GB2635652A

GB2635652A - Optical sensing

Info

Publication number: GB2635652A
Application number: GB2316119.3A
Authority: GB
Inventors: Mark James Dickens Anthony; Stephen Thomas David; Sinjab Faris; Joan Mccool May; Spencer Bayraktar Adem
Original assignee: Cambridge Consultants Ltd
Current assignee: Cambridge Consultants Ltd
Priority date: 2023-10-20
Filing date: 2023-10-20
Publication date: 2025-05-28
Also published as: GB202316119D0; WO2025083421A1

Abstract

An optical sensor arrangement and method for determining a concentration in a plurality of liquid samples, comprising an integrated two-dimensional array of optical detectors 110, a corresponding array of liquid vessels 102 for receiving said liquid samples 104 and at least one light source 108 arranged to direct light into the array of liquid vessels. Each of the optical detectors is arranged to detect a intensity of light emanating from a respective liquid vessel. The array of detectors may be arranged to monitor the array of vessels in parallel. Each optical detector of the array may be individually addressable. A set of lenses may be arranged between the detectors and vessels. The optical detectors may comprise photodiodes, and each photodiode may further comprise a filter or filter array. The vessels may be separated from the detectors by an optical window.

Description

Optical Sensing

BACKGROUND OF THE INVENTION

This invention relates to optical sensing of a liquid sample.

During analytical research and clinical diagnostic testing, it is common to require sensing of multiple small volumes (e.g. 10 nL to 10 mL) of liquid samples, such as within a well plate or test tube, to observe optical phenomena indicative of a characteristic being tested. Sensing may be used to determine any of various parameters of the samples, such as concentration of a given cell culture. This may be done throughout research processes, or as standard testing of a sample during manufacturing.

Liquid samples are usually measured sequentially, for example by scanning or probing each individual sample. This can be time-consuming, and expensive, especially considering the number of wells within a standard well-plate can vary anywhere between 6 to over 1000 wells. Measurements also often take places 'offline', which can be inaccurate and require samples to be moved around into different environments, which may lead to errors.

The present invention aims to address the problems outlined above.

SUMMARY OF THE INVENTION

From a first aspect, the invention provides an optical sensor arrangement suitable for determining a concentration in a plurality of liquid samples, comprising: an integrated two-dimensional array of optical detectors; a corresponding array of liquid vessels for receiving said liquid samples; and at least one light source arranged to direct light into the array of liquid vessels; wherein each of the optical detectors is arranged to detect an intensity of light emanating from a respective liquid vessel.

From a second aspect, the invention provides a method of determining a concentration in a plurality of liquid samples in an integrated two-dimensional array of liquid vessels; the method comprising: directing light from at least one light source into the array of liquid vessels; using an integrated two-dimensional array of optical detectors corresponding to the array of liquid vessels to detect an intensity of light emanating from each liquid vessel to the respective optical detector, said intensity of light being indicative of said concentration.

Thus it will be seen that, in accordance with the invention, that contents of each liquid vessel in an array of liquid vessels can be individually optically monitored by a respective detector. Each optical detector is arranged to detect the light emanating from each liquid vessel, wherein the light may be at least partially transmitted through the liquid vessel from the light source(s), e.g. by transmission, scattering and/or backscattering within each liquid vessel, or by fluorescence or excitation of the contents of each liquid vessel.

The array of optical detectors are integrated with each other, e.g. the optical detectors are arranged on the same substrate. By arranging each liquid vessel of the array of liquid vessels so that it maps onto a respective detector of the array of optical detectors, the contents of each liquid vessel can be monitored lnline'; i.e. without having to remove the vessels from a process to analyse them 'offline'. For example, the optical detectors may be arranged to analyse the contents of each well of a well-plate, where each well of the well plate comprises a liquid vessel.

As will be appreciated by the skilled person, it is difficult to perform optical monitoring of a large number of small liquid vessels to detect an optical signal indicative of concentration, e.g. liquid vessels containing less than 4 mL of liquid. Optical sensors in accordance with the present invention may be able to detect a volume of a liquid sample within a liquid vessel of between approximately 10 nL -10 mL, e.g. a volume held by typical well-plates.

In some prior arrangements, optical monitoring of a plurality of liquid vessels (e.g. a well plate) takes place by scanning each liquid vessel with an external sensor. This may take a significant amount of time to scan each individual well, and it is not possible to scan all wells at the same time. Furthermore, the wells cannot be monitored together over time during processing of the liquid sample within each well, -3 -as measurements typically happen offline. For example, biomass sensing (e.g. with optical density measurements) typically uses bench-top lab equipment, which is both manual and has low throughput.

The present invention may allow for lower cost, scalable optical sensing in well plates.

Optical sensors in accordance with the present invention may also be miniaturised, with improved optical coupling compared to optical sensors according to the prior art, since having the optical detectors arranged close to the liquid vessels may allow the same resolution and accuracy of measurements of known larger devices to be achieved. Furthermore, the optical sensors can be a self-contained unit including a well-plate, detectors, and a light source.

The compact form factor allowed by the present invention may enable greater capability for automated data capture of many cell cultures, e.g. in several plates stacked in an incubator simultaneously. This may improve the throughput and screening efficiency in many processes, for example in biotechnology involving well-plate based cell cultures.

In a set of embodiments, the array of optical detectors monitor the array of liquid vessels in parallel. For example, all measurements may be taken by the array of optical detectors at the same time. This may be advantageous when taking time-sensitive measurements across the array of liquid vessels, e.g. to monitor cell concentration during cell growth.

In a set of embodiments, each optical detector of the array of optical detectors is individually addressable. This may be useful in taking selective measurements of different liquid vessels at any given time. The optical detectors may take measurements in sequence, or in a specific order, e.g. as programmed by a processor connected to the array of optical detectors.

Optical sensor arrangements in accordance with the present invention are able to detect the intensity of light transmitted through the array of liquid vessels. For example, the light transmitted through the array of liquid vessels may be absorbed, backscattered or scattered by the plurality of liquid samples, e.g. light scattered or backscattered from cells, particulates, and/or droplets of immiscible liquids and other -4 -substances in the plurality of liquid samples. This may be used to determine parameters of a particular species within the liquid sample in a liquid vessel, e.g. concentration. In a set of embodiments, the light source(s) has (have) a known spectral profile, and a known intensity. This may be used to determine the absorbance and/or scattering of light at a specific wavelength, based on the light received at the detector, which can be used to determine concentration of a particular species in the sample using information known to the skilled person e.g. the molar extinction coefficient for a particular solvent.

In a set of embodiments, the light emitted from the light source(s) may be varied with pulse width modulation. For example, the light source(s) may be adapted to emit pulses of light, or emit waveforms such as a square wave. The light source(s) may also be modulated to improve detection sensitivity, e.g. by using lock-in amplification.

A single light source arranged to transmit light through the array of liquid vessels could be provided. Alternatively, a plurality of light sources may be provided. For example, light strips transmitting light to a row of liquid vessels in the array, and/or light sources transmitting light to respective subsets of liquid vessels in the array could be provided.

In a set of embodiments, an array of light sources are provided, with each light source corresponding to a respective liquid vessel and respective optical detector. For example, each light source may be arranged adjacent to the respective optical detector, with a separation of approximately 1 mm, e.g. between 0.5 mm and 1.5 mm. Each light source may have a width of approximately 3 mm, e.g. between 2 mm and 4 mm. Each optical detector may have a width of approximately 3 mm, e.g. between 2 mm and 4mm.

The plurality of light sources may be individually variable such that a different intensity of light may be transmitted through different liquid vessels. The plurality of light sources may have the same spectral profile, or may transmit different wavelengths, such that the absorbances of different wavelengths can be probed for different liquid vessels.

In a set of embodiments, the array of optical detectors and the light source(s) are integrated. For example, the optical detectors and light source(s) may be arranged on -5 -a single substrate. In these embodiments, the array of liquid vessels may be placed on top of the array of optical detectors and light source(s). The optical detector may detect light back-scattered by the liquid samples within the array of liquid vessels. This may be useful where the liquid vessels are open, e.g. an open well-plate where substances are added to the wells during sensing.

The width and separation of each optical detector and the respective light source may define a measurement area for a single liquid vessel, e.g. the measurement area may be approximately 7 mm, e.g. between 5 mm and 10 mm. The size of this measurement area may be scaled to form a tiled array of detectors and light sources, which may be matched to a tiled array of liquid vessels. Alternatively, or in addition, the measurement area may be defined by the separation of liquid vessels, e.g. the separation of wells in a standard well plate.

The optical detector may have a detection area that is optimised to the size of the liquid vessel, in order to capture a maximum amount of light scattered by the liquid sample. For example, the optical detector may be the same size as the area of the bottom of the liquid vessel.

In a set of embodiments, the optical sensor comprises a set of lenses arranged between the optical detector and the respective liquid vessel. Alternatively, or in addition, the optical sensor may comprise a set of lenses arranged between the light source(s) and the respective liquid vessel(s). The lenses may be arranged to focus the light emitted from the light source(s) into the liquid vessel(s), such that the liquid vessel(s) receive the maximum amount of light, and/or to minimise reflection, which may affect the accuracy of the measurement. The lenses may also be arranged to focus the light transmitted through the liquid vessel onto the respective optical detector, such that the detector captures the maximum amount of light scattered by the liquid sample.

In a set of embodiments the array of optical detectors are arranged on a different substrate to the light source. For example, the light source may be arranged underneath the array of liquid vessels, and the array of optical detectors may be arranged above the array of liquid vessels. In this arrangement, the optical detectors -6 -are arranged to detect light transmitted through the liquid vessels. The respective substrates could be physically connected to each other -e.g. in a clamshell arrangement. This set of embodiments may allow arrangements in which a standard well or microtiter plate is sandwiched or clamped between the respective substrates.

The light source(s) may be placed on the side of the array of liquid vessels, with the array of optical detectors placed above or below the array of liquid vessels. In this arrangement, the optical detectors can be arranged to detect light scattered at an angle by the liquid sample.

In a set of embodiments, multiple optical detectors arranged to sense the liquid sample in a given liquid vessel are provided. For example, for each liquid vessel a respective lattice of optical detectors may be provided. Each optical detector within the lattice may be arranged to detect a specific wavelength of light, for example to determine the absorbance of different wavelengths and hence concentration of multiple different species within a single liquid vessel at the same time. The lattice of optical detectors may be integrated with a lattice of light sources, e.g. for simple switching between the wavelength of light emitted for different measurements.

For example, the lattice of optical detectors may comprise three optical detectors per vessel, each adapted to detect the intensity of light at different wavelength colours (e.g. red, green, and blue), such that the optical detectors may be able to detect the colour of the liquid sample in the respective liquid vessel. The optical detectors may alternatively, or in addition, comprise a set of filters to change the wavelength of light and hence colour of the sample detected.

Furthermore, the optical detectors may be arranged to surround the liquid vessels, such that light backscattered, scattered, and transmitted through the liquid vessels can be detected, such that many parameters of each liquid sample may be detected at 30 once.

In a set of embodiments, the optical detector comprise photodiodes. The photodiodes may detect light emanating from each liquid vessel and output a photocurrent corresponding to the intensity of light received by the photodiode. This may be correlated with the intensity of the light source to determine the amount of light -7 -absorbed by the liquid sample. The skilled person will appreciate however that any suitable optical sensor may be used to detect the light transmitted through the liquid vessel, e.g. phototransistors or photoconductive devices. Furthermore, these optical sensors may be used to detect intensity of light transmitted, as well as other parameters e.g. fluorescence and/or luminescence of the sample.

The detected photocurrent or other signal may be increased with an amplifier circuit. The optical detector may further comprise an on-board transimpedance amplifier to amplify the signals prior to being sent to an external system e.g. by a wired or wireless 10 connection.

Alternatively, or in addition, a camera may provide the array of optical detectors, wherein a single pixel or group of pixels of the camera corresponds to an optical detector for a respective liquid vessel. The camera may detect an intensity of light transmitted through each liquid sample, which may be correlated with the intensity of the light source to determine the amount of light absorbed by the liquid sample.

The optical sensor may further comprise an analogue-to-digital converter. This may convert the signal detected at each optical detector to a digital signal to be input to a processor, which may be able to process the signal and yield a parameter for each liquid sample. A processor (e.g. a parallel processor) may be provided on-board, e.g. for analysis or multiplexing of signals, such that all the signals from the array of optical detectors may be processed at the same time.

In a set of embodiments, the optical sensor further comprises a power supply. The optical sensor may be portable, such that it may be used in a variety of lab environments.

In a set of embodiments, each optical detector is individually addressable. This may be used to turn a particular optical detector on or off, in order to detect transmitted light for a given amount of time. This may be used to take measurements over a particular amount of time for a respective liquid vessel. This may be useful in monitoring reactions taking place in a given liquid vessel. -8 -

The control of the optical detector may be integrated with the control of the light source via a processor. For example, the light from the light source may be used to trigger a reaction, e.g. by emitting UV light to catalyse an organic reaction. The array of optical detectors may be programmed to start taking measurements when the light source is turned on, and stop taking measurements when the light source is turned off. The processor may also be arranged to control the array of optical detectors, e.g. to take measurements in a particular order.

In a set of embodiments, the array of optical detectors output a plurality of signals to a processor. The processor may be able to analyse the signals from the array of optical detectors to determine the concentration of different species within each liquid vessel. For example, the processor may be connected to a memory, where the memory stores different constants for determining concentration of particular species.

The processor may additionally be configured to filter out background signals. For example, the light detected at different optical detectors can be compared to determine and hence filter out the background light.

The processor may also be in communication with the light source, in order to vary the intensity and the waveform of the light emitted from the source. The processor may store the intensity and waveform of emitted light in a memory, and use this to determine the concentration of the species within each liquid sample in combination with the intensity of light detected at each optical detector.

In a set of embodiments, the array of liquid vessels comprise a multi-well plate. For example, the array of liquid vessels may comprise a 6, 12, 24, 48, 96, or 384 well plate, or any other suitably sized well plate. The array of liquid vessels may be integrated into a single plate of liquid vessels, or may be provided on multiple separate plates. The latter may be useful where a array of liquid vessels are to be analysed at the same time, but the liquid samples have been prepared in different environments.

Optical sensor arrangements in accordance with the present invention may be arranged to accommodate a specific, e.g. standard, size of well plate, or may be arranged to accommodate a variety of sizes. For example, where the number of liquid -9 -vessels is smaller than the number of optical detectors, the optical detectors that do not have a corresponding liquid vessel may be turned off.

In a set of embodiments, array of liquid vessels is accessible during optical monitoring.

For example, the array of optical detectors may be arranged underneath the array of liquid vessels, leaving the top of the array of liquid vessels open. Furthermore, the liquid vessels may have a lid covering them. This may prevent spillage of liquid samples onto the detectors, e.g. during positioning of the liquid vessels. The lid may additionally prevent unwanted background light from reaching the detector through the liquid vessels.

The array of liquid vessels may be transparent, e.g. a transparent plastic well plate. This may be useful for calorimetric assays. Alternatively, only the one or two sides of the liquid vessels may be transparent, i.e. where the light enters and exits each liquid vessel. For example, liquid vessels with opaque sides may prevent cross-talk between liquid vessels.

Black pigmented liquid vessels may be useful for sensing concentration, e.g. by absorbance or backscatter, and may also be used for sensing fluorescent biological assays. Alternatively, or in addition, the liquid vessels may have white sides, to increase reflectivity. This may be useful where the optical sensor is used for optical absorbance or luminescence detection.

Each liquid vessel may be curved at the point where light enters the liquid vessel. This may focus the light into the liquid sample, and/or focus the light entering the detector.

This may prevent diffusion of the light reducing the signal detected at each optical detector, and reduce noise in the detected signal.

The array of liquid vessels may be made from any suitable material, e.g. polystyrene, polypropylene, or cyclo-olefin. The liquid vessels may be formed from a composite microplate, e.g. a well-plate with a built-in filter, to prevent particular wavelengths of light from reaching the liquid samples.

In a set of embodiments, the array of liquid vessels is separated from the array of optical detectors by an optical window. The optical window may have a thickness of approximately 1 mm, e.g. between 0.5 and 5 mm. This may allow for the optical sensor to be highly compact. The thickness of the optical window may be optimised (e.g. with respect to the position of the light source and respective optical detector) to maximise the light entering the vessel and light received by the respective detector. The thickness of the optical window may also be selected to reduce sources of background noise, e.g. due to reflections within the optical sensor arrangement.

The optical window may have a matching refractive index to the liquid sample, to maximise transmission of light and reduce noise. Alternatively, or in addition, the components e.g. the optical detectors and light sources may be coated with a refractive index matching material, e.g. optical grade silicone, such that there are no air gaps within the device, in order to maximise signal transmission. For example, the refractive index matching material may be in contact with both the light source(s) and optical window, and/or the array of optical detectors and optical window. Fitted optical inserts may also be clamped onto the light source and array of optical detectors in order to improve transmission within the optical sensor.

The optical window may be curved, e.g. to focus light from the light source into the liquid vessel, and/or to focus light from the liquid vessel into the detector. For example, the optical window may include miniaturised lenses for steering/scanning of the light from the light source. These miniaturised lenses may also be positioned within each liquid vessel.

The optical window may have a variable thickness, and/or the array of optical detectors may be moved away from the array of liquid vessels, in order to vary the optical path length of the light transmitted. This may be used in determining various parameters of the liquid sample.

The optical window may be manufactured with materials with a high transmission at the optical wavelengths used for sensing, e.g. cyclic olefin copolymer (COO) for visible -near infrared, or optical grade polycarbonate.

In a set of embodiments, the optical window comprises a mask. The mask may be arranged to block or attenuate light from the light source from reaching each detector without passing through the respective liquid vessel, for example by blocking light travelling at oblique angles. This may also prevent light from adjacent liquid vessels reaching the wrong detector.

For example, the mask may cover the area of the optical window between an adjacent light source and optical sensor. The mask may additionally or alternatively cover the area at the edge of the detector and liquid vessel, separating each detector. This may also prevent interference between adjacent detectors, reducing crosstalk and/or interfacing between detectors. The mask may comprise spatial regions machined to selectively transmit light.

In a set of embodiments, the optical window comprises a filter. The filter may be used to filter out particular wavelengths of light from reaching each liquid vessel and/or each detector whilst allowing other wavelengths of light to transmit. For example, the filter may cover the light source and/or each detector. The filter may additionally reduce unwanted background light from reaching the detector.

This may be useful where only certain wavelengths of light scattered by the liquid sample are useful for detecting a given parameter. This may be also be useful where the liquid sample is particularly sensitive to certain wavelengths of light, e.g. where the liquid sample contains a cell culture which denatures when exposed to UV light. There may be multiple filter layers included in the optical window, and/or the optical filters may be layered such that they are removable.

In a set of embodiments, the optical sensor includes one or more temperature sensors.

A single temperature sensor could be arranged to detect the temperature of the entire device, or a plurality of temperature sensors, e.g. a temperature sensor for each respective liquid vessel and detector, could be provided. The temperature sensor(s) may be used to calibrate the optical sensor arrangement, using an associated temperature measurement for each optical measurement. The optical sensor arrangement may include a heater and/or cooler arranged adjacent to the array of liquid vessels, e.g. on the same substrate as the array of optical detectors. This may allow for steps such as incubation of the liquid sample to occur within the optical sensor itself, and for continuous optical monitoring of the liquid sample during said incubation.

-12 -The array of optical detectors may be integrated with the array of liquid vessels, e.g. such that the optical sensor is single-use or washable.

In a set of embodiments, the array of liquid vessels is removable from the device. This may allow for the optical sensor to be cleaned and reused for a different liquid sample.

Furthermore, this may allow different method steps to be carried out on the same liquid sample between measurements. For example, a liquid sample could be sensed before and after a particular reagent is added.

The Applicant has appreciated that it is desirable to have an optical sensor which may accommodate a generic array of liquid vessels, in order for the optical sensor to be useful with liquid vessels already in use, e.g. well-plates containing pre-made samples, and/or disposable well-plates, which can be taken in and out of the optical sensor.

Therefore, when viewed from a second aspect, the invention provides an optical sensor arrangement suitable for determining a concentration in a plurality of liquid samples, wherein the optical sensor arrangement is arranged to receive a plate comprising an array of liquid vessels having said samples therein, the optical sensor comprising: an integrated two-dimensional array of optical detectors; and at least one light source arranged to direct light into the array of liquid vessels; wherein each of the optical detectors is arranged to detect an intensity of light emanating from a respective liquid vessel.

Features of any aspect or embodiment described herein may, wherever appropriate, be applied to any other aspect or embodiment described herein. Where reference is made to different embodiments or sets of embodiments, it should be understood that these are not necessarily distinct but may overlap.

BRIEF DESCRIPTION OF THE DRAWINGS

Certain preferred embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings, in which: Figure 1 shows schematically a well and associated components forming part of an arrangement according to a first embodiment of the invention; Figure 2a shows schematically a PCB on which an array of the light sources and detectors shown in Figure 1 is provided; Figure 2b is a cross-section showing the PCB shown in Figure 2a coupled to a well plate; Figure 3 shows schematically a PCB arrangement which can be used with the embodiments of the invention shown in Figures 1 and 2.

Figure 4 shows schematically a well arrangement according to a second embodiment of the invention; Figure 5 shows schematically a well arrangement according to a third embodiment of the invention; Figure 6 shows schematically an optical mask which can be used with the embodiments of the invention shown in Figures 1-5; Figure 7 shows schematically an optical filter which can be used with the embodiments of the invention shown in Figures 1-6.

DETAILED DESCRIPTION

Figure 1 shows part of an optical sensor arrangement in accordance with the invention comprising a first optical sensor 100, a liquid vessel 102 holding a liquid sample 104, an optical window 106 beneath the liquid vessel and a light detector in the form of a photodiode 110. The liquid vessel 102 is an individual well in a well plate, e.g. a 6, 12, 24, 48, 96, 384 or 1536 well plate.

The optical window 106 may advantageously be made from a material with a refractive index similar to the refractive index of the liquid sample 104, to maximise the transmission of the light. The optical window 106 may be manufactured from a material with high transmission at the optical wavelengths emitted by the light source 108 and scattered by the liquid sample 104, and low transmission at optical wavelengths which are not useful for sensing, e.g. background wavelengths. The thickness of the window may be a maximum of 5 mm, e.g. between 1 mm and 5 mm thick. The optical window 106 may be manufactured in layers, in order to incorporate different components within the window, e.g. lenses or filters, to enhance the transmission of light.

The light source 108 may be an LED and is positioned on the same substrate (omitted for clarity) as the detector 110, with the liquid vessel 102 is positioned on the top of the substrate so that the light source 108 is positioned directly underneath the liquid vessel 102.

In use light from the light source 108 enters the liquid vessel 102 via the optical window 106 and is backscattered by the liquid sample 104 so that it exits through the optical window 106 to the photodiode 110. The photodiode detector 110 measures a photocurrent signal using the light signal received from the liquid sample 104 within a specified time interval. The specified time interval may be adjusted to optimise the signal-to-noise ratio of the measured photocurrent signal. The photocurrent signal may also be amplifier using an amplifier at a specified gain, and digitised with an analogue-to-digital converter.

The light source 108 could be adjustable such that it can be set at a specified level of optical power output, such that the photocurrent signal detected at the detector 110 may be compared to the power form the light source 108, to sense an absorption of light by the liquid sample 104. The detected photocurrent can for example be used to determine a concentration of a particular cell species within the liquid sample 104 since this concentration will determine how much of the incident light is back-scattered.

Figure 2a shows how the light source 104 and detector 110 of Figure 1 form a sensing unit 114 which is part of an integrated two dimensional array on a printed circuit board 116 which forms the aforementioned common substrate. The layout of the sensing units 114 corresponds to a standard well plate -e.g. of 48 or 96 wells.

The light source 108 and detector 110 of each unit are spaced by a distance of approximately 0.5 mm and 1 mm apart. The light source 108 and the detector 110 are each approximately 4 mm in size such that each optical sensor 114 unit has a width of less than 10 mm, e.g. between 3 mm and 10 mm.

Figure 2b shows how the optical sensing arrangement can be assembled by placing a well plate 118 on top of the PCB 114 shown in Figure 2a with the optical window 106 sandwiched therebetween. This therefore provides an array of liquid vessels 102 arranged on top of the array of light sources 108 and detectors 110, such that each liquid vessel 102 is arranged on top of a respective light source 108 and detector 110. This allows for each sensing unit 114 to detect the light signal backscattered through the liquid sample 104 within a respective liquid vessel 102. Each well 102 is separated from adjacent wells by a vessel wall 120.

In an alternative embodiment the well plate 118 could be integrated or attached to the PCB 112 Alternatively, the well plate 118 could be removable, but interlock with the array of light sources 108 and detectors 110 in use to ensure alignment between the wells 102 and light sources 108 and detectors 110. This may allow different well plates and liquid samples to be used, and/or allow for the well plate to be cleaned separately from the rest of the apparatus, to limit damage to the electrical components.

The device of Fig 2b is able to perform measurements of the respective liquid samples 104 in the wells 102 in parallel. This allows for the well 102 to hold different liquid samples 204 for analysis. This may also be useful for parallel detection of many different parameters of a substance. For example, if multiple wells contain the same sample, different indicators may be added to each well 202, such that the backscattering measurements performed by each optical sensor 114 will detect a different parameter of the sample.

In operation, at least one light source 108 in the array of optical sensors 118 is switched on to a specified level of optical power output.

An example set of components for on-board processing of the data from the array of optical sensors is shown in Figure 3. Each optical detector 164 in the array of optical sensors is connected to processing circuitry, for example an amplifier and analogue-to-digital converter 166. The photocurrent signal from each detector 164 may be amplified using the amplifier 166 at a specified gain, and digitized with an analogue-todigital converter 166, all provided on the same PCB 174. The output from each analogue-to-digital converter 166 is received by an on-board multiplexer 168, also on the PCB 174, in order to process the many signals from each optical detector 164 in parallel. The information from the multiplexer 168 is stored in a memory 170 also on the PCB 174, although this memory 170 may also be off-chip, for example if the data is immediately transmitted from the multiplexer 168 wirelessly to a remote computer 172.

If it is stored on-board, the information regarding the detected signals from the optical detectors 164 can be transferred to an external receiver, e.g. the computer 172, which is not contained on the PCB 174 at a later time. The data may be transmitted by a wired connection, e.g. a cable connected to the PCB 174, or wirelessly e.g. using WiFi.

At the computer 172, the signals from the optical detectors 164 may be analysed.

The power output level of each light source 108 may be individually controlled e.g. with an applied electric current. The measurement time interval may also be varied for each optical sensor 118, e.g. to optimise the signal-to-noise ratio. This may also be useful in monitoring the liquid sample 104 over a longer period of time, e.g. to determine how a particular analyte decomposes over time and thus monitor a decline in the concentration of the analyte.

Figure 4 shows an alternative arrangement in which light from a light source 122 is directed into a vessel 124 through a window 126. A liquid sample 128 in the vessel 124 scatters the light such that it is directed to a detector 130 through a second optical window 132. The detector 130 is thus on a different side of the vessel 124 to the light source 122, such that it is light that is scattered at an angle by the liquid sample 128 that is detected at the detector 130. In the example shown in Figure 4, light that is scattered at approximately 90 degrees by the liquid sample is detected by the detector 130, however the detector 310 may be positioned anywhere along the wall of the vessel 124to detect light scattered at a different angle.

In all other respects such as the constructions, signal analysis etc., this arrangement may be similar to the previously described embodiments. Figure 5 shows another possible arrangement of the light source 134 and detector 136. In this arrangement the detector 136 is on an opposite side of the vessel 138 to the light source 134, such that it detects light which is transmitted through the liquid sample 140, e.g. light which is not scattered or absorbed.

The light from the light source 134 enters the vessel 402 via an optical window 142.

Transmitted light exits the vessel 138 via the open top of the well 138, although equally an optically transparent lid could be provided.

The embodiment of Figures 2a and 2b uses optical sensors 118 integrated on a single substrate 112. However in the arrangement shown in Figures 4 and 5, the detectors 130, 136 are more conveniently provided on different substrates from the respective light sources 122, 134. For example using the arrangement shown in Figure 5, the array of light sources 134 may be arranged on a substrate below the wells 138, and the array of detectors 136 may be arranged on a different substrate above the wells 138, such that the well plate, is 'sandwiched' between the two substrates. For example, the two substrates could be attached coupled via a hinge, with a gap in the middle for receiving the well plate. This would ensure alignment of the detectors 136 and light sources 134 with each other and the wells 138. The well plate could be slotted into the arrangement, such that it can removed from the device, e.g. to dispose of it and allow the device to be re-used.

Figure 6 shows another embodiment of the invention similar to the first embodiment of Figures 2a and 2b which also includes a mask 142 arranged between the optical window 144 on one hand, and the light source 146 and detector 148 on the other hand. The mask has a first aperture 150 over the top of the light source 146, and a second aperture 152 over the top of the detector 148. The mask 142 is made from a light-blocking material e.g. graphite. The first aperture 150 allows light to be transmitted from the light source 146 to the liquid vessel 154 and prevents light from the light source 146 from escaping elsewhere, e.g. directly to the detector 1148 without passing through the liquid vessel 154, or to an adjacent optical sensor. The second aperture 152 allows light to be scattered from the liquid sample 156 to be received by the detector 510 without interference from background light.

Figure 7 shows an embodiment similar to that of Figure 6, except that instead of an aperture above the detector 148' a mask 142' has a filter 160. The filter 160 selectively blocks certain wavelengths of light from reaching the detector 148', whilst allowing other wavelengths of light to pass. This may be useful where only certain wavelengths of light scattered by the liquid sample 156' are useful for detecting a given parameter, thus wavelengths of light which are not useful are reduced.

Alternatively, or in addition, a filter could be provided over the light source 146', in order to block certain wavelengths of light from reaching the liquid sample 156'. This may be useful where the liquid sample 156' is particularly sensitive to certain wavelengths of light, e.g. it contains a cell culture which denatures when exposed to UV light.

Multiple filter layers could be provided and/or different filters provided over the light source 146' and detector 148' respectively. The filter 160 may also be removable, such that different filters may be used with the same optical sensor arrangement.

Also shown in Figure 7 is an indicator 162 in the liquid vessel 154'. The indicator material may be used in combination with the filter 160, or may be used without the filter. The indicator 162 may change the colour of the liquid sample 156' based on the presence of different analytes. This may be useful in detecting the concentration of specific analytes within the liquid sample 156' which are colourless without use of an indicator.

The indicator 162 may be a solid indicator placed inside the liquid vessel 154', or another substance dissolved into the liquid sample 156'. Alternatively or in addition, the indicator 162 may be a fluorescent or colorimetric layer on the bottom of the liquid vessel 154'.

It will be appreciated by those skilled in the art that the invention has been illustrated by describing one or more specific embodiments thereof, but is not limited to these embodiments; many variations and modifications are possible, within the scope of the accompanying claims.

Claims

-19 -CLAIMS 1. An optical sensor arrangement suitable for determining a concentration in a plurality of liquid samples, comprising: an integrated two-dimensional array of optical detectors; a corresponding array of liquid vessels for receiving said liquid samples; and at least one light source arranged to direct light into the array of liquid vessels; wherein each of the optical detectors is arranged to detect an intensity of light emanating from a respective liquid vessel.
2. An optical sensor arrangement as claimed in claim 1, wherein the array of optical detectors is arranged to monitor the array of liquid vessels in parallel.
3. An optical sensor arrangement as claimed in claims 1 or 2, wherein each optical detector of the array of optical detectors is individually addressable.
4. The optical sensor arrangement as claimed in any preceding claim, comprising an array of light sources corresponding to the array of optical detectors.
5. The optical sensor arrangement as claimed in any preceding claim, further comprising a set of lenses arranged between the optical detector and the respective liquid vessel.
6. The optical sensor arrangement as claimed in any preceding claim, wherein the light source is integrated with the array of optical detectors.
7. The optical sensor arrangement as claimed in any of claims 1-5, wherein the array of optical detectors is arranged on a different substrate to the light source.
8. The optical sensor arrangement as claimed in any preceding claim, wherein multiple optical detectors are arranged to sense the liquid sample in a given liquid vessel.
9. The optical sensor arrangement as claimed in any preceding claim, wherein the array of optical detectors comprises an array of photodiodes.
10. The optical sensor arrangement as claimed in any preceding claim, further comprising a power supply.
11. The optical sensor arrangement as claimed in any preceding claim, wherein the array of optical detectors is arranged to output a plurality of signals to a processor.
12. The optical sensor arrangement as claimed in any preceding claim, wherein the array of liquid vessels comprises a multi-well plate.
13. The optical sensor arrangement as claimed in any preceding claim, wherein the array of liquid vessels is arranged to be accessible in use.
14. The optical sensor arrangement as claimed in any preceding claim, wherein the array of liquid vessels is separated from the array of optical detectors by an optical 15 window.
15. The optical sensor arrangement as claimed in claim 14, wherein the optical window comprises a mask.
16. The optical sensor arrangement as claimed in claims 14 or 15, wherein the optical window comprises a filter.
17. The optical sensor arrangement as claimed in any preceding claim, further comprising at least one temperature sensor.
18. The optical sensor arrangement as claimed in any preceding claim, wherein the array of liquid vessels is removable from the device.
19. A method of determining a concentration in a plurality of liquid samples in an integrated two-dimensional array of liquid vessels; the method comprising: directing light from at least one light source into the array of liquid vessels; using an integrated two-dimensional array of optical detectors corresponding to the array of liquid vessels to detect an intensity of light emanating from each liquid -21 -vessel to the respective optical detector, said intensity of light being indicative of said concentration.