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WO2020239823A1 - Dispositif de mesure d'un paramètre dans un liquide - Google Patents

Dispositif de mesure d'un paramètre dans un liquide Download PDF

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Publication number
WO2020239823A1
WO2020239823A1 PCT/EP2020/064675 EP2020064675W WO2020239823A1 WO 2020239823 A1 WO2020239823 A1 WO 2020239823A1 EP 2020064675 W EP2020064675 W EP 2020064675W WO 2020239823 A1 WO2020239823 A1 WO 2020239823A1
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WO
WIPO (PCT)
Prior art keywords
wall
light
measuring device
light transmission
transmission signal
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2020/064675
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English (en)
Inventor
Vilhelm Krarup MØLLER
Jesper MØLLER
Poul Fogh
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Bifrost Biolabs Ivs
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Bifrost Biolabs Ivs
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Filing date
Publication date
Application filed by Bifrost Biolabs Ivs filed Critical Bifrost Biolabs Ivs
Publication of WO2020239823A1 publication Critical patent/WO2020239823A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • G01N21/03—Cuvette constructions
    • G01N21/031—Multipass arrangements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/41—Refractivity; Phase-affecting properties, e.g. optical path length
    • G01N21/4133—Refractometers, e.g. differential
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47—Scattering, i.e. diffuse reflection
    • G01N21/49—Scattering, i.e. diffuse reflection within a body or fluid
    • G01N21/53—Scattering, i.e. diffuse reflection within a body or fluid within a flowing fluid, e.g. smoke
    • G01N21/534—Scattering, i.e. diffuse reflection within a body or fluid within a flowing fluid, e.g. smoke by measuring transmission alone, i.e. determining opacity
    • 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
    • G01N21/78—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 producing a change of colour
    • G01N21/80—Indicating pH value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/41—Refractivity; Phase-affecting properties, e.g. optical path length
    • G01N21/4133—Refractometers, e.g. differential
    • G01N2021/4153—Measuring the deflection of light in refractometers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6432—Quenching
    • 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

Definitions

  • the present invention relates to a measuring device suitable for measuring a specified parameter in a liquid comprising a first responding part and a second communication part adapted to be mounted opposite each other on a wall transmissive to a first light transmission signal having a specified wavelength.
  • the invention also concerns the individual first and second parts as well as kits of part and a method of measuring a specified parameter.
  • Optical density (OD) or turbidity has been measured by a sensor system in the industry since 1939.
  • An in situ monitoring technology with online sensors is available and can be used for measuring dissolved oxygen, solution pH, oxygen uptake rate and carbon dioxide evolution rate.
  • only a few products in the market can be used for direct cell density verification.
  • CGQ Cell Growth Quantifier
  • the setup of the CGQ consists of a sensor plate (works similarly to SFR vario) and a base station that bundles the data from all the monitored flasks (up to 8) and sends it to the CGQuant software.
  • flasks from 100 ml to 5000 ml can be used for the measurements.
  • the device again is not very versatile as it cannot be used e.g. in falcon tubes and additional adapters have to be purchased when changing the flask size.
  • the product is very expensive, and the shake flasks have to be darkened with a cover to ensure high-quality measurements.
  • BugLab (Concord, USA) developed an OD Scanner for shake flasks.
  • the sensor has to be pointed into a shake flask and allows noninvasive analyses by measuring through the vessel wall.
  • it is an offline measurement of scattered light, the device has to be held with the hand and the measurements are not automated.
  • ODity.bio (Lyngby, Denmark) is another DTU startup from the Novo Nordisk center (CFB).
  • the company has a patent pending for its technology (WO2018096143A1), however, no additional information is available.
  • the present inventors have designed a device which overcome many of the daily problems experienced with measuring different parameters in a liquid, such as oxygen
  • the present invention relates to a measuring device suitable for measuring a specified parameter in a liquid comprising a first responding part and a second communication part adapted to be mounted opposite each other on a wall transmissive to a first light transmission signal having a specified wavelength wherein i) the first responding part comprising a material configured for providing a response as a reaction to the first light transmission signal, and ii) the second communication part is adapted to receive current when in operation and comprises a transmitter of the first light signal, a receiver of the response to light signal, a communication means for providing the measured parameter in a computer readable output.
  • the first responding part is a first reflector part, wherein the first reflector part comprises a light reflecting material adapted for reflecting the first light transmission signal and wherein the first reflector part and the wall define a volume within the circumference of the reflector part for the liquid to fill out when the device is in operation.
  • the present invention relates to a measuring device suitable for measuring a specified parameter in a liquid comprising a first reflector part and a second communication part adapted to be mounted opposite each other on a wall transmissive to a first light transmission signal having a specified wavelength wherein i) the first reflector part comprises a light reflecting material adapted for reflecting the first light transmission signal, and ii) the second communication part is adapted to receive current when in operation and comprises a transmitter of the first light signal, a receiver of the reflected light signal, a communication means for providing the measured parameter in a computer readable output, wherein the first reflector part and the wall define a volume within the circumference of the reflector part for the liquid to fill out when the device is in operation.
  • the first responding part is a first conductor part, wherein the first conductor part comprises a light conducting material adapted for conducting the first light transmission signal and wherein the first conductor part and the wall define a volume within the circumference of the conductor part for the liquid to fill out when the device is in operation.
  • the present invention relates to a measuring device suitable for measuring a specified parameter in a liquid comprising a first conductor part and a second communication part adapted to be mounted opposite each other on a wall transmissive to a first light transmission signal having a specified wavelength wherein i) the first conductor part comprises a light conducting material adapted for conducting the first light transmission signal, and ii) the second communication part is adapted to receive current when in operation and comprises a transmitter of the first light signal, a receiver of the conducted light signal, a communication means for providing the measured parameter in a computer readable output, wherein the receiver is a multipoint reception array adapted to detect a relative position of the conducted return signal, wherein the first conductor part and the wall define a volume within the circumference of the conductor part for the liquid to fill out when the device is in operation.
  • the first responding part is a first emissive part, wherein the first emissive part comprises a container transmissive to the first light transmission signal, wherein the container is permeable to the liquid and comprises the emissive material adapted for providing a response to the first light transmission signal.
  • the present invention relates to a measuring device suitable for measuring a specified parameter in a liquid comprising a first emissive part and a second communication part adapted to be mounted opposite each other on a wall transmissive to a first light transmission signal having a specified wavelength
  • the first emissive part such as a fluorescence or luminescence material
  • the container is permeable to the liquid and comprises the emissive material adapted for providing a response to the first light transmission signal
  • the second communication part is adapted to receive current when in operation and comprises a transmitter of the first light signal, a receiver of the response to the first light transmission signal, a communication means for providing the measured parameter in a computer readable output.
  • first responding part and the second communication part are individual parts mounted by means of magnets.
  • first reflector part has 1, 2 or 4 magnets matching 1, 2 or 4 magnets on the second light transmission part.
  • the first responding part and the second communication part are in direct contact with the wall when mounted on said wall.
  • the wall is made of glass, such as quartz glass.
  • the wall is made of a plastic material.
  • the wall is a part of a flask, such as a conical flask, a water tank, a falcon tube, a cell growth reactor, a fermentor, a fish tank, or a view glass.
  • a flask such as a conical flask, a water tank, a falcon tube, a cell growth reactor, a fermentor, a fish tank, or a view glass.
  • the volume is an open chamber, semi-open chamber or closed chamber.
  • the volume is a semi-open chamber adapted to reduce bobbles in the liquid when the device is in operation.
  • the semi-open chamber has at least one opening said chamber being adapted to be filled with the liquid through said opening when the device is in operation.
  • the at least one opening is two or three openings, such as two.
  • the second communication part comprises: i) a second receiver of the first light transmission signal having the specified wavelength, or ii) a second receiver of a second light transmission signal having the same specified wavelength as the first light transmission signal; wherein the second receiver is adapted to use the transmitted signal as a reference signal.
  • the second communication part comprises a temperature sensor.
  • the specified parameter is Optical Density (OD). In another embodiment of the above aspects the specified parameter is a refractive index.
  • the specified wavelength is selected from a specific wavelength in a range from 200-1200 nm or a range of wavelengths from 200-1200 nm.
  • the specified wavelength typically comes from at least one light emitting diode, such as two diodes.
  • the light reflecting material is selected from a mirror, a chromed metal covered by a transparent coating, a silvered metal or a plastic or aluminized plastic.
  • the light conducting material is selected from at least two prisms wherein the light transmission signal is adapted to pass through the liquid between the prisms.
  • the light conducting material is selected from four prisms.
  • the prisms conduct the light signal through a sample liquid in at least two pathways, to measure a refractive index of the sample liquid and measure a distance between the first conductor part and the second communication part.
  • the position indicator uses a different optical pathway than the first light transmission signal and a software adjustment algorithm.
  • the first emissive part comprises a material reactive to oxygen, such as a fluorescence quenching ruthenium complex.
  • the first emissive part comprises a material reactive to pH change, such as a Carboxyfluorescein derivative (e.g. 5- or 6- Carboxy-2',7'-dichlorosulfonefluorescein, optionally with a diacetate and other functional groups attached), a BCECF-compound (e.g. an ester, such as (2’,7’-bis-(2-carboxyethyl)-5-(and-6)- carboxyfluorescein acetoxymethyl ester)).
  • a Carboxyfluorescein derivative e.g. 5- or 6- Carboxy-2',7'-dichlorosulfonefluorescein, optionally with a diacetate and other functional groups attached
  • a BCECF-compound e.g. an ester, such as (2’,7’-bis-(2-carboxyethyl)-5-(and-6)- carboxyfluorescein acetoxymethyl ester
  • the present invention relates to a first reflector part adapted to be mounted on a wall transmissive to a first light transmission signal having a specified wavelength as part of the measuring device of the second aspect or any embodiment hereof comprising a light reflecting material adapted for reflecting the first light transmission signal.
  • the present invention relates to a second communication part adapted to be mounted on a wall transparent to a first light transmission signal having a specified wave length as part of the measuring device of the second aspect or any embodiment hereof comprising a transmitter of the first light signal, a receiver of the reflected light signal, a communication means for providing the measured parameter in a computer readable output.
  • the present invention relates to a kit of parts comprising the first reflector part of the fifth aspect and the second communication part of the sixth aspect, as two individual parts and optionally a current supply.
  • the present invention relates to a method of measuring a specified parameter in a liquid comprising mounting the first reflector part and the second communication part of the measuring device of the second aspect or any embodiment hereof on opposite sides of a wall transmissive to a first light transmission signal having a specified wave length wherein the first reflector part and the wall define a volume within the circumference of the reflector part for the liquid to fill out and supply current to the second communication part, and providing the measured specified parameter in a computer readable output.
  • the present invention relates to a first conductor part adapted to be mounted on a wall transmissive to a first light transmission signal having a specified wavelength as part of the measuring device of the third aspect or any embodiment hereof comprising a light conducting material adapted for conducting the first light transmission signal.
  • the present invention relates to a second communication part adapted to be mounted on a wall transparent to a first light transmission signal having a specified wave length as part of the measuring device of the third aspect or any embodiment hereof comprising a transmitter of the first light signal, a receiver of the conducted light signal, a communication means for providing the measured parameter in a computer readable output.
  • the present invention relates to a kit of parts comprising the first conductor part of the ninth aspect and the second communication part of the tenth aspect, as two individual parts and optionally a current supply.
  • the present invention relates to a method of measuring a specified parameter in a liquid comprising mounting the first conductor part and the second communication part of the measuring device of the third aspect or any embodiment hereof on opposite sides of a wall transmissive to a first light transmission signal having a specified wave length wherein the first conductor part and the wall define a volume within the circumference of the conductor part for the liquid to fill out and supply current to the second communication part, and providing the measured specified parameter in a computer readable output.
  • the present invention relates to a first emissive part adapted to be mounted on a wall transmissive to a first light transmission signal having a specified wavelength as part of the measuring device of the fourth aspect or any embodiment hereof comprising a container transmissive to the first light transmission signal, wherein the container is permeable to the liquid and comprises the emissive material adapted for providing a response to the first light transmission signal.
  • the present invention relates to a second communication part adapted to be mounted on a wall transparent to a first light transmission signal having a specified wave length as part of the measuring device of the fourth aspect or any embodiment hereof comprising a transmitter of the first light signal, a receiver of the response signal, a communication means for providing the measured parameter in a computer readable output.
  • the present invention relates to a kit of parts comprising the first emissive part of the thirteenth aspect and the second communication part of the fourteenth aspect, as two individual parts and optionally a current supply.
  • the present invention relates to a method of measuring a specified parameter in a liquid comprising mounting the first emissive part and the second communication part of the measuring device of the fourth aspect or any embodiment hereof on opposite sides of a wall transmissive to a first light transmission signal having a specified wave length wherein the liquid fills the container so that the emissive material provides a response to the first light transmission signal and supply current to the second communication part, and providing the measured specified parameter in a computer readable output.
  • the present invention relates to use of a measuring device suitable for measuring a specified parameter in a liquid
  • a measuring device suitable for measuring a specified parameter in a liquid
  • a first responding part such as a reflector, a conductor or an emissive part
  • a second communication part adapted to be mounted opposite each other on a wall transmissive to a first light transmission signal having a specified wavelength in connection with any one selected from a test tube (typically from 20-50 mL), a shake flask (typically from 100ml to 2 liter), a falcon tube (typically 50 ml), a table top fermentor
  • Figure 1 illustrates an embodiment of the present invention seen in perspective concerning a reflector part.
  • Figure 2 illustrates the embodiment of figure 1 seen from one side and showing the position of the light reflecting material.
  • Figure 3 illustrates another embodiment of the present invention seen in perspective concerning a reflector part.
  • Figure 4 illustrates the embodiment of figure 3 seen from the front side and showing the position of the light reflecting material.
  • Figure 5 illustrates an embodiment of the second communication part of the device of the present invention seen from the front side.
  • Figure 6 illustrates the embodiment of figure 5 second part seen in perspective.
  • Figure 7 illustrates the embodiment of figure 5 second part seen from the opposite site.
  • Figure 8 illustrates the embodiment of figure 6 second part as a cross sectional view made through an imaginary center line from one end to the opposite end.
  • Figure 9 illustrates a conical flask and the device of the present invention when mounted correctly on the glass wall of the flask.
  • Figure 10 illustrates a further embodiment of the device of the present invention seen as a cross sectional view of one side of the device.
  • Figure 11 illustrates the embodiment of the device of the present invention seen as a cross sectional view of the opposite side of the device.
  • Figure 12 illustrates a still further embodiment of the device of the present invention. DESCRIPTION OF THE INVENTION
  • the OD sensor is comprised of a transmitter and a receiver.
  • the transmitter emits light, typically at 600nm, and the receiver detect the light.
  • the absorbance of light is lower, the more particles (cells) are blocking the path of the light.
  • Temperature sensitivity and a reference point for the liquid without growth are amongst the factors needed to be determined to get a reliable measurement.
  • shaker flasks typically arranged on a shaker board, where conical flasks of volumes from 250 to 5000mL are arranged in parallel.
  • the device is suitable for measuring a specified parameter in a liquid.
  • a specified parameter means any desired parameter in the liquid, such as temperature, pH, dissolved oxygen level, which parameters can be used to predict an outcome of a reaction, give status of a process, cell growth, etc
  • the liquid is any liquid such as water, organic solvent/suspension and mixtures hereof in which the parameter is desired to be measured, such as OD, pH, turbidity, refractive index, as well as any parameter which can be deducted from a measured parameter such as cell growth rate based on OD.
  • the device comprises a first responding part, such as a reflector part, a conductor part, or an emissive part, and the second communication part work together and are intended to be mounted on opposite sites of a wall.
  • a first responding part such as a reflector part, a conductor part, or an emissive part
  • the second communication part work together and are intended to be mounted on opposite sites of a wall.
  • Such mounting can be gluing each part on the wall or by the use of magnets, or other suitable means as long as the two parts are mounted opposite each other before applying current to the system.
  • refractive index Similar to turbidity for cell growth, a key parameter in chemical synthesis optimization is refractive index. Industry standard today is either a hand-held sampling device, or a process monitor designed for a steel pipe. Neither are useful for getting trend data from a shake flask or batch-reactor.
  • the present invention allows a light beam to pass into the container, be refracted by the sample, and returned to the outer part, where a linear array of sensors detect the refraction by measuring the movement of the focus point.
  • a reference signal is transmitted through a parallel path, and then reflected obliquely back through the wall, the movement of this return signal being proportional with the distance between the parts, pending some influence from the wall refractive properties, which also are compensated for by this method.
  • a wall transmissive to a light transmission signal means a transparent wall made of a transmissive material such as glass, plastic, quartz, wherein the light signal or a part of the light signal can pass through the wall and communicate with the second communication part of the present invention.
  • the light signal will transmit 100% through the wall, but realistically it will be less, such as 90% or less, as long as a small fraction of the light signal travels through the wall and communicates with the second communication part of the present invention.
  • a wall may be a part of a flask, such as a conical flask, a water tank, a falcon tube, a cell growth reactor, a fermentor, a fish tank, or a view glass.
  • a specified wavelength as used herein in connection with the light transmission signal means any electromagnetic radiation having a known and desired wavelength, such as LED transmitting a wavelength of 600 nm or could be more LEDs transmitting known and desired wavelengths within a range from for instance 600 to 900 nm as an example, which wavelength travels through the transmissive wall when the device is in operation.
  • operation means that the device is placed correctly on the wall and either ready to measure or performing measures.
  • operation means that current is supplied and that the device is performing its measuring as described herein.
  • a first responding part means a passive part which is intended to send a response back through the wall, as a result of the light transmission signal from the second communication part, to be received by the second communication part and if necessary translated to a computer readable output.
  • the first responding part is typically a reflector made of a material such as a mirror, a chromed metal covered by a transparent coating, a silvered metal or a plastic or aluminized plastic.
  • the first responding part may also be a conductor made of a light conducting material such as prisms.
  • the first responding part may also be a first emissive part comprising a container transmissive to the first light transmission signal, wherein the container is permeable to the liquid and comprises the emissive material adapted for providing a response to the first light transmission signal.
  • the emissive material is typically a fluorescence material or a luminescence material such as a fluorescence quenching ruthenium complex, a Carboxyfluorescein derivative (e.g. 5- or 6-Carboxy-2',7'-dichlorosulfonefluorescein, optionally with a diacetate and other functional groups attached), a BCECF -compound (e.g. an ester, such as (2’,7’-bis-(2- carboxyethyl)-5-(and-6)-carboxyfluorescein acetoxymethyl ester)).
  • a second communication part means a part which is adapted to receive current, such as by means of a battery (although a battery is heavy and may make the use of for instance magnets less suitable) or a wire providing AC or DC.
  • the second communication part has as a minimum a transmitter of the first light signal, a receiver of the response to light signal, and a communication means for providing the measured parameter in a computer readable output.
  • a transmitter of the first light signal means any element transmitting electromagnetic radiation of a measurable wavelength, such as a light emitting diode (LED), an incandescent light bulb, a traditional laser or a Radio Frequency/microwave emitter.
  • a receiver of the response to light signal means any element such as a sensor, for instance a photo diode or a Light Emitting Diode. These may be arranged in a multipoint reception array, such as a line shaped or 2-dimensional shape
  • connection in connection with providing the measured parameter in a computer readable output means without limitation a means able to receive the input from the signal response and capable of translating it into a different signal that can be send to a computer for monitoring the measured parameter and report the parameters.
  • connection is in the form of a wired connection, which is a custom or standard communication protocol (e.g. I2C, RS-232 or one-wire).
  • the connection can also be wireless, using any standard or non-standard communication protocol.
  • a space or volume will be created between the wall and the circumference of the reflector or conductor part. This volume as used herein may be open, semi -closed or closed.
  • the volume created can be filled with the liquid when the device is in operation. If the volume is an open chamber there is no substantial barriers to the liquid and the liquid may enter and leave the volume during operation. If the volume is a semi -closed chamber there are one or more openings for the liquid to enter the chamber, and this reduces the formation of bubbles which are usually formed when the liquid is moved such as by means of a magnetic stirrer in a conical flask.
  • the liquid can only enter the chamber through a small crack or multiple cracks created between the reflector/conductor part and the wall, thus the chamber will fill slowly and empty slowly which may be an advantage in some instances such as a filtering effects in heterogeneous liquids, foam reduction, stable liquid level during
  • the volume is a semi-open chamber adapted to reduce bobbles in the liquid when the device is in operation.
  • the semi-open chamber has at least one opening said chamber being adapted to be filled with the liquid through said opening when the device is in operation.
  • the at least one opening is two or three openings, such as two. Such openings are preferably located in the upper part of the chamber when the device is placed on the wall for operation, and typically there are two openings opposite each other in the chamber and the openings are located in the upper one third of the chamber.
  • the dimension of each opening is any suitable dimension such as a square or circular and each opening may have a diameter or diagonal length from 0.2-1 cm 2 .
  • a multipotent reception array in connection with communication means for providing the measured parameter in a computer readable output, means an array such as 2-128, such as 2-64, such as 2-16, such as 4, such as 8 receivers arranged in a geometry that aligns with the change in focus of the received light.
  • the two parts may be aligned towards each other by means of magnets.
  • the important is sizing of magnets, as too big magnets make it clumsy, and too small magnets impose severe size limitations.
  • magnets provide a very effective way of bringing the two parts together and holding them together.
  • the first responding part and the second communication part are individual parts mounted by means of magnets.
  • the first responding part has 2 magnets matching 2 magnets on the second communication part, and preferably such magnets are placed adjacent the circumference of each of the two parts and spaced apart to create suitable space for the sensors and the like.
  • Magnetic attachment is a known technique.
  • the main challenge of the attachment is to ensure centering and that the position is kept during shaking and movement. It is obvious to the expert that a single, ring formed magnet also will ensure centering of the two parts. This has the disadvantage of taking up space and creating a relatively large magnetic field that can disturb other processes.
  • the preferred embodiment of the present invention prefers to have one or two magnets adjacent the circumference or at each end if the parts are shaped with a cross section as a square and connect them with a metal shield that enhance and focus the magnetic field. As the distance between the two parts in some applications is above 3 mm, such as 3-10mm another preferred embodiment has an outer shell around each part of the invention, containing additional magnets.
  • the outer shell typically adds 5- 10mm in all dimensions of the parts.
  • the first responding part has magnets matching magnets on the second communication part, and preferably such magnets are placed adjacent the circumference of each of the two parts and spaced apart, and a first metal shield that enhance and focus the magnetic field is placed to connect the magnets on the first part and a second metal shield that enhance and focus the magnetic field is placed to connect the magnets on the second part.
  • Measuring pH and Oxygen by optical quenching is a well-known technology, and companies such as Presens of Regensburg has marketed such equipment for long time, selling spots of sensor material that can be placed in a transparent container and measured from the outside.
  • the magnetic fastening of this invention solves the particular problem of how to measure during the time the flask is moving.
  • a thin material could be placed between the first responding part and the second communication part either in direct contact with the first responding part and the wall or in direct contact with the second communication part on the opposite site of the wall, such material may be a light modifying material, e.g. a color filter or a polarizing filter, or the first responding part and the second communication part are in direct contact with the wall when mounted on said wall for operation.
  • a temperature sensor means a sensor adapted to be placed in the second communication part and measure the temperature in the close vicinity of the various sensors of the second part. Temperature sensors are a well-developed technology that the skilled person can select and such appropriate sensors may be Thermocouples, Thermistors, Thermostats and Resistive Temperature Devices and infrared measurements devices.
  • a specified wavelength means a specific wavelength, such as 400nm, 600nm or lOOOnm, or is a range of wavelengths such as from lOOnm to 2000nm.
  • the specified wavelength is a specific wavelength, such as a wavelength selected from 200-1200nm, such as 400- lOOOnm, such as 600-900nm.
  • the specified wavelength is selected form a range of wavelengths between 100-2000nm, such as between 400- 1200nm. It is intended that when a light transmission signal is sent as a range of wavelengths such as the range is from 50nm to 200nm it is comprised by the range of wavelengths between 100- 2000nm since it overlaps. Similarly, a light transmission signal sent as a range of wavelengths from 200nm to 1200nm or 400nm to 2200nm is comprised by the range of wavelengths between 100- 2000nm since it overlaps or is encompassed.
  • the light conducting material is selected from at least two prisms wherein the light transmission signal is adapted to pass through the liquid between the prisms.
  • the light conducting material is selected from four prisms.
  • the prisms conduct the light signal through a sample liquid in at least two pathways, to measure a refractive index of the sample liquid and measure a distance between the first conductor part and the second communication part.
  • a position indicator means the position indicator uses a different optical pathway than the first light transmission signal and a software adjustment algorithm.
  • One way of making a suitable position indicator is to arrange an alternate light path, where the liquid has no effect on the light beam, but the return pathway from the inner part to the outer is done at an oblige angle, converting distance to lateral movement, that is detected with a multipotent sensing array.
  • a material reactive to oxygen means any material capable of changing properties and emitting a signal due to reaction with oxygen.
  • a material reactive to pH change means any material capable of emitting a signal due to a pH change, such as a Carboxyfluorescein derivative (e.g. 5- or 6- Carboxy-2',7'-dichlorosulfonefluorescein, optionally with a diacetate and other functional groups attached), a BCECF-compound (e.g. an ester, such as (2’,7’-bis-(2-carboxyethyl)-5-(and-6)- carboxyfluorescein acetoxymethyl ester)).
  • a Carboxyfluorescein derivative e.g. 5- or 6- Carboxy-2',7'-dichlorosulfonefluorescein, optionally with a diacetate and other functional groups attached
  • a BCECF-compound e.g. an ester, such as (2’,7’-bis-(2-carboxyethyl)-5-(and-6)- carboxyfluorescein acetoxymethyl ester
  • the first responding part such as the reflector part, emissive part or conductor part, can be sold separately from the second communication part and vice versa and as such the present invention also concerns these individual parts as preferred aspects of the present invention.
  • first and second parts are provided in a package to be sold together with a leaflet explaining how the device works as well as other relevant information such as security
  • Such a package is referred to as a kit of parts.
  • Figure 1 illustrates an embodiment of the present invention seen in perspective concerning a reflector part (10) (which is an embodiment of the first responding part of the present invention).
  • the reflector part (10) as shown consist of two magnets (16, 18) located on opposite sides of the light reflecting material (12) and placed on a metal plate (20).
  • the metal plate can be made of chrome and constitute the light reflecting material (12).
  • the light reflecting material (12) is placed on a glass (14) (or acryl) to modify the distance the light has to travel through the liquid, when the device is in operation.
  • the magnets (16, 18) are covered by a plastic and are 5x5x11 mm in size, and in order to strengthen the magnetic flux the magnets are placed reversed north south, so the first magnet (16) is north south and the second magnet (18) is south north.
  • the reflector part (10) is placed correctly with the light reflecting material facing the transparent wall (not shown) a space or volume is created between the wall and the light reflecting material (12) and the two magnets (16, 18) and the circumference of the reflector part (10) and is considered an open chamber because no further walls are placed to keep the liquid inside the open chamber when the device is in operation.
  • Figure 2 illustrates the embodiment of figure 1 seen from one side and showing the position of the light reflecting material (12), such as a mirror being a chrome plated metal plate, placed on the glass (14) to modify the distance the light has to travel.
  • the reflector part (10) as shown consist of two magnets (16, 18) located on opposite sides of the light reflecting material (12) and placed on the metal plate (20), wherein the metal plate may be chrome plated and constitute the light reflecting material (12).
  • Figure 3 illustrates another embodiment of the present invention seen in perspective concerning a reflector part (30) (which is an embodiment of the first responding part of the present invention).
  • the reflector part (30) as shown consist of two magnets (34, 36) located on opposite sides of the light reflecting material (40) and placed on a metal plate (32).
  • the magnets (34, 36) and the metal plate (32) are molded in a plastic covering view to the two magnets (34, 36), and in order to strengthen the magnetic flux the magnets are placed reversed north south, so the first magnet (34) is north south and the second magnet (36) is south north.
  • the plastic is molded to form a volume defined by the inner wall (38) of the chamber having the reflective material (40) and an outer wall (46).
  • the reflector part (30) When the reflector part (30) is placed correctly with the light reflecting material (40) facing the transparent wall (not shown) a space or volume is created between the wall (not shown) and the light reflecting material (40) and the two magnets (34, 36) and the inner wall (38) of the reflector (30) thereby creating a semi-open chamber adapted to receive the liquid when in operation.
  • the light reflecting material (40) is typically a mirror which reflects the transmitted light so that the distance of the travelled light is doubled.
  • the chamber so formed is considered a semi-closed chamber because two openings (42, 44) are located in the outer wall (46) which openings are placed opposite each other to create an ideal flow.
  • Figure 4 illustrates the embodiment of figure 3 seen from the front side and showing the position of the light reflecting material (40), such as a mirror.
  • the reflector part (30) as shown consist of two magnets (34, 36) located on opposite sides of the light reflecting material (40) and placed on the metal plate (not shown) and molded in a suitable plastic, and a volume is created by the inner wall (38) and the outer wall (46), and two openings (42, 44) are located in the outer wall (46).
  • Figure 5 illustrates an embodiment of the second communication part (50) of the device of the present invention seen from the front side (60) facing the wall when the device is mounted on the wall (not shown).
  • the second part (50) has two openings (52, 54) for LEDs to transmit light such as warm white or IR red to the reflector part as shown in figures 1-3. Adjacent the LEDs for transmission of light are two openings (56, 58) for LED sensors wherein one is a red LED receiving a specific wavelength, such as 600nm, and the second is an IR LED receiving a specific wavelength, such as 940nm.
  • the second part (50) is made of two parts, that is an inner part (60) and an outer part (62) and typically the inner part (60) is made of black polypropylene, ABS, POM or polyethylene plastic and the outer part (62) is made of white plastic of the same type.
  • the front part (60) which will face the wall such as a conical flask wall can be made curved so that it has a good fit to the outside of the wall.
  • the second part (50) has a rectangular cross section when seen from the front (60) and ideally two magnets (not shown) are placed opposite each other adjacent to the edges (64, 66) of the rectangular shaped second part (50).
  • Figure 6 illustrates the embodiment of figure 5 second part (50) seen in perspective with the LED openings (52, 54), openings (56, 58) having LEDs for receiving the transmitted light, and the inner (60) and outer part (62) of the molded device second part (50) as well as the part (70) for the wire for applying current to the second part (50).
  • Figure 7 illustrates the embodiment of figure 5 second part (50) seen from the opposite site wherein the outer part (62) covers the inner part (not seen) and a inlet part (70) adapted for applying current via a wire is located at the center of the second part (50) back side.
  • Figure 8 illustrates the embodiment of figure 6 second part (50) as a cross sectional view made through an imaginary center line from one end (64) to the opposite end (66) and between the openings (52, 58) on one side and the openings (54, 56) on the other side.
  • the second part (50) has the inlet part (70) for the current wire (not shown) and is covered by the outer part (62).
  • the two magnets (64, 66) are illustrated and placed on opposite sides adjacent the ends of the rectangular shape cross section to make better room for the sensor parts.
  • the magnets (64, 66) have a size of 5x5x11 mm each and are linked to a metal plate (78) and in order to strengthen the magnetic flux the magnets are placed reversed north south, so the first magnet (64) is north south and the second magnet (66) is south north.
  • From the cross-sectional view 3 LEDs (68, 72, 74) can be seen (another three LEDs not seen are located adjacent the 3 LEDs 68, 72, 74) each having a size of 5mm in diameter and 8 mm in length.
  • the LED (72) is for transmission of light and the LED (74) is for receiving a specific wavelength, and the LED (68) is used as a reference together with an adjacent LED (not seen) and the one sensor transmit light into the second to calibrate for
  • a second metal plate (76) is placed on the back side (the side opposite the transmitting/receiving parts facing towards the first reflector part as shown in figures 1-4) of the LEDs and this plate is preferably chrome plated to resist corrosion.
  • Figure 9 illustrates a conical flask (80) and the device (88, 90, 92, 94) of the present invention typically for measuring cell density, when mounted correctly on the glass wall of the flask (82).
  • the flask (80) is shown as a cross section together with a cross section of the device and the flask contains a liquid (86) to be measured by the present device (88, 90, 92, 94).
  • the liquid line (84) moves to cover the present device (shown) and moves to lower the liquid line (84) so that the device is not covered (not shown), and this happens multiple times during operation of the flask.
  • the device of the present invention is correctly placed on the flask wall (82) so that the inner part (90) also designated the first reflector part (90) via a magnetic system is mounted on the wall (82) and thereby creating a space or volume (92) for the liquid (86) to enter when the liquid line (84) covers the first reflector part (90).
  • the outer part (88) also designated the second communication part (88) is placed correctly on the wall (82) of the flask (80) and via a magnetic system is mounted on the wall (82).
  • the magnetic system is explained in more detail above in connection with explanation of figures 1-8 since magnets facing north south are facing each other and maintain the position of the device when mounted on the flask wall (82).
  • the current supply via a wire is indicated at the inlet part (94) on the back side opposite the side facing the wall (82).
  • Figure 10 illustrates a further embodiment of the device (100) of the present invention, typically for measuring refractive index in a cell culture, seen as a cross sectional view of one side of the device (100) consisting of a first conductor part (102, 104, 106, 108 110, 112, 114, 116) and the second communication part (120, 122, 124, 126, 128, 130, 132) and the space between the two parts is the transmissive (such as transparent) wall (not shown).
  • a first conductor part 102, 104, 106, 108 110, 112, 114, 116
  • the second communication part 120, 122, 124, 126, 128, 130, 132
  • the first conductor part consists of an outer shell (102) typically made of polypropylene, ABS, POM or polyethylene plastic, and two magnets (104, 106) are placed opposite each other adjacent the ends of the first conductor part and a metal plate (110) for strengthen the magnetic flux is placed in the back facing away from the wall and the second communication part and is connecting the two magnets (104, 106).
  • the first conductor part is further defined by a transparent plate (108) for the light to pass, which plate is typically made of acrylic plastic or glass, and two prisms (112, 114) typically also made of acrylic plastic or glass and having the dimensions 60x45x75° and 5mm high, are seen and placed in a liquid chamber (116) where the liquid, such as water, surrounds all the prisms to provide a liquid prism effect defining a 60x60x60° liquid prisms.
  • the second communication part consisting of an outer shell (120) typically made of a plastic material, and two magnets (122, 124) are placed opposite each other adjacent the ends of the second communication part and a metal plate (126) for strengthen the magnetic flux is placed in the back facing away from the wall and the first conductor part and is connecting the two magnets (122, 124).
  • the magnets are 15 mm in height and 5x11 mm with half spherical ends.
  • the second communication part is further defined by a transparent plate (128) for the light to pass, which plate is typically made of acrylic plastic or glass, and the light transmissive LED (130) is seen on one side and an array (132) consisting of 8 small LEDs is next to the LED (130) which 8 LEDs (132) are used to measure the angle of the returning light from the prisms (112, 114) and the liquid prism (116).
  • a dashed line is shown starting from the LED (130) with arrows showing the direction of the light signal and the light returning after being led through the prisms back to the array (132).
  • the prism effect is obtained because the light signal from the LED (130) is sent to hit the first prism (114) with an angle of 45° for refraction of the light signal through the liquid (116) and the second prism (112).
  • Figure 11 illustrates the embodiment of the device (100) of the present invention seen as a cross sectional view of the opposite side (shown in figure 10) of the device (100) consisting of a first conductor part (107, 109, 111, 113, 115, 117) and the second communication part (119, 121, 123, 125, 127, 129, 131) and the space between the two parts is the transmissive (such as transparent) wall (not shown).
  • the first conductor part consists of an outer shell (107) typically made of polypropylene, ABS, POM or polyethylene plastic, and two magnets (103, 105) are placed opposite each other adjacent the ends of the first conductor part and a metal plate (109) for strengthen the magnetic flux is placed in the back facing away from the wall and the second communication part and is connecting the two magnets (103, 105).
  • the first conductor part is further defined by a transparent plate (111) for the light to pass, which plate is typically made of acrylic plastic or glass, and two prisms (115, 117) typically also made of acrylic plastic or glass and wherein 115 has the dimensions 90x45x45° and 5mm high and wherein 117 has the dimensions 90x90x60x30° and 5mm high, are seen and placed in a liquid chamber (113) where the liquid, such as water, surrounds all the prisms to provide a liquid non-prism effect defining a 90x90x90x90° liquid square.
  • the second communication part consisting of an outer shell (127) typically made of a plastic material, and two magnets (129, 131) are placed opposite each other adjacent the ends of the second communication part and a metal plate (125) for strengthen the magnetic flux is placed in the back facing away from the wall and the first conductor part and is connecting the two magnets (129,
  • the second communication part is further defined by a transparent plate (123) for the light to pass, which plate is typically made of acrylic plastic or glass, and the light transmissive LED (119) is seen on one side and an array (121) on the other side consisting of 8 small LEDs is next to the LED (119) which 8 LEDs (121) are used to measure the angle of the returning light from the prisms (115, 117) and the liquid (116).
  • a dashed line is shown starting from the LED (119) with arrows showing the direction of the light signal and the light returning after being led through the prisms back to the array (119).
  • the non-prism effect is obtained because the light signal from the LED (119) is sent to hit the first non-prism (115) with an angle of 45° for non-refraction of the light signal through the liquid (113) and the second non-prism (117).
  • Figure 12 illustrates a still further embodiment of the device (140) of the present invention, typically for measuring pH and O2 in a cell culture, seen as a cross sectional view of the device (140) consisting of a first emissive part (142, 144, 146, 148, 150, 152, 154) and the second communication part (156, 158, 160, 162, 164, 166, 168, 170, 172, 174) and the space between the two parts is the transmissive (such as transparent) wall (not shown).
  • a first emissive part 142, 144, 146, 148, 150, 152, 15
  • the second communication part 156, 158, 160, 162, 164, 166, 168, 170, 172, 174
  • the transmissive such as transparent
  • the first emissive part consists of an outer shell (142) typically made of polypropylene, ABS, POM or polyethylene plastic, and two magnets (144, 146) are placed opposite each other adjacent the ends of the first emissive part and a metal plate (152) for strengthen the magnetic flux is placed in the back facing away from the wall and the second communication part and is connecting the two magnets (144, 146).
  • the first emissive part is further defined by a transparent plate (148) for the light to pass, which plate is typically made of acrylic plastic or glass, and a liquid chamber (154) in which chamber an emission material (150) is placed in a matrix of water permeable material, such as silicon rubber, Polyamide or fluorocarbon-polymers, such as a fluorescent material, is placed adjacent the transparent plate (148).
  • a transparent plate (148) for the light to pass which plate is typically made of acrylic plastic or glass
  • a liquid chamber (154) in which chamber an emission material (150) is placed in a matrix of water permeable material, such as silicon rubber, Polyamide or fluorocarbon-polymers, such as a fluorescent material, is placed adjacent the transparent plate (148).
  • the second communication part consisting of an outer shell (156) typically made of a plastic material, and two magnets (158, 160) are placed opposite each other adjacent the ends of the second communication part and a metal plate (162) for strengthen the magnetic flux is placed in the back facing away from the wall and the first emissive part and is connecting the two magnets (158, 160).
  • the second communication part is further defined by a transparent plate (166) for the light to pass, which plate is typically made of acrylic plastic or glass, and a light transmissive LED (170) is seen on one side and a sensor LED (172) on the other side connected to a circuit board (174), (such as a PCB made of cupper and glass fibers) for support.
  • An opening (164) for a current wire is shown.
  • An empty space or a space filled with acrylic is shown as 168.
  • a dashed line is shown starting from the LED (170) with arrows showing the direction of the light signal and the light returning after being reflected from the emission material (150) and back to the sensor LED (172).
  • “a” and“an” and“the” and similar referents as used in the context of de scribing the invention are to be construed to insert both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
  • “a” and“an” and“the” may mean at least one, or one or more.

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Abstract

La présente invention concerne un dispositif de mesure approprié pour mesurer un paramètre spécifié dans un liquide comprenant une première partie de réponse et une seconde partie de communication conçues pour être montées l'une en face de l'autre sur une paroi transmettant un premier signal de transmission de lumière ayant une longueur d'onde spécifiée.
PCT/EP2020/064675 2019-05-28 2020-05-27 Dispositif de mesure d'un paramètre dans un liquide Ceased WO2020239823A1 (fr)

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EP19176948.8 2019-05-28
EP19176948 2019-05-28

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5164796A (en) * 1988-03-15 1992-11-17 Akzo N.V. Apparatus and method for detection of microorganisms
WO2007001248A1 (fr) 2005-06-13 2007-01-04 Hong Peng Appareil et procede de suivi d’une culture biologique cellulaire
WO2012127650A1 (fr) * 2011-03-23 2012-09-27 エイブル株式会社 Dispositif de mesure de turbidité
US20160186123A1 (en) * 2013-09-09 2016-06-30 Hitachi, Ltd. Cell culture apparatus and cell culture method
WO2018096143A1 (fr) 2016-11-25 2018-05-31 Danmarks Tekniske Universitet Dispositif de laboratoire pour mesurer automatiquement la croissance de culture de cellules de manière non invasive

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5164796A (en) * 1988-03-15 1992-11-17 Akzo N.V. Apparatus and method for detection of microorganisms
WO2007001248A1 (fr) 2005-06-13 2007-01-04 Hong Peng Appareil et procede de suivi d’une culture biologique cellulaire
WO2012127650A1 (fr) * 2011-03-23 2012-09-27 エイブル株式会社 Dispositif de mesure de turbidité
US20160186123A1 (en) * 2013-09-09 2016-06-30 Hitachi, Ltd. Cell culture apparatus and cell culture method
WO2018096143A1 (fr) 2016-11-25 2018-05-31 Danmarks Tekniske Universitet Dispositif de laboratoire pour mesurer automatiquement la croissance de culture de cellules de manière non invasive

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