FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION

Optical density (OD) or turbidity has been measured by a sensor system in the industry since 1939. Several attempts to apply this for bio-tech laboratory automation has been made. 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. However, only a few products in the market can be used for direct cell density verification.

The technology and working of the sensor is well understood, and prior art dates back to at least 1939. Work has been done to increase automation, and several new technologies, such as a spectroscopy approach is disclosed in the application W02007001248. The actual granted US patent discloses a method where diffuse light is passed from the bottom, and similarly extracted and analyzed, but with severe restrictions on sampling rate. One commercially available system is the SFR vario device (PreSens, Regensburg, Germany), a noninvasive system correlating the cell density to light backscattered through the bottom of a transparent shake flask without interrupting the rotation. The measurement device is mounted on an incubator tray, and the flask is attached to the reader through a clamp over the sensor spot. However, the continuous rotation causes variable penetration depths of light within the rotation cycle. This phenomenon makes the transfer of the measured signal to the cell density challenging.

Another available product on the market is CGQ, Cell Growth Quantifier (Aquila biolabs, Aachen, Germany). 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. By purchasing an extra adapter, flasks from 100 ml to 5000 ml can be used for the measurements. Nevertheless, 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. Furthermore, 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. However, 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.

SUMMARY OF THE INVENTION

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

concentration, optical density (OD), refractive index, pH etc.

In such environments, sensors inserted from the opening becomes impractical and a nuisance with connecting wires imposing a risk on operation. Sensors fixed in the shaker board limit the type and number of flasks on the board and may require special fixtures. What is needed is a flexible type of sensor with any wiring kept out of the flask and kept low as not to cause toppling of the flasks. Further it would be of great interest to keep the sensor element in-situ as small as possible in order not to disturb the flasks motion and the liquids movement.

In a first aspect 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. In an embodiment of the first aspect 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.

In a second aspect 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.

In another embodiment of the first aspect 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.

In a third aspect 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.

In a further embodiment of the first aspect 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.

In a fourth aspect 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 wherein i) the first emissive part, such as a fluorescence or luminescence material, 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, 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 the first light transmission signal, a communication means for providing the measured parameter in a computer readable output.

In a further embodiment of the above aspects the first responding part and the second communication part are individual parts mounted by means of magnets. In individual embodiments the first reflector part has 1, 2 or 4 magnets matching 1, 2 or 4 magnets on the second light transmission part.

In a further embodiment of the above aspects the first responding part and the second communication part are in direct contact with the wall when mounted on said wall. In a still further embodiment of the above aspects the wall is made of glass, such as quartz glass. In another embodiment the wall is made of a plastic material.

In further embodiments of the above aspects 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.

In a still further embodiment of the first or second aspect the volume is an open chamber, semi-open chamber or closed chamber. Typically, the volume is a semi-open chamber adapted to reduce bobbles in the liquid when the device is in operation. Preferably, 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. In a further embodiment the at least one opening is two or three openings, such as two.

In a further embodiment of the above aspects 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.

In a still further embodiment of the above aspects the second communication part comprises a temperature sensor.

In a further embodiment of the above aspects the specified parameter is Optical Density (OD). In another embodiment of the above aspects the specified parameter is a refractive index.

In a still further embodiment of the above aspects 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. In still further embodiments of the first or second aspect 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.

In a further embodiment of the first or third aspect 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. In a typical embodiment the light conducting material is selected from four prisms. In another embodiment 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.

In a still further embodiment of the above aspects the device comprises a position indicator adapted to adjust for misalignment of the first conductor part and the second

communication part, wherein the position indicator uses a different optical pathway than the first light transmission signal and a software adjustment algorithm.

In a further embodiment of the first or fourth aspect the first emissive part comprises a material reactive to oxygen, such as a fluorescence quenching ruthenium complex.

In a still further embodiment of the first or fourth aspect 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)).

In a fifth aspect 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.

In a sixth aspect 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. In a seventh aspect 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.

In an eight aspect 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.

In a ninth aspect 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.

In a tenth aspect 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.

In an eleventh aspect 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.

In a twelfth aspect 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. In a thirteenth aspect 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.

In a fourteenth aspect 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.

In a fifteenth aspect 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.

In a sixteenth aspect 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.

In a seventeenth aspect the present invention relates to use of a measuring device suitable for measuring a specified parameter in a liquid comprising a first responding part, such as a reflector, a conductor or an 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 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

(typically from 100 to 500 ml), a glass and/or plastic fermentor (typically from 0.5 to 20 liters) wherein the device first and second parts are mounted on the wall. Any one of the above

embodiments of the aspects and embodiments hereof are contemplated with this specified use. Further objects and advantages of the present invention will appear from the following description, and claims.

BRIEF DESCRIPTION OF DRAWINGS

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

When growing biological culture, monitoring the liquid gives valuable information of the growth rate. This is irrespective whether the growth is of microbiological cells, human cells, animal cells or other. While Temperature, pH, dissolved oxygen level etc. are relevant parameters for the cell growth rate, the actual cell growth rate can quantitively be measured by measuring the turbidity or optical density of the liquid. The two expressions are considered identical and will for convenience be referred to as OD in this text.

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.

The most used methods of growing such cultures in laboratory and small-scale production, are shaker flasks, typically arranged on a shaker board, where conical flasks of volumes from 250 to 5000mL are arranged in parallel.

In accordance with the various aspects of the present invention the device is suitable for measuring a specified parameter in a liquid. As used herein“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, and 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. 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.

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.

In a preferred embodiment, in order to determine the distance the light has travelled and the“base refraction” from transmission through the wall, 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.

The term“a wall transmissive to a light transmission signal” as used herein 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. Optimally 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. Such 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.

The term“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.

When the device is in operation as referred to herein it simply means that the device is placed correctly on the wall and either ready to measure or performing measures. Typically, operation means that current is supplied and that the device is performing its measuring as described herein.

As used herein the term“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)).

As used herein the term“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. As used herein“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.

As used herein“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

As used herein“a communication means” 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. Typically, 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. In connection with the first reflector part or first conductor part 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. When the reflector or conductor part is mounted on the wall 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. If the volume is a closed chamber 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

In a still further embodiment of the first or second aspect the volume is a semi-open chamber adapted to reduce bobbles in the liquid when the device is in operation. Preferably, 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. In a further embodiment 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 .

As used herein the term“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.

As mentioned above 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. However, in general magnets provide a very effective way of bringing the two parts together and holding them together. In a further embodiment of the above aspects the first responding part and the second communication part are individual parts mounted by means of magnets. In one embodiment 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.

Thus, in a further embodiment 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.

In principle 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. As used herein the term“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.

The term“a specified wavelength” as used herein means a specific wavelength, such as 400nm, 600nm or lOOOnm, or is a range of wavelengths such as from lOOnm to 2000nm. In one embodiment the specified wavelength is a specific wavelength, such as a wavelength selected from 200-1200nm, such as 400- lOOOnm, such as 600-900nm. In another embodiment 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.

In a further embodiment of the first or third aspect 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. In a typical embodiment the light conducting material is selected from four prisms. In another embodiment 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 term“a position indicator” as used herein 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.

As used herein“a material reactive to oxygen” means any material capable of changing properties and emitting a signal due to reaction with oxygen. Non-limiting examples of such are a fluorescence quenching ruthenium based pyridine complexes, stabilized in polystyrene, such as [Ru(bpyPS2)3](PF6)2 (bpy = 2,2'-bipyridine, PS = polystyrene).

As used herein“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)).

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.

Typically, such 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

measurements and handling. Such a package is referred to as a kit of parts.

The term“current” or“current supply” are used interchangeably and as used herein means AC, DC from a wire or a battery or combinations hereof.

DRAWINGS

The invention will now be described more fully with reference to the appended drawings illustrating typical embodiments of the invention. These drawings are by no means limiting the scope of the present invention and are only intended to guide the skilled person for better understanding of the present invention.

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). In this respect 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. When 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). 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. The liquid will enter the chamber when the device is in operation and the liquid will stay in the chamber for a time sufficient to be measured. The liquid will enter the chamber form either the left and right when the device is in operation and the form of the chamber ensures flushing of the old liquid to be replaced by fresh liquid continuously when the device is in operation. 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

temperature fluctuations. 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). When the liquid (86) in the flask is moving because the flask is shaken during the process, 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). On the outside of the wall (82) 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). 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. On the opposite side of the wall (the gap between the first and second parts) is 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). Typically, 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. On the opposite side of the wall (the gap between the first and second parts) is 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,

131). Typically, 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 (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). 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). On the opposite side of the wall (the gap between the first and second parts) is 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).

All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Recitation of ranges of values herein are merely intended to serve as a short method of referring individually to each separate value falling within the range, unless other-wise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Unless otherwise stated, all exact values provided herein are representative of corresponding approximate values ( e.g ., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also provide a corresponding approximate measurement, modified by "about", where appropriate).

All methods described herein can be performed in any suitable order unless other-wise indicated herein or otherwise clearly contradicted by context.

The terms“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. Thus,“a” and“an” and“the” may mean at least one, or one or more.

The term“and/or” as used herein is intended to mean both alternatives as well as each of the alternatives individually. For instance, the expression“xxx and/or yyy” means“xxx and yyy”;“xxx”; or“yyy”, all three alternatives are subject to individual embodiments.

The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise indicated. No language in the specification should be construed as indicating any element is essential to the practice of the invention unless as much is explicitly stated.

The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability and/or enforceability of such patent documents.

The description herein of any aspect or embodiment of the invention using terms such as“comprising”,“having”,“including” or“containing” with reference to an element or elements is intended to provide support for a similar aspect or embodiment of the invention that“consists of’, “consists essentially of’, or“substantially comprises” that particular element or elements, unless otherwise stated or clearly contradicted by context ( e.g ., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

This invention includes all modifications and equivalents of the subject matter re-cited in the aspects or claims presented herein to the maximum extent permitted by applicable law. The features disclosed in the foregoing description may, both separately and in any combination thereof, be material for realizing the invention in diverse forms thereof.