
Further, in a preferred embodiment, the reflective surface (19) is shaped in such a manner that it comprises a focus point being located at the optical sensor (12). If, for example, the at least one reflective surface (19) is formed in the bottom surface of the channel(s) of the detection section (4) (or part of or the whole of the fluid communicating network (2)), this shaping with a focus point may be formed by shaping the heights (20) of the channel(s) by introducing varying heights (20) so that the bottoms of the channels would 'fit' to a parabolic surface.
Fig. 6 shows an alternative way of introducing a reflective surface (19)
especially suited when the material of the first body of the fluidic part (1) is of an at least partly transparent material. The reflective surface (19) then could be introduced below the fluid communicating network (2), for example, at the bottom surface of the first body of the fluidic part (1), or even within this first body.
The present invention may comprise one of or any combination of the
embodiments described above.

Claims

Claims
1. Analysis device with a fluidic part comprising,
a fluid communicating network, where at least a part of the fluid communicating network has a transparent wall section, and,
an electronic part comprising an detector configured in connection with the transparent part of the fluid communicating network,
wherein, the electronic part further comprises a light emitting device adapted to estimate the temperature of the fluid(s) in the fluid communicating network.
2. Device according to claim 1 , wherein the analysis is based on optical detection formed by reactions in fluids present in the fluid communicating network, the detector being an optic detector.
3. Device according to any of the preceding claims, wherein the transparent wall section and the electronic part is separated by a transparent body.
4. Device according to claim 3, wherein the light emitting device additionally is adapted to estimate the transparency of the transparent body and/or the transparent wall section by reflection.
5. Device according to any of the preceding claims, wherein the light emitting device is a light diode.
6. Device according any of the preceding claims, wherein a temperature responsive element having reflection characteristics related to its temperature is positioned into or in connection with the fluid communicating network
7. Device according to claim 6, wherein a heating element is positioned in contact with the fluid communicating network.
8. Device according to any of the preceding claims, wherein the fluidic part further comprises at least one optically reflective surface.
9. Device according to claim 8, wherein the reflective surface is formed at the internal surface(s) of the fluid communicating network at least where the wall section is transparent.
10. Device according to claim 8, wherein the reflective surface is formed at the side opposite to the detector of the fluid communication network at least where the wall section is transparent.
11. Device according to one of claims 8-10, wherein the reflective surface is shaped having a focus point roughly at the position of the detector.
12. Device according to any of the preceding claims, wherein the fluidic part is a fluidic chip where ridges are formed in the surface of at least a first body, the ridges formed into channels by covering the first body with a second body having at least a transparent area.
13. Method according to claim 12, wherein the light emitting device emits light at a narrow spectral span being substantially different to the light formed by the reactions in the fluids.
14. Method of estimating the temperature of the fluids and the fluid communicating network by means of the device of claim 7 or 8, the method being to detect light emitted from the light source being reflected by the temperature responsive element, and comparing the detected value(s) or spectral distribution to reference value(s) or a reference spectral distribution.
15. Method of regulating the temperature of the fluid of the device according to claim 14, wherein the method is to regulate the temperature of the heating element in accordance with the estimated temperature.
PCT/DK2011/000001 2010-01-13 2011-01-12 Microfluidic system comprising a light emitting device WO2011085728A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US13/519,692 US20130052085A1 (en) 2010-01-13 2011-01-12 Microfluidic system comprising a light emitting device
CN2011800060149A CN102782476A (en) 2010-01-13 2011-01-12 Microfluidic system comprising a light emitting device
EP11702569A EP2524206A1 (en) 2010-01-13 2011-01-12 Microfluidic system comprising a light emitting device

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA201000023 2010-01-13
DKPA201000023 2010-01-13

Publications (1)

Publication Number Publication Date
WO2011085728A1 true WO2011085728A1 (en) 2011-07-21

Family

ID=43826947

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK2011/000001 WO2011085728A1 (en) 2010-01-13 2011-01-12 Microfluidic system comprising a light emitting device

Country Status (4)

Country Link
US (1) US20130052085A1 (en)
EP (1) EP2524206A1 (en)
CN (1) CN102782476A (en)
WO (1) WO2011085728A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013069942A1 (en) * 2011-11-09 2013-05-16 Samsung Electronics Co., Ltd. Microfluidic apparatus and microfluidic system having the same

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107532995B (en) * 2015-04-24 2021-02-05 株式会社岛津制作所 Optical analysis device and method for manufacturing the same
CN108917949B (en) * 2018-06-27 2020-08-18 武汉工程大学 Signal controller for temperature alarm

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4452887A (en) 1981-06-17 1984-06-05 Fuji Photo Film Co., Ltd. Integral multi-layered element containing glucose oxidase for determining glucose
WO1991005872A1 (en) 1989-10-17 1991-05-02 British Technology Group Ltd Enhanced chemiluminescent assay
WO1999039629A1 (en) 1998-02-04 1999-08-12 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona, Acting For And On Behalf Of Arizona State University Chemical sensors having microflow systems
EP1262764A1 (en) * 2001-05-25 2002-12-04 Corning Incorporated Method and device for the detection of reactions and metabolic changes with temperature-sensitive fluorescent material
CA2218008C (en) * 1996-12-23 2005-03-01 Bayer Corporation Use of thermochromic liquid crystals in reflectometry based diagnostic methods
EP1926010A2 (en) * 2006-11-22 2008-05-28 FUJIFILM Corporation Temperature regulation method of microfluidic chip, sample analysis system and microfluidic chip
WO2008089764A1 (en) 2007-01-26 2008-07-31 Diramo A/S Sensor for an analysis system
JP2009109321A (en) * 2007-10-30 2009-05-21 Sony Corp Measurement method of fluid temperature and measurement apparatus
JP2009128024A (en) * 2007-11-20 2009-06-11 Sony Corp Temperature control method for liquid flowing in passage
WO2009123359A1 (en) * 2008-04-02 2009-10-08 Canon Kabushiki Kaisha Scanning imaging device

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4452887A (en) 1981-06-17 1984-06-05 Fuji Photo Film Co., Ltd. Integral multi-layered element containing glucose oxidase for determining glucose
WO1991005872A1 (en) 1989-10-17 1991-05-02 British Technology Group Ltd Enhanced chemiluminescent assay
CA2218008C (en) * 1996-12-23 2005-03-01 Bayer Corporation Use of thermochromic liquid crystals in reflectometry based diagnostic methods
WO1999039629A1 (en) 1998-02-04 1999-08-12 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona, Acting For And On Behalf Of Arizona State University Chemical sensors having microflow systems
EP1262764A1 (en) * 2001-05-25 2002-12-04 Corning Incorporated Method and device for the detection of reactions and metabolic changes with temperature-sensitive fluorescent material
EP1926010A2 (en) * 2006-11-22 2008-05-28 FUJIFILM Corporation Temperature regulation method of microfluidic chip, sample analysis system and microfluidic chip
WO2008089764A1 (en) 2007-01-26 2008-07-31 Diramo A/S Sensor for an analysis system
JP2009109321A (en) * 2007-10-30 2009-05-21 Sony Corp Measurement method of fluid temperature and measurement apparatus
JP2009128024A (en) * 2007-11-20 2009-06-11 Sony Corp Temperature control method for liquid flowing in passage
WO2009123359A1 (en) * 2008-04-02 2009-10-08 Canon Kabushiki Kaisha Scanning imaging device

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013069942A1 (en) * 2011-11-09 2013-05-16 Samsung Electronics Co., Ltd. Microfluidic apparatus and microfluidic system having the same

Also Published As

Publication number Publication date
CN102782476A (en) 2012-11-14
EP2524206A1 (en) 2012-11-21
US20130052085A1 (en) 2013-02-28

Similar Documents

Publication Publication Date Title
US20210109088A1 (en) Method and device for generating a corrected value of an analyte concentration in a sample of a body fluid
US7758744B2 (en) Dual glucose-turbidimetric analytical sensors
CN111344552B (en) Multiplexed biometric device with electronic readout
JP4627774B2 (en) Sampling device for liquid samples
JP5522190B2 (en) Measuring apparatus and measuring method
JP6539369B2 (en) Normalized calibration of analyte concentration determination
US20090110603A1 (en) Method For Detecting And Compensating An Underdosage Of Test Strips
US20210293740A1 (en) Devices, systems, and methods for performing optical and electrochemical assays
US20210310978A1 (en) Techniques for performing optical and electrochemical assays with universal circuitry
US20220113246A1 (en) Devices, systems, and methods for performing optical assays
US20130052085A1 (en) Microfluidic system comprising a light emitting device
US20210285972A1 (en) Devices, systems, and methods for measuring biomarkers in biological fluids
CN110709699B (en) Metabolite detection device and method of detecting metabolites
US20150316533A1 (en) Methods and systems for point-of-care coagulation assays by optical detection
US11982680B2 (en) Devices, systems, and methods for measuring biomarkers in biological fluids
RU218353U1 (en) Butyrylcholinesterase test strip
EP3463058B1 (en) A transmittance based system/kit for point-of-care quantification of biomarkers sample and use thereof
JP2005237283A (en) Sensor chip for visually quantifying specific test specimen contained in test solution

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201180006014.9

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11702569

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 5629/DELNP/2012

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2011702569

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 13519692

Country of ref document: US