GB2555816A

GB2555816A - Analyser

Info

Publication number: GB2555816A
Application number: GB1619023.3A
Authority: GB
Inventors: Mowlem Matthew; Slavik Greg; Broeders Jeroen
Original assignee: Natural Environmental Research Council
Current assignee: Natural Environmental Research Council
Priority date: 2016-11-10
Filing date: 2016-11-10
Publication date: 2018-05-16
Also published as: WO2018087548A1

Abstract

A fluid handling device, e.g. a microfluidic fluid handling device, suitable for use in an analyser, the device comprising a substrate 10 comprising a first layer 1 having at least one fluid flow channel 2a, 2b, a second layer 5 and at least one valve wherein each valve comprises a pocket 11 in-line with the fluid flow channel(s) and a discrete resiliently deformable membrane 8 disposed at least partially within the pocket, wherein a portion of the discrete resiliently deformable membrane is embedded between the first layer and the second layer thereby retaining, e.g. compressing, the membrane within the substrate, wherein upon actuation of the valve, the membrane is caused to reversibly deform to restrict or prevent fluid flow through the pocket, and/or, upon actuation of the valve, the membrane is caused to reversibly deform to allow an increased fluid flow through the pocket. The membrane maybe engaged with a plurality of alignment features such as a post, pillar or pin. A pumping system comprising syringe pump with plunger, motor, control unit and sensor for monitoring the position of the plunger. An analysis system is also disclosed.

Description

(54) Title of the Invention: Analyser

Abstract Title: An analyser, fluid handing device, pumping system and valve (57) A fluid handling device, e.g. a microfluidic fluid handling device, suitable for use in an analyser, the device comprising a substrate 10 comprising a first layer 1 having at least one fluid flow channel 2a, 2b, a second layer 5 and at least one valve wherein each valve comprises a pocket 11 in-line with the fluid flow channel (s) and a discrete resiliently deformable membrane 8 disposed at least partially within the pocket, wherein a portion of the discrete resiliently deformable membrane is embedded between the first layer and the second layer thereby retaining, e.g. compressing, the membrane within the substrate, wherein upon actuation of the valve, the membrane is caused to reversibly deform to restrict or prevent fluid flow through the pocket, and/or, upon actuation of the valve, the membrane is caused to reversibly deform to allow an increased fluid flow through the pocket. The membrane maybe engaged with a plurality of alignment features such as a post, pillar or pin. A pumping system comprising syringe pump with plunger, motor, control unit and sensor for monitoring the position of the plunger. An analysis system is also disclosed.

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ANALYSER

The present invention relates to analysers and microfluidic fluid handling devices, for example chemical, bio-chemical, biological and/or molecular analysers. More particularly, the present invention relates to a valve and/or a pump suitable for use in an analyser, and/or a microfluidic fluid handling device comprising the valve and/or the pump.

A microfluidic fluid handling device controls the motion and location of fluid in microfluidic channels or pipes in a device or network of channels. Microfluidic channels or pipes have typical dimension of <1 mm.

An analyser evaluates the chemical, biological, bio-chemical, and/or physical properties of a sample. The sample may comprise a fluid, e.g. a liquid or a gas, or particles suspended in a fluid. The sample may be suspended or mixed into a solution or other fluid before analysis.

Typically, an analyser comprises a plurality of sensors, measurement devices, and/or detectors to analyse and/or monitor the properties of a sample. For example, analysers may use optical analysis, e.g. colorimetric and/or fluorescence and/or luminescence analysis, and/or electrical analysis, e.g. electrochemistry or impedance analysis.

Analysers (e.g. chemical or bio-chemical analysers) are used in many different fields such as the pharmaceutical industry, medical testing, environmental research (e.g. to assess water quality), materials development and forensic science.

For example, the detection of specific aqueous chemicals is crucial for understanding biogeochemical processes at work in the oceans, or other marine or aquatic environments. These processes can in turn help to assess the state of marine ecosystems and/or provide an insight into the effect of industrial activities. Chemical parameters are traditionally measured by taking water samples at various depths and locations (e.g. using a sampler) and analysing the samples using analysers based on land or on research vessels.

However, known laboratory-based analysers are often very expensive to purchase, run and maintain. The process of transporting samples to an analyser is also inconvenient, slow, and costly. It can also lead to inaccuracies in the measured data, contamination or breakage of the samples, or a variety of other problems (e.g. changes in the chemical or biochemical properties of the sample during transportation).

Portable (e.g. hand-held) and in situ analysers overcome many of the problems associated with laboratory-based analysers and remote sampling methods. These devices generally combine a sampler with an analyser, and can remove the need for any transportation of samples.

Typically, in situ analysers provide a means for direct and less interrupted measurements of samples at remote locations. It is also known to deploy in situ analysers on unattended observatories, autonomous vehicles, drones and gliders, to allow the location of the analyser to be controlled remotely.

It is often not convenient or economically viable to power in situ analysers by means of hard wiring them to a central power source, such as the electrical grid. It is therefore desirable for in situ analysers to have a small power consumption, so as to increase the amount of time that the analyser can be left in situ without requiring the power source (e.g. batteries) to be changed and/or charged.

If the in situ analyser is mounted on an autonomous vehicle (e.g. an autonomous land, underwater, or air-based vehicle) decreasing the power consumption of the analyser also increases the distance that the vehicle can travel using a given amount of power.

Portable (e.g. hand-held) and in situ analysers often need to be more lightweight and/or smaller than laboratory-based analysers. This is particularly important for analysers which are mounted on gliders, or drones. It is known to use lab-on-chip microfluidic devices to reduce the size and weight of analysers.

The acquisition of a sample or samples may be controlled, and typically interspersed with either fluidic blanks or standards or may be split into at least two sub-samples, allowing each sub-sample to be subjected to a different test and/or measurement. This generally requires the use of valves to control the separation of the samples, subsamples, blanks or standards. Known types of analysers, particularly chemical or biochemical analysers, include Stop Flow Analysers (StFA), Continuous Flow Analysers (CFA), Flow Injection Analysers (FIA) and Segmented Flow Analysers (SFA).

In a StFA the sample, standard or blank is passed to an analytical hold chamber or reactor where reagents may be added and a wait time with no flow is used to allow for chemical reactions or other processes (e.g. lysis of cells) to occur. Upon completion or during the time-dependent process (e.g. chemical reaction) an analysis and/or measurement of the analytical signal (e.g. optical response) may be made. Subsequently the StFA is flushed and a new sample, standard or blank introduced. In CFA the sample, standard or blank flows continuously through the analyser where chemical reactions or other tests occur prior to analysis. In FIA systems, each subsample is separated from a subsequent sub-sample by a carrier reagent, or reagent is injected periodically into a continuous sample stream to create discrete measurements. In SFA a sample is divided by air bubbles, or other separation medium into discrete sub-samples (or segments) in which chemical reactions, or other tests, occur. Droplet based analysers in which a discrete droplet of analytical fluid (typically sample and reagent) is separated from other droplets with a fluid (e.g. an oil) is a type of SFA.

There is therefore a need for valves in analysers to control the separation of a sample into sub-samples, and to control the flow of various substances in the analyser. For example, in chemical analysers, valves are needed to select between reagents, sample, blank and standard solutions.

Analysers also require at least one pump to propel fluid(s) (e.g. samples, reagents, standard solutions) within the analyser. In in situ analysers, one or more pumps may be operable to extract the sample into the analyser for testing.

Known pump types suitable for use in an analyser include peristaltic, osmotic, electoosmotic, piston, solenoid and syringe pumps. Often, these pumps are required to be large to meet operating requirements (e.g. provide sufficient pumping force) and are thus inconvenient for smaller, and/or lightweight analysers. Such pumps can also require a relatively high power source, which is difficult to achieve using, and/or can significantly reduce the lifetime of, a battery or other power source typically used in in situ and/or portable analysers.

According to a first aspect of the invention, there is provided a fluid handling device, e.g. a microfluidic fluid handling device, suitable for use in an analyser, the device comprising: a substrate comprising a first layer having at least one fluid flow channel therein; a second layer; and at least one valve; wherein each valve comprises a pocket in-line with the fluid flow channel(s) and having a predetermined size and shape and a discrete resiliently deformable membrane disposed at least partially within the pocket, wherein a portion of the discrete resiliently deformable membrane is embedded between the first layer and the second layer thereby retaining, e.g. compressing, the membrane within the substrate; wherein, upon actuation of the valve, the membrane is caused to reversibly deform to restrict or prevent fluid flow through the pocket, and/or, upon actuation of the valve, the membrane is caused to reversibly deform to allow an increased fluid flow through the pocket. Accordingly, the fluid handling device may comprise a valve that is open in its unactuated state and closed in its actuated state, and/or a valve that is closed in its unactuated state and open in its actuated state.

Providing a valve having a pocket in-line with a fluid flow channel in a substrate and in which a portion of a discrete resiliently deformable membrane is embedded into the substrate, several advantages may be realised, including: reduced system complexity and/or size; decreased internal or unflushed volume in the valve and connecting fluidic network; and increased speed of responsiveness of the valve. Such advantages may be realised, for example, in comparison with known valves mounted externally to a substrate.

Advantageously, by embedding the resiliently deformable membrane within the substrate, in line with fluid channels, within a pocket that has a predetermined size and shape, the valve of the present invention may require less pressure or force to actuate than known valves. This may ensure efficient and continuous flow of fluid (e.g. a water sample) through the valve.

In an embodiment, the discrete resiliently deformable membrane may at least partially define a side of the pocket.

The discrete resiliently deformable membrane may extend across the pocket.

A second aspect of the invention provides a fluid handling device, e.g. a microfluidic fluid handling device, suitable for use in an analyser, the device comprising: a substrate comprising a first layer having at least one fluid flow channel therein; a second layer; and at least one valve; wherein each valve comprises a recessed area, in which is disposed at least partially a discrete resiliently deformable membrane, the discrete resiliently deformable membrane being in engagement with a plurality of alignment features located within the recesses area, thereby laterally constraining the membrane; wherein a portion of the discrete resiliently deformable membrane is constrained between the first layer and the second layer thereby retaining, e.g. compressing, the membrane within the substrate; wherein, upon actuation of the valve, the membrane is caused to reversibly deform to restrict or prevent fluid flow through the pocket, and/or, upon actuation of the valve, the membrane is caused to reversibly deform to allow an increased fluid flow through the pocket.

For instance, the alignment features may each comprise a post, a pillar or a pin.

In some embodiments, the substrate may be a chip.

The on-chip (or on-substrate) valve design of the present invention reduces the internal volume of the valve and connecting network, which may decrease the volume of sample required for each valid measurement and may reduce the amount of reagent required in an analyser compared with a microfluidic device using known actuated valve designs mounted externally to a substrate. This may increase analytical throughput, reduce fluidic volumes per measurement and reduce costs, as reagents are usually quite expensive.

Optionally, the membrane may comprise a polymer, or an elastomer. The membrane may comprise for example a synthetic rubber or fluoropolymer elastomer, such as Viton®. In some embodiments, the membrane may comprise polytetrafluoroethylene (PTFE), polyether ether ketone (PEEK), EPDM (ethylene propylene diene monomer) rubber, nitrile compounds and/or silicone compounds.

The membrane must be resiliently deformable and may be configured to have a minimum degree of compression necessary for sealing the valve (e.g. sealing at the point where the flow channel contacts an edge of the membrane).

The membrane may comprise fluid vias and/or one or more recesses. These features may be formed using laser cutting, moulding, die-cutting or punching, or scribing.

Optionally, the first layer and/or the second layer of the substrate (or chip) may comprise a material that is more rigid (has a higher Young’s Modulus) than the membrane material.

In some embodiments, the first layer and/or the second layer of the substrate (or chip) may for example comprise, or consist essentially of, a thermoplastic material.

In some embodiments, the first layer and/or the second layer may comprise or consist essentially of: acrylic (PMMA), Cyclic Olefin Co-Polymer (COC), Cyclic Olefin Polymer (COP), polycarbonate, polystyrene, Polyether ether ketone (PEEK), silicone, fluoro- and chloro-polymers, sapphire, silicon, silicon oxides (e.g. silica) and silicon nitrides and/or a glass.

In some embodiments, the first layer and/or second layer of the substrate (or chip) may be fabricated by laser milling, micro-milling, casting, embossing, injection moulding and/or lithography.

The portion of the resiliently deformable membrane may be embedded between the first layer and the second layer of the substrate without the use of an adhesive or bonding technique. In other embodiments, an adhesive (e.g. a glue), or bonding technique may be used. An adhesive or bonding technique may be applied between the layers of the substrate and/or between the substrate and the membrane.

Optionally, the membrane may be constrained, e.g. at least partially embedded (or encapsulated) in the pocket, between the first and second layers of the substrate by bonding the first layer and the second layer using direct bonding. Direct bonding may include surface activated (e.g. chemical (e.g. silane), plasma, UV-Ozone) bonding, or diffusion bonding (e.g. thermal, solvent assisted), clean surface bonding (e.g. glassglass bonding), or localised welding (e.g. ultrasonic, laser, RF, friction, localised thermal).

For example, the first and second layers of the substrate may be cleaned, e.g. highly cleaned, until they adhere when brought into contact, thereby encapsulating the membrane disposed between the layers. Optionally, there may be glass-glass bonding, or silica-silica bonding between the layers of the substrate.

A possible advantage of using glass for the first and second layers of the substrate is that it performs better at high temperatures compared with other suitable materials, such as acrylic or PMMA. Glass is also hard wearing, has high hydro-fluidity and high geometrical and/or dimensional stability. Silica or silicon also has similar properties to glass.

Optionally, the first layer and second layer of the substrate may be at least partially bonded using surface activated (e.g. chemical, plasma, UV-Ozone) bonding, or diffusion bonding (e.g. solvent assisted), clean surface bonding (e.g. glass-glass bonding), or localised welding (e.g. ultrasonic). These are generally low temperature bonding techniques, which may reduce manufacturing costs and/or may make the manufacturing process more environmentally friendly. Alternatively high temperature bonding may also be used e.g. thermal assisted diffusion bonding or localised thermal welding (e.g. laser, RF, friction).

In some embodiments, the membrane may be partially bonded to the first and/or second layer, such that the membrane is still free to resiliently deform into the pocket. In some embodiments, after bonding, the first layer and second layer of the substrate may form a monolithic or substantially continuous structure. There may be no visible join or seam between the first layer and the second layer once bonded.

The reversible (and/or resilient) deformation of the membrane may be caused by an actuator or a controlled pressure differential across the membrane. Thus, the device may comprise an actuator operable to cause, in use, reversible deformation of the membrane. The actuator may be a mechanical, thermal, magnetic, electromechanical, electromagnetic, piezoelectric, electrostatic, hydraulic or pneumatic actuator. The actuator may be latching in one or more state, i.e. requiring no input or power in either or both the open or closed state. In other words, the at least one on-chip (or onsubstrate) valve may be an active valve (i.e. an actuated valve), or a passive valve (e.g. a non-return or check valve).

The second and/or first layer of the substrate may comprise a perforation, aperture or recess disposed over the portion of the pocket formed in the other of the first layer or the second layer. This may allow the membrane to resiliently deform due to an increase in fluid flow through the pocket (e.g. to form a passive check valve).

Optionally, the second layer may comprise a through hole disposed over the pocket in the first layer. The through hole may allow a mechanical actuator and may be operable to exert a force on the membrane, thereby causing the membrane to resiliently deform.

In an embodiment, a rod or other elongate member may be disposed in the through hole such that an actuator can exert a force on the rod or elongate member and cause the rod or elongate member to contact the membrane.

Optionally, the device may comprise at least one actuator configured to control at least one actuated valve.

In an embodiment, a valve seat may be disposed within the pocket. The valve seat and the discrete resiliently deformable membrane may be arranged such that the discrete resiliently deformable membrane contacts the valve seat when the valve is closed.

In some embodiments, the device may comprise a plurality of valves. The plurality of valves may comprise at least one actuated valve and/or at least one passive (e.g. check) valve.

An advantage of a passive valve compared with an actuated valve is that the valve requires no power (e.g. electrical power) at all. Check (or non- return) valves typically may also be much cheaper to manufacture.

The on-chip actuated valve of the present invention may also require less power to operate than known microfluidic valves, as the amount of pressure required to actuate the valve may be lower, often significantly lower.

Thus, the valves of the present invention may significantly reduce the power consumption of the fluid handling device, in some cases by up to approximately 80% relative to continuously powered externally mounted valves. This is environmentally beneficial and may greatly reduce running costs of an analyser. This may be particularly important for in situ analysers, or portable analysers, as it may significantly increase the amount of time that the analyser can be used before the power source must be charged or replaced.

The fluid handling device, e.g. the microfluidic fluid handling device, may be configured to withstand deployment in relatively high pressure environments, such as ambient pressures two or more times higher than standard atmospheric pressure. Optionally, the device may be watertight.

Optionally, the device may be adapted to be deployed in a body of fluid, such as a river, lake, sea or ocean. Preferably, the device may be suitable for use down to full ocean depth. For example, the fluid handling device may be suitable for use in an in situ fluid analyser (e.g. a water sensor or a marine/oceanography sensor).

In a third aspect of the invention, there is provided a pumping system for use in an analyser (e.g. a chemical or bio-chemical analyser), the pumping system comprising: a syringe pump having a plunger and a motor; a control unit configured to drive the motor; and at least one sensor in communication with the control unit, wherein the at least one sensor is operable to monitor the position of the plunger to allow a precise dose of fluid to be extracted by, and output from, the pump.

Advantageously, the syringe pump has been found to consume less power than known peristaltic pumps and to have a reduced temperature sensitivity compared with known peristaltic and osmotic pumps. Conveniently, the syringe pump also typically has a faster flow rate than many known osmotic pumps and/or a more continuous flow compared with the pulsed flow characteristics of many peristaltic and solenoidactuated diaphragm pumps. In addition, unlike a syringe pump, the volume pumped by peristaltic and osmotic pumps can often fluctuate due to back pressure.

The syringe pump may be configured to extract a fluid sample from an external body of fluid.

Optionally, the syringe pump may also be configured to extract (or pump) a measured dose of one or more reagents, or other fluids. For example, the pump may be in communication with one or more vessels (e.g. bags, barrels, bottles etc.) suitable for containing a reagent, enzyme, solution, sample or other fluid. Preferably, the vessels may be resistant to chemical degradation.

The control unit may comprise a microcontroller. The microcontroller, or control unit, may use closed-loop control of the pumping system to check that current draw is minimised as needed for moving specific fluids, while power increases automatically when needed. Thus, the control unit (or microcontroller) may be operable to ensure that minimal power is consumed by the pumping system, thereby increasing the maximum lifetime of the power supply used to power the pumping system and/or analyser.

The pumping system of the present invention may have a power consumption that is up to 50% smaller than known pumping systems suitable for use in an analyser, particularly in a portable or in situ analyser.

Optionally, the motor may be a stepper motor. This may be advantageous, as a stepper motor has a high holding torque and better open loop positioning compared with many similar actuators.

The motor may be driven by a motor driver. For instance, the stepper motor may be driven by a micro stepping motor driver. Optionally, the micro stepping motor driver may be controlled by the microcontroller (or control unit).

A controllable potentiometer (e.g. a digital potentiometer) may be connected between the control unit (or the microcontroller) and the motor driver, and this potentiometer may be operable to allow the control unit (or the microcontroller) to control the output current of the driver. In embodiments, such control may be provided by a control means other than a potentiometer, e.g. a variable voltage source.

Optionally, the at least one sensor may be a non-contact sensor, such as a capacitive, inductive, optical, electro-optical, or electromagnetic sensor. For example, the at least one sensor may use the Hall Effect to monitor the position of the plunger.

A Hall Effect sensor is essentially a transducer that varies its output voltage in response to the presence of a magnetic field. If one or more magnets are coupled to the syringe plunger then movement of the plunger will cause a change in the voltage of the Hail Effect sensor, allowing the position of the plunger to be determined. An example of a suitable Hall Effect sensor is an Allegro MicroSystems A1324LLHL sensor.

Alternatively or additionally, the system may comprise a step counter in communication with the motor, e.g. the stepper motor. This would provide an estimate of the position of the syringe plunger, but would not provide any means for detecting motor slip. The step counter is therefore less accurate than a non-contact sensor, but could be used to provide a back-up position estimate.

Alternatively or additionally, the system may comprise a shaft encoder on the motor (e.g. an optical or magnetic encoder) to detect motor position. This would provide an estimate of the position of the syringe plunger, but would not provide any means of detecting backlash or shaft to drive plate nut slip.

The pumping system may be disposed on, integrated in, or connected to a substrate or chip, such as the substrate of the fluid handling device of the first aspect of the invention.

The pumping system may be configured to withstand high pressures. For example, the pumping system may be capable of operating deep in a body of fluid, such as at full ocean depth. Thus, the pumping system may be suitable for use in a deep-sea water sampler.

For example, at least one (preferably all of) the components of the pumping system may be provided within a pressure-balanced housing. The pressure-balanced housing may contain a non-conducting fluid (e.g. mineral oil) and a flexible membrane configured to ensure that the internal pressure of the housing is similar to the external (ambient) pressure.

Thus, the pumping system may provide a power-efficient way of handling ocean samples and reagents at full ocean depth (e.g. on an in situ analyser).

The pumping system may comprise a means of interfacing to other components in the analyser (e.g. other chemical, or biochemical sensors or analysis devices). For example, the pumping system may comprise a bus (a communication system that transfers data between components inside a computer, or between computers), such as an Γϋ bus (or inter-integrated bus).

The pumping system electronics may be integrated in a printed circuit board (PCB). Optionally, the PCB may be mounted directly on the pump assembly.

In some embodiments, the pumping system may comprise a plurality of syringe pumps.

In a fourth aspect of the present invention, there is provided an analyser (e.g. a chemical or biochemical analyser) comprising: at least one pumping system, the at least one pumping system comprising at least one pump; at least one fluid handling device of the first aspect of the invention in fluid communication with the at least one pumping system; at least one sensor for analysing the chemical, biological, biochemical, and/or physical properties of a sample, the at least one sensor being in fluid communication with the fluid handling device; and, optionally, at least one power source.

In embodiments, the fluid handling device may be located upstream or downstream of the pumping system. The sensor may be located downstream of the fluid handling system.

In some embodiments, the analyser may be a chemical or biochemical analyser. Optionally, the analyser may be a portable (e.g. hand-held) and/or an in situ analyser. The power source may comprise at least one battery, preferably at least one rechargeable battery.

The at least one pumping system may be configured to extract measured doses of one or more fluids (e.g. reagents) and/or extract a precise sample from a body of fluid.

Optionally, the analyser may comprise at least one pumping system according to any embodiment of the second aspect of the invention.

Optionally, the analyser may comprise a mounting apparatus. The mounting apparatus may be suitable for mounting the analyser on a vehicle, preferably an autonomous vehicle, drone, submarine and/or glider.

Optionally, the analyser may be configured to withstand high pressures (e.g. have a high pressure tolerance), for example up two or more times standard atmospheric pressure. Preferably, the analyser may be watertight, and/or may comprise a watertight housing. Thus, the analyser may be suitable for use underwater, preferably down to significant depths.

In a fifth aspect of the present invention, there is provided an analyser (e.g. a chemical or biochemical analyser) comprising: at least one pumping system according to any embodiment of the third aspect of the invention; a fluid handling device in fluid communication with the pumping system, the fluid handling device including at least one valve operable to control fluid flow in the analyser; at least one sensor for analysing the chemical, biological, bio-chemical, and/or physical properties of a sample in fluid communication with the fluid handling device; and, optionally, at least one power source.

Optionally, the analyser may comprise at least one fluid handling device according to any embodiment of the first aspect of the invention.

In some embodiments, the analyser may be a chemical or biochemical analyser. Optionally, the analyser may be a portable (e.g. hand-held) and/or an in situ analyser.

The power source may comprise at least one battery, preferably at least one rechargeable battery.

Optionally, the analyser may be configured to withstand high pressures (e.g. the analyser may have a high pressure tolerance). Preferably, the analyser may be watertight, and/or may comprise a watertight housing. Thus, the analyser may be suitable for use underwater, preferably down to significant depths.

In a sixth aspect of the invention there is provided a vehicle (e.g. an autonomous vehicle, drone, submarine or glider) comprising at least one analyser according to any embodiment of the fourth or fifth aspects of the invention.

For example, the autonomous vehicle may be an unmanned submarine configured to be controlled remotely (e.g. from land or from a research vessel).

Optionally, the vehicle may comprise a means for generating electricity. The electricity may be used to recharge one or more power sources, and/or supply power to the analyser and/or to the vehicle.

For example, the vehicle may comprise a propeller or turbine attached to a generator, and/or a solar cell, and/or a thermoelectric generator. Conveniently, this may further reduce the need for manual intervention in order to replace or recharge the power source(s), thereby extending the duration of use of the vehicle and/or analyser.

A seventh aspect of the invention provides use in the analysis of a fluid of a fluid handling device according to the first aspect of the invention, a fluid handling device according to the second aspect of the invention, a pumping system according to the third aspect of the invention, an analyser according to the fourth aspect of the invention, an analyser according to the fifth aspect of the invention or a vehicle according to the sixth aspect of the invention comprising: submerging at least partially the fluid handling device according to the first aspect of the invention, the fluid handling device according to the second aspect of the invention, the pumping system according to the third aspect of the invention, the analyser according to the fourth aspect of the invention, the analyser according to the fifth aspect of the invention or the vehicle according to the sixth aspect of the invention in a body of fluid.

Typically, the body of fluid may comprise water.

In embodiments, the fluid handling device according to the first aspect of the invention, the fluid handling device according to the second aspect of the invention, the pumping system according to the third aspect of the invention, the analyser according to the fourth aspect of the invention, the analyser according to the fifth aspect of the invention or the vehicle according to the sixth aspect of the invention may be submerged at least partially in the body of fluid for a period of: up to or at least one minute; up to or at least five minutes; up to or at least 30 minutes; up to or at least one hour; and/or up to or at least one day.

In embodiments, the fluid handling device according to the first aspect of the invention, the fluid handling device according to the second aspect of the invention, the pumping system according to the third aspect of the invention, the analyser according to the fourth aspect of the invention, the analyser according to the fifth aspect of the invention or the vehicle according to the sixth aspect of the invention may be submerged at least partially in the body of fluid for a period of: at least one day; up to or at least a week; up to or at least a month; and/or up to or at least a year.

Embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings, in which:

Figure 1 shows in cross-section the components of a valve according to the invention, the valve being in a partially assembled state;

Figure 2a is a schematic cross-section through a portion of a microfluidic fluid handling device of the present invention, wherein the valve is in a closed position;

Figure 2b shows the valve of Figure 2a in an open position;

Figure 3 shows a schematic cross-section through a portion of another microfluidic fluid handling device of the present invention, wherein the valve is in an open position;

Figure 4 shows a schematic horizontal cross-section of the microfluidic fluid handling devices of Figures 2a, 2b and 3;

Figure 5 shows a schematic horizontal cross-section of another microfluidic fluid handling device of the present invention;

Figure 6 shows a diagram of a pumping system of the present invention; and

Figure 7 is a graph showing the system response of the pumping system of Figure 6 when varying the load.

Figure 1 shows in cross-section the components of a valve according to the invention, the valve being in a partially assembled state.

A first layer 1 has formed in a face thereof a pair of fluid channels 2a, 2b, the fluid channels 2a, 2b each being an open channel. A recess 3 is formed in the face of the first layer 1. The recess 3 is connected to each of the pair of fluid channels 2a, 2b, such that the recess 3 is in line with fluid channels 2a, 2b, one fluid channel being upstream, in use, of the recess 3 and the other fluid channel being downstream, in use, of the recess 3. Within the recess 3, there is a protrusion 4 which serves, in use, as a valve seat.

A second layer 5 comprises a recess 6 formed in a face thereof. The recess 6 comprises a stepped side wall 7. A discrete resiliently deformable membrane 8 is disposed in the recess 6. An edge portion of the discrete resiliently deformable membrane 8 sits on a ledge provided by the stepped side wall 7 of the recess 6. The resiliently deformable membrane 8 comprises an optional perforation 9. When sitting on the ledge provided by the stepped side wall 7 of the recess 6, the thickness of the resiliently deformable membrane 8 is such that, in this example embodiment, the resiliently deformable membrane 8 stands proud of the surface of the second layer 5. In other embodiments, the resiliently deformable membrane 8 may not stand proud of the surface of the second layer 5.

Figures 2a and 2b show a cross-section of a portion of a microfluidic fluid handling device 10 according to the invention. The microfluidic fluid handling device 10 comprises a valve formed by bringing together the components illustrated in Figure 1. The microfluidic fluid handling device 10 comprises a substrate 12 formed from the first layer 1 and the second layer 5.

The valve comprises a pocket 11 formed by the recess 3 in the first layer 1 and the recess 6 in the second layer 5 being arranged in registry with each another. The discrete resiliently deformable membrane 8 is disposed within the pocket 11 and embedded between the first layer 1 and the second layer 5. Hence, the discrete resiliently deformable membrane 8 is retained within the substrate 12 by virtue of an edge portion of the discrete resiliently deformable membrane 8 being compressed between the first layer 1 and second layer 5, when, during manufacture of the microfluidic fluid handling device 10, the first layer 1 and the second layer 5 are brought together. The pocket 11 is disposed in line with the fluid flow channels 2a, 2b, one fluid channel being upstream, in use, of the pocket 11 and the other fluid channel being downstream, in use, of the pocket 11.

In Figure 2a the valve is in a closed position. The membrane 8 is in an un-deformed state, in which the membrane 8 sits on the valve seat provided by the protrusion 4. In the closed position, the valve operates to restrict fluid flow through the pocket 11.

In Figure 2b the valve is shown in an open position. The membrane 8 is deformed, thereby lifting the membrane 8 away from the valve seat 4 into recess 6, which allows fluid to flow through the pocket 11. When the pressure causing the membrane 8 to deform is removed, the membrane 8 will return to the position shown in Figure 2a. Thus, the membrane 8 is reversibly or resiliently deformable.

The perforation 9 in the membrane 8 facilitates self-sealing of the valve in the reverse direction (i.e. to prevent back flow of the fluid). The perforation is not an essential feature of a valve according to the invention. The perforation may be beneficial particularly in an embodiment of a passive non-return valve according to the invention.

In embodiments, the valve may be an active valve (e.g. an actuated valve) or a passive non-return valve (e.g. a check valve). Thus, the reversible (or resilient) deformation of the membrane may be caused by an actuator or a controlled pressure differential across the membrane. In a passive check valve (e.g. as shown in Figures 2a, 2b), the resilient deformation of the membrane is caused, in use, by the increase in the fluid pressure.

In embodiments, the device may comprise a plurality of valves.

The first layer or the substrate may comprise a plurality of fluid channels in communication with a plurality of pockets.

The first layer 1 and second layer 5 may be fabricated by micro-milling PMMA (or acrylic) layers. A cast PMMA sheet forming the first layer 1 and/or the second layer 5 may be machined to provide at least one fluid channel in communication with at least one recess.

The recess 6 (or recesses) should have a depth which allows for the required degree of deformation of the membrane to open and close the valve. Other techniques which may meet the dimensional accuracy requirements and may be used to manufacture the fluid channel(s) and recess(es) in the first layer and and/or the second layer include, but are not limited to, casting, embossing, injection moulding, and lithography.

The first layer and/or the second layer could be fabricated from any substantially rigid materials that are capable of direct bonding, e.g. thermal, solvent assisted, photodegredation, ozone or oxygen plasma modification or ultrasonic welding.

The first layer and/or the second layer may comprise or consist essentially of a thermoplastic material. The first layer and/or the second layer may comprise or consist essentially of silicon, silica or glass.

The discrete resiliently deformable membrane may be cut from a sheet of material, e.g. using laser cutting. During the cutting process the laser parameters such as intensity, pulse frequency, and scan rate may be optimised to ensure precise cutting. In embodiments, the discrete resiliently deformable membrane may be made of Viton®. In other examples, the membrane may comprise other pliable, resiliently deformable materials, such as a polymer, an elastomer, or another synthetic rubber and fluoropolymer elastomer. In some embodiments, the membrane may comprise PTFE, EPDM rubber, nitrile compounds and/or silicone compounds.

Optionally, the second layer 5 may be directly bonded to the first layer 1, for example by thermoplastic bonding. Typically, an adhesive may not be required.

In some embodiments the second layer may be bonded to the first layer using surface activated bonding, diffusion bonding, clean surface bonding or localised welding.

After bonding, the first layer and the second layer together may form a monolith. Thus, the substrate may comprise a monolith.

The bonding between the first layer and the second layer must provide sufficient bond strength to resist any counter force from the resilient deformation of the membrane.

Figure 3 shows a cross-section through a portion of another example of a microfluidic fluid handling device 20 according to the present invention. The fluid handling device 20 comprises an active (i.e. actuated valve).

A substrate 32 comprises a first layer 21 directly bonded to a second layer 25 to form a monolith.

The first layer 21 has formed in a face thereof a pair of fluid channels 22a, 22b. A recess 23 is formed in the face of the first layer 21. The recess 31 is connected to each of the pair of fluid channels 22a, 22b, such that the recess 23 is in line with fluid channels 22a, 22b, one fluid channel being upstream, in use, of the recess 23 and the other fluid channel being downstream, in use, of the recess 23. Within the recess 23, there is a protrusion 24, which serves, in use, as a valve seat.

The second layer 25 comprises a recess 29 formed in a face thereof. The recess 29 comprises a stepped side wall 30. A discrete resiliently deformable membrane 26 is disposed in the recess 29. An edge portion of the discrete resiliently deformable membrane 31 is adjacent a ledge provided by the stepped side wall 30 of the recess 29.

The valve comprises a pocket 31 formed by the recess 23 in the first layer 21 and the recess 26 in the second layer 25 being arranged in registry with each other. The discrete resiliently deformable membrane 28 is disposed within the pocket 26 and embedded between the first layer 21 and the second layer 25. Hence, the discrete resiliently deformable membrane 28 is retained within the substrate 32 by virtue of an edge portion of the discrete resiliently deformable membrane 28 being compressed between the first layer 21 and the second layer 25, when, during manufacture of the microfluidic fluid handling device 20, the first layer 21 and the second layer 25 are brought together. The pocket 31 is disposed in line with the fluid flow channels 22a, 22b, one fluid channel being upstream, in use, of the pocket 31 and the other fluid channel being downstream, in use, of the pocket 31.

The second layer 25 comprises a through hole located above the pocket 31 in the first layer 21. A rod 27 is disposed in the through hole, such that a mechanical actuator (not shown) may apply a force to rod 27, thereby causing the membrane 28 to resiliently deform. The rod 27 may be, but not necessarily, integrally connected with membrane 28. Thus, the valve in Figure 3 is an active actuated valve.

In Figure 3 the valve is in an open position. The membrane 28 is in a deformed state, thereby allowing fluid to flow through the pocket 31.

When the second layer 25 is bonded to the first layer 21 (e.g. by direct bonding, surface activated bonding, diffusion bonding, or clean surface bonding), the first layer 21 and the second layer 25 may form a substrate 32 comprising or consisting essentially of a monolith or substantially continuous structure.

The join between the first layer 21 and the second layer 25 may not be visible externally.

Figure 4 shows a schematic horizontal cross-section of the microfluidic fluid handling devices 10 and 20 of Figures 2 and 3, respectively, as both share the same geometry in this cross-section. Located within the substrate 12; 32, the pocket 11; 31 is rectangular in horizontal cross-section. The fluid flow channels 2a, 2b; 22a, 22b each pass through the substrate 12; 32 to the pocket 11;31. The fluid flow channels 2a, 2b; 22a, 22b open into the recess 6; 26 at diametrically opposed locations. The protrusion 4; 24 extends across the recess 6; 26 in a direction perpendicular to the fluid flow channels 2a, 2b; 22a, 22b.

Figure 5 shows a schematic horizontal cross-section of another example embodiment of a microfluidic fluid handling device 40 according to the invention. The microfluidic fluid handling device 40 comprises a valve operable in a similar manner to the valves discussed above. The valve may be a passive valve or an active valve.

The microfluidic fluid handling device 40 comprises a pair of fluid flow channels 42a, 42b, which open into a recess 46 at diametrically opposed locations. A protrusion 44 extending across the recess 46 in a direction perpendicular to the fluid flow channels 42a, 42b provides, in use, a valve seat for a discrete resiliently deformable membrane 52 (edges not shown). The membrane 52 is perforated at a plurality of points, where the membrane 52 engages with a post 51 disposed within a pocket. In this embodiment, four posts 51 are disposed within the pocket. The perforations in the membrane 52 are arranged on top of the posts 51. The posts 51 extend nearly through the thickness of the membrane 52. The posts 51 constrain the membrane 52 laterally. The posts 51 are directly bonded between two layers of substrate, thereby retaining the membrane 52 within the pocket. At least the portions of the membrane 52 adjacent the posts will be compressed.

The posts 51 are an example of a suitable alignment and bonding feature. Other suitable alignment and bonding features may comprise pillars or pins.

When assembling the microfluidic fluid handling device 40, the two layers of the substrate may be bonded by any suitable means. In some embodiments, after bonding of the two layers, the substrate may have the form of a monolith.

Figure 6 is a diagram illustrating a pumping system 60 of the present invention, suitable for use in an analyser.

The pumping system 60 is mounted on (or connected to or integrated in) a substrate or chip or a fluid handling device, such as devices 10 or 20 shown in Figures 2a, 2b and

3.

The pumping system 60 comprises a syringe pump having a plunger 61. Two magnets 65 are connected to the plunger 61, one at the top end and one at the bottom end of the plunger 61.

A contactless Hall Effect sensor 64 is positioned proximate the plunger 61 and the magnets 65. The sensor 64 detects the change in position of the magnets 65 using the Hall Effect, thereby allowing the position of the plunger 61 to be determined.

The sensor 64 may be an Allegro MicroSystems A1324LLHL Hall Effect Sensor, which may be placed facing the horizontal plane between the magnets’ 65 North and South poles. The magnetic field lines of the magnets 65, as depicted in Figure 65, should cross the sensing face of the sensor 64. Ideally, the sensor 64 is positioned such that the magnetic field strength from the magnets 65 is high, while maintaining a linear magnetic field as a function of the distance moved by the plunger 61.

In the example depicted in Figure 6, the magnets were spaced approximately 3mm to 5mm away from the sensor 64.

The magnets 65 may be rare earth sintered cobalt magnets. Other, e.g. cheaper, magnets may be used, but this may affect the accuracy of the position sensing system.

In other embodiments, other types of contactless sensor may be utilised, such as capacitive, optical, electro-optical, or electromagnetic sensors.

The movement of the syringe plunger 61 is driven by a stepper motor 62. The stepper motor 62 is in turn controlled by a stepper driver 63, preferably a micro stepper driver.

A microcontroller 66 is in communication with the contactless sensor 64, the stepper driver 63, a potentiometer 67 and a computing bus 68. In this embodiment, the bus 68 is an I²C (Inter-Integrated Circuit) bus. The bus 68 provides a means of interfacing the pumping system 60 to other systems, e.g. to other components in an analyser (e.g. other chemical, or biochemical sensors or analysis devices).

The microcontroller 66 is configured to use closed-loop control of the pumping system 60 to check that current draw of the pumping system is minimised as needed for moving specific fluids, while power increases automatically when needed

An example of such control-loop instructions is given below.

An analogue input pin on the microcontroller 66 (not shown) may set the output current of the motor driver 63. The potentiometer 67, operating in voltage divider mode, may be connected to this pin to give the microcontroller 66 control over the stepper driver 63 output current. The potentiometer 67 may be a digital potentiometer.

The speed of the motor 62 may be controlled by a pulse width modulation (PWM) signal applied from the microcontroller 66 to the stepper driver 63.

The microcontroller 66 may calculate the expected sensor 64 bit change per 100ms from the set PWM frequency and may increase the stepper driver 63 output current if the expected movement rate is not achieved. Likewise, the stepper driver 63 current may be decreased at a rate of 0.1 mA every 100ms until a decrease in movement speed becomes noticeable.

This ensures current draw is kept to a minimum at all times. However, when more force is required from the syringe plunger 61, e.g. when the sample inlet filter gets filled with particles, the stepper driver 63 current may be increased by the microcontroller 66 up to a set limit, thereby increasing the torque of the motor 62.

Figure 7 is a graph showing the response of the syringe plunger 61 for varying loads. Line 70 is the plunger position as a function of time and line 72 is the current draw of the system as a function of time.

The test was done using a National Instruments USB-to-I²C interface and was controlled via LabVIEW software. Linear displacement of the plunger 61 was measured using digital callipers and force gauges. A plunger position measurement resolution of 2.6 pm is achieved, which results in 21 ni of fluid resolution when using 3.2 mm diameter barrels. The practical fluid resolution is however limited to 27 ni due to step size of the stepper motor 62.

A sliding plate driving the syringe plunger 61 was subjected to varying load forces by means of a spring-based force gauge. The pump 61 was set to move continuously between two end points. Both position and current draw were monitored at a rate of 0.1 Hz via I²C bus 68.

As shown in Figure 7 the system’s current draw is about 18 mA when no external load is present, i.e. on upward movement. An increasing load causes the current to increase linearly. However, due to the closed-loop control of the microcontroller 66, linear movement is maintained between the end points. A current spike of 4 mA above the unloaded current draw occurs when the plunger 61 changes direction.

Thus, the microcontroller 66 and pumping system 60 of the present invention reduces 5 power consumption compared to known pumping systems, in some cases by up to around 50%.

The above embodiments are described by way of example only. Many variations are possible without departing from the invention.

Claims

1. A fluid handling device, e.g. a microfluidic fluid handling device, suitable for use in an analyser, the device comprising: a substrate comprising a first layer having at least one fluid flow channel therein; a second layer; and at least one valve;wherein each valve comprises a pocket in-line with the fluid flow channel(s) and having a predetermined size and shape and a discrete resiliently deformable membrane disposed at least partially within the pocket, wherein a portion of the discrete resiliently deformable membrane is embedded between the first layer and the second layer thereby retaining, e.g. compressing, the membrane within the substrate; wherein, upon actuation of the valve, the membrane is caused to reversibly deform to restrict or prevent fluid flow through the pocket, and/or, upon actuation of the valve, the membrane is caused to reversibly deform to allow an increased fluid flow through the pocket.

2. A fluid handling device, e.g. a microfluidic fluid handling device, suitable for use in an analyser, the device comprising: a substrate comprising a first layer having at least one fluid flow channel therein; a second layer; and at least one valve; wherein each valve comprises a recessed area, in which is disposed at least partially a discrete resiliently deformable membrane, the discrete resiliently deformable membrane being in engagement with a plurality of alignment features located within the recesses area, thereby laterally constraining the membrane; wherein a portion of the discrete resiliently deformable membrane is constrained between the first layer and the second layer thereby retaining, e.g. compressing, the membrane within the substrate; wherein, upon actuation of the valve, the membrane is caused to reversibly deform to restrict or prevent fluid flow through the pocket, and/or, upon actuation of the valve, the membrane is caused to reversibly deform to allow an increased fluid flow through the pocket.

3. A device according to claim 2, wherein the alignment features may each comprise a post, a pillar or a pin.

4. A device according to claim 1, claim 2 or claim 3, wherein the membrane comprises a polymer, or an elastomer.

5. A device according to any one of the preceding claims, wherein the first layer and/or the second layer of the substrate comprise, or consist essentially of, a thermoplastic material.

6. A device according to any one of claims 1 to 4, wherein the first layer and/or the second layer of the substrate comprise, or consist essentially of: acrylic (PMMA), Cyclic Olefin Co-Polymer (COC), Cyclic Olefin Polymer (COP), polycarbonate, polystyrene, Polyether ether ketone (PEEK), silicone, fluoro- and chloro-polymers, sapphire, silicon, silicon oxides (e.g. silica) and silicon nitrides and/or a glass.

7. A device according to any one of the preceding claims, wherein the resiliently deformable membrane is constrained, e.g. embedded, between the first layer and the second layer of the substrate with or without the use of an adhesive or bonding technique.

8. A device according to any one of the preceding claims, wherein the first layer and the second layer of the substrate are joined together using direct bonding.

9. A device according to any one of claims 1 to 7, wherein the first layer and second layer of the substrate are at least partially bonded using surface activated (e.g. chemical (e.g. silane), plasma, UV-Ozone) bonding, or diffusion bonding (e.g. thermal, solvent assisted), clean surface bonding (e.g. glass-glass bonding), or localised welding (e.g. ultrasonic, laser, RF, friction, localised thermal).

10. A device according to any one of the preceding claims, wherein, after bonding, the first layer and second layer of the substrate form a monolithic or substantially continuous structure.

11. A device according to any one of the preceding claims further comprising an actuator operable to cause, in use, reversible deformation of the membrane.

12. A pumping system for use in an analyser (e.g. a chemical or bio-chemical analyser), the pumping system comprising: a syringe pump having a plunger and a motor; a control unit configured to drive the motor; and at least one sensor in communication with the control unit, wherein the at least one sensor is operable to monitor the position of the plunger to allow a precise dose of fluid to be extracted by, and output from, the pump.

13. A pumping system according to claim 12, wherein the syringe pump is configured to extract a fluid sample, reagents, blank or standard solutions from an external body of fluid.

14. A pumping system according to claim 12 or claim 13, wherein the control unit uses closed-loop control of the pumping system to check that power draw is minimised as needed for moving specific fluids, while power increases automatically when needed.

15. A pumping system according to claim 12, claim 13 or claim 14, wherein the motor is a stepper motor.

16. A pumping system according to any one of claims 12 to 15, wherein the motor is driven by a motor driver.

17. A pumping system according to claim 16 further comprising a control means operable to allow the control unit to control the output current of the motor driver.

18. A pumping system according to any one of claims 12 to 17, wherein the at least one sensor is a non-contact sensor, such as a capacitive, inductive, optical, electro-optical, or electromagnetic sensor.

19. A pumping system according to any one of claims 12 to 18 comprising a step counter in communication with the motor.

20. A pumping system according to any one of claims 10 to 17 comprising a shaft encoder in communication with the motor.

21. A pumping system according to any one of claims 12 to 20, wherein at least one of the components of the pumping system may be provided within a pressurebalanced housing.

22. An analyser (e.g. a chemical or biochemical analyser) comprising: at least one pumping system, the at least one pumping system comprising at least one pump; at least one fluid handling device according to any one of claims 1 to 11 in fluid communication with the at least one pumping system; and at least one sensor for analysing the chemical, biological, bio-chemical, and/or physical properties of a sample, the at least one sensor being in fluid communication with the fluid handling device.

23. An analyser according to claim 22 comprising at least one power source.

24. An analyser according to claim 22 or claim 23, comprising at least one pumping system according to any one of claims 12 to 21.

25. An analyser (e.g. a chemical or biochemical analyser) comprising: at least one pumping system according to any one of claims 12 to 21; a fluid handling device in fluid communication with the pumping system, the fluid handling device including at least one valve operable to control fluid flow in the analyser; at least one sensor for analysing the chemical, biological, bio-chemical, and/or physical properties of a sample in fluid communication with the fluid handling device.

26. A vehicle comprising at least one analyser according to any one of claims 22 to

25.

27. Use in the analysis of a fluid of a fluid handling device according to any one of claims 1 to 11, a pumping system according to the any one of claims 12 to 21, an analyser according to any one of claims 22 to 24, an analyser according to claim 25 or a vehicle according to claim 26 comprising: submerging at least partially the fluid handling device according any one of claims 1 to 11, the pumping system according to any one of claims 12 to 21, the analyser according to any one of claims 22 to 24, the analyser according to claim 25 or the vehicle according to claim 26 in a body of fluid.

28. A fluid handling device substantially as described herein with reference to the accompanying drawings.

29. A pumping system substantially as described herein with reference to the accompanying drawings.

30. An analyser substantially as described herein with reference to the 5 accompanying drawings.

Intellectual

Property

Office

Application No: GB1619023.3 Examiner: Miss Elizabeth Price