Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
  • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
  • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
  • B01L3/502723—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by venting arrangements
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/06—Fluid handling related problems
  • B01L2200/0673—Handling of plugs of fluid surrounded by immiscible fluid
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/16—Reagents, handling or storing thereof
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/08—Geometry, shape and general structure
  • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
  • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2400/00—Moving or stopping fluids
  • B01L2400/04—Moving fluids with specific forces or mechanical means
  • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
  • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2400/00—Moving or stopping fluids
  • B01L2400/04—Moving fluids with specific forces or mechanical means
  • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
  • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
  • B01L2400/049—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics vacuum
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2400/00—Moving or stopping fluids
  • B01L2400/06—Valves, specific forms thereof
  • B01L2400/0622—Valves, specific forms thereof distribution valves, valves having multiple inlets and/or outlets, e.g. metering valves, multi-way valves
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2400/00—Moving or stopping fluids
  • B01L2400/06—Valves, specific forms thereof
  • B01L2400/0633—Valves, specific forms thereof with moving parts

Definitions

• the invention relates to, but not limited to, a microfluidic apparatus for joining two or more liquid samples.
• this may be to join two or more liquids before loading into another device, for example, a microfluidic process flow cell module, by way of example only.
• the ability to analyse biological samples, and in particular environmentally collected biological samples, to identify the presence of particular biological markers might have a range of applications, for example, including the detection of environmental biological hazards, monitoring and/or control of pollution, monitoring and/or control of airborne pathogens and the like.
• the ability to identify specific target biological hazards may have particular value in this regard.
• Laboratory based technology for analysis of biological samples is relatively well established.
• Known analysis techniques include genomic sequencing of material isolated from a biological sample.
• Laboratory based technology for processing and preparation of biological samples to isolate and prepare genomic material for analysis is relatively well established.
• microfluidic lab-on-chip principles Laboratory based technology for subsequent processing and analysing of biological samples using microfluidic lab-on-chip principles finds increasing application.
• suitable microfluidic processes for further processing and for example analysis and for example molecular biological analysis such as genomic analysis of collected samples of biological material in a fluid medium is of increasing significance as a means of automating the process and producing rapid and reliable results.
• sample collection and where applicable preliminary processing operations can be at least partly automated and reduced in scale, for example allowing it to be performed at least partly at a distributed location, and for example deployed in a portable manner. This may particularly be the case in relation to the analysis of biological samples collected in the field, and for example from the air at a monitored location or site, to detect the presence of biological threats.
• patent application No PCT/GB2021/050575 describes a sample collection module which may be amenable to microfluidic principles for the collection of material from a gas stream, and for example from air, that might be particularly suited to application to collect biological samples from the air in a sampling location into an aqueous buffer.
• patent application No PCT/GB2022/050889 describes a sample preparation module which may be amenable to microfluidic principles and which may be used as part of a sample collection module or system for the automation of sample collection and preliminary processing operations to prepare a sample for analysis.
• the collection of samples for testing could be, for example, manual or automated collection of wastewater, soil, or other media containing biological material, for example for further sample preparation or loading in an automated system.
• Microfluidic sample collection modules applying on these and other principles might be used to collect samples, such as biological samples, into a fluid medium for subsequent processing and analysis, and in particular for molecular biological analysis such as genomic analysis, using suitable microfluidic process flow cell modules as above mentioned.
• the sample priming of standard known microfluidic process flow cell modules and for example to standard known microfluidic process flow cell modules for genomic analysis, using collected sample material is effected manually.
• a microfluidic loading system needs to be developed that is capable of loading a prepared sample into such flow cell.
• the collection of a prepared sample is also automated it is desirable to develop a microfluidic loading system intended to sit fluidly between a microfluidic sample collection module and a microfluidic process flow cell module to effect this.
• a process flow cell module that has been traditionally designed for use by scientists with manual pipettes is not ideal for integrating into an automated system and the design of such a microfluidic loading system is not straightforward. While the problems with conventional systems may vary with precise design and loading protocols, in a typical process flow cell designed for sequencing they may include some or all of the following.
• microfluidic loading system that is thereby adapted to sit fluidly between a microfluidic sample collection module and a microfluidic process flow module to effect a more automated loading of a sample from the former into the latter. More completely, it is desirable to provide a system comprising such a microfluidic sample collection module, microfluidic loading system, and microfluidic process flow module fluidly in series.
• microfluidic loading it is important to be able to join two or more liquids and this may be to join two liquids by removing gas in and or between the two or more liquid samples. There are other reasons that two or more liquid samples may be required therefore the present invention is not limited to microfluidic loading or testing; or flow cell process module.
• a microfluidic apparatus for removing air from, or joining, liquid samples, comprising:
• the wall, or a portion of the wall of the first flow conduit comprises the selectively permeable membrane.
• the wall of the first flow conduit may be the outer wall of the first flow conduit.
• the configuration of the wall, or portion of the wall, of the first flow conduit comprising the selectively permeable membrane may assist in withdrawing gas within a fluid, the said fluid being within the first flow conduit.
• the selectively permeable membrane may allow gas to pass through the said membrane, but not liquid, thus the selectively permeable membrane can assist in the removal of gas from a fluid where the said fluid contacts the selectively permeable membrane.
• any transport of a fluid past the selectively permeable membrane along the length of the first flow conduit may expose the fluid to the selectively permeable membrane and thus may assist in the removal of gas within the first flow conduit or a fluid within the first flow conduit.
• Fluid within the first flow conduit may come into contact with the selectively permeable membrane and enable gas to flow from the fluid within the first flow conduit, across the selectively permeable membrane and out of the first flow conduit.
• the microfluid apparatus of the present invention can be used with different types of other devices, for example, testing devices like for example, microfluidic process flow modules.
• the present invention can be used with practically any equipment that are able to be fitted in fluid communication with the present invention. Therefore, the present invention may enable fluid joining and or loading to various types of microfluidic devices for example process flow modules to enable testing of fluids.
• the invention may be explained for use with a particular other device like a microfluidic process flow module however, it is not intended that the invention be limited to use only with that particular testing device.
• the present invention may by joining two or more liquids, may supply a sample of fluid for testing while minimising the risk of air or gas reaching the testing unit.
• Many types of cell testing equipment are only suitable for testing fluids that are largely liquids and are extremely sensitive to exposure of air or gas that may quickly and severely damage the testing equipment.
• Inevitably by adding a fluid sample for testing, even by adding a liquid sample there will usually also be an amount of air or gas.
• transporting a sample of target liquid for testing inevitably also lead to an amount of gas or air being introduced too that could potentially reach and damage the testing equipment.
• Use of buffer liquids to help transport liquid samples or clean testing equipment also have risks that an amount of gas or air may reach the testing equipment.
• the present invention helps address this issue.
• the present invention helps reduce air or gas in any fluid sample.
• the present invention helps reduce air or gas being introduced to any testing equipment.
• the present invention helps reduce any gas or air being left between fluid samples and or buffer type fluids used for transporting a target sample or cleaning the testing equipment.
• the other device, or vessel, that embodiments of the present invention are connected to is a microfluidic device in particular in that all flow conduits and valves are microfluidic elements.
• Some embodiments of the present invention may aptly be designed to interface with and automate delivery of fluids, for example liquid samples and buffer, to, and removal of waste from, another device for example, a microfluidic process flow module, having a spot on port, a priming port and an outlet port of the type that will be familiar to the skilled person.
• some embodiments of the present invention may have an inlet port and an outlet port, or port ends, each adapted to effect a fluid communicating engagement with the respective ports on other testing devices, for example a microfluidic process flow module, and a suitable arrangement of conduits and valves.
• a spot-on port may be the inlet port for a sample of liquid for joining with another liquid or that may be for testing, for example in another device.
• the present invention may offer a solution in which a microfluidic loading system can be engaged with such microfluidic process flow modules and provide an automated loading solution.
• the present invention may reduce gas or air in a sample of fluid, reducing the gas element of the sample to be more liquid, ideally mostly liquid that little gas remains in the sample, and ideally that so little gas remains in the sample that there is not enough gas remaining in the sample to cause damage to any testing equipment if the liquid sample reaches a testing device.
• the microfluidic apparatus is a microfluidic loading apparatus or system or a microfluidic liquid joining apparatus or system; or both a microfluidic loading and liquid joining apparatus or system.
• the plurality of inlet ports may be in fluid communication with the first flow conduit.
• a plurality of inlet ports may allow, for example, a sample liquid or buffer fluid or cleaning fluid or other types of fluid to be provided to the first flow conduit and the microfluidic apparatus.
• a plurality of inlet ports may increase the efficiency and reduce time to add target samples and or buffer type fluids to the first flow conduit or microfluidic apparatus.
• the microfluidic loading system comprises a plurality of outlet ports.
• a plurality of outlet ports may assist in removal of tested samples, used buffer fluid or the like, or waste, form the microfluidic loading system.
• an inlet port, or an outlet port, or first port end or second port end may comprise a valve.
• the valve is operable selectively to open and close a flow path through the inlet port or outlet port or first port end or second port end.
• both a first port end and a second port end comprise a valve.
• one or more or all or none, inlet ports or outlet ports, or both inlet and outlet ports comprise a valve.
• one or more or all, first port end or second port ends, or both first port end and second port end comprise a valve.
• valves are selectively operable to open and close. In some embodiments a user may selectively open and close one or more or all or none of valves to be able to control flow of fluid through the apparatus or system.
• valve at the first port end of a flow conduit, for example a first flow conduit.
• valve at the first port end of, for example, a first flow conduit or a second flow conduit or a third flow conduit, or any combination of a first, second or third flow conduits.
• valve at the second port end of a flow conduit, for example a first flow conduit.
• valve at the second port end of, for example, a first flow conduit or a second flow conduit or a third flow conduit, or any combination of a first, second or third flow conduits.
• valves are three-way valves. This is advantageous as may take up less space, but also the three-way may be configured not to be open to a first opening when one to a second opening for example not opened to a fluid store when opened to the pump, thus a particular liquid can be prevented going the wrong way.
• one or more or all or none of the valves are selectively operable automatically by a controller.
• the controller is in electrical communication with a sensor.
• the controller is configured to be responsive to the measurements from a sensor and further configured to close or open valves as required.
• the controller is electrical communication with one or more pumps, and is configured to activate or deactivate pumps, in response to measurements from one or more sensors to move liquid along the apparatus.
• the first flow conduit of a microfluidic apparatus comprises a first port end wherein the said first port end comprises a valve.
• the said valve may be operable selectively to open and close a flow path between the inlet port end and within the first flow conduit.
• the microfluidic apparatus or system comprises, at least one valve operable selectively to open and close a flow path between the first port end and the selectively permeable membrane. This may allow isolation of the selectively permeable membrane from fluids that may enter from the first port end, to enable loading of fluids into the first flow conduit from the second port end. For example, shutting the valve of the first port end and activating a vacuum pump in communication with the outside of the selectively permeable membrane may draw in fluid, into the first flow conduit via the second port end, if fluids or liquids are in fluid communication with the second port end, for example if the second port end is in fluid communication with a vessel wherein the vessel contains a liquid.
• the port interfaces may use any simple fluidly sealed engagement to seal with the respective ports.
• simple O-rings may be provided.
• the microfluidic apparatus may comprise: an inlet port adapted to receive a buffer liquid.
• the inlet port is selectively in fluid communication with the first flow conduit. For example, when the valves positions along the route are open.
• the microfluidic apparatus may comprise a priming inlet port adapted to receive a priming buffer liquid.
• the priming inlet port is selectively in fluid communication with the first flow conduit.
• the priming buffer inlet port may comprise a valve operable selectively to open and close a flow path between the priming inlet and the first flow conduit. This may allow for the dispensing of priming fluid to the first flow conduit and ultimately to any testing device for example a microfluidic process flow module, that the present invention is connected to.
• the priming inlet port may be the same as, or fluidly parallel to, or discrete from, the inlet port or liquid sample source.
• the microfluidic apparatus may comprise a push fluid inlet port adapted to receive push fluid.
• the push fluid inlet port may comprise a push fluid conduit between the push fluid inlet and the first flow conduit.
• the push fluid inlet port comprises a push valve operable selectively to open and close a flow path between the push fluid inlet or source and the first flow conduit.
• a particular inlet port need not be limited to a particular type of fluid and the inlet ports may, in some embodiments, be used for more than one type of fluid, or not.
• a person skilled in the art will understand the general working of microfluidic apparatuses and therefore such general workings are not explained in detail here. Likewise the person skilled in the art will understand various conduits and valves may be used without needing to describe in detail here.
• the first flow conduit comprises a first valve positioned at the first port end of the first flow conduit, the first valve is selectively operable to open and close a fluid flow path between the first inlet port and the portion of the first flow conduit comprising a selectively permeable membrane.
• the microfluidic apparatus comprises a pump.
• the microfluidic apparatus comprising a pump wherein the pump is in fluid communication with at least, the first valve at the first port end of the first flow conduit and the pump is configured to enable fluids to be moved along the first flow conduit, when the said first valve is open.
• the pump is an air push pump.
• One or more pumps may be an air push pump.
• the air from an air push pump may enable fluids, for example, liquids to be pushed along conduits in the apparatus or system for example along the first flow conduit.
• the pump is an air flow pump and is configured to comprise a flow rate equal to, or less than, the gas flow rate across the selectively permeable membrane of a flow conduit, for example a first flow conduit.
• the pump is an air flow pump and is configured to comprise a flow rate equal to, or less than, the gas flow rate across the selectively permeable membrane of a flow conduit, for example, a first flow conduit, when a negative pressure is applied to the outer surface of the selectively permeable membrane of the flow conduit.
• the gas flow rate across the selectively permeable membrane is at least 5 percent or 10 percent greater than the gas flow rate from the pump.
• the gas flow rate across the selectively permeable membrane is at least 5 percent or 10 percent greater than the gas flow rate from the pump, when a negative pressure is applied to the outer surface of a selectively permeable membrane.
• the flow rate of the pump is greater than the flow rate of gas across the selectively permeable membrane of a flow conduit when there is not a negative pressure applied across the sad selectively permeable membrane.
• the pump is an air flow pump and is configured to comprise a flow rate equal to, or less than, the gas flow rate across the selectively permeable membrane of the first flow conduit, when the outer surface of selectively permeable membrane is exposed to a negative pressure.
• the rate of negative pressure exposed to the outside surface of the selectively permeable membrane can be varied as desired.
• the flow rate of an air flow pump can be varied.
• the set air flow rate of the air pump will be set as a flow rate equal to or less than the flow rate across the selectively permeable membrane at a set rate of negative pressure across the selectively permeable membrane.
• this enables an automated system to push a liquid to this region and hold the liquid in this region.
• the system or a controller in a sense knows where the liquid has been moved to so that in any next step the liquid can be moved from that position.
• this enables a liquid to be moved from one part, for example, may be from the liquid source or a holding conduit, to a region in a conduit, for example, the region in the first flow conduit comprising a selectively permeable membrane, to be able to join with another liquid.
• this process of joining liquids may be automated, that the system can position the first liquid, then through activation or deactivation of various valves and pumps move a second liquid along side the first liquid for example within the first flow conduit, and due to the selectively permeable membrane any gas between the two liquids may be expelled out of the first flow conduit so that the liquids join.
• the process may be repeated as desired so that a number of liquid samples can be joined. These may be samples of the same liquid or of different liquids.
• the negative pressure applied to the outer surface of a selectively permeable membrane may be in the range of 5 to 10 percent below atmospheric pressure. In some embodiments the negative pressure applied to the outer surface of a selectively permeable membrane may be in the range of 4 to 70 percent below atmospheric pressure.
• the negative pressure applied to the outer surface of a selectively permeable membrane may be in the range of 5 to 10 percent below the pressure on the inside surface of the selectively permeable membrane, or inside of the flow conduit. In some embodiments the negative pressure applied to the outer surface of a selectively permeable membrane may be in the range of 4 to 70 percent below the pressure on the inside surface of the selectively permeable membrane, or inside the flow conduit.
• the pressure difference across the selectively permeable membrane only needs to be less in pressure on the outer surface to assist in drawing gas through the selectively permeable membrane. Gas tends to move towards the lower pressure.
• the "negative pressure" only needs to be relative, lower than another to move the gas and create a flow of gas.
• the vacuum pressure of the vacuum pump is minus 250 mBar or 25000 Pascals. In some embodiments the vacuum pressure of the vacuum pump is in a range of between minus 100 mBar and minus 300 mBar, or minus 10000 Pascals and minus 30000 Pascals.
• the air pump pressure is 150 mBar or 15000 Pascal. In some embodiments the air pump pressure is in the range of between 100 mBar and 200 mBar, or 10000 Pascals and 20000 Pascals.
• the microfluidic apparatus comprises a pump.
• the pump comprises an air pump.
• the pump is configured to pump gas along the first flow conduit and second flow conduit.
• the pump comprises a fluid pump, configured to pump, or move, fluid.
• the pump comprises a liquid pump configured to pump or move liquids, or the like.
• the air pump is configured to pump or move compressed air.
• the pump of the microfluidic apparatus or system when in use, is in fluid communication with the first and/or a second or second and third flow conduits and is configured to move fluid along the first flow conduit, or second flow conduit, or third flow conduit, or both the first and second flow conduit, or both the second and third flow conduit, or all of the first, second and third flow conduits. Consequently, in some application of some embodiments of the present invention, moving a fluid along the first flow conduit may move fluid through a microfluidic apparatus and to another device when that other device is connected in fluid communication with the first flow conduit, when in use. In some embodiments there may be a plurality of flow conduits.
• this may allow easy aligning up of different liquids for joining together.
• Any number of flow conduits comprising selectively permeable membrane may be used as required, joining together by known means.
• the pump is configured to enable movement of fluids, for example liquids, from the first flow conduit out of the first flow conduit to another device when that other device is selectively fluidly connected to the first flow conduit.
• fluids for example liquids
• the pump is configured to enable movement of fluids, for example liquids, from a plurality of flow conduits to the first flow conduit.
• the microfluidic apparatus comprises a pump in selectively fluid communication with the first and second and third flow conduits and the pump is configured to selectively enable fluids to be moved along the first or second or third flow conduits, or any combination of first, second and third flow conduits.
• the pump is selectively in fluid communication with the first, second and third flow conduits, due to the pump being activated or deactivated as required, or due to valves in the flow path being open or closed as required when the pump is activated thus a user or a controller can select to move liquids alone the flow path of the first, second or third flow conduits as required.
• the pump is in fluid communication with one or more inlet ports, or port ends, for example, port ends of a flow conduit.
• the pump is in fluid communication with the first flow conduit and is configured to enable selective pushing of fluid within the first flow conduit to and through the first flow conduit, or to the region of the first flow conduit comprising a selectively permeable membrane.
• the present invention is able to move and place or hold a liquid at a desired flow conduit comprising a selective permeable membrane.
• an air push pump the apparatus or system of the present is able to move and hold in desired positions samples of liquid and selectively join these liquids as required.
• the microfluidic apparatus or system comprises a controller.
• the controller may be part of a automated system that once programmed can open and close valves, activate or deactivate pumps as required to move fluid and join fluid, remove gas as required.
• the pump or pumps may be configured to assist in loading whatever required fluid is required from whatever inlet port, and then may be configured to push a sample of fluid or various samples of fluid, along a flow conduit.
• the pump may be configured that it may selectively expel liquid from another connected device when the other connected device is in fluid communication with the present invention and the pump of the present invention.
• a user may use the pump to push a tested sample from a microfluidic flow module when a microfluidic flow module is connected fluidly to the present invention and in particular in fluid connection with the pump of the present invention. to the outlet port.
• the pump may pull fluid samples towards the pump in direction.
• the pump may apply a push fluid to the sample and reagents to ensure as much liquid as possible is pushed into a connected microfluidic process flow module.
• the push fluid is air
• the present invention however helps address some of the issues of joining and loading liquid sample by removing the gas between and in liquid samples.
• the present invention in preferred embodiments may use an air push type pump but due to the selectively permeable membrane and aligning and joining liquid samples there is little risk of air reaching a connected device even though there is use of an air pump to push the liquids along and selectively in some embodiments to another device which may be sensitive to gas.
• the microfluidic apparatus or system may comprise a drawing means to draw fluid in a direction towards the said drawing means.
• the drawings means comprises a syringe pump.
• the drawing means for example a syringe pump may be configured to selectively enable drawing fluid from the apparatus or from a liquid source for example.
• a pump or a drawing means may be used selectively to draw fluid from another device when the said other device is in fluid communication with the present invention.
• a drawing means configured to selectively move fluid in the first or second or third flow conduits or any combination of first, and second and third flow conduits.
• there may be a different number of flow conduits and the in some of these alternative embodiments a drawing means may draw fluid from some or all or none of the flow conduits.
• the drawing means comprises a syringe or pump or vacuum pump.
• the microfluidic loading system comprises, at least, a valve operable selectively to open and close a flow path between the inlet and the outlet.
• the selectively permeable membrane is configured to enable gas to pass through the selectively permeable membrane but prevent the passage of liquid.
• the company Sartorius sells such membranes.
• the selectively permeable membrane is configured to have an air permeability between 1.2 to 1.6 litres per square meter at a pressure of 200 Pascal, or a pressure difference of 200 Pascals.
• the selectively permeable membrane comprises olephobic polymers.
• the selectively permeable membrane comprises polyethersulfone (PESU). In some embodiments, the selectively permeable membrane comprises polytetrafluoroethylene (PTFE). Other materials that enable a suitable selective permeability for the invention to work may be used in other embodiments.
• PESU polyethersulfone
• PTFE polytetrafluoroethylene
• a portion of the selectively permeable membrane is configured to be between 135 and 145 micrometres (um).
• the portion of the flow conduit, for example the first flow conduit, that comprising a selectively permeable membrane is configured that the selectively permeable membrane is in the range of between 10 percent and 90 percent of the entire circumferential length of the flow conduit at the portion of the flow conduit comprising a selectively permeable membrane.
• the portion of the flow conduit, for example the first flow conduit, that comprising a selectively permeable membrane is configured that the selectively permeable membrane is in the range of between 1 percent and 10 percent of the entire circumferential length of the flow conduit at the portion of the flow conduit comprising a selectively permeable membrane
• the portion of the flow conduit, for example the first flow conduit, that comprising a selectively permeable membrane is configured that the selectively permeable membrane is in the range of between 10 percent and 90 percent of the width of the flow conduit at the portion of the flow conduit comprising a selectively permeable membrane.
• the portion of the flow conduit, for example the first flow conduit, that comprising a selectively permeable membrane is configured that the selectively permeable membrane is in the range of between 1 percent and 10 percent of the width of the flow conduit at the portion of the flow conduit comprising a selectively permeable membrane.
• the portion of the flow conduit, for example the first flow conduit, that comprising a selectively permeable membrane is configured that the selectively permeable membrane is in the range of between 10 percent and 90 percent of the diameter of the flow conduit at the portion of the flow conduit comprising a selectively permeable membrane.
• the portion of the flow conduit, for example the first flow conduit, that comprising a selectively permeable membrane is configured that the selectively permeable membrane is in the range of between 1 percent and 10 percent of the diameter of the flow conduit at the portion of the flow conduit comprising a selectively permeable membrane.
• the portion of the flow conduit that comprises a selectively permeable membrane is configured that the selectively permeable membrane comprises greater than 50 percent of the circumference of a cross section of the flow conduit at the portion of the flow conduit comprising a selectively permeable membrane.
• the flow conduit is configured that the selectively permeable membrane comprises, greater than 10 percent, or greater than 20 percent, or greater than 30 percent, or greater than 60 percent, or greater than 70 percent, or greater than 80 percent, or greater than 90 percent, of the entire circumference of a cross section of the flow conduit at the portion of the flow conduit comprising a selectively permeable membrane.
• the gas within the fluid within the flow conduit can reach the membrane and escape from the said flow conduit.
• the flow conduit is configured that the selectively permeable membrane comprises, greater than 1 percent, or greater than 2 percent, or greater than 5 percent, or greater than 7 percent, or greater than 10 percent, or greater than 25 percent, or greater than 50 percent of the entire length of the flow conduit.
• the length of the selectively permeable membrane is of a length that is in the range between 5 percent and 60 percent of the entire length of the flow conduit.
• the portion of the flow conduit that comprises a selectively permeable membrane is configured that the surface area of the selectively permeable membrane is, greater than 1 percent, or greater than 2 percent, or greater than 5 percent, or greater than 10 percent, or greater than 25 percent, or greater than 50 percent, of the internal surface area of the flow conduit at the portion comprising a selectively permeable membrane.
• the portion of the selectively permeable membrane is configured that the surface area of the selectively permeable membrane is, greater than 1 percent, or greater than 2 percent, or greater than 5 percent, or greater than 10 percent, or greater than 25 percent, or greater than 50 percent, of the internal surface area of the entire flow conduit.
• the cross-section of a flow conduit is 1.1 millimetres in diameter. In some embodiments the cross-section of a flow conduit is square or rectangular in shape. The flow conduit need not be circular in cross-section.
• the width of the selectively permeable membrane is between 0.5 millimetres and 1.5 millimetres. In some embodiments, the width of the selectively permeable membrane is between 0.75 millimetres and 1.25 millimetres.
• the flow conduit is square or rectangular in cross-sectional shape and comprises a width in the range of 0.5 millimetres and 1.5 millimetres; and a depth in the range of 0.5 millimetres to 1.5 millimetres. In some embodiments the flow conduit is square or rectangular in cross sectional shape and comprises a width in the range of 0.25 millimetres and 2 millimetres; and a depth in the range of 0.25 millimetres to 2 millimetres.
• the length of the selectively permeable membrane is between 20 millimetres and 40 millimetres. In some particular embodiments, the length of the selectively permeable membrane is between 25 millimetres and 35 millimetres.
• the ratio of surface area of the selectively permeable membrane in millimetres squared to the volume of the flow conduit along the portion of the flow conduit in millimetres cubed comprising a selectively permeable membrane is in the range 0.5 to 1 and 3 to 1. In some embodiments, the ratio of surface area of the selectively permeable membrane in millimetres squared to the volume of the flow conduit along the portion of the flow conduit in millimetres cubed comprising a selectively permeable membrane is in the range 0.125 to 1 and 8 to 1.
• the portion of the flow conduit comprising a selectively permeable membrane may be defined as the corresponding length of the flow conduit wherein the wall of the selectively comprises the selectively permeable membrane and thus to the same length of the selectively permeable membrane.
• the surface area to volume ratio, of the surface area of the selectively permeable membrane to the volume of flow conduit for the portion of the flow conduit comprising a selectively permeable membrane comprises between, 0.75 to 1 and 1 to 1.
• the microfluidic apparatus comprises a sensor.
• the senor is configured to determine the presence of gas within the flow conduit, for example the first flow conduit.
• the senor is configured: to measure the flow rate of gas across the selectively permeable membrane; or measure the pressure difference across the selectively permeable membrane; or measure the power usage of the vacuum pump, in order to determine the presence of gas within a liquid within the first flow conduit at the portion comprising the selectively permeable membrane.
• the sensor is configured to measure, or enable measurement of, the flow rate of gas across the selectively permeable membrane.
• the flow rate across the selectively permeable membrane may be measured directly, or indirectly and the flow rate determined, relatively at least.
• a person skilled in the art will understand that the exact flow rate need not necessarily be determined that relative comparison of flow rate may be enough for some certain embodiments to work, to have an understanding of the flow rate across the selectively permeable membrane.
• the flow rate of gas across the selectively permeable membrane can be used to determine the quantity, or relative quantity, of gas within a fluid within the first flow conduit. Therefore, this can be used to determine if any gas between two or more sample fluids has been removed and the sample fluids have been joined.
• this can be used to ensure that a fluid, to be moved to another device, for example, a testing device, for example a microfluidic process flow cell module, connected to the present invention, is low in gas and therefore less risk in damaging the other device.
• a testing device for example a microfluidic process flow cell module
• the said fluid within the first flow conduit may assist in lowering the risk of damaging the testing device by presenting for testing a fluid with too much gas contained within or around the fluid, that may cause damage.
• By measuring the flow rate across the selectively permeable membrane and determining the amount of gas within a fluid within the first flow conduit may assist in removing enough gas from a fluid within the first flow conduit, before presenting the fluid for testing, and risking damaging the testing device, for example a microfluidic flow cell module. Should a fluid, for example a sample of target fluid for testing, be determined to have a high level of gas, or a level of gas that may cause damage to the testing device, then the fluid can be held for a longer time exposed to the selectively permeable membrane to assist in withdrawing more gas from the fluid exposed to the selectively permeable membrane.
• the senor may measure the vacuum pump activity. By measuring the vacuum pump activity this may be measuring indirectly the rate of flow of gas across a selectively permeable membrane that the negative pressure from the vacuum pump is fluidly in contact with.
• the sensor is in electrical communication with a controller configure to convey measured data to the controller, wherein the controller is configured to use the measured data to determine the presence of or amount of gas within a flow conduit.
• a controller may indicate the quantity of gas within a fluid within a flow conduit, for example the first flow conduit. In some embodiments, the controller may indicate when a fluid within a flow conduit, for example the first flow conduit, is below a pre-set quantity of gas. In some embodiments, the controller may prevent further movement of the fluid in the testing machine direction until the fluid is below a pre-set quantity of gas.
• the fluid within a flow conduit may be agitated.
• the said fluid may be agitated to increase the withdrawing of gas from a fluid exposed to the selectively permeable membrane.
• the fluid may be agitated.
• the fluid may be agitated by pushing the fluid back and forth along a flow conduit, for example a first flow conduit.
• the fluid within a flow conduit may be agitated by vibrations to the said flow conduit.
• the fluid within a flow conduit may be agitated by ultrasound directed to the first flow conduit.
• the rate of withdrawing of the gas from a fluid within a flow conduit can be increased by exposing the outer surface of the selectively permeable membrane to a vacuum, or low air pressure.
• the outer surface of a selectively permeable membrane is exposed to a vacuum or negative pressure or vacuum pump.
• the vacuum may act to increase the rate of withdrawing a gas from the fluid on the other side of the selectively permeable membrane, i.e. from within a flow conduit for example the first flow conduit.
• a microfluidic apparatus or system comprises a vacuum pump, wherein the vacuum pump is configured to be in fluid communication with the outer surface of a or the selectively permeable membrane.
• the vacuum pump is configured to be in fluid communication with the outer surface of a or the selectively permeable membrane.
• this may increase the rate of drawing gas through the selectively permeable membrane, from a flow conduit, for example from the first flow conduit.
• a vacuum pump is in fluid communication with the outer surface of the selectively permeable membrane, the said vacuum pump configured that when activated a negative pressure is applied, at least, to the outside surface of the selectively permeable membrane of the first flow conduit to assist flow of gas across the selectively permeable membrane from the inside of the first flow conduit.
• the vacuum pump is configured: to be selectively activated or deactivated such that a negative pressure may be turned on or off; or have a selective negative pressure range; or is gated by one or more valves to selectively expose the outer surface of the selectively permeable membrane to negative pressure; or any combination of, to be selectively activated such that a negative pressure may be turned on or off; have a selective negative pressure range; or is gated by one or more valves to selectively expose the outer surface of the selectively permeable membrane to negative pressure.
• the vacuum pump is configured: to be selectively activated or deactivated such that a negative pressure may be turned on or off; or have a selective negative pressure range; or is gated by one or more valves to selectively expose the outer surface of the selectively permeable membrane to negative pressure; or any combination of, to be selectively activated such that a negative pressure may be turned on or off; have a selective negative pressure range; or is gated by one or more valves to selectively expose the outer surface of the selectively permeable membrane to negative pressure.
• the senor is configured to measure the pressure difference across the selectively permeable membrane. In some embodiments, the sensor is configured to enable measurement of the pressure difference across the selectively permeable membrane. The pressure difference across the selectively permeable membrane can be used to indicate the flow rate across the selectively permeable membrane. In some embodiments, the controller is configured to determine the flow rate of gas across the selectively permeable membrane from the pressure difference across the selectively permeable membrane.
• the microfluidic apparatus or system comprises a controller, the said controller is configured to receive measurements from the sensor.
• the microfluidic apparatus or system comprises a controller, the controller is configured to receive measurements from the sensor and wherein the controller is configured to determine the presence of gas or relative gas quantity within a flow conduit, for example a first flow conduit or within a fluid, wherein the said fluid is within a flow conduit, for example a flow conduit, for example the first flow conduit.
• the microfluidic apparatus or system comprises a controller, the controller is configured to receive measurements from the sensor and the controller is configured to determine relative gas quantity within a fluid within the first flow conduit, and the wherein the controller is configured to indicate to a user the determined relative gas quantity within a fluid within a flow conduit, for example a first flow conduit.
• the microfluidic apparatus comprises a controller configured to receive measurements from the sensor and wherein the controller is configured to determine and indicate to a user the gas quantity within a fluid wherein the said fluid is within a flow conduit, for example, a first flow conduit.
• the controller is configured to enable an indication to a user of the flow rate across the selectively permeable membrane, or the amount of gas within a liquid at the portion of a flow conduit comprising a selectively permeable membrane, for example the first flow conduit.
• the controller is configured to enable an indication to a user that: the majority of the air in a liquid sample has been removed from one or more samples; or that two liquid samples have joined together; or both, that the majority of the air has been removed from one or more samples and that two samples have been joined together.
• the controller is configured, in response to the received measurements from the sensor to automatically open or close at least the said first valve and selectively activate or deactivate the said pump and or the vacuum source, to join two or more liquid samples.
• the controller is configured to activate or deactivate pumps; or open or close valves; or both activate and deactivate pumps and open or close valves in response to information from one or more sensors.
• the flow should be lamina and there should be minimal mixing.
• the controller comprises an alarm.
• the controller is configured to activate an alarm if a user tries to move a fluid towards a testing device wherein the said fluid comprising gas above a pre-set amount.
• the controller may therefore help prevent damage to a fluidic testing device, or other connected devices that are sensitive to gases.
• the controller is configured that if the gas quantity of the fluid within a flow conduit, for example a first flow conduit, is not below a pre-set amount of gas, the controller will prevent the said fluid being moved, or activate an alarm should a user try to move the said fluid to a microfluidic process flow cell module.
• the first flow conduit is of a known volume and is configured to fluidly connect with a vessel containing liquid, via the second port end of the first flow conduit.
• the first flow conduit is configured that volume of the first flow conduit is equal to or greater than the volume of the device containing a liquid that the first flow conduit is configured to fluidly connect with. In this way enough fluid to potentially be moved to the vessel containing a liquid, in particular applications and use of the present invention, has enough liquid to fill the vessel containing a liquid.
• first or second or third flow conduits are configured of a known internal volume.
• first or second or third fluid conduits, or any combination of the first, second and third fluid conduits are configured to be in fluid communication with each other. In some embodiments, the first or second or third fluid conduits, or any combination of the first, second and third fluid conduits are configured to be in selective fluid communication with each other. Valves or other means may be used to selectively control if a flow conduit is in fluid communication with another flow conduit or other device.
• first or second or third fluid conduits are configured to be in fluid communication with each other and with the pump when the said first valves of the first, second and third flow conduits are open such that the air push from the pump may be in fluid communication with the first, second and third flow conduits.
• liquids for joining together can first be loaded up into individual, for example first, second or third etc, flow conduits, wherein the flow conduit comprises a selectively permeable membrane.
• the flow conduit comprises a selectively permeable membrane.
• a liquid may be drawn into the flow conduit when fluidly connected with the source of the particular liquid.
• each flow conduit may be connected to a particular liquid source and this fluid connection would be controlled by the use of one or more valves that when open will allow fluid communication from the liquid source to the flow conduit at the region where the fluid conduit comprises a selectively permeable membrane.
• the flow conduits can be of a known volume and thus will fill up when the negative pressure is applied as mentioned.
• various known size flow conduits comprising a selectively permeable membrane can be used.
• the flow conduits can be configured that they fill up with liquid on application of, or assistance of, the negative pressure to the outside of the selectively permeable membrane as explained, one can usually always be reassured that the drawn-out liquid will be of a known volume consistently.
• the flow conduits can be used to quickly and efficiently draw out consistent known volumes.
• these flow conduits will be configured in series also such that the flow conduits are configured to selectively be in fluid communication with each other and with a pump.
• the pump is an air push pump.
• This series arrangement is such that in some embodiments the air pump for example can push any loaded liquids in the series of flow conduits along the flow conduits to an end point, or be held at a selectively permeable membrane when the negative pressure at that particular selectively permeable membrane is activated and present, this is because the selectively permeable membrane will allow gas to pass through but not liquid, hence when the negative pressure is on the outer surface of the selectively permeable membrane, the selectively permeable membrane will allow gas to pass through but will hold the liquid at the selectively permeable membrane.
• the liquid samples may be loaded and held there, provided the valves are open to have the fluid connection to the liquid source.
• valves in the undesired direction would be closed, for example the valve to the fluid source, and the valves in the desired direction of movement would be opened.
• the pump activated that is configured to have an air push along the series of flow conduits, probably in some embodiments of the direction of third flow conduit, then the second flow conduit and then the first flow conduit.
• the pump activated that is configured to have an air push along the series of flow conduits, probably in some embodiments of the direction of third flow conduit, then the second flow conduit and then the first flow conduit.
• one may shut off the negative pressure to the third and second flow conduit, to prevent the air push simply escaping and not being as effective as it could be to push the samples along.
• the air push would push the or any liquid sample in the third flow conduit towards the second fluid conduit and join with the or any liquid held at the second flow conduit, as air between these sample liquids pass the selectively permeable membranes of the third or second flow conduits gas in or between liquid samples may be expelled, but the air push is of great a flow to push the liquid samples along.
• the valve or valves to the first flow conduit are open and fluid communication is allowed the liquid sample or samples may be pushed along to the first flow conduit also comprising a selectively permeable membrane.
• the vacuum pump would still be activated, and the valves open in order to allow a negative pressure to still be applied to the outside surface of the selectively permeable membrane of the first flow conduit.
• the negative pressure to the outside of the selectively permeable membrane of the first flow conduit may ensure that gas is removed from the liquids and from between the liquids as the liquids are pushed together by the air pump, and along a selectively permeable membrane.
• the air pump, or air push is prevented from pushing the liquids any further passed the selectively permeable flow conduit by the negative pressure top the outside of the selectively permeable membrane.
• the flow of the air push is equal to or less than the gas flow across the selectively permeable membrane when negative pressure is applied. The air push will push the liquids to expose a portion of a or the selectively permeable membrane such that the air or gas then escapes out of the flow conduit via the selectively permeable membrane hence potentially does not push the liquid any further.
• the liquids joined together and that have had the gas removed from within the liquids or from between the liquids can be held there, by either leaving the negative pressure on, or by shutting off first the air push and then the negative pressure that is being applied to the outer surface of the selectively permeable membrane, or lowering the pressure of the air push that it is less than the flow of gas across the selectively permeable membrane.
• the pump for example air pump, can be activated and the air push or other type of push can move the liquid along the first flow conduit to a desired location.
• a plurality of flow conduits comprising selectively permeable membranes, in selective fluid communication with each other, and an air pump, by a series of conduits and operable valves to open or close the fluid communication as desired, can be arranged to offer infinite possibilities of easily and quickly and by an automated process of joining consistent volumes of liquid in desired orders and transporting these joined liquids to desired positions.
• the apparatus of the invention can be added to and increased in features to give infinite possibilities to join liquids and remove gas from or between liquids.
• a more complex apparatus and system will now be described by way of example only.
• Other embodiments may have different features of combination of features or may be applied in different order.
• microfluidic system comprising a microfluidic apparatus as herein described.
• system there further comprises a vessel comprising a liquid wherein the vessel comprising a liquid is configured to be selectively in fluid communication with the first flow conduit so that fluid may be allowed to flow between the vessel containing a liquid and the first flow conduit.
• the system there comprises a plurality of flow conduits each comprising a selectively permeable membrane.
• liquid stores in selective communication with at least one flow conduit comprising a selectively permeable membrane.
• each flow conduit comprising a selectively permeable membrane, wherein the plurality of flow conduits are arranged in series such that each flow conduit is selectively in fluid communication with each other and a pump.
• each flow conduit comprising a selectively permeable membrane further comprises an operable valve, wherein the said valve is configured to open and close such that when open the flow conduit is in fluid communication with a pump but when the valve is closed the flow conduit is not is fluid communication with the pump.
• system there comprises a plurality of operable valves configured to open and close.
• the system there comprises a liquid source.
• a liquid source in some embodiments there is a plurality of liquid sources in selective communication with the first flow conduit.
• the liquid source contains buffer solution.
• a liquid source in selective fluid communication with, a flow conduit comprising a selectively permeable membrane and a valve, configured such that when the valve is open there is fluid communication with the liquid source and the flow conduit but when the valve is closed there is not fluid communication between the fluid source and the flow conduit.
• the vacuum pump is gated by operable valves wherein the valves are configured that when open the negative pressure from the vacuum pump is in fluid communication, for example with the selectively permeable membrane, but when the valve is closed there is not fluid communication with the selectively permeable membrane.
• the valves are configured that when open the negative pressure from the vacuum pump is in fluid communication, for example with the selectively permeable membrane, but when the valve is closed there is not fluid communication with the selectively permeable membrane.
• some or all of the plurality of fluid conduits comprising a selectively permeable membrane are configured that a vacuum pump is selectively in fluid communication with the outer surface of the selectively permeable membrane such that when the vacuum pump is activated and in fluid communication with the outer surface of the selectively permeable membrane the negative pressure produced by the vacuum pump assistance in the flow of gas across the selectively permeable membrane from the inner side of the selectively permeable membrane to the outer side of the selectively permeable membrane.
• microfluidic apparatus or microfluidic system is an automated system comprising a controller, for example a computer.
• the controller is configured to be preprogrammed by a user. Therefore, once the liquid sources are fitted and the microfluidic apparatus or system is turned on and activated to function, the controller may in some embodiments join the liquid samples and move the joined samples to a connected device, for example a testing device, without further user input.
• the system there comprises sensors wherein the sensors are able to detect liquid or the presence of gas and the sensors are configured to be in electrical communication with the controller able to convey this detected information to the controller such that the controller is able to detect any problems that the controller can either stop the joining of further liquid and further movement of liquids or inform a user of any issues.
• the microfluidic apparatus of the first aspect of the invention is provided selectively fluidly coupled to a testing device, or a microfluidic process flow cell module.
• the method further comprising the step of: when connecting the first flow conduit, via the second port end, to a vessel containing a liquid such that the first flow conduit via the second port end is in fluid communication with a liquid in a vessel containing a liquid, that this connecting is to a flow cell device or a nano pore sequencing device, containing a liquid.
• the method further comprising the step of: adding a known volume of a third liquid, by means of an air push, into the said first flow conduit via the first port end.
• the method further comprising the step of: applying the said air push at a flow rate that is equal to or less than the flow rate of gas across a selectively permeable membrane of a flow conduit.
• the method further comprising the step of: applying the said air push at a flow rate that is equal to or less than the flow rate of gas across the selectively permeable membrane of a flow conduit when a negative pressure is applied to the outside of the said selectively permeable membrane.
• the method further comprising the step of: applying the said air push at a flow rate that is greater than the flow rate of gas across a selectively permeable membrane of a flow conduit.
• the method further comprising the step of: applying the said air push at a flow rate that is at least 5 percent or at least 10 percent greater than the flow rate of gas across a selectively permeable membrane of a flow conduit.
• Having the flow rate of the air pump greater than the flow rate across a selectively permeable membrane means that a liquid can be push along, past a selectively permeable membrane, and that some of the air may flow out of the flow conduit across the selectively permeable membrane but not all the air or gas flow from the pump, thus a liquid can be pushed past a selectively permeable membrane when required.
• the liquid within flow conduit for example the first flow conduit
• the selectively permeable membrane at least some, if not all, gas, within the sample of liquid, or between the sample of liquid and the any other fluids in front or behind the sample of liquid e.g. first liquid, may be removed from the first flow conduit.
• the gas between liquid samples when the gas between liquid samples is removed the liquid samples may be joined.
• enough gas is removed so that there is not potential damage to a testing device, for example, microfluidic process flow cell module, when the fluid is later presented or moved to that other device for example, for testing.
• the method may further comprise the step of: testing the sample of liquid.
• the method may further comprise the step of:
• the method may further comprise the step of: selectively operating a valve at the first port end of the flow conduit to supply a buffer or pusher fluid, for example an air push.
• a buffer or pusher fluid for example an air push.
• the method may further comprise the step of:
• the method may further comprise the step of:
• the method may further comprise the step of:
• the method further comprises the step of: loading a liquid sample through the first or second or both first and second port ends of a flow conduit, for example a first flow conduit.
• the method for loading a liquid sample into a flow conduit comprising the step of: transporting a liquid sample from a first or second port end pass the selectively permeable membrane of the flow conduit.
• the method comprising the step of: transporting a liquid sample pass the selectively permeable membrane to another container or device, for example, microfluidic flow process cell module.
• the method comprises the step of joining two or more liquids as described herein and transporting the joined liquid to another container or device, for example, a microfluidic flow process cell module.
• the method further comprising the step of: using buffer solution to push the first liquid sample along one or more flow conduits for example the first flow conduit.
• the system may comprise a process flow module which is configured to perform, for example molecular biological analysis such as genomic analysis.
• the process flow module may comprise a genetic sequencer and the process may be sequencing.
• the flow conduits comprise plastic. It is foreseen that the flow conduits and many other components of the present invention may be manufactured of plastic. Advantageously plastic can be made to be air and liquid tight and easily shaped to the requirements of the present invention. The skilled person will understand how to manufacture the particular components of the invention from the description herein.
• the present invention especially in an automated embodiment offers advantages of efficiency and consistency over a manual protocol based on a manually operated pipette.
• An effective adaptation is made to reduce likelihood of introduced air bubbles that may damage the sequencing array of a flow cell.
• the invention may offer an effective automated microfluidic loading solution to manage the addition of reagents and sample to and removal of waste fluids from the testing device for example a microfluidic process flow cell.
• any inlet, outlet, flow path, valve, flow conduit or other component will be understood to may include the plural, and in particular plural flow paths in series or in parallel as dictated by the requirements of the function may be provided for any feature of the invention. Likewise, the plural term may include the singular.
• first, second third etc and the like may be used herein to help describe various elements or features but need not necessarily be limited by these terms, these terms are used to distinguish one element or feature from another.
• a first feature or element may be termed a second element or feature and similarly a second element or feature may be termed a first element or feature without departing from the scope of the embodiment described.
• buffer or “buffer fluid” or “pusher fluid” or the like as used herein this term is used in meaning to include a fluid that is not the sample fluid for testing.
• Many other fluids that are not the fluid for testing may be used to ensure the testing device is not exposed to gas or air, and thus these other fluids may be used, for example, to clean the system or push the sample for testing along.
• circumferential length or circumference
• this term is used to mean the greatest circumferential length regardless if of a true circle or not, of a cross section of the item referred to, for example, the first flow conduit.
• diameter is not limited to circular shapes but is used to include in meaning the greatest cross-sectional length of an object even if of an irregular shape, for example.
• flow conduit and the like as used herein this includes in meaning a conduit configured to enable flow along the inside of the conduit.
• fluid communication and the like as used herein includes in meaning “when in use” such that the fluid communication is possible when in particular use, and thus does not necessarily exclude situations when not in fluid communication, for example when a valve is closed, the term includes selectively in fluid communication. The person skilled in the art would understand this.
• liquid and the like as used herein this term is used in meaning to also include solutions and mixtures that have a consistency of a liquid but may comprises non-liquid components.
• microfluidic process flow cell module as used herein this term is used to mean a testing device able to test microfluidic samples.
• negative pressure is used to include in meaning a gas pressure that is below another gas pressure, thus also includes relative pressure differences that the "negative pressure” is below, or less than, the pressure of another, thus acts to draw other gases towards it. This therefore does not have to be relative to atmospheric pressure or below atmospheric pressure, but merely below, or less than another pressure.
• port end as used herein this is used to include in meaning an end of the conduit, in some embodiments this may be an open end or at least selectively open to enable passage of fluid.
• sample as used herein this is used to mean amount, often but not necessarily limited to mean a small amount relatively.
• selective permeable membrane and the like as used herein this term is used to mean a membrane that will enable the passage of gas through or across the membrane but not enable the passage of a liquid across the membrane.
• selective fluid communication includes in meaning that a user or controller can change the state to and from, or from and to fluid communication or not in fluid communication thus the term includes that the two elements referred to may be in fluid communication in particular situations or states, and that a user or control may change the state between the two states of, in fluid communication and not in fluid communication.
• vacuum and “vacuum pump” and the like, are used in a pragmatic way and their meaning is not necessarily limited to a complete vacuum, but includes in meaning that of a lower pressure compared to another or lower than atmospheric pressure. For example, a vacuum creates a lower pressure, than previously, and thus may be able to attract other items into the created lower pressure area.
• valve and the like, as used herein this includes in meaning that the valve is operable, in other words working and functions as a valve does, able to change between at least the two states of open and close.
• the term includes complex valves for example three-way valves that may have more than two states, as there will be a number of different combinations of open and close for the three directions. A person skilled in the art will understand that there are even more complex valves then three-way valves and these are not excluded by the meaning of the term used herein.
• FIG 1 shows a cut away side view of a microfluidic apparatus 11 shown generally as 11 according to an embodiment of the present invention.
• a first flow conduit 11 comprising a selectively permeable membrane 20 ( as also shown in Figure 2 by a cut away enlarged view).
• a first valve 11V At the first port end 16 is shown a first valve 11V that is configured to open and close such that when closed the valve 11V prevents fluid communication through the valve 11V but when open the valve1 1V enables fluid communication through the valve 11V.
• a sensor 21 wherein the sensor in this particular embodiment is configured to detect the flow rate of gas G across the selectively permeable membrane.
• a sensor 21 may be configured to measure other parameters while in some embodiments there is not any sensor. Also shown in this embodiment but is an optional feature and may not be present in other embodiments is a controller 22.
• the controller 22 is in electrical communication with the sensor 21 such that measurements from the sensor 21 can be sent to the controller 22.
• the controller 22 in this embodiment is configured to determine the present or absence of gas G within the flow conduit 11.
• the controller 22 may be configured to have other functions or there may not be a controller 22..
• the outer surface of the selectively permeable membrane 20 may be exposed to a negative pressure in the conduit 24 produced by a vacuum pump 25 (not shown) in the direction of arrow A. In practice gas G within the flow conduit 11 may pass through, or across, the selectively permeable membrane 20 in the direction indicated by arrow B.
• the user may set up a microfluidic apparatus or system 10 by fluidly connecting the first flow conduit 11 to a vessel containing a liquid L for example a testing device 33 (not shown in Figure 1 ).
• a testing device 33 may be damaged if the testing elements is exposed to gas G or air it is likely that the testing device 33 will be stored with a fluid low in gas, for example a liquid L1, in contact with the testing elements of the testing device 33. Care therefore needs to be taken, in these applications of some embodiments, to ensure no air reaches the testing elements of the testing device 33.
• a sensor 21 may be configured and operable to determine the amount of gas flow across the selectively permeable membrane 20 and this information communicated to the controller 22 and optionally in some embodiments ultimately a user, by for example by a display screen. Aptly to enable free flow of fluid through the microfluidic system 10 many, or all, of the valves in the flow path from push pump to the first flow conduit will be open.
• the liquid sample may be loaded into the flow conduit 11 by opening valve 11V and connecting the first port end 16 of the flow conduit 11 to be in fluid communication with a liquid source.
• the liquid source may be a buffer solution or a liquid sample for testing or for joining to another liquid. Loading the liquid through the first port end 16 may happen by a number of different means. If the fist port end 16 is in fluid communication with a liquid source of a liquid sample that is to be loaded up, then the vacuum pump 25 (not shown in Figure 1 ) may be activated, and the vacuum pump P so configured such that a negative pressure is applied to the outer surface of the selectively permeable membrane 20.
• the negative pressure on the outer surface of the selectively permeable membrane 20 may be enough alone to draw fluid into the flow conduit via the valve 15 and first port end 16 from the liquid source when in fluid communication. In some embodiments this drawing the liquid in via the first port end 16 may be assisted if a valve (not shown) at the second port end 17 is closed, or if the second port end is blocked by liquid already in the flow conduit at that end or as the second port end is connected to a vessel or other device containing liquid.
• the negative pressure and selectively permeable membrane 20 is going to draw the air out thus more likely going to draw any air of the first port end 16 and thus more likely to draw liquid from a connection on that side if the second port end 17 is blocked by a valve or liquid.
• the liquid does not pass though the selectively permeable membrane 20 the liquid only travels as far as the selectively permeable membrane 20 and is held there.
• a push pump P in selective communication with the valve 11V and the flow conduit 11 via the first port end 16, that is configured to push any liquid already loaded up into any fluidly connected channel between the flow conduit 11 and the pump source (not shown in this figure 1 ). Then by activating the pump P the push pressure can push along any liquid sample or samples in the fluidly connected path between the pump P and the first flow conduit 11 to the selectively permeable membrane 20 or other desired location along the flow conduit.
• the pump may be a fluid or liquid or air push pump.
• the pump is an air push pump and in selective fluid communication with the first flow conduit 11 advantageously when the air push is applied it may push any liquid sample or samples to the selectively permeable membrane of the first flow conduit and be held there.
• No sensor 21 is necessarily needed as if the air push flow is equal to or less than the flow of gas across the selectively permeable membrane 20 the push air flows out of the selectively permeable membrane 20 and the liquid is held there. No sensors or indicators are required.
• liquid sample or samples joined may be held there in the flow conduit 11 until required to be moved.
• To move one may turn off the vacuum pump P or source or block negative pressure reaching the selectively permeable membrane or at least turn the vacuum pump down or increase the air push pressure to be greater than the flow of gas across the selectively permeable membrane to enable the air push from the first port end to move the liquid in the second port end direction and out of the first flow conduit 11 to wherever required.
• the flow conduit 11 has a known internal volume, for example from the valve 16 to the selectively permeable membrane 20 and is configured such that the negative pressure when applied draws in the same know volume every time.
• this arrangement can be easily automated to consistently load samples into a flow conduit of a known fixed volume, which can then be joined to other liquids without air between the liquid samples, and to be moved to where required.
• the flow should be lamina and there should be minimal mixing.
• This described embodiment can be altered to have any number of liquid sources in various orders gated with valves to load up and position various liquid samples in selectively fluid communication to join together and position in a flow conduit 11.
• a sample for testing may be pushed into the first flow conduit 11 until the sample to be tested is exposed to the selectively permeable membrane 20, once the sample is in contact with or exposed to the selectively permeable membrane 20 the air push is stopped and a small volume of the flow cell priming buffer is used to push the sample the rest of the way into the testing device 13 for example a sequencing array.
• FIG. 2 shows an enlarge view of the portion of a flow conduit 11 comprising a selectively permeable membrane 20.
• the flow conduit 11, in this example, is shown with upper outer wall 11a and lower wall 11b and the internal channel 11d. Also shown here is the vacuum channel 24 on the outer surface of the selectively permeable membrane 20.
• gas from the inner channel 11d of the first flow conduit 11 would flow in direction of arrow B, especially when a negative pressure is exposed to the outer surface of the selectively permeable membrane 20.
• gas may travel along the vacuum channel 24 in direction of arrow A.
• a skilled person would understand that a true vacuum is not actually required, but that any lower pressure gradient will assist in drawing gas from the inner channel 11d of the first flow conduit 11 through the selectively permeable membrane 20 into the vacuum channel 24.
• a first port end may be in the direction indicated by arrow C, while a second port end of the flow conduit comprising a selectively permeable membrane may be at the opposite end (both port ends not shown).
• Figures 3 and 4 show an enlarged view of an example of a sensor suitable for use with some embodiments of the present invention. Some embodiments may not have a sensor 21, and in some other embodiments, different sensors 21 may be used. In some embodiments more than one sensor 21 may be used. Shown in Figure 3 are fittings for piping 1, mesh for holding screws 2 the actual mesh 3, body 4, printed circuit board 5 and sensor clip 6 of generally the sensor 21.
• the sensor 21 shown here in this embodiment uses a microelectromechanical sensor (MEMS). Other embodiments may use different sensors 21 or none.
• MEMS microelectromechanical sensor
• microelectromechanical sensor consists of upstream temperature measuring sensor Ru (as shown in Figure 4 ) and downstream temperature measuring sensor Rd, which are placed symmetrically from the centre of a platinum this film coated heater Rh mounted on a membrane, and an ambient temperature sensor Ra for measuring gas temperature.
• the principle is as shown in Figure 4(a) and 4(b).
• Figure 4(a) shows when the gas flow is static, the temperature distribution of heated gas centred around Rh is uniform, and Ru and Rd have the same resistance.
• Figure 4(b) shows when the gas flows from the left side direction as indicated by the flow arrow, it upsets the balance of the temperature distribution of heated gas, and the resistance of Rd becomes greater than that of Ru.
• the difference in resistance between Ru and Rd is proportional to the gas velocity of the gas.
• Ra is used to compensate the gas and /or ambient temperature. From this sensor, a relative value of flow rate can be indicated and by comparison, the controller can determine when the gas amount in the fluid is low enough to have a low of minimal risk of damaging the testing device 13.
• Figure 5 One example of a curve of a graph of readings of flow of gas across the selectively permeable membrane 20 on the x-axis against time on the y-axis is shown in Figure 5 .
• Embodiments need not be limited to this curve of graph and other embodiments may have a different curve graph, but this is described here as one example to many possible examples to help explained the invention.
• the Figure 5 embodiment uses a device and set up as shown and explained in Figure 1 .
• the flow rate of gases (millilitres per second) across the selectively permeable membrane is shown on the x-axis, with over time (seconds) on the y-axis.
• the fluid sample to be tested is positioned to be in contact with the selectively permeable membrane, and as you can see the rate of flow of gas across the selectively permeable membrane increases and peaks at time point c. After an initial peak at time point c, the rate of change of flow of gas steadies at a level higher than seen between time points a and b the background leakage level.
• This steady flow between time points c and d may be the steady rate of gas being removed from the sample fluid to be tested when the gas amount in the sample fluid to be tested is high.
• the rate of flow across the selectively permeable membrane will eventually fall as the gas amount in the sample fluid to be tested falls too, as seen by time points between d and e.
• the rate of flow will eventually fall back at a low steady flow of gas across the selectively permeable membrane 20 as seen between time points e and f, where again this may be the background leakage.
• a pressure sensor 21 that measure the gas pressure gradient across the selectively permeable membrane one may be able to determine when the majority of the gas, if not all, has been removed.
• the power rate of the vacuum pump can be measured to determine the air flow across the selectively permeable membrane 20.
• Figure 6a and 6b there is preloading of the liquid samples to be joined.
• Figure 6a and 6b shows a means to pre-load a flow conduit and in this example what may be the second flow conduit 12 in a series of flow conduits, this second flow conduit is identified as 12, a second flow conduit 12 to distinguish from other to be described in more detail later with reference to other figures.
• First flow conduit 11 and third flow conduit 13 are however shown also in Figure 6a and Figure 6b .
• the second flow conduit 12 need not be connected to the first 11 or third 13 flow conduits in order to load up a liquid, and in other uses or other embodiments these may not be connected during this loading of a liquid.
• a vacuum source 25 is also shown, as is a sample source or sample store 27 and a buffer source or store 26.
• the vacuum source 25 may be the same source for the three selectively permeable membranes 20 shown but the applying the negative source 25 to the individual selectively permeable membrane 20 may be independent in some embodiments, in this example the applying of the negative pressure 25 to the selectively permeable membrane 20 is independent and can be separately applied without the need to apply negative pressure to the other selectively permeable membranes 20, in this example the negative pressure 25 is gated by valves not shown to enable independent application or deactivation of applying negative pressure to the desired selectively permeable membrane 20.
• a user or controller 22 in an automated system would close, or ensure that, the first valve 11V of the first fluid conduit 12 is closed.
• valve 12V is a three-way valve selectively enabling fluid communication between:
• the vacuum source 25 is activated and configured such that a negative pressure is applied to the outer surface of the selectively permeable membrane 20 of the second flow conduit 12.
• This negative pressure 25 on the outer surface of the selectively permeable membrane 20 of the second flow conduit 12 assists in drawing liquid from the sample store 26.
• This drawing of liquid into the second flow conduit 12 may or should continue until the liquid reaches the selectively permeable membrane 20 of the second flow conduit 12 and covers the selectively permeable membrane 20 as shown in Figure 6b , the liquid will then be held. There may still be a small amount of gas G at the second end port 17 area.
• the valve 12v can then be closed to block any further liquid leaving the sample store 26.
• valve 12V Once the valve 12V is closed the negative pressure applied to the outer surface of the selectively permeable membrane 20 can be turned off or prevented reaching the surface of the selectively permeable membrane 20 by a valve or the like.
• the internal volume between the valve 12V and the selectively permeable membrane 20 is known then consistently the volume of liquid drawn into the second flow conduit 12 in this way, will be the same volume.
• a known volume can quickly be repeated time and time again by the activation or deactivation of the mentioned valves and the negative pressure.
• Optional connect in some embodiments is a vessel 33 containing liquid, which may for example be an analysis device with internal chamber for analysing a liquid in the chamber.
• the chamber may usually contain liquid of some form or other, for storage for example and during use.
• the vessel 33 containing a liquid may have a waste outlet 37.
• the flow conduits 11, 12 and 13 and the pump source P and the analysis chamber 33 are shown to be selectively in fluid communication with each other, and that there is a series of valves 13V, 12V and 11V able to open or close the fluid communication.
• typical vacuum pressure from the vacuum pimp used may be minus 250 mBar and typical air pressure from the air pump may be 150 mBar.
• Other pressures may be used in this embodiment and other embodiments.
• the pressure difference, for example across the selectively permeable membrane, is more important than actual pressure values, but by changing the pressures one is able to move liquids as required.
• FIGS 7a and 7b illustrates another pre-loading step that may be used in some embodiments. This is similar in process as seen for the second flow conduit 12 but now for the third flow conduit 13. From a starting stage as shown in Figure 7a , valve 12V is closed to all fluid communication. Then valve 13V is opened to enable fluid communication between a buffer store 27 containing buffer liquid 27 and the third flow conduit 13. Negative pressure 25 from a vacuum source or vacuum pump 25 is applied to the outer surface of a selectively permeable membrane of the third selectively permeable membrane 13.
• Liquid may be drawn into the third flow conduit 13 by the negative pressure applied to the outer surface of the selectively permeable membrane 20 continues until the liquid reaches and covers the selectively permeable membrane, as shown in Figure 7b here it is held as the liquid cannot cross the selectively permeable membrane 20 and can go no further.
• the valve 13 V can then be closed to prevent fluid communication between the buffer store 27 and the third flow conduit 13.
• the negative pressure source 25 may be switched off or gated by valves to stop any negative pressure to be in contact with the selectively permeable membrane 20, but this will not move the liquid that may just sit there until actively required to be moved.
• typical vacuum pressure from the vacuum pimp used may be minus 250 mBar and typical air pressure from the air pump may be 150 mBar.
• Other pressures may be used in this embodiment and other embodiments.
• the pressure difference, for example across the selectively permeable membrane, is more important than actual pressure values, but by changing the pressures one is able to move liquids as required.
• FIGS 8 to 15 show various steps of using an apparatus and system of the present invention and methods of joining two or more liquids.
• Figure 8 shows an embodiment in what may be a typical starting point for working some embodiments of the invention, but not necessarily all embodiments of the invention. This typical starting point may be after the pre-steps described with reference to Figures 6a and 6b and Figure 7a and 7b , but in other embodiments there may be other means to have the liquids loaded up or these may be in a different order.
• the second flow conduit is filled with a liquid sample L2 which in this embodiment is ultimately to be analysed in the analysis chamber 33.
• the third flow conduit is filled with buffer liquid L3.
• the first flow conduit 11 is connected to a vessel 33 containing a liquid and in this embodiment the vessel 33 containing a liquid L1 is an analysis device 33 and the liquid L1 is a primer liquid, but in other embodiments, or application of other embodiments, other liquids may be used. Valves 11V, 12V and 13V are closed or opened, the liquid L1, L2, L3 should not move.
• gas G in the flow path from the pump source P to the analysis chamber 33, for example in the connecting area between the first flow conduit and the analysis chamber 33; and likewise between the first 11 and second 12 flow conduits and between the second 12 and third 13 flow conduits. It is inevitable that there will be some gas G within the fluid flow pathway from the pump source P to the analysis chamber 33 initially however the present invention may enable reduction or removal of this gas, and joining of two or more liquids.
• the analysis chamber 33 is connected, at a connection 38 to the flow conduit 11 at the second port end 17, such that there is fluid communication between the first flow conduit 11 and the analysis device 33. There will likely be air or gas G in the first flow conduit 11.
• Valve 11V is closed or ensured closed, to prevent fluid communication across or through valve 11V.
• the vacuum pump or source 25 is activated and configured to apply a negative pressure 25 to the selectively permeable membrane 20 of the first flow conduit 11.
• a negative pressure 25 is applied to the selectively permeable membrane liquid L1 from the analysis device 33 is drawn into the first flow conduit 11 towards the selectively permeable membrane 20 as shown in Figure 8a .
• Air or gas within the first selectively permeable membrane is reduced in volume and amount as it passes out of the first flow membrane 20.
• Figure 8b shows the completion of this step as the liquid L1 from the analysis device 33 is drawn fully to the selectively permeable membrane 20 covering the selectively permeable membrane and being held there as the liquid L1 cannot pass through the selectively permeable membrane.
• Air or gas within the first selectively permeable membrane is reduced in volume as it passes out of the first flow membrane 20, however there may be some gas G remaining between the valve 11V and the selectively permeable membrane.
• this step may be completed without the first flow conduit 11 being connected to the second flow conduit and this connection being made after loading liquid L1 from the analysis device.
• typical vacuum pressure from the vacuum pimp used may be minus 250 mBar and typical air pressure from the air pump may be 150 mBar.
• Other pressures may be used in this embodiment and other embodiments.
• the pressure difference, for example across the selectively permeable membrane, is more important than actual pressure values, but by changing the pressures one is able to move liquids as required.
• FIG 9 shows an alternative embodiment with initial method steps of some embodiments of the present invention wherein initially valve 11V is left closed from the previous method step shown, and this embodiment is similar to that shown in Figure 8 , 8a and 8b .
• Valve 11C is located at a first port end 16 of the first flow conduit 11. There is fluid communication between the first flow conduit 11 and the connected analysis device 33, this may include opening any valves in this fluid pathway between the first flow conduit 11 and the analysis device 33.
• the vacuum source 25 is configured to apply a negative pressure to the outer surface of the selectively permeable membrane 20 of the first flow conduit 11. When the negative pressure 25 is applied to the outer surface of the selectively permeable membrane 20, this may assist in drawing liquid within the analysis device 33 towards the selectively permeable membrane 20.
• the negative pressure 25 to the outer surface of the selectively permeable membrane 20 may be applied until the liquid within the analysis device L1 is in contact with the selectively permeable membrane 20 and no more liquid is drawn into the first flow conduit 11.
• This sensor 21 may be a simple means that can identify a change in the vacuum pressure of power of the vacuum pump. After expiry of a period of time it may be assumed that the total amount of liquid that can be drawn into the first flow conduit 11 has been drawn into the first flow conduit 11.
• the liquid that is drawn into first flow conduit will stop when the liquid reaches the selectively permeable membrane 20 as the liquid is prevent from passing through the selectively permeable membrane 20 while any gas within the first fluid flow conduit between the selectively permeable membrane 20 and the liquid within the analysis device 33 will be drawn along and through the selectively permeable membrane 20 to be expelled from the first flow conduit 11.
• typical vacuum pressure from the vacuum pimp used may be minus 250 mBar and typical air pressure from the air pump may be 150 mBar.
• Other pressures may be used in this embodiment and other embodiments.
• the pressure difference, for example across the selectively permeable membrane, is more important than actual pressure values, but by changing the pressures one is able to move liquids as required.
• Figure 10 shows method steps of some embodiments that may follow method steps from Figure 9 or Figure 8 , in order to remove gas G between the primer liquid L1 from the analysis device 33 (that at this stage, a portion at least, of the primer liquid L1 is situated at the selective permeable membrane 20 region of the first flow conduit 11) and the sample liquid L2 within the second flow conduit 12. There is likely to be gas G between the two liquids primer L1 and the liquid sample L2 to be tested.
• the vacuum source 25 is switched on, or at least ensured that there is a negative pressure 25 applied to the outer surface of the selectively permeable membrane 20 of the first flow conduit 11.
• valve 11V is opened or ensured that it is open, to enable fluid communication between the first flow conduit 11 and the second flow conduit 12.
• Valve 12 V is opened to enable fluid communication between the second flow conduit 12 and the third flow conduit 13.
• Valve 13V is also opened to enable fluid communication between the third flow conduit and the pump source p.
• the pump source P is an air pump configured to push air away from the pump P and along the flow path selectively due to the valves (13V, 12V, 11V), via the third flow conduit 13, the second flow conduit 12, first flow conduit 11 and to the analysis device 33. All valves between the pump P and the analysis device 33 are open to enable fluid communication between, but not open to the sample or buffer stored 26, 27.
• the air pump P is activated and the air pressure pushes the liquid in the third flow conduit 13, the buffer liquid, along towards the second flow conduit 12.
• any gas between the buffer liquid L3 and the liquid sample L2 to be tested, and between the liquid sample L2 to be tested and the primer liquid L1 may be slightly compressed but there may be, after a short period of time, movement of both the buffer liquid L3 towards the sample liquid to be tested and movement of the sample liquid to be tested towards the primer liquid. This may be seen in Figures 10 .
• the movement and pressure from the air pump P may push the primer liquid L1 slightly towards the analysis device 33 and in doing so will expose a portion of the inside surface of the selectively permeable membrane 20, and in doing so gas G between the primer liquid L1 and the sample liquid L2 to be tested will escape through the selectively permeable membrane 20, expelled from the first flow conduit 11, until all or most of the gas G is expelled and the sample liquid L2 to be tested is joined, at point 40, with the primer liquid L1, with no gas between as the gas was expelled through the selectively permeable membrane 20. As shown in Figure 11 .
• the liquids L1, L2 and L3 are moved along, by the air pressure from the air pump P the first flow conduit 11 in the direction of the analysis device 33 until again a portion of the selectively permeable membrane 20 is exposed again when any gas G between the liquid sample L2 to be tested and the buffer liquid L3 (that was in the third flow conduit 13) is expelled from the first flow conduit 11 via the selectively permeable membrane 20.
• the gas G between the buffer liquid L3 and the sample liquid L2 to be tested may all or mostly be expelled and the buffer liquid L3 may be joined with the sample liquid to be tested.
• further pump pressure may move the joined liquid, buffer, sample liquid to be tested, primer towards and into the analysis device 33 so that the liquid L2 to be tested in in position with testing elements within the analysis device 33.
• the air pump P may be deactivated to hold the joined liquid L1, L2 L3 and sample liquid L2 to be tested in place for testing or whatever other function is required.
• the flow rate of the air pump P can be selected to be less than the gas flow rate across the selectively permeable membrane 20 of the first flow conduit when negative pressure is applied to the selectively permeable membrane of the first flow conduit, especially at the stage that the buffer liquid L1 is passing through the first flow conduit, so that the flow of the joined liquids (L1, L2, L3) will be prevented moving further along, thus the liquid sample L2 for testing will be safely positioned at the testing elements of the testing device 33.
• the air push pump P or the negative pressure amount or both the negative pressure amount of the air push flow and the negative pressure amount may be altered according to control movement or holding of the liquids as required.
• the volumes of the first second and third flow conduits as well as the internal volume of the vessel containing a liquid or testing device are known thus a user or controller may determine how far along the flow path of the flow conduits and testing device 33 is needed to position the liquid sample L2 for testing in the correct position for testing within the testing device 33.
• the system and apparatus and method described for this embodiment may enable joined liquids with minimal or no gas G between and able to move these in a well-controlled manner.
• typical vacuum pressure from the vacuum pimp used may be minus 250 mBar and typical air pressure from the air pump may be 150 mBar.
• Other pressures may be used in this embodiment and other embodiments.
• the pressure difference, for example across the selectively permeable membrane, is more important than actual pressure values, but by changing the pressures one is able to move liquids as required.

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